Review
catalysts
Recent Advancements in Stereoselective Olefin Review Metathesis Using Ruthenium Catalysts Recent Advancements in Stereoselective Olefin T. Patrick Montgomery , Adam M. Johns , and Robert H. Grubbs * Metathesis Using Ruthenium Catalysts 1
2
1,
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California1Institute Pasadena, CAGrubbs 91125, USA; 1, *
[email protected] (T.P.M.); T. Patrick Montgomery , Adam of M.Technology, Johns 2 and Robert H. 2 Materia, Inc., Pasadena, CA 91107, USA;
[email protected] (A.M.J.) 1 The Arnold and
[email protected]; Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical * Correspondence: Tel.: +1-626-395-6003 Engineering, California Institute of Technology, Pasadena, CA 91125, USA;
[email protected] Academic Editors: Albert Demonceau,
[email protected] Dragutan and Valerian Dragutan 2 Materia, Inc., Pasadena, CA 91107, USA; Received: 4 February 2017; Accepted: 9 March 2017; Published: 14 March 2017 * Correspondence:
[email protected]; Tel.: +1-626-395-6003 1
Academic Editors: Albert Demonceau, Ileana Dragutan Valerian Dragutanof organic molecules. Recent Abstract: Olefin metathesis is a prevailing method and for the construction Received: 4 February 2017; Accepted: 9 March 2017; Published: 14 March 2017 advancements in olefin metathesis have focused on stereoselective transformations. Ruthenium olefin metathesis catalysts have had a particularly impact of in organic the areamolecules. of stereoselective Olefin metathesis is a prevailing method pronounced for the construction Recent Abstract: olefin metathesis. The development of three categories of Z-selective olefin metathesis catalysts has advancements in olefin metathesis have focused on stereoselective transformations. Ruthenium made Z-olefins easily accessible to both laboratory and industrial chemists. Further design olefin metathesis catalysts have had a particularly pronounced impact in the area of stereoselective enhancements to asymmetric olefin of metathesis catalystsof have streamlined the construction of olefin metathesis. The development three categories Z-selective olefin metathesis catalysts complex understanding in these areas has extended to the employment of has mademolecules. Z-olefins The easily accessible to gained both laboratory and industrial chemists. Further design ruthenium catalysts to stereoretentive olefin metathesis, the first example of a kinetically E-selective enhancements to asymmetric olefin metathesis catalysts have streamlined the construction of complex process. These as well in asthese synthetic developed catalysts, molecules. The advancements, understanding gained areasapplications has extendedoftothe thenewly employment of ruthenium are discussed. catalysts to stereoretentive olefin metathesis, the first example of a kinetically E-selective process.
These advancements, as well as synthetic applications of the newly developed catalysts, are discussed. Keywords: ruthenium; catalysts; stereoselective; asymmetric; Z-selective; olefin; metathesis Keywords: ruthenium; catalysts; stereoselective; asymmetric; Z-selective; olefin; metathesis
1. Introduction 1. Introduction Organic molecules, by definition, are composed of carbon–carbon bonds; thus, their construction is central to strategies aimed at the formation of useful, products. One thus, method that has found Organic molecules, by definition, are composed ofcomplex carbon–carbon bonds; their construction wide application in this endeavor is olefin metathesis (OM) [1–8]. Initially viewed as a strange olefin is central to strategies aimed at the formation of useful, complex products. One method that has found rearrangement reaction [9,10], the utility of OM now ranges from synthetic organic chemistry [11,12] wide application in this endeavor is olefin metathesis (OM) [1–8]. Initially viewed as a strange olefin to materials chemistry [13,14]. onOM OM have further the understanding of this rearrangement reaction [9,10], theStudies utility of now ranges fromenhanced synthetic organic chemistry [11,12] to process, promoting the development of interesting and useful metathesis catalysts. The generally materials chemistry [13,14]. Studies on OM have further enhanced the understanding of this process, accepted was originally proposed by Chauvin and catalysts. Hérisson (Scheme 1) [15]. Upon promotingmechanism the development of interesting and useful metathesis The generally accepted generation a metal-carbene, an olefin chelateand to the metal species. [2+2] cycloaddition can occur, mechanismofwas originally proposed bycan Chauvin Hérisson (Scheme 1) [15]. Upon generation of forming a metallacyclobutane, which can then cyclorevert, forming a new olefin and metal-carbene a metal-carbene, an olefin can chelate to the metal species. [2+2] cycloaddition can occur, forming a species. metallacyclobutane, which can then cyclorevert, forming a new olefin and metal-carbene species. R
R [M] R"
[M] R'
R"
[M] R'
R"
R R'
Scheme 1. 1. Generally Generally accepted accepted mechanism mechanism for for olefin olefin metathesis metathesis (OM) (OM) proceeding proceeding through a [2+2] cycloaddition followed by cycloreversion to generate a new olefin.
Traditional methods of control in OM have relied on the intrinsic reactivity of an olefin, as well Traditional methods of control in OM have relied on the intrinsic reactivity of an olefin, as well as as thermodynamic selectivities, but recent developments in OM catalysts have allowed for tailoring thermodynamic selectivities, but recent developments in OM catalysts have allowed for tailoring of the of the catalytic scaffold to impart some stereochemical control on the olefinic products. Early catalytic scaffold to impart some stereochemical control on the olefinic products. Early stereoselective OM research focused on the desymmetrization of achiral olefins to provide chiral molecules through Catalysts 2016, 6, 87; doi:10.3390/catal7030087 www.mdpi.com/journal/catalysts the alteration of the ligand scaffold [11,16,17]. As understanding for the stereochemical arrangement Catalysts 2017, 7, 87; doi:10.3390/catal7030087
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stereoselective OM research focused on the desymmetrization of achiral olefins to provide chiral 38 molecules through the alteration of the ligand scaffold [11,16,17]. As understanding for2 ofthe stereochemical arrangement of the metallacycle intermediate progressed, further variations were made continual pursuit of oneprogressed, of the unmet challenges in OM: kinetic of the in metallacycle intermediate further variations were madeZ-selectivity in continual[18–20]. pursuitAn of incredible amount of effort in has been devoted to these[18–20]. quests,An which have opened doorhas to one of the unmet challenges OM: kinetic Z-selectivity incredible amount the of effort numerous discoveries. This review will present recent advancements (since 2010) in stereoselective been devoted to these quests, which have opened the door to numerous discoveries. This review OM present employing ruthenium catalysts which directly convey stereochemical control on the products will recent advancements (since 2010) in stereoselective OM employing ruthenium catalysts for synthetic Also, muchcontrol progress made in the use of stereoselective which directlyapplications. convey stereochemical onhas the recently productsbeen for synthetic applications. Also, much molybdenum and tungsten metathesis catalysts [16,17,21–23]; however, this willmetathesis focus on progress has recently been made in the use of stereoselective molybdenum andreview tungsten ruthenium-based metathesis catalysts. catalysts [16,17,21–23]; however, this review will focus on ruthenium-based metathesis catalysts. Catalysts 2017, 7, 87
2. Z-Selective Olefin Metathesis 2.1. General Introduction far reaching reaching impact impact on on organic organic chemistry, chemistry, and many exciting exciting developments developments Metathesis has had a far oneone of the challenges in ruthenium-catalyzed OM was aOM kinetically have occurred. occurred.Until Untilrecently, recently, ofunmet the unmet challenges in ruthenium-catalyzed was a Z-selective process [18,20]. Because OM is reversible and secondary metathesis readily occurs, the ratio kinetically Z-selective process [18,20]. Because OM is reversible and secondary metathesis readily of E- and reflects typically the thermodynamic differenceenergy between the two between isomers, occurs, theZ-olefins ratio of typically E- and Z-olefins reflects the energy thermodynamic difference which is about 9:1, E:Z [24]. This presents a synthetic problem, because many natural products and the two isomers, which is about 9:1, E:Z [24]. This presents a synthetic problem, because many natural biologically active molecules contain Z-olefins. Furthermore, activity of these compounds can products and biologically active molecules contain Z-olefins.the Furthermore, the activity of these require high can stereopurity to obtain the desired effect.the Nevertheless, methods for separating olefin compounds require high stereopurity to obtain desired effect. Nevertheless, methods for isomers through purification exist, although these are difficult and time consuming. Indirect methods separating olefin isomers through purification exist, although these are difficult and time consuming. to deliver Z-olefins been developed, alkyne metathesis and subsequent reduction Indirect methods tohave deliver Z-olefins havesuch beenas developed, such as alkyne metathesispartial and subsequent of the alkyne [25,26]. There have also been substrate dependent methods for Z-selectivity partial reduction of the alkyne [25,26]. There have also been substrate dependent methods[27–30], for Zbut a universal method for Z-selective OM remained elusive. selectivity [27–30], but a universal method for Z-selective OM remained elusive. demands for for aakinetically kineticallyZ-selective Z-selectiveOM OMdepend dependononthe the ruthenacyclobutane (Figure The demands ruthenacyclobutane (Figure 1). 1). If If the ruthenacyclobutane forms with the substituents in an anti-arrangement, (II), (sterically favored), the ruthenacyclobutane forms with the substituents in an anti-arrangement, (II), (sterically favored), cycloreversion will generate an E-olefin. However, if the ruthenacyclobutane forms with substituents (sterically lessless favored), cycloreversion furnishes the Z-isomer. Two factors in aa syn-arrangement, syn-arrangement,(IV), (IV), (sterically favored), cycloreversion furnishes the Z-isomer. Two favor the E-isomer over the Z-isomer: kinetics from the ruthenacyclobutane stereochemistry and factors favor the E-isomer over the Z-isomer: kinetics from the ruthenacyclobutane stereochemistry thermodynamics of the formed. To develop a Z-selective catalyst, olefin coordination to the and thermodynamics of olefin the olefin formed. To develop a Z-selective catalyst, olefin coordination to ruthenium-carbene would need to be limited occur from one side, generated ruthenacycle, the ruthenium-carbene would need to be to limited to occur fromand onethe side, and the generated following [2+2]following cycloaddition, need to form in aneed way to to form generate all syn-ruthenacyclobutane. ruthenacycle, [2+2] would cycloaddition, would in aanway to generate an all synUpon cycloreversion,Upon a Z-olefin would be obtained. ruthenacyclobutane. cycloreversion, a Z-olefin would be obtained.
Figure 1. Catalytic Catalytic cycle cyclefor forolefin olefinmetathesis metathesis(OM) (OM) illustrating how stereochemical relationships in Figure 1. illustrating how stereochemical relationships in the the ruthenacyclobutane affect the stereochemistry of the formed olefin. ruthenacyclobutane affect the stereochemistry of the formed olefin.
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2.2. Cyclometalated Catalysts 2.2. Cyclometalated Catalysts 2.2.1. Cyclometalated Catalysts Development 2.2.1. Cyclometalated Catalysts Development Studies from Grubbs and coworkers aimed at generating a Z-selective ruthenium metathesis Studies from Grubbs andtocoworkers generating a Z-selective in ruthenium catalyst originally attempted employ aaimed large at sulfonate or phosphonate place of metathesis one of the catalyst attempted to employ a large sulfonate or phosphonate in this placestrategy of one of the chloride chlorideoriginally ligands on 1 [31]. Unfortunately the levels of Z-selectivity using were modest, ligands 1 [31]. evaluated Unfortunately of Z-selectivity using this strategy were modest, and the and the on catalysts werethe of levels low stability. Computational studies suggested that a pivalate catalysts were stability. Computational studies suggested a pivalate group in evaluated place of one of of thelow chlorides would enhance Z-selectivity. When that attempts were group made in to place of one thediscovered chlorides would enhance Z-selectivity. When attempts were made to generate 2, generate 2, itof was that C–H activation of an ortho-methyl in N-2,4,6-trimethylphenyl (Mes) it was discovered that aC–H activation ofcatalyst, an ortho-methyl in 2). N-2,4,6-trimethylphenyl (Mes) occurred occurred to generate cyclometalated 3 (Figure Although cyclometalated ruthenium to generate have a cyclometalated catalyst, 3 (Figure 2). Although cyclometalated complexes been reported as catalyst decomposition products [32,33], 3ruthenium performedcomplexes the cross have been reported catalyst decomposition products [32,33],in 3 performed the cross metathesis (CM) metathesis (CM) of as allylbenzene and cis-1,4-diacetoxybutene moderate conversion (58%) and the of allylbenzene and cis-1,4-diacetoxybutene in metathesis moderate conversion and41% the highest observed highest observed Z-selectivity for a ruthenium catalyst (at (58%) the time), Z [34]. Following Z-selectivity a ruthenium catalyst (at the time), 41% Z(NHC) [34]. Following this result, was this result, itfor was proposed metathesis that a larger N-heterocyclic carbene could enhance the itsteric proposed a larger N-heterocyclic (NHC) could so enhance demands thereplaced catalyst, demands that of the catalyst, favoring an carbene all syn-ruthenacycle, one ofthe thesteric N-Mes groupsof was favoring an all syn-ruthenacycle, so C–H one of the N-Mes groupson was with an N-adamantyl. with an N-adamantyl. Surprisingly, activation occurred thereplaced N-adamantyl group (4), which Surprisingly, on the N-adamantyl group (4), which resulted in a more selective resulted in a C–H moreactivation selective occurred OM catalyst (88% Z in the CM of allylbenzene and cis-1,4-diacetoxy-2OM catalyst butene) [34].(88% Z in the CM of allylbenzene and cis-1,4-diacetoxy-2-butene) [34].
SurprisingC–H C–H activation leading toinitial the initial cyclometalated ruthenium metathesis Figure 2.2.Surprising activation leading to the cyclometalated ruthenium metathesis catalyst. catalyst.
Computational and experimental studies were carried out to understand the Z-selectivity Computational and experimental studies were carried out to understand the Z-selectivity imparted by these cyclometalated catalysts [35,36]. The reaction is believed to proceed through a imparted by these cyclometalated catalysts [35,36]. The reaction is believed to proceed through a sideside-bound ruthenacyclobutane due to complex steric and electronic effects. Also, the cyclometalation bound ruthenacyclobutane due to complex steric and electronic effects. Also, the cyclometalation locks the N-aryl group in place. Thus, it is postulated that the N-aryl group resides directly over the locks the N-aryl group in place. Thus, it is postulated that the N-aryl group resides directly over the forming ruthenacylobutane, forcing all the substituents down in a syn-arrangement (Figure 3, VII). forming ruthenacylobutane, forcing all the substituents down in a syn-arrangement (Figure 3, VII). Cycloreversion furnishes a Z-olefin. For formation of the E-product, an anti-ruthenacycle Cycloreversion furnishes a Z-olefin. For formation of the E-product, an anti-ruthenacycle (Figure 3, (Figure 3, VIII) must form, which is sterically unfavored due to the N-aryl group blocking the top of VIII) must form, which is sterically unfavored due to the N-aryl group blocking the top of the the ruthenacycle. ruthenacycle. Building on these discoveries, the catalytic scaffold was tuned to enhance stability, activity, and Building on these discoveries, the catalytic scaffold was tuned to enhance stability, activity, and selectivity. Initial variations were made to the X-type ligands on the ruthenium center [37]. It was found selectivity. Initial variations were made to the X-type ligands on the ruthenium center [37]. It was that monodentate ligands were unreactive. When screening various bidentate X-type ligands, it was found that monodentate ligands were unreactive. When screening various bidentate X-type ligands, observed that replacing the pivalate with a nitrate (Figure 4a) enhanced both the activity and selectivity it was observed that replacing the pivalate with a nitrate (Figure 4a) enhanced both the activity and (58% conversion and 91% Z in the CM of allylbenzene and cis-1,4-diacetoxy-2-butene) [37]. Further selectivity (58% conversion and 91% Z in the CM of allylbenzene and cis-1,4-diacetoxy-2-butene) [37]. efforts to improve the cyclometalated catalyst focused on the free N-aryl group. It was found that Further efforts to improve the cyclometalated catalyst focused on the free N-aryl group. It was found replacing the N-Mes group with a more bulky N-2,6-diisopropylphenyl (DIPP) (9) greatly improved that replacing the N-Mes group with a more bulky N-2,6-diisopropylphenyl (DIPP) (9) greatly the activity and selectivity (Figure 4b) [38]. Using 9, the product of allylbenzene dimerization was improved the activity and selectivity (Figure 4b) [38]. Using 9, the product of allylbenzene obtained in >95% conversion and >95% Z. dimerization was obtained in >95% conversion and >95% Z.
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Figure 3. Depiction Depiction of the steric interactions leading to to the favored Z-selective metathesis pathway Figure Figure 3. 3. Depiction of of the the steric steric interactions interactions leading leading to the the favored favored Z-selective Z-selective metathesis metathesis pathway pathway using 4. 4. using using 4.
4. improvements in cyclometalated catalysts. (a) (a) Discovery of the Figure Figure 4. Modifications Modifications leading leading to to improvements in cyclometalated cyclometalated catalysts. (a) Discovery Discovery of the ligand enhanced the performance of 6; (b) Employing the N-2,6-diisopropylphenyl (DIPP) group nitrate ligand enhanced the performance of 6; (b) Employing the N-2,6-diisopropylphenyl nitrate ligand enhanced the performance of 6; (b) Employing the N-2,6-diisopropylphenyl (DIPP) (DIPP) further improved the reactivity and selectivity of the cyclometalated catalysts. group further improved the reactivity and selectivity of the cyclometalated catalysts. group further improved the reactivity and selectivity of the cyclometalated catalysts.
Efforts improve the the reactivity reactivity and and selectivity selectivity of cyclometalated catalysts have resulted resulted Efforts to to improve of cyclometalated catalysts 66 and and 99 have in the preparation of novel cyclometalated complexes with varying carbene moieties including those in the preparation of novel cyclometalated cyclometalated complexes with varying carbene moieties including those with chelating beyond N-1-adamantyl (Figure 5) The activity of with chelatingN-substituents N-substituents beyond N-1-adamantyl (Figure 5) [39–41]. The metathesis chelating N-substituents beyond N-1-adamantyl (Figure 5) [39–41]. [39–41]. The metathesis metathesis activity activity of these these complexes was evaluated using standard terminal olefin homodimerization reactions of allylbenzene, of these complexes was evaluated usingterminal standard terminal olefin homodimerization reactions of complexes was evaluated using standard olefin homodimerization reactions of allylbenzene, 4-penten-1-ol, or Complex aa 6-membered was to allylbenzene, 4-penten-1-ol, or methyl-10-undecenoate. Complex 10, possessing aNHC, 6-membered NHC, 4-penten-1-ol, or methyl-10-undecenoate. methyl-10-undecenoate. Complex 10, 10, possessing possessing 6-membered NHC, was found found to be inactive in the test reactions [40]. Complex 11 showed good activity and retained high Z-selectivity was found to in the test Complex 11 showed activity and high be inactive in be theinactive test reactions [40].reactions Complex[40]. 11 showed good activity good and retained highretained Z-selectivity in the of but the β-methylstyrene through Z-selectivity in the homodimerization of allylbenzene, but it generated the undesired β-methylstyrene in the homodimerization homodimerization of allylbenzene, allylbenzene, but it it generated generated the undesired undesired β-methylstyrene through isomerization of the the olefin olefin in the the starting material [40]. Catalyst 12 Catalyst displayed12low low to poor poor low activity and through isomerization of the olefin in the starting[40]. material [40]. displayed to poor isomerization of in starting material Catalyst 12 displayed to activity and modest Z-selectivity [40]. Complexes 13 and 14 both displayed good selectivity, but 13 showed superior activity Z-selectivity and modest[40]. Z-selectivity [40]. Complexes 13 and 14 good both displayed but 13 modest Complexes 13 and 14 both displayed selectivity, good but 13selectivity, showed superior activity 14 Catalyst 15, aa four-membered showed to largely showedto superior [41]. Catalyst 15, bearingchelate, a four-membered chelate, showed little to activity to 14 [41]. [41]. activity Catalystto 15,14bearing bearing four-membered chelate, showed little little to no no reactivity reactivity largely ascribed to catalyst instability [41]. Complex 16, the DIPP variant of 3, showed slightly higher selectivity no reactivity largely ascribed to catalyst instability [41]. Complex 16, the DIPP variant of 3, showed ascribed to catalyst instability [41]. Complex 16, the DIPP variant of 3, showed slightly higher selectivity and stability when compared 3, is to aa product sterically larger N-aryl DIPP slightly higher selectivity andto compared 3, whichof thought to be a product the and stability when compared tostability 3, which whichwhen is thought thought to be be to product ofisthe the sterically larger N-arylof DIPP [39]. Complex 17, containing a monodentate chloride ligand, was found to be E-selective [39]. It was sterically larger17, N-aryl DIPP [39]. Complex 17, containing a monodentate ligand,[39]. was It found [39]. Complex containing a monodentate chloride ligand, was found tochloride be E-selective was postulated that monodentate nature the chloride ligand metathesis to through aa to be E-selective [39]. It was postulated monodentate nature of the chloride ligand allows postulated that the the monodentate nature of ofthat the the chloride ligand allows allows metathesis to proceed proceed through bottom-bound ruthenacycle, thus favoring E-products. Complex 18 featuring a nitrite X-type ligand bottom-bound ruthenacycle, thus favoring E-products. Complex 18 featuring a nitrite X-type ligand
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metathesis to proceed through a bottom-bound ruthenacycle, thus favoring E-products. Complex 18 displayed slower initiation rates displayed in comparison comparison to initiation [42]. Z-Selectivity Z-Selectivity was retained retained at longer reaction featuring aslower nitriteinitiation X-type ligand slower rates in comparison to 9 at [42]. Z-Selectivity displayed rates in to 99 [42]. was longer reaction times where the nitrite catalyst could achieve similar conversions. was retained at longer reactioncould timesachieve where the nitrite catalyst could achieve similar conversions. times where the nitrite catalyst similar conversions.
Figure 5. Various Various cyclometalated catalyst catalyst scaffolds scaffolds evaluated. Figure 5. Various cyclometalated evaluated. Figure
A detailed discussion discussion of the development development of of cyclometalated ruthenium ruthenium OM catalysts can be A A detailed detailed discussion of of the the development of cyclometalated cyclometalated ruthenium OM OM catalysts catalysts can can be be found in a previous review from Grubbs and coworkers [24]. A more recent review of the synthetic found found in in aa previous previous review review from from Grubbs Grubbs and and coworkers coworkers [24]. [24]. A A more more recent recent review review of of the the synthetic synthetic applications of Z-selective cyclometalated ruthenium ruthenium catalysts catalysts has has also also been been revealed revealed [43]. [43]. applications applications of of Z-selective Z-selective cyclometalated 2.2.2. Z-Selective Homodimerization 2.2.2. Z-Selective Z-Selective Homodimerization Homodimerization 2.2.2. Table 1. 1. Homodimerization Homodimerization of of terminal terminal olefins olefins using using cyclometalated cyclometalated catalysts. catalysts. Table Table 1. Homodimerization of terminal olefins using cyclometalated catalysts.
Entry R Entry
Cat Cat Cat (xx mol %)%) (xx mol
Yield Yield (%)(%)Z Z (%) (%) Z (%) Yield (%) (xx mol %) 1 CH2 PhCH2Ph 4 (2) 92 (2) 81 81 92 44 (2) 11 CH PhCH 2Ph 81 92 2 6 (0.1) 91 92 2 6 (0.1) (0.1) CH22Ph Ph 91 >95 92 22 CH2 PhCH 91 92 3 96 (0.1) >95 9 (0.1) 3 CH 2Ph >95 >95 4 CH Ph 9 (0.01) 74 >95 9 (0.1) 3 >95 >95 2 CH2Ph 5 (CH ) CO Me 4 (2) >95 73 9 (0.01) 4 CH 2 Ph 74 >95 2 9 (0.01) 4 2 8 CH 2Ph 74 >95 6 (CH ) CO Me 6 (0.1) 85 91 2 8 2 (2) (CH22))88CO CO22Me Me >95 73 44 (2) 55 (CH >95 73 7 (CH2 )8 CO2 Me 9 (0.1) >95 >95 6 (0.1) 6 (CH 2)8CO2Me 85 91 (0.1) 6 (CH2(CH 2)8CO2Me 85 67 91 8 )3 OH 66 (0.1) 81 9 (0.1) (0.1) (CH 2)8CO2Me >95 77 >95 9 )3 OH 99 (0.1) 95 77 (CH2(CH 2)8CO2Me >95 >95 6 (0.1) 8 (CH 2)3OH 67 81 6 (0.1) 8 (CH2)3OH 67 81 9 (0.1) (0.1) 9 (CH22))33OH OH 77 95 9 9 (CH 77 Initial investigations into the homodimerization of olefins utilized954 (Table 1, entries 1 and 5) [44]. A wide substrate scope was tolerated such as alcohols, amines, esters, and ethers (selected Initial investigations investigations into into the the homodimerization homodimerization of olefins olefins utilized utilized 44 (Table (Table 1, 1, entries entries 11 and and 5) 5) Initial examples to compare catalysts are found in Table 1).of Surprisingly, optimal reaction temperature [44]. A wide substrate scope was tolerated such as alcohols, amines, esters, and ethers (selected [44]. A wide substrate wasthough tolerated alcohols, group amines, esters, andcatalyst ethers initiation. (selected ◦ C, even was determined to be 35scope thesuch largeas adamantly could inhibit examples to to compare compare catalysts catalysts are are found found in in Table Table 1). 1). Surprisingly, Surprisingly, optimal optimal reaction reaction temperature temperature was was examples determined to be 35 °C, even though the large adamantly group could inhibit catalyst initiation. determined to be 35 °C, even though the large adamantly group could inhibit catalyst initiation. Furthermore, aa high high concentration concentration of of olefin olefin was was required required for for good good reactivity, reactivity, which which could could aid aid in in Furthermore, catalyst initiation. initiation. These These transformations transformations were were performed performed under under static static vacuum vacuum to to promote promote removal removal catalyst Entry
R R
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of ethylene, driving the reaction forward. Problematic substrates in homodimerization included Furthermore, a high of olefin was required for good reactivity, which could aid in of those ethylene, driving theconcentration reactionAs forward. Problematic substrates incatalyst, homodimerization included of ethylene, driving the reaction forward. Problematic substrates in homodimerization included with driving allylic substitution. improvements were made to thein 6 and 9 wereincluded evaluated of ethylene, driving the reaction forward. Problematic substrates in homodimerization included of ethylene, the reaction forward. Problematic substrates homodimerization of ethylene, driving the reaction forward. Problematic substrates in homodimerization included catalyst initiation. These transformations were performed under static vacuum to promote removal of those with allylic substitution. substitution. As improvements were made made to the the catalyst, and were evaluated evaluated those with allylic As improvements were to catalyst, 666 and 999 were in the homodimerization of As olefins (Table 1, entries 2–4 and 6–9)catalyst, [37,38,41]. 9 showed exceptional those with allylic substitution. As improvements were made to the catalyst, and were evaluated those with allylic substitution. improvements were made to the 6 and 9 were evaluated those with allylic substitution. As improvements were made to the catalyst, 6 and 9 were evaluated ethylene, driving the reaction forward. Problematic substrates in[37,38,41]. homodimerization those in reactivity the homodimerization homodimerization of olefins olefins (Table 1, entries numbers 2–4 and 6–9) 6–9) [37,38,41]. showedincluded exceptional Catalysts 2017, 7, 87 of 6>95% of 36 Z (Table in the (Table 1, entries 2–4 and 99 showed exceptional and Z-selectivity, reaching 7400 1, turnover while maintain selectivity in the homodimerization of olefins (Table 1, entries 2–4 and 6–9) [37,38,41]. showed exceptional in the homodimerization of olefins (Table entries 2–4 and 6–9) [37,38,41]. 9999showed exceptional in the homodimerization of olefins (Table 1, entries 2–4 and 6–9) [37,38,41]. showed exceptional with allylic substitution. As improvements were made to the catalyst, 6 and were evaluated in reactivity and Z-selectivity, reaching reaching 7400 7400 turnover turnover numbers numbers while while maintain maintain selectivity selectivity >95% >95% Z Z (Table (Tablethe reactivity and Z-selectivity, 1, entry and 4).of Z-selectivity, reactivity and Z-selectivity, reaching 7400 turnover numbers while maintain selectivity >95% Z (Table reactivity reaching 7400 turnover numbers while maintain selectivity >95% Z (Table ethylene,of driving the(Table reaction forward. Problematic substrates in homodimerization included reactivity and Z-selectivity, reaching 7400 turnover numbers while maintain selectivity >95% Z (Table homodimerization olefins 1, entries 2–4 and 6–9) [37,38,41]. 9 showed exceptional reactivity 1, entry entry 4). 4). 1, those with allylic substitution. As improvements were made to the catalyst, 6 and 9 were evaluated 1, entry 4). 1, 4). 1, entry entry 4). and Z-selectivity, reaching 7400ofturnover numbers while maintain selectivity >95% Z (Table 1, entry 4). in the homodimerization olefins (Table 1, entries 2–4 and 6–9) [37,38,41]. 9 showed exceptional 2.2.3. Z-Selective Cross Metathesis 2.2.3. Z-Selective Cross Metathesis reactivity and Z-selectivity, reaching 7400 turnover numbers while maintain selectivity >95% Z (Table 2.2.3. Z-Selective Cross Metathesis 2.2.3. Z-Selective Cross Metathesis 2.2.3. Z-Selective Cross 2.2.3. Z-Selective Metathesis 2.2.3. Z-Selective Cross Metathesis The CM of twoMetathesis olefins is more difficult than the homodimerization because a CM can 1, entry 4).Cross The CM CM of of two olefins olefins is more moreproducts: difficulthomodimerization than the the homodimerization homodimerization because CM can The two is difficult than because CM can theoretically provide three different of each olefinbecause and the aaaaCM product. The CM of two olefins is more difficult than the homodimerization because CM can The CM of two olefins is more difficult than the homodimerization CM can The CM of two olefins is more difficult than the homodimerization because a CM The CM of two olefins is more difficult than the homodimerization because a CM cancan 2.2.3. Z-Selective Cross Metathesis theoretically provide three different products: homodimerization of each each olefin olefin and the the CM product. product. theoretically provide three different products: homodimerization of and CM The understanding developed from previous generations of ruthenium metathesis catalysts [45] was theoretically provide three different products: homodimerization of each olefin and the CM product. theoretically provide three different products: homodimerization of each olefin and the CM product. theoretically provide three different products: homodimerization of each olefin and the CM product. theoretically provide three different products: homodimerization of each olefin and the CM product. The understanding developed from previous previous generations of homodimerization ruthenium metathesis catalysts [45] was The CMcyclometalated of two from olefins iscatalysts. more difficult than using the because a CM the can[45] The understanding developed generations of ruthenium metathesis catalysts was applied to the new Studies 4 commenced by probing reactivity The understanding developed from previous generations of ruthenium metathesis catalysts [45] was The understanding developed from previous generations of ruthenium metathesis catalysts [45] was The understanding developed from previous generations ruthenium metathesis catalysts [45] was The understanding developed from previous generations of 4of ruthenium metathesis catalysts [45] was theoretically provide three different products: homodimerization of each olefin andprobing the CM product. applied to the the new cyclometalated catalysts. Studies using commenced by probing the reactivity reactivity applied to new cyclometalated catalysts. Studies using 44 commenced by the and selectivity with a CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2, applied to the new cyclometalated catalysts. Studies using commenced by probing the reactivity applied to the new cyclometalated catalysts. Studies using 4 commenced by probing the reactivity applied the new cyclometalated catalysts. Studies using 4 commenced probing the reactivity The understanding developed from previous generations of 4ruthenium metathesis catalysts [45] applied to to the new cyclometalated catalysts. Studies using commenced by by probing thewas reactivity and selectivity with CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2,Zand selectivity with aaa desired CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2, entry 1) [34]. The CM products were isolated in moderate yield, but high levels of and selectivity with CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2, applied toa cyclometalated catalysts. Studies using 4and commenced by probing the reactivity(Table and selectivity with CM system that included allylbenzene cis-1,4-diacetoxy-2-butene 2, and selectivity with a new CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table and selectivity with athe CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2, 2, entry 1) [34]. The desired CM products were isolated in the moderate yield, but but high levels of ZZentry 1) [34]. The desired CM products were isolated in moderate yield, high levels of and selectivity with CM aAs CM system that included allylbenzene and cis-1,4-diacetoxy-2-butene (Table 2, scaffolds selectivity were observed. modifications were made to cyclometalated catalysts, new entry 1) [34]. The desired CM products were isolated in moderate yield, but high levels of Zentry 1) [34]. The desired products were isolated in moderate yield, but high levels of Zentry 1) [34]. The desired CM products were isolated in moderate yield, but high levels of Z-selectivity entry 1) [34]. The desiredAsCM products were isolated in moderate yield,catalysts, but highnew levels of Zselectivity were observed. modifications were made to the the cyclometalated scaffolds entryobserved. 1) [34]. 2, The desired CM products were isolated in moderate yield, to butdate high[37–40,42]. levelsnew of Zselectivity were As modifications were made to the cyclometalated catalysts, scaffolds were assessed (Table entries 2–4), but 9made proved to be best catalyst selectivity were observed. As modifications were made to the cyclometalated catalysts, new scaffolds selectivity were observed. As modifications were made to the cyclometalated catalysts, new scaffolds were observed. As modifications were to the cyclometalated catalysts, new scaffolds were selectivity were observed. As modifications were made to the cyclometalated catalysts, new scaffolds selectivity observed. As modifications were to the cyclometalated new scaffolds were assessed assessed (Tablewere 2, entries entries 2–4), but 99 proved proved tomade be the the best catalyst to tocatalysts, date [37–40,42]. [37–40,42]. were (Table 2, 2–4), but to be best catalyst date were assessed (Table 2, entries 2–4), but proved to be the best catalyst to date [37–40,42]. were assessed (Table 2, 999but proved to be catalyst to [37–40,42]. assessed (Table 2, entries 2–4), butbut 92–4), proved to be best catalyst totodate [37–40,42]. were assessed (Table 2, 2–4), entries 9 proved to thebest best catalyst date [37–40,42]. were assessed (Table 2, entries entries 2–4), but proved tothe bebethe the best catalyst to date date [37–40,42]. Table 2. Comparison of cyclometalated catalysts using cross metathesis (CM). Table 2. 2. Comparison Comparison of of cyclometalated cyclometalated catalysts catalysts using using cross cross metathesis metathesis (CM). (CM). Table 2. Comparison of cyclometalated catalysts using using cross metathesis (CM).(CM). Table 2. Comparison of cyclometalated catalysts using cross metathesis (CM). Table 2. of catalysts cross metathesis Table 2.Table Comparison of cyclometalated catalysts using cross metathesis (CM). Table 2. Comparison Comparison of cyclometalated cyclometalated catalysts using cross metathesis (CM).
Entry Entry
Entry
Entry 1*Entry 1* Entry Entry 1* 2 2 1* 1* 1* 3 1* 222 3 4 2 32 3 333 4 44 444
Entry R’ R” Cat (xx mol %) Yield (%) Z (%) R RR R’ (xx Yield (%)Z (%) Z (%) R’ R”R” Cat4Cat (xx molmol %)%) Yield (%) 1* CH2Ph CH2OAc CH2OAc (5) 60 84 R’ R” Cat (xx mol %) Yield (%) Z (%) (%) R R’ R” Cat (xx mol %) Yield (%) R CH Ph OAc CH (5) Yield 60 Z 84 CH 2Ph CH OAc 22OAc 4mol (5)4 %) 60 84 R’ R” Cat (xx mol %) (%) Z (%) R 22CH 2 OAc 2R CH2Ph CH 2OAc CH CH OAc 6 (1) 58 R’ R” Cat (%) (%) R’ R” Cat (xx (xx mol %) Yield Yield (%)91 Z Z 84 (%) R22Ph CH CH 2 OAc CH 2 OAc 4 (5) 60 CH CH 6 (1) 58 84 91 CH 2OAc CH 2CH OAc (5) 3 222Ph (CH2)3CH Me (CH 2)7OAc H 64 (0.5) 70 60 91 22OAc 2 OAc CH 2 Ph CH OAc CH 2 OAc 6 (1) 58 91 CH Ph CH 2 OAc CH 2 OAc 4 (5) 60 84 CH CH 22OAc CH 44 (5) 84 CH42222)Ph Ph CH OAc CH222OAc OAc (5) 6 (0.5) 71 60 60 >95 84 (CH (CH )7 OAc 70 91 91 CH Ph CH OAc CH OAc 6(0.5) (1) 58 91 (CH2)3CH Me 2)7OAc HH 96 3 Me 2(CH CH 2Ph 22OAc CH 2OAc (1) 58
(CHPh 2)3Me CH (CH 2)7OAc CH H (0.5) CH CH OAc CH OAc (1) CH 222OAc 222OAc 666 6(1) CH22222))Ph Ph CH CHcarried OAc (1)THF. (CH Me (CH (CH )*Entry Hout in refluxing 9 (0.5) 3Me 2OAc 7 OAc1 was (CH )OAc H (0.5) (CH 2)33Me (CH 22) 77OAc H 666 (0.5) (CH 2 ) 3 Me (CH 2 ) 7 OAc H 9 (0.5) (CH 2 ) 3 Me (CH 2 ) 7 OAc H (0.5) (CH 22))33Me (CH 22))77OAc H 6 (0.5) (CH Me (CH OAc H 6 (0.5) out in refluxing (CH22))33Me Me (CH (CH22))*77Entry OAc 1 was carried H (0.5)THF. (CH OAc H 99 (0.5) Table 3. CM of allylically substituted using 9. *Entry 1 was carried out in refluxing THF. (CH Me (CH ))777OAc OAc H (0.5) (CH 222) H 999olefins (0.5) (CH222)))333Me Me (CH (CH OAc H (0.5)THF. *Entry 1 was carried out in refluxing
70 91 58 91 58 58 91 71 91 70 91 70 91 71 >95 70 91 70 91 70 91 71 >95 71 >95 71 >95 71 >95 71 >95
>95
*Entry 1 was carried out in refluxing THF. *Entry was carried out in refluxing THF. *Entry *Entry 111 was was carried carried out out in in refluxing refluxing THF. THF. Table 3. CM of allylically substituted olefins Table 3. CM of allylically substituted olefins using using 9. 9. Table 3. 3. CM CM of of allylically allylically substituted substituted olefins olefins using using 9. 9. Table Table 3. CM of allylically substituted olefins using 9. Table 3. CM of allylically substituted olefins using 9. Entry Yield (%) Z (%) R Table 3. CM of allylically substituted olefins using 9. 1
82
>95
70 (%) >95Z (%) Entry2 Yield R R Z (%) YieldYield (%) (%) Z (%) (%) R Yield (%) Z R Entry Yield (%) Z (%) R Entry Yield (%) Z (%) R 3 44 94 Entry Yield 82 (%) Z (%) R 1 >95 82 82 >95 >95 1 >95 111 82 82 >95 11 82 >95 82 >95 4 81 92 2 70 >95 70 70 >95 >95 222 70 2 >95 70 >95 22 70 >95 40 >95 70 >9594 3 5 44 44 94 33 44 94 44 94 94 333 allylic substitution proved 44 94 As previously3mentioned, be a problem in homodimerization and 44 to44 94 4 this challenge. Vinyl acetals 81 were shown 92 to be excellent coupling CM. Investigations using 9 met 4when employing 9, affording81 81the desired92 92 partners with 1-dodecene 4 CM products in good yields and 81 92 444 81 92 4 92 81 to81 92 excellent excellent selectivities (Table 3, entries 1–2) [46]. In addition vinyl acetals, selectivities were 40 >95 5 observed with a cyclic alkane, vinylboronic acid pinacol ester and 2-vinyl oxirane (Table 3, entries 3– 40 >95 40 >95 555 40 >95 5), though the products were afforded in moderate yield. Interestingly, under conditions similar to 40 >95 5 40 >95 5 5 40 >95 Table 3, entry 1, 1 affords excellent yields of product in the thermodynamic As previously mentioned, allylic substitution provedhighly to be enriched a problem in homodimerization and AsInvestigations previously mentioned, mentioned, allylic substitution proved to be be aawere problem in homodimerization homodimerization and As previously allylic substitution proved to problem in and CM. using 9 met this challenge. Vinyl acetals shown to be excellent coupling As previously mentioned, allylic substitution proved to be a problem in homodimerization and As previously allylic substitution proved to aa problem in and As previously mentioned, mentioned, substitution proved to be bewere problem intohomodimerization homodimerization and CM. Investigations using metallylic this challenge. Vinyl acetals shown be excellent coupling CM. Investigations using 999 when met this challenge. Vinyl acetals were shown to be excellent coupling As previously mentioned, allylic substitution proved be a problem inbe homodimerization and partners with 1-dodecene employing 9, affording thetodesired CM products in goodcoupling yields and CM. Investigations using met this challenge. Vinyl acetals were shown to be excellent coupling CM. Investigations using 9 met this challenge. Vinyl acetals were shown to excellent CM. Investigations using when 9 metemploying this challenge. Vinyl acetals were CM shown to be in excellent coupling partners with 1-dodecene 9, affording the desired products good yields and partners with 1-dodecene when employing 9, affording the desired CM products in good yields and CM. Investigations using 93,met this 1–2) challenge. acetals were shown to be excellent coupling excellent selectivities (Table entries [46]. In Vinyl addition to vinyl acetals, excellent selectivities were partners with 1-dodecene when employing 9, affording the desired CM products in good yields and partners 1-dodecene when employing 9, the CM in good and partners with with 1-dodecene when employing 9, affording affording thetodesired desired CM products products inselectivities good yields yieldswere and excellent selectivities (Table 3,when entries 1–2) [46]. [46]. Inaffording addition vinyl acetals, excellent excellent selectivities (Table 3, entries 1–2) In addition to vinyl acetals, excellent selectivities were partners with 1-dodecene employing 9, the desired CM products in good yields and observed with a cyclic alkane, vinylboronic acid pinacol ester and 2-vinyl oxirane (Table 3, entries 3– excellent selectivities (Table 3, entries 1–2) [46]. In addition to vinyl acetals, excellent selectivities were excellent (Table 3, 1–2) In addition to acetals, excellent selectivities were excellent selectivities selectivities (Table 3, entries entries 1–2) [46]. [46]. Inpinacol addition to vinyl vinyl acetals,oxirane excellent selectivities were observed with a cyclic alkane, vinylboronic acid ester and 2-vinyl (Table 3, entries 3– observed with a cyclic alkane, vinylboronic acid pinacol ester and 2-vinyl oxirane (Table 3, entries 3– 5), though the products were afforded inacid moderate yield. Interestingly, under conditions similar to observed with cyclic alkane, vinylboronic acid pinacol ester and 2-vinyl oxirane (Table 3, entries 3– observed with aaa cyclic vinylboronic ester and oxirane (Table entries observed with cyclic alkane, alkane, vinylboronic acid pinacol pinacol ester and 2-vinyl 2-vinylunder oxirane (Table 3, 3, similar entries 3– 3– 5), though the products were afforded afforded in yields moderate yield. Interestingly, conditions to 5), though the products were in moderate yield. Interestingly, under conditions similar to Table 3, entry 1, 1 affords excellent of product highly enriched in the thermodynamic 5), though the products were afforded in moderate yield. Interestingly, under conditions similar to 5), the were afforded moderate yield. under conditions similar 5), though though the products products wereexcellent afforded in in moderate yield. Interestingly, Interestingly, under similar to to Table 3, entry entry 1, 11 affords affords yields of product product highly enriched enriched in conditions the thermodynamic thermodynamic Table 3, 1, excellent yields of highly in the Table 3, entry 1, 1 affords excellent yields of product highly enriched in the thermodynamic Table 3, entry 1, 1 affords excellent yields of product highly enriched in the thermodynamic Table 3, entry 1, 1 affords excellent yields of product highly enriched in the thermodynamic
Entry Entry Entry
Catalysts 2017, 7, 87
7 of 38
excellent selectivities (Table 3, entries 1–2) [46]. In addition to vinyl acetals, excellent selectivities were observed with a cyclic alkane, vinylboronic acid pinacol ester and 2-vinyl oxirane (Table 3, entries 3–5), Catalysts 2017, 7, 87 7 of 36 Catalysts 2017, 7, 7,the 87 products were afforded in moderate yield. Interestingly, under conditions similar77 to of 36 36 though Table 3, Catalysts 2017, 87 of Catalysts 2017, 7, 87 7 of 36 Catalysts 2017, 7, 87 7 of 36 entry 1, 1 affords yields product highlyinenriched in the olefin thermodynamic (92% stereoisomer (92%excellent yield, 95% E).ofFunctionalities the terminal were alsostereoisomer tolerated; esters, stereoisomer (92% yield, 95% E). Functionalities in the terminal olefin were also tolerated; esters, stereoisomer (92% yield, 95% E). Functionalities in the terminal olefin were also tolerated; esters, yield, 95% E). Functionalities in the terminal olefin were also tolerated; esters, alcohols, and halides all stereoisomer yield, 95% E). Functionalities the terminal olefin alcohols,(92% and halides all afforded good yieldsin and selectivities. stereoisomer (92% yield, 95% E).good Functionalities in theexcellent terminal olefin were were also also tolerated; tolerated; esters, esters, alcohols, and halides all afforded yields and excellent selectivities. alcohols, and halides halides all afforded afforded good yields yields and excellent excellent selectivities. afforded good yields and excellent selectivities. alcohols, alcohols, and and halides all all afforded good good yields and and excellent selectivities. selectivities. 2.2.4. Z-Selective Macrocyclic Ring-Closing Metathesis 2.2.4. 2.2.4. Z-Selective Macrocyclic Ring-Closing Metathesis Z-Selective Macrocyclic Ring-Closing Metathesis 2.2.4. Z-Selective Macrocyclic Ring-Closing Metathesis 2.2.4. Macrocyclic Ring-Closing Metathesis 2.2.4. Z-Selective Z-Selective Macrocyclic Ring-Closing Metathesis Macrocycles are important moieties in natural products and other valuable molecules [47]. Macrocycles are important important moieties in natural natural products and other other valuable molecules [47]. [47]. Macrocycles are important moieties in natural products and other valuable molecules Macrocycles moieties products valuable [47]. Macrocycles are important moieties in natural products and other valuable molecules [47]. Recently, theare fragrance industry has in become interested inand molecules termed molecules macrocyclic musks, Macrocycles are important moieties in natural products and other valuable molecules [47]. Recently, the fragrance industry has become interested in molecules termed macrocyclic musks, Recently, the fragrance industry has become interested in molecules termed macrocyclic musks, Recently, the fragrance industry has become interested in molecules termed macrocyclic musks, Recently, the fragrance industry has become interested in molecules termed macrocyclic musks, which are less hazardous than some of the traditionally used fragrance compounds [48]. Recently, theless fragrance industry has become interested in molecules termed macrocyclic musks, which are hazardous than some of the traditionally used fragrance compounds [48]. which are less hazardous than some of the traditionally used fragrance compounds [48]. Unfortunately, which are less hazardous than some of the traditionally used fragrance compounds [48]. which are less hazardous than some of the traditionally used fragrance compounds [48]. Unfortunately, macrocyclic ring-closing (mRCM)used suffers from some drawbacks[48]. not seen which are lessmacrocyclic hazardous than somemetathesis of metathesis the traditionally fragrance compounds Unfortunately, ring-closing (mRCM) suffers from some drawbacks drawbacks not seen macrocyclic ring-closing metathesismetathesis (mRCM) suffers from somefrom drawbacks not seen innot ring-closing Unfortunately, macrocyclic ring-closing (mRCM) suffers some seen Unfortunately, macrocyclic ring-closing metathesis (mRCM) suffers from some drawbacks not seen in ring-closing metathesis (RCM) of smaller ring systems. Oligomerization can occur more readily, Unfortunately, macrocyclic(RCM) ring-closing metathesis (mRCM) suffers from some not seen in ring-closing metathesis of smaller ringOligomerization systems. Oligomerization can drawbacks occur more readily, metathesismetathesis (RCM) of smaller ring systems. can occur more readily, so high dilutions in ring-closing (RCM) of smaller ring systems. Oligomerization can occur more readily, in ring-closing metathesis (RCM) of smaller ring systems. Oligomerization can occur more readily, so high dilutions and(RCM) catalyst loadingsring aresystems. necessary. Moreover, former methods to form in ring-closing metathesis of smaller Oligomerization can occur moreused readily, so high dilutions and catalyst catalyst loadings are necessary. Moreover, former methods used to form anddilutions catalyst loadings are necessary. Moreover, former methodsformer used tomethods form macrocycles via RCM so high and loadings are necessary. Moreover, used to form so high dilutions and catalyst loadings are necessary. Moreover, former methods used to form macrocycles via RCM suffered from generating the desired products in unpredictable ratios of Z- and so high dilutions and catalyst loadings are necessary. Moreover, former methods used to form macrocycles via RCM suffered from from generating the desired desired products in inratios unpredictable ratios of ZZ- and and sufferedvia from generating the desired products in unpredictable of Z- and ratios E- isomers. Catalyst macrocycles RCM suffered generating products unpredictable of macrocycles via RCM suffered from generating the products in unpredictable ratios of Zand E- isomers. Catalyst 6 was employed in the thedesired synthesis of Z-macrocycles through mRCM [49]. A macrocycles via RCM suffered from generating the desired products in unpredictable ratios of Zand Eisomers. Catalyst 6 was employed in the synthesis of Z-macrocycles through mRCM [49]. A ring 6 was employed in the synthesis of Z-macrocycles through mRCM [49]. A number of different E- isomers. isomers. Catalyst 6 was employed in the synthesis of Z-macrocycles through mRCM [49]. A ECatalyst 6 was employed in the synthesis of Z-macrocycles through mRCM [49]. numberCatalyst of different ringemployed sizes were in constructed in good yield and good through Z-selectivities (Table 4).A E- isomers. 6 was the synthesis of Z-macrocycles mRCM [49]. ASome number of different ring sizes were constructed in good yield and good Z-selectivities (Table 4). Some sizes were constructed inwere goodconstructed yield and good Z-selectivities (Table 4). Some limitations still persist, number of different ring sizes in good yield and good Z-selectivities (Table 4). Some number of different ring sizes were constructed in good yield and good Z-selectivities (Table 4). Some limitations still persist, such as the need for high dilution and static vacuum to promote mRCM. The number of different ringsuch sizesaswere constructed indilution good yield good Z-selectivities (Table 4). Some limitations still persist, the need for high andand static vacuum to promote promote mRCM. The that such as the need for high dilution and static vacuum to promote mRCM. The authors noted limitations still persist, such as the need for high dilution and static vacuum to mRCM. The limitations still persist, such as the need for high dilution static vacuum to promote mRCM. The authors noted that macrocycles containing alcohols and ketones displayed increased Z-degradation limitations stillthat persist, such as the need for alcohols high dilution and static vacuumincreased to promote mRCM. The authors noted macrocycles containing and ketones ketones displayed Z-degradation macrocycles containing alcohols and ketones displayed increased Z-degradation over time (as low as authors noted that macrocycles containing alcohols and displayed increased Z-degradation authors noted macrocycles alcohols and ketones Z-degradation over time that (as low as 50% Z containing after 24 h), but no reasoning was displayed provided. increased As improvements were made authors noted that macrocycles containing alcohols and ketones displayed increased Z-degradation over time (as low as 50% Z after 24 h), but no reasoning was provided. As improvements were made 50% Z after 24 h), but no reasoning was provided. As improvements were made to thewere cyclometalated over time (as low as 50% Z after 24 h), but no reasoning was provided. As improvements made over time (as low as 50% Z after 24 h), but no reasoning was provided. As improvements were made to the cyclometalated catalyst scaffold, 9 was also evaluated in various mRCM, delivering exceptional over time (as low as 50% Z after 24 h), but no reasoning was provided. As improvements were made to the thecatalyst cyclometalated catalyst scaffold, wasinalso also evaluated in various various mRCM, delivering exceptional scaffold,catalyst 9 was also evaluated various mRCM, delivering exceptional levels of Z-selectivity to cyclometalated scaffold, 999 was evaluated in mRCM, delivering exceptional to the cyclometalated catalyst scaffold, was also evaluated in various mRCM, delivering exceptional levels of Z-selectivity (Table 4) [38]. to the cyclometalated catalyst scaffold, 9 was also evaluated in various mRCM, delivering exceptional levels(Table of Z-selectivity Z-selectivity (Table 4) 4) [38]. [38]. 4) [38]. (Table levels of levels levels of of Z-selectivity Z-selectivity (Table (Table 4) 4) [38]. [38]. Table 4. Z-Selective macrocyclic ring-closing metathesis (mRCM) employing 6 and 9. Table Table 4. Z-Selective Z-Selective macrocyclic ring-closing metathesis (mRCM) employing and 69. 9.and 9. 4. Z-Selective macrocyclic ring-closing metathesis (mRCM) employing Table 4. macrocyclic ring-closing metathesis (mRCM) employing 66 and Table Table 4. 4. Z-Selective Z-Selective macrocyclic macrocyclic ring-closing ring-closing metathesis metathesis (mRCM) (mRCM) employing employing 66 and and 9. 9.
Product Cat Yield (%) Z (%) EntryEntryEntry Product Product Cat Cat Yield (%) Yield Z (%)(%) Entry Entry Entry
1
111 1
2
2 222
3
333 3
4
444 4
555 5
666 6
Product Product Product
1
2
3
4
Cat Cat Cat 6 666
6 666
666 6
6 666 999 9
5
6 666 999 9
6
6 666 999 9
Yield (%) Yield Yield (%) (%) 6 6
6 6
6 6
6 96 9
6 9
6 9
40 40 40 40
58 58 58 58
72 72 72 72
71 71 71 71 64 64 64 64
50 50 50 50 36 36 36 36
56 56 56 56 45 45 45 45
40
58
72
Z (%) Z Z (%) (%) 8640 86 86 86
8558 85 85 85
84 84 84 8472
86
Z (%)
86
85 85
84
71 64
89 89 89 89 8971 >95 >95 >95 >95 64 >95
50 36
68 68 68 68 68 >95 >95 >95 >95 >95
56 45
65 65 65 65 65 >95 >95 >95 >95 >95
84
89 >95
66
33
72 72
84 84
Catalysts 2017, 7, 87
8 of 38
71 Table 66 4. Cont. 71
44
99
Entry
Product
64 64 Cat
89 89 >95 >95 Yield (%)
Z (%)
5
55
66 99
6 9
50 50 36 36
6850 68 36 >95 >95
68 >95
6
66
66 99
6 9
56 56 45 45
6556 65 >95 45 >95
65 >95
Catalysts 2017, 7, 87
8 of 36
2.2.5. 2.2.5. Z-Selective Z-Selective Ethenolysis Ethenolysis The is is known to to perform kinetically ZThe aforementioned aforementioned cyclometalated cyclometalatedruthenium rutheniumcatalyst, catalyst,6, 6, known perform kinetically selective homodimeriztions andand CM,CM, generating a disubstituted olefin and and ethylene gas (Tables 1 and1 Z-selective homodimeriztions generating a disubstituted olefin ethylene gas (Tables 2). any any CM CM is inisequilibrium withwith the the backback reaction, ethenolysis, which is the cleavage of andHowever, 2). However, in equilibrium reaction, ethenolysis, which is the cleavage an internal olefin to generate two terminal olefins. Furthermore, ethenolysis of internal olefins has of an internal olefin to generate two terminal olefins. Furthermore, ethenolysis of internal olefins has received and fuels from renewable sources such as seed oil received attention attentionas asaamethod methodtotoaccess accessmaterials materials and fuels from renewable sources such as seed derivatives [50–55]. It was postulated that 6 could bebeemployed oil derivatives [50–55]. It was postulated that 6 could employedininaaZ-selective Z-selectiveethenolysis ethenolysis as as aa method method to to purify purify E-olefins. E-olefins. Unfortunately, Unfortunately, no protocol protocol to generate generate E-olefins E-olefins kinetically kinetically was was available available when employing employingaaruthenium ruthenium catalyst [56]. This an issue extremely pure quantities of a catalyst [56]. This is anisissue whenwhen extremely pure quantities of a specific specific olefinare isomer are required, such as in medicinal chemistry. olefin isomer required, such as in medicinal chemistry. Cyclometalated Cyclometalated complex complex 66 was was found found to to promote promote ethenolysis ethenolysis of of internal internal Z-olefins Z-olefins as as a method to to purify an E/Z-mixture E/Z-mixtureof ofvariously variouslysized sizedand andfunctionalized functionalizedmacrocycles macrocycles(Table (Table 5) 5) delivering delivering the the E-macrocycles in inhigh highpurity purity[49]. [49]. Additional studies found that linear internal olefinic mixtures Additional studies found that linear internal olefinic mixtures could could be purified this technique, providing E-olefins exclusively [57]. Complex be purified using using this technique, providing E-olefins almostalmost exclusively (Table(Table 6) [57].6)Complex 6 was 6found was found to tolerate wide variety of functional such free alcohols 6, 3), entry 3), to tolerate a widea variety of functional groupsgroups such as freeasalcohols (Table(Table 6, entry esters esters 6, entries 2 and 4), amines 6,5), entry and ketones entry 6). Additionally, (Table(Table 6, entries 2 and 4), amines (Table (Table 6, entry and5), ketones (Table (Table 6, entry6,6). Additionally, low to low to moderate ethylene pressures were operable. moderate ethylene pressures were operable. Table Table 5. Z-Selective Z-Selective ethenolysis ethenolysis furnishing E-isomer enriched macrocycles.
Entry 1 1 2 2 3 3
Entry
Substrate Initial E (%) Final E (%) Substrate Initial E (%) Final E (%) 19 55 >95 19 55 >95 2020 80 80 >95 >95 2121 80 80 >95 >95
Table 6. Z-Selective ethenolysis of symmetric internal olefins providing E-isomer enrichment.
Entry
R
n
Initial E (%)
Final E (%)
Entry 1 2 3
Catalysts 2017, 7, 87
Substrate 19 20 21
Initial E (%) 55 80 80
Final E (%) >95 >95 >95
9 of 38
Table 6. Z-Selective ethenolysis of symmetric internal olefins providing E-isomer enrichment. Table 6. Z-Selective ethenolysis of symmetric internal olefins providing E-isomer enrichment.
Entry R R 1 Me Me 2 OAcOAc OHOH 3 CO2 Me 4 CO2Me NHPh 5 C(O)Me NHPh 6 C(O)Me
Entry 1 2 3 4 5 6
E (%)E (%) Final E (%) nn InitialInitial Final E (%) 33 52 52 90 90 77 78 78 >95 >95 90 44 68 68 90 6 80 >95 6 80 >95 3 80 >95 32 80 72 >95 >95 2 72 >95
The study of 66 in in ethenolysis ethenolysis also also provided provided aa better better mechanistic mechanistic understanding understanding for for CM CM and and 9 of 36 mRCM. ItIt was was observed observed that that the the CM CM of of two two internal internal Z-olefins Z-olefins cannot cannotdirectly directlyoccur, occur, but but each each olefin olefin mRCM. must first be ethenolyzed to the terminal olefins, which can subsequently participate in metathesis to generate new internal Z-olefin [57]. E-olefins not can participate in thisparticipate process; therefore, this isto a must firstabe ethenolyzed to the terminal olefins,will which subsequently in metathesis generate a new internal Z-olefin [57]. E-olefins will not participate in this process; therefore, this is a promising method to separate Z- and E-isomers. promising method to separate Z- and E-isomers.
The study Catalysts 2017, 7, 87 of
2.2.6. Chemoselectivity in Z-Selective Olefin Metathesis 2.2.6. Chemoselectivity in Z-Selective Olefin Metathesis The ability of 6 to selectively react with terminal or Z-olefins, as was seen in the ethenolysis The ability of 6 to selectively react with terminal or Z-olefins, as was seen in the ethenolysis methodology, offered a platform to perform chemoselective OM on substrates containing multiple methodology, offered a platform to perform chemoselective OM on substrates containing multiple olefins. It was reported by Grubbs and coworkers that 9 was able to differentiate between terminal olefins. It was reported by Grubbs and coworkers that 9 was able to differentiate between terminal olefins and internal E-olefins with great discretion, providing 1,4-diene CM products in good yields olefins and internal E-olefins with great discretion, providing 1,4-diene CM products in good yields with excellent selectivities (Table 7) [58]. Carbonyl and amine functionality was also tolerated (Table with excellent selectivities (Table 7) [58]. Carbonyl and amine functionality was also tolerated 7, entries 2–7). They also found that internal Z-olefins reacted preferentially to E-olefins and (Table 7, entries 2–7). They also found that internal Z-olefins reacted preferentially to E-olefins chemoselective RCM formed macrocyclic dienes. and chemoselective RCM formed macrocyclic dienes. Table 7. Chemoselective CM with trans-1,4-hexadiene using 9. Table 7. Chemoselective CM with trans-1,4-hexadiene using 9.
Entry Entry 1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8
RR CH CH2 Ph2Ph (CH )8CHO (CH 2 )82CHO (CH (CH )2COMe 2 )22COMe (CH 2 )72CO 2 Me (CH )7CO 2Me CH2 NHPh CH2NHPh CH2 NHBoc CH 2NHBoc CH2 OCO 2 Me CH22OCO BPin 2Me CH CH2BPin
Yield Yield(%) (%) 63 63 70 70 49 49 82 82 68 68 54 54 79 65 79 65
Z (%) Z (%) >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95 >95
Stereoselective coupling of terminal olefins with 3E-1,3-dienes was demonstrated with 9, affording Table 8. Z-Selective CM of 3E-1,3-dienes with terminal olefins. functionally diverse E, Z conjugated dienes in excellent selectivity [59]. The transformation was conducted in neat substrate, and good yields were obtained for substrates bearing alcohols, allylic ethers, and esters while halides, amides, ketones, carbonates and aldehydes afforded moderate yields (Table 8). Nitriles and dienes in conjugation with aromatic rings resulted in poor yields (Table 8, entries 11, 13–14). 9 Entry R’ Yield (%) R (xx mol %) 1 (CH2)7OH (CH2)9Me 2 84 2 CH2OCH2CCPh (CH2)9Me 3 82 3 CH2NHBoc (CH2)9Me 4 60 4 (CH2)8CHO (CH2)9Me 4 59 5 CH2BPin (CH2)9Me 4 60 6 (CH2)4OAc (CH2)9Me 4 69 7 CH2CH2COMe (CH2)9Me 4 41
4 5 6 7 8
Catalysts 2017, 7, 87
(CH2)7CO2Me CH2NHPh CH2NHBoc CH2OCO2Me CH2BPin
82 68 54 79 65
>95 >95 >95 >95 >95
10 of 38
Table 8. Z-Selective CM of 3E-1,3-dienes with terminal olefins. Table 8. Z-Selective CM of 3E-1,3-dienes with terminal olefins.
9 9 Yield (%) Yield (%) (xx mol (xx %) mol %) (CH22))77OH OH (CH 2)9Me 2 84 84 1 1 (CH (CH 2 2 )9 Me CH22OCH CCPh (CH 2)92Me 3 82 82 2 2 OCH22CCPh (CH )9 Me 3 3 3 CH22NHBoc (CH )9 Me 4 CH NHBoc (CH 2)92Me 4 60 60 4 (CH2 )8 CHO (CH2 )9 Me 4 4 (CH2)8CHO (CH2)9Me 4 59 59 5 CH2 BPin (CH2 )9 Me 4 60 CH2)BPin (CH 2)9Me 4 60 69 6 5 (CH (CH 4 2 4 OAc 2 )9 Me (CH 2)24COMe OAc (CH 2)92Me 4 69 41 7 6 CH (CH )9 Me 4 2 CH 8 7 CH OCO Me (CH ) Me 4 CH22CH2COMe (CH2)92Me 4 41 42 2 9 9 8 (CH ) Br (CH ) Me 4 2 6 2Me 9 CH2OCO (CH2)92Me 4 42 34 10 (CH2 )2 CN (CH2 )9 Me 4 12 9 (CH2)6Br (CH 2)9Me 4 34 75 Catalysts 2017, 7, 87 10 of 36 11 (CH2 )7 OH (CH2 )4 OAc 4 (CH22))72OH CN (CH2)9Ph Me 4 12 15 12 10 (CH 4 yields (Table 8). Nitriles in conjugation 13 11 and dienes (CH 4 resulted (CH22))77OH OH (CH4-MeOPh 2)4with OAcaromatic 4 rings 75 in25poor yields (Table 8, entries 11, 13–14). 12 (CH2)7OH Ph 4 15 Homodimerization of 3E-1,3-dienes afforded E,Z,E-trienes in moderate yields. ROCM was 13 (CH 2)7OH 4-MeOPh 4 25 Homodimerization of 3E-1,3-dienes afforded E,Z,E-trienes in moderate yields. ROCM was conducted with dienes and norbornene or cyclobutene derivatives, providing the ring-opened conducted with dienes and norbornene or cyclobutene derivatives, providing the ring-opened products products in excellentcoupling yield (>89%) and Z-selectivity (>20:1). Stereoselective of terminal olefins with 3E-1,3-dienes was demonstrated with 9, in excellent yield (>89%) and Z-selectivity (>20:1). affording functionally diverse E, Z conjugated dienes in excellent selectivity [59]. The transformation 2.3. Catalyst was conducted in neat substrate, and good yields were obtained for substrates bearing alcohols, 2.3. Monothiolate Monothiolate Catalyst allylic ethers, and esters while halides, amides, ketones, carbonates and aldehydes afforded moderate Monothiolate Catalyst Development and Applications Entry Entry
R R
R’R’
Early examples for Z-selective Z-selective OM catalysts catalysts were were based based on Mo and W modified by monoalkoxide–pyrrolide ligands [60–63]. These catalytic designs built the previously used monoalkoxide–pyrrolide ligands [60–63]. These catalytic designs built on the on previously used scaffolds scaffolds of the nonselective and WGrubbs catalysts. Grubbs and coworkers briefly a catalytic of the nonselective Mo and WMo catalysts. and coworkers briefly looked at a looked catalyticatsystem that system thata employed a similar to the nonselective ruthenium catalysts by one of employed similar design to thedesign nonselective ruthenium catalysts by replacing onereplacing of the chloride the chloride with aorsulfonate or phosphonate [31].these Because these catalysts were plagued by ligands withligands a sulfonate phosphonate [31]. Because catalysts were plagued by modest modest selectivities andlow showed lowthis stability, this idea was when the cyclometalated selectivities and showed stability, idea was shelved whenshelved the cyclometalated catalysts were catalysts were discovered. Jensen and coworkers continued build ona the idea thatscaffold a Z-selective discovered. Jensen and coworkers continued to build on thetoidea that Z-selective could scaffold could be similar to the traditional ruthenium metathesis catalysts. They performed a be similar to the traditional ruthenium metathesis catalysts. They performed a substitution on 1 to substitution 1 tochlorides displacewith one of the chlorides with 2,4,6-triphenylbenzenethiol, forming [64]. displace one on of the 2,4,6-triphenylbenzenethiol, forming 22 [64]. This very large22 X-type This very large X-type ligand can act as a barrier to one side of the catalyst, forcing all the substituents ligand can act as a barrier to one side of the catalyst, forcing all the substituents of the metallacycle to of the metallacycle to reside in a syn-arrangement, generating Z-olefins(Figure upon cycloreverison (Figure reside in a syn-arrangement, generating Z-olefins upon cycloreverison 6, IX). When assaying 6, When assaying 22 the dimerization terminal it was found to deliver highconversion Z-content 22IX). in the dimerization ofinterminal olefins, itof was foundolefins, to deliver high Z-content at low at low 9). conversion (Table isomerization 9). Unfortunately, isomerization persisted (Table Unfortunately, problems persistedproblems (Table 9, entry 1). (Table 9, entry 1).
Figure 6. Model of 22’s mode of selectivity by shielding one side of the ruthenacycle.
Table 9. Homodimerization of olefins employing 22 and 24.
Entry
R
Cat
Solvent
T (°C)
Time (h)
Yield (%)
Z (%)
Catalysts 2017, 7, 87
11 of 38
Figure 6. Model of 22’s mode of selectivity by shielding one side of the ruthenacycle. Table Homodimerization of of olefins 2222 and 24.24. Table 9. 9. Homodimerization olefinsemploying employing and
1
Cat Entry Solvent R Cat (xx mol %) Solvent R (xx mol %) 1 CH2Ph 22 (0.25) THF CH2 Ph 22 (0.25) THF
2
2 CH2Ph 24 (0.25) THF CH2 Ph 24 (0.25) THF
Entry
3 4 5 6
3 CH2SiMe3 22 (0.25) CH2 SiMe3 22 (0.25) 4 CH 2SiMe3 24 (0.25) CH2 SiMe3 24 (0.25) 5 (CH 2 ) 5 Me 22 (0.01) (CH2 )5 Me 22 (0.01) 6 (CH 2 ) 5 Me 24 (0.01) (CH2 )5 Me 24 (0.01)
THF THF THF THF neatneat neatneat
T (°C) Time (h) Yield (%) Z (%) T (◦ C) Time (h) Yield (%) 40 0.5 12 80 40 12 39 2 0.5 14 14 88 40 0.5 2 6 40 0.5 6 2 10 56 2 10 60 18 12 95 60 18 12 60 16 9 60 16 9 96 60 2 20 60 2 20 86 60 1.5 13 60 1.5 13 88
Z (%) 80 39 88 56 95 96 86 88
Expanding on early catalyst architecture which led to promising Z-selectivities at low
Expanding on early architecture which led anionic to promising Z-selectivities at low conversion, conversion, the Jensencatalyst group replaced the remaining chloride ligand with an isocyanate, the Jensen group replaced the remaining anionic comparisons chloride ligand an isocyanate, affording affording 24 (Scheme 2) [65]. Initial head-to-head with with the parent catalyst showed Catalysts 2017, 7, 87 Initial 11 of 36 24 (Scheme 2)Z-selectivity [65]. comparisons the2,parent catalyst showed improved improved at head-to-head the expense of reactivity (Table with 9, entries 4, and 6). Interestingly, this new Z-selectivity at the expense of reactivity (Table 9, entries 2, 4, and 6). Interestingly, this new catalyst was catalyst was found to be quite robust and, unlike 22, can be purified using standard chromatographic found to be quite robust and, unlike 22, can be purified using standard chromatographic conditions conditions (silica gel and unpurified solvents). Spurred by this finding, reactions conducted with 24 (silica gel and unpurified solvents). Spurred by this finding, reactions conducted with 24 under air or in under air or in the presence of an acid under argon were shown to reduce the amount of isomerization the presence under argon (chain-walking) were shown to and reduce the amount of isomerization observed observedofinan theacid starting material product (Z:E). Additional studies were aimedin the starting material (chain-walking) and product (Z:E). Additional studies were aimed at understanding at understanding the effect of changing the identity of the donor ligand (NHC in 22 and 24). the effect of changing theoridentity of the donor ligand (NHC in 22 and 24). Phosphine supported, Phosphine supported, first-generation, analogues of 22 (Figure 7) were prepared, characterized crystallographically, and studied computationally generally demonstratedcrystallographically, lower activities and and or first-generation, analogues of 22 (Figure 7) were but prepared, characterized Z-selectivities [66]. studied computationally but generally demonstrated lower activities and Z-selectivities [66].
Scheme 2. 2. Formation Formation ofof24. Scheme 24.
Figure 7. Phosphine monothiolatecatalysts catalysts evaluated. Figure 7. Phosphineand andbidentate bidentate monothiolate evaluated.
2.4. Dithiolate Catalysts 2.4.1. Catalyst Development Expanding on their own work in conjunction with Schrock and coworkers developing
Catalysts 2017, 7, 87
12 of 38
2.4. Dithiolate Catalysts 2.4.1. Catalyst Development Expanding Catalysts 2017, 7, 87
on their own work in conjunction with Schrock and coworkers developing 12 of 36 molybdenum and tungsten Z-selective OM catalysts [60–63], the Hoveyda group sought to utilize of 29ligand to the scaffold more demanding CM of terminal with internal olefins this The largeapplication versus small idea in ruthenium-catalyzed Z-selective OMnecessitated (Figure 8). catalyst improvements for enhanced stability. Catalyst decomposition was proposed to occur via They believed if a side-bound ruthenacycle was operative, the large axial ligand could force an all syn migratory insertion of(Figure the propagating carbene into the ruthenium-sulfur bond trans to the NHC [69]. ruthenacyclobutane 8a). As has been previously discussed, traditional metathesis catalysts Incorporation electron-withdrawing halogen ruthenacyclobutane substituents into thedue backbone of the steric dithiolate are believed toof proceed through a bottom-bound to unfavorable and moiety theoretically experimentally resulted in improved efficiency. Though considered reactivities electronic factors in and the side-bound isomer (Figure 8b). Thuscatalyst Hoveyda and coworkers and selectivities catalystsspecies 30–34 were similar a(Figure 9), 30 ruthenacycle, has the practical advantage being using a bidentatefordianionic to promote side-bound providing theof desired readily prepared from commercially available 3,6-dichloro-1,2-benzenedithiol. Complex 30 was catalytic scaffold to achieve a Z-selective OM (Figure 8c). Replacing the chlorides with catecholate or subsequently demonstrated to catalyze CMthe of cis-2-butene-1,4-diol with both a variety terminal catechothiolate (29), furnished catalyststhe with anticipated ligand arrangement, which of performed olefins bearingmetathesis a wide range of functionalities and internal cis-olefin bearing substrates,(ROCM) oleyl alcohol ring-opening polymerization (ROMP) and ring-opening cross metathesis with and acid. and Z-selectivity [29,67,68]. higholeic efficiency
Design process process for for 29. 29. (a) (a) Mimicking Mimicking the the design design of of the the Mo Mo and and W W Z-selective Z-selective catalyst; catalyst; Figure 8. Design bottom-bound ruthenacycle is favored; (c) Employing a bidentate chelate (b) Observations Observations showing showingthe the bottom-bound ruthenacycle is favored; (c) Employing a bidentate that would side-bound ruthenacyclobutane. chelate that induce would ainduce a side-bound ruthenacyclobutane.
The application of 29 to the more demanding CM of terminal with internal olefins necessitated catalyst improvements for enhanced stability. Catalyst decomposition was proposed to occur via migratory insertion of the propagating carbene into the ruthenium-sulfur bond trans to the NHC [69]. Incorporation of electron-withdrawing halogen substituents into the backbone of the dithiolate moiety theoretically and experimentally resulted in improved catalyst efficiency. Though reactivities and selectivities for catalysts 30–34 were similar (Figure 9), 30 has the practical advantage of being readily prepared from commercially available 3,6-dichloro-1,2-benzenedithiol. Complex 30 was subsequently demonstrated to catalyze the CM of cis-2-butene-1,4-diol with both a variety of terminal olefins bearing a wide range of functionalities and internal cis-olefin bearing substrates, oleyl alcohol and oleic acid.
Figure 9. Various dithiolate catalysts synthesized by Hoveyda and coworkers.
Figure 8. Design process for 29. (a) Mimicking the design of the Mo and W Z-selective catalyst; Observations showing the bottom-bound ruthenacycle is favored; (c) Employing a bidentate Catalysts 2017, (b) 7, 87 chelate that would induce a side-bound ruthenacyclobutane.
Catalysts 2017, Catalysts 2017, 7, 7, 87 87 Catalysts Catalysts 2017, 2017, 7, 7, 87 87
13 of 38
13 of 13 of 36 36 13 13 of of 36 36
FigureFigure 9. Various dithiolate catalysts Hoveyda coworkers. 9.Cross Various dithiolate catalysts synthesized synthesized byby Hoveyda andand coworkers. 2.4.2. Z-Selective Metathesis 2.4.2. Z-Selective Ring-Opening Ring-Opening Cross Metathesis 2.4.2. 2.4.2. Z-Selective Z-Selective Ring-Opening Ring-Opening Cross Cross Metathesis Metathesis Until recently the only ruthenium-catalyzed Z-selective ring-opening/cross metathesis (ROCM) Until recently the only ruthenium-catalyzed Z-selective ring-opening/cross metathesis (ROCM) 2.4.2. Z-Selective Ring-Opening Cross Metathesis Until recently the only ruthenium-catalyzed Z-selective ring-opening/cross metathesis (ROCM) Until recently the only ruthenium-catalyzed Z-selective ring-opening/cross metathesis (ROCM) was substrate dependent and relied on complex catalytic design [70]. The dithiolate-based catalyst was substrate dependent and relied on complex catalytic design [70]. The dithiolate-based catalyst was substrate dependent and relied on complex catalytic design [70]. The dithiolate-based Catalysts 2017, the 7, 87and 13 of catalyst 36 (ROCM) was substrate dependent relied on complex catalytic design [70]. The dithiolate-based catalyst Until recently only ruthenium-catalyzed Z-selective ring-opening/cross metathesis saw initial success in this relatively uncharted area [29,67,68]. Hoveyda and coworkers provided the saw initial success in this relatively uncharted area [29,67,68]. Hoveyda and coworkers provided the saw initial success in this relatively uncharted area [29,67,68]. Hoveyda and coworkers provided the sawexamples initial success in this relatively uncharted area [29,67,68]. Hoveyda and coworkers provided the was substrate dependent and relied on complex catalytic design [70]. The dithiolate-based catalyst first of ROCM involving styrenes (Table 10, entries 1 and 2). They continued pursuing the 2.4.2. Z-Selective Ring-Opening Cross Metathesis first examples of ROCM involving styrenes (Table 10, entries 1 and 2). They continued pursuing the first examples of ROCM involving styrenes (Table 10, entries 1 and 2). They continued pursuing the first examples of ROCM involving styrenes (Table 10, entries 1 and 2). They continued pursuing the the saw initial success in this relatively uncharted area [29,67,68]. Hoveyda and coworkers provided scope of this transformation it aa variety of useful olefins including heteroaryl olefins scope of this transformation to expand itit to to of useful olefins including heteroaryl olefins Until recentlyto theexpand only ruthenium-catalyzed Z-selective ring-opening/cross metathesis (ROCM) scope of this transformation to expand to aa variety variety of useful olefins including heteroaryl olefins scope of this transformation to expand it to variety of useful olefins including heteroaryl olefins first examples of ROCM involving styrenes (Table 10, entries 1 and 2). They continued pursuing the (Table 10, entries and 7) and dienes (Table entries 88 and 9) as well employing free alcohols on was6 dependent and relied 10, on complex catalytic design [70].as The dithiolate-based catalyst (Table 10, entries 66substrate and 7) and dienes (Table 10, entries and 9) as well as employing free alcohols on (Table 10, entries and 7) and dienes (Table 10, entries 8 and 9) as well as employing free alcohols on (Table 10, entries 6initial and 7) It andindienes (Table 10, entries 8[29,67,68]. andof9)useful as wellolefins as employing free alcohols on scope of this transformation to expand it to a area variety including heteroaryl olefins saw success this relatively uncharted Hoveyda and coworkers provided the the norbornene (Table 10). noted that allyl ethers performed much poorer than the free alcohols the norbornene (Table 10). ItItwas was noted that allyl ethers performed much poorer than the free alcohols the norbornene (Table 10). was noted that allyl ethers performed much poorer than the free alcohols first examples of ROCM involving styrenes (Table 10, entries 1 and 2).well They continued pursuing the the norbornene (Table 10). It was noted that allyl ethers performed much poorer than the free alcohols (Table 10, entries 6 and 7) and dienes (Table 10, entries 8 and 9) as as employing free alcohols as coupling partners in ROCM. It that there is significant trans influence conveyed from on as coupling partners ROCM. ItItis isisproposed proposed that isisaaaof significant trans influence conveyed scope ofin this transformation to expand it tothere a variety useful olefins including heteroaryl olefins from as coupling partners in ROCM. proposed that there significant trans influence conveyed as coupling partners in ROCM. It is proposed that there is a significant trans influence conveyed from the norbornene (Table 10). It was noted that allyl ethers performed much poorerWhen than employing the freefrom alcohols the NHC to the axial thiolate, thus some electronic charge builds up on the thiolate. the NHC to the axial thiolate, thus some electronic charge builds up on the thiolate. When employing (Table 10, entries 6 and 7) and dienes (Table 10, entries 8 and 9) as well as employing free alcohols on the NHC to the axial thiolate, thus some electronic charge builds up on the thiolate. When employing NHC to the axial thiolate, thus some electronic charge builds up on the thiolate. When employing as coupling partners in ROCM. It is proposed that there is a significant trans influence conveyed from aathe free alcohol as the coupling partner, hydrogen bonding can occur to dissipate the electron repulsion the norbornene (Table 10). It was noted that allyl ethers performed much poorer than the free alcohols alcohol as the coupling partner, hydrogen bonding can occur to dissipate the electron repulsion aafree free alcohol as the coupling partner, hydrogen bonding can occur to dissipate the electron repulsion free alcohol as the coupling partner, hydrogen bonding can occur to dissipate the electron repulsion the NHC to the axial thiolate, thus some electronic charge builds up on the thiolate. When employing as coupling partners in ROCM. It is proposed that there is a significant trans influence conveyed from experienced by placing and sulfur in proximity is experienced by placing the the oxygen oxygen and sulfur in proximity (Figure (Figure 10, 10, X). X). If IfIfan an allyl allyl ether ether isisused, used, no no experienced by oxygen and sulfur in ether no NHC to the the axial thiolate, thus some electronic charge(Figure builds up10, on X). the When employing experienced bytheplacing placing the oxygen and sulfur in proximity proximity (Figure 10, X). If an an allyl allyl ether is used, used, no a free bonding alcohol ascan the coupling partner, hydrogen bonding can occur to thiolate. dissipate the electron repulsion hydrogen occur, so the two heteroatoms experience repulsion and destabilize the hydrogen bonding can occur, so the two heteroatoms experience repulsion and destabilize the a free alcohol as the coupling partner, hydrogen bonding can occur to dissipate the electron repulsion the hydrogen bonding can occur, so the two heteroatoms experience repulsion and destabilize hydrogen bonding occur, theXI). two experience repulsion experienced by can placing theso oxygen andheteroatoms sulfur in proximity (Figure 10, X). and If andestabilize allyl ether the is used, ruthenacycle intermediate 10, ruthenacycle intermediate (Figure 10, XI). experienced by(Figure placing the oxygen and sulfur in proximity (Figure 10, X). If an allyl ether is used, no ruthenacycle intermediate (Figure 10, XI). ruthenacycle intermediate (Figure 10, XI). no hydrogen bonding can occur, so the two heteroatoms experience repulsion and destabilize the hydrogen bonding can occur, so the two heteroatoms experience repulsion and destabilize the ruthenacycle intermediate (Figure 10,10, XI). ruthenacycle intermediate (Figure XI). Table Ring-opening/cross metathesis (ROCM) Table 10. 10. Ring-opening/cross metathesis (ROCM) of of norbornene norbornene diols diols with with terminal terminal olefins. olefins.
Table Table 10. 10. Ring-opening/cross Ring-opening/cross metathesis metathesis (ROCM) (ROCM) of of norbornene norbornene diols diols with with terminal terminal olefins. olefins. Table 10. Ring-opening/cross metathesis (ROCM) of norbornene diols with terminal olefins. olefins. Table 10. Ring-opening/cross metathesis (ROCM) of norbornene diols with terminal
Entry Entry 11 1 1 21 2 2 2 32 3 33 3 4 4 44 4 5 5 55 5
Entry Entry Entry
Time (h) EntryR 29 (xx%) mol %) Time R 29 29 (xx (xx mol mol %) Time (h)(h) RR mol Time RR 2929 (xx(xx mol %) %) Time(h) (h) 29 (xx mol %) Time 1 Ph Ph 1 1(h) 1 1 Ph 1 1 Ph 1 Ph6H4 m-FC6H4 1 1 1 11 2 Ph m-FC 11111 m-FC 6H4 11 m-FC 6 H 4 118 m-FC H 1 3 (CH 2 ) 2 OTBS 5 6 6H 44 m-FC (CH 2)2OTBS 51 881 (CH 4 222)))222OTBS (CH2)2C(O)NHPh 5 55 5 (CH OTBS (CH OTBS 888 (CH 2)2OTBS 5 (CH 2)25C(O)NHPh 88888 (CH2)7Me 5 (CH )2 C(O)NHPh 55 (CH 2)22C(O)NHPh 5 (CH 2)2C(O)NHPh (CH(CH 2)2C(O)NHPh (CH 222))777Me (CH Me (CH (CH Me 6 22))77Me
77 7 7
7 8 8 88 998 99 9 10 10 10 10 10 11 11 11 11 11
5
8 8888 88 2
93 93 93 93 97
93 93 93
5
22 2 22 2 22 22 22 2 2 22 22212 22 2 2222 222 12 12 12 12 12
84 97 97 97 80 97 95 84 84 80 84 84 80 80 80 80 95 95 95 95 80 80 80 80
>98 >98 97>98 >98
55 5
6 6 6
66
5 55
5 55 5
55
7 8 9 10 11 nBu O nBu O nBu O n nBu Bu OO SEt SEt SEt SEt SEt
55 55
OnBu SEt
5 2 2 22 552 5 5 25 22 2 52 5 5 5 5
Yield (%) (%) Yield (%) ZZ (%) Yield (%) Z (%) Yield (%) Z (%) Yield (%) Yield (%) Z (%) 92 97 92 97 92 97 92 97 92 97 92 93 96 93 96 93 96 93 93>98 96 68 93 96 68 >98 68 >98 65 68>98>98 68 68 >98 65 >98 58 65>98 65 >98 65 >98 65 >98 58 >98 58 58 >98 58 58 >98 93 93>98
2 5 2 5
93 >98 93 91
>98 >98 91 91 849291 91 >98 >98 >98 >98 80 >98 >98 >98 >98 95 92 92 80 92 92
Figure 10. Different reactivity observed between allylic alcohols and allylic ethers believed to be a product of electron density buildup on the sulfur atom trans to the N-heterocyclic carbene (NHC).
Z (%) 97 96 >98 >98 >98 93
>98 91 >98 >98 92
7
5
2
97
>98
8 9 10 Catalysts 2017, 7, 87 11
2 5 2 5
2 2 2 12
84 80 95 80
91 >98 >98 92
OnBu SEt
14 of 38
Figure 10. Different reactivity observed observed between between allylic allylic alcohols alcohols and allylic allylic ethers believed believed to be a density buildup buildup on on the the sulfur sulfur atom atom trans trans to to the the N-heterocyclic N-heterocyclic carbene carbene (NHC). (NHC). product of electron density Catalysts 2017, 7, 87 Catalysts 2017, 7, 87 87 Catalysts 2017, 7, 2.4.3. Z-Selective Cross Catalysts 2017, 7, 87 2.4.3. Z-Selective Cross Metathesis Metathesis
14 of 14 of of 36 36 14 14 of 36 36
2017, 7, 87 14 of 36 andCatalysts coworkers were able ablewere to employ employ dithiolate catalyst 30 to to address this ruthenium issue [69]. [69]. They found that Many made the field fieldcatalyst of Z-selective Z-selective CM using using ruthenium catalysts, but some Many advances advances made in in the of CM catalysts, but some and were to dithiolate 30 this found that and coworkers coworkers were ablewere to employ dithiolate catalyst 30 to address address this issue issue [69]. They They found that cis-2-butene-1,4-diol participated in CM with sterically hindered partners (Table 11), but elevated unmet challenges existed: CM to allyl alcohols and use of sterically hindered Hoveyda unmet challenges existed: CM to afford allylsterically alcohols ofpartners sterically hindered olefins. Hoveyda cis-2-butene-1,4-diol participated in CM with hindered 11), but cis-2-butene-1,4-diol participated in afford CMdithiolate with sterically hindered partners (Table 11),olefins. but elevated elevated and coworkers were able to employ catalystand 30 use to address this (Table issue [69]. They found that cis-2-butene-1,4-diol participated in CM with sterically hindered partners (Table 11), but elevated catalyst loadings are required. Additionally, functionality such as aldehydes (Table 11, entry 7) andthat and coworkers were able to employ dithiolate catalyst 30 to address this issue [69]. They found catalyst loadings are required. Additionally, functionality such as aldehydes (Table 11, entry 7) and cis-2-butene-1,4-diol participated in CM with stericallysuch hindered partners(Table (Table11, 11), but7)elevated catalyst loadings are required. Additionally, functionality as aldehydes entry and free carboxylic acids (Table 11, 8) in CM. Allyl ether was also (Table 11, cis-2-butene-1,4-diol participated CM with sterically partners (Table 11), elevated free carboxylic acids (Table 11, entry 8) partook in CM. Allyl ether also tolerated (Table 11, entry freecatalyst carboxylic acids are (Table 11, entry entry 8)inpartook partook in CM. Allyl hindered ether was also tolerated tolerated (Table 11, entry entry loadings required. Additionally, functionality suchwas as aldehydes (Table 11, but entry 7) and free carboxylic acids (Table 11, entry 8) partook in CM. Allyl ether was also tolerated (Table 11, entry 4), which is somewhat surprising considering the issue with these substrates in ROCM previously catalyst loadings are required. Additionally, functionality such as aldehydes (Table 11, entry 7) 4), which is somewhat surprising considering the issue with these substrates in ROCM previously 4), which is somewhat surprising considering the issue with these substrates in ROCM previously carboxylic acids surprising (Table 11, entry 8) partook CM.with Allylthese ethersubstrates was also tolerated 11, entry 4), free which is somewhat considering the in issue in ROCM(Table previously discussed. Modifications were made to the dithiolate catalyst to make the dithiolate less electron rich andwhich freeModifications carboxylic acids (Table entry 8) partook in CM. Allyl was also tolerated (Table discussed. were made to the to the dithiolate electron rich 4), is somewhat surprising considering thecatalyst issue with theseether substrates inless ROCM previously discussed. Modifications were made11, to the dithiolate dithiolate catalyst to make make the dithiolate less electron rich 11, to exhibit higher stability. Using computational studies, it was proposed that reducing the electron entry 4), which is somewhat surprising considering the issue with these substrates in ROCM previously to exhibit higher stability. Using computational studies, it was proposed that reducing the electron to exhibit exhibit higher stability. Using Using computational studies,catalyst it was was proposed proposed that reducingless theelectron electronrich discussed. Modifications were computational made to the dithiolate to make the dithiolate to higher stability. studies, it that reducing the electron density on the theModifications dithiolate by by adding adding the chlorides chlorides in 30 30 would would also weaken the trans influence, influence, thusrich discussed. were made to the dithiolate catalyst to make the dithiolate less electron density on dithiolate the in also weaken the trans thus to exhibit higher stability. Using computational it was that reducing the electron density on the dithiolate by adding the chlorides instudies, 30 would alsoproposed weaken the trans influence, thus stabilizing the interaction between two heteroatoms seen in Figure 10. Complex 30 also displayed to exhibit stability. computational wasalso proposed that the electron stabilizing the interaction between two heteroatoms seen in 10. Complex 30 also displayed density on the dithiolate byUsing adding the chloridesstudies, in 30 would weaken thereducing trans influence, thus stabilizing thehigher interaction between two heteroatoms seen initFigure Figure 10. Complex 30 also displayed great utility in the CM of disubstituted olefin feedstocks, such as oleic acid, with cis-2-butene-1,4-diol density dithiolate by addingolefin the chlorides in 30 would alsoacid, weaken the trans thus great utility in the CM of feedstocks, such as cis-2-butene-1,4-diol great utilityon inthe the interaction CM of disubstituted disubstituted olefin feedstocks, such as oleic acid, with cis-2-butene-1,4-diol stabilizing between two heteroatoms seen in oleic Figure 10.with Complex 30 influence, also displayed great utility in the CM of disubstituted olefin feedstocks, such as oleic acid, with cis-2-butene-1,4-diol to generate high-value Z-olefin products. stabilizing the interaction between two heteroatoms seen in as Figure Complex 30 also displayed to high-value Z-olefin products. great utility in the CM of disubstituted olefin feedstocks, such oleic10. acid, with cis-2-butene-1,4-diol to generate generate high-value Z-olefin products. great utility in the CM of disubstituted olefin feedstocks, such as oleic acid, with cis-2-butene-1,4-diol to generate high-value Z-olefin products. TableZ-olefin 11. CM CM scope of cis-1,4-butene cis-1,4-butene diol with with terminal olefins. olefins. to generate high-value products. Table of Table 11. 11. CM scope scope of cis-1,4-butene diol diol with terminal terminal olefins.
Table 11. CM scope of cis-1,4-butene diol with terminal olefins. Table 11. CM scope of cis-1,4-butene diol with terminal olefins.
Entry Time (h) Yield (%) Z (%) R Entry Time R Entry Time (h) (h) Yield Yield (%) (%) Z Z (%) (%) R Entry Time (h) Yield (%) Z (%) R 1 (CH 22)99Me 4 72 96 1 (CH 2 ) 9 Me 4 72 96 Time (h) Yield (%)(%)96Z (%) R Entry 1Entry (CHR Time 2)9Me 4 (h) 72 Yield (CH 2) ))222OTBS OTBS 65 93 2222 1 (CH 4444 4 65 93 222(CH (CH OTBS 65 93 96 2 ) 9 Me 72 (CH ) 2 OTBS 65 1 (CH2 )9 Me 4 72 93 3 (CH 22)22OPNP 4 74 96 33 2 (CH 2 ) 2 OPNP 4 74 96 2 (CH ) OTBS 4 65 2)2OTBS (CH(CH 22)22OPNP 4 4 74 65 96 93 nBu CH)222O OOPNP 12 4 57 91 n n 3 74 91 444 3 (CH CH 12 57 2 22O (CH 2n)Bu 2OPNP 4 74 96 CH Bu 12 57 91 n Bu (CH CO 2Bn 80 98 4 CH222)))2222O 5555 4 (CH 4444 12 80 222Bn nBu (CH CO Bn 80 57 57 98 98 91 2O 12 (CH 2CH )2CO CO Bn 80 98 5 (CH 80 98 (CH 4Phth 4 4 64 2 )222)CO 2 Bn 666 5 (CH 22))4442Phth 64 (CH )2CO2Bn 44 44 (CH Phth 64 80 64 98 98 98 6 (CH Phth 2))84CHO 777 (CH 2 4 80 94 444 44 80 94 222) 888CHO (CH ) CHO 80 94 2 ) 4 Phth 64 98 7 6 (CH (CH CHO 80 94 7 (CH(CH ) CHO 80 2 8 (CH ))333CO CO H 44 4 70 96 8888 7 (CH 22)) 22H H 4 70 96 2 2 8 (CH CO 70 (CH CO H 70 96 2 3 2 2)8CHO (CH(CH 2)3CO 2H 4 4 70 80 96 94 9* Ph 53 94 9* 9* Ph Ph 444 44 53 (CH 9* 8 Ph2)3CO2H 53 70 53 94 94 96 10 10 10 Cy 59 98 Cy 4444 44 59 10 9* Cy Ph 59 53 59 98 98 94 10 Cy 59 98 11 11 11 11 10 11
4444 44
73 73 98 73 59 73 98 98 73 98 73 66 95 66 95 66 66 95 66 95 63 92 63 92 63 66 63 92 92 63 56 96 56 56 63 56 96 96
96 93 96 91 98 98 94 96 94 98
98
98
98
95
95
92
92
96
56 96 54 87 54 87 54 87 54 54 87 8 Catalyst 87 15 *Entry *Entry 99 was was carried carried out out using using Catalyst54 32. 32.
87
11 12 12 12 12 12
13 13 13 13 12 13 14 13 14 14 14 14 15 15 15 15 15
Cy
Z (%)
8888 84 8888 88 888 88 8888 88
*Entry 99 was out using Catalyst 32. *Entry* Entry was9carried carried out out using Catalyst was carried using Catalyst32. 32. *Entry 9 was carried out using Catalyst 32.
3. Asymmetric Asymmetric Olefin Metathesis Metathesis 3. 3. Asymmetric Olefin Olefin Metathesis 3. Asymmetric Olefin Metathesis 3.1. General Introduction 3.1. 3.1. General General Introduction Introduction 3.1. General Introduction Asymmetric catalysis 3.1. General Introduction Asymmetric catalysis represents an important area in synthetic organic chemistry. Many Asymmetric catalysis represents represents an an important important area area in in synthetic synthetic organic organic chemistry. chemistry. Many Many Asymmetric catalysis represents an important area in synthetic organic chemistry. Many asymmetric catalysts find their origins in achiral transformations, but through structural asymmetric catalysts find their origins in achiral transformations, but through structural asymmetric catalysts find their origins in achiral transformations, but through structural Asymmetric represents area in syntheticbut organic chemistry. Many asymmetric catalystscatalysis find their originsaninimportant achiral transformations, through structural manipulations manipulations of of the the catalyst, catalyst, the the transformation transformation is is rendered rendered asymmetric. asymmetric. OM OM is is no no exception. exception. Early Early
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3. Asymmetric Olefin Metathesis 3.1. General Introduction Asymmetric catalysis represents an important area in synthetic organic chemistry. Many asymmetric catalysts find their origins in achiral transformations, but through structural manipulations of the catalyst, the transformation is rendered asymmetric. OM is no exception. Early work employed non-selective molybdenum-, ruthenium-, and tungsten-based catalysts to perform metathesis [1,2,4,5]. Recently, catalytic scaffolds have been modified to create a synthetic pathway to asymmetric structures through metathesis [11,16,17]. Although OM promotes the formation of carbon–carbon double bonds, asymmetric structures can be made indirectly through the desymmetrization of meso-compounds. The first example of asymmetric OM using a ruthenium catalyst employed a chiral NHC ligand [71]. This catalyst performed a desymmetrization of achiral trienes through asymmetric ring-closing metathesis (ARCM), furnishing the cyclic products in high enantioselectivities (Scheme 3). Since this seminal work from Grubbs and coworkers, many studies have commenced with the goal of Catalysts 2017, 7, selective 87 15 of[11,17,21]. 36 developing a more and efficient ruthenium metathesis catalyst for asymmetric OM Catalysts 2017, 7, 87 15 of 36 There have been a variety of catalyst designs to address this issue (Figure 11). Subsequent reports developing a more selective and efficient ruthenium metathesis catalyst for asymmetric OM developing a more selective and efficient metathesisofcatalyst for asymmetric to OM from Grubbs andThere coworkers continued use ruthenium the gearing-effect the NHC tailor the [11,17,21]. have been a variety ofto catalyst designs to address this issue (Figurebackbone 11). Subsequent [11,17,21]. There have been a variety of catalyst designs to address this issue (Figure 11). Subsequent steric environment aroundand thecoworkers ruthenium catalyst (Figure 11a) [72,73]. TheNHC Hoveyda group employed reports from Grubbs continued to use the gearing-effect of the backbone to tailor reports from Grubbs and coworkers continued to use the gearing-effect of the NHC backbone to tailor the steric environment around ruthenium catalyst (Figure 11a) [72,73]. The group C1 -symmetric bidentate NHC’s that the induced chirality at the ruthenium center toHoveyda control orientation of the steric environment around the ruthenium catalyst (Figure 11a) [72,73]. The Hoveyda group employed C 1 -symmetric bidentate NHC’s that induced chirality at the ruthenium center to control olefin complexation (Figure 11b) [74–76]. Monodentate ligands have been studied 1 -symmetric employed C1-symmetric bidentate NHC’s that induced C chirality at the ruthenium centeralso to control olefin complexation (Figure 11b) [74–76]. Monodentate C1-symmetric ligands have also in theseorientation processesof 11c) [77,78].(Figure The following sections on various asymmetric will orientation of(Figure olefin complexation 11b) [74–76]. Monodentate C1-symmetric ligands metatheses have also been studied in these processes (Figure 11c) [77,78]. The following sections on various asymmetric studied in these processes focus onbeen advancements made since (Figure 2010. 11c) [77,78]. The following sections on various asymmetric metatheses will focus on advancements made since 2010. metatheses will focus on advancements made since 2010.
3. Seminal example of asymmetricOM OM employing employing a aC2C -symmetric, chiralchiral N-heterocyclic SchemeScheme 3. Seminal example of asymmetric N-heterocyclic 2 -symmetric, Scheme 3. Seminal example of asymmetric OM employing a C2-symmetric, chiral N-heterocyclic (NHC) ligand. carbenecarbene (NHC) ligand. carbene (NHC) ligand.
Figure 11. Various catalyst designs used to achieve asymmetric OM. (a) C2-symmetric NHC ligands
Figure 11. Various catalyst designs used to achieve asymmetric OM. (a) C2-symmetric NHC ligands Figure 11. Various used to(b) achieve asymmetric OM.employed (a) C2 -symmetric NHC employed bycatalyst Grubbs designs and coworkers; Bidentate NHC ligands by Hoveyda and ligands employed by Grubbs and coworkers; (b) Bidentate NHC ligands employed by Hoveyda and coworkers; (c) Geared NHC ligands byNHC the Collins andemployed Grisi groups. employed by Grubbs and coworkers; (b)employed Bidentate ligands by Hoveyda and coworkers; coworkers; (c) Geared NHC ligands employed by the Collins and Grisi groups. (c) Geared NHC ligands employed by the Collins and Grisi groups.
3.2. Asymmetric Ring-Closing Metathesis 3.2. Asymmetric Ring-Closing Metathesis Much progress has been made employing chiral ruthenium catalysts in ARCM to obtain cyclized Much progress has been made employing chiral ruthenium catalysts in ARCM to obtain cyclized products in good enantioselectivities and high conversions [71,72,75,77,78]. A persisting challenge in products in good enantioselectivities and high conversions [71,72,75,77,78]. A persisting challenge in ARCM is the formation of tetrasubstituted olefins. Collins and coworkers revealed ruthenium ARCM is the formation of tetrasubstituted olefins. Collins and coworkers revealed ruthenium catalysts bearing a C1-symmetric NHC ligand that performed ARCM to desymmetrize meso-trienes, catalysts bearing a C1-symmetric NHC ligand that performed ARCM to desymmetrize meso-trienes, furnishing tetrasubstituted olefinic products (Table 12) [79]. All the catalysts bearing C1-symmetric furnishing tetrasubstituted olefinic products (Table 12) [79]. All the catalysts bearing C1-symmetric NHC ligands were isolated as mixtures of both the syn- and anti-isomers due to difficult separations
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3.2. Asymmetric Ring-Closing Metathesis Much progress has been made employing chiral ruthenium catalysts in ARCM to obtain cyclized products in good enantioselectivities and high conversions [71,72,75,77,78]. A persisting challenge in ARCM is the formation of tetrasubstituted olefins. Collins and coworkers revealed ruthenium catalysts Catalysts 87 16 of 36 bearing2017, a C17,-symmetric NHC ligand that performed ARCM to desymmetrize meso-trienes, furnishing tetrasubstituted olefinic products (Table 12) [79]. All the catalysts bearing C1 -symmetric NHC ligands observed, with the highest levels of asymmetry obtained using 45 anti (Table 12, entry 5). Sixwere isolated as mixtures of both the syn- and anti-isomers due to difficult separations (syn refers to membered ring formation was also operable when employing 45 anti. the alkyl group on the NHC ligand residing on the same side as the ruthenium-carbene). Interestingly, Many of the catalysts employed in asymmetric metathesis employ a disubstituted NHC slight separation of 45 could be obtained furnishing a mixture of 1:8 syn:anti (45 anti). Upon assessing backbone, but the Blechert group has explored mono-substituted NHC backbones with two different Catalysts 2017, 7, 87 of these catalysts in the ARCM to generate a tetrasubstituted olefin moderate to 16 high of 36 the performance N-substituents (46–48) [80]. The idea behind this design was to induce significant perturbation on one yields were obtained (Table 12). Unfortunately, modest enantioselectivities were observed, with the of the N-substituents to enhance the of chiral pocket ofobtained the catalyst. Moderate levels of enantioselectivity observed, withofthe highest levels asymmetry (Table 12,ring entry 5). Sixhighest levels asymmetry obtained using 45 anti (Table 12,using entry 45 5). anti Six-membered formation were observed in the ARCM of trienes (Table 13). membered ring formation was also operable when employing 45 anti. was also operable when employing 45 anti. Many of the catalysts employed in asymmetric metathesis employ a disubstituted NHC Table but 12. Asymmetric ring-closing metathesis (ARCM) to form tetrasubstituted olefins backbone, Blechert group has explored mono-substituted NHC backbones with twousing different Asymmetric ring-closing metathesis (ARCM) to form tetrasubstituted olefins using Table 12. the unsymmetrical N-heterocyclic carbene (NHC) ligands. N-substituents (46–48) [80]. The idea behind thisligands. design was to induce significant perturbation on one unsymmetrical N-heterocyclic carbene (NHC) of the N-substituents to enhance the chiral pocket of the catalyst. Moderate levels of enantioselectivity were observed in the ARCM of trienes (Table 13). Table 12. Asymmetric ring-closing metathesis (ARCM) to form tetrasubstituted olefins using unsymmetrical N-heterocyclic carbene (NHC) ligands.
Entry Cat Cat Conversion (%) ee (%)ee (%) Conversion (%) 42 1 95 8 1 42 95 8 43 2 9595 38 2 43 38 3 9090 52 3 4444 52 4 4545 50 4 8686 50 5 45 anti 46 59 45Cat anti Conversion 5 46 (%) ee59 Entry (%) 42 1 95 8 Table of unsymmetrical ligands95in ARCM by Blechert andacoworkers. Many13.ofEmployment the catalysts employed asymmetric metathesis disubstituted NHC 43inNHC 2 38employ backbone, but the Blechert group mono-substituted NHC 44 3 has explored 90 52 backbones with two different N-substituents (46–48) [80]. The4idea behind 45 this design 86 was to induce 50 significant perturbation on one of the N-substituents to enhance5 the chiral pocket of the levels of enantioselectivity 45 anti 46 catalyst. Moderate 59 were observed in the ARCM of trienes (Table 13). Entry
Table 13. Employment of unsymmetrical NHC ligands in ARCM by Blechert and coworkers. Table 13. Employment of unsymmetrical NHC ligands in ARCM by Blechert and coworkers.
Entry 1 2 3
Cat 46 47 48
Conversion (%) >98 58 87
ee (%) 59 50 66
Ruthenium catalysts ARCM typically use an imidazoline ring system as the NHCEntry in Cat Conversion (%) ee (%) ee (%) Entryemployed Cat Conversion (%) backbone, but Grela and coworkers synthesized a 1,2,4-triazole backbone to assess in ARCM [81]. 1 >98>98 59 1 4646 59 Unfortunately, the ruthenium catalyst modified by this interesting NHC-scaffold failed to provide 2 4747 50 2 58 58 50 any improvement when3compared catalysts ring-opening/cross 4848 87 ARCM and 66 3 to known 87for 66 asymmetric metathesis (AROCM). The Grisi group investigated unsymmetrical NHC use ligands containing an N-alkyl well Ruthenium catalysts employed in ARCM typically an imidazoline ring systemgroup as theas NHCas phenyl groups on the (49–52) (Table 14) [82,83]. As previously the NHC backbone backbone, but Grela andbackbone coworkers synthesized a 1,2,4-triazole backbone seen, to assess in ARCM [81]. substitution proved effective in enhancing the stereochemical properties of the catalysts, providing Unfortunately, the ruthenium catalyst modified by this interesting NHC-scaffold failed to provide the product in moderate enantioselectivity. inring-opening/cross N-substitution on any ring-closed improvement when compared to known catalysts for However, ARCM anddifferences asymmetric enantioselectivity proved to be negligible. It was also observed that the addition of NaI increased the metathesis (AROCM).
Lastly, treatment of ruthenium-carboxylate 54b with sodium nitrate furnished ent-6. When choosing a substrate for ARCM, many methods use substituted olefins because additional substituents can aid in the differentiation of enantiotopic faces of olefins; however, this extra substitution can limit the synthetic utility of the ARCM products. Hence, terminal olefins were chosen as substrates for ent-6. Catalysts 2017, 7, 87 17 that of 38 Additionally, 6 is known to be sensitive to steric bulk at the allylic position, so it was postulated formation of the alkylidene on the allyl fragment would be favored over carbene formation on one of the enantiotopic trienes containing silyl ethers amides were in the Ruthenium olefins. catalystsTerminal employed in ARCM typically use anand imidazoline ringassessed system as the ARCM, generating the ring-closed products in modest to high yields and good enantioselectivities NHC-backbone, but Grela and coworkers synthesized a 1,2,4-triazole backbone to assess in ARCM [81]. (Table 15). It was also found catalyst that when forming stable rings, ethylene removal played an Unfortunately, the ruthenium modified by less this interesting NHC-scaffold failed to provide important role in limiting the reversibility ofcatalysts the reaction, thus enhancing the enantioenrichment of any improvement when compared to known for ARCM and asymmetric ring-opening/cross the isolated product (Figure 12). As was observed in the formation of seven-membered rings, when metathesis (AROCM). performing thegroup transformation in aunsymmetrical closed system,NHC a racemic product is isolated, but when allowing The Grisi investigated ligands containing an N-alkyl group as well the generated ethylene to escape, modest levels of enantioselectivty are detected (Figure 12a). as phenyl groups on the backbone (49–52) (Table 14) [82,83]. As previously seen, the NHC backbone Ethylene-induced reversibility is not an issue when forming a stable ring system such as fivesubstitution proved effective in enhancing the stereochemical properties of the catalysts, providing membered rings (Figure 12b). Cyclometalated complexes employing achiral and enantiopure the ring-closed product in moderate enantioselectivity. However, differences in N-substitution on carboxylate ligands (similar to 54b) were also assessed in this transformation but provided inferior enantioselectivity proved to be negligible. It was also observed that the addition of NaI increased the results compared to ent-6. selectivity of the ARCM (Table 14, entries 2, 4, 6, and 8). Table 14. Effects of the N-alkyl groups on the enantioselectivity of ARCM using unsymmetric NHC Table 14. Effects of the N-alkyl groups on the enantioselectivity of ARCM using unsymmetric NHC ligands ligands are are negligible. negligible.
(xx %) mol %)Solvent Solvent Entry Entry Cat Cat (xx mol 1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8
49 (2.5) 49 (2.5) 49 49 (4.0) (4.0) 50 (2.5) 50 (2.5) 50 (4.0) 50 (4.0) 51 (2.5) 51 (2.5) 51 (4.0) 51 (4.0) 52 (2.5) 52 (4.0) 52 (2.5) 52 (4.0)
DCM DCM THF THF DCM DCM THF THF DCM DCM THF THF DCM THF DCM THF
Additive Additive -NaI NaI -NaI NaI NaI NaI NaI NaI
Conversion (%) Conversion (%) ee (%) ee (%) >98>98 18 18 >95>95 53 53 33 >98>98 33 >98 50 >98 50 >98 19 >98>95 19 52 >95>98 52 33 47 >98>98 33 >98 47
The cyclometalated Z-selective ruthenium catalysts presented an interesting opportunity for a chiral-at-ruthenium approach to ARCM [84]. Initially, catalyst 6 was resolved so that a single enantiomer of the catalyst could be used (Scheme 4). This was accomplished through ligand exchange of 6 nitrate for iodide, which was further exchanged for a chiral silver-carboxylate to form 54a and 54b. Complex 54b was then separated from the other diastereomer using trituration techniques. Lastly, treatment of ruthenium-carboxylate 54b with sodium nitrate furnished ent-6. When choosing a substrate for ARCM, many methods use substituted olefins because additional substituents can aid in the differentiation of enantiotopic faces of olefins; however, this extra substitution can limit the synthetic utility of the ARCM products. Hence, terminal olefins were chosen as substrates for ent-6. Additionally, 6 is known to be sensitive to steric bulk at the allylic position, so it was postulated that formation of the alkylidene on the allyl fragment would be favored over carbene formation on one of the enantiotopic olefins. Terminal trienes containing silyl ethers and amides were assessed in the ARCM, generating the ring-closed products in modest to high yields and good enantioselectivities (Table 15). It was also found that when forming less stable rings, ethylene removal played an important role in limiting the reversibility of the reaction, thus enhancing the enantioenrichment of the isolated product (Figure 12). As was observed in the formation of seven-membered rings, when performing the transformation in a closed system, a racemic product is isolated, but when allowing the generated ethylene to escape, modest levels of enantioselectivty are detected (Figure 12a). Ethylene-induced reversibility is not an issue when forming a stable ring system such as five-membered rings (Figure 12b).
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Catalysts 2017, 7, 87 18 of 36 Cyclometalated complexes employing achiral and enantiopure carboxylate ligands (similar to36 Catalysts 2017, 7, 7, 87 87 18 of of 3654b) Catalysts 2017, 18 Catalysts 2017,2017, 7, 87 87 18 of of 36 36 Catalysts Catalysts 2017, 7, 18 Catalysts 2017, 7, 87 7, 87 of18 36of 36 were also assessed in this transformation but provided inferior results compared to ent-6. 18
Scheme 4. Synthesis of ent-6 was carried out through separation of the two diastereomeric salts Scheme 4. Synthesis Synthesis of of ent-6 was carried out through separation separationofof of the the two diastereomeric salts Scheme 4. of ent-6 was carried out through separation two diastereomeric salts Scheme 4. metalation Synthesis wascarried carriedout out through two diastereomeric saltssalts formed Scheme 4. Synthesis of ent-6 was separation ofthe the two diastereomeric formed by ofent-6 (S)-methoxyphenylacetate followed by nitration. Scheme 4. Synthesis ent-6 was carried through separation of two the two diastereomeric Scheme 4. Synthesis of ent-6 was carried out out through separation of the two diastereomeric saltssalts Scheme 4. Synthesis of ent-6 was carried out through separation of the diastereomeric salts formed by metalation of (S)-methoxyphenylacetate followed by nitration. formed by metalation metalation of (S)-methoxyphenylacetate (S)-methoxyphenylacetate followed by nitration. nitration. by metalation of (S)-methoxyphenylacetate followed by nitration. formed by of followed by formed by metalation of (S)-methoxyphenylacetate followed by nitration. formed by metalation of (S)-methoxyphenylacetate followed by nitration. formed by metalation of (S)-methoxyphenylacetate followed by nitration. Table 15. Scope of ent-6 in the ARCM. Table 15. Scope Scope of ent-6 ent-6 in the the ARCM. Table 15. of in ARCM. Table 15. of in the Table 15. Scope of ent-6 in the ARCM. Table 15. Scope Scope of ent-6 ent-6 inARCM. the ARCM. ARCM. Table 15. Scope of ent-6 in the ARCM. Table 15. Scope of ent-6 in the
Entry Product Product Yield (%) ee (%) ee (%) Entry Entry Yield (%) Product Yield (%) (%) ee (%) (%) Entry Product Yield ee Entry Product Yield (%) (%) ee (%) (%) EntryProduct ProductYield Yield ee (%) Entry (%) ee
1
11 11
1 1
65 65 65 65 65 65 65
69 69 69 69 69 69
69
2
22 22
2 2
29 29 29 29 29 29 29
67 67 67 67 67 67
67
3
33 33
3 3
95 95 95 95 95 9595
54 54 54 54 54 54
54
4
44 44
4 4
72 72 72 72 72 7272
47 47 47 47 47 47
47
5
55 55
5 5
90 90 90 90 90 90 90
57 57 57 57 57 57
57
Catalysts 2017, 7, 87 Catalysts 2017, 7, 7, 87 87 Catalysts 2017, Catalysts 2017, 7,7,8787 Catalysts 2017, Catalysts Catalysts 2017,2017, 7, 877, 87
19 of 36 19 of 36 19 of 36 1919 ofof 36 19 19 of36 36of 38
Catalysts 2017, 7, 87
19 of 36
Figure 12. Effects of ethylene removal on asymmetric ring-closing metathesis (ARCM). (a) Effect of 12. Effects of of ethylene on asymmetric asymmetric ring-closing metathesis (ARCM). (a) Figure 12. Effects ethyleneremoval removal on ring-closing metathesis (ARCM). Effect FigureFigure 12. Effects Effects of ethylene ethylene removal on asymmetric asymmetric ring-closing metathesis (ARCM). (a)(a) Effect ofofEffect Figure 12. removal on ring-closing metathesis (ARCM). (a) Effect of ethylene in of ARCM to form seven-membered rings; (b) Effect of ethylene in ARCM to form fiveFigure 12. Effects of ethylene removal on asymmetric ring-closing metathesis (ARCM). (a) Effect of of 12. ethylene in ARCM toremoval formseven-membered seven-membered rings; (b)ethylene Effect ofinethylene in to ARCM toofform ethylene in ARCM to form rings; (b) Effect of ethylene in ARCM form fiveFigure Effects of ethylene on asymmetric ring-closing metathesis (ARCM). (a) Effect ethylene in ARCM to form seven-membered rings; (b) (b) Effect of ARCM to form fiveFigure 12. Effects of ethylene removal on asymmetric ring-closing metathesis (ARCM). (a) Effect of ethylene in ARCM to form seven-membered rings; Effect of ethylene in ARCM to form fivemembered rings. ethylene inmembered ARCM torings. form seven-membered rings; (b) Effect ofofethylene in ARCM totoform fivefive-membered rings. ethylene membered rings. ethylenein inARCM ARCMtotoform formseven-membered seven-memberedrings; rings;(b) (b)Effect Effect ofethylene ethyleneininARCM ARCM toform formfivefivemembered rings. membered rings. membered rings. membered rings. 3.3. Asymmetric Ring-Opening/Cross Metathesis 3.3. Asymmetric Ring-Opening/Cross Metathesis
3.3. Asymmetric Ring-Opening/Cross Metathesis 3.3. Asymmetric Asymmetric Ring-Opening/Cross Metathesis 3.3. Ring-Opening/Cross Metathesis 3.3. Asymmetric Ring-Opening/Cross Metathesis Ruthenium-catalyzed AROCM hasreceived received much much attention thethe lastlast fewfew years [73–76]. It Ruthenium-catalyzed AROCM has attentionover over years [73–76]. It 3.3. Asymmetric Ring-Opening/Cross Metathesis 3.3.Ruthenium-catalyzed Asymmetric Ring-Opening/Cross Metathesis Ruthenium-catalyzed AROCM has received much attention few years [73–76]. AROCM has received much attention over the theover last the fewoflast years [73–76]. It seems this method of asymmetric metathesis is more more easily controlled because the inherent facial Ruthenium-catalyzed AROCM has received much attention over last few years [73–76]. It seems this method of asymmetric metathesis is easily controlled because of the inherent facial Ruthenium-catalyzed AROCM has received much attention over the last few years It facial AROCM has received much attention over the last years [73–76]. ItRuthenium-catalyzed seems this method asymmetric iscomplex more easily controlled because of the[73–76]. inherent seemsselectivity this method of asymmetric metathesis iswhich more easily controlled because of the inherent facial Ruthenium-catalyzed AROCM hasmetathesis received much attention over the last few years [73–76]. It selectivity for the of norbornene substrates which through the exo face offew the olefin [85]. Thus,It seems this method asymmetric metathesis is more easily controlled because of the inherent facial for of the norbornene substrates complex through the exo face of the olefin [85]. Thus, seems this method of asymmetric metathesis is more easily controlled because of the inherent facial seems this method ofofasymmetric metathesis is more easily controlled because ofofof the inherent facial selectivity for the norbornene substrates which complex through the exoofface the olefin [85]. Thus, selectivity for the norbornene substrates which complex through the exo face the olefin [85]. Thus, only the propagating species and its orientation must be controlled. AROCM has become a powerful seems this method asymmetric metathesis is more easily controlled because the inherent facial selectivity for the norbornene substrates complex through the exo face of olefin [85]. Thus, only the propagating species and itswhich orientation must be controlled. AROCM has become a powerful selectivity for the norbornene substrates complex through the exo face ofofthe the olefin [85]. Thus, selectivity for the norbornene substrates which complex through the exo face the olefin [85]. only the propagating species and itswhich orientation must be controlled. AROCM has become aThus, powerful method for the formation of enantioenriched dienes, which contain differentiated olefins poised for only the propagating species and its orientation must be controlled. AROCM hasofbecome become a powerful powerful selectivity for the norbornene substrates which complex through the exo face the olefin [85]. Thus, only the propagating species and its orientation must be controlled. AROCM has a method for the formation of enantioenriched dienes, which contain differentiated olefins poised for only the propagating species and its orientation must bebecontrolled. AROCM has become a apowerful chemoselective derivations [11,86]. only the propagating species and its orientation must controlled. AROCM has become powerful method for the formation of enantioenriched dienes, which contain differentiated olefins poised for method for the formation of enantioenriched dienes, which contain differentiated olefins poised for only the propagating species and its orientation must be controlled. AROCM has become a powerful method for the formation of enantioenriched dienes, which contain differentiated olefins poised for chemoselective derivations [11,86]. method for the formation ofofenantioenriched dienes, which contain differentiated olefins poised for method for the formation enantioenriched dienes, which contain differentiated olefins poised for chemoselective derivations [11,86]. chemoselective derivations [11,86]. method for the formation[11,86]. of enantioenriched dienes, which contain differentiated olefins poised for chemoselective derivations Table 16. Asymmetric ring-opening/cross metathesis (AROCM) of various substrates with styrene. chemoselective derivations [11,86]. chemoselective derivations [11,86]. chemoselective derivations [11,86]. Table 16. Asymmetric ring-opening/cross metathesis (AROCM) of various substrates with styrene. 16. Asymmetric ring-opening/cross metathesis (AROCM) of various substrates with styrene. Table Table 16. Asymmetric Asymmetric ring-opening/cross metathesis (AROCM) of various various substrates with styrene. styrene. Table 16. ring-opening/cross metathesis (AROCM) of substrates with Table 16. Asymmetric ring-opening/cross metathesis (AROCM) of various substrates with styrene. Table Table16. 16.Asymmetric Asymmetricring-opening/cross ring-opening/crossmetathesis metathesis(AROCM) (AROCM)ofofvarious varioussubstrates substrateswith withstyrene. styrene.
Entry
Substrate
T (°C)
E:Z
Conversion (%)
ee (%)
Entry Substrate Substrate T (◦ C)T (°C) E:Z Conversion (%) (%) ee (%) ee (%) Entry E:Z Conversion >98 82 Entry Substrate T (°C) (°C) 25E:Z E:Z 24:1 Conversion (%) ee ee (%) (%) 1Substrate Entry T Conversion (%) Entry Substrate TT(°C) E:Z Conversion >98(%) 92 Entry Substrate (°C) −10 E:Z 13:1 Conversion (%) eeee(%) (%) Entry 1 11 11 11
Substrate
T (°C)25 E:Z24:1Conversion >98(%) ee (%) 82 25 24:1 >98 82 82 25 24:1 >98 25 24:1 >98 82 −10 13:1 >98 92 24:1 >98 82 −25 10 13:1 >98 92 25 24:1 >98 >98 82 −10 13:1 >98 9282 25 25 24:121:1 >98 82 −10 13:1 >98 92 2 −10 13:1 >98 92 >98 90 −10 >98 92 −10 −1013:1 13:123:1 >98 92 25 21:1 >98 82 2 25 21:1 21:1 >98 >98 82 25 −10 >98 82 82 25 21:1 23:1 >98 2 22 25 21:1 >98 828286 90 3 25 19:1 61 25 21:1 >98 − 10 23:1 >98 90 −10 23:1 >98 90 22 25 23:1 21:1 >98 82 −10 >98 90 −10 23:1 >98 9090 2 −10 23:1 >98 −10 23:1 >98 90 3 25 19:1 61 86 25 4 3 25 19:1 >30:1 61 >98 86 76 3 25 19:1 61 86 2525 19:1 6161 33 3 19:1 61 8686 86 19:1 3 25 19:1 61 86 −10 21:1 >98 70 76 25 >30:1 >98 4 5 25 >30:1 >98 76 25 >30:1 >98 76 444 25 >30:1 >30:1 >98 >98 4 44 2525 >98 7676 76 25 >30:1 >30:1 >98 76 Blechert and coworkers employed 48 in the AROCM of norbornene derivatives with styrene 5 −10 21:1 >98 70 (Table 16) the desired diene −10 catalyst 21:1 provided >98 >98 70 products in good 555 [80]. It was found that this −10 21:1 70 −10 21:1 >98 70 >98 5 55 −−10 10 >98 70 70 −10 21:1 21:1 21:1 >98 70 Blechert and coworkers employed 48 in the AROCM of norbornene derivatives with styrene Blechert and and coworkers coworkers employed employed 48 48 in in the the AROCM AROCM of of norbornene norbornene derivatives derivatives with with styrene styrene Blechert (Table 16) [80]. It was employed found that catalyst provided the desired diene products in good Blechert and coworkers 4848this ininthe AROCM ofofnorbornene derivatives with styrene Blechert and coworkers employed the AROCM norbornene derivatives with styrene (Table 16) [80]. It was found that this catalyst provided the desired diene products in good Blechert and coworkers employed 48 in the AROCM of norbornene derivatives with styrene (Table 16) [80]. It was found that this catalyst provided the desired diene products in good (Table 16) [80]. It was found that this catalyst provided the desired diene products in good (Table (Table 16) 16) [80]. [80]. ItIt was was found found that that this this catalyst catalyst provided provided the the desired desired diene diene products products inin good good
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Blechert and coworkers employed 48 in the AROCM of norbornene derivatives with styrene (Table 16) [80]. It wasa major found preference that this catalyst provided They the desired dienecooling products in good enantioselectivity with for the E-isomer. found that the reaction enantioselectivity with a major preference for the E-isomer. They thatgroup cooling the reaction increased enantioselectivity (Table 16, entries 1 and 2). Later the found Blechert investigated a increased enantioselectivity (Table 16, entries 1 and 2). Later the Blechert group investigated quinoline-based ligand scaffold [87]. This quinoline-based system restricted rotation of one N-aryl a quinoline-based ligand scaffold thus [87]. enhancing This quinoline-based system for restricted rotation of one group, anchoring it in position, the chiral pocket the formation the N-aryl group, anchoring it in position, thus enhancing chiral pocket for the of the ruthenacyclobutane, providing the desired diene in goodthe enantioselectivity (up toformation 99% conversion ruthenacyclobutane, providing the desired diene in good enantioselectivity (up to 99% conversion and and 98% ee). 98% Hoveyda ee). and coworkers have investigated bidentate NHC ligands with an aryloxy bridge, coworkers have investigated bidentate NHC ligands an aryloxythese bridge, which whichHoveyda provideand a stereogenic-at-ruthenium catalyst for AROCM [70,88].with Interestingly, catalysts provide a stereogenic-at-ruthenium catalyst for AROCM [70,88]. Interestingly, these catalysts furnish furnish the tetrahydropyran products of AROCM, favoring the Z-isomer of the disubstituted olefin the tetrahydropyran products of AROCM, favoring the Z-isomer of the 17). disubstituted olefin when using when using an enol ether or thiol ether as the coupling partner (Table It is believed that a Curtinan enol ether or thiol ether as the coupling partner (Table 17). It is believed that a Curtin-Hammett Hammett scenario is in effect (Figure 13). The exo- (39a) and endo-intermediates (39b) are in scenario is inIfeffect (Figure proceeds 13). The exo(39a) the andexo-intermediate endo-intermediates (39b) are is in more equilibrium. If the equilibrium. the reaction through (39a), which stable due to reaction through the from exo-intermediate which is more ruthenium-carbene, stable due to the ether the ether proceeds group pointing away the chelating(39a), group, the resulting 39a group III, is pointing fromofthe chelating group, the ruthenium-carbene, 39a III, is less because less stableaway because steric clash between theresulting generated tetrahydropyranyl carbene andstable the chelating of steric(Figure clash between generated tetrahydropyranyl carbene unstable and the chelating group the (Figure 13a). group 13a). Inthe addition to creating a more sterically intermediate, stability In addition creating more sterically unstable intermediate, the stability imparted bythe thereaction Fischer imparted bytothe Fischera carbene is lost to the generation of a C-substituted carbene. If carbene isthrough lost to the of a C-substituted If the reaction proceedsdue through the proceeds the generation endo-intermediate (39b), whichcarbene. is the least stable intermediate to steric endo-intermediate (39b), the least intermediate duethe to steric interactions between the interactions between thewhich vinylisether andstable the chelating group, resulting ruthenium-carbene vinyl ether chelating theofresulting species,the 39btetrahydropyranyl III, is more stable species, 39band III, the is more stablegroup, because a lack ofruthenium-carbene steric interaction between because and of a lack of steric interaction between theEven tetrahydropyranyl carbene and the chelating group carbene the chelating group (Figure 13b). though resonance stabilization of the Fischer (Figure 13b). Even though resonance stabilization of the Fischer(39b carbene lost,there a sterically more stable carbene is lost, a sterically more stable intermediate is formed III),isand is also the driving intermediate is formed (39b III), and there is also the driving force from eliminating ring-strain due to force from eliminating ring-strain due to the ring-opening event. When using a carbon-substituted the ring-opening event. When using a carbon-substituted coupling instead of[74–76,89]. an enol ether, coupling partner instead of an enol ether, this Curtin-Hammett effectpartner is not observed this Curtin-Hammett effect is not observed [74–76,89]. Table 17. AROCM with enol and thiol ethers using a bidentate ruthenium aryloxide. Table 17. AROCM with enol and thiol ethers using a bidentate ruthenium aryloxide.
Entry 1 2 3 4 5 6
Yield (%) Entry R Yield (%) R 1 On Bu OnBu 80 80 6464 2 OCy OCy 6767 3 OPMPOPMP OCH2 CF3 65 4 OCH2CF3 65 O(CH2 )2 Cl 63 5 SPh O(CH2)2Cl 6763 6 SPh 67
Z:E Z:E ee (%) 95:5 95:5 96 98:2 98:2 96 95:5 95:5 94 94:6 94:6 92 95:5 95:5 91:9 96 91:9 92
ee (%) 96 96 94 92 96 92
Building on the previously discussed work from the Hoveyda group which used Building on the previously discussed work from the Hoveyda group which used heteroatomheteroatom-substituted terminal olefins as cross partners in AROCM to furnish the Z-isomeric substituted terminal olefins as cross partners in AROCM to furnish the Z-isomeric products, Grubbs products, Grubbs and coworkers employed ent-6 in the AROCM of norbornene and cyclobutene and coworkers employed ent-6 in the AROCM of norbornene and cyclobutene derivatives with derivatives with terminal olefins to furnish enantioenriched dienes containing a Z-olefin [84,90,91]. terminal olefins to furnish enantioenriched dienes containing a Z-olefin [84,90,91]. When performing When performing AROCM on norbornene substrates, they found good tolerance for ether containing AROCM on norbornene substrates, they found good tolerance for ether containing norbornenes norbornenes (Table 18, entries 1, 4–5). A rigid norbornene derivative also participated in the AROCM (Table 18, entries 1, 4–5). A rigid norbornene derivative also participated in the AROCM (Table 18, (Table 18, entry 3). Interestingly, it was observed that both the Z- and E-products were formed entry 3). Interestingly, it was observed that both the Z- and E-products were formed with identical with identical enantioselectivity. This offered a glimpse into the mechanism (Figure 14a). It was enantioselectivity. This offered a glimpse into the mechanism (Figure 14a). It was proposed that the proposed that the enantiodetermining step most likely precedes the olefin geometry-determining step. enantiodetermining step most likely precedes the olefin geometry-determining step. The The enantioselectivity is governed by the approach of the methylidene to the exo-face of the norbornene. enantioselectivity is governed by the approach of the methylidene to the exo-face of the norbornene. Also, the N-Mes group forces all the bulk in the down direction due to steric effects. Conversely, the Also, the N-Mes group forces all the bulk in the down direction due to steric effects. Conversely, the enantioselectivity of AROCM of cyclobutenes is different for both the Z- and E-isomers. In the case enantioselectivity of AROCM of cyclobutenes is different for both the Z- and E-isomers. In the case of cyclobutenes, it is believed both the enantio- and diastereodetermining step occur simultaneously (Figure 14b). This could occur if the cyclobutene substrates participate in AROCM with an alkylidene
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Catalysts 2017, 7, 87 21 of 36 of cyclobutenes, Catalysts 2017, 7, 87 it is believed both the enantio- and diastereodetermining step occur simultaneously 21 of 36 Catalysts 2017,7,14b). 7,87 87 This could occur if the cyclobutene substrates participate in AROCM with an21 21ofof36 36 (Figure alkylidene Catalysts 2017,
(norbornene only only reacts reacts with methylidenes methylidenes because of steric steric demands). demands). Since, cyclobutenes are more (norbornene Since, cyclobutenes cyclobutenes are are more more (norbornene only reacts with methylidenes because of steric demands). Since, strained and possess less steric bulk than norbornene species, cyclobutanes are able to react directly (norbornene onlypossess reactswith with methylidenes because steric demands). Since,cyclobutenes cyclobutenes aremore more strainedonly and possess lessmethylidenes steric bulk bulk than than norbornene species, cyclobutanes are able able to toare react directly (norbornene reacts because ofofsteric demands). Since, strained and less steric norbornene species, cyclobutanes are react directly withand an alkylidene. alkylidene. strained possessless lesssteric stericbulk bulkthan thannorbornene norbornenespecies, species,cyclobutanes cyclobutanesare areable abletotoreact reactdirectly directly with an strained and possess with an alkylidene. with an alkylidene. (a) (a)
Me Me N N OH Me Me N N OH Me Me Me I N N Ru OH Me N Me N I Ru O OH Me O MeI I RO Me Ru Ru RO O O OH O OH RO O RO 39a I OH O OH O 39a I Me 39a I Me 39a I OH Me N N Me OH Me Me N N Me I Ru OH N N OH N Me N I Ru O O O Me I RO O O Me I Ru RO O Ru O OR Not Favored OO OR O RO ONot Favored OH RO O OH OR 39a Not Favored ORIII Not Favored 39a III OH OH 39a III 39a III Me Me Me N N Me OH Me Me O N N OR OR OH O Me Me N MeNI N N I ORRu OHMe O OR Ru OH Me O Me I I Ru Ru O OH O O OH O 39b I 39b I OH O OH O 39b I 39b Me39b Me 39b I Me Me Me N N Me N N OH Me Me Me Me N N Me Me N N OH Me I Me I Me N MeNI Ru O Me N MeNI Ru O OR Me N N Ru Me N N Ru OH OH OR O O OR Me I O Me I O Me I O Ru Me I O OR Ru O OR Ru ORO Ru O O O OOR OR OR O OOR OH OH Favored Product O O OH 39b II OH 39b III O Favored Product OR O OR 39b II 39b III OH OH Favored Product OH 39b II OH 39b III Favored Product 39b II 39b III in asymmetric ring-opening/cross Figure 13. Curtin-Hammett effect of Fischer carbene (a) (a)
Me Me Me Me
Me Me
N N N N Me I Me N N Ru Me N Me N I Ru O OO O MeI I RO Me Ru Ru RO O O RO RO 39a 39a Me 39a Me 39a Me N N Me Me Me N N Me I Ru Me N N Me Me N Me N I Ru O Me O Me I Me I Ru RuO O OR O OR O OH OR OR OH O 39a II O 39a II OH OH 39a II 39a II (b) (b) Me Me (b) Me N N (b) Me Me Me N N OR OR Me Me N MeNI Me N N I ORRu O OO OR Ru Me O Me I I Ru Ru O O 39b 39b
O O
Figure 13. Curtin-Hammett effect of Fischer carbene in asymmetric ring-opening/cross metathesis metathesis Figure 13. Curtin-Hammett effect of Fischerancarbene in asymmetric ring-opening/cross metathesis (AROCM). (a) AROCM proceeding through exo-intermediate; (b) AROCM proceeding through an (AROCM). (a) AROCM proceeding through an exo-intermediate; (b) AROCM proceeding through an Figure 13.Curtin-Hammett Curtin-Hammett effectofofFischer Fischer carbene asymmetric(b) ring-opening/cross metathesis Figure 13. carbene ininasymmetric ring-opening/cross metathesis (AROCM). (a) AROCM effect proceeding through an exo-intermediate; AROCM proceeding through an endo-intermediate. endo-intermediate. (AROCM). (a)AROCM AROCMproceeding proceedingthrough throughan anexo-intermediate; exo-intermediate;(b) (b)AROCM AROCMproceeding proceedingthrough throughan an (AROCM). (a) endo-intermediate. endo-intermediate. endo-intermediate. Table 18. Z-Selective AROCM of norbornenes using the ent-6. Table Table 18. 18. Z-Selective Z-Selective AROCM AROCM of of norbornenes norbornenes using using the the ent-6. ent-6. Table18. 18.Z-Selective Z-SelectiveAROCM AROCMofofnorbornenes norbornenesusing usingthe theent-6. ent-6. Table
Entry Substrate Yield (%) Z:E ee (%) Entry Substrate Yield (%) Z:E ee (%) Substrate Yield (%) ee (%) Substrate Yield(%) (%) Z:E Z:E Z:E ee(%) (%) Entry Substrate Yield ee 1 64 95:5 93 1 64 95:5 93 64 95:5 93 1 11 64 95:5 93 64 95:5 93
Entry Entry
2 22
33 44 55
2 2
3 3 4 4 5 5
58 58 58
55 55
58 58
98:2 75 98:2 75 98:2 98:275 75 98:2
55 55
76:24 >98 76:24 >98 76:24 >98 >98 76:24
56 56
94 94
15:85 15:85 56 15:85 94 56 15:85 94 40 70:30 40 70:30 40 70:30 95 40 70:30 95
95 95
75
Catalysts 2017, 7, 87
Entry Entry Entry
Substrate Substrate Substrate
Yield (%) (%) Yield Yield (%)
Z:E Z:E Z:E
ee (%) (%) ee ee (%)
64 64 64
95:5 95:5 95:5
93 93 93
58 58
98:2 98:2 98:2
Z:E75
3 3 3
3
55 55 55 55
76:24 76:24 >98 76:24 >98 76:24 >98
>98
4 4 4 4
56 56 56 56
15:85 15:85 94 15:85 94 15:85 94
94
5 5 55
40 40 40 40
70:30 95 70:30 95 70:30 70:30 95
95
111
22 of 38
Table 18. Cont.
22
Entry2
Substrate
58 (%) Yield
75 75
ee (%)
Catalysts Catalysts 2017, 2017, 7, 7, 87 87
22 22 of of 36 36
Figure 14. Proposed Proposed mechanistic mechanistic differences differences for for AROCM AROCM of of norbornenes norbornenes and and cyclobutenes cyclobutenes with with Figure terminal olefins. Enantiodetermining step occurs before the diastereodetermining step; (b) Enantioterminal olefins.(a)(a) Enantiodetermining step occurs before the diastereodetermining step; andEnantiodiastereodetermining events occurevents in the same (b) and diastereodetermining occur step. in the same step.
Further of cyclobutenes led to of various 1,2-anti-diols (Table Further evaluating evaluatingthe thescope scope of cyclobutenes ledthe toformation the formation of various 1,2-anti-diols 19), which can be derivatized to useful monosaccharides. (Table 19), which can be derivatized to useful monosaccharides. Table Table 19. 19. Z-Selective Z-Selective AROCM AROCM of of cyclobutenes cyclobutenes using using ent-6. ent-6.
Entry 1 2 3 4
Entry R 1 H 2 Bz 3 Bn 4 Bn
R H Bz Bn Bn
R’ R’ Bz Bz H H Ac Ac CH CH222C(O)Me C(O)Me
Yield (%) Yield (%) 67 67 69 69 7979 6565
Z:E 75:25 75:25 85:15 90:10
ee Z (ee E) (%) ee Z (ee E) (%) 91 (67) 75:25 91 (67) 96 (82) 75:25 96 (82) 95 85:15 95 90:10 92 (84) 92 (84) Z:E
The Grisi group evaluated the previously discussed unsymmetrical NHC ligands (Table 14) in The Grisi group evaluated the previously discussed unsymmetrical NHC ligands (Table 14) in AROCM of cis-5-norbornene-endo-2,3-dicarboxlic anhydride and styrene [83]. It was found that the AROCM of cis-5-norbornene-endo-2,3-dicarboxlic anhydride and styrene [83]. It was found that the catalyst with the more sterically demanding N-cyclohexyl rings (49 and 51) furnished the diene catalyst with the more sterically demanding N-cyclohexyl rings (49 and 51) furnished the diene products in higher enantioselectivities than the catalyst with the N-methyl groups (50 and 52). The products in higher enantioselectivities than the catalyst with the N-methyl groups (50 and 52). larger cyclohexyl rings are thought to create a more defined chiral pocket, thus imparting a higher degree of asymmetry on the approach of the carbene species to the norbornene species. 3.4. Asymmetric Cross Metathesis Asymmetric cross metathesis (ACM) seems to be the most difficult of the asymmetric metathesis transformations due to the requirement of the catalyst to control the stereochemistry of the
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The larger cyclohexyl rings are thought to create a more defined chiral pocket, thus imparting a higher degree of asymmetry on the approach of the carbene species to the norbornene species. 3.4. Asymmetric Cross Metathesis Asymmetric cross metathesis (ACM) seems to be the most difficult of the asymmetric metathesis transformations due to the requirement of the catalyst to control the stereochemistry of the propagating species and the enantiotopic facial selectivity of the olefin. Since the first example of ACM was published by Grubbs and coworkers [73], progress in the field of ACM has been slower than both ARCM and AROCM. Grubbs and coworkers demonstrated the power of cyclometalated 6 through ACM [84]. By using the previously discussed chiral resolution techniques, they were able to perform ACM with ent-6, employing this catalyst in the desymmetrization of a meso-diene. Complex ent-6 delivered modest levels of enantioselectivity (Scheme 5) and furnished the Z-isomer of the product, Catalystsis 2017, 7, 87 23 of 36 which complementary to previous methods which provide the E-isomer [73].
Scheme 5. Asymmetric cross metathesis (ACM) of meso-silyl ether using ent-6.
Metathesis 4. Stereoretentive Olefin Metathesis thermodynamically preferred As have been previously discussed, E-olefins are usually the thermodynamically products of OM. Recent studies have aimed at the development of a kinetically products kinetically Z-selective metathesis catalyst, but unfortunately unfortunately aa catalyst catalyst that that kinetically kinetically selects selects for for E-olefins E-olefins remained remained elusive elusive [56]. [56]. Methods for generating E-olefins, such as Z-selective ethenolysis, ethenolysis, require additional additional manipulations. manipulations. One idea ideaforfor a kinetically E-selective is an to environment create an environment promotes a kinetically E-selective catalystcatalyst is to create that promotes that stereoretention. stereoretention. A number ofOM tungsten-based catalysts have shown stereoretention selfA number of tungsten-based catalysts haveOM shown stereoretention in the self-metathesisinofthe olefinic metathesis of olefinic [92–94]. Upon further investigation, 30 wasthe found to promote the hydrocarbons [92–94].hydrocarbons Upon further investigation, 30 was found to promote self-metathesis of self-metathesis of both Zand E-olefins, affording products that retained the stereochemistry of the both Z- and E-olefins, affording products that retained the stereochemistry of the starting material starting material[95]. in high [95]. is believed that the largeon N-aryl groups on the the substituents NHC force the in high fidelity It is fidelity believed thatItthe large N-aryl groups the NHC force at substituents at the 2- and 4-positions of the ruthenacyclobutane (Figure 15).using ThusZ-olefins, when using the 2- and 4-positions of the ruthenacyclobutane down (Figure down 15). Thus when all Z-olefins, all the substituents on the ruthenacyclobutane aredown syn, inorientation, the down orientation, deliver the substituents on the ruthenacyclobutane are syn, in the and deliverand Z-olefinic Z-olefinic products. When are E-olefins are employed, 2- and 4-positions of the ruthenacyclobutane products. When E-olefins employed, the 2- andthe 4-positions of the ruthenacyclobutane are still are still forced down, but there is a space between the large N-aryl groups of the NHC that allow the forced down, but there is a space between the large N-aryl groups of the NHC that allow the 3-position 3-position adopt an up (Figure orientation 15).rise This rise to an anti-ruthenacyclobutane, to adopt antoup orientation 15). (Figure This gives to gives an anti-ruthenacyclobutane, favoring the favoring the formationand of E-olefins, delivering a stereoretentive OM of proposed E-olefins.stereochemical The proposed formation of E-olefins, deliveringand a stereoretentive OM of E-olefins. The stereochemical model the observed stereoretention was bycatalysts evaluating catalysts model explaining the explaining observed stereoretention was supported bysupported evaluating with NHC with NHC ligands of encumbrance. varied steric encumbrance. It was the size of the on ortholigands of varied steric It was discovered that discovered as the size ofthat the as ortho-substituents the substituents the N-aryl group(i Pr began to>decrease (iPr > Meof > F), reactivity the catalyst with N-aryl groupon began to decrease > Me F), the reactivity thethe catalyst with of E-olefins increased. E-olefins increased. Thus, smaller ortho-substituents lead to larger open space for3-position the substituent at Thus, smaller ortho-substituents lead to a larger open space fora the substituent at the to point the 3-position to point up, furnishing syn to the NHC ligand, E-olefins. effect is observed inand the up, syn to the NHC ligand, E-olefins. Thisfurnishing effect is observed in This the CM of trans-4-octene CM of trans-4-octene and trans-1,4-diacetoxy-2-butene (Table 20). Stereoretention of Z-olefins follows trans-1,4-diacetoxy-2-butene (Table 20). Stereoretention of Z-olefins follows the same stereochemical the same stereochemical model invoked model invoked in Z-selective OM [67–69].in Z-selective OM [67–69].
Figure 15. Stereochemical model illustrating the steric environment governing stereoretentive OM. Table 20. Effects of N-aryl ortho-substituents on the reactivity of stereoretentive olefin methathesis (OM).
withNHC NHCligands ligandsofofvaried varied steric steric encumbrance. encumbrance. ItIt was of of thethe orthowith was discovered discoveredthat thatasasthe thesize size orthoiPr >>Me substituentsononthe theN-aryl N-arylgroup groupbegan began to decrease decrease ((iPr ofof thethe catalyst with substituents Me>>F), F),the thereactivity reactivity catalyst with E-olefins increased. Thus, smaller ortho-substituents lead to a larger open space for the substituent at at E-olefins increased. Thus, smaller ortho-substituents lead to a larger open space for the substituent 3-positiontotopoint pointup, up,syn synto tothe the NHC NHC ligand, ligand, furnishing is is observed in the thethe 3-position furnishingE-olefins. E-olefins.This Thiseffect effect observed in the CM of trans-4-octene and trans-1,4-diacetoxy-2-butene (Table 20). Stereoretention of Z-olefins follows CM of trans-4-octene and trans-1,4-diacetoxy-2-butene (Table 20). Stereoretention of Z-olefins follows Catalysts 2017, 7, 87 24 of 38 same stereochemicalmodel modelinvoked invoked in in Z-selective Z-selective OM thethe same stereochemical OM[67–69]. [67–69].
Figure 15. Stereochemical model illustrating the steric environment governing stereoretentive OM. Figure governing stereoretentive stereoretentive OM. OM. Figure 15. 15. Stereochemical Stereochemical model model illustrating illustrating the the steric steric environment environment governing Table 20. Effects of N-aryl ortho-substituents on the reactivity of stereoretentive olefin methathesis Table 20.Effects EffectsofofN-aryl N-aryl ortho-substituents on the reactivity of stereoretentive methathesis (OM). Table 20. ortho-substituents on the reactivity of stereoretentive olefinolefin methathesis (OM). (OM).
Entry 1 2 3 4 5 6 7 8 9 10 11 12
Entry Cat Cat 30 1 Entry30 Cat 30 2
1 30 30 2 30 30 30 55 55 55 55 56 56 56 56
Time (h) (h) Yield (%) Time YieldZ:E (%) 1 0
