Chapter I Aromatic Steroids : a Review I

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 -âromatic 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^î^^ <Xr X 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 ArndtÊistert 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 hydrogenation afforded the tetraene(34), which was subjected to further reduction with potassium in liquid ammonia.

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