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ScienceDirect Procedia Chemistry 13 (2014) 3 – 12

International Seminar on Natural Product Medicines, ISNPM 2012

Development of Palladium-Catalyzed Cycloalkenylation and Its Application to Bioactive Natural Product Synthesis Masahiro Toyora* Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan

Abstract Stereoselective total syntheses of (±)-aphidicolin and ()-serofendic acids A and B have been achieved by means of palladiumcatalyzedcycloalkenylation. © Published by Elsevier B.V. B.V. This is an open access article under the CC BY-NC-ND license ©2014 2014The TheAuthors. Authors. Published by Elsevier (http://creativecommons.org/licenses/by-nc-nd/3.0/). Peer-review under responsibility of the School of Pharmacy, Bandung Institute of Technology. Peer-review under responsibility of the School of Pharmacy, Bandung Institute of Technology Keywords:Palladium acetate; Catalytic reaction; Oxidative Cyclization; bicyclic compounds; Bioactive natural products

1. Introduction Among catalytic carboncarbon bond formation reactions1,2, the palladium-catalyzed cycloalkenylation (1 ĺ 2) developed by us is one of the most efficient protocols for the synthesis highly functionalized natural products (Fig. 1.)3–8.One of the characteristics of the catalytic reaction is that functionalizedbicyclo[3.2.1]octanes are easily produced in high yield. Additionally, bicyclo[2.2.2]octanes can be efficiently constructed from the corresponding bicycle[3.2.1]octanes using homoallylhomoallyl radical rearrangement process discovered by us. Therefore, the palladium-catalyzed cycloalkenylation has been successfully adapted for the syntheses of polycyclic natural products, such as ()-methyl atis-16-en-19-oate (3), ()-kaur-16-en-19-oate (4), ()-methyl trachyloban-19-oate (5), and C20 gibberellins (68) as shown in Fig. 2.

* Corresponding author. Tel.: +81-72-254-9164, fax: +81-72-254-9164. E-mail address:[email protected]

1876-6196 © 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Peer-review under responsibility of the School of Pharmacy, Bandung Institute of Technology doi:10.1016/j.proche.2014.12.002

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Masahiro Toyora / Procedia Chemistry 13 (2014) 3 – 12

R3SiO

n

R1

Pd(OAc)2 (cat.)

1

O2 (1 atm) DMSO (n=0, 1)

R2

O

R1

n

R2 2

Fig.1. Palladium – catalyzed cycloalkenylation of silylenol ethers.

H MeO2C

H

H MeO2C

methyl atis-16-en19-oate (3)

H

methyl kaur-16-en19-oate (4) H

R1 R2

H MeO2C

H

methyl trachyloban19-oate (5)

CO2Me

MeO2C 1

GA12: R =H, R2=H (6) GA111: R1=OH, R2=H (7) GA112: R1=H, R2=OH (8)

Fig. 2. Structures of diterpenoids

The search for improvement of the palladium-catalyzed cycloalkenylation has been continued, with the goal of increasing the diversity of possible substrates and reaction products. In this review we report some notable results of the above catalytic reaction. Nomenclature NMR Nuclear Magnetic Resonance COSY Correlation Spectroscopy NOESY Nuclear OverhauserEffect Spectroscopy TPAP Tetrapropylammoniumperruthenate THF Tetrahydrofuran 2. Formal Total Synthesis of Aphidicolin Aphidicolin (9) is a tetracyclic diterpenoid that exhibits significant antiviral and antitumor activity9,10. Since its isolation and the demonstration of its potential pharmacological uses, numerous synthetic approaches to aphidicolin (9) have been developed11–15. The synthetic analysis of aphidicolin (9) was shown in Fig. 3. We anticipated that intramolecular Diels-Alder reaction of triene11 would proceedstereoselectively to construct the pentacyclic ring system in 10, a potential precursor of aphidicolin (9). We believed that steoselective introduction of the diene and dienophile parts in 11 and the oxirane group in 12 would be achieved by exploiting the characteristics of the bicycle[3.2.1]octane ring unit. Finally, intermediate 13 would be synthesized by employing palladium-catalyzed cycloalkenylation of the cross conjugated silylenol ether 14.

5

Masahiro Toyora / Procedia Chemistry 13 (2014) 3 – 12 Me

Me Me

HO

O

H Me

HO H HO

Me

O

O O

H Me

H Me

H

Me

R1O

OH

R1 O

Me

Me

10

11

aphidicolin (9)

OTBS

O

O

2

RO 13

14

OR2

12

OR2

Fig. 3. Retrosynthetic analysis of aphidicolin

Our challenge started with the preparation of bicyclic compound 19 by the route depicted in Figure 4. Carbomethoxylation of 15 gave the corresponding ester, which was subjected to sequential reduction, acid treatment, and etherification. After transformation of the resulting enone16 into the corresponding cross conjugated silylenol ether, cycloalkenylation is performed using 5 mol % Pd(OAc)2 to produce the desired compound 17 in 89% yield. Selective reduction of 17 was then achieved by using L-Selectride. To introduce the oxirane moiety stereoselectively, we used the CoreyChaykovsky method. The desired stereoisomer 18 was obtained as the major product and was easily separated from the minor isomer by silica gel column chromatography. The proton and carbon resonances in the NMR spectra of 18 were assigned by using 1H1H COSY and 1H13C COSY techniques. The relative stereochemistry of 18 was established by employing NOESY correlations between the olefinic and methylene protons as shown in Fig. 5. Basic treatment of 18 followed by protection of the resulting diol afforded the acetonide 19. OiBu

O

15

O

(1) LDA; MeO2CCN (93%) (2) LiAlH4; 10% HClO4; MOMCl, iPr2NEt (76%)

(1) LDA; TBSCl (91%)

MOMO

O

(2) Pd(OAc)2 (5 mol %) (89%)

16

Me

(1) L–Selectride (93%)

O

(1) aq. KOH

(2) Me2S(O)CH2 (89%)

OMOM

18

Fig. 4. Stereoselective preparation of bicyclo[3.2.2]octane 19. NOE H

H H O

MOMO 18

Fig. 5. Significant NOESY correlation in 18.

H

(2) acetone PPTS (91% for 2 steps)

Me

O O 19

OMOM

17

OMOM

6


Triene 26, required for the intramolecular DielsAlder reaction, was prepared as shown in Fig. 6. Allylation of the ketone, resulting from ozonolysis of olefin 19, gave rise to 20 as a single diastereoisomer. Compound 20 was stereoselectively converted to Į-alcohol 21 by hydroboration oxidation, followed by protection and hydride reduction. Alcohol 22 was synthesized from 21 by thioimidazolide formation, syn-elimination, deprotection, and hydrogenation. The hydrogenation occurred preferentially from the convex face of the corresponding olefin. Sequential benzylation of alcohol 22, acid treatment, and reprotection of the partially generated 1,2-diol furnished alcohol 23. Formation of the dienophile moiety is achieved by successive functional group manipulations of 23. Accordingly, Parikh oxidation of 23 followed by methyllithium addition and TPAP oxidation provides methyl ketone 24, which is converted to 25 by Wittig olefination, reductive debenzylation and oxidation. Emmons olefination of 25 followed by silylenol ether formation gave triene 26. Intramolecular Diels-Alder reaction of 26, conducted in toluene at 230 °C in a stainless steel autoclave, yields the desired cycloadduct 27 (75%) as a single stereoisomer. Me Me

Me

(1) O3; Me2S (96%)

O O OMOM

19

Me

(1)

O O

(2) LDA;

(86% for 3 steps)

Me

°

(2) 250 C OTBS

MOMO

O

22

Me

OBn

23

H O

(49% for 3 steps)

24

Me Me

(53% for 2 steps)

(1) Ph3P=CH2 (85%)

(3) TPAP, NMO 4A MS

HO

OH

O O

(2) MeLi

H

(3) acetone, TsOH

Me

(1) SO3 Py, DMSO, Et3N

O

(2) 10% HClO4

MOMO

(74% for 4 steps)

Me Me

H

(3) Bu4NF (4) H2, PtO2

21

(1) BnBr, NaH (77%)

O O

O OH

(3) NaBH4

Me

(1) (imid)2C=S O

OMOM

20

(92%)

Me

(2) Li, liq. NH3 (3) SO3 Py, DMSO, Et3N (83% for 2 steps)

OBn

Me O

O

H Me

Me

(1) (EtO)2P(O)CH(Me)COMe NaH (95%)

O O

H Me

(2) TBSOTf, iPr2NEt (93%)

OHC Me 26 Me O

O O

O

H Me

Me

H

H

TBSO

Me

TBSO

27 single stereoisomer !

Fig. 6. Stereoselective construction of tetracyclic compound 27.

Me

H 27

Me Me

230 °C stainless autoclave (75%)

TBSO

25

Me

BH; HOO

(2) TBSCl, imidazole

I

Me

2

O

7


The high degree of stereoselectivity observed in the intramolecularDiels-Alder reaction of 26is attributed to the strong conformational bias favoring transition state 26A, in which 1,3-allylic strain between the olefinichydrogen of the isopropenyl group and a ring proton is minimized, and theabsence of a nonbonded interaction between the equatorialhydrogen and the methyl group on the diene portion that is present in transition state26B (Fig. 7.).

Me

H

Me

H

Me

TBSO R

R

R

26A

Me

TBSO

H

R

26B

favored ( R=acetonide )

Fig. 7. Plausible conformations for intramolecular Diels – Alder reactions.

Finally, the requisite C-4 hydroxymethyl group is introduced by reaction with formaldehyde in the presence of anhydrous tetrabutylammonium fluoride in THF. The NMR spectroscopic data of 28, the key synthetic intermediate formed in this process, were identical to those previously reported (Fig. 8.)16. In conclusion, a novel and improved diastereoselective formal total synthesis of aphidicolin has been achieved by exploiting the characteristics of a bicyclo[3.2.1]octane ring system that was poduced by employment of a palladiumcatalyzed cycloalkenylation process. In this sequence, highly diastereoselectiveoxirane formation was employed to install C-16 functionality. The strategy used in this aphidicolin synthesis, relying on the combined use of palladiumcatalyzed cycloalkenylation and intramolecular Diels-Alder reactions for diastereoselective polycyclic ring system formation, should be broadly applicable to the preparation of targets with related structural features. Me

Me Me

O O

H Me H

TBSO

Me

Bu4NF (anhydrous) then CH2O (gas)

Me

O

HO H Me

O H O

(44%)

27

Me OH

28

Ireland

H Me

HO H HO

Me OH

aphidicolin (9)

Fig. 8. Formal total synthesis of (±)-aphidicolin (9).

3. Total Synthesis of SerofendicAcids A and B Serofendic acids A (29a) and B (29b) are neuroprotective agents that were isolated from fetal calf serum in 2002 by Akaike, Sugimoto, and co-workers17 The unique structures of 29a and 29b, determined by NMR analysis, were shown to consist of bicyclo[2.2.2]octane ring systems bearing an unusual sulfoxide side chain (Fig. 9.). The serofendic acids are attractive targets for total synthesis, not only due to their neuroprotective activity, but also because of the challenge of their structures, which feature nine stereocenters and an atisane framework. Prior to this report, the Eisai group’s syntheses of 29a and 29b, starting from (-)-isosteviol, stood as the only published synthetic work in this field. In a prior report, we demonstrated the utility of the homoallyl-homoallyl radical rearrangement for construction of the bicyclo[2.2.2]octane ring system, the CD ring part of methyl atisirenoate30. In an effort to further expand the utility of this rearrangement, we have focused on the development of tin-free conditions for promoting this useful reaction. In this part, we describe the total syntheses of the serofendic acids (29), wherein the key step involves the successful implementation of a tin-free homoallyl-homoallyl radical rearrangement for construction of the bicyclo[2.2.2]octane ring system.

8


S H HO2C

S

O

OH

H

H

HO2C

Serofendic Acid A (29a)

O

OH

H

Serofendic Acid B (29b)

Fig. 9. Structures of serofendic acids A (29a) and B (29b).

S H HO2C

O

OH

H

H

H

MeO2C

(_)-serofendic acids (29)

H

CO2Me

(_)-methyl arisirenoate (30)

31

O

H PivO 32

OTBS

H PivO 33

PivO 34

Fig. 10. Retrosynthetic analysis of serofendic acids (29).

Our plan for the preparation of serofendic acids A and B (29) is based on three strategic disconnections: an intramolecular Diels-Alder reaction (31 ĺ 30) to synthesize the AB ring part of 29, a tin-free homoallyl-homoallyl radical rearrangement (33 ĺ 32) to generate the bicyclo[2.2.2]octane ring system, and a palladium-catalyzed cycloalkenylation of 34, the absolute stereochemistry of which arises from an asymmetric ene reaction to construct the bicyclo[3.2.1]octane moiety (Fig. 10.). The key transformation in our plan was the novel tin-free homoallyl-homoallyl radical rearrangement; therefore, so its feasibility was examined first. The requisite ketone 33 was synthesized as shown in Fig. 11. Namely, regioselectiveallylic oxidation of cyclohexene 35 was achieved by applying Ishii’s protocol to give enone36, which was transformed into the bicyclo[3.2.1]octane 37 by means of silylenolate formation followed by palladiumcatalyzed cycloalkenylation. Conjugate addition of an isopropenyl group to 37 proceeded with excellent diastereoselectivity and yielded the desired ketone 33 as the sole stereoisomer (Fig. 11.).

Fig. 11. Preparation of keton 33.

9


With ketone 33 in hand, the crucial homoallyl-homoallyl radical rearrangement was attempted under a variety of conditions, a few of which are listed in Fig. 11. Among the traditional methods examined for triggering the homoallylhomoallyl radical rearrangement, the best result was obtained by employing the BartonMcCombiedeoxygenation protocol18. Ketone 33 was reduced, and the resulting alcohol was converted to the corresponding thioimidazolide. Subjection of the thioimidazolide to standard tin hydride conditions promoted the desired rearrangement and afforded the thermodynamically stable bicyclo[2.2.2]octane product in 82% yield (entry 1). While this method proved effective, it required the use of potentially toxic organotin compounds. In an effort to avoid the use of such reagents, we examined procedures for radical generation under tin-free conditions. Myers has described a deoxygenation protocol that likely proceeds through a radical intermediate19. Disappointingly, when ketone 38 was subjected to the Myers procedure (entry 2), it produced none of the expected rearrangement product. On the other hand, the application of Taber’s technique10 for radical generation under tin-free conditions proved successful for the desired rearrangement20. Treatment of the tosylhydrazone derived from 33 with NaBH3CN in the presence of ZnCl2 effected homoallyl-homoallyl radical rearrangement to produce the sought-after bicyclo[2.2.2]octane compound 32 in 75% yield (entry 3). It is worth noting that whereas the mechanism of radical generation by the Taber protocol has been investigated, it appears to have been little utilized for natural product synthesis. The conversion of diene 32 to tetraene 31, required for the intramolecular Diels-Alder reaction, was achieved as depicted in Fig. 12. After reductive deprotection of pivaloyl group of 32, Parikh oxidation of the resulting alcohol gave aldehyde 38, which was subjected to Stillolefination to afford E-olefin 39 as a single isomer. Suzuki cross-coupling reaction of 39 was next accomplished under Molander’s conditions to furnish tetraene 31, poised for the second key transformation. Intramolecular Diels-Alder reaction of 31 was conducted at 200 °C in a stainless steel autoclave to yield the desired tetracyclic compound 40 (84%). Regioselective reduction of 40 followed by stereoselective methylation gave rise to ()-methyl atisirenoate (30) as a single stereoisomer (Fig. 12.). O conditions H

H PivO PivO

32

33

entry

yield (%)

conditions

1

(1) NaBH4 (2) (imid)2C=S (3) Bu3SnH, AIBN, toluene, reflux

2

(1) NaBH4 (2) PPh3, DEAD, NBSHb, THF

3

TsNHNH2, THF, reflux; NaBH3CN, ZnCl2, reflux

82a 0 75

a; 3-step yield b; o-nitrobenzenesulfonylhydrazine

33

H

H

32

Fig. 12. Homoallyl-homoallyl radical rearrangement of 32.

The complete stereoselectivity observed in the DielsAlder reaction of 31 can be rationalized by considering thetwo likely pre-transition state conformations shown in Fig. 13. The isopropenyl unit is expected to be oriented so as to minimize 1,3-allylic strain between the olefinic hydrogen and the angular hydrogen as shown in 31A and 31B.

10


While conformer 31B is destabilized by nonbonding interactions between the axial hydrogen and the ester group on the diene part, the above interaction is absent in the conformer 31A, which leads to the desired cycloadduct40. (1) LiAlH4, THF (92%)

H

(2) SO3 Py, Et3N DMSO, CH2Cl2

PivO

OHC

38

32

BF3K

(CF3CH2O)2P(O)CHBrCO2Me t-BuOK, 18-crown-6, THF _

78 °C

H

PdCl2(dppf) CH2Cl2 Cs2CO3, THF, H2O reflux (51%)

39

toluene

(1) Mg, MeOH

200 °C

(92%)

(84%)

31

H MeO2C

H

(2) LDA, THF; MeI, HMPA

40

(91%)

single stereoisomer !

(_)-methyl arisirenoate (30)

H MeO2C

Br

in stainless autoclave

CO2Me

H

MeO2C

(88% for 2 steps)

H

H

Fig. 13. Synthesis of methyl atisirenoate (30).

The requisite side chain on the D ring system of 29 was introduced as shown in Fig. 13..Allylic oxidation of 30 with benzeneseleninic anhydride produced enone41 (80%). The required thiomethyl group was introduced directly through Michael addition of sodium thiomethoxide, which gave a 1:1 mixture of the Į- and ȕ-thiomethyl ketones. Direct reduction of this mixture of ketones afforded the four separable thiomethyl alcohols shown, from which the desired product, 42C, was isolated in 27% overall yield. Attempts to improve the diastereoselectivity of this addition-reduction sequence proved fruitless. Finally, hydrolysis of 42C followed by Davis oxidation of the resulting sulfide provided serofendic acids A (29a) and B (29b) as a 1:2 separable mixture. The spectroscopic properties and specific rotations of both synthetic materials were identical with those reported for the naturally occurring compounds. H H

MeO2C

H

Me Me CO2Me

31A

31B

Fig. 14. Plausible conformations 31A and 31B for cycloaddition.

In conclusion, a total synthesis of both (-)-serofendic acids A (29a) and B (29b) has been accomplished. The synthetic strategy involved the use of a tin-free homoallyl-homoallyl radical rearrangement for the construction of

11


bicyclo[2.2.2]octane ring system. The methodology developed here should also provide access to synthetic analogues of serofendic acids. (1) NaSMe THF, H2O

(PhSeO)2O H H

MeO2C

(80%)

MeO2C

(2) BH3 THF THF

H

41

_

( )-methyl arisirenoate (30)

SMe

SMe

+

OH

O

H

C6H6, reflux

OH

42A

+

OH 42C

42B

42D

anti (54%)

LiSPr HMPA

SMe

MeO2C

OH

(1 : 1)

syn (18%)

H

SMe

SMe

+

SMe

OH

H

HO2C

42C S

Davis Oxaziridine H

(100%) HO2C

OH

H

43

S

O H

+

H

serofendic acid A

OH

H

(80%)

HO2C

(1 : 2)

O

OH

H

serofendic acid B

Fig. 15. Conversion of 30 to serofendic acids A and B (29).

4. Summary Palladium-catalyzed cycloalkenylation developed by us was successfully applied to the syntheses of aphidicolin and serofendic acids. The significant features of our catalytic cycloalkenylation are as follows: (1) the reaction proceeds smoothly under higher concentration, and (2) the reaction is adaptable on a large scale synthesis. References 1. Stahl SS. Palladium Oxidase Catalysis: Selective Oxidation of Organic Chemicals by Direct Dioxygen-Coupled Turnover. Angew Chemie Int Ed 2004;43:3400–20. 2. Beccalli EM, Broggini G, Martinelli M, Sottocornola S. CíC, CíO, CíN Bond Formation on sp2 Carbon by Pd(II)-Catalyzed Reactions Involving Oxidant Agents. ChemRev 2007;107:5318–65. 3. Toyota M, Wada T, Fukumoto K, Ihara M. Total Synthesis of (±)-Methyl Atis-16-en-19-oate via HomoallylíHomoallyl Radical Rearrangement. J AmChemSoc 1998;120:4916–25.

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Masahiro Toyora / Procedia Chemistry 13 (2014) 3 – 12 4. Toyota M, Wada T, Ihara M. Total Syntheses of (í)-Methyl Atis-16-en-19-oate, (í)-Methyl Kaur-16-en-19-oate, and (í)-Methyl Trachyloban19-oate by a Combination of Palladium-Catalyzed Cycloalkenylation and HomoallylíHomoallyl Radical Rearrangement. J Org Chem 2000;65:4565–70. 5. Toyota M, Rudyanto M, Ihara M. Application of palladium-catalyzed cycloalkenylation reaction to terpenoid synthesis—novel approach to tricyclo[5.3.1.02,6]undecane derivative and its transformation into bicyclo[5.3.1]undecane ring system. TetrahedronLett 2000;41:8929–32. 6. Toyota M, Odashima T, Wada T, Ihara M. Application of Palladium-Catalyzed Cycloalkenylation Reaction to C20 Gibberellin Synthesis: Formal Syntheses of GA12, GA111, and GA112. J Am Chem Soc 2000;122:9036–7. 7. Toyota M, Sasaki M, Ihara M. Diastereoselective Formal Total Synthesis of the DNA Polymerase Į Inhibitor, Aphidicolin, Using PalladiumCatalyzed Cycloalkenylation and Intramolecular DielsíAlder Reactions. Org Lett 2003;5:1193–5. 8. Toyota M, Asano T, Ihara M. Total Synthesis of Serofendic Acids A and B Employing Tin-Free HomoallylíHomoallyl Radical Rearrangement. Org Lett 2005;7:3929–32. 9. Bucknall R. A. Antiviral Effects of Aphidicolin, a New Antibiotic Produced by Cephalosporium aphidicola. Antimicrob Agents Chemother 1973;4:294. 10. Ikegami S S. Aphidicolin prevents mitotic cell division by interfering with the activity of {DNA} polymerase-alpha. Nature 1978;275:458– 60. 11. Toyota M, Ihara M. Total synthesis of aphidicolane and stemodane diterpenes. Tetrahedron 1999;55:5641–79. 12. Toyota M, Nishikawa Y, Fukumoto K. An expeditious and efficient formal synthesis of (±)-aphidicolin. Tetrahedron Lett 1994;35:6495–8. 13. Toyota M, Nishikawa Y, Seishi T, Fukumoto K. Aphidicolin synthesis (I)—formal synthesis of (±)-aphidicolin by the successive intramolecular Diels-Alder reactions. Tetrahedron 1994;50:10183–92. 14. Toyota M, Nishikawa Y, Fukumoto K. Enantioselective total synthetic route to (+)-aphidicolin. Tetrahedron Lett 1995;36:5379–82. 15. Toyota M, Nishikawa Y, Fukumoto K. Synthesis of a cancer growth-inhibiting diterpene—Stereoselective formal synthesis of (+)aphidicolin. Tetrahedron 1996;52:10347–62. 16. Ireland RE, Dow WC, Godfrey JD, Thaisrivongs S. Total synthesis of (.+-.)-aphidicolin and (.+-.)-.beta.-chamigrene. J Org Chem 1984;49:1001–13. 17. Kume T, Asai N, Nishikawa H, Mano N, Terauchi T, Taguchi R, et al. Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum. Proc Natl Acad Sci 2002;99:3288–93. 18. Barton DHR, McCombie SW. A new method for the deoxygenation of secondary alcohols. J Chem Soc{,} Perkin Trans 1 1975:1574–85. 19. Myers AG, Movassaghi M, Zheng B. Single-Step Process for the Reductive Deoxygenation of Unhindered Alcohols. J Am Chem Soc 1997;119:8572–3. 20. Taber DF, Wang Y, Stachel SJ. Alkyl radical generation by reduction of a ketone tosylhydrazone. TetrahedronLett 1993;34:6209–10.