Synthesis of Unnatural Steroids Using the Bistro Strategy

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P. Maurin et al. AccountSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2015, 26, A–Laccount

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Synthesis of Unnatural Steroids Using the Bistro StrategyPhilippe Maurina Delphine Moraledab Hélène Pellissierb Raphaël Rodriguezc Maurice Santelli*d

a Ecole Normale Supérieure de Lyon, Université de Lyon, Laboratoire de Chimie, UMR CNRS UCBL 5182, Lyon, France

b Aix-Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France

c Institut Curie Research Center, Organic Synthesis and Cell Biology Group, 26 rue d’Ulm, 75248, Paris Cedex 05, France

d Aix-Marseille Université, CNRS, ICR UMR 7273, 13397, Marseille, [email protected]

X1

R3

SiMe3

SiMe3

Me3SiCl+

Li

Bistro

1.R1

O

R1O

O

or

O

O

2.

X1

X3

X2

X4

HH

HR2

X1 = R4C, N X2 = R5C, C=O, O, S, R6N

X4 = OH, Me, CF3, Ph

70% yield

X3 = CH2, O, C=O

~250unnaturalsteroidsor ...

R3 = I, OMs, COCl

R2

+

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Received: 07.10.2014Accepted after Revision: 15.12.2014Published online: 17.02.2015DOI: 10.1055/s-0034-1379991; Art ID: st-2014-a0840-a

Abstract Lithium-mediated reductive dimerization of buta-1,3-dienein the presence of chloro(trimethyl)silane readily provides 1,8-bis(trimethylsilyl)octa-2,6-diene, commonly known as ‘Bistro’. This bis-allylsilane can react with various electrophilic reagents to give 1,1-disubstituted 2,5-divinylcyclopentanes, which are precursors of the Drings of steroids. After slight alterations, these precursors can be cou-pled with benzocyclobutene derivatives. Heat induces ring opening ofthe benzocyclobutene to form an o-xylylene that subsequently under-goes intramolecular cycloaddition with a vinyl substituent to form theskeleton of a new unnatural steroid, according to the A + D → AD →ABCD strategy. In this way, more than 250 steroids have been prepared,including 3-, 11-, 12-heterosteroids bearing a 17-vinyl group that canbe readily modified to form a 17-acetyl or 17-(2-oxoethyl) group, aswell as some steroid building blocks. The steroids were obtained in fewsteps from buta-1,3-diene and benzocyclobutene derivatives in overallyields in excess of 25%. This powerful strategy, which has not yet beenexhausted, paves the way towards various related synthetic pathways.1 Introduction2 Series A3 Series B4 Series C5 Series D6 Series E7 X-Ray Crystallographic Data8 Conclusion

Key words unnatural steroids, Bistro, benzocyclobutenes, cyclization,Wacker process, kinetic resolution

1 Introduction

The synthesis of steroids was a major scientific advanceof the twentieth century.1,2 Although the importance of ste-roids in medicine remains unparalleled, there has been arecent decline in efforts devoted to the total synthesis ofsteroids.3 Yet, according to the Monthly Index of Medical

Specialties (UK),4 one-third of available drugs listed are ei-ther steroids or contain steroids, and over 10,000 structuresare referenced in the Dictionary of Steroids (according to theBelstein library, close to 100,000 steroids are known).5Moreover, among the 200 top-selling drugs in 2012, 15were steroids or derivatives thereof.6 From the natural ste-roid structure, a diversity of syntheses can be explored,many of which lead to relevant bioactive products.7 Somerecent reviews summarize the various approaches to ste-roid synthesis.8

Recently, the importance of neuroactive steroids hasbeen recognized,9 and the production and use of steroidalantibiotics, including helvolic acid10 and fusidic acid11, havebeen studies. Gestogenic and estrogenic 19-norsteroids areimportant because many of these compounds exhibitmore-pronounced biological activities than their methylat-ed analogues.12

The classical approach to drug development from aknown lead structure involves systematic variation of thesubstitution pattern and of the stereochemistry. The tre-mendous efforts made by the various groups involved inthe discovery of the first progesterone antagonist, mifepris-tone (RU 486),13 can be viewed as a typical example.14

Over recent decades, we have established a convergentsynthesis of steroids based on the A + D → AD → ABCD ap-proach. This strategy takes advantage of the remarkable re-activity of 1,8-bis(trimethylsilyl)octa-2,6-diene (1), whichis known by the acronym ‘Bistro’. Bistro can be easily pre-pared on a multigram scale (batch size 2 mole) from buta-1,3-diene and purified by distillation.15 The addition of Bis-tro (1) to various electrophilic reagents, such as anhydrides,acyl chlorides, or ketals, gives 1,1-disubstituted 2,5-divinyl-cyclopentane precursors of the D ring of steroids. Subse-quent steps involve the intramolecular cycloaddition of o-xylylenes to generate the BC ring system; this procedurewas developed independently by Oppolzer et al.16 and by

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–L

B


Kametani et al.17 In this manner, about 250 unnatural ste-roids have been synthesized, as well as some relevant ste-roid building blocks.

With respect to the addition of Bistro (1) to variouselectrophilic reagents, we will discuss five different strate-gies corresponding to Series A to E (Scheme 1).

Biographical sketches

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Philippe Maurin gained his Ph.D.in chemistry from the University ofAix-Marseille III in 2001, workingunder the guidance of ProfessorMaurice Santelli on the total syn-thesis of non-natural steroids. Hethen spent 18 months as a post-doctoral researcher in Professor JinKun Cha’s group, initially at the

University of Alabama, Tuscaloosa,and then at Wayne State Universi-ty, Detroit, where he performedmechanistic studies of the anionicoxy-Cope rearrangement of trans-1,2-dialkenylcyclobutanols. Since2004, he has been an associateprofessor in the chemistry depart-ment of the Ecole Normale

Supérieure de Lyon, France. His re-search interests are in bioorganicchemistry and organic synthesis inthe domains of activatable con-trast agents for magnetic reso-nance imaging, and in the designand synthesis of small moleculesfor biological applications.

Delphine Moraleda (34 yearsold) completed her Ph.D. in 2007under the supervision of ProfessorMaurice Santelli at the Universityof Marseille III (France), where sheworked on enantioselective totalsynthesis of steroids and on allylsi-lane reactivity towards electro-philes. This work was the subject of

eight publications. She then joinedProfessor Gérard Buono’s group atthe University of Marseilles as anAttaché Temporaire de l’Enseigne-ment et de la Recherche. After aone-year postdoctoral fellowship inProfessor Jérôme Lacour’s researchgroup at the University of Geneva(Switzerland), she was appointed

Maître de Conférences at Aix-Mar-seille Université (IUT), associatedto the UMR CNRS 7313–Institutdes Sciences Moléculaires de Mar-seille (iSm2). Her research interestsare in asymmetric synthesis of P-stereogenic compounds, organo-metallic catalysis, and coordinationchemistry.

Hélène Pellissier carried out herPh.D. researches under the super-vision of Dr. G. Gil at Marseille(France) in 1987. The work focusedon the reactivity of isocyanides. In1988, she entered the Centre Na-tional de la Recherche Scientifiqueas a researcher. After a postdoctor-

al period in Professor K. P. C.Vollhardt’s group at the Universityof California, Berkeley, she joinedProfessor M. Santelli’s group inMarseille in 1992, where shefocused on the chemistry of 1,8-bis(trimethylsilyl)octa-2,6-diene(Bistro) and its applications in the

development of novel, short, totalsyntheses of steroids starting frombuta-1,3-diene and benzocy-clobutenes. She is currentlyChargée de Recherche (CNRS) at Aix-Marseille Université.

Raphaël Rodriguez is currentlyCharge de Recherche at the FrenchNational Centre for Scientific Re-search (CNRS). He carried out hisPh.D. studies in the laboratories ofMaurice Santelli (Aix-Marseille Uni-versity, France) and Sir Jack E.Baldwin (University of Oxford, UK),

during which he completed chemi-cal syntheses of a series of naturalproducts by means of biomimeticpericyclic processes. He then didpostdoctoral training under thementorship of Shankar Balasubra-manian (University of Cambridge,UK) to evaluate the existence of

G-quadruplex structures in thehuman genome and to unraveltheir functional consequences. Hisresearch is focused on the synthe-sis of small molecules to studymammalian cell biology. RaphaëlRodriguez’s homepage iswww.rodchembiolab.com.

Maurice Santelli was born inMarseille. He graduated in chemis-try from the Ecole Supérieure deChimie de Marseille (now EcoleCentrale Marseille) in 1961. Hegained his Ph.D. in chemistry,working with Professor M. Bertrand(homoallenylic participation, non-classical ions). He then took a post-

doctoral position with Professor R.A. Raphael at the University ofCambridge (UK) in 1973. This wasfollowed by an appointment at theUniversity of Oran, Algeria (1975–77). He is presently Emeritus Pro-fessor of Chemistry at the Aix-Mar-seille University. His main researchareas are physical organic chemis-

try, electrophilic activation, allylsi-lane chemistry (Bistro), palladium-chemistry with new ligands (Tedic-yp), radical chemistry, and the syn-thesis of bioactive products(polyunsaturated fatty acids,Prelog–Djerassi lactone, and non-natural steroids).


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Scheme 1

2 Series A

Acylation of Bistro (1) with succinic anhydride gave thecorresponding (±)-spiro-γ-lactone 2 in 80% yield. With theaim of enhancing the nucleophilic character of the enolate,lactone 2 was acylated with dimethyl carbonate to provideester 3 (87% yield). Subsequently, alkylation of the malonic

derivative 3 was carried out in refluxing acetone in thepresence of anhydrous potassium carbonate and only 1.3equivalents of the precious iodobenzocyclobutenes 4. Re-markably, the stereoselectivity of the reaction was excellentand occurred on the face of the enolate bearing the vinylgroup anti to the lactone ring–oxygen linkage.18 Upon ther-molysis of 5 in refluxing 1,2,4-trichlorobenzene, only onevinyl group underwent an intramolecular Diels–Alder reac-tion, and the resulting cycloadducts were formed throughan exo cyclization mode of the (E)-o-xylylene intermediate6. The relative configurations of the six stereogenic centersof steroids 7 were controlled during the cycloaddition pro-cess (Scheme 2).19 Steroids 7 were obtained in five stepsfrom buta-1,3-diene and iodobenzocyclobutenes 4 with anoverall yield of 27–33%.

Scheme 2

From the primary steroids 7, many modified analogueswere obtained through various classical reactions (Scheme3).

R

O

O

O

SiMe3Me3Si

MeO

O

HH

O

MeO2CH

MeO

O

HH

O

H

MeO

O

O

O

Br MeO2C

HH

H

Br

MeO2C

HH

H

Br

O

O

O

H

H

H

O

H

H

H

R

O

R

O

O

RO

MeO

HH

H

O

or

+ +

+

R = MeR = CF3

R = CHF2

+

or

or

or

MeO MeO

Series A

Series B

Series D

Series E

O

O

O

or

X

OH

HH

H

MeO

X

OH

HH

H

MeOor

Series C X = O, S, NR

Bistro 1, Z,Z/Z,E = 60:40, 65–70% yield

Li + Me3SiCl +

MeO MeO

MeO2C MeO2C

Cl

Cl

SiMe3

SiMe3

OO

O

Me3Si

N

Me3Si

Li

OMe

OMe

O

O

O

MeO2C

R1

R2

I

OO

R1

R2

MeO2CO

O

MeO2C

R1

R2

H

OO

MeO2C

R1

R2

HH

H

+

1.

2.

dl, 2, 80% yield

3, 87% yield

K2CO3, acetone

5, 91–93% yield

a: R1 = R2 = H; b: R1 = OMe, R2 = H; c: R1 = H, R2 = OMe; d: R1 = R2 = OMe;e: R1 = O-t-Bu, R2 = H; f: R1 = H, R2 = O-t-Bu; g: R1 = OH, R2 = H;h: R1 = H, R2 = OH; i: R1 = F, R2 = H; j: R1 = H, R2 = F; k: R1 = H, R2 = Br

4

214 °C

16 h

7, 95% yield

o-xylylene or o-quinodimethane (6)

1, Bistro

O

O

TiCl4

CH2Cl2

MeNO2

R1

R2O

MeO2C

O

H

H

≡


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Scheme 3

The vinyl group of 7 was unmasked by means of a cata-lytic oxidation reminiscent of the Wacker process to give anacetyl group. Palladium-catalyzed oxidation gave unsatis-factory results when cuprous chloride and oxygen wereused as co-reagents.20 Fortunately, however, palladium ace-tate–benzoquinone oxidation, performed in the presence ofperchloric acid,21 gave the expected ketones 9 in goodyields, sometimes accompanied by the corresponding alde-hydes 10, formed through an anti-Markovnikov hydroxy-palladation (Scheme 4). These results have been rational-ized in terms of the occurrence of intramolecular coordina-tion of the palladium with the oxygen atom of the lactonefunction.22

Scheme 4

With the view to preparing steroids with a trans-anti-trans configuration, we first performed a demethoxycarbo-nylation23 of 5. Epimerization occurred, giving rise to a mix-ture of two precursors 11 and 12. Upon heating, these un-derwent cyclization to give the two isomeric steroids 13and 14, respectively (Scheme 5).

Among the numerous steroids obtained, the dextrorota-ry isomer of 15, prepared from 14b, exhibited positive inot-ropy in vivo and in vitro with various cardiac muscle prepa-rations.24 Introduction of various nitrogenated or oxygenat-ed groups at the C11 position of substrate 16 failed toimprove the biological efficacy of the compound (Scheme6).25

A straightforward strategy based on the conjugate addi-tion of the allyltrimethylsilane to ethylenic ketones such as17 permitted the introduction of a 19-methyl group(Scheme 7).26

Scheme 7

OO

MeO2C

R1

R2

HH

H

OHMeO2C

MeO2C

R1

R2

HH

H

OHMeO2C

R1

R2

HH

H

a: R1 = R2 = H; b: R1 = OMe, R2 = H; c: R1 = H, R2 = OMe

7a–c

MeOH

BF3•OEt2

OO

R1

R2

HH

H

NaCNDMSO

8a–c

MeOH

BF3•OEt2

Pd(OAc)2 (10%)benzoquinoneHClO4 (0.3 M)

MeCN

O OO

MeO2C

R1

R2

HH

H

9

7 +

OO

MeO2C

R1

R2

HH

H

10

O

H

Scheme 5

NaCN

DMSO5

OO

R1

R2

+

OO

R1

R2

Δ

OO

R1

R2

HH

H

OO

R1

R2

HH

H

Δ

>80% yield, ~1:1

11 12

13 14

Scheme 6

O OO

MeO

HH

H14b

88% yield

1. K2CO3

EtOH, Δ

2. (COCl)2

3. MeOH

O

MeO

HH

H

MeO2C

15, 55% yield

O

MeO

HH

H

R

R = CO2Et, CH2OH, CN, CONH2, CONR'2, MeCO, MeO, NH2,

O

N

16

O

HH

H

MeO2C

MeO

SiMe3

TiCl4, CH2Cl2

O

HH

H

MeO2C

MeO

18, 71% yield17

1. O3–O2 MeOH

2. Me2S

3. H3O+

O

HH

H

MeO2C

MeO

H

O

77% yield

RhCl(PPh3)3

CH2Cl2

O

HH

H

MeO2C

MeO

56% yield


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Moreover, conjugate hydrocyanation of ketones such as17 by using dimethylaluminum(III) cyanide (the Nagata re-action) allowed the introduction of an angular cyano groupat the C13 position. Subsequent reduction of the nitrilegroup gave various functionalized steroids.27

On the other hand, acylation of the lithium enolate of(±)-spiro-γ-lactone 2 (3 equiv) by the methyl (–)-O-tert-bu-tyl(dimethyl)silyl-(S)-lactate, the methyl O-tert-butyl(di-methyl)silyl-(S)-mandelate, or diacetone-D-glucose carbon-ate (1 equiv each) occurred with some level of kinetic reso-lution. The best results were obtained with methyl O-tert-butyl(dimethyl)silyl-(S)-lactate, because the lithium eno-late of (S,S)-2 was more reactive than the (R,R)-isomer[(S,S)-19/(R,R)-19 =4.5:1], whereas the lithium enolate of(R,R)-2 reacted selectively with methyl O-tert-butyl(di-methyl)silyl-(S)-mandelate.28,29 Various steroids of knownabsolute configuration bearing a methoxy group in positionC2 or C3 have been obtained (Scheme 8). These resultsshould be considered as examples of double asymmetric in-duction.30 A density functional theory investigation clearlyshowed that tetrahedral intermediates that contained twolithium cations were formed from an antiperiplanar transi-tion state.31

Scheme 8

Depending on the reagent used, fluoride-mediateddeprotection of relevant steroids, such as (–)-20, gave vari-ous products, such as 22 and 23, which have known abso-

lute configurations (Scheme 9). The structures of 20 and 21(and those of other steroids obtained by kinetic resolution)have been confirmed by X-ray crystallographic analysis.

Scheme 9

The use of the 4-aza-1-mesylbenzocyclobutene 2432 inthe alkylation of spiro lactone 3 gave the corresponding 3-aza steroids 25–27 in good yields (Scheme 10).33,34

Scheme 10

Oxidation of the nitrogen atom of steroid 25, followedby a Wacker-like process, gave the corresponding ketone 28and aldehyde 29 (Scheme 11).34

3 Series B

Acyclic anhydrides reacted with Bistro (1) to give (dl)-2,5-divinylcyclopentanols 30. Esterification of cyclopenta-nols 30a, 30c, and 30d with a benzocyclobutene carbonylchloride, followed by thermolysis, gave the correspondingtrans-anti-cis steroids 31a, 30c, and 30d, in excellent yieldsand high stereoselectivities.35 These steroids contain a 19β-methyl group that, in turn, can be fluorinated (Scheme 12).

O

O

O

O

(S,S)-2

+

(R,R)-2

racemic mixture, (3 equiv)

O

OMe

TBSO

O

O

+

S

S

O

TBSO

S

S

O

O

R

R

O

TBSO S

(S,S)-19, 60% yield (R,R)-19, 13% yield

(1 equiv)

1. (Me3Si)2NLi, THF (3 equiv)

2.

O

O

S

S

O

TBSO S

(S,S)-19

OO

MeO

HH

H

OTBSO

4.5:1

(–)-20, 41% yield

OO

MeO

HH

H

OTBSO

(–)-21, 18% yield

(–)-20HF•py

OH

MeO

HH

H

O O

O

(+)-22, 82% yield

(–)-20

OO

MeO

HH

H

OHO

23, 52% yield

THF

(n-Bu)4NF•3H2O

THF

O

O

MeO2C

N

OMs

+ K2CO3

acetone

OO

N

MeO2C

82% yield

OO

NHH

H +

OO

NHH

H

OO

NHH

H+

77% yield, 25/26/27 = 3:2:1

25 26 27

24

3


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The vinyl group oxidation of 31c and 31d gave the cor-
responding aldehydes 32 as single products through aWacker process (Scheme 13).

Scheme 13

From these steroids, many derivatives were obtained ingood yields, particularly the 12-oxasteroids 34 via the seco-diol 33 (Scheme 14).

Scheme 14

Addition of phenyllithium to the lactone 31d gave the11-phenyl-12-oxasteroids 35 and 36 (Scheme 15).

Scheme 15

Heating diols 33 in phosphoryl chloride promoted aWagner–Meerwein rearrangement to the B(9a)-homo-C-nor-3-methoxy-12-oxa-17-vinyl-estra-1,3,5(10)-trienes 37,which were subsequently oxidized to form the aldehydes38 (Scheme 16).36

Scheme 16

4 Series C

Addition of Bistro (1) to chloroacetic anhydride gave the(dl)-spiro epoxide 39, a key product for the first total syn-thesis of 11-heterosteroids (Scheme 17).

Scheme 11

25MCPBA

CH2Cl2

86% yield

Pd(OAc)2 (10%)

benzoquinoneHClO4, H2O

THF

O OO

NHH

H

OO

NHH

H

O

O

OO

NHH

H

O

H

O

+

28 29

78% yield, 28/29 = 8:1

Scheme 12

R

R

O

R

O

O

HO+

30a, 74% yield30b, 60% yield30c, 88% yield

TiCl4

CH2Cl2

MeNO2

1

Bistro

a, R = Meb, R = CF2Clc, R = CF3

30b

F2CH

HO

n-Bu3SnH

30d, 98% yield

MeO

O

Cl

30a,c,d n-BuLi

RO

MeO

O

a, 67% yield (37% conversion)c, 75% yield (48% conversion)d, 78% yield (43% conversion)

RO

MeO

HH

H

O

31a, R = Me, 76% yield31c, R = CF3, 82% yield31d, R = CHF2, 83% yield

Cl

ClCl

Δ

trans-anti-cis

31c,dPd(OAc)2 (10%)


THF

RO

MeO

HH

H

O H

O

32c, 80% yield; 32d, 85% yield

31a,c,dLiAlH4

Et2O

RHO

MeO

HH

H

HO

33a,c,d, 98% yield

RO

MeO

HH

H

34c,d, 98% yield

1. n-BuLi, THF

2. TsCl, THF

F2CH

O

MeO

HH

H

F2CH

O

MeO

HH

H

35, 40% yield 36, 17% yield

31d +

RHO

MeO

HH

H

HOPOCl3

O

MeO

H

HR

H

37a, R = Me, 78% yield 37c, R = CF3, 98% yield 37d, R = CHF2, 85% yield

Pd(OAc)2 (10%)


THF

O

MeO

H

HR

H

O

H

38c, 74%; 38d, 82% yield

33a,c,d


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Scheme 17

Interestingly, two microbial epoxide hydrolases weresuccessfully used in a biocatalyzed hydrolytic kinetic reso-lution of the racemic (dl)-spiro epoxide 39 (Scheme 18).37

Scheme 18

Hydrolysis of the (dl)-spiro epoxide 39 gave the diol 40,which was alkylated in the presence of iodobenzocy-clobutenes 4 to give benzocyclobutenes 41. Thermolysis of41 gave a mixture of two 11-oxa steroids 42 and 43 in anoverall yield of 55% (Scheme 19).

Scheme 19

Wacker-type oxidation of the vinyl group of 42 led tothe corresponding ketones 44 and aldehydes 45 (Scheme20).38

Scheme 20

Alkylation of diol 40 by the 4-aza-1-iodobenzocyclobu-tene 46 gave the corresponding 3-aza-11-oxasteroids 47and 48 in 60% overall yield (Scheme 21).34

Scheme 21

The amino alcohol 49, synthesized in four steps frombuta-1,3-diene in 34% overall yield was readily convertedinto the 11-aza steroids 50 and 51 (Scheme 22).39

Scheme 22

It is noteworthy that the (dl)-spiro epoxide 39 could alsobe used in a three-step synthesis of the 11-thiasteroids 53–55 (Scheme 23).40

OH

OCl

Cl O

O

Cl

t-BuOK

EtOH

O

+

dl, 74% yield(dl/meso = 20:1)

39, 85% yield

TiCl4

CH2Cl2MeNO2

1

Bistro

O

(±)-39

OH

HO

Aspergillus niger

Rhodococcus erythropolis

O

S

S

OR

R

(–)-39; 99% ee; 26% yield (–)-40; 47% ee; 63% yield

(+)-39; 99% ee; 25% yield

OH

HO

(+)-40; 54% ee; 54% yield

S

S

R

R

O

39

OH

HO

40, 62% yield

R1

R2

I

1. KH, DMF

2.

OH

R1

R2

O

41, 60% yield

Δ

xylene

OH

O

R1

HH

H

R2

OH

O

R1

HH

H

R2

43, 11% yield

a, R1 = OMe; R2 = Hb, R1 = H; R2 = OMe

42, 44% yield

H2O

Δ

4

OH O

O

R1

HH

H

R2

44, 56% yield

42

OH

O

R1

HH

H

R2

45, 14% yield

+

O

H

OH

HO

40

OH

O

NHH

H

OH

O

NHH

H

48

47

3:1

N

I

46

60% yield

OH

H2N

39

NH3

100 °C

46 bar

49, 78% yield

MeCOCl

Et3N

MeO O

1.

2. NaBH3CN

OH

MeOHN

75% yield

OH

MeOMeCON

88% yield

OH

MeCON

MeO

HH

H140 °C

xylene+

OH

MeCON

MeO

HH

H

50, 89% yield

O

51, 10% yield


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Scheme 23

Starting from thiasteroids 53, various 11-sulfoxides,such as 56 and 57, and 11-sulfones, such as 58–60, havebeen easily prepared (Figure 1).

Figure 1

The 3-aza-11-thiasteroids 61 and 62 were readily ob-tained by using 4-aza-1-iodobenzocyclobutene 46 (Scheme24).34

Scheme 24

Oxidation of the heteroatoms of steroid 61 provided avariety of new polyfunctionalized steroids (Scheme 25).41

Scheme 25

5 Series D

We were also interested in the synthesis of new steroidsbearing a 13-(4-bromophenyl) group and various substitu-ents in the C3, C11, C13, and C17 positions. The 4-bro-mophenyl group is a useful precursor of a 4-(dimethylami-no)phenyl group42 or even a 4-boronatophenyl group thatcan be used in Suzuki cross-coupling reactions.43 A 13-[4-(dimethylamino)phenyl] group is an interesting generalpharmacophore, as it is present at the C11 position of theprogesterone antagonist RU 486.13 It is noteworthy thatonly five 13-phenyl steroids have been synthesized, andthat these were prepared during the 1960s by Windholz etal.44

Bistro (1) reacted with activated ethyleneketals as theiracetophenone ethyleneketal derivative 63 to give the 1,1-disubstituted 2,5-divinylcyclopentane 64 as inseparablemixtures of dl- and meso-isomers (2.33:1). Interestingly,following methoxycarbonylation, alkylation with 4 oc-curred with valuable kinetic separation, because only (dl)-

O

39

R1

R2

I

OH

R1

R2

S Δ

xylene

OH

S

R1

HH

H

R2

OH

S

R1

HH

H

R2

R1 = OMe; R2 = H, 60% yieldR1 = H; R2 = OMe, 70% yieldR1 = Br; R2 = H, 75% yield

MeCOSK–MeCOSH

CH2Cl2

OH

MeCOS

52, 51% yield

1. NaBH4, EtOH

2. t-BuOK

OH

S

R1

HH

H

R2




4

OH

S

R1

HH

H

R2

O

OH

S

R1

HH

H

R2

O

O

OH O

S

R1

HH

H

R2

O

OH O

S

R1

HH

H

R2

O

O

56a–c 57a–c

58a–c 59a–c

O

S

R1

HH

H

R2

O

O

60a–c

N

I

OH

N

S

Δ

xylene

OH

S

NHH

H

61, 68% yield

OH

MeCOS

52

1.

2. K2CO3,

OH

S

NHH

H

62, 14% yield

N

H

, MeCN

70% yield

+

46

10% yield64% yield

61MCPBA

CH2Cl2

OH

S

NHH

H

O

O

O

85% yield

Pd(OAc)2 (10%)


THF

OH O

S

NHH

H

O

O

O+

OH

S

NHH

H

O

O

O

O

H


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65 reacted. Finally, thermolysis of 66 gave the 17-vinyl ste-roids 67 and 68 exclusively in 72% and 10% yields, respec-tively (Scheme 26).

Scheme 26

The two 17-vinyl steroids 67 and 68 were readily con-verted into the corresponding 17-acyl steroids 69 and 70respectively, through a Wacker process (Figure 2).45

Figure 2

6 Series E

Because our previous strategies could not provide ste-roids bearing a 19-methyl group, we designed a fifth strate-gy starting from biacetyl. At low temperatures, its biseth-ylene ketal 71 reacted as expected with Bistro (1) to give aseparable mixture of dioxadecalines 72 and 73. Each ofthese, on further treatment with titanium(IV) chloride, un-derwent a selective pinacol-like rearrangement to give the1-acetyl-2,5-divinylcyclopentanes 74 and 75, respectively(Scheme 27).46

Scheme 27

Remarkably, optically pure (R,R)-75 was obtained as themajor product through the reaction of the chiral dioxane(–)-77 with Bistro (1). Dioxane (–)-77 was, in turn, ob-tained by the Ley procedure47 from (S)-(+)-1-phenylethane-1,2-diol (76), prepared by reduction of cheap mandelic acid(Scheme 28).48

Scheme 28

By adopting our previous procedure, we obtained thenew nonracemic unnatural steroids 79 and 80 from 1-ace-tyl-2,5-divinylcyclopentane 75 (Scheme 29).

Bistro 1TiCl4

MeNO2

CH2Cl2

+

O

OO

Br

MeO

Br

O

MeO

MeO OMe

O

LiHMDS

Br

MeO2C

MeO2C

I

MeO

Cs2CO3, NaIacetone

Br

MeO2C

MeO

MeO2C

H

H

H

Br

MeO2C

MeO

Δ

THF

64, 86% yield

Br

MeO2C

MeO

MeO2C

H

H

H

65, 62% yield

66, 91% yield [from (dl)-65]

MeO2C 67, 72% yield

68, 10% yield

63

4

Br

MeO2C

O

MeO

MeO2C

H

H

H

Br

MeO2C

O

MeO

MeO2C

H

H

H

69, 62% yield 70, 58% yield

O

O HO OH

O

O

O

O Bistro 1

TiCl4, MeNO2–CH2Cl2

O

O

O

O

TiCl4

TiCl4

O

74, 95% yield

71

72, 27% yield

O

75, 95% yield73, 33% yield

OO TiCl4

OO TiCl4

–90 °C

–50 °C

–50 °C

H+

O

O

+

OH

OH

Ph

(S)-(+)-76

MeOHO

O

OMe

OMe

(–)-77, 95% yield

Ph

Bistro 1

TiCl4

MeNO2–CH2Cl2

–90 to –60 °C

O

(+)-(R,R)-75, 60% yield

R

R

O

(meso)-74, 7% yield

+ + (S)-(+)-76

(35% yield)

OO

OMe

OMe

Ph

H+


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Scheme 29

The same procedure applied to 74 gave steroids 81 and82. In addition, the 17-vinyl group of 80a was oxidized togive the corresponding ketone (+)-83a (Figure 3).

Figure 3

Useful approaches to the construction of the vitamin Dtrans-hydrindane building block 88 from the meso-acetyl-cyclopentane 74 have been described (Scheme 30).49 Asym-metric reduction of 74 by borane–tetrahydrofuran complexand (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrro-lo[1,2-c][1,3,2]oxazaborole [(R)-2-methyl-CBS-oxazaboroli-dine] gave the epoxy ketone (+)-86 with good optical activ-ity.

An efficient route and high-yielding route was devel-oped for a multigram synthesis of a trans-hydrindane unitfrom 74. Compound 90 represented an advanced interme-

diate suitable for the Julia–Kocienski coupling used in theelaboration of the trienic system of vitamin D analogues(Scheme 31).49,50

Scheme 31

7 X-Ray Crystallographic Data

Structures of the following steroids or intermediateshave been confirmed by X-ray crystallographic analysis:8a;19a 8c;51 14i;19c 18;26 (+)-22;28 37d;35 (+)-39;37 50;39a

53b;40a 53c;40b 61;41 69 and 70;45 (–)-80a, 81b, 82a, and83b;48 87 and 88;49b and 90.50

O

1. NaH, THF

2. (MeO)2C=O

O

MeO2C

IR1

R2

Cs2CO3acetone

O

MeO2C

R1

R2

a, R1 = OMe; R2 = Hb, R1 = H; R2 = OMe

(+)-78, 78% yield(+)-(R,R)-75

R1

R2

O

H

H

H

R1

R2

HO

H

H

H

MeO2C

R3

85–95% yield

79a, R3 = H; 27% yieldΔ

(−)-80a, 63% yield(−)-80b, 55% yield

79b, R3 = CO2Me; 25% yield

4R

R

R2

O

H

H

H

MeO

HO O

H

H

H

MeO2C

81a,b

(+)-83a, 63% yield from 80a

O

H

H

H

R3

R1

R2

R1

82a, R3 = CO2Me82b, R3 = H82c, R3 = CO2Me

Scheme 30

OH

O

+

OHO

88:12

Dess–Martin

O

O

1. NaI, CeCl3MeCN

O

2. DHP THPO

I

O

HTHPO

t-BuOK

74

MeO

MeO

OMe

OMe

+ 1

O

74, 55% yield

+

O

75, 23% yield

Me-(R)-CBSBH3•THF

toluene

OH

(S)-(+)-84, 70% yield

97:3 er

t-BuOOHVO(acac)2

85, 43% yield

(+)-86, 98% yield 87, 90% yield

88, 89% yield; 31% yield from 74

Me-(R)-CBS = (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole

CH2Cl2

CH2Cl2 THF

O

LDA, THF

S

SS

OEt

S

EtO

O

SEtO

S

lauroylperoxide

O

HSEtO

S

HHS

OO

HO2S

OO

N

S

7475% yield

89, 70% yield 76% yield 90, 50% yield


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8 Conclusion

Our novel short strategy permits the synthesis of 17-vi-nyl steroids. It is noteworthy that natural steroids bearing a17-vinyl group are present in soft corals,52 octocorals,53 gor-gonians,54 sponges,55 and plants,56 predominantly as 20-progestene derivatives.

Our strategy is based on the use of benzocyclobutenederivatives, and their recent synthesis by C–H activation ofmethyl group has opened new perspectives57 as well as anew procedure for the 2+2 coupling of arynes with acetal-dehyde enolates.58,59

An impressive number of unnatural steroids have be-come accessible on the basis of these extremely short totalsyntheses starting from buta-1,3-diene and benzocy-clobutenes. The versatility of this powerful protocol makesthis chemistry a useful and attractive canvas for the synthe-sis of a range of important complex molecules of biologicalimportance.

Acknowledgment

M.S. would like to thank his co-workers for their contributions to thework reported here: Douniazad El Abed (University of Oran, Algeria),Arlette Tubul, Philippe Ouvrard, Pierre-Yves Michellys, GuillaumeBurtin, Serge Wilmouth, Malika Ibrahim-Ouali, Patrick Bazzini,Frédéric Cachoux, Natacha Mariet, Cyril Ollivier (Université Paris VI,France), Khalil Oumzil, Anne-Sophie Chapelon, Chahinez Aouf, andNicolas Galy. M.S. thanks Dr. Robert Faure for performing NMR exper-iments. X-ray structure determinations have been performed by Dr.Loïc Toupet (Université de Rennes I, France) and by Dr Michel Giorgi.M.S. warmly thanks Dr. Jean-Luc Parrain (CNRS) and Professor SylvainMarque for their aid, and Dr. Bernard Vacher (Pierre Fabre Médica-ments, Castres, France) for his helpful comments and encouragement.The CNRS and the Ministère de la Recherche are thanked for their fi-nancial support.

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Synthesis of Unnatural Steroids Using the Bistro Strategy