Recent Advances in the Mitsunobu Reaction - Ingenta Connect

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Current Organic Chemistry, 2009, 13, 1610-1632

Recent Advances in the Mitsunobu Reaction: Modifications and Applications to Biologically Active Molecules Reynolds, A. J.1 and Kassiou, M.1,2,3* 1 3

School of Chemistry, University of Sydney, NSW 2006; 2Brain and Mind Research Institute, Camperdown, NSW 2050; Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia Abstract: The Mitsunobu reaction involves the “redox” condensation of an acidic pronucleophile with a primary or secondary alcohol promoted by a reactive phosphonium salt derived from an alkyl or aryl phosphine and an azo compound. The synthetic utility of the reaction is demonstrated by the wide range of acidic pronucleophiles that are tolerated including carboxylic acids, phenols, imides, hydroxamates, thiols, thioamides, fluorinated alcohols, oximes, pyridinium and imidazolium salts, pyrimidine bases, -ketoesters and trimethylmethane tricarboxylate (TMET) thereby generating a variety of functionally diverse molecules. The focus of this review is to highlight the recent development of new or alternative reagents and purification strategies for the Mitsunobu reaction with a discussion of their suitability for modern drug design supported by selected examples from the literature.

1. INTRODUCTION The Mitsunobu reaction involves the “redox” condensation of an acidic pronucleophile with a primary, secondary or, in rare cases, tertiary alcohol promoted by a reactive phosphonium salt derived from an alkyl or aryl phosphine, typically triphenylphosphine, and an azo compound, most commonly diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). The mechanism of the Mitsunobu reaction has been thoroughly investigated [1-9] and one of the current generally accepted pathways (Fig. 1) involves initial nucleophilic addition of triphenylphosphine (1) to DEAD (2) to generate a reactive betaine intermediate 3. In the presence of an acidic pronucleophile 4, the betaine intermediate 3 is protonated to give 6 and then nucleophilic attack by the alcohol 7 affords an alkoxyphosphonium species 9 with concomitant loss of diethyl hydrazinedicarboxylate (8), the reduced form of DEAD. SN2 displacement of triphenylphosphine oxide (10) by the conjugate base form of the pronucleophile 5 affords the coupled product 11 with complete inversion of configuration for chiral secondary alcohols. A wide range of acidic pronucleophiles are tolerated, the most commonly employed being carboxylic acids, for the preparation of esters, and phenols, for the synthesis of aryl ethers. This scope, along with the mild reaction conditions and stereospecificity, make the Mitsunobu reaction a popular choice within the fields of organic synthesis and medicinal chemistry. However, difficulties are often encountered during product isolation and purification due to the presence of stoichiometric reagent-derived by-products, triphenylphosphine oxide and a hydrazinedicarboxylate. This obviously limits the utility of the reaction in a medicinal chemistry environment where product purity, potential for automation/parallel synthesis and efficiency are paramount.

*Address correspondence to this author at the Brain and Mind Research Institute, 100 Mallett Street Camperdown, NSW 2050 Australia; Tel: + 612 9351 0894; Fax: + 612 9351 0652; E-mail: [email protected] 1385-2728/09 $55.00+.00

Several modifications to the reaction have been developed in order to overcome these inherent isolation and purification issues with varying degrees of success. This review will focus on these developments with a particular emphasis on their suitability for modern drug design. A few select examples of important biologically active molecules that feature the Mitsunobu reaction as a key synthetic step are also discussed. For a comprehensive overview of the Mitsunobu reaction please refer to the many excellent published reviews which already exist for this purpose [10-17]. 2. MODIFIED REAGENTS TO SIMPLIFY PURIFICATION In order to simplify the isolation and purification of the Mitsunobu coupled product several new reagents have been developed as alternatives to triphenylphosphine and DEAD or DIAD. These have been extensively reviewed [14-17] but what follows is a brief overview with a discussion of the advantages and disadvantages from a modern medicinal chemistry perspective. 2.1. Reagent Tagging The use of one or more tagged reagents in the Mitsunobu reaction has been exploited by many research groups to facilitate the removal of tagged reaction by-products from the untagged product by phase separation or affinity chromatography. This strategy is attractive from a combinatorial chemistry or parallel synthesis perspective since no additional reactions are required to effect separation. 2.1.1. Supported Reagents The use of insoluble solid polymer-supported triphenylphosphine (12) (Fig. 2) in solution-phase Mitsunobu reactions facilitates removal of the phosphine oxide by-product, and any unreacted phosphine reagent, by filtration [18,19]. This is far more efficient than the traditional workup protocol which involves precipitating triphenylphosphine oxide using pentane or diethyl ether for subsequent filtration and/or © 2009 Bentham Science Publishers Ltd.

Recent Advances in the Mitsunobu Reaction

Current Organic Chemistry, 2009, Vol. 13, No. 16

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Fig. (1). Commonly accepted mechanism for the Mitsunobu reaction employing PPh3 and DEAD.

separation by flash chromatography, especially challenging when dealing with small, polar drug-like molecules that tend to co-elute in most solvent systems.

P

12 PS-PPh3

Fig. (2). Solid polymer-supported triphenylphosphine 12.

Despite the use of solid polymer-supported triphenylphosphine, the problem of removing the hydrazinedicarboxylate by-product and any unreacted substrate/s or excess reagent/s remains and any chromatography is both difficult and undesirable, especially in the context of combinatorial or parallel drug discovery platform. There also seems to be a high degree of variability among the commercially available sources of solid polymer-supported triphenylphosphine, presumably due to the presence of phosphine oxide contaminant

or, less likely, a consequence of different resin loadings [20]. At present solid polymer-supported triphenylphosphine is expensive and while the cost-benefit ratio is favourable in a small-scale drug discovery environment, particularly where parallel synthesis and automation are desired, it would be cost prohibitive to initiate pilot scale preparations using this reagent. It is possible to recycle the solid polymer-supported phosphine oxide by-product using reducing conditions [21]. Solid polymer-supported triphenylphosphine is often used in conjunction with modified azodicarboxylates and this will be discussed in due course. Vederas and co-workers have described the preparation and use of solid polymer-supported methyl azodicarboxylate 13 (Fig. 3) as an alternative to DEAD or DIAD in solutionphase Mitsunobu reactions [22]. O O

N

N

OMe

O 13

Fig. (3). Solid polymer-supported azodicarboxylate 13.

1612 Current Organic Chemistry, 2009, Vol. 13, No. 16

Reynolds and Kassiou

Fig. (4). Preparation of soluble oligomeric triphenylphosphine 18. O

1. COCl2, PhMe OH 20

MesN Cl

21

NMes

PCy3 Cl

Ru

Cl

Ph

OEt O

1. 19 (3.3 mol%) CH2Cl2, 50 °C, 96%

Ru

Cl

Ph

PCy3

PCy3

19

24

2. 24 (2 mol%) H2 (1000 psi), 50 °C, 80%

O O

H N N H

O 2. NH2NHCO2Et, NEt3 DMAP, THF, 55%

O N

N

OEt

O

Br2, pyr O

N H

H N

OEt O

CH2Cl2, 86% 23 (HO-DEAD)

22

Fig. (5). Preparation of soluble oligomeric azodicarboxylate 23.

The solid polymer-supported hydrazine by-product and any excess azodicarboxylate reagent is removed by filtration as part of the reaction workup. It can thus be reoxidised in the presence of N-bromosuccinimide and recycled in this manner several times without loss of activity. Solid polymer-supported azodicarboxylates are now commercially available and while not inexpensive the fact that they can be recycled several times makes them attractive alternatives to DEAD or DIAD in Mitsunobu reactions for medicinal chemistry and drug discovery. Despite the obvious benefits of solid polymer-supported phosphines and azodicarboxylates these reagents cannot be employed simultaneously in solution phase Mitsunobu reac-

tions due to a lack of reactivity [14]. Furthermore, Mitsunobu reactions involving sterically hindered substrates often suffer reduced reactivity due to the less accessible reagent. Slower reaction kinetics also present a problem due to the biphasic nature of the reaction mixture and thus a large excess of relatively expensive solid polymer-supported reagent is often employed in order to circumvent this. Toy and co-workers [23] have simultaneously employed soluble oligomeric triphenylphosphine (OTTP, 18), first prepared by Barrett et al. [24] from known monomeric phosphine 17 via ring-opening metathesis polymerisation (Fig. 4), and soluble oligomeric azodicarboxylate 23 (Fig. 5) in solution-phase Mitsunobu reactions.


MeO

O

Current Organic Chemistry, 2009, Vol. 13, No. 16 1613

MeO

Me OH

+

O

OTPP (2 equiv.) HO-DEAD (2 equiv.)

HO

Me O

25 °C, THF 70%

Ph OH

BocHN

Ph

OTPP (2 equiv.) HO-DEAD (2 equiv.) +

HO

O

O2N

O

BocHN

25 °C, THF 73%

O

O2N OTPP (2 equiv.) HO-DEAD (2 equiv.) OH

+

HO

Ph

O

Ph

25 °C, THF 73%

O

O OH

+

OTPP (2 equiv.) HO-DEAD (2 equiv.)

HO OMe

O

O

25 °C, THF 90%

OMe

O

OTPP (2 equiv.) HO-DEAD (2 equiv.) OH

+

HO

O 25 °C, THF 84%

O NH

O

OTPP (2 equiv.) HO-DEAD (2 equiv.) +

HO

N 25 °C, THF 69%

O

O

OMe

O

OMe

OTPP (2 equiv.) HO-DEAD (2 equiv.) OH

+

HO

Ph

O 25 °C, THF 76%

MeO OMe

O Ph

MeO OMe

Fig. (6). Scope of the Mitsunobu reaction with oligomeric reagents.

At the end of the reaction any excess polymeric reagents and their by-products were precipitated upon addition of ethyl acetate and filtered through a plug of silica gel. In this way a range of acidic pronucleophiles and alcohols were coupled to give the desired products in 69-90% yield (Fig. 6) without the need for chromatographic purification. The main

disadvantage was the need to employ a large excess (5 equivalents) of each reagent. Janda and co-workers [25] reported the synthesis of the poly(ethylene glycol) (PEG)-phosphine conjugate 28 via a 3 step sequence (Fig. 7) starting from commercially available benzyloxycarbonyl (Cbz) protected 4-bromophenethylamine



Fig. (7). Synthesis of poly(ethylene glycol) conjugate-phosphine 28.

(25) which underwent a nucleophilic aromatic substitution reaction in the presence of potassium diphenylphosphide to give triarylphosphine derivative 26. Cleavage of the Cbz protecting group in 26 under hydrogenolysis conditions was followed by reaction with the bis-p-nitrophenyl carbonate derivative of PEG3400 to afford the PEG-phosphine reagent 28 which precipitated from diethyl ether. The soluble PEG-triarylphosphine reagent 28 was successfully used in liquid-phase homogeneous Mitsunobu reactions between phenol and a range of simple alcohols in the presence of DEAD. The oxidised PEG-phosphine by-product was readily removed at the end of the reaction by precipitation from diethyl ether to give the desired aryl alkyl ethers in analytically pure form without the need for chromatographic purification. The utility of this approach may be limited in cases where the Mitsunobu products are insoluble in diethyl ether, a common occurrence when dealing with the small, highly functionalised aromatic molecules typical in medicinal chemistry. The need to purify the intermediate triarylphosphine derivative 26 by chromatography also potentially

x

limits the preparation of the PEG-phosphine conjugate on larger scales. Charette et al. [26] have used soluble non-cross-linked polystyrene-supported triphenylphosphine 29 (Fig. 8) for the Mitsunobu reaction. 2-(S)-Octanol (30) reacted with benzoic acid in the presence of DEAD and soluble non-cross-linked polystyrenesupported triphenylphosphine 29 to give the inverted benzoate ester 31 in 83% yield compared with 65% yield when insoluble cross-linked polymer-supported triphenylphosphine was used (Fig. 9).

y

PPh2

29

Fig. (9). Mitsunobu esterification with non-cross-linked polystyrene PPh3 29.

Fig. (8). Soluble non-cross-linked polystyrene-supported triphenylphosphine 29.

Similarly, ethyl (S)-lactate (32) reacted with pnitrobenzoic acid in the presence of DEAD and soluble noncross-linked polystyrene-supported triphenylphosphine 29 to

O



PPh2

PPh2 NiBr2, PPh3 X

Br

Ph3P

PhCN, reflux 4 h, 78% 34

35, X = Br

LiClO4, MeCN CH2Cl2, 15 min, 95%

36, X = ClO4 37, X = PF6

LiPF6, MeCN, CH2Cl2 H2O, 1 h, 95%

Fig. (10). Tetraarylphosphonium appended phosphines 36 and 37. Cl Cl

NiBr2, PPh3

PPh3

PhCN, reflux, 2 h

Br

38

39

O Ph3P

N

LiClO4, CH2Cl2, MeOH 15 min, O3, -78 °C then NaBH4 (77% over two steps)

1. triphosgene, pyridine CH2Cl2, -78 °C then NH2NHCO2Et -78 °C to RT, 95%

O ClO4

Br

Ph3P

OH ClO4

N CO2Et

41

Ph3P

2. pyridine, NBS 0 °C, 30 min, 91%

40

Fig. (11). Tetraarylphosphonium appended DEAD 41.

give the inverted p-nitrobenzoate ester 33 in 71% yield compared with 91% yield when triphenylphosphine was used (Fig. 9). In this case, the authors attributed the lower yield when using non-cross-linked polystyrene supported triphenylphosphine to possible trapping of the product in the polymer following precipitation with methanol at the end of the reaction. Charette and co-workers more recently reported the synthesis of novel triphenylphosphines 36 and 37 (Fig. 10) and DEAD 41 (Fig. 11) reagents appended to a tetraarylphosphonium salt as a solubility control group [27,28]. The arylphosphonium bromide 35, prepared via a nickelmediated coupling between bromophosphine 34 and triphenylphosphine, underwent an anion-exchange reaction to afford either the perchlorate or hexafluorophosphate salts 36 or 37 (Fig. 10). The DEAD reagent 41 was synthesised via a five step sequence in 60% overall yield from commercially available 4chlorobenzaldehyde without recourse to chromatography (Fig. 11). Specifically, double Horner reaction between triphenylphosphine and 4,4’-dichlorostilbene (38), prepared from McMurray coupling of 4-chlorobenzaldehyde, afforded the bis(phosphonium) salt 39 which underwent an anionexchange reaction followed by reductive ozonolysis to give benzyl alcohol 40. In situ formation of an intermediate chlorocarbonyl pyridium salt upon treatment of 40 with triphosgene was followed by addition of ethyl carbazate to furnish a hydrazine dicarboxylate which was subsequently oxidised in the presence of NBS to afford 41.

The authors showed that 36 and 37 have similar reactivity to triphenylphosphine in a range of Mitsunobu reactions involving secondary alcohols and p-nitrobenzoic acid as the acidic pronucleophile (Fig. 12). In the case of 2-octanol (46), two supported reagents 36 (1.5 equiv.) and 41 (1.5 equiv.) were successfully employed simultaneously to afford the desired Mitsunobu ester 47 in excellent yield. The excess reagents and their by-products were quantitatively removed at the end of the reaction following addition of diethyl ether and filtration of the resulting precipitate. The reactions were, by necessity, conducted in toluenedichloromethane (2:1) in order to dissolve the phosphine which, along with its oxidised by-product, could be precipitated and subsequently filtered off during the workup by adding diethyl ether, toluene or hexane. Recycling of the phosphine 36 is possible by reducing the phosphine oxide by-product 50 in the presence of trichlorosilane and dimethylaniline (Fig. 13). 2.1.2. Basic Phosphines A range of basic phosphines have been successfully employed in the Mitsunobu reaction, and examples include (pdimethylamino-phenyl)diphenylphosphine (DAP-DP) (51) [29] (2-pyridyl)diphenylphosphine (PyPPh2) (52) [30] (Fig. 14). The crude reaction mixture is routinely washed with a concentrated Brønstead acid to effect protonation and aqueous extraction of the phosphine and its oxide by-product but chromatography is still required to separate the Mitsunobu coupled product from the hydrazinedicarboxylate and any excess azodicarboxylate.



Fig. (12). Mitsunobu esterification using 36 or 37 and DEAD or 41. *triphenylphosphine or other supported phosphine. O PPh2

PPh2 Cl3SiH, PhNMe2

ClO4

ClO4

Ph3P

50

PhCN, 170 °C, 2 h then LiClO4 93%

Fig. (13). Reducing conditions for recycling phosphine oxide by-product 50.

Ph3P

36



P

reactions [31]. The ferrocene group of the phosphine oxide by-product is readily oxidised in the presence of iron(III) chloride during workup to generate a cationic species that is extracted into the aqueous phase. Similarly crown ether-tagged triarylphosphines 55 and 56 (Fig. 16) can be utilised in the Mitsunobu reaction [32]. phosphine oxide by-product and any unreacted phosphine reagent are readily removed by passing the crude reaction mixture through an ArgoPoreTM ammonium trifluoroacetate column.

P

N

N

52 PyPPh2

51 DAP-DP

Fig. (14). Phosphines with basic nitrogen atoms.

2.1.4. Fluorous Reagents

DAP-DP (51) and PyPPh2 (52) are commonly employed in conjunction with di-tert-butylazodicarboxylate (53, DBAD, Fig. 15) which, along with its reduced form, decomposes to give gaseous products (isobutylene, carbon dioxide and nitrogen) and water-extractable hydrazine upon acidic workup (see section 2.3.1) [30].

It is possible to use fluorous DEAD and/or fluorous triphenylphosphine in Mitsunobu reactions with significant advantages in terms of product isolation and purification [33,34]. Fluorous reaction by-products and any excess fluorous reagents can be routinely removed by either fluorous solid-phase extraction (FSPE) or by simply partitioning between a fluorous solvent and an organic solvent in the case of molecules with a higher fluorine content (typically above 60 wt%). FSPE is conducted using commercially available fluorocarbon-bonded silica gel and common organic solvents for both the fluorophilic and fluorophobic eluents. This is particularly advantageous in combinatorial and parallel synthesis protocols commonly utilised in drug design and development [35]. The major drawback is the cost of the commercially available fluorous silica gel and the need to prepare some fluorous reagents, for example, fluorous DEAD is synthesised in three steps from commercially available perfluorohexyl ethanol in 63-85% overall yield. In Mitsunobu reactions involving weakly acidic pronucleophiles and/or sterically hindered alcohols fluorous DEAD with an ethylene spacer 57 (Fig. 17) is less effective

O N O

O

N O 53 DBAD

Fig. (15). Di-tert-butylazodicarboxylate (53, DBAD), an acid-labile azodicarboxylate.

While highly amenable to a combinatorial synthesis approach this protocol is unsuitable for the large majority of drug candidates which contain basic nitrogens or other acidlabile functional groups. 2.1.3. Tagged Phosphines The ferrocenyl tagged triphenylphosphine 54 (Fig. 16) has been used in combination with DBAD in Mitsunobu

O

O

O

O

O

P Fe

O

O

O

O O O

O

N H

P

P

O 55

54

56

Fig. (16). Tagged phosphines. O C6F13

O

O N

N

O

C6F13

C6F13

O

N

N

O

O

57

58 O

C6F13

O

N

N

O O

59

Fig. (17). Fluorous reagents.

O

C6F13



Fig. (18). Mitsunobu alkylation of a polymer-supported substrate 62.

than regular DEAD. This problem has been addressed with two new fluorous azo reagents 58 and 59 (Fig. 17) which feature extra methylene units between the fluorous tails and the azo groups. 2.2. Substrate Tagging As is the case with tagged reagents and their by-products, suitably tagged substrates can be isolated by phase or affinity separation at the end of the Mitsunobu reaction. The main disadvantage is the additional reactions required for installation and subsequent removal of the functionalised tag. Typically either the alcohol or acidic pronucleophile is first attached to an insoluble polymer support and the Mitsunobu product is simply filtered off and used in the next step of the sequence or cleaved from the resin. Alternatively, the substrate may carry a fluorinated tag which facilitates simple product isolation. When the aim is to invert the configuration of a chiral secondary or tertiary alcohol one can utilise a fluorous-tagged carboxylic acid since the ester product is readily isolated and the tagged component is conveniently removed during the subsequent hydrolysis step. Chaturvedi [36] published a patent which detailed the Mitsunobu alkylation reaction of a solid polymer-supported starting material, either the acidic pronucleophile or the alcohol, in the presence of solution phase reagents. In this way

a large number of novel compounds were prepared by varying the nature of the active methylene reagent (Fig. 18). 2.3. Phase Switching: Scavenging Several alternative reagents for the Mitsunobu reaction have been developed which enable their derived by-products to be easily removed via phase switching following unmasking of a functionalised tag or latent functional group. 2.3.1. Acid-Labile Reagents and By-Products As mentioned in Section 2.1.2, Kiankarimi and coworkers successfully employed DBAD and (2-pyridyl) diphenylphosphine in the Mitsunobu reaction between a range of alcohols and acidic pronucleophiles [30]. The workup involved treatment with hydrogen chloride in dioxane to decompose the hydrazine by-product and any excess azodicarboxylate, evaporation, washing with aqueous acid to extract any excess phosphine and its oxide byproduct and short path chromatography on silica gel. Pelletier and Kincaid have successfully synthesised a 3 5 parallel library of compounds via a Mitsunobu reaction employing DBAD and polymer-supported triphenylphosphine followed by a workup comprising treatment with trifluoroacetic acid, filtration through Celite®, evaporation,



O P

O

O

N H

O N

N

O

O 66

H N

O

O 67

Fig. (19). Masked carboxylic acid-tagged reagents.

aqueous acid wash and filtration [37]. Products were obtained in >80% purity with unreacted pronucleophile starting material identified as the major impurity. The latter could be removed by treating with resin bound carbonate followed by filtration.

acid tag in the Mitsunobu reaction [39].

O P

2.3.2. Masked Acids

O

Flynn and co-workers utilised a tert-butyl ester as a masked carboxylic acid tag on both phosphine 66 and azodicarboxamide 67 (Fig. 19) for a range of Mitsunobu reactions [38]. The workup involved treatment with trifluoroacetic acid to hydrolyse the tert-butyl ester functional groups of the reaction by-products and any excess reagents and the unmasked carboxylic acids thus obtained were sequestered using a basic ion-exchange resin. This protocol has the added advantage of removing any unreacted acidic pronucleophile but in some cases unreacted alcohol remains as a contaminant. In these cases, DBAD is used instead of 67 and addition of tetra-fluorophthalic anhydride (TFPA), an alcohol sequestering reagent, during workup affords the desired products in excellent purity without chromatography. While attractive for the parallel synthesis of compound libraries using the Mitsunobu reaction this approach has limited utility for target molecules which possess basic nitrogen atoms or other acid labile functional groups. Yoakim et al. used DIAD and a phosphine containing a trimethylsilyl ethyl ester 68 (Fig. 20) as a masked carboxylic

SiMe3

68

Fig. (20). Silyl ester-tagged triphenylphosphine.

At the end of the reaction the carboxylic acid tag was unmasked upon treatment with tetra-n-butylammonium fluoride with concomitant liberation of ethylene gas. Washing with aqueous sodium hydroxide removed the acid-tagged phosphine and its oxide by-product and silica gel chromatography was employed to isolate the desired product free from the reduced DIAD by-product. The need for chromatography obviously limits the application of this approach where automated parallel synthesis of drug libraries is desired. 2.3.3. Impurity Annihilation Barrett and co-workers used insoluble polymer-supported triphenylphosphine and bis(5-norbornenyl-2-methyl) azodicarboxylate (72, DNAD, Fig. 21) for the Mitsunobu reaction between a range of alcohols and acidic pronucleophiles [40]. In each case the desired products were obtained in moderate to excellent yield (43-100%) and 86-

COCl2, PhNMe2, PhMe 83%

OH

69

O O

70

Cl

NH2NH2 Na2CO3 EtOH, 88%

O O

PhI(OAc)2, CH2Cl2 N

N

O

O 83% O

72 (DNAD)

Fig. (21). Preparation of bis(5-norbornenyl-2-methyl) azodicarboxylate (DNAD, 72).

O

N H

H N

O O

71



O N

O O

O O

Ph2P

O N

N

O OEt

73

13

74

Fig. (22). Anthracene-tagged triphenylphosphine 73, polymer-supported azodicarboxylate 13 and polymer-supported maleimide 74.

to excellent yield (43-100%) and 86-96% purity as determined by 1H NMR spectroscopy following filtration and ring-opening metathetic polymerization (ROMP) of the norbornene-derived hydrazinedicarboxylate by-product in the presence of Grubbs second generation ruthenium alkylidene catalyst. The polymer thus obtained was precipitated with hexanes and removed by filtration and the desired Mitsunobu product was obtained without need for chromatography. This methodology is attractive but suffers in cases where the substrates contain functional groups that are capable of coordinating to ruthenium. The cost of Grubbs ruthenium catalyst for ROMP may also be cost prohibitive for pilot scale reactions. Highly polar drug-like molecules may coprecipitate with the norbornene-derived polymer upon addition of hexanes thereby presenting additional problems for purification.

3. ALTERNATIVE REAGENTS AND WORKUP PROTOCOLS 1,2-Bis(diphenylphosphino)ethane (75, DPPE, Fig. 23) has been successfully used as a replacement for triphenylphosphine in Mitsunobu reactions [42]. The bis(phosphine oxide) by-product derived from DPPE is considerably more polar than triphenylphosphine oxide and thus more readily removed at the end of the reaction by filtration and the crude product is purified by flash chromatography to remove the hydrazinedicarboxylate.

P

P

2.3.4. By-Product Capture on Polymer Support Parlow et al. developed an anthracene-tagged phosphine 73 (Fig. 22) which was successfully used in conjunction with polymer-supported azodicarboxylate in the Mitsunobu reaction [41]. At the end of the reaction the anthracene-tagged phosphine and its oxide by-product can be removed by sequestration through a Diels-Alder reaction using a polymerbound maleimide dienophile 74 (Fig. 22). Filtration of the polymer-supported azodicarboxylate 13 and its reduced hydrazine by-product affords the desired Mitsunobu product without need for chromatography. Excess alcohol starting material is also conveniently removed by the polymersupported azodicarboxylate. This methodology is extremely attractive for the parallel synthesis of drug libraries using the Mitsunobu reaction. Apart from the need to synthesise the anthracene-tagged triphenylphosphine and the associated costs with using commercially available polymer-supported azodicarboxylate the only real limitation exists in cases where the target compound contains functional groups which might react with the polymer-bound dienophile.

75 DPPE

Fig. (23). 1,2-Bis(diphenylphosphino)ethane (75, DPPE).

Curran and co-workers prepared two new azodicarboxylates, bis-(1-adamantylmethyl) azodicarboxylate (76, BadMAD, Fig. 24) and bis-(2-(1-adamantyl)ethyl) azodicarboxylate (77, BadEAD, Fig. 24), with adamantyl tags to facilitate separation of the hydrazine by-product generated in the Mitsunobu reaction using a Sumichiral OA7500 methylated cyclodextrin bonded silica gel column [43]. The high cost and relative lack of commercial sources for methylated cyclodextrin bonded silica gel prohibits large scale use of this technique at present. Humphries et al. prepared a range of compounds which display agonist activity towards peroxisome proliferatoractivated receptors (PPARs) which have wide-ranging effects on key transcriptional pathways for lipid handling, insulin sensitivity, inflammation and other functions [44].

O O

O N

N

O

O

N

N

O

O

O

76 (BadMAD)

77 (BadEAD)

Fig. (24). Adamantane-tagged azodicarboxylates 76 and 77.


Current Organic Chemistry, 2009, Vol. 13, No. 16 1621 O H N

EtO

N CO2Et

O +

Ph OH

Ph THF, RT, 16 h, 54%

HO

78

O

O

N

N

PS-PPh3, DEAD

CO2Et

O +

O

N

N

O

79

OEt

N O

81

Ph 82

Fig. (25). By-product formation for less acidic pronucleophiles.

in conjunction with polymer-supported triphenylphosphine for the synthesis of a range of aryl ethers in excellent yield and purity following filtration and washing of the reaction mixture [20]. Beal and Véliz reported the use of triisopropyl phosphite as an alternative to triphenylphosphine in the Mitsunobu reaction between a nucleoside analog and a range of alcohols [45]. The phosphite, upon oxidation, generates a phosphate, which is more water soluble than the triphenylphosphinederived oxide and thus isolation and purification of the product is greatly simplified. Knight and co-workers reported an alternative workup protocol for Mitsunobu reactions that avoids chromatography and uses standard commercially available reagents, DIAD and triphenylphosphine [46]. The crude reaction mixture is washed with a solution of 15% aqueous hydrogen peroxide prior to addition of aqueous sodium sulphite to reduce any residual peroxides. Following filtration through silica gel the coupled product is obtained in excellent yield and purity. Toy and But have developed a Mitsunobu reaction that is catalytic in the azodicarboxylate (DEAD, DIAD or ADDP) and uses a hypervalent iodine species as the stoichiometric co-oxidant [47]. Thus, the amount of hydrazine by-product is minimised and the iodobenzene and acetic acid by-products from the stoichiometric oxidant are easy to remove. Lipschutz and co-workers [48] reported the preparation of di-p-chlorobenzyl azodicarboxylate (DCAD, 89) from commercially available 4-chlorobenzyl alcohol (85) and 1,1’-carbonyldiimidazole (86) in a 2 step sequence involving

The authors found that using polymer-supported triphenylphosphine and DEAD for the Mitsunobu reaction between alcohol 78 and pyridinol 79, the coupled product 81 was obtained in 54% yield along with a major by-product 82 (Fig. 25). In such cases where the acidic pronucleophile has a pKa >11 yields are generally lower and using either N,N,N’,N’-tetramethylazodicarboxylate (83, TMAD) or 1,1’(azodicarbonyl)dipiperidine (84, ADDP, Fig. 26) broadens the scope of the reaction, often in conjunction with more basic phosphines such as trimethyphosphine or tributylphosphine. O

O N N

N

N

N

N

N

N O

O 83 (TMAD)

84 (ADDP)

Fig. (26). Azodicarboxylates which generate more basic betaine intermediates.

In the presence of 1,1'-(azodicarbonyl)dipiperidine (ADDP) and polymer-supported triphenylphosphine Humphries and co-workers prepared a small library of peroxisome proliferator-activated receptor (PPAR) ligands using the Mitsunobu reaction without need for chromatographic purification [44]. This methodology is highly amenable to a parallel synthesis approach although it was reported that some functional groups such as basic amines, benzimidazoles, indoles, etc failed to react under these conditions. Valeur and Roche surveyed a range of commercially available azodicarboxylates and found success using TMAD

O

O THF

OH

+

N

N

N

0 °C to RT 1-2 h

Cl 85

86

N

N

O O

Cl

N

N

Cl 87 H2N-NH2, Et3N, heat overnight 85-92%

Cl

O O

O

N

O NBS, pyridine PhMe, 1-2 h 98%

89 (DCAD)

Fig. (27). Synthesis of di-p-chlorobenzyl azodicarboxylate (89, DCAD).

O

N H

H N

O O

Cl 88

Cl


in situ formation of a carbamate (87) followed by treatment with hydrazine to afford the corresponding dicarboxylate derivative (88) which was subsequently oxidised in the presence of N-bromosuccinimide (NBS) and pyridine (Fig. 27). The DCAD is obtained in excellent overall yield (8390%) and without recourse to chromatographic purification as a bright-orange coloured crystalline solid which is indefinitely stable at room temperature. Studies to date suggest that DCAD gives Mitsunobu products with comparable yields to reactions performed using DEAD or DIAD with the added advantage that the reduced hydrazine by-product is insoluble in dichloromethane and readily recycled upon reexposure to NBS. 4. APPLICATIONS OF THE MITSUNOBU REACTION IN DRUG DESIGN The Mitsunobu reaction is often employed for the synthesis of biologically active molecules, particularly those which contain aryl ethers. One such example is the class of compounds targeting nicotinic acetylcholine receptor subtypes. Lin and co-workers reported the synthesis and biological evaluation of a range of novel 3-pyridyl ethers 90 (Fig. 28) with sub-nanomolar affinity for central neuronal nicotinic acetylcholine receptors [49]. n N R

O * 90 n = 1 or 2 R = H or Me * = R or S

N

Fig. (28). Novel 3-pyridyl ethers.

Fig. (29). Mitsunobu approach to pyridyl ethers.

Fig. (31). Synthesis of L-N-MCd4T (100), a potent anti-HIV compound.


Compounds were prepared via Mitsunobu coupling between an appropriately protected imino alcohol 91 or 93 and pyridinol (92) (Fig. 29). A-85380 (95, Fig. 30) possesses ca. 50 pM affinity for rat brain [3H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human 42 nAChR subtype and is not stereoselective in the assays examined. A84543 (96, Fig. 31) exhibits 84-fold selectivity to stimulate ion flux at human 42 nAChR subtype compared to human ganglionic type nAChRs and is stereoselective. O

HN

O N N

Me

95

N 96

Fig. (30). Biologically active pyridyl ethers.

Moon et al. reported the synthesis of the potent anti-HIV agent, L-N-MCd4T (100) (Fig. 31) wherein one of the key steps involves the Mitsunobu coupling between (2S)-97 and N3-benzoylthymine (98) [50]. Gentles and co-workers have demonstrated the applicability of the Mitsunobu reaction to parallel automated synthesis, using phenol 101 and a range of primary, secondary and tertiary alcohols in the presence of polymer-supported triphenylphosphine and DBAD (Fig. 32) [51]. Winiewski and co-workers synthesized a new class of cyclic peptides, the most potent of which were 103 and 104 (Fig. 33) which displayed high affinity for the human cloned oxytocin receptor (Ki = 2.8 and 4.0 nM respectively) and maintained activity as oxytocin antagonists [52].



OH OR

Cl

Cl PS-PPh3, DBAD R

+

OH RT, 3 h

101 102

Fig. (32). Gentles’ automated parallel synthesis of aryl ethers.

O HN

H N

O

NH2

O H N

N H

O

O HN

NH

S O

n

NH2

103 n = 0, Ki = 2.8 nM, ID50 = 17 nmol/kg 104 n = 1, Ki = 4.0 nM, ID50 = 5.4 nmol/kg

Fig. (33). New oxytocin antagonists.

The synthesis (Fig. 34) involved a Mitsunobu reaction between an amino alcohol 106 and thiolacetic acid in the presence of triphenylphosphine and DEAD followed by base-promoted hydrolysis and alkylation. The tert-butyl ester 108 thus obtained was hydrolysed with trifluoroacetic acid with concomitant cleavage of the N-Boc protecting group and the newly liberated amine was protected as the corresponding Fmoc derivative 109 prior to loading onto trityl resin. The linear peptide was assembled via a sequence of N,N'-diisopropylcarbodiimide/N-hydroxybenzotriazole couplings with the appropriate amino acid building blocks. After cleaving from the resin, the linear peptide was cyclised and CbzHN

any side-chain protecting groups were removed to give the target compound. There are many examples in the literature of biologically important molecules which have employed the Mitsunobu reaction in its most generic form, sometimes without success, and in some cases alternative strategies have been used. One such example is the synthesis of the pyrazolopyrimidine, 111 (DPA-714, Fig. 35), part of a new series of selective high affinity ligands for the translocator protein (TSPO) 18 kDa, which is implicated in a number of neurodegenerative diseases [53]. The phenol 110 was alkylated using sodium hydride and either 1-fluoro-2-tosyloxyethane or 1,2-di(tosyloxy)ethane to give non-radiolabelled DPA-714 (111) and the tosyloxy derivative 112 respectively (Fig. 35). Both of these compounds could be prepared via a Mitsunobu reaction between the phenol 110 and the appropriate alcohol and in this way a library of new TSPO ligands could be accessed in an efficient manner. The choice of phosphine and azodicarboxylate requires careful consideration since the target compounds contain basic nitrogen atoms precluding the use of acidic workup conditions employed for DAP-DP, PyPPh2 or DBAD. DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline in rat C6 glioma cells. The tosyloxy derivative 112 served as starting material for the radiosynthesis of [18F]-DPA-714 which was used for in vivo positron

CbzHN

CbzHN

1. NMM, ClCO2iBu

n OH

BocHN

PPh3, DEAD, THF

n OH

BocHN

2. NaBH4

HS

n S

BocHN

Me

O

Me O

105

106

O

107

1. NaOH 2.

n = 0 or 1

O

Br

CbzHN

FmocHN

CbzHN

O

n S

O

n OH

109

Fig. (34). Synthesis of key building block for new oxytocin antagonists.

BocHN

OtBu

S

OtBu

108



F N

N

NaH, THF, reflux, 16 h

N

OH

N

F

TsO

N O

N

O

O NEt2

NEt2

110

111 (DPA-714)

NaH, THF, reflux, 16 h OTs

TsO

OTs N

N

K[18F]F-K222, K2CO3 DMSO, 165 °C, 5 min followed by

18F

N

N O

O cartridge purification (Prep-SepTM C-18) and HPLC purification (X-TerraTM RP-18)

N O NEt2

N O NEt2 [18F]-111 (DPA-714)

112

Fig. (35). Synthesis of DPA-714. OTs HO

HO

HO

Bu3Sn

Na125I, EtOH

N

N

N

Bu4NOH MeCN, 80 °C 113

chloramine-T 115

HO

O

[125I]-116

O

125I

Bu3Sn OTs F

I2, CHCl3, RT

Bu4NOH MeCN, 80 °C HO

HO

N

N

114

116 O

F

O I

Fig. (36). Synthesis of benzovesamicol analogues.

emission tomography (PET) imaging of a baboon brain [54] and lesioned rat brain [55]. Mavel and co-workers have reported the synthesis and biological evaluation of several new benzovesamicol analogues [56-58]. These compounds show promise as potential

radioligands for PET imaging of the vesicular acetylcholine transporter (VAChT), changes in which are linked to the progression of Alzheimer’s disease (AD). The authors used an alkylation protocol of the phenol 113 to prepare the fluoropropyl aryl ether 114 and allylstannyl



aryl ether 115 (Fig. 36). The latter could be converted to the iodo derivative 116 or radiolabelled to afford [125I]-116 which was used to study ex vivo biodistribution of the VAChT in rats. Of the new compounds, [(R,R)-116] and [(R,R)-114] displayed the highest binding affinities for the VAChT (Kd = 0.45 and 0.77 nM, respectively), which suggest that elongation of the substituent chain from 5-idodo, as in the case of ()-5-IBVM (117, Fig. 37) (Kd = 0.30 nM), to a five member 5-O-halogenoalkyl or alkenyl chain, had limited effect on affinity for the VAChT. There is clearly merit in exploring substitution at this position with longer alkyl ethers and a Mitsunobu approach is highly amenable to this.

benzenesulfonamide (nosyl-amide) derivatives of primary amines undergo smooth alkylation in the presence of alcohols under Mitsunobu conditions to give N-alkylated sulfonamides [61]. The key intermediate 120 in the synthesis of the pyrazino [1,2-b]isoquinoline 123 (Fig. 39) was accessible from commercially available D-tryptophan via a 4-step reaction sequence. The intramolecular Mitsunobu alkylation reaction of 120 proceeded in the presence of DIAD and triphenylphosphine to afford 121. Boc-protection of the indole nitrogen was followed by cleavage of the nosyl group to give the cyclic secondary amine 123 which could be acylated prior to global deprotection in the presence of hydrogen chloride in dioxane to give 124. Alternatively, 123 could be alkylated prior to global deprotection to furnish 125. Similarly, starting with commercially available Ltryptophan methyl ester it was possible to access epi-123 which was further elaborated to give epi-125 and 126 (Fig. 40). The pyrrolo [1,2-a]pyrazine scaffold 130 was accessed via the analogous key intramolecular Mitsunobu alkylation of amide 127 in the presence of DIAD and triphenylphosphine (Fig. 41). Boc-protection of the indole nitrogen was followed by cleavage of the nosyl group to afford secondary amine 130 which was acylated and deprotected to furnish 131. Marsault and co-workers [62] reported the solid phase parallel synthesis of a small library of chemically and conformationally diverse macrocyclic peptidomimetics. These macrocycles are composed of a tripeptide cyclised backboneto-backbone by a nonpeptidic tether. The compounds encompass a range of different side-chain functionalities; combinations of (L), (D), -, - and -amino acids as well as Nmethylated and ,-substituted amino acids; and a variety of tether groups (e.g. acetylene, ether, amine, aromatic, and heteroaryl). In each case a Fukuyama-type Mitsunobu alkylation was used to attach the N-protected amino alcohol tether 133 to the amino terminus of the polystyrenesupported tripeptide 132, bearing a benzothiazole-2-sulfonyl (Bts) protecting group (Fig. 42). Prakash et al. [63] exploited the Mitsunobu reaction for the monofluorination of alcohols using 1-fluorobis(phenylsulfonyl)methane (136) as the acidic pronucleophile in the presence of DIAD and triphenylphosphine in

HO N

I 117 (-)-5-IBVM

Fig. (37). (-)-5-IBVM.

An automated parallel Mitsunobu approach would enable a small library of new aryl ether benzovesamicol derivatives to be rapidly prepared from the phenol 113 and a range of alcohols. Suitable protection of the chiral secondary alcohol in 113 would be required to avoid potential undesired Mitsunobu reaction at this site. If reagents such as DBAD and/or one of the basic phosphines were employed then a protecting group that is labile under the acidic workup conditions, e.g. tert-butyl ester, would be highly desirable to avoid additional steps in the synthetic sequence. Alizadeh [59] reported that triphenylphosphine reacts with DIAD under anhydrous conditions and in the presence of isocyanates or isothiocyanates 118 to give 1,2,4-triazole derivatives 119 (Fig. 38). Compounds containing the 1,2,4triazole motif have been shown to possess interesting biological properties. Zapf and co-workers [60] synthesized two novel heterocyclic scaffolds with utility in peptidomimetic drug design, specifically targeting somatostatin subtype receptors. The key step involved an intramolecular Mitsunobu alkylation between a primary alcohol and a nosyl-protected secondary amine. Fukuyama had previously reported that 2-nitro-

X

O O O

anhydrous CH2Cl2

N N

O

N

+

C

X

R

O

O

N

N

N PPh3, RT

118

O 119

R = Ph R = m-MeC6H4

X=O X=O

98% 98%

R = PhCH2 R = n-Bu

X=O X=O

80% 70%

R = Ph R = Me

X=S X=S

90% 77%

Fig. (38). Synthesis of isocyanates and isothiocyanates under Mitsunobu reaction conditions.

R


OH

O NosylHN


NosylHN

N

N

DIAD, PPh3

NosylHN

N

Boc2O, DMAP O

HN

O MeCN

THF NH

120

NBoc

121

122 PhSH, DBU, DMF 41% over 3 steps

N

HN

N

N

O

O

NH

NBoc

H2N

125

123

O N

N O

H2N NH 124

Fig. (39). Synthesis of novel heterocyclic scaffolds using the intramolecular Mitsunobu reaction.

O

O N

N

HN

O

N

N O

PivHN

N O

H2N

H2N NH

epi-125

Fig. (40). Novel compounds targeting somastatin subtype receptors.

NBoc

epi-123

NH

126



OH

O NosylHN

NosylHN

N

N

NosylHN

DIAD, PPh3

N

Boc2O, DMAP O

HN

O

THF

MeCN NH

127

NBoc

128

129 PhSH, DBU, DMF 33% over 3 steps

O N

N

HN

N

O

O

NH

NBoc

H2N

130

131

Fig. (41). Synthesis of novel heterocyclic scaffolds using the intramolecular Mitsunobu reaction. R2

O S

R1

N H

R3

1. PPh3, DIAD THF

O

H N O

HN

+

DdzHN

TETHER

OH

H N

S 2. TFA, Et3SiH CH2Cl2

133

Bts

R2

O

CF3CO2

O R1

N H

R3

O

H3N

TETHER

N

Bts

134

132

1. Ag(OCOCF3), iPr2NEt, THF, MP-carbonate 2. PS-thiophenol, KOTMS THF-EtOH 3. THF, Et3SiH, CH2Cl2 R2 O O Bts =

N

S

Ddz =

OMe

O

R3 NH

HN

R1

O HN

S

O

O

O

OMe

TETHER

NH

135

Fig. (42). Solid-phase synthesis of macrocyclic peptidomimetic compounds 135. O O

F

H

DIAD, PPh3

O

S

S

Ph

Ph

O

+

R

OH benzene, RT

136

O O

F

R S

Ph

Ph 137

activated Mg

O

S

O MeOH, 0 °C

F

R H

H 138

Fig. (43). Monofluorination of alcohols using the Mitsunobu reaction.

benzene at room temperature (Fig. 43). The authors showed that the reaction proceeds with complete inversion of configuration with a range of simple secondary alcohols. Fluori-

nated compounds are of great interest and utility to medicinal chemists and hence this mild and selective route is particularly attractive.


O O

F

H


DIAD, PPh3

O

S

S

Ph

Ph

+

O

benzene, RT 58%

H

H

136 CH2

CH2 F

HO 139

R

R

140, R = SO2Ph

Mg, MeOH 0 °C, 67%

141, R = H

Fig. (44). Monofluorination of vitamin D3. OH O O

F

H

AcO

O

S

S

Ph

Ph

CF(SO2Ph)2

O

DIAD, PPh3

AcO

benzene, RT

AcO

O

+

O

AcO

OAc

OAc

OAc

136

OAc

142

143

Fig. (45). Monofluorination of 1,2,3,4-tetra-O-acteyl--D-glucopyranose (142). DTAD, PS-PPh3 R

OH

+ S 144

O

CH2Cl2 -10 °C to RT

R O

S 145

R

N

N 78%

N

49%

O

N OiPr

51%

N O

OiPr

O OiPr

N

66%

O

CH3

N 66%

94% O N

69%

Fig. (46). Method A: 2(5H)-thiophenone (144) added to a suspension of PS-TPP-O-R.

Using this methodology vitamin D3 (139) was converted to the corresponding monofluoromethylated derivative 141 (Fig. 44) following reductive desulfonation in the presence of activated magnesium in methanol at 0 °C. The authors also demonstrated the synthetic utility of this methodology by preparing the monofluoromethyl adduct 143 of 1,2,3,4-tetra-O-acteyl--D-glucopyranose (142) (Fig. 45). Harris and co-workers [64] successfully used the Mitsunobu alkylation reaction to access a range of functionally di-

verse thiophene ethers 145 at C-2 from 2(5H)-thiophenone (144) (Figs. 46 and 47) after the existing Ullman-style methodology and classical alkylation conditions returned primarily eliminated by-products. Two general methods for the Mitsunobu alkylation were developed depending on the alcohol but in both cases it was essential that the DTAD was completely consumed in the formation of the intermediate betaine prior to addition of the thiophenone or else electrophilic substitution at C-3 was observed.



DTAD, PS-PPh3 R

OH

+

O

S

CH2Cl2 -10 °C to RT

144

R S

O

145

R

N N 64% MeO2C

N H 58%

53% O

N

OiPr

49%

83%

41%

Fig. (47). Method B: solution of 2(5H)-thiophenone (144) and alcohol added to a stirred solution of betaine. OH

Cl

N H

OH

DIAD, PPh3

OH

MeCN, 92%

H

OH

H2, PtO2.H2O OH

N

93%, 95% de

Cl

Cl

OH 146

147

OH

NH

148

KOH, 95%

H

N

OH OH

1-epi-lentiginosine (149)

Fig. (48) Synthesis of 1-epi-lentiginosine (149).

Bischoff et al. [65] reported a concise route to the biologically relevant indolizidine alkaloids, (-)-lentiginosine (150) and its epimers, 1-epi-lentiginosine (149), (Fig. 48) and 8aepi-lentiginosine (151), (Fig. 49). The key step in the synthesis involves the intramolecular cyclisation of a pyridiniumpolyol 146 under Mitsunobu conditions to furnish a dihydroxylated bicyclic pyridinium salt 147 (Fig. 48) which could be isolated free of the usual Mitsunobu reaction byproducts by simple extraction into water. H

N

OH

H OH

(-)-lentiginosine (150)

N

OH OH

8a-epi-lentiginosine (151)

Fig. (49). Indolizine alkaloids, (-)-lentiginosine (150) and 8a-epilentiginosine (151).

This Mitsunobu methodology may also be applicable to the synthesis of other biologically active azabicyclic alkaloids such as swainsonine and castanospermine. Montero and co-workers [66] reported an efficient stereoselective synthesis of L-imino-C-gulosides. Such aza-Cglycosides have been shown to be powerful and selective inhibitors of many glycosidases. In this case the authors utilised an intramolecular Mitsunobu reaction to effect ring closure with complete inversion of configuration. Thus, it is possible to access an L-iminosugar precursor 154 from an abundant D-sugar starting material 152 (Fig. 50). Some arylglycines are known to selectively modulate the activity of metabotronic glutamate receptors (mGluRs), and have been used to develop new drugs for neurodegenerative disease. Villalgordo et al. [67] synthesized a range of pyrimidinyl arylglycines 159 via a strategy employing Mitsunobu and Petasis reactions (Fig. 51). Selective O-alkylation of 2-(alkylsulfanyl)-4(3H)-pyrimidinones 155 with various


O


HO

O

O

O

O O

O

O

O

DEAD, PPh3

O

PhMe

O

NHR

O

O

N R

OH CN

CN

153

152

154 R = Bn, Bu, allyl

Fig. (50). Synthesis of L-iminosugar precursor 154 via an intramolecular Mitsunobu reaction. Boc O

O DIAD, PPh3

HN Bn

S

N

N

R1

THF, RT, 1-5 h

R2

N Bn

S

N

155

R3

H N

O TFA, CH2Cl2 (1:1)

R1

0 °C to RT 30 min to 1 h

N Bn

S

R1

N

156

R3

R2

157 O O OH PhB(OH)2 O

HO

Boc

Boc

NH

NH

HO

Boc HO

N

Me

Ph N

HO

N

Bn

S

R3

R2

N

Boc

N

Ph

Me

R1

159

N

O MeI, Cs2CO3 DMF RT, 1 h

S

R3

R2

N Bn

CO2H

N

R1

158

Fig. (51). Synthesis of pyrimidinyl arylglycines 159 via Mitsunobu and Petasis reactions.

primary and secondary N-Boc--aminoalcohols occurred under Mitsunobu conditions to afford 4-alkoxypyrimidines 156 in good yields. 5. CONCLUSIONS Numerous workup strategies and new, or modified, reagents have been developed to simply the purification or scope of the Mitsunobu reaction. The use of polymersupported phosphines and azodicarboxylates greatly simplifies the isolation of pure products since the by-products and any excess reagent can be removed by filtration at the end of the reaction. Less desirable is the fact that polymersupported triphenylphosphine cannot be employed simultaneously with polymer-supported azodicarboxylate due to lack of reactivity in solution-phase reactions. Soluble oligomeric reagents overcome this limitation to a certain extent but still rely on precipitation in non-polar organic solvents prior to filtration at the end of the reaction. With small, polar target molecules this can present problems with co-

precipitation. By far the most attractive modification to the Mitsunobu reaction, at least from a combinatorial or parallel medicinal chemistry perspective, is the use of fluoroustagged phosphine and azodicarboxylate. Both reagents and their by-products can be isolated by phase or affinity separation using fluorous media and both techniques are highly amenable to automation. Other modifications have focused on phase-switchable reagents, and by extension their byproducts, following one or more additional chemical reactions. The applicability of this is very much determined by the functional groups present in the target molecule. For example, targets containing one or more basic nitrogen atoms are not compatible with the acidic conditions required to decompose DBAD or to protonate basic phosphines such as DAP-DP and PyPPh2. Similarly, reagents with functionalised tags designed to be sequestered impose restrictions on the type of functional groups present in the target molecule. Compounds containing a suitable diene may react in the presence of polymer-bound maleimide designed to sequester anthracene-tagged reagents for example.


Most of the examples of the Mitsunobu reaction within medicinal chemistry tend to be for the synthesis of libraries of simple molecules containing aryl ethers. This is in contrast to traditional organic synthesis of natural products and their derivatives where the Mitsunobu reaction is commonly used to form macrolactones between a carboxylic acid functional group and a secondary alcohol with inversion of configuration. It is also common for the Mitsunobu reaction to be used to form esters of secondary or tertiary alcohols with complete inversion of configuration and subsequent hydrolysis. No doubt as techniques for the rapid purification and isolation of Mitsunobu products are refined we will see a wider adoption of these strategies by medicinal chemists to construct libraries of biologically active compounds with varying degrees of automation and concomitant gains in efficiency. REFERENCES [1]

[2]

[3]

[4] [5] [6] [7]

[8]

[9]

[10] [11] [12] [13]

[14] [15]

[16]

Von Itzstein, M.; Jenkins, I. D. The mechanism of the Mitsunobu reaction. II. Dialkoxytriphenylphosphoranes. Aust. J. Chem., 1983, 36, 557-563. Grochowski, E.; Hilton, B. D.; Kupper, R. J.; Michejda, C. J. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates. J. Am. Chem. Soc., 1982, 104, 6876-6877. Adam, W.; Narita, N.; Nishizawa, Y. On the mechanism of the triphenylphosphine-azodicarboxylate (Mitsunobu reaction) esterification. J. Am. Chem. Soc., 1984, 106(6), 1843-1845. Varasi, M.; Walker, K. A.; Maddox, M. L. A revised mechanism for the Mitsunobu reaction. J. Org. Chem., 1987, 52, 4235-4238. Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J., A mechanistic study of the Mitsunobu esterification reaction. J. Am. Chem. Soc., 1988, 110, 6487-6491. Ahn, C.; Correia, R.; DeShong, P. Mechanistic study of the Mitsunobu reaction. J. Org. Chem., 2002, 67(6), 1751-1753. Kumar, N. S.; Kumar, K. P.; Kumar, K. V. P. P.; Kommana, P.; Vittal, J. J.; Swamy, K. C. K. Diverse modes of reactivity of dialkyl zzodicarboxylates with P(III) compounds: Synthesis, structure, and reactivity of products other than the Morrison-Brunn-Huisgen intermediate in a Mitsunobu-type reaction. J. Org. Chem., 2004, 69(6), 1880-1889. Schenk, S.; Weston, J.; Anders, E., Density functional investigation of the Mitsunobu reaction. J. Am. Chem. Soc., 2005, 127(36), 12566-12576. Swamy, K. C. K.; Kumar, K. P.; Kumar, N. N. B. Further characterization of Mitsunobu-type intermediates in the reaction of dialkyl azodicarboxylates with P(III) compounds. J. Org. Chem., 2006, 71(3), 1002-1008. Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis, 1981, 1-28. Hughes, D. L. The Mitsunobu reaction. Org. React., 1992, 42, 335656. Hughes, D. L. Progress in the Mitsunobu reaction. A review. Org. Prep. Proced. Int., 1996, 28, 127-164. Dodge, J. A.; Jones, S. A. Advances in the Mitsunobu reaction for the stereochemical inversion of hindered secondary alcohols. Recent Res. Dev. Org. Chem., 1997, 1, 273-283. Dandapani, S.; Curran, D. P. Separation-friendly Mitsunobu reactions: A microcosm of recent developments in separation strategies. Chem. Eur. J., 2004, 10, 3130-3138. Dembinski, R. Recent advances in the Mitsunobu reaction: Modified reagents and the quest for chromatography-free separation. Eur. J. Org. Chem., 2004, 2763-2772. But, T. Y. S.; Toy, P. H. The Mitsunobu reaction: Origin, mechanism, improvements, and applications. Chem. Asian J., 2007, 2, 1340-1355.

Current Organic Chemistry, 2009, Vol. 13, No. 16 1631 [17]

[18] [19]

[20]

[21] [22]

[23] [24]

[25]

[26] [27]

[28]

[29] [30]

[31]

[32] [33] [34]

[35] [36] [37]

[38] [39]

[40] [41]

Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Mitsunobu and related reactions: Advances and applications. Chem. Rev., 2009, 109(6), 2551-2651. Amos, R. A.; Emblidge, R. W.; Havens, N. Esterification using a polymer-supported phosphine reagent. J. Org. Chem., 1983, 48(20), 3598-600. Tunoori, A. R.; Dutta, D.; Georg, G. I. Polymer-bound triphenylphosphine as traceless reagent for Mitsunobu reactions in combinatorial chemistry: Synthesis of aryl ethers from phenols and alcohols. Tetrahedron Lett., 1998, 39, 8751-8754. Valeur, E.; Roche, D. Efficient, mild, parallel, and purification-free synthesis of aryl ethers via the Mitsunobu reaction. Tetrahedron Lett., 2008, 49, 4182-4185. Wang, Y.; Jiang, H.; Liu, H.; Liu, P. Polymeric tertiaryphosphine as a green and recyclable organocatalyst for stereoselective isomerization reaction. Tetrahedron Lett., 2005, 46(22), 3935-3937. Arnold, L. D.; Assil, H. I.; Vederas, J. C. Polymer-supported alkyl azodicarboxylates for Mitsunobu reactions. J. Am. Chem. Soc., 1989, 111, 3973-3976. Harned, A. M.; Song He, H.; Toy, P. H.; Flynn, D. L.; Hanson, P. R., Multipolymer solution-phase reactions: Application to the Mitsunobu reaction. J. Am. Chem. Soc., 2005, 127, 52-53. Åarstad, E.; Barrett, A. G. M.; Hopkins, B. T.; Koebberling, J., ROMPgel-supported triphenylphosphine with potential application in parallel synthesis. Org. Lett., 2002, 4(11), 1975-1977. Wentworth, P. Jr.; Vandersteen, A. M.; Janda, K. D. Poly(ethylene glycol) (PEG) as a reagent support: The preparation and utility of a PEG-triarylphosphine conjugate in liquid-phase organic synthesis (LPOS). Chem. Commun. (Cambridge), 1997, 8, 759-760. Charette, A. B.; Janes, M. K.; Boezio, A. A. Mitsunobu reaction using triphenylphosphine linked to non-cross-linked polystyrene. J. Org. Chem., 2001, 66(6), 2178-2180. Poupon, J.-C.; Boezio, A. A.; Charette, A. B. Tetraarylphosphonium salts as solubility-control groups: Phosphonium-supported triphenylphosphine and azodicarboxylate reagents. Angew. Chem., Int. Ed., 2006, 45(9), 1415-1420. Charette, A.; Poupon, J.-C.; Boezio, A. Phosphonium salts derivatives and their use as solubility controlling auxiliaries. WO 2005097812, Oct 20, 2005. Camp, D.; Jenkins, I. D. The use of a phosphine containing a basic group in the Mitsunobu esterification reaction. Aust. J. Chem., 1988, 41, 1835-1839. Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P. Diphenyl 2-pyridylphosphine and di-tert-butyl azodicarboxylate: Convenient reagents for the Mitsunobu reaction. Tetrahedron Lett., 1999, 40, 4497-4500. Fleckenstein, C. A.; Plenio, H. Redox-switchable phase tags - Facile Mitsunobu reactions using ferrocenyl-tagged triphenylphosphine. Adv. Synth. Catal., 2006, 348, 1058-1062. Jackson, T.; Routledge, A. Synthesis and application of crown ether tagged triarylphosphines. Tetrahedron Lett., 2003, 44, 13051307. Dandapani, S.; Curran, D. P. Fluorous Mitsunobu reagents and reactions. Tetrahedron, 2002, 58, 3855-3864. Dobbs, A. P.; McGregor-Johnson, C. Synthesis of fluorous azodicarboxylates: Towards cleaner Mitsunobu reactions. Tetrahedron Lett., 2002, 43, 2807-2810. Zhang, W. Fluorous technologies for solution-phase highthroughput organic synthesis. Tetrahedron, 2003, 59, 4475-4489. Chaturvedi, S. Solid phase synthesis of compounds by carboncarbon bond-forming Mitsunobu reactions. WO 2000010942, March 2, 2000. Pelletier, J. C.; Kincaid, S. Mitsunobu reaction modifications allowing product isolation without chromatography: Application to a small parallel library. Tetrahedron Lett., 2000, 41, 797-800. Starkey, G. W.; Parlow, J. J.; Flynn, D. L. Chemically tagged Mitsunobu reagents for use in solution-phase chemical library synthesis. Bioorg. Med. Chem. Lett., 1998, 8, 2385-2390. Yoakim, C.; Giluse, I.; O'Meara, J. A.; Thavonekham, B. Removable phosphine reagents for the Mitsunobu reaction. Synlett, 2003, 473-476. Barrett, A. G. M.; Roberts, R. S.; Schröder, J. Impurity annihilation: chromatography-free parallel Mitsunobu reactions. Org. Lett., 2000, 2(19), 2999-3001. Lan, P.; Porco Jr, J. A.; South, M. S.; Parlow, J. J. The Development of a Chromatography-Free Mitsunobu Reaction: Synthesis


[42]

[43]

[44] [45]

[46] [47] [48]

[49]

[50] [51]

[52]

[53]

[54]

[55]


and Applications of an Anthracene-Tagged Phosphine Reagent. J. Comb. Chem., 2003, 5, 660-669. O'Neil, I. A.; Thompson, S.; Murray, C. L.; Kalindjian, S. B. DPPE: A convenient replacement for triphenylphosphine in the Staudinger and Mitsunobu reactions. Tetrahedron Lett., 1998, 39, 7787-7790. Dandapani, S.; Newsome, J. J.; Curran, D. P. Separation tagging with cyclodextrin-binding groups: Mitsunobu reactions with bis(2(1-adamantyl)ethyl) azodicarboxylate (BadEAD) and bis(1adamantylmethyl) azodicarboxylate (BadMAD). Tetrahedron Lett., 2004, 45, 6653-6656. Humphries, P. S.; Do, Q.-Q. T.; Wilhite, D. M. ADDP and PSPPh3: An efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists. Beilstein J. Org. Chem., 2006, 2, (21). Véliz, E. A.; Beal, P. A. Mitsunobu reactions of nucleoside analogs using tri-isopropyl phosphite-DIAD. Tetrahedron Lett., 2006, 47, 3153-3156. Proctor, A. J.; Beautement, K.; Clough, J. M.; Knight, D. W.; Li, Y. Chromatography-free product separation in the Mitsunobu reaction. Tetrahedron Lett., 2006, 47, 5151-5154. But, T. Y. S.; Toy, P. H. Organocatalytic Mitsunobu reactions. J. Am. Chem. Soc., 2006, 128, 9636-9637. Taft, B. R.; Swift, E. C.; Lipshutz, B. H. A convenient preparation of di-p-chlorobenzyl azodicarboxylate (DCAD) for Mitsunobu couplings. Synthesis, 2009, 2, 332-334. Abreo, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.; Hettinger, A.-M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y. C.; DonnellyRoberts, D. L.; J., A. D.; Sullivan, J. P.; Williams, M.; Arneric, S. P.; Holladay, M. W. Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors. J. Med. Chem., 1996, 39(4), 817-825. Park, A.-Y.; Moon Hyung, R.; Kim Kyung, R.; Chun Moon, W.; Jeong Lak, S. Synthesis of novel L-N-MCd4T as a potent anti-HIV agent. Org. Biomol. Chem., 2006, 4(22), 4065-7. Gentles, R. G.; Wodka, D.; Park, D. C.; Vasudevan, A. Standardization protocols and optimized precursor sets for the efficient application of automated parallel synthesis to lead optimization: A Mitsunobu example. J. Comb. Chem., 2002, 4, 442-456. Winiewski, K.; Trojnar, J.; Riviere, P.; Haigh, R.; Yea, C.; Ashworth, D.; Melin, P.; Nilsson, A. The synthesis of a new class of oxytocin antagonists. Bioorg. Med. Chem. Lett., 1999, 9(19), 28012804. Damont, A.; Hinnen, F.; Kuhnast, B.; Schollhorn-Peyronneau, M.A.; James, M.; Luus, C.; Tavitian, B.; Kassiou, M.; Dollé, F. Radiosynthesis of [18F]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET. J. Label. Compd. Radiopharm., 2008, 51(7), 286-292. James, M. L.; Fulton, R. R.; Vercoullie, J.; Henderson, D. J.; Garreau, L.; Chalon, S.; Dollé, F.; Selleri, S.; Guilloteau, D.; Kassiou, M. DPA-714, a new translocator protein-specific ligand: Synthesis, radiofluorination, and pharmacologic characterization. J. Nucl. Med., 2008, 49(5), 814-822. Chauveau, F.; Van Camp, N.; Dollé, F.; Kuhnast, B.; Hinnen, F.; Damont, A.; Boutin, H.; James, M.; Kassiou, M.; Tavitian, B. Comparative evaluation of the translocator protein radioligands

Received: 06 April, 2009

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64]

[65] [66]

[67]

Revised: 24 July, 2009

11 C-DPA-713, 18 F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J. Nucl. Med., 2009, 50(3), 468-476. Zea-Ponce, Y.; Mavel, S.; Assaad, T.; Kruse, S. E.; Parsons, S. M.; Emond, P.; Chalon, S.; Giboureau, N.; Kassiou, M.; Guilloteau, D. Synthesis and in vitro evaluation of new benzovesamicol analogs as potential imaging probes for the vesicular acetylcholine transporter. Bioorg. Med. Chem., 2005, 13(3), 745-753. Emond, P.; Mavel, S.; Zea-Ponce, Y.; Kassiou, M.; Garreau, L.; Bodard, S.; Drossard, M.-L.; Chalon, S.; Guilloteau, D. (E)-[125I]-5AOIBV: A SPECT radioligand for the vesicular acetylcholine transporter. Nucl. Med. Biol., 2007, 34(8), 967-971. Giboureau, N.; Emond, P.; Fulton, R. R.; Henderson, D. J.; Chalon, S.; Garreau, L.; Roselt, P.; Eberi, S.; Mavel, S.; Bodard, S.; Fulham, M. J.; Guilloteau, D.; Kassiou, M. Ex vivo and in vivo evaluation of (2R,3R)-5-[18F]-fluoroethoxy- and fluoropropoxybenzovesamicol, as PET radioligands for the vesicular acetylcholine transporter. Synapse, 2007, 61(12), 962-970. Alizadeh, A., Synthesis of some new 1,2,4-triazole derivatives by Mitsunobu chemistry. Helv. Chim. Acta., 2005, 88(10), 2777-2780. Zapf, C. W.; Del Valle, J. R.; Goodman, M. Utilizing the intramolecular Fukuyama-Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design. Bioorg. Med. Chem. Lett., 2005, 15 (18), 4033-4036. Fukuyama, T.; Jow, C.-K.; Cheung, M. 2- and 4Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines. Tetrahedron Lett., 1995, 36(36), 6373-6374. Marsault, E.; Hoveyda, H. R.; Gagnon, R.; Peterson, M. L.; Vezina, M.; Saint-Louis, C.; Landry, A.; Pinault, J.-F.; Ouellet, L.; Beauchemin, S.; Beaubien, S.; Mathieu, A.; Benakli, K.; Wang, Z.; Brassard, M.; Lonergan, D.; Bilodeau, F.; Ramaseshan, M.; Fortin, N.; Lan, R.; Li, S.; Galaud, F.; Plourde, V.; Champagne, M.; Doucet, A.; Bherer, P.; Gauthier, M.; Olsen, G.; Villeneuve, G.; Bhat, S.; Foucher, L.; Fortin, D.; Peng, X.; Bernard, S.; Drouin, A.; Deziel, R.; Berthiaume, G.; Dory, Y. L.; Fraser, G. L.; Deslongchamps, P. Efficient parallel synthesis of macrocyclic peptidomimetics. Bioorg. Med. Chem. Lett., 2008, 18(16), 4731-4735. Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Stereoselective monofluoromethylation of primary and secondary alcohols by using a fluorocarbon nucleophile in a Mitsunobu reaction. Angew. Chem., Int. Ed. 2007, 46(26), 49334936. Harris, C. S.; Germain, H.; Pasquet, G. Facile preparation of thiophene C2-ethers using the Mitsunobu reaction. Tetrahedron Lett., 2008, 49(41), 5946-5949. Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. A concise synthesis of lentiginosine derivatives using a pyridinium formation via the Mitsunobu reaction. J. Org. Chem., 2008, 73(3), 1154-1157. Bussière, A.; Barragan-Montero, V.; Oumzil, K.; Winum, J.-Y.; Montero, J.-L. Expeditious stereoselective synthesis of Liminosugar precursors via a Mitsunobu reaction. Synlett, 2009, 6, 978-980. Font, D.; Heras, M.; Villalgordo, J. M. Synthesis of pyrimidinyl arylglycines through subsequent Mitsunobu and Petasis reactions. Tetrahedron, 2008, 64(22), 5226-5235.

Accepted: 27 July, 2009