Stereogenic Center in Steroid Side Chain - ACS Publications

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A Concise Account of Various Approaches for Stereoselective Construction of the C‑20(H) Stereogenic Center in Steroid Side Chain Bapurao B. Shingate*,†,‡ and Braja G. Hazra*,‡ †

Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India

‡

4.13. Organoboron Reagents 4.14. Organocopper Reagents 4.14.1. Alkylidene Oxiranes 4.14.2. C-17(20)-en-16-keto Steroids 4.14.3. C-17(20)-en-16-Pivalates/Carbamates 4.15. Organozirconocene Reagents 4.16. Hydrovinylation Reaction 4.17. Miscellaneous 5. Conclusions Author Information Corresponding Authors Notes Biographies Acknowledgments Dedication Abbreviations References

CONTENTS 1. Introduction and Scope 1.1. Steroids with C-20 Natural Configuration 1.2. Steroids with C-20 Unnatural Configuration 1.3. Other Compounds with Sterol-like Side Chains 2. Spectroscopic Method for Determining the Configuration of C-21 Methyl Group in the Steroid Side Chain 3. X-ray Crystallographic Analysis for Determining the Configuration at C-20 4. Methods for Stereoselective Generation of C20(H) Stereogenic Center in Steroid Side Chain 4.1. Catalytic Hydrogenation of Steroidal C-20 Double Bonds 4.2. Ionic Hydrogenation 4.3. C-20 Alkylation 4.3.1. Alkylation of Steroidal C-21 Esters 4.3.2. Alkylation of Unsaturated Steroidal C-21 Esters 4.3.3. Alkylation of C-20 Cyano Steroid 4.3.4. Alkylation of Des-AB Steroids 4.4. Ring-Opening of Steroidal C-20,22-Oxirane 4.5. Ene Reaction 4.5.1. Ene Reaction with Propiolate Esters 4.5.2. Ene Reaction with Acrylates 4.5.3. Carbonyl−Ene Reaction 4.6. Aldol Reaction 4.7. Michael Addition Reaction 4.8. Mukaiyama−Michael Conjugate Addition Reaction 4.9. Chirality Transmission Approach 4.10. Claisen and Claisen-type Rearrangements 4.11. Wittig Rearrangement 4.12. Organopalladium Reagents © XXXX American Chemical Society

A B C

W X X Y Z Z AB AB AC AD AD AD AD AD AE AE AE

1. INTRODUCTION AND SCOPE Sterols are compounds containing a perhydro-1,2-cyclopentenophenanthrene ring system and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of natural and synthetic members of this class depends on variation in side-chain substitution (primarily at C-17), degree of unsaturation, degree and nature of oxidation, and stereochemical relationship at the ring junctions.1 The most frequently encountered sterol of animal origin is the highly lipophilic compound cholesterol, 1, which is metabolized to bile acids in the liver and also serves as starting material for the synthesis of steroid hormones. A wide variety of sterols have been reported2 to possess modified iso-octyl (cholesterol-type) side chains and the unit being attached to the polycyclic nucleus at C-17 with (R) or (S) stereochemistry at C-20.3 During the early and middle years of sterol and related terpenoid chemistry, synthetic efforts were focused primarily on the ring system and some of the more simple functional side chains. Comparatively, little attention was paid to the side chain except for two carbon units present in corticosteroids and other pregnane derivatives and interconversions between the side chains of cholesterol, plant sterols, and bile acids. The last few decades have witnessed intensive research on side-chain synthesis, yielded many imaginative syntheses of general interest, and contributed to a great extent to the development of stereospecific chiral carbon formation.4,5 The biological significance of both the C-20 epimers of naturally occurring

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Received: July 29, 2013

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dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXX

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and/or synthetic sterol molecules provided not only steroid chemists but also natural product chemists an opportunity to pursue new syntheses of sterols or compounds with similar chain structures. This review is limited to sequences commencing upon generation of both epimers at C-20. The aim of this review is to survey the synthesis of sterols, terpenes, and vitamin side chains with natural and unnatural configurations at C-20 (Figure 1).

Figure 4. Cholic acid 9, deoxycholic acid 10, lithocholic acid 11, taurocholic acid 12, and glycocholic acid 13. Figure 1. (A) Natural configuration at C-20; (B) unnatural configuration at C-20.

Vitamin D refers to a group of seco-steroids that possess a common conjugated triene system of double bonds.5 Vitamin D3 (cholecalciferol) 14 and vitamin D2 (ergocalciferol) 15 are well-known examples with C-20 natural stereochemistry (Figure 5). Vitamin D3 is a prohormone that is converted into physiologically active form, primarily 1,25-dihydroxyvitamin D3 16, by successive hydroxylations in the liver and kidney.

1.1. Steroids with C-20 Natural Configuration

There are many classes of natural and synthetic sterols, best known for their wide array of biological activity.1 Representative members of the naturally occurring sterols such as cholesterol 1, β-sitosterol 2, stigmasterol 3, ergosterol 4, and ecdysone 5 have the C-20 natural stereochemistry (Figure 2).

Figure 5. Vitamin D3 (cholecalciferol) 14, vitamin D2 (ergocalciferol) 15, and 1,25-dihydroxyvitamin D3 16.

Naturally occurring and commercially important sapogenins, particularly diosgenin 17, hecogenin 18, and tigogenin 19, also possess the natural configuration at C-20 (Figure 6). These

Figure 2. Cholesterol 1, β-sitosterol 2, stigmasterol 3, ergosterol 4, and ecdysone 5.

These sterols 1−5 are widely distributed in the animal and vegetable kingdoms and are used in the pharmaceutical industry as raw materials for obtaining drugs by chemical, enzymatic, and microbiological methods. Sterols with additional methyl groups on the ring skeleton are found in many plants and fungi and abundantly in the wool fat of sheep. The best examples are lanosterol 6, agnosterol 7, and 4,4′-dimethyl-5α-cholesta-8,14,24-trien-3β-ol 8 [FF-MAS (follicular fluid meiosis-activating sterol)], a naturally occurring sterol isolated6 from human follicular fluid (Figure 3). Bile acids, derivatives of cholesterol, are found predominantly in the bile of mammals. The two major bile acids are cholic acid 9 and deoxycholic acid 10 (Figure 4). Other bile acid derivatives such as lithocholic acid 11, conjugates of taurocholic acid 12, and glycocholic acid 13 are all found in human intestinal bile with C-20 natural stereochemistry.

Figure 6. Diosgenin 17, hecogenin 18, and tigogenin 19.

sapogenins are important source of starting materials for the commercial steroid industry, owing to their relative abundance in easily cultivated plants and their ease of isolation.1 Commercially important plant growth-promoting steroid brassinolide7 20, recently isolated sterol polyamine conjugate8 squalamine 21, saponin9 OSW-1 22, and contignasterol10 23 have natural C-20 stereochemistry (Figure 7). The bioactivities of these naturally occurring steroids and their synthetic analogues have been exploited in the development of steroidal drugs. Certonardosterol D2 24, a polyhydroxysterol isolated from the starfish Certonardoa semiregularis, has exceptionally potent antitumor activity.11 Agosterol A 25, isolated from marine sponges of Spongia sp., is a reversing substance to multidrug resistance (MDR) in human carcinogenic cell lines and also has been synthesized by Kobayashi and co-workers.12 Furthermore, physanolide A 26, a new steroid skeleton isolated from Physalis angulata;13 amaranzole A 27, a 24-Nimidazolyl steroid alkaloid from Phorbas amaranthus;14 and

Figure 3. Lanosterol 6, agnosterol 7, and FF-MAS 8. B


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Figure 9. Plakinamine I 29.

Sargassum ringgoldianum and its structure was proposed as (20S)-fucosterol 30 (Figure 10) on the basis of degradation

Figure 10. (20S)-Fucosterol 30, 20-epi-cholesta-5,22-dien-3β-ol 31, 20-epi-cholesterol 32, and 20-epi-halosterol 33.

products by Tsuda et al.20 Idler et al.21 reported the presence of 20-epi-cholesta-5,22-dien-3β-ol 31 in the scallop Placopecten magellanicus. Koreeda and co-workers22 reported that 20-epicholesterol 32 with C(20S) stereochemistry showed significant in vitro inhibitory activity for the conversion of cholesterol to 3β-hydroxypregn-5-en-20-one (pregnenolone). Similarly, the naturally occurring halosterol 33, in which the side chain has been shortened by one methylene (CH2) group, possesses unnatural configuration at C-20.23 Vanderah and Djerassi24 described the isolation of four sterols 34−37 (Figure 11), having the unnatural C(20S)

Figure 7. Brassinolide 20, squalamine 21, saponin OSW-1 22, contignasterol 23, certonardosterol D2 24, and agosterol A 25.

withaferin A 28, a cytotoxic steroid isolated15 from Vassobia breviflora, all have C-20 natural configuration (Figure 8).

Figure 8. Physanolide A 26, amaranzole A 27, and withaferin A 28.

Li et al.16 described the chemistry, bioactivity, and geographical diversity of steroidal alkaloids isolated from Veratrum and Fritillaria sp. of the Liliaceae family, which contain derivatives of pyridine/piperidine heterocycle attached to the C-20 position of steroid backbone with C-20(H) natural/ unnatural stereogenic center. Similarly, Atta-ur-Rahman and Choudhary17 have also reviewed the isolation of various steroidal alkaloids. Introduction of a heteroatom in the steroidal ring or side chain could have a biological impact; there has been progress in the field of thia- and azasteroids.18 A new cytotoxic steroidal alkaloid, plakinamine I 29 (Figure 9), with an unprecedented 3α-amino-19-acetoxy nucleus, and other similar type of compounds were isolated19 from a Corticium sp. sponge.

Figure 11. 20-epi-Cholanic acid derivatives 34−37 and methyl (20S,22E)-3-oxochola-1,4,22-trien-24-oate 38.

stereochemistry, from a sea pen, Ptilosarcus gurneyi and also devised methods for their synthesis. Methyl (20S,22E)-3oxochola-1,4,22-trien-24-oate 38, isolated from Alcyonium gracillimum and Dendronephthya sp. of the order Alcyonacea, showed no antifouling activity against barnacle (Balanus amphitrite) larvae but lethality to barnacle larvae at a concentration of 100 μg/mL (LD100).25 20-epi-1α,25-Dihydroxyvitamin D3 (20-epi-calcitriol) 39 is more potent26 in regulating cell growth and cell differentiation than the corresponding natural C-20 stereoisomer (Figure 12). Analogue 39 exhibits immunosuppressive properties27 and 1αfluoro-16,23-diene-20-epi hybrid deltanoid (Ro 26-9228) 40 is undergoing human clinical trials for the treatment of osteoporosis.28

1.2. Steroids with C-20 Unnatural Configuration

Sterols/steroids with unnatural configuration at C-20 or C-20 epimers are attracting attention because of interesting biological activities, and hence methods for their stereoselective synthesis are highly desirable. Sargasterol has been isolated from C


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steroid nomenclature system) generally has its signal more downfield in proton NMR than the 20α-isomer (unnatural C20 epimer). In ambiguity to this, for steroids bearing/ possessing a double bond at C-16(17), the 20α-isomer shows more downfield than 20β-isomer. Representative values for C21 methyl protons of C-20 epimers are shown in Table 1. Table 1. Representative Values for C-21 Methyl Protons of C-20 Epimers Figure 12. 20-epi-Calcitriol 39 and deltanoid (Ro 26-9228) 40.

1.3. Other Compounds with Sterol-like Side Chains

Sesterterpenoids such as gascardic acid 41, (+)-ophiobolin A 42, (+)-ophiobolin C 43, (+)-ceroplastol I 44, (+)-ceroplastol II 45, and (+)- albolic acid 46 bearing sterol-like iso-octyl side chains on C ring skeleton were also reported29 (Figure 13).

Figure 13. Gascardic acid 41, (+)-ophiobolin A 42, (+)-ophiobolin C 43, (+)-ceroplastol I 44, (+)-ceroplastol II 45, and (+)- albolic acid 46.

Shi and co-workers30 reported incisterols 47−49, possessing a highly degraded 1−5,10,19-heptanorergosterane skeleton isolated from Phellinus igniarius (Figure 14). Demethylincisterol A3 50 and chaxine A 51 (Figure 14) were isolated from the Chinese mushroom Agrocybe chaxingu and are potent osteoclast-forming suppressing agents.31

Figure 14. Incisterols 47−49, demethylincisterol A3 50, and chaxine A 51.

2. SPECTROSCOPIC METHOD FOR DETERMINING THE CONFIGURATION OF C-21 METHYL GROUP IN THE STEROID SIDE CHAIN Information on the spectral properties of steroidal C-20 epimers is now available and permits us to make some generalizations. The spectra are influenced by several factors; therefore the generalizations may not be always directly applicable to new compounds. Possibly, the most informative method for stereochemical assignment has been the use of NMR spectroscopy. For elucidating C-20 stereochemistry in sterol/steroid, the C-21 methyl protons give the best diagnostic signal.4a,32 The 20β-isomer (natural C-20 epimer, according to

3. X-RAY CRYSTALLOGRAPHIC ANALYSIS FOR DETERMINING THE CONFIGURATION AT C-20 Crystal structure data33,43 of sterols with natural configuration at C-20 show that the conformation about 17(20) bond in the usual view of the molecule is to the right, meaning the side chain is to the right side of the steroid skeleton. The righthanded rotational isomer probably derives from its having the smallest of the groups on C-20 (the H atom) in front and therefore, adjacent to C-18 in a pseudo 1,3-diaxial fashion. In D


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the case of C-20 unnatural configuration, the left-handed conformer is skew and possesses the least steric compression, that is, an opposite conformational preference compared to the natural one. Linker et al. described the syntheses44a and crystal structures44b,c of methyl (20S,22E)-3-oxochola-1,4,22-trien-24oate 38 and methyl (20R,22E)-3-oxochola-1,4,22-trien-24-oate 52 (Figure 15).

Table 2. Selected Torsion Angles for Compounds 38 and 52 C(17)−C(13)−C(14)−C(15), C(13)−C(14)−C(15)−C(16), C(14)−C(15)−C(16)−C(17), C(14)−C(13)−C(17)−C(16), C(15)−C(16)−C(17)−C(13), C(13)−C(17)−C(20)−C(21), C(16)−C(17)−C(20)−C(21), C(17)−C(20)−C(22)−C(23), C(21)−C(20)−C(22)−C(23),

deg deg deg deg deg deg deg deg deg

38

52

46.8 (2) −34.7 (3) 9.0 (3) −40.3 (2) 19.6 (3) 174.6 (2) 54.3 (3) 143.4 (3) −92.8 (4)

45.9 (2) −32.3 (3) 5.7 (3) −41.0 (2) 22.1 (3) −66.0 (3) 172.8 (2) −132.3 (3) 103.0 (3)

system.4,5,7,45 Introduction of the properly functionalized side chains onto tetracyclic steroidal starting materials has been the subject matter of several investigations. An important aspect or problem that arises in this approach is the stereoselective control of C-20 stereochemistry; formation of the C-20 stereogenic center with hydrogen (H) at that position is of great interest. Various stereoselective methods used for generation of both the C-20 natural and unnatural epimers (Figure 1) are discussed.

Figure 15. Methyl (20S,22E)-3-oxochola-1,4,22-trien-24-oate 38 and methyl (20R,22E)-3- oxochola-1,4,22-trien-24-oate 52.

All bond lengths and angles of the steroidal skeleton are within normal range and in accordance with the epimeric product. For 38, the D ring adopts a conformation between 13β,14α-half chair [Δ = 12.84°, ψm = 47.1°). The substituents at C-20 are staggered with respect to those at C-17, but in this case C-22 is anti to C-16. The side chain is oriented toward the ring system44b (Figure 16A). For 52, the calculated values of Δ

4.1. Catalytic Hydrogenation of Steroidal C-20 Double Bonds

Uskokovic and co-workers46 reported catalytic hydrogenation of a mixture of E- and Z-olefins 53 and 54 over platinum oxide catalyst in 95% ethanol to furnish approximately 1.5:1 mixture of saturated ketones 55 (C-20 natural configuration) and 56 (C-20 unnatural configuration) (Scheme 1). Similarly, catalytic Scheme 1

hydrogenation of a mixture of 57 and 58 over platinum oxide catalyst led to 20(R)-ketone 60 (50% yield), which was readily separated from the 20(S)-isomer 59 by crystallization with 95% ethanol. A similar selective hydrogenation of a C-20(22) double bond was also reported by Ikan et al.47 in their synthesis of βsitosteryl acetate. Synthesis of (22R)-22,25-dihydroxysterol and its 6-oxo derivatives has been achieved48 from 63. Compound 62, obtained from 3β-acetoxypregn-5-en-20-one (pregnenolone acetate) 61, upon chemoselective catalytic hydrogenation with Pd/C furnished the 20S-63 in quantitative yield (Scheme 2). Compounds 65 and 68 have been used49 for efficient syntheses of 3β-hydroxy-5α-cholanic acid 66 and 3β-hydroxy-5en-cholanic acid 69, respectively. Catalytic hydrogenation of C20(22)-olefinic compounds 64 and 67 (both obtained from corresponding C-20 tert-alcohols followed by dehydration with POCl3−pyridine) with PtO2 in ethanol resulted into the corresponding saturated compounds 65 and 68 in 97% yields49

Figure 16. Views of (A) 3844b and (B) 52.44c

= 20.15°, ψm = 45.2° indicate a D ring conformation midway between a 13β-envelope and a 13β,14α-half chair. The substituents at C-20 are staggered with respect to those at C17, with the methyl C-21 anti to C-16. The remainder of the side chain extends away from the steroid rings44c (Figure 16B). Significant differences between the two epimers in the sidechain torsion angles44b,c are as shown in Table 2.

4. METHODS FOR STEREOSELECTIVE GENERATION OF C-20(H) STEREOGENIC CENTER IN STEROID SIDE CHAIN The total synthesis of sterols/steroids has represented one of the great challenges to synthetic chemists and culminated in establishing elegant and practical approaches to this ring E


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Scheme 2

Scheme 5

with C-20R natural configuration (Scheme 3). Kametani et al.50 reported the first asymmetric total synthesis of (+)-chenodeoxScheme 3

hydrogenation of steroidal olefin 82 to lactone 83 occurred in 92% yield.53 Similar type of catalytic hydrogenation of olefin 84 over 5% Rh−Al2O3 in ethyl acetate afforded54 lactone 85 with C-20 natural configuration in 92% yield (Scheme 6). Again, ycholic acid 72 via hydrogenation of the 20(22)-dehydro compound 70 with Pt in methanol, resulting in 71 in 97% yield with C-20 natural configuration (Scheme 3). The obtained 71 was converted to chenodeoxycholic acid 72 after some synthetic manipulations. Catalytic hydrogenation of 73 with Rh−Al2O3 gave 74 in 90% yield as a mixture of C-20 epimers (20S:20R 4:3).51 In the same report,51 catalytic hydrogenation of 75 with Pd/C gave a mixture of C-20 hydrogenated product 76 in 56% yield (mixture at C-20) and deoxygenated product 77 in 34% yield (also mixture at C-20) (Scheme 4).

Scheme 6

Scheme 4

reduction of steroidal C-20(21)-ene 86 over 5% Rh−Al2O3 in ethyl acetate afforded tetraacetylcastasterone 87 (natural configuration at C-20) and its C-20 epimer 88 in 92% yield in the ratio 1:1. This indicates that the position of double bond in the present substrate 86 under similar reaction conditions may profoundly affect the configuration of the product. Honda et al.55 described catalytic hydrogenation of a mixture of olefins 89 and 90 over Pd/C in ethyl acetate, resulting in 91 as a C-20 epimeric mixture in 89% yield (Scheme 7). Stereoselective and catalytic reduction of steroidal 5ylidenetetronate derivative to control the stereochemistry of the contiguous four acyclic chiral centers has been described.52 The steroidal Z-isomer 78, upon catalytic hydrogenation over rhodium−alumina, afforded52 the saturated lactone 79 as the sole product (90% yield) (Scheme 5). Again, the steroidal Eisomer 80, upon catalytic hydrogenation over rhodium− alumina, resulted in lactone 81 in 92% yield. Similarly, catalytic

Scheme 7

F


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The reaction condition/method played an important role in the stereoselective hydrogenation of double bonds. Catalytic hydrogenation56 of all three olefinic double bonds at C-16, C20, and C-24 in 92 with Pd/C in EtOAc−EtOH provided C-20 epimeric compound 93 in 98% yield [diastereomeric ratio (dr) 2.5:1 20S:20R] (Scheme 8).

Scheme 11

Scheme 8

Stereoselective and chemoselective reduction57 of dienol 94 by use of Raney nickel in ethanol at 50 °C provided 95a as a major product (20R:20S ≈ 4:1), which upon cleavage of tetrahydropyranyl (THP) ether by p-toluenesulfonic acid (PTSA)−MeOH afforded 95b in 52% yield over two steps (Scheme 9).

saturated compound 105 in 89% yield with 100% stereoselectivity (Scheme 12).

Scheme 9

Scheme 12

Chemoselective transfer hydrogenation58 of 96, with a catalytic amount of 10% Pd/C and excess triethylsilane in methanol, afforded 97 and 98 as a C-20 epimeric mixture (Scheme 10).

Ionic hydrogenation reaction involves a carbocation−silane hydride transfer reaction. Ionic hydrogenation of olefins generates the carbocation at the more substituted carbon, followed by hydride transfer reaction.62a In the present case, there is formation of carbocation at C-22 to give the sulfurstabilized intermediate62b 104A (Figure 17). Protonation hy

Scheme 10

Zhang and Danishefsky59 reported the total synthesis of (±)-aplykurodinone 1 (101), in which stereoselective installation of the C-13 methyl group through hydrogenation with homogeneous catalyst is the key step. Upon hydrogenation in the presence of Crabtree catalyst in dichloromethane, the trisubstituted olefin 99 was reduced in diastereoselective fashion (>5:1) to afford 100 in 50% yield (Scheme 11). Compound 100 bears all the stereocenters of aplykurodinone 1 101. In the same report,59 stereoselective and chemoselective reduction of disubstituted olefin 102 by Wilkinson’s catalyst under atmospheric hydrogen in benzene resulted 13-epiaplykurodinone 1 103 (>6:1) in 67% yield.

Figure 17. Mechanism of ionic hydrogenation of the C-20,22-ketene dithioacetal 104.

trifluoroacetic acid at C-20 position in 104 from the less hindered α-face of the steroid backbone leads to formation of carbocation at C-22, followed by transfer of hydride (from Et3SiH) at C-22, resulting in the exclusive formation of C(20R)-methyl product 105. Ionic hydrogenation63 is an effective method for the removal of steroidal tertiary alcohols. Ionic hydrogenation of steroidal C-20 tert-alcohol 108 by use of triethylsilane and trifluoroacetic acid64 gave the deoxygenated product 105, with unnatural C(20R) stereochemistry, in low yield (41%). The same reaction with Et3SiH and boron trifluoride etherate (BF3·OEt2) in place of trifluoroacetic acid gave the C-20 deoxygenated product 10565,66 in 94% yield (Scheme 13). Similarly, 106, upon exposure to similar reaction conditions (Et3SiH, BF3·OEt2) leading to deoxygenation of the C-20 tert-alcohol along with

4.2. Ionic Hydrogenation

Ionic hydrogenation of the steroidal C-20,22-ketene dithioacetal 104, obtained from commercially available60 16-dehydropregnenolone acetate (3β-acetoxypregna-5,16-dien-21-one), by use of triethylsilane (Et 3 SiH) and trifluoroacetic acid (CF3COOH) in dichloromethane afforded61 the C(20R) G


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gave methyl ester 119 in 86% yield. The intermediate pregnenoic acid ester 115 was synthesized by Wittig−Horner reaction69 on steroidal C-20 ketone 114, followed by Mg− MeOH reduction.70 Stereoselective synthesis of (20S)-cholest5-en-3β-ol from 3β-(tetrahydropyran-2-yloxy)androst-5-en-17one via ethyl (20R)-3β-(tetrahydropyran-2-yloxy)-23,24-bisnorchol-5-en-22-oate in high yield has been described by Jarzebski and Wicha.71 In this report,71 methylation of ethyl ester of 115 with LDA/MeI furnished the (20R)-methyl derivative as the sole product. The stereoselective synthesis of 25(R),26- and 25(S),26dihydroxycholesterols were accomplished72,73 by the C-20 alkylation−reduction method. Steroidal ester 115 was alkylated with iodide 120 in the presence of LDA to afford monoalkylated ester 121 in 80% yield (Scheme 15). Similarly, when esters 115 and 124 were alkylated with 122 and 120, monoalkylated esters 123, 125, and 126 were obtained in 84%, 85%, and 85% yield, respectively (Scheme 15).

Scheme 13

deprotection of the 3β-tert-butyldimethylsilyl (TBDMS) group, gives 109 in 90% yield. The same product 109 was obtained under identical reaction conditions on 3,20-diol 107 in excellent yield (92%). Compound 111, upon ionic hydrogenation with Et3SiH and BF3·OEt2 in dichloromethane, afforded 112 in 94% yield (Scheme 13). The obtained intermediates 105 and 112 were transformed to the corresponding unnatural steroidal C(20R) aldehydes 110 and 113, respectively. The steroidal unnatural C(20R) aldehydes 110 and 113 are ideal starting materials66 for the synthesis of large number of naturally occurring steroids with unnatural stereocenter at C-20.

Scheme 15

4.3. C-20 Alkylation

4.3.1. Alkylation of Steroidal C-21 Esters. Wicha and Bal67 reported stereoselective C-20 alkylation of steroidal ester 115 [obtained from 3β-acetoxyandrost-5-en-20-one 114 via Reformatsky reaction followed by dehydration, selective hydrogenation of C-17(20) double bond, and exchange of protecting group] with bromo compound 116 in the presence of LDA (lithium diisopropylamide) and HMPA (hexamethyl phosphorotriamide), affording 117 in 66% yield (Scheme 14). Alkylation68 of steroidal ester 115 with methyl iodide in tetrahydrofuran (THF), with slight excess of LDA in HMPA, gave 118 in 91% yield (Scheme 14). Similarly, alkylation of ester 115 with 1-bromo-4-methylpentane (isohexyl bromide) An epimer of natural hormone 17-epi-calcitriol was synthesized via 17-epi-cholesterol as described.74 One of the key steps in this synthesis was C-20 alkylation of steroidal ester 130. The C-17-epi-steroidal ester 130 was synthesized from 127. Compound 127, upon reaction with methyl diazoacetate in the presence of palladium(II) acetate, afforded epimers 128a and 128b in 92% yield (7:1) (Scheme 16). Treatment of 128a with lithium in liquid ammonia in the presence of THF as a cosolvent and tert-butyl alcohol as a proton donor gave a mixture of alcohol and aldehyde. The crude product was reduced with LiAlH4 to give 129 in 90% yield. Compound 129 was oxidized with dimethyl sulfoxide (DMSO)−PySO3, further oxidized with KMnO4 in tert-butanol, and then treated with diazomethane to afford 130. C-20 alkylation74 of 17-epi ester 130 by use of LDA−methyl iodide−HMPA gave diastereomerically pure product 131 in almost quantitative yield (Scheme 16). In this case, the orientation of C-17 hydrogen plays a role in stereoselective generation of the C-20 chiral center from 130 to 131. Similarly, diastereoselective alkylation of pregnanoic acid ester 132 afforded product 133 in 98% yield. Alkylation75 of steroidal ester 134 with (Z)-1-bromo-3trimethyl-4-methylpent-2-ene 135 afforded stereoselective

Scheme 14

H


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142b (ratio 94:6) in 94% combined yield (Scheme 19). Similarly, when 141 was alkylated with LDA and isohexyl

Scheme 16

Scheme 19

iodide, products 143a and 143b (ratio 94:6) were obtained in 98% yield. Analogously, when enoates (E)-ethyl 3β-(tertbutyldimethylsiloxy)-5α-pregn-17(20)-en-21-oate 144 and (E)-ethyl 6β-methoxy-3α,5-cyclo-5α-pregn-17(20)-en-21-oate 146 are reacted with LDA followed by methyl iodide, formation of (20S) alkylated products 145 and 147 takes place in 89% and 94% yield, respectively (Scheme 19). 4.3.3. Alkylation of C-20 Cyano Steroid. C-20 cyano steroid 148 was prepared from 3β-hydroxyandrost-5-en-20-one via Wittig reaction followed by reduction of α,β-unsaturated nitrile with Mg−MeOH in quantitative yield.78 C-20 cyano steroid 148, upon condensation/alkylation with (S)-benzyl 2,3epoxypropyl ether or (R)-benzyl 2,3-epoxypropyl ether in the presence of lithium hexamethyldisilazide [LiN(SiMe3)2] in THF, gave78 a C-20 epimeric mixture of cyano alcohols 149a and 149b (Scheme 20).

product 136 in 75% yield (Scheme 17). Similarly, alkylation of ester 134 with (Z)-1,3-dibromo-4-methylpent-2-ene 137 produced 138 in 80% yield. Scheme 17

Scheme 20

Guo and co-workers76 reported stereoselective alkylation of steroidal ester 139 with LDA and isohexyl bromide in the presence of HMPA at −78 °C, resulting in (20R) ester 140 in 75% yield (Scheme 18). Scheme 18

4.3.4. Alkylation of Des-AB Steroids. Interest in steroid synthesis has been characterized by the development of imaginative new ways of synthesizing hydrindanone and hydrindenone derivatives, which represent the C,D-ring system and side-chain unit of the steroids. The alkylation method shown for the steroid skeleton is also applicable for des-AB steroids having cis or trans ring junctions. The obtained products are useful starting materials for the synthesis of vitamins. Clase and Money79 have described stereoselective alkylation of ketal ester 151 (synthesized from 150 via Wittig reaction followed by Mg−MeOH reduction) with 5-iodo-2-methylpent2-ene 152 to afford 153 in 95% yield (Scheme 21). Similarly, ester 151 was alkylated80 with isohexyl iodide 154 to give 155 in 71% yield. Treatment of 156 with LDA in HMPA−THF, followed by addition of side-chain synthon 157, resulted in the

4.3.2. Alkylation of Unsaturated Steroidal C-21 Esters. Stereoselective synthesis of 20S and 20R steroidal side chains via a facile alkylation process starting from unsaturated ester precursor was reported.40,77 Reaction of (E)-ethyl 3β-(tertbutyldimethylsiloxy)pregna-5,17(20)-dien-21-oate 141, with excess LDA, followed by alkylation with methyl iodide in the presence of HMPA, furnished methylated products 142a and I


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Scheme 21

Scheme 24

Scheme 25

efficient formation of alkylated ester 158 in 87% yield81 (Scheme 21). Van Gool et al.82 reported the alkylation of cis-fused isomer 162 (obtained from Hajos−Wiechert ketone 159 via a sequence of reactions) with LDA and MeI to furnish 163 in 92% yield with complete diastereoselectivity (Scheme 22).

asymmetric carbon atoms in rings C/D and side chain (C-13, C-14, C-17, and C-20), was synthesized from intermediates 174, 175, and 177 and was shown to have a significant affinity for the vitamin D receptor.85 Michalak and Wicha86 reported stereoselective alkylation of des-AB 17-epi-steroid, used for the synthesis of 17-epi-calcitriol derivatives. Cyclopropane carboxylic ester 178 was reduced with lithium in liquid ammonia−THF in the presence of tertbutanol, followed by oxidation with Jones reagent and treatment with diazomethane, afforded ester 179. Treatment of 179 with LDA in THF at −78 °C, followed by MeI, afforded methyl derivative 180 in 95% yield (Scheme 26)

Scheme 22

Scheme 26

Stereoselective alkylation 83 of ester 164 and cyano compound 165 with bromo derivative 166 in the presence of LDA afforded 167 and 168 in 70% and 95% yield, respectively, with different configurations (Scheme 23). Scheme 23

4.4. Ring-Opening of Steroidal C-20,22-Oxirane

Koreeda and Koizumi22a described the reaction of isoamylmagnesium bromide in THF with epoxide 182, derived from pregnenolone derivative 181. The rearranged alcohol 183 was produced with unnatural configuration at C-20, and 100% stereoselective hydride shift occurred during the transformation (Scheme 27). Scheme 27 Alkylation of ketal ester 169 with LDA/THF, followed by methyl bromoacetate and a catalytic amount of tetrabutylammonium iodide, afforded84 ketal diester 170 in 93% yield with >99% diastereoselectivity (Scheme 24). Selective alkylation of 173 (obtained from 171 via Wittig reaction followed by catalytic hydrogenation) at the α-position of carboethoxy group, by use of LDA, isohexyl iodide, and HMPA, gave 174 in 75% yield85 (Scheme 25). Alkylation of 173 with MeI and bromoderivative 176 under analogous conditions afforded 175 and 177 in 75% and 76% yield, respectively.85 1α,25-Dihydroxyvitamin D3 diastereomer, differing from the parent compound in configuration at four J


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Schauder and Krief87 described the stereoselective hemisynthesis of 20S-isolanosterol (20-epi-lanosterol) via a sequence of reactions. The stereoselective hydride shift during the reaction between an epoxide and the Grignard reagent (derived from ethoxyacetylene) have been discussed. Epoxide 186 was obtained from C-20 ketone 184 via a sequence of reactions. Reaction of epoxide 186 and ethoxyacetylene magnesium bromide in ether−benzene afforded 187 via C-22 aldehyde formed in situ in 67% yield with unnatural configuration at C20 (Scheme 28).

Scheme 29

Scheme 28 propiolate in the presence of EtAlCl2 afforded41a ene products 189a, 194, and 197, respectively, in excellent yields with C-20 natural configuration (Scheme 30). Scheme 30

4.5. Ene Reaction

The Lewis acid-mediated/catalyzed ene reaction represents an important alternative method for the addition of an allyl group to a carbonyl group. The resulting secondary homoallylic alcohols are amenable to a number of structural modifications and constitute useful synthetic building blocks. These homoallylic alcohols are formally the synthetic equivalent of aldol addition products, because the olefin of the products can be a surrogate for carbonyl functionality. The configuration at C-20 in the product of the ene reaction depends on the 17(20)olefin. The Z-olefin, upon ene reaction with a variety of enophiles, usually gives the natural configuration, and E-olefin gives the unnatural configuration. Another major difference is that the yield of the product derived from Z-olefin is greater as compared to E-olefin. 4.5.1. Ene Reaction with Propiolate Esters. Lewis acidinduced reactions of acetylenic esters with alkenes provide a versatile method for formation of new carbon−carbon double bonds with a great deal of stereo- and regiocontrol. Snider et al.88 described ene reaction of nonsteroidal substrates with acetylenic esters and also proposed the mechanism. Diethylaluminum chloride (Et2AlCl) catalyzed89 the ene reaction of steroidal 17(20)-(Z)-enes 188a and 188b with methyl propiolate in benzene to afford trienes 189a and 189b, respectively, in 95% yield (Scheme 29). The same reaction conditions were employed to convert the ethylidene derivative of estrone methyl ether 190 via ene reaction to ester 191 in 90% yield. The 17(Z)-ethylidene steroids 188a, 193, and 196 were synthesized via Wittig reaction of corresponding C-17-ketones 114, 192, and 195, followed by acetylation.41a The ene reaction of (17Z)-ethylidene steroids 188a, 193, and 196 with methyl

(17E)-3β-Acetoxy-5,17(20)-pregnadiene 199 was synthesized from 114 via Wittig−Horner reaction followed by reduction−bromination−reduction and acetylation.41b Dauben and Brookhart41b reported that the EtAlCl2-catalyzed ene reaction between (17E)-3β-acetoxy-5,17(20)-pregnadiene 199 and methyl propiolate proceeded stereospecifically from the αface to yield methyl (20S)-3β-acetoxy-5,16,22-trienoate 200 with unnatural configuration at C-20 (Scheme 31). The ene Scheme 31

reaction with the steroidal E-olefin proceeds at least an order of magnitude less rapidly than with the Z-isomer, but the reaction proceeds in a stereospecific manner. In this case, configuration of the steroidal olefin describes the stereochemical outcome of the reaction. The unnatural enantiomer of desmosterol (ent-desmosterol) was synthesized by Westover and Covey90 via ene reaction is K


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the key step. The C-17(20)-Z-olefin 202 was synthesized by Wittig reaction of 201, followed by acetylation. The ene reaction90 of olefin 202 with methyl propiolate in the presence of Et2AlCl afforded 203 with C(20R) configuration (Scheme 32). Synthesis of enantiomeric deoxycholic acid, lithiocholic

Scheme 34

Scheme 32

that contain the natural steroid configuration at C-20. Treatment of (Z)-3-acetoxypregna-5,17(20)-diene 188a with paraformaldehyde (CH2O)n in the presence of boron trifluoride etherate (BF3·Et2O) in acetic anhydride (Ac2O)/dichloromethane at room temperature afforded diacetate 215a in 59% yield (Scheme 35). Scheme 35 acid, and chenodeoxycholic acid was reported by Katona et al.91 In their synthesis, ene reaction of 205 and 208 was the key step. The C-17(20)-Z-olefins 205, 208a, and 208b was prepared by Wittig reaction of 204, 207a, and 207b followed by acetylation. The ene reaction of steroidal olefin 205 with methyl propiolate in the presence of MeAlCl2 gave 206, which is the precursor of ent-deoxycholic acid, in good yield (Scheme 32). Again, steroidal olefins 208a and 208b, upon reaction with methyl propiolate catalyzed by Et2AlCl, lead to 209a and 209b, respectively.91 In all cases, the configuration at C-20 was the same. Acetylated compound 210, upon ene reaction with ethyl propiolate in the presence of EtAlCl2, produced92 211 in 96% yield (Scheme 33).

Hazra et al.94 described the application of cation-exchange resins as catalysts for the ene reaction. Ene reaction of 188c with (CH2O)n in the presence of Ac2O, with various cationexchange resins as catalyst, stereospecifically afforded the C-22 acetate 215d (Scheme 35) in excellent yields. Again, the 22acetate 215d was obtained in 82% yield by ene reaction of tosylate 188c with (CH2O)n, Ac2O, and titanium triisopropoxy chloride as a Lewis acid in dichloromethane.95 Me3SiCl and tBuMe2SiCl have also yielded the same acetate in 81% and 74% yields, respectively, under similar reaction conditions.95 In all cases, the configuration at C-20 is natural. Nakai and co-workers96 reported Lewis acid-catalyzed ene reaction with glyoxylate. The ene reaction of steroidal olefin 216 with methyl glyoxylate in the presence of Me2AlCl afforded (20S,22R)-erythro product 217 as a single stereoisomer in 67% yield (Scheme 36). Similarly, ene reaction of 216 with αhaloaldehyde was shown to exhibit a high anti-diastereofacial selection or syn-diastereoselection to afford an efficient method for preparing stereochemically defined β-haloalcohols including the 22R-hydroxy side chain unit in steroids.97 The ene reaction of 216 and chloroacetaldehyde with Me2AlCl gave 20S,22R-syn product 218 as a single natural C-20 epimer in 73% yield (Scheme 36). Again, Me2AlCl-promoted ene approach to either (22S)- or (22R)-hydroxy steroid side chain has been described by the same group.98 In this case, the ene reaction was based on the concept of chelation versus nonchelation control of the carbonyl−ene reaction; the choice of Lewis acid and protecting group of α-alkoxyaldehyde enophiles allows control of the reaction. Ene reaction of steroidal olefin 216 with α-

Scheme 33

4.5.2. Ene Reaction with Acrylates. Acid-mediated ene reaction of steroidal Z-ene with acrylate-type dienophiles is also well documented.93 Acetate 188a, upon treatment with methyl acrylate and EtAlCl2 in dichloromethane at room temperature, afforded93 212 in 85% yield (Scheme 34). The use of αsubstituted acrylic esters, namely, methyl 2-chloroacrylate in the ene reaction, was also demonstrated for the introduction of two chiral centers in steroid side chain. Accordingly, 213 and 214 were obtained from acetate 188a and methyl 2-chloroacrylate in the ratio 6:1 (Scheme 34). 4.5.3. Carbonyl−Ene Reaction. Uskokovic and co-workers93 described a simple and efficient method for highly stereoselective introduction of steroid side chains (at C-17 and C-20), which are suitably functionalized for further elaboration. The ene reaction of (17Z)-ethylidene steroids with various enophiles, such as formaldehyde leads93 to useful intermediates L


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Scheme 36

Table 3. Ene Reactions of Steroidal Olefin 216 with Aldehydes 224a−d99 entry

aldehyde

yield (%)

22R:22S

1 2 3 4

224a 224b 224c 224d

0 quant 90 quant

>95:5 90:10 90:10

232, respectively, in good yields (Scheme 39). Matsuya et al.103 reported the ene reaction of 221 and 226 with (CH2O)n in the Scheme 39

silyloxyaldehyde 219 and Me2AlCl afforded (22R)-hydroxy product 220 with C-20 natural configuration as a single stereoisomer in 90% yield (Scheme 37). Ene reaction of 221 Scheme 37

with α-benzyloxyaldehyde 222 and SnCl4 gave the corresponding product (22S)-223 in 91% yield with >99% diastereoselectivity without cleavage of the silyl protecting group. Brassinosteroids have a 22R-hydroxy group in the side chain, and attention has been focused on the development of methodologies/routes for the stereocontrolled generation of steroidal side chain. Nakai and co-workers99 reported the ene reaction approach for concurrent control over the chiral centers at C-20 and C-22 of steroid side chain. Ene reactions of (Z)steroidal olefin 216 with acetylenic aldehydes 224 (having silyl and alkyl parts) in the presence of Me2AlCl produce (20S,22R)erythro-22-hydroxy-23,24-acetylenic steroid side chain 225 with high diastereofacial selectivity (Scheme 38, Table 3). Ene reaction of 221,100 229a,101a 229b,101b and 231102 with paraformaldehyde in the presence of catalytic amounts of BF3· Et2O leads to the corresponding alcohols 227, 230a, 230b, and

presence of Me2AlCl to the corresponding alcohols 227 and 228 (Scheme 39). Similarly, stereospecific ene reaction104 of ketone 233 with (CH2O)n in the presence of BF3·Et2O afforded 5α-23,24-bisnorchol-16-en-22-ol-3-one 234 in 98% yield (Scheme 39). All products are obtained with C-20 natural configuration. (Z)-17-Ethylidene steroid 196 was subjected105 to stereoselective ene reaction with paraformaldehyde in the presence of boron trifluoride etherate to give C-22 alcohol 235 as a single product in 80% yield (Scheme 40). Synthesis of C2-symmetric bis(20S)-5α-23,24-bisnorchol-16en-3β,6α,7β-triol-22-terephthaloate, active as a Na+-transporting transmembrane channel, was reported106 from 3βhydroxyandrost-5-en-17-one 236 via stereospecific functional-

Scheme 38

Scheme 40

M


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ization of the side chain by ene reaction. The starting steroidal material 239 was synthesized from 3β-hydroxyandrost-5-en-17one 236 via a sequence of reactions in which Wittig reaction is a key step. Transformation of (Z)-17(20)-ethylidene 239 to the (20S)-22-hydroxy side-chain compound 240 with (CH2O)n in the presence of BF3·Et2O in 79% yield was the key step in their synthesis (Scheme 41).

Table 4. Me2AlCl-Mediated Ene Reactions of Pregnadiene 188a with Various Aldehydes108

Scheme 41

Compound 188c was subjected107 to ene reaction with (CH2O)n in the presence of Et2AlCl as catalyst, and 22-hydroxy derivative 241 was obtained in 74% yield (Scheme 42). In

aromatic aldehydes produced predominantly (20S,22S)-22acetates. Lewis acid-mediated carbonyl−ene reaction has been used109 for the synthesis of 6-deoxoteasterone, a brassinolide biosynthetic intermediate, and its 20-epimer from steroidal C17(20)-olefin and chiral α-alkoxyaldehyde. The carbonyl−ene reaction between aldehyde 246 and (Z)-3β-acetoxypregna5,17-diene 188a with MeAlCl2, furnished ene adduct 247 in 65% yield, with C-20 unnatural configuration (Scheme 44).

Scheme 42

Scheme 44

addition, 3β-chloro-17-ethylidene steroid 242 was isolated as byproduct; the latter was formed as a result of partial transformation only at the C-3 center. Ene reaction of olefin 243 with (CH2O)n in the presence of Et2AlCl in CH2Cl2 afforded 22-hydroxy compound 244 in 68% yield (Scheme 42). Dimethylaluminum chloride-mediated ene reaction of aldehydes with (Z)-3β-acetoxy-5,17(20)-pregnadiene 188a at low temperatures, followed by acetylation of the resulting alcohols, has been shown to produce108 stereoselectively 22acetoxylated steroid derivatives 245 in good to excellent yields (Scheme 43, Table 4). Stereochemical outcome of these ene reactions depends on the size of the aldehyde employed; the less sterically hindered aldehydes, such as 4-methylpentanal and cyclohexane carboxaldehyde, afforded (20S,22R)-22-acetoxy products stereoselectively, whereas benzaldehyde and other

This stereochemical outcome was unusual compared with hitherto-known ene reactions between (Z)-ethylidene steroid and various enophiles, which gave only 20-natural steroid. To this comparison, the ene reaction between 246 and (E)-3βacetoxypregna-5,17-diene 199 was reported to proceed smoothly under the same conditions as those for (Z)-isomer, and ene adduct 248 with natural configuration at C-20 was obtained in 52% yield. Similarly, ene reaction of 188a and (R)2-benzyloxy-3-methylbutanal 249 in the presence of EtAlCl2, followed by hydrolysis, gave 250 in 53% yield for two steps.110

Scheme 43

N


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The four models of contignasterol’s side chains have been stereospecifically synthesized by the Me2AlCl-mediated ene reaction between steroidal derivative 231 and pseudoenantiomeric aldehydes 251 and 254111 (Scheme 45). Reaction

Scheme 47

Scheme 45

ene reaction if the experiment was carried out for prolonged time or at over −60 °C. The carbonyl−ene reaction is also applicable for not only A,B,C-ring-containing compound but also des-AB steroids. Ene reaction of (Z)-ethylidene derivative 267 with (CH2O)n in the presence of Me2AlCl proceeded115 stereoselectively to afford 268 in 86% yield (Scheme 48). Scheme 48

with aldehyde 251 led to formation of 252 and 253 in 80% and 16% yield, respectively, as an epimeric mixture at C-22, with C20 natural configuration. Again, reaction with aldehyde 254 gave 255 and 256 in 50% and 10% yield, respectively. Similar type of Me2AlCl-mediated ene reaction on 257 with aldehyde 258 gave112 (22S,24R) adduct 259 (72%) and epimer (22R,24R) adduct 260 (18%) (Scheme 45). Kumar and Covey113 reported an efficient total synthesis of the enantiomer of cholesterol from ent-testosterone. The Me2AlCl-mediated ene reaction of Z-olefin 261 with 4methyl-1-pentanal gave a quantitative yield of the inseparable epimeric 22-hydroxy steroid 262 (Scheme 46). As observed

Ene reaction of 210, 269, and 271 with (CH2O)n, catalyzed by BF3·Et2O/Me2AlCl and BF3·Et2O, gave 270116a−c and 272116d stereospecifically (Scheme 49). Similarly, ene reaction of 274 (obtained from 273 via reduction) with (CH2O)n and BF3·Et2O lead exclusively117 to alcohol 275 in 82% overall yield (Scheme 49). 4.6. Aldol Reaction

Shi et al.118 described a novel and efficient approach to construction of the 16β,17α-dihydroxycholest-22-one steroidal architecture characteristic of the saponin OSW-1 (22, Figure 7)

Scheme 46

Scheme 49

previously for steroids of naturally occurring absolute configuration, stereocontrol at C-20 was achieved due to the presence of the methyl group at C-13, which in this case precludes the reaction taking place from the α-face of the steroid. Nemoto and co-workers114a reported the synthesis of estrane analogues of OSW-1 from estrone 263. The 17(20)-ene 265 was synthesized from estrone derivative 264 via Wittig reaction (Scheme 47). Hydroxymethylation accompanied by the formation of a new chiral center was achieved through stereoselective ene reaction of 265 with (CH2O)n and Me2AlCl, which approaches from the less congested α-side to afford the alcohol 266 in 61% yield.114 Reaction time and temperature were important for satisfactory results in this reaction, as aromatic hydroxymethylation on the A-ring competed with the O


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addition of nitroacetate 286 to α,β-unsaturated ketone 285 (Eenone) afforded 287 in 40% yield, which was utilized for the synthesis of diosgenin (Scheme 52).

family in which aldol condensation was the key reaction. Aldol condensation of ketones 276−278 (Scheme 50), with lithium Scheme 50a

Scheme 52

Synthesis of solanidine was achieved via Michael addition of methyl 5-nitro-2S-methyl pentanoate 288 with α,β-unsaturated ketone 285, resulting121 in intermediates 289 and 290 in 20% and 26% yield, respectively (Scheme 53).

Reagents and conditions: Method A, (i) i-Pr2NH, n-BuLi, −78 °C, 15 min; (ii) −78 °C, HMPA, THF, propionate, 0.5 h; (iii) 276−278, −78 °C. Method B, (i) i-Pr2NH, n-BuLi, −78 °C, 15 min; (ii) propionate, HMPA, THF, −78 °C, 0.5 h; (iii) 276−278, −78 °C. Method C, similar to method B but without addition of HMPA. a

Scheme 53 E-enolate of ethyl propionate predominantly led to the desired product with 20(S) configuration. The 17α-hydroxy(silyloxy)20S-products 279a, 280a, and 281a were formed in 41%, 63%, and 43% yield, respectively (method A, Table 5). Without Table 5. Aldol Condensation with Propionate Enolates118 entry

ketone

propionate

method

1 2 3 4 5 6 7

276 277 278 277 277 277 277

ethyl ethyl ethyl ethyl ethyl isobutyl dodecyl

A A A B C C C

Michael addition of nitromethane or sodium cyanide on ketones 285 and 292 (Z-enone) provided122 the corresponding compounds 291, with C-20 natural configuration, and 293, with unnatural configuration at C-20 (Scheme 54). The stereochemical outcome of the Michael addition depends on the starting steroidal enone.

product (yield, %) 279a 280a 281a 279a 280a 282a 283a

(41),279b (0) (63), 280b (0) (43), 281b (0) (41), 279b (29) (75), 280b (12) (78), 282b (0) (81), 283b (0)

Scheme 54

control of the exclusive generation of E-enolate of ethyl propionate, reaction of ketone 276 provided the natural 20S product 279a in a comparable 41% yield, but its 20R isomer 279b was also obtained in 29% yield (method B). However, reaction of ketone 277 under similar conditions in the absence of HMPA (method C) afforded the desired 280a in a 75% yield, with its 20R-isomer 280b in 12% yield. Condensation of 277 with isobutyl and dodecyl propionate (method C) provided the desired 17α-hydroxy-20(S) adducts 282a and 283a in good yields (78% and 81%, respectively). Aldol condensation119 of 3β-hydroxyandrost-5-en-17-one 236 with propionitrile and LDA at −78 °C afforded 284 as epimeric mixture in excellent yield (Scheme 51). 4.7. Michael Addition Reaction

4.8. Mukaiyama−Michael Conjugate Addition Reaction

A stereospecific protocol for the steroid side chain construction based on Michael addition of nitroalkanes to steroidal 17(20)en-16-ones has been developed120 for the synthesis of sapogenin, steroidal alkaloid, and cholesterol also. Michael

Sterol C/D side-chain fragments were synthesized from ketene acetal derived from 6-methylheptanoic acid, 2-methylcyclopent2-en-1-one, and allyl methyl carbonate, with Mukaiyama− Michael conjugate addition and Tsuji alkylation as the key steps.123,124 Reaction of enone 294 with ketene acetal 295 in the presence of trityl hexachloroantimonate (TrSbCl6), followed by quenching with pyridine-2-methanol, afforded a mixture of O-trimethylsilyl enol ether 296 and corresponding ketone 297 in 76% yield (Scheme 55). The carbon framework of des-AB cholestane was obtained by the one-pot three-component reaction of ketene acetal, unsaturated ketone, and ketal previously described.125 Reaction of ketene acetal 298 with α,β-unsaturated ketone 294 in the

Scheme 51

P


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Scheme 55

Scheme 58

presence of TrSbCl6 gave adduct 299 in 46% yield125 (Scheme 56). Similarly, reaction of 300 and 294 in the presence of TrSbCl6 gave the adduct, which upon reaction with 301 and a mixture of TiCl4−Ti(OiPr)4 gave the product 302 in 68% yield. Scheme 56 radical cyclizations, was extended to many types of reactions. C−C bond formation via free-radical-mediated cyclization reactions now has a firmly established role in synthetic organic chemistry as a highly versatile and often indispensable method of skeleton construction.128 Koreeda and George129 described the synthesis of 22hydroxylated steroid side chain in which the regio- and stereocontrolled synthesis lies in the generation of the two stereocenters, C-17 and C-20 in a single, radical cyclization step as a result of chirality transmission from the stereodirecting 16hydroxy derivative. Both 309 (17E,16α) and 312 (17E,16β) underwent exclusively 6-endo cyclization that furnished, after desilylation, diols 311 and 314, respectively, as single diastereomers (Scheme 59). This mode of cyclization could Scheme 59 Ketene acetal 298, upon treatment with enone 294 in the presence of a catalytic amount of TrSbCl6 and then addition of the reaction mixture to 1-thiophenylbut-3-en-2-one 303 as the second Michael acceptor, gave diketone 304 in 72% yield126 (Scheme 57). Scheme 57

Wicha and co-workers127 described the diastereoselective Mukaiyama−Michael addition reaction of selected optically active ketene acetals with 2-methylcyclopent-2-en-1-one. Reaction of 294 with 305 in the presence of TrSbCl6, followed by 303, gave 306 in 55% yield. Similarly, reaction of 294 with 307 and 303 afforded 308 in 75% yield (Scheme 58). Products 306 and 308 are precursors for synthesis of 1α,25dihydroxyvitamin D3 and its enantiomer.127

result from conformational rigidity and a lower degree of substitution at C-20 versus C-17. Chirality at C-16 was cleanly transmitted to C-20. Also, a remarkable feature is the exclusive formation of 17-α-H for both 310 and 311. Treatment of 309 with (n-Bu)3SnH in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) induced cyclization of the resulting radical to give 310. Oxidation of 310 with H2O2 resulted into the C-16,22-diol 311 with natural configuration at C-20. Similarly, C-16β,α-bromosilyl ether 312 produced the cyclized product 313 in 65% yield, and a similar protocol of oxidation resulted in 314 with unnatural configuration at C-20.

4.9. Chirality Transmission Approach

Radical cyclization has been one of the most productive applications of the temporary silicon connection. The temporary silicon connection transforms a potential intermolecular one by transiently connecting both partners through a silicon linkage. Generally, these temporary connections are ethers. Temporary connectivity endows the reaction with entropic advantages as well as regiospecificity, and often stereoselectivity.128 The silicon-based protocol, first applied in Q


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This suggests that the chirality at C-16 determines the stereochemical outcome of the product. Again, radical cyclization of bromide 315 with Bu3SnH and AIBN provides cyclic 316, with natural configuration at C-20 and chair conformation, and its C-22 epimer 317 in a ratio of 4:1 in 65% yield130 (Scheme 60). Treatment of the major

Scheme 61

Scheme 60

Scheme 62

compound 316 with KOH in DMSO was found to substitute a methyl by a hydroxy group, generating silanol 318 (65% yield) as well as the protiodesilylation product 16α-hydroxycholesterol 319 (10−20% yield). The obtained silanol 318 under standard Tamao oxidation conditions afforded diol 320 in 75% yield. The silyl connector at the C-22 hydroxyl represents another approach to the stereoselective construction of steroid side chains. Wicha and co-workers131 described the radical cyclizations of 17(E) 321 and 17(Z) 325: they were virtually nonstereoselective at C-20, with the ratio of protiodesilylation products 323 (with natural configuration at C-20) to 324 (with unnatural configuration at C-20) being nearly 1:1 (Scheme 61). The approach from the β-face of the Z-double bond of 325 is poorly reflected in this product distribution. In contrast to 321 and 325, the cyclizations of isopentyl derivatives 326 and 327 were totally stereoselective, yielding products 328 and 329 (natural configuration at C-20). This can be viewed as the minimization of allylic interactions between C-16 and C-22 substituents. The use of diastereomeric silafuran mixture 322 (derived from 321 and 325) produced oxetane 330. Reaction of 330 with lithium acetylide derivative 331 in the presence of BF3·Et2O led to highly selective ring-opening and only one diastereomer, 332, in 83% yield (Scheme 61).

Carroll rearrangement of allylic ester 337 in boiling xylene afforded132 a single rearranged material 338 (90% yield) with natural configuration at C-20 (Scheme 63). Similarly, isomeric Z-allylic keto acetate 339, upon Carroll reaction, afforded 340 (62% yield) with C-20 unnatural configuration. Nakai and co-workers133 reported the synthesis of 20-epicholesterol, which relies on the unprecedented β-face Claisen rearrangement of an E-vinyloxy steroid, leading exclusively to Scheme 63

4.10. Claisen and Claisen-type Rearrangements

Claisen rearrangement reaction, with a highly ordered sixmembered transition state in the concerted cyclic process, leads to high stereoselectivity.132 Stereospecific control of the C-20 configuration in cholesterol and other sterols/steroids is possible. From analysis of the respective transition states of rearrangement of both possible allyl alcohols, it can be deduced that C-17(E)-isomer 333 will produce the natural configuration (20R) at C-20 in 334, whereas the C-17(Z)-isomer 335 produces steroidal unnatural C-20 isomer 336 (Scheme 62). R


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Allylic alcohol 350 was subjected to Johnson−Claisen rearrangement and afforded137 ester 351 as a single isomer in 87% yield with natural configuration at C-20 (Scheme 68). Product 351 is utilized for the synthesis of candicanoside A 352, a potent antitumor saponin.

the unnatural 20S chirality. The allylic alcohol 341 was treated with ethyl vinyl ether, in the presence of mercuric(II) acetate, and the rearranged C(20S) aldehyde 342 was obtained in 84% yield as a single unnatural C-20 stereoisomer. Aldehyde 342, after some synthetic manipulations, was converted to 20-epicholesterol133 (Scheme 64).

Scheme 68 Scheme 64

Claisen−Ireland sigmatropic rearrangement of 343 with LDA and trimethylsilyl chloride, followed by methylation with CH2N2, afforded134 (22R)-erythro product 344 as a single stereoisomer in 88% yield with natural configuration at C-20 (Scheme 65). Scheme 65

Enantioselective syntheses of both (20R)- and (20S)-des-ABcholest-8(14),22-dien-9-one, which are potential intermediates leading to vitamin D3, steroids and their analogues, were achieved.138,139 Claisen rearrangement of vinyl ether 353 gave the single product 354 in quantitative yield (Scheme 69). Similarly, epimer 355 gave a single product, 356. Scheme 69

Steroidal allylic alcohol 345, subjected to the conditions of orthoester Claisen rearrangement (triethyl orthoacetate, propionic acid, heating in xylene), afforded135 rearranged ester 346 as a single isomer in 98% yield with natural configuration at C-20 (Scheme 66). Scheme 66

Enantiomerically pure C,D-ring allylic alcohol 357 stereospecifically undergoes [3,4]-sigmatropic rearrangements to give140 C-23-functionalized 16-ene vitamin D3 side-chain units with natural C-20(S) configuration (Scheme 70). Reaction of allylic alcohol 357 with ethyl vinyl ether and mercury diacetate afforded the desired enol ether 358, which underwent thermal rearrangement in situ to give aldehyde 359 in 97% yield, with only one diastereomer (Scheme 70). Johnson orthoester rearrangement of alcohol 357 with trimethyl orthoacetate, in the presence of a catalytic amount of 2,4,6-trimethylbenzoic acid, afforded methyl ester 361 in 83% yield via 360 (Scheme 70). An anion-assisted Carroll reaction, performed via the β-keto ester 362, resulted in 94% yield from the reaction of 357 with diketene. This β-keto ester 362, upon reaction with 2 equiv of sodium hydride, smoothly underwent rearrangement and in situ decarboxylation at 140 °C to give the 16-ene-23-methyl ketone 363 in 96% yield. Conversion of allylic alcohol 357 into an α-sulfide ester 364

Xestobergsterol A 349, a potent inhibitor of histamine release, was synthesized from dehydroepiandrosterone (androstenolone) via the orthoester Claisen rearrangement.136 Compound 347 was subjected to orthoester Claisen rearrangement with triethyl orthoacetate and propionic acid to give the rearranged ester 348 with natural configuration at C-20 as a single isomer in 88% yield (Scheme 67). Scheme 67

S


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369 as a single stereoisomer in 75% yield (Scheme 71), whereas introduction of the silyl group in 368 induced the reversal of

Scheme 70

Scheme 71

distereoselection to give the (20S,22R)-erythro product 225b as a single stereoisomer. Products 369 and 225b serve as key intermediates for the synthesis of many important side-chainmodified steroids, such as insect hormone ecdysones and plantgrowth-promoting brassinosteroids, respectively. Upon reaction with n-BuLi, the sterically congested β-face in steroid 370 exhibits the usual erythro selection to afford 225b as a single stereoisomer144 (Scheme 72).

by use of (phenylthio)acetyl chloride proceeded in 95% yield. This ester 364 was then methenylated by use of Tebbe’s reagent to form the corresponding allylic vinyl ether 365, which thermally rearranged into β-keto phenyl sulfide 366 in 89% yield.

Scheme 72

4.11. Wittig Rearrangement

The concept of stereochemical transmission via [2,3]-Wittig rearrangement has several applications in steroid side-chain synthesis.141,142 One general and simple application is to employ the [2,3]-Wittig strategy for specifically transferring a configurationally defined chirality on the steroidal side chain to another center within the side-chain framework, analogous to simple acyclic counterparts.141,142 [2,3]-Wittig rearrangement can also be used for specifically transmitting an epimerically defined chirality at C-16 of the steroidal nucleus to the new chiral centers at C-20 and C-22 of the side chain (Figure 18).

Castedo et al.145 reported the stereocontrolled synthesis of steroidal C-20 epimers via [2,3]-Wittig sigmatropic rearrangement under mild conditions. An efficient and closely related alternative relies on a primary α-oxycarbanion-induced [2,3]Wittig sigmatropic rearrangement as the key step for stereospecific synthesis of three-carbon side chain, suitably functionalized for further elaborations. Treatment of steroidal stannyl derivative 371 at −78 °C with n-BuLi resulted in homoallylic 20S alcohol 372 in 83% yield (Scheme 73). Under similar reaction conditions, n-butyllithium-induced rearrangement of steroidal stannyl derivative 373 afforded homoallylic 20R alcohol 374 in 70% yield.145 The stereochemical outcome at C-20 position depends on the configuration of starting steroidal olefin. Again, Castedo et al.146 reported the steroidal β-face [2,3]sigmatropic rearrangement of alkoxy-organolithium intermediate to stereospecific construction of the unnatural configuration at C-20 in steroid. The α-alkoxy organostannane steroid compound 375, upon treatment with t-BuLi in refluxing THF, gave 374 in 89% yield (Scheme 74). Stereoselective [2,3]-Wittig rearrangement on 17(20)-ethylidene-16α-(carbomethyl)oxy steroid 376 with LDA in THF at

Figure 18. Wittig rearrangement.

Its significant feature is that it allows concurrent control of absolute and relative configurations at C-20 and C-22 through the proper combination of exo-olefin geometry, configuration (α or β) at C-16, and the key G group.141,142 Nakai and co-workers143 successfully demonstrated the utility of this approach in the stereocontrolled synthesis of either 22(S)- or 22(R)-hydroxy-23-acetylenic side chains from the single precursor with natural 20(S) configuration in both cases. The most significant feature in this example is dianion rearrangement of 367 to afford the (20S,22S)-threo product T


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Scheme 73

Scheme 77

Scheme 74

−56 °C, followed by esterification with CH2N2, afforded147 αhydroxy ester 377 in 85% overall yield (Scheme 75). Scheme 75 yields, respectively. In disparity to this, 17Z(20)-ethylidene-16(2-furyl)methoxy steroids 387 and 389 led to the corresponding 2,3-rearranged products in low yields [25% for (20R,22S)22-hydroxy steroid 388; 31% for (20S,22R)-22-hydroxy steroid 382]. Tsubuki et al.150 utilized Wittig rearrangement of 17E(20)ethylidene-16α-(4′-methyl-2′-thienyl)methyloxy steroid for construction of saponin OSW-1 and its analogues. Treatment150 of steroid 391 with n-BuLi (10 equiv) in THF at −78 °C, followed by warming to 0 °C, gave [2,3]-rearranged products 382, 393, and [1,2]-rearranged 394 in a ratio of 23:23:54, respectively, in 97% total yield (Scheme 78) (Table 6, entry 1). Again, reaction of 391 with s-BuLi (3 equiv) in THF at −78 °C produced 392−394 in a ratio of 19:34:47 in

One-step introduction148 of both the steroidal double bond at C-16 and a side chain with the natural 20R stereocenter and the 25-hydroxy group of the principal metabolites of vitamin D in 379 was achieved via [2,3]-Wittig sigmatropic rearrangement of steroid 378 in better yield (Scheme 76). Scheme 76

Scheme 78

Tsubuki et al.149 reported Wittig rearrangement of 17(20)ethylidene-16-furfuryloxy steroids in the stereoselective construction of the steroid side chain. Reaction of 17E(20)ethylidene-16α-(2-furyl)methoxy steroid 380 with t-BuLi in THF afforded (20S,22S)- and (20S,22R)-22-hydroxy steroids 381 and 382 and 17Z(20)-ethylidene-16α-(2-furyl)hydroxymethyl steroid 383 in 61%, 28%, and 9% yields, respectively (Scheme 77). Similarly, treatment of 17E(20)ethylidene-16β-(2-furyl)methoxy steroid 384 with base gave (20R,22R)-22-hydroxy steroid 385 and 17Z(20)-ethylidene16β-(2-furyl)hydroxymethyl steroid 386 in 60% and 17% U


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Table 6. Wittig Rearrangement150 of Thiophenemethyl Ether 391 entry

base

yield (%)

ratio of 392/393/394

1 2 3

n-BuLi s-BuLi t-BuLi

97 62 90

23:23:54 19:34:47 40:18:42

Scheme 80

moderate yield (62%) (Table 6, entry 2). Use of t-BuLi for the [2,3]-rearrangement gives better results (Table 6, entry 3). Similarly, treatment of 395 with t-BuLi (5 equiv) in THF at −78 °C gave [2,3]-rearranged product 396 (22α:22β alcohols in a ratio of 78:22) in 59% yield (Scheme 78). 4.12. Organopalladium Reagents

Trost and co-workers151−153 extensively studied the stereocontrolled introduction of side chains at C-20 by use of steroidal (Z)-C-17(20)-olefin compounds and palladium chemistry. 17(20)Z-3-Methoxy-19-norpregna-1,3,5(10),17(20)-tetraene 190, obtained from estrone methyl ether by the Wittig reaction, was converted to its π-allylpalladium complex 397 (Scheme 79). Complex 397 underwent C-20 alkylation by Scheme 79 Scheme 81

dimethyl malonate and methyl phenylsulfonyl acetate nucleophiles, separately in the presence of a phosphine, preferably 1,2bis(diphenylphosphino)ethane (dppe), which proceeded highly regio- and stereoselectively to 398 and 399 with unnatural stereochemistry at C-20 in 81% and 82% yields, respectively. The reaction was carried out151−153 catalytically, starting from allylic acetates 400, 402, and 404, to afford 401, 403, and 405 in 83%, 86%, and 85% yield, respectively, with overall retention and natural configuration at C-20 (Scheme 80). The two pathways, using stoichiometric and catalytic amounts of palladium, led to products with opposite stereochemistry at C20. Palladium-catalyzed 1,4-addition of carbon nucleophiles was applied to the regio- and stereoselective introduction of 15βhydroxy group and side chain to steroid moiety. Upon reaction of steroidal C-15(16)-epoxy compound 406 with the dimethyl malonate nucleophile, the 1,4-adducts 407 and 408 were obtained154,155 in 83% yield with 95:5 ratio (Scheme 81). Similarly, exposure of steroid 409 to β-keto ester 410 furnished C-22 epimeric compound 411 in 86% yield with unnatural configuration at C-20. Palladium-catalyzed regioselective hydrogenolysis of allylic carbonates with triethylammonium formate was applied to the introduction of steroidal C-20 side chains.37,156 The steroid side chain with C-20 natural configuration was generated stereospecifically by palladium-catalyzed hydrogenolysis of C-20 (Z)-

allylic carbonates with triethylammonium formate. The steroid side chain with C-20 unnatural configuration was generated from C-20 (E)-allylic carbonates.37,156 Palladium-catalyzed hydrogenolysis of C-23 allylic formate 412 afforded terminal olefin 413 regioselectively (Scheme 82). The reaction was not stereoselective and shows that the product 413 is a 1:1 mixture of stereoisomers at C-20. The intermediate π-allylpalladium complex 414 can rotate freely, and hydride transfer takes place from both α and β sides to give both isomers. Steroidal (E)-carbonate 415 and (Z)-carbonate 416 were subjected to palladium catalysis with an excess of formic acid Scheme 82

V


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and triethylamine to give the unnatural C-20 isomer 417 and natural C-20 isomer 418, respectively,37,156 in 92% and 91% yield (Scheme 83). Similarly, (E)-carbonate 419 and (Z)-

Scheme 85

Scheme 83

upon treatment with chloroacetonitrile and base 426, produces cyano steroid 427 possessing the natural configuration at C-17 and C-20. Furthermore, 17(20)-E-ethylidene isomer 199 undergoes hydroboration to produce 429 with the unnatural configuration at C-20. Midland and Kwon160 studied the hydroboration reaction for steroidal olefins. Predominantly, hydroboration occurs from the top (si) face to provide the 20S product (Scheme 86). Scheme 86 carbonate 420, upon palladium-catalyzed hydrogenolysis, afforded the corresponding compounds 421 with unnatural stereochemistry at C-20 and 422 with C-20 natural configuration in excellent yields (Scheme 83). 4.13. Organoboron Reagents

Bottin and Fetizon157 studied the hydroboration of C-20(21) steroidal olefins that leads to (20S)-21-hydroxy steroids in good yields. Tetrahydropyranyl steroidal derivative 423, upon treatment with an excess (1:5) of disiamylborane and then hydrogen peroxide, afforded (20S)-alcohol 424 in 45% yield (Scheme 84). Use of the calculated amount of diborane leads to

Table 7. Hydroboration160 of 430

Scheme 84

entry

reducing agent

431:432

1 2 3 4 5 6

BMS thexylborane 9-BBN disiamylborane dicyclohexylborane bis(trans-2-methylcyclohexyl)borane

1:1 4:1 14:1 22:1 26:1 54:1

Hydroboration of 430 with borane (Table 7, entry 1) afforded products 431 and 432 unselectively (dr = 1:1), whereas use of reagents such as 9-BBN (Table 7, entry 3) and dicyclohexylborane (Table 7, entry 5) furnished 431 as the major product with 14:1 and 26:1 diastereomeric ratio, respectively. With a hindered borane such as bis(trans-2-methylcyclohexyl)borane, greater than 98% purity of 431 was obtained. Pregnenolone is readily converted into E-trisubstituted olefin 433 by the Wittig reaction, followed by hydroboration of 433 with 9-BBN, which proceeds in a highly chemoselective and stereoselective manner to produce 434 in excellent yield.160 Although deprotection of acetate took place, the 5(6) double bond remains intact. The 20S,22R isomer is essentially the only product (20S,22R:20R:22S = 300:1) (Scheme 87). Stereoselective and chemoselective hydroboration161 of 435 with dicyclohexylborane provided alcohol 436 with 20S

a 40:60 mixture of 20R and 20S isomers. Furthermore, Trivedi and co-workers158 also reported the hydroboration of 423 with 9-borabicyclo[3.3.1]nonane (9-BBN), followed by oxidation with H2O2/NaOH, which gave 424 in 78% yield. The use of stereoselectively formed organoboron intermediates as blocking groups for carbon−carbon bond-forming reactions has been developed.159 An efficient approach for the construction of steroid backbones via hydroboration of steroid with 9-BBN, followed by carbon−carbon bond-forming reactions, was developed.159 The approach of borane from the β-face is apparently blocked by the angular methyl group. Hydroboration of 17(20)-(Z)-ethylidene steroid 188a (Scheme 85) with 9-BBN proceeds in a highly selective manner from the α-face of the steroid.159 The resulting 9-BBN derivative 425, W


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reaction. Compound 444, upon treatment with 9-BBN in THF followed by H2O2 and NaOH, gave 445 in 70% yield with lower stereoselectivity (66% diastereomeric excess, de) (Scheme 91). This can be attributed due to the absence of the 18-angular methyl group substituent in 444.

Scheme 87

Scheme 91 configuration as the predominant product (dr 26:1) (Scheme 88). Scheme 88 4.14. Organocopper Reagents

4.14.1. Alkylidene Oxiranes. Marino and co-workers165 reported the regiospecific and stereospecific 1,4-addition of alkyl cyanocuprates to cyclic vinyl oxiranes to give the corresponding alcohols. This strategy was utilized for the stereospecific construction of side chains from substituted exomethylene epoxycycloalkanes: mixed cyanocuprates can selectively generate trans-4-alkylcyclohex-2-enols. The methodology is greatly extended to a chiral alkylideneoxirane of known configuration, where there exists the possibility for a 1,4chirality transfer in which two asymmetric centers are generated in a 1,4-relationship165 (Figure 19).

Pregnenolone (3β-hydroxypregn-5-en-20-one) 437 was stereoselectively converted into (25R)-26-hydroxycholesterol 441 via stereoselective hydroboration, asymmetric reduction, and stereospecific [2,3] sigmatropic rearrangement (Scheme 89).162 Stereoselective and chemoselective hydroboration of the steroidal 20(22)-double bond in 438 with 9-BBN provided alcohol 442 in 95:5 ratio (20R:20S) (Scheme 89). Scheme 89

Figure 19. 1,4-Chirality transfer.

1,4-Trans additions of alkyl cyanocuprates to alkylideneoxiranes of sterols provide the stereospecific methodology for concomitant introduction of the C-20 asymmetric center and the 15β-hydroxyl group. Stereospecific conversions of dehydroepiandrosterone to cholesterol, isocholesterol, and their 15β-hydroxy derivatives were described via 1,4-trans-addition reaction by Marino and Abe.166 Steroidal oxirane 409, upon reaction with excess lithium isohexylcyanocuprate in ether at −78 °C, produced isomerically pure 1,4-adduct 446 with C-20 natural configuration in 82% yield (Scheme 92). Steroidal oxirane 406, upon addition of lithium methylcyanocuprate, formed equal amounts of 1,4- and 1,2-adducts 447 and 448,

The stereochemistry at C-17 and C-20 in ent-steroids was set by hydroboration163 of steroidal C-17(20)-ene with 9-BBN, which enters from the top face of alkene 261. Coupling of the resulting hindered trialkylborane with chloroacetonitrile in the presence of hindered base gave nitrile 443 as a single isomer in 47% yield (Scheme 90). This product, 443, was further utilized for the synthesis of ent-cholesterol.163 Vandewalle and co-workers164 reported the total synthesis of 1α,25-dihydroxy-18-norvitamin D3, in which the construction of C-20 stereocenter was achieved by the hydroboration

Scheme 92

Scheme 90

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substrates lead to stereocontrolled introduction of the side chain with either of the C-20 epimers.35 Reaction of C-17(20)en-16-keto steroid 462 with lithium isoamylcuprate 463 and lithium diisohexylcuprate 465 leads to α-face attack, giving exclusively corresponding products 464 and 466, having the C20 natural configuration (Scheme 95).

respectively (Scheme 92). Intermediate 447 was utilized for synthesis of 20-epi-cholesterol (32, Figure 10). Treatment of 449 with magnesium cyanocuprate of 2-(2bromoethyl)-isopropyl-1,3-dioxolane 450 gave 1,4-adduct 451 in excellent yield167 (Scheme 93). Stereochemistry at C-20 in Scheme 93

Scheme 95

The α-alkoxy vinyl cuprate 469, upon 1,4-addition reaction to Z-enone 468 (synthesized from 467 via Dess−Martin periodinane oxidation) in the presence of TMSCl, afforded170 silyl enol ether 470 with the C-20 unnatural configuration in 92% yield (Scheme 96). Similarly, TMSCl-activated 1,4-

451 results from attack of the mixed cuprate on the α-face of the E-17(20)-alkene. Similarly, organocuprate 452, upon treatment with 449, gave exclusively the 1,4-addition product 453. Highly efficient168 conjugate 1,4-addition of organocuprate 455 to steroidal 15β,16β-epoxy-17(20)(E)-ethylidene 454 gave 456 in 93% yield (Scheme 93). McMorris and co-workers169 reported the synthesis of 15βhydroxy-24-oxocholesterol 457 from 3β-acetoxyandrost-5-ene17-one 114, with 1,4-conjugate addition reaction as the key step (Scheme 94). Reaction of (17E)-3β-(dimethyl-tert-

Scheme 96

Scheme 94

addition of α-alkoxy vinyl cuprate 469 to E-enone 471 (synthesized from 221 via allylic hydroxylation followed by Swern oxidation) gave silyl enol ether intermediate 472 in good yield (having the C-20 natural configuration), which was further utilized for synthesis of OSW-1. Danishefsky and co-workers171 reported the first total synthesis of neurotrophic compound NGA0187 (476) via stereoselective conjugate addition of vinyl cuprate to enone. Stereoselective addition of vinyl cuprate 474 from the si face of the steroidal C-17(20)-en-16-one 473a,b, followed by kinetic protonation of the resultant enolate from the same face, furnished steroid 475a,b, respectively, with the desired stereochemistry at C-17 and C-20 (Scheme 97). Conjugate addition5c of lithium dimethyl cuprate to enones 477 and 478 resulted in natural C-20 isomer 479 (67%) and unnatural C-20 isomer 480 (37%), respectively (Scheme 98).

butylsilyloxy)-15β,16β-epoxypregna-5,17(20)-diene 409 with magnesium cyanocuprate derivatives of 3-(1,3-dioxolan-2-yl)4-methylpentyl bromide 458 gave (20R)-3β-(dimethyl-tertbutylsilyloxy)-15β-hydroxy-24-oxocholesta-5,16-diene-24-ethylene acetal 459 in 80% yield (Scheme 94). Similarly, 409, upon reaction with 460 in the presence of CuCN, furnished 461 in 82% yield. 4.14.2. C-17(20)-en-16-keto Steroids. Reactions of organocuprates with various C-17(20)-unsaturated steroid Y


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by Li2Cu3R5 is carried out. Carbamate 486 is used for preparation of vitamin D analogues with the unnatural configuration at C-20. Compounds 487a−e were obtained in high yields by reaction of 486 with Li2Cu3R5 (Scheme 100).

Scheme 97

Scheme 100

Scheme 98

4.14.3. C-17(20)-en-16-Pivalates/Carbamates. Reaction of C-17(20)-en-16α-pivaloyloxy steroid 481 and 16β-pivaloyloxy steroid 484 separately with lithium isohexylcyanocuprate 482 in ether proceeded35 in a regio- and stereocontrolled manner. The former 16α-compound 481 gave exclusively the unnatural 20S-isomer 483, while the latter 16β-compound 484 gave exclusively the natural 20R-isomer 485 (Scheme 99).

Treatment of carbamate 488 with different higher-order cuprates (Li2Cu3R5) gave compounds 489a−d, with the natural configuration at C-20, as a single isomer in high yields. When carbamate 490 was treated with Li2Cu3R5, an inseparable 1:1 mixture of the protected vitamin D3 491 and its 5,6-trans isomer 492 was obtained. Again, reaction of 493 with the higher-order cuprates Li2Cu3R5 (R = Me, n-Bu, Ph) proceeded cleanly to give vitamin D analogues 494a−c with unnatural configuration at C-20. Carbamate 495 was subjected with Li2Cu3R5 to produce 496a,b vitamin D analogues with the natural configuration at C-20 by SN2′ syn displacement of the carbamoyl moiety. Both routes gave the desired allyl products in high yields.

Scheme 99

4.15. Organozirconocene Reagents

Organozirconocenes have emerged as a useful classes of transition metal derivatives, used in organic synthesis. A wide range of zirconocene-mediated organic transformations and the relative ease of preparation of alkenyl- and alkyl chlorozirconocenes contribute to the broad appeal of this chemistry. Schwartz and co-workers172,173 have studied the coupling of steroidal (π-allylic)palladium complexes with organozirconium species as a new route for steroid synthesis. The regiochemistry of the coupling product could be controlled with the use of

Mourino and co-workers26a developed two efficient synthetic routes to 1α,25-dihydroxy-16-dehydrovitamin D3 and their C20 analogues. The salient feature common to both routes is the introduction of side chains functionalized at the C-20 position. In the first route, C,D side-chain fragments were prepared by SN2′ syn displacement of allylic carbamates by Li2Cu3R5. In the second route, SN2′ syn displacement of the carbamate moiety Z


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exogeneous olefins. Coupling of palladium complex 497 and zirconium complex 498 is slow and is inhibited172 by the addition of PPh3 at room temperature (Scheme 101). However,

Scheme 103

Scheme 101

acetate 402, upon reaction with zirconocene 502 in the presence of maleic anhydride and PdCl2, leads to 503 and 511 in 5:1 ratio (Scheme 104). Scheme 104 in the presence of maleic anhydride, the reaction proceeds to completion within 5 min, even at −78 °C. The regiochemistry of this coupling is affected by the olefins. In absence of ligands, coupling products 499 and 500 were obtained in the absence of ligands and formed by reaction at the C(20) and C(16) carbons, respectively, in a 2:3 ratio (51% yield). The C(20) coupling product was obtained in the presence of maleic anhydride with greater than 7:1 selectivity of 499 to 500 (96% yield). Similar work was described173 for the construction of unnatural stereochemistry at C-20 from the E-17(20)-isomer of steroidal backbone. The coupling reaction of steroidal (E)isomer 501 with zirconocene complex 502 in the presence of maleic anhydride, predominantly at C(20) over the temperature range −78 to 25 °C, resulted in formation of 503 in 85% yield with unnatural configuration at C-20 (Scheme 102).

Regioselective opening of vinyl cyclopropane ring-containing substrates via complexation with a stoichiometric amount of Cp2Zr was established.175 This strategy was utilized in the stereocontrolled preparation of steroidal side chain in natural and/or unnatural forms and showed a high possibility of constructing the new analogues.175 Steroidal vinyl cyclopropanes 512 and 514 were prepared via a sequence of reactions including Simon−Smith reaction. Cp2Zr complexation of 512, followed by addition of acetone and deprotection of TBDMS group, gave C-20-epi-steroid 513 in 60% yield (Scheme 105). Similarly, 514 gave the C-20 naturally configured steroid 515 in 47% yield.

Scheme 102

Synthesis of 25-hydroxycholesterol and 25-hydroxy-20-epicholesterol were described by use of a dimetalated coupling reagent via (η3-allyl)palladium-based systems by Riediker and Schwartz.42 Steroidal (Z)-17(20)-isomer 504, upon reaction with organozirconocene 505 in the presence of maleic anhydride, yielded 506 in 70% yield with C(20R) natural configuration and side product 507 in 18% yield (Scheme 103). A similar coupling reaction, using the steroidal (E)-17(20)isomer 508 with 505, yielded 509 with C(20S) unnatural configuration in 82% and 510 in 11% yield. Selective coupling between allylic acetates and alkenylzirconium complexes via (π-allylic)Pd(II) complex can serve as a catalyst precursor.174 Reaction between C-20 acetate compound 402 and zirconocene 502, in the presence of Pd(PPh3)4 and Ph3P as a ligand, resulted a mixture of C-20-alkylated 503 and C-16-alkylated 511 in 35:65 ratio.174 Furthermore, C-20

Scheme 105

AA


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4.16. Hydrovinylation Reaction

Scheme 107

Addition of vinyl group and hydrogen across a double bond is known as a hydrovinylation reaction, a promising method in synthetic organic chemistry. Transition-metal-catalyzed hydrovinylation holds tremendous potential as a generally useful C− C bond forming reaction, because a cheap feedstock (ethylene) is used and the reaction proceeds in an atom-economical fashion. Donaldson and co-workers176 described hydrovinylation of steroidal diene 516 with excess ethylene in the presence of catalyst 517 to give a single diastereomer 518 in 88% yield with unnatural 20(S) configuration (Scheme 106). The Scheme 106

stereochemistry in the neighborhood of the diene moiety determined the stereochemistry of the newly constructed chiral center at C-20. Intermediate 518 was utilized for synthesis of the Roche vitamin D3 analogue Ro 26-9228, which was reported to increase bone mineral density in rats. A similar method was also used by Rajanbabu and coworkers177 with various chiral ligands. Ni(II)-catalyzed hydrovinylation of 1,3-dienes by use of finely tuned phosphoramidite ligands lead to exclusively C-20(R) or C-20(S) steroids without mutual contamination, depending on the type of enantiomeric ligands. Steroidal 1,3-dienes 516 and 520 were subjected to hydrovinylation with [(allyl)2NiBr]2 and sodium salt of borate, in the presence of ligand 523 along with atmospheric pressure of ethylene, to give the corresponding 20(S)-hydrovinylation adducts 518 and 521, respectively. In place of ligand 523, other ligands 524 and 525 gave 20(R) adducts 519 and 522, respectively, with C-20 natural configuration (Scheme 107).

Scheme 108

4.17. Miscellaneous

Stereospecific nucleophilic displacement (SN2) of secondary tosylate 526 with the carbanion derived from 527 resulted in product 528 in 70% yield (Scheme 108).178 Tosylate 529, obtained from pregnenolone, underwent inversion of configuration at C-20 when it was treated179 with the anion of the protected cyanohydrin 530, which gave intermediate 531 with natural configuration at C-20 (Scheme 108). Intermediate 531, upon treatment with PTSA−MeOH followed by base treatment of the resulting cyanohydrin with NaOH, gave corresponding enone 532 in 83% overall yield without C-20 epimerization. Application of the anionic oxy-Cope rearrangement in steroid synthesis was documented by Koreeda et al.180 (Scheme 109). Treatment of steroidal C-16 tert-alcohol 533 with potassium hydride in refluxing dioxane produced the rearranged (20R)-keto olefin 534 as a single stereoisomer at C-17 and C-20 in 94% yield. Product 534 provided a versatile intermediate for synthesis of vitamin D metabolite and steroids incorporating modified side chains. A similar type of anionic oxy-Cope rearrangement on steroid substrate has been reported by Voss and co-workers.181 Compound 535, upon reaction with KH in 1,2-dimethoxyethane under reflux conditions followed by quenching with water at −10 °C, gave 17R,20R-keto olefin 536 as a single

Scheme 109

diastereomer in 91% yield (Scheme 110). Analogously, under similar conditions followed by quenching of the intermediate at 0−25 °C, the 17S-epimer 537 was obtained in 20−40% yield. The sterol/steroid-type side chain can be achieved via oxidative cleavage of diol 538 with sodium metaperiodate (NaIO4) followed by sodium borohydride reduction, which AB


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Keto acid 547 was obtained by ozonolysis of 546, followed by hydrolysis of the resulting acid anhydride, and then converted into acetal carboxylic acid 548 (by use of ethylene glycol and camphorsulfonic acid, CSA) in 70% overall yield185 (Scheme 114).

Scheme 110

Scheme 114

β-Hydroxy ketone 549, upon exposure to sodium hydride in THF, proceeded smoothly in retro-aldol condensation followed by isomerization of the ring methyl group, giving (2R,3R)-2methyl-3-[(R)-1-methyl-3-oxobutyl)]-cyclopentanone 550 in 75% yield186 (Scheme 115). The absolute (R) configuration of both methyl groups present in 550 are in agreement with those at C-17 and C-20 of steroidal substrates.

afforded182 monocyclic diol 539 in 87% overall yield (Scheme 111). Scheme 111

Scheme 115

Baeyer−Villiger oxidation of 540 with H2O2, followed by treatment with TsOH in benzene, gave rearranged lactone 541 in 79% yield.183 Lactone 541, upon reduction with LiAlH4 and selective protection of the primary alcohol with TBDMSCl, gave 542 in 95% overall yield (Scheme 112). The critical centers corresponding to C-13 and C-20 have been created with the correct relative configuration.183

Vandewalle and co-workers187 described the synthesis of a vitamin D analogue with a six-membered D-ring and the absence of C-ring. In their synthesis, construction of the C-20 side chain was achieved from spirolactones 551 and 552, which upon reduction with LiAlH4 followed by silylation gave 553 and 554, respectively, in 85% over two steps (Scheme 116).

Scheme 112 Scheme 116

Bicyclic ketone 543, upon Baeyer−Villiger oxidation with basic hydrogen peroxide in aqueous methanol−THF, gave184 the sensitive hydroxy acid 544, which upon treatment with BF3· Et2O gave the rearranged intermediate 545 (85% overall yield) with the transfer of chirality from C-14 to C-16 (steroid numbering) (Scheme 113).

5. CONCLUSIONS This review presents a collection of highly interesting and useful methods for stereoselective construction of the C-20(H) stereogenic center in steroid side chain. These methods may be useful for synthesis of newly isolated sterols/steroids with natural and unnatural configuration at C-20. The various methods for construction of the steroidal C-20 stereogenic center, by use of named/unnamed reactions/rearrangements, organometallic compounds, and others, are also shown in Figure 20 to illustrate the importance and scope of future work. These methods are useful for the synthesis of naturally

Scheme 113

AC


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syntheses of steroidal unnatural C(20R) aldehydes by ionic hydrogenation and their elaboration to naturally occurring 20-epi-cholanic acid derivatives. In addition to this, he has carried out stereoselective syntheses and ionic hydrogenation of steroidal C-20 tertiary alcohols with aliphatic, vinylic, aromatic, 5- and 6-membered heterocyclic side chains, and also synthesized various oxygenated lanosterol derivatives. His current research interests include asymmetric synthesis, total synthesis of natural products, multicomponent reactions, heterocyclic synthesis, and green chemistry. In 2008, he joined as an Assistant Professor in the Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad. He has published about 50 research articles in journals of international repute and contributed a chapter of a book. He is a recipient of prestigious Indo-U.S. Research Fellowship 2013 award for carrying out advanced research in chemical sciences at the University of California, Irvine, CA.

Figure 20. Various methods for construction of the steroidal C-20 stereogenic center.

occurring steroids such as cholesterol, bile acids, corticosteroids, ecdysones, brassinosteroids, squalamine, and many more that have natural C-20 configuration, as well as compounds with the unnatural C-20 configuration such as 20-epi-sterols/steroids, epi-cholesterol (different activity than natural cholesterol), 20-epi-cholanic acid derivatives, other 20epi-steroids (whose biological activity has not been explored yet), and 20-epi-vitamin D3, particularly 20-epi-calcitriol, which is is more active than the natural enantiomer.

Braja Gopal Hazra was born in Bankura District of West Bengal in 1943. He received an M.Sc. degree in chemistry from Calcutta University (1965) followed by a Ph.D. from Jadavpur University (1971). Subsequently he worked as a postdoctoral research associate at Sheehan Research Institute, Cambridge, MA (1974−1975); at Brandeis University, Waltham, MA (1975−1976; and as a JSPS Visiting Scientist at University of Tokyo, Japan (Host Scientist Professor Kenji Mori) (1984−1985). He was an elected fellow of the Maharashtra Academy of Sciences. He retired from National Chemical Laboratory, Pune (CSIR) as a senior scientist in 2003 and was an emeritus scientist at National Chemical Laboratory until 2008. He has more than 4 decades of research experience in synthetic organic chemistry, particularly synthesis of natural products and analogues having biological and commercial importance. He developed and commercialized technology of (22S,23S)-homobrassinolide, (a highly potent plant growth promoter). He has trained and supervised more than 25 M.Sc. students in chemistry for their project work and supervised 8 Ph.D. students in synthetic organic chemistry. More than 70 research publications in international journals, four U.S. patents, and 31 Indian patents are to his credit.

AUTHOR INFORMATION Corresponding Authors

*Telephone 91-240-2403311-313; fax 91-240-2403113; e-mail [email protected]. *E-mail [email protected]. Notes

The authors declare no competing financial interest. Biographies

ACKNOWLEDGMENTS We sincerely acknowledge many colleagues and friends for the reprints or preprints that they furnished and also for their valuable/critical suggestions and helpful discussions. We thank Drs. V. S. Pore, N. P. Argade, D. B. Salunke, N. S. Vatmurge, S. N. Bavikar, N. G. Aher, P. S. Sagar, A. P. Thakur, H. V. Thulasiram, M. S. Shingare, R. A. Mane, and B. R. Sathe for their timely help and co-operation during the preparation of this review. We thank the University Grants Commission, and Council of Scientific and Industrial Research, New Delhi, for financial assistance in the form of fellowships. B.B.S. thanks to Indo-US Science and Technology Forum, New Delhi, for the

Bapurao B. Shingate was born in Salagara (Divati), Osmanabad District of Maharashtra State, India, in 1975. He obtained his B.Sc. and M.Sc. degrees from Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS), India. He earned his Ph.D. degree from University of Pune, Pune (MS), under the supervision of Dr. Braja G. Hazra at the Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune. His Ph.D. work focused on the stereoselective AD


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TsCl TsOH TrSbCl6 Z

award of Indo-US Research Fellowship to carry out advanced research in chemical sciences.

DEDICATION We dedicate this review to all the researchers that have contributed to this field of steroids, terpenoids, vitamins, and natural products, and we hope that it will inspire current and future chemists to utilize and expand the field of construction of steroidal C-20(H) stereogenic center.

p-toluenesulfonyl chloride p-toluenesulfonic acid trityl hexachloroantimonate zusammen in IUPAC nomenclature

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ABBREVIATIONS Ac acetyl AIBN azobis(isobutyronitrile) aq aqueous Ar aryl 9-BBN 9-borabicyclo[3.3.1]nonane BMS borane-methyl sulfide Bn benzyl (CH2O)n paraformaldehyde Cp cyclopentadienyl CSA camphorsulfonic acid DCM dichloromethane DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DMSO dimethyl sulfoxide dppe 1,2-diphenylphosphinoethane dr diastereomeric ratio E entgegen in IUPAC nomenclature EE ethoxyethyl ent enantiomeric epi epimeric EtOAc ethyl acetate HMPA hexamethylphosphoramide HMPT hexamethylphosphorous triamide iso isomeric LD lethal dose LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide or lithium bis(trimethylsilyl) amide MEM β-methoxyethoxymethyl MOM methoxymethyl NaN(SiMe3)2 sodium bis(trimethylsilyl)amide Pd(acac)2 palladium acetylacetone Pd3(TBAA)3 tris(tribenzylideneacetyl acetone)tripalladium ppm parts per million PTSA p-toluenesulfonic acid Py pyridine quant quantitative rt room temperature SN2 bimolecular nucleophilic substitution sp species St steroid TBS tert-butyldimethylsilyl TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TES triethylsilyl THF tetrahydrofuran THP tetrahydropyranyl TMBA 2,4,6-trimethyl benzoic acid TMSCl trimethylsilyl chloride TMS trimethylsilyl Ts p-toluenesulfonyl AE


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