CHAPTER I AROMATIC STEROIDS : A REVIEW I. INTRODUCTION
Steroids are widely distributed in nature. The basic skeleton consists of 17-carbon atoms arranged in the form of perhydrocyclopentanophenanthrene. They play an important role in the vital activity of the living organisms. Testosterone is the male sex hormone, estrone, estradiol and progesterone are female sex hormones. Hydrocortisone is a hormone of adrenal cortex.
The four types of aromatic steroids viz. ring-A, ring-B, ring-C and ring-D (C-nor D-homo) occur in nature (Scheme 1). Estrone (1) the first known steroid hormone isolated by Diosy et al from the urine of pregnant women is a ring-A aromatic steroid. The structural isomer (2) of estrone isolated by 2 Heard e_t al_ from the nonphenolic fraction of equine pregnancy urine is a ring-B aromatic steroid. Viridin (3) an antifungal metabolite of Glyocladium virens is the first naturally occurring ring-C aromatic steroid which was reported as early as in 1945. Later the complete structure and stereochemistry of the compound 4 was established as represented in structure (3). Moffat and co-workers have isolated another ring-C aromatic steroid, namely
viridiol (4) from the culture filters of Trichoderma viride.
Veratrol (5) an alkaloid of veratrum album represents modified
ring-D (C-nor D-homo) aromatic system.
These aromatic steroids have been synthesized from known steroids by chemical transformations or through total synthesis. In the present review both the approaches are briefly discussed McO
SCHEME 1 in the order, ring-A followed by ring-B, ring-C and ring-D aromatic steroids.
II. SYNTHESIS OF A-RING AROMATIC STEROIDS J. TRANSFORMATION OF KNOWN STEROIDS
Estrogens (ring-A aromatic steroids) have received most attention from the synthetic angle. Besides their total synthesis primary interest was directed towards the conversion of naturally occurring steroids into estrogens by selective aromatization of ring-A dienones. The acid catalyzed isomerization of the ring-A dienones, customarily referred to as the "dienone phenol rearrangement" has been used to convert known steroids to -^aromatic steroids. Two different substituted aromatic steroids are formed in the above rearrangement. The mechanisms are shown in Scheme 2.
The position of the various functional groups in the steroid nucleus, as well as the conditions for the reaction, determine the nature of the phenols viz. whether the phenol is of the "para'' type (path A) or of the "meta" type (path B) . Any functional group which can stabilize the incipient positive charge on the secondary carbon atom (C-l) in preference to that on the tertiary carbon atom (C-5) will favour "meta" type rearrangement. Groups which fail to exert any influence both steric and electronic, will direct rearrangement leading to the formation of phenols of the "para1, type, via the inherently more stable tertiary carbonium ion. The dienone-phenol re arrangement has been extensively studied from these two aspects, Path A
HO HO^^i^^
Path B H^ HO SCHEME 2 Ac2O.H2S04 a r.t. 3-5 hr (92#/.) OAc Ac20' H2SOA r.t. 3hr (90*/.) Ac20,05-8hr^ ^SO* orTsOH AcO (72V.) H17 Ac?0,TsOHr 100S7hr SCHEME 3 and a comprehensive review of the available methods has appeared i 7 _ g in -j I Some typical examples of "para" and "meta" ' type rearrangements are shown in Scheme 3. In example (c) the complete conjugation of double bonds in the intermediate cation stabilizes the positive charge at C-l. The partial destabilizing effect on the generated positive charge by the dipole of the carbonyl group affords the driving force in example (d). Another method of preparing ring-A aromatic steroids from known steroids is by dehydration of the ring-A dienols. This transformation is known as the "dienol-benzene rearrange ment" . The rearrangement proceeds through a path which is entirely analogous to that of the dienone-phenol rearrangement, The only difference is the loss of water during the incipient stages. The accepted mechanism which is mediated through a spiran intermediate is given below. rO, r^S, -H® 2. TOTAL SYNTHESIS The isolation of estrone in 1929 paved the way for many ingenious total syntheses, each in its own way reflecting, to some extent, the state of the art of the synthesis at that time. The various approaches to the total synthesis of estrone are not only methods of its preparation but are also major 12 contributions to the synthesis of 19-norsteroids . There are eight well appreciated routes to the synthesis of estrone. Some of the typical syntheses from each route are described in the following paragraphs. (i) AB —» ABC —>• ABCD The first sjlynthesis of natural estrone by Anner and Miescher is shown in Scheme 4. The starting material viz. Robinson's ketone was synthesized from the diacid (6). Hydrogenation and esterfication of this acid gave the diester (7) Dickmcnn cyclization followed by angular methylation afforded the keto ester (8). The major product was found to possess the "natural" configuration and was designated keto ester (8A) . The Reformatsky reaction of (8A) followed by dehydration led to a mixture of isomers (9) and (10) which were separated by crystallization. A mixture of isomers (11A) and (11B) was obtained by the hydrogenation of (2J , which was 'separated by crystallization. The diester (11A) after selective hydrolysis was submitted to Arndt^Eistert reaction . Subsequent alkaline hydrolysis and cyclization gave estrone methyl ether (13). Demethylation with pyridine hydrochloride led to dl-estrone(14). COOMe S^\^COOM c MeO MtO 8 COOMe COOMe COOMe MeO MeO MeO' 8A 10 COOMe COOMe COOMe COOMe i (9) MeO MeO 11A II B .COOMe COOMc (i) CH2N2(ii) NaOH (in) S0C12 dv) CH2N2 (11)A (v)Ag20 MeOH MeO 12 13 R =Me OH H R =H (11*) MeO' MeO 15 16 SCHEME 4 In this synthesis a carbon atom is first added to the primary side chain of dimethyl marrianolate methyl ether (ItQ) and subsequently removed after cyclization. Sheehan and 16 co-workers improved the synthesis by carrying out an acyloin condensation on the diester (12$. The resulting 16-oxo derivative (15) on sodium borohydride reduction gave a mixture of epimeric alcohols (16). Dehydration of this mixture by heating with pyridine hydrochloride at 200-220 resulted in the formation of estrone (14) . m (ii) AC —» ABC —» ABCD In this approach the starting materials are biphenyl derivatives which on elaboration result in the A and C rings. Johnson's 17 ' 18 so-called second synthesis of estrone is the major contribution in this approach. The Friedel-Crafts acylation of anisole with glutaric anhydride and subsequent esterification gave the keto ester (17). Stobbe condensation with diethyl succinate, hydrogenation of the reaction product and esterification led to the formation of the triester (18) (Scheme 5). Dickmann cyclization of triester (18) with sodium hydride followed by methylation of the resulting sodio- derivative of the $-keto ester gave, the keto ester (19) of the required stereochemistry. Reformatsky reaction resulted in (20) which was ring closed by intramolecular Friedel-Crafts reaction. Acid catalyzed hydrogenation removed the 6-keto group and the double bond was saturated. The resulting dl- marrianolic acid methyl ester (21) on acyloin condensation afforded the 16-oxo derivative (15). A mixture of cis and MeO COOH MeO COOR 17 18 XOOR COOR CHCOOR MeO MeO COOR COOR 19 20 XOOR XOOR ppTH2,COOR MeO 21 15 16 SCHEME 5 trans-glycols (16)was obtained by sodium borohydride reduction of (15), which on fusion with pyridine hydrochloride (200 ) was dehydrated to estrone methyl ether (13). (Hi) AB —» ABCD The interest in the synthesis of estrone lies in the utilization of easily available starting materials such as 6-methoxy tetralone (22). Johnson and Walker 19 employed diene condensation of l-vinyl-6-methoxy-3,4-dihydronaphthalene(24) and p-benzoquinone as shown in Scheme 6. The adduct contains a double bond flanked by two carbonyl groups and which is easily reduced by zinc and acetic acid to give (25). In (25) the less hindered carbonyl group was selectively ketalized to (26). Wolff-Kishner reduction of the other carbonyl group also led to the inversion at C-14 to form the more stable C/D trans ring junction which on deketalization resulted in (27). The alkylation of benzylidene ketone 20 (28) with methyl iodide and potassium t-butoxide gave a mixture of products in which the desired trans product (29) predominated. The diacid (30) was obtained by the oxidation of (29) with alkaline hydrogen peroxide. Reduction of the conjugated 9A10-double bond with sodium in liquid ammonia resulted in the formation of the dl-homomarrionolic acid methyl ether (31), which was converted into estrone methyl ether (13). The three approaches discussed so far in this review have only historical importance since they have not been further developed. CH2 = CHMgBr 5102 McO MeO McO 22 23 24 0 MeO OMe MeOH.AcOH i)N2H^-K0H ii)AcOH Y 0 i) Additio0 n MeO ii)Zn/AcOH 26 CH.Ph Mel-tBuOK MeO COOH H ~~ Na,NH3 COOH COOH PbC03 (13) 300f McO 31 SCHEME 6 (iv) AB —*- ABD —>• ABCD By far the most important synthesis of estrone methyl 21 ether (13) is by Torgov and Aanchenko which is shown in Scheme 7. 6-Methoxy-l-vinyl~l-tetralol (23) was prepared from 6-methoxy-l~tetralone (22) and vinyl magnesium bromide. Condensation of 2-methyl-l,3-cyclopentadione with vinyl alcohol (23) gave the ABD intermediate (32) , which was ring closed by acid catalysis to the methyl ether of 3-hydroxy- 1,3,5(10),8,14-estrapentaen-17-one (33). Catalytic hydro- genation afforded the tetraene(34), which was subjected to further reduction with potassium in liquid ammonia. Some reduction of the 17-oxo group occurred simultaneously, which necessitated oxidation with chromic oxide to obtain racemic estrone methyl ether (13). This approach is the shortest synthetic route to estrone. (v) BC •—*• BCD —>> ABCD 2 2 The total synthesis developed by Velluz and co-workers following BC —*• BCD —*• ABCD approach is based on the fundamental necessity of performing an early resolution, which opened the way, starting from common optically active intermediates , to a whole series of new compounds having the configuration of natural steroids. Tricyclic intermediate (36) was prepared from 6-methoxytetralone (35A) and was resolved through its carboxylic group (Scheme 8). 6-Methoxytetralone (35A) was coverted into the cyanoketone (35B) by successive fomylation, formation of an isoxazole and methylation. Stobbe condensation with dimethyl succinate in the presence of potassium t-butoxide it MeO 32 (13) MeO MeO 33 34 SCHEME 7 COOH ,xr MeO MeO 35 A RW=H 36 37 A R=H 35 B R1*Me R2=CN 37 B R=Bz OBz OBz OH MeO 38 39 40 SCHEME 6 If yielded the tricyclic keto ester, which upon reduction with sodium borohydride and saponification gave the hydroxy acid (36). Decarboxylation by heating and catalytic reduction afforded the trans-benzohydrindane derivative (37A). Birch reduction of benzoate (37B) followed by acid hydrolysis gave unsaturated tricyclic ketone (38). Alkylation of (38) with 1,3-dichloro- 2-methyl-2-butene via the pyrrolidine enamine and subsequent hydrolysis introduced at C-10 the elements of ring-A. Ring closure afforded 9-dehydro-19~nortestosterone derivative (39), which was converted into optically active estradiol (40). (vi) CD —*• BCD —*- ABCD v 4 Another development in the synthesis of optically active 23 estrone involves the resolution of the CD synthon . Condensation of 5~keto-6-heptenoic ester (41) with 2-methyl-l,3-cyclopentadione afforded (42) (Scheme 9). The ring closure led to a bicyclic structure (43). The CD intermediate (43) was resolved with ephedrine to give optically active (43). Alkaline solution of (43) on treatment with sodium borohydride gave (44). The formate of (44) was hydrogenated in the presence of Pd/C and hydrolyzed to give (45). Treatment of (45) with sodium acetate in acetic acid gave acetoxy 6-lactone (46). Condensation with (JL^J^*^1 Grignard reagent prepared from the 5^bromo~2,2~ethylenedioxy- pentane yielded (47) . Treatment of (47) with t_-AmONa gave (48) , which was converted into optically active estradiol (40). 0^\0^ 0^^ MeOOC M€OOCv HOOC 41 42 43 HOOC oA0 47 48 40 SCHEME 9 (vii) CD —» ACD —*• ABCD After Anner and Miescher's synthesis of natural estrone (Scheme 4), Johnson and co-workers in 1950 developed a new estrone synthesis following CD—yACD—+ABCD approach. The synthesis involved the construction of D-homo estrone ring followed by conversion of the six to five membered ring as shown in Scheme 10. 27 Cohen and co-workers reported an asymmetric synthesis of estradiol by this approach (Scheme 11). The main feature of the synthesis is the conjugate addition of m-methoxybenzyl- magnesium chloride to the optically active enone (49) in the presence of cuprous ion to give the key tricyclic ketone intermediate (50) in 80-90% yield. The 1,2-adduct (51) is formed only in minor amounts. Cyclization of the tricyclic ketone (50) to the tetraene (52) followed by catalytic hydro-? genation resulted in estratriene (53A). Treatment of (53A) with trifluroacetic acid gave estradiol methyl ether (53B). Oxidation of (53B) led to the formation of estrone methyl ether (53C) [a] +153.98°. 29 Bryson and co-workers using hydroboration-carbonylation procedure for highly functionalized 1,4-dienes prepared trans- hydrindanones, which are synthons for norpregnenolone, estrone and related estradiol derivatives. They prepared norpregne- 30 nolone (60) which has been degraded to estradiol derivatives In their synthetic route (Scheme 12) the 1 r4-diene (58) was prepared by addition of the Grgnard reagent of m-methoxyphenethy It 1) H2,Pd 0 OH ,CH 2)HCOOH Mc0 Me0 M„0 CH.C6H5 O3JH2O2 MG0 COOH COOH SCHEME 10 *)*& ^ **- 0!Bu MgCl MeO MeO 49 r^^ 51 (50) MeO 53 A R = 0* Bu 52 53 B R =0H 53 C R = 0 SCHEME 11 54 A ,< = CI 56 57 54 B X=MgCI \ / 1 <^ YS\J f\ f U. JJ MeO MeO 59 60 58 SCHEME 12 chloride (54) to ketal carboxaldehyde (55) to give alcohol (56). Acetamide acetal rearrangement in refluxing xylene with (56) afforded the amide (57). The amide (57) was reduced to amine. The N-oxide of the amine was prepared by treating with mj-chloro- perbenzoic acid, which on Cope elimination (heating 135 under vacuum 0.1 mm) gave the 1,4-diene (58). Hydroboration (thexyl- borane from H B S (CH ) and 2,3~dimethyl-2-butene in THF at 0°, 15h) of 1,4-diene (58) followed by carbonylation (KCN, TFAA, then H.0 ) resulted in the formation of hydrindanone (59) with desired stereochemistry, which was converted to norpregnelonone by known procedure. Baeyer Villiger oxidation of (60) with m-chloroperbenzoic acid followed by alkaline hydrolysis and Jone's oxidation afforded estrone methyl ether (13). (viii) AD —V ABCD Smith et al used this approach for the synthesis of estrogenic hormones and their derivatives. In general the AD fragment containing keto group at C--9 and C-14 are prepared. Condensation with the participation of these two keto groups was carried out either successively or in a single stage. In the synthesis of estrone methyl ether condensation of the vinyl ketone (61) with 2-methyl-l,3-cyclopentadione was carried out to give the bicylic triketone (62) (Scheme 13). Cyclization of bicyclic ketone in presence of pr-toluenesulfonic acid gave estrapentaenone (63) which was converted into the methyl ether of estrone (13). Recent advances in the total synthesis of steroids include t > Ki HCHC.Na.NH3 HNEt2,CH20 MeO MeO' r^ NEt2 0- H20,HgSOA Distill. H2SO/, KOH, MeOH MeO MeO 61 p-TsOH,Ph 62 63 1) H2>Pd 2)NaBHA 3) Li/NH3 A)Cr03 MeO SCHEME 13 acetylenic participation in polyolefinic cyclization developed by Johnson and co-workers. A fascinating total synthesis of ( + ) 32,33 progesterone has been reported based on this approach. Johnson and co-workers explored a new approach to estrone 34 synthesis via cat ionic olefinic cyclizations as shown in Scheme 14. The reduction of ester (64) with Red-Al gave the aldehyde (65). Wittig condensation of this aldehyde with the o ketal phosphnium iodide (66) afforded the diketal (67). The cyclopentenone (68) was obtained by hydrolysis of the diketal followed by cyclodehydration. The cyclopentenone (68) was reduced with Red-Al to cyclopentenol (69). The cyclization of cyclopentenol (69) with stannic chloride resulted in the formation of the isomers (70A) and (70B) in 59% and 12% yields respectively. Recrystall ization afforded the 3'-methoxy isomer ( Stereoselective formation of the desired a-epoxide was accomplished via the chlorohydrin (71 and 72), The phenolic epoxide (73) on treatment with borontri fluoride gave dl-estrone Among the recently reported syntheses of estrone the application of annelation reactions via pyridine route by 35 Danishefsky and co-workers may be considered as a novel synthes and a deviation from the above described approaches. The synthetic importance of this approach is the conversion of a prochiral intermediate (75) to optically active (76A) with high asymmetric specificity via an aromatic amino acid. Reaction of tris annelating agent (74) and 2^-methyl-l , 3-cyclo- pentadione in presence of an acidic catalyst gave racemic hydrindendione (76A). Alternatively (75^ was prepared in high 23 ,^\ C00CH3 CHO McO 64 65 0^ R1 .R2 r^ ^!S r^N ^ 0 0 \J MeO' R 67 68 = 0 >• 69 R1= OH . R2= H MeO 70 A Me CI IvvOH and 73 SCHEME U U 24 ^ ^^ A o\o^ McT^N 1U 75 RUR2 Me Me^^N 76A >- ° 77A R oCH 77B R /3H 76 B R1= OH ; R2= H RVR2 H H Me^N R1 78 79 80A ^> = 0 R2 80 B R1-= OH ; R2= H 81 SCHEME 15 2S yield by treating (74) and 2-methyl-1,3-cyclopentadione in ethyl acetate containing triethylamine. Cyclization of (75) with L-phenylalanine and perchloric acid in acetonitrile gave optically active (76A) of 86% optical purity. Selective reduction of (76A) with sodium borohydride led to (76B) (86% optically pure). Catalytic hydrogenation of (76B) over Pd/C catalyst in ethanol containing traces of perchloric acid followed by ketalization resulted in the formation of compounds (77A) and (77B) in 45 and 17% respectively. Hydrogenolysis product (78) was also obtained in 21% yield. The reductive hydrolysis of (77) was followed by hydrolytic cyclization in alkaline medium. The ketal function was removed during acid work-up to give (79). Jones oxidation of (79) was followed by cyclodehydration. The dienone (80) was isomerized with acetyl bromide and acetic anhydride, and the phenolic estrone acetate was hydrolyzed to give (81) (Scheme 15). A single crystallization (EtOH-MeOH) gave optically active estrone (53) [aj +160 . 3. BY INTRAMOLECULAR CYCLOADDITION Ring-A aromatic steroids have been synthesized starting with either one or several of the rings containing appropriate functionality as suitable precursors for the addition of the remaining rings by cycloadditions, condensations and other bond forming reactions. Of the many successful strategies the AD—* ABCD approach has not been fully exploited. Some of the 31 examples include the Smith-Hughes synthesis employing a double 34 . . condensation and the Johnson-Bartlett approach utilizing a cationic olefin cyclization. In a retrosynthetic analysis of estrone one notices that an alternative to the Smith-Hughes AD —«r ABCD approach which might allow the stereospeci fie construction of the B and C rings in one step is an intra molecular Diels-Alder reaction of an appropriate intermediate of the type (82) . The latter contains an oj-quinodimethane moiety which can be generated from a variety of precursors. During the last five years several elegant, creative and convergent total syntheses of racemic A-ring aromatic steroids have been developed. 82 63 A common feature of these approaches is the use of an intra molecular Diels-Alder cyclization of an o.-quinodimethane (82) to produce a 19-norsteroid such as (83) having the natural stereochemical configuration at all chiral centres. Several groups exploited this convenient approach for the synthesis of aromatic steroids. This type of cycloaddition reaction was first applied to the synthesis of D-homo estrone methyl ether (88) by Kametani and co-workers ' ( Scheme 16). 0 27 J H 85 t-BuOK MeOO 2, Hydrolysis MeO 84 86 MeO MeO MeO S7 88 SCHEME 16 O-Li McO u> MeO p*~ «* uV &\\ 92 A XsN-OCHjPh <*** 92B X rO SCHEME 17 Jtt* The enolate of substituted cyclohexanone (85) was alkylated with 2-(4-methtfoxybenzocyclobutenyl)ethyl iodide (84). Hy.drolysis of n-butylthiomethy lene group with base gave a mixture of diastereomers of (86). Thermolysis of (86) resulted in racemic O-methyl D-homoestrone (88). The reaction is remarkably stereospecifie and gives the thermodynamically preferred trans-anti-trans steroidal framework. In the above approach the alkylation yield of enolate of cyclohexanone (85) with benzocyclobutene (84) was poor. 39 Oppolzer improved the coupling of the benzocyclobutene unit with the dienophile carrying the D-ring part of the steroid by employing a reactive alkylating agent (89) (Scheme 17). One equivalent of a-bromo oxime (89) was added to two equivalents of the enolate of 2-methyl-3-vinyl~cyclopentanone (90). The desired benzocyclobutene (91A) was obtained in 77% yield, which was then benzylated to give benzocyclobutene (91B). Thermolysis of (91B) furnished cycloadduct (92A) with "unnatural" "cis-anti- trans" stereochemistry via exclusive en_do_ cycloaddition. Hydrogenolysis followed by acid treatment resulted in the formation of 11-oxosteroid (92B). The factors that control preferential formation of exo product in one case and endo product in the other are more difficult to understand e.g. a minor variation of the synthetic scheme to (92B) allows the synthesis of optically pure material in the desired trans-anti-trans 39 configuration (Scheme 18). In this approach the acid (93) is first resolved [(+ ) -ephedrine~j then converted into acid chloride (94) and subsequently coupled with anion (95) to give MeO 95 MeO 0 •I 1 96 R = -C - O-Bu MeO 97 SCHEME 18 OBu t OBu OBu 4-k ^\ 10 Steps r H MeO 100 98 99 MeO 40 SCHEME 19 product (96). Thermolysis of (96) after removal of the ester group afforded (97) [a] + 387 . A small amount of the cis-anti-trans (10%) was also obtained. Following the cycloaddition approach a new type of • asymmetric total synthesis of estradiol (40) in high optical 40 purity was achieved by Kametani and co-workers (Scheme 19). The key intermediate viz the optically active 2-benzocyclo- butenylcyclopentane (100) was prepared from optically active CD synthon (98) . The iodide (99) was coupled with 1-cyano- 4-methoxybenzocyclobutenyl • anion to give benzocyclobutene (100). Thermolysis of (100) resulted in the formation of B and C rings with the desired stereochemistry of (+) estradiol (40), which 41 42 was identical with natural estradiol, Kametani et_ al_ ' by an improved procedure synthesized 14a-hydroxy estrone methyl ether via an appropriately modified precursor. 43 Grieco and co-workers developed an unusual synthesis of dl-estrone (Scheme 20), which employs the rigid carbocyclic bicyclo \2,2,1\ heptene derivative (102) for the elaboration of ring-D and involves the use of the intramolecular cyclo- addition of o_-quinodimethane for generation of the BC ring system. The critical importance to the success of the scheme is the stereospecific introduction of benzocyclobutenyl moiety at C-7 position of the bicyclo \_2,2,l} heptene (101) during alkylation of ester (101) with 2(4-methoxybenzocyclobutenyl) ethyl iodide. In a series of transformations the bicyclo [2,2,1"] heptene (102) was transformed to (103). Baeyer-Villiger 31 ^^OMe COOMe 1)NaOH,H202 2) CH2 N2 101 102 103 H2>Pt02 MeO MeO 105 104 1)0-N02C6Hz,5eCN ^^ LiAIHA Bu3P H 2) 2°2 MeO 106 107 MeO 14 SCHEME 20 oxidation of (103) unleashed the five membered D-ring and subsequent esterification of the resultant hydroxy carbocyclic acid resulted in cyclopentenol (104). Subsequently the double bond was hydrogenated, the ester moiety was converted to vinyl group. Thermolysis of (107) at 200 in o-dichlorobenzene afforded racemic estrone (14) . 44 r -i Nicolaou and co-workers used 1, 3-dihydrobenzo\_C\ thiophene-2,2-dioxide precursor for the generation of o_-quinodimethane . Racemic estra-1 , 3 , 5 (10) trien-17-one (109) was prepared by intramolecular capture of o-quinodimethane generated by cheletropic elimination of sulphur dioxide from appropriately substituted sulfone (108) (Scheme 21). Despite advances in approaches aimed at improving the general availability of benzocyclobutenes the drawback of the above methodology has been the relative difficulty in constructing variably substituted members of the series by simple and effective reactions. A convergent approach viz. cobalt-mediated co-oligomerization of hexa-1,5-diynes is an improved synthetic 44-47 route to benzocyclobutenes. Vol lhardt et^ a_l^ synthesized racemic A-ring aromatic steroids based on the co-oligomerization of substituted 1,5-hexadiyne with monoalkyne as shown in the Scheme 22. Treatment of 1,5-hexadiyne (110) with butyl lithium (3 equiv.) and TMEDA (1 equiv.) generated the trilithio- compound, which was regiospecifically monoalkylated at the 3-position using ethylene oxide to give after protonation the hexynol (111) . The hexynol CHI) was converted to the A 108 109 SCHEME 21 .OH 110 111 112 OSiMe3 SiMe- II! I 113 5iMe3 1U 0 Me35i. MeoS + Me3Si Me3S II H 115 116 (116) MeO 13 SfHFME 17 p-toluenesulfonate which on exposure to NaT in acetone gave the iodide (112). The enolate was generated regiospecifically from the enol ether (113) with LiNH2 in liquid ammonia and then alkylated with the iodide (112) (3 eguiv.) to give cyclo- pentanone (114). Co-oligomerization of (114) with bistrimethyl- o silylacetylene catalyzed by Cp Co (CO) resulted in a mixture of benzocyclobutene (115) and estratrienone (116) in 56% and 18% yield respectively. The yield of (116) was increased to 95% by heating the mixture in decane. Protodesilylation of (116) in CC1 , CF COOH, at -30 C followed by oxidative aryl-silicon cleavage resulted in racemic estrone (13). This constitutes the first successful completion of a D —> ABCD route to the steroid nucleus and the first in which three rings are constructed simultaneously. Using the photochemical approach for the generation of 4 8 — 50 o-quinodimethane Quinkert and co-workers reported a synthesis of estrone as shown in Scheme 23. The aldehyde (117) on treatment with Grignard compound prepared from 1-bromovinyl (trimethyl) silane afforded (118), which on oxidation with chromic acid furnished (119). The alkylation of the cyclopentanone enolate (90) with enone (119) gave after protodesilylation, the Michael adduct (120) in 43% yield. Photoenolization of (120) afforded stereospecifically the 9a-hydroxyestrone (122) via intramolecular exo cycloaddition of o-quinodimethane (121). 9a-Hydroxy estrone (122) was converted to estrone methyl ether (13) in two steps. Using optically active starting material asymmetric total synthesis of (+) estrone has also been achieved by the same approach 0 0-U Si(Me)3 MeO^^/^( MeO 120 121 122 SCHEME 23 N N N XOOH 0 MeO MeO MeO CH3 MeO 123 124 125 126 5iMe3 <^ 05iMe3 HO OH H II H 113 —>- MeO ^^ 1 MeO MeO SiMc 127 3 128 SiMe3 129 5iMe3 MeO ^| MeO 130 5iMe3 131 SCHEME 24 Magnus and co-workers reported extremely mild conditions for the generation of o_-quinodimethane using organosilicon compounds. Making use of Torgov and o-guino- dimethane strategies ring A-aromatic steroids have been prepared in high yields. Useful aspects of organosilicon chemistry has been applied to synthesis of dl_ lla-hydroxy- estrone methyl ether (131) (Scheme 24). Aldehyde (127) was converted to vinyl carbinol (128) on treatment with vinyl magnesium bromide. Treatment of (128) w.th enolate (113) in di-hloromet ane with zinc bn.. tide affolded benzyl' ilane (129). The key feature of the synthesis is conversion of (129) to A-ring aromatic steroids, which is triggered by the addition of an appropriate electrophile to the electron rich 9,11- double bond, followed by the cleavage of Si-C bond to generate the o^-quinodimethane moiety. Epoxidation of (129) wxth m-chloroperbenzoic acid gave (130). The epoxide (130) on treatment with cesium fluoride in diglyme at room temperature afforded lla-hydroxyestrone methyl ether (131) in '0% yitid. III. SYNTHESIS OF B-RING AROhATIC STEROIDS 1. CONVERSION OF KNOWN STEROIDS 52 One of the earliest reports on the selective aromatiza- tion of ring-B is the conversion of ergosterol to neoergosterol (neosterol) by photoirradiation in absence of oxygen followed A 37 by pyrolysis of the 7,7'-bisergostatrienol product C9H17 EtOH 0rC6H65-6h C9HA7 n C9HV7 180 ? 0-1 mn -12 2. PARTIAL SYNTHESES_ Ring B-aromatic steroids have been prepared from equilenin and its derivatives. Ruzicka and Muller prepared the aiol (133A) and its 3a-epimer (133B) by catalytic hydrogenation and by sodium and alcohol reduction of equilenin (132) respectively as shown in Scheme 25. Configuration of the C-3 position was assigned on the assumption that 3&-hydroxy compound should have more negative optical rotation and lower m.p. than the 3a-epimer. _ ^ 132 Catalytic hydrogenation Na/C2H5OH HO. ,H 133A 133 B SCHEME 25 (132) Hydrogenation under high pressure OH H OH H 133 A 133 B I Controlled Controlled y Jones Oxidation ,,Jones Oxidation 0 0 H HO* 134 A 134 B SCHEME 26 K, NH3 MeO MeO 135 136 SCHEME 27 Birch reduction MeO MeO H0 ^ vNC = C.Cl MeO MeO ACSCXI H • SCHcME 28 Later Banerjee and co-workers synthesized (133A) and its 3a -epimer (133B) by catalytic hydrogenat ion of dl~egui lenin (Scheme 26) and assigned the configuration at C-3 position. The 3-keto B-ring aromatic steroid (136) was prepared 55 by the Birch reduction of (135) (Scheme 27). 17-Chloroethynylated B-ring aromatic steroid (137) was synthesized from 3-methoxy-l,3,5,7,9-estrapentaen-17$ -ol as shown in Scheme 28. The synthesis involves Birch reduction followed by Oppenauer oxidation. The C-17 ketone obtained was chloroethynylated and hydrolyzed with acid to give 17a -chloro- ethynyl-5 ,7 ,9-estratrien-17$-ol-3-one (137) . IV. SYNTHESIS OF C-RING AROMATIC STEROIDS 1. CONVERSION OF KNOWN STEROIDS Conversion of a known steroid to a ring-C aromatic steroid involves aromatization of ring-C, which necessitates (i) C-18 methyl migration from C-13 to C-17 or to C-12 and (ii) generation of the required degree of unsaturation around ring-C. The required degree of unsaturation around ring-C can be produced prior to the methyl migration or after methyl migration. Different techniques have been used for the introduction of additional double bonds in unsaturated steroids. These include bromination-dehydrobromination and hydroxylation followed by dehydration. 57 Stevenson et_ aj^ reported aromatization of ring-C when 7 ,11,12 .13-tetrabromoergosta-8-en-3&-yl-acetate (138) Th G4o8 was passed through chromatographic alumina. The aromatic ring results from the partial dehydrobromination accompanied Ac0 58 Later the same authors utilized a Wagner-Meerwein shift of the C-18 methyl group from C-13 to C-12 in methyl -3a-acetoxy- 12a.-hydroxy-5$-chola-7 ,9 (11)-dienote (140) by treating with P O in benzene. Methyl-3a-acetoxy-12-methyl-5&-18-norchola-8, 11,13-trienate (141) was obtained in 50% yield. COOCH3 AcO* H 140 H Another rearrai gement leading to ring-C aron t:'zation in which C-18 methyl group migrates from C-13 to C I ( cheme 29) was reported by Turner ' . When 17a-methyl-A -testo sterone (142) was treated with acid, the rearranged 17,17- dimethylandrosta-4,8,11,13-tetraen-3-one (143) was obtained. HO Me 142 HO. .Me MECHANISM #*> ' :142) 144 145 -*- (143) 146 SCHEME 2 9 ^Me AcO 148 HCL .Me 149 150 SCHEME 30 The mechanism of the rearrangement is shown in the Scheme 29. The elimination of hydroxy group is most readily accompanied by rearrangement when the tertiary 14a-hydrogen is ally lie or benzylic. Under acid conditions since 14a-hydrogen is subject to allylic activation in its thermodynamically preferred enolic form (144) dehydration is most favoured. 61 Hewett and co-workers have described elimination-migration in a steroid already containing two potential double bonds in ring-c, in the form of either, an a,^-unsaturated ketone or an a-bromo ketone to give 11-hydroxy ring-C aromatic steroids (Scheme 30). Treatment of 3$-acetoxy-17$-hydroxy-l7a-methyl- 5a~androst-8-en-ll-one (147) with formic acid resulted in the formation of 3B-acetoxy-ll<-hydroxy-17 ,17 -dimethyl-1 8-nor-5ct- androsta-8,11,13-triene (148). Similarly formic acid rearrange ment of 9a-bromo-17$-hydroxy-17a-methylandrost-4-ene-3,11- dione (149) afforded ll^-hydroxy-17,17 -dimethyl-18-norandrosta- 4,8,11,13rtetraen-3-one (150). Later on the same authors using bromination followed by dehydrobrommation technique for introducing additional double ft 0 bonds, prepared 18-norandrosta-8 11,13-trienes from 18-norandrost- 13-ones (Scheme 31). Bromination of 17,17-dimethyl-18-nor-5a- androst-13-en-3$-y1-acetate (151) followed by treatment with sodium iodide in acetone,gave 17,17-dimethyl-18-nor-5a-androsta- 7,13-dien-3$-yl-acetate (153). The reaction is presumed to proceed by direct addition of bromine to the 13,14-double bond to give the dibxomo compound (152) , which is stable at -70 Br2 -6CT below-U AcO AcO 51 152 -HBr above -14 Bro (153 )=* ^- NaI,Br2 AcO ArO SCHEME 31 MECHANISM cC^vXt^/ -.JOT H H SCHEME 32 155 but loses hydrogen bromide in two stages as the temperature is rised. Further bromination of (153) resulted predominantly in the formation of a stable dibromide (154) which on dehydro- bromination afforded 17 ,17-dimethy2-18-nor-5a-androsta- 8 ,11 ,1 3- trien3&-yl-acetate (155). The mechanism of bromination and susbeguent aromatization is shown in Scheme 32. Attack of the less hindered 7,8-double bond of the 7,13- diene (153) may lead to the formation of ana-bromonium ion, which yields the dibromo-ene (154) via an intermediate carbonium ion. The dibromide (154) loses one mole of hydrogen bromide to give the intermediate bromo-diene, which on loss of a second mole of hydrogen bromide afforded the 7,9(11), 13-triene, which isomerizes to the 8 ,11,13-triene (155). Bromination followed by dehydrobromination technique was applied for the synthesis of derivatives of lo.-amino-17,17- 63 dimethyl-18-norandrosta-8,11,13-triene by Hewett and co-workers (Scheme 33). Bromination followed by dehydrobromination of lo.-benzoyloxy-17,17-dimethyl-18-nor-5o.-androsta-13-ene (156) resulted in la-benzoyloxy-17 ,17-dimethyl-18-nor-50L-androsta- 7,13-diene (157), which on subsequent bromination followed by dehydrobromination and saponification gave 17 ,17-dimethyl-* 18- nor-5a-androsta-8,11,13-triene-la-ol (158) . The aromatic lo.-alcohol (158A) was oxidized with Jones reagent to the ketone (159A). The oxime (159B) was reduced with lithium aluminium hydride or with sodium in refluxing propan-3-ol to give ict-amine (158C) . 158 A R=OH 159 A R = 0 158B R=OBz 159 B R=NOH 158C R=NH2 SCHEME 33 \ H?0 > H 162 H 164 / H (161) - 2° / SCHEME 34 7-Hydroxy derivatives of ring-C aromatic steroids were prepared by allylic hydroxylation followed by dehydration 39>-Hydroxy-17 ,17-dimethyl-18-nor-5a-androst-13-ene (160) on treatment with selenium dioxide afforded, in one step, 7ct-hydroxy-l 7 ,1 7 -dimethyl-18-nor-5a-androsta- 8 ,11,13-triene (161) (Scheme 34). Allylic hydroxylation of the 13,14-double bond at either position 8 or 12 gave the unsaturated alcohols (162) or (163). Dehydration resulted in diene (164). Hydroxylation of the diene (164), again in the allylic positions gave the 7,11-diols (165), which loses the 11-hydroxy group along with the 9a-proton, possibly also with allylic rearrangement within ring-C, to give the 7a-hydroxy-18-norandrosta-8,11,13-triene (161). Work on C-ring aromatic steroids was extended to the partial synthesis of C-ring aromatic steroids with pregnane side chain by Redpath and co-workers . They have prepared 3$,16&-diacetoxy- 11-hydroxy-l 7&-methyl -18-nor-5a-pregna-8 ,11 ,13~triene-7 ,20-dione (17Q) by Lewis acid treatment on 3&-aceboxy-16a, 17&-epoxy 5a-pregn-8-ene-7,11,20 ,(166) as shown in Scheme 35. 3&, 17a- A Diacetoxy-5&-pregna-8,14-diene-7,11,20-trione (168) was also formed. The mechanism involving the opening of the J6a, 17a- epoxide (167) proceeds by two competing pathways. The inter mediate (167) formed by attack of the Lewis acid on the epoxide (166) undergoes rearrangement by a concerted mechanism with loss of C-12 proton to give the 17&-methyl intermediate (1&&). Enolization followed by displacement of the Lewis acid gives the aromatic 16a-acetate (168). PZnCli 067) (169) ^-* SCHEME 35 H Ac0^j/CH20Ac AcO H -OH )^CH20Ac 174 SCHEME 36 The competing epoxide opening reaction leads to the formation of the C-16 carbocation. Loss of proton from C-15 results in A intermediate, Attack by acetic anhydride on 17a-oxygen atom to displace the Lewis acid is followed by allylic rearrangement of the 15,16-double bond to bring it into conjugation with 8,9-double bond. This results in the formation of the 8,14-diene-17a-acetate (170). 66 Cambell and co-workers reported an efficient route to ring-C aromatic pregnanes. Treatment of 13a, 14a-epoxy-173- methyl-18-nor-5B~17a-pregnane-Ja,11$,20&-trione (171) with formic acid afforded ll-hydroxy-17&-methyl-18-nor-5&-17a- pregna-8,11,13-triene~3,20-dione (172) . 171 172 67.68 More recently Cheung and co-workers converted pregnanes and corticoids to C-aromatic steroids of 178-pregnane series with oxygen functions on a 17a-side chain as shown in the Scheme 36, In their strategy the required degree of unsaturation around ring-C is generated prior to the methyl migration step. 20a,21 -Diacetoxy-9a,lla-epoxy-17a-hydroxy- pregn-4-en-3-one (173) on treatment with boron trifluoride- diethyl ether resulted m C-aromatic product 20a ,21-diacetoxy 17S>-methyl-18-norpregna-4,8,11,13-tetraen-3-one (174). 2. TOTAL SYNTHESIS Besides these rearrangements independant total syntheses of rmg-C aromatic steroids are also reported. Windholz et al 69 used Torgov's approach for the preparation of aromatic C-ring analogue of 18-norestrone (176) by the condensation of 1,2,3,4- tetrahydro-6-methoxy-l-vinyl-l-naphthol (175) with 2-chlorocyclo- penta-1,3-dione in re fluxing xylene, containing t-BuOH and catalytic amount of triton B. CI MeO MeO Cyclopentenophenanthrene derivative (177) was used as a starting material for the synthesis of a ring-C aromatic bis- 70 norsteroid (180B) by Birch and Subba Rao (Scheme 37). When compound (177B) was subjected to metal ammonia reduction the initial product (178) resulted from the reduction of 17-carbonyl to 17-OH and saturation of 6,7-double bond. As the compound (178) incorporates a benzyl structure and a p-methoxy diphenyl structure hydrogenolysis of benzylic hydroxy group at C-17 takes place to a large extent on further reduction, However, the use of phenol (177A) resulting in the phenoxide anion prevented MeO MeO 178 177 A R = H 179 A R=H 177 B R = Me 179 B R=Me 180A R = H 180 B R = Me SCHEME 37 M^O COOH (CH2)2 COOR' 181 182 A R^R^H 182B R1=Me,R2=H 182C R1=R*=Me MeO. (CH2)2COOR (CH2)2COOH 183A R=Me 183B R = H hydrogenolysis of the benzyl alcohol and altered the behaviour of the ring AC system from a diphenyl to that one in which ring-A carries only electron repelling substituent. The product expected would be (179A) in which the 5(10) double bond also protected from reduction by the phenoxide charge. Reduction of **e (177A) with excess of lithium in liquid ammonia followed by mild acid hydrolysis gave (180A) as the main product which on treatment with diazomethane gave (180B). Ring-C aromatic steroid (185) , which contains both C-ll- methoxy and C-19 angular methyl group was synthesized by 71 72 Chatterjee and co-workers ' . The route involves BC —*• ABC ABCD approach (Scheme 38). Reduction of (181) with sodium in liquid ammonia followed by mild acid hydrolysis gave (182A). The corresponding methyl ester (182B) was alkylated via enamine to furnish (182C), which on treatment with methiodide of l-diethylaminobutan-3-one resulted in (183A). Reduction of the corresponding acid (183B) using Na in liquid ammonia resulted in (184) which was cyclized to (185) with poly phosphori acid. 7 3 Chakravarti et_ a_l_ have reported synthesis of 17-hydroxy- ll-methoxy-18-norandrosta-4,8,11,13-tetraen-3-one (19 2) starting from 3'-hydroxy-4,6-dimethoxy-1,2-cyclopentenonaphthalene (187) as shown in the Scheme 39. 74 Dalzell and co-workers have reported an improved synthesis of 17-hydroxy-11-methoxy-18-norandrosta-4,8 ,11,13- tetraen-3-one based on an earlier synthetic route. In the 53 MeO MeO Li/NH- NaBH/» McO MeO 187 186 OH MeO McO-^r^/^ MeO MeO' 189 188 ® NaOMe/Mel H (188) 191 190 192 SCHEME 39 54 reduction of acid (181) to keto acid (182A) it has been reported that conditions for this reaction are critical, with slight changes giving undesired tetralin acid (193) as the major 7 4 product. Dalzell and co-workers have found that the use of t_-butul alcohol as the proton source in the reduction medium improved this situation considerably. COOH MeO MeO (CH2)9C00H (CH2)2COOH MeO 181 182 A 193 The formation of (193) can be rationalized as due to the prot'onation of an intermediate anion at C-7 rather than at C-5. The use of a hindered alcohol like t-butyl alcohol, as a proton source favoured the formation of the desired product (182A) and supressed the formation of (193) -* 182A OMc MeO •*• 193 COOH si The reduction of the diketone (194) to give testosterone analogue is complicated by the competitive reduction of the 3-keto group in ethanol, the reaction mixture consists of 7% diketone, 6% 3-ol, 48% 17a-ol, 37% 17%-ol and 1% each of isomers of diol as characterized by LC. These compounds were separated by HPLC to give about a 20% yield of each 194 195 196 of the C-17-epimers. V. SYNTHESIS OF D-RING AROMATIC STEROIDS 1 . INTRAMOLECULAR DIELS-ALDER APPROACH The intramolecular cycloaddition of O-quinodimethane has been successfully applied to the synthesis of D-ring 75 aromatic steroids having 19-methyl group. Kametani et_ aj^ reported a stereocontrolled synthesis of D-ring aromatic steroid having 19-methyl group and nitro group at C -position b (Scheme 40). The olefinic ester (198) was prepared by 1,4- addition of vinylmagnesium bromide, in the presence of Cul, to Hegemann's ester (197). The ester (198) was converted to AcQ AcO Me »r" + OTs COOMe COOEt 200 197 19fi 199 OMe II AcO A^V^N, NO- 201 202 OMe AcO NO2 204 SCHEME A0 OMe OMe 206 SCHEME 41 tosylate (199) by successive reduction (LiAlH , in THF) selective tosylation (TsCl in pyridine) and acetylation (Ac 0, in pyridine). The nitro derivative (200) was prepared from tosylate (199) through the iodide, by successive treatment of (199) with NaT in acetone and NaNO in DMF. The nitro derivative C200) on treatment with formalin and diethylamine gave the Mannich base (201) , which on treatment with hydrogen chloride in re fluxing benzene gave the nitro olefin (202). Michael addition of l-cyano-4-methoxy benzo~ cyclobutene to the nitro olefin (202) m the presence of NaNH in liquid ammonia yielded the key intermediate (203) , which on thermolysis gave the D-ring aromatic steroid (204). 7 6 Kametani and co-workers using optically active starting material prepared the key intermediate optically active l-ethynyl-4-hydroxy-2\_2- (4-methoxybenzocyclobutenyl) ethyl"} -1- methylcyclohexane (205), which on thermolysis gave optically active D-ring aromatic steroid (206) (Scheme 41). 2, TOTAL SYNTHESIS via OPGANOIRON COMPLEXES 77 Recently Pearson and co-workers reported new methodology for total synthesis of D-ring aromatic steroid via organoiron complexes (Scheme 42). Dienyl iron complex is used as a ring*-A precursor. The key feature of the synthesis is the regiospecific attack of the tetralone carboxylic ester enolate (208) at the methylated terminus of dienyl iron complex (207) to give an equimolar mixture of distereoisomers MeOOC Fe(CO)3 207 209 A R=*-COOMe 209 B R =p-COOMe OMe 210 A R=*-COOMe 211 212 A R = H 210 B R = l»-COOMe 212 B R = CH2OMe 210 C R = ^-H 210 D R=f>-H OMe MOMO' J4° 213 2H A -C-H R = CHO 2U B |>-H R = CHO 214 C R= H OMe MOMO' H 215 A R=CHO 215 B R=H SCHEME 42 59 (209A) and (209B). Removal of iron (10 equiv. anhydrous Me NO in benzene at 55 C) followed by hydrolysis (oxalic acid, HO at 20 ) gave the mixture of diastereomeric enones (210A) and 210B). Decarboxylation (Me N OAC , HMPA at 95 ) gave a mixture of diastereoisomers (210C) and (210V) which was separated by chromatography. Cuprate addition of epimer (210D) with 4-butenylmagnesium bromide (CuBr, Bu P, THF -40 C) gave 1,4-addition product (211), which was converted to alcohol (212A) by sodium borohydride reduction. 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