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Total synthesis of natural and non-natural steroid hormones
Jourrrul q/ Stmid Biocbrrnisrrr. Vol. t I. pp. 55 to 60 Perpmon Press Lid 1979. Prhed in Great Britain
1. Advances in Steroid Chemistry TOTAL
SYNTHESIS OF NATURAL AND NON-NATURAL STEROID HORMONES ULRICH EDER
Schering AG Research Laboratories, Berlin~3ergkamen. Federal Republic of Germany SUMMARY A number of steroid total syntheses. such as the synthesis of oestradiol, a 7/?- and 7cr-methyt oestrogen, an Sa-oestradiol analogue and a total synthesis of A, 19-dinorsteroids, are described starting from the optically-active, CD-synthon 3. In addition, a preparation of C-nor-D-homosteroids is also discussed. During the course of our work concerned with steroid total synthesis, we found that prochiral ketones of the type I or 4 could be cyclized to optically active CD-partial structures 2 or 5 (Fig. 1). Parallef to our studies, Hajos and Parrish of ~offmann-La Roche developed independently similar procedures for this transformation [l, 23. In this reaction, the triketones are cyclized in the presence of catalytic amounts (3-40 mol per cent) of S-aminoacids to give the corresponding, ring-closed ti, p-unsaturated ketones in chemical and optical yields of 85-97’4. Starting from the tert-butyl ether 3, which can be prepared from the optically-active diketone 2 by selective reduction and subsequent treatment of the resulting alcohol with isobutylene [3], we have completed a number of steroid total syntheses. The first of these which shaI1 be described is the preparation of oestradiol (Fig. 2). Alkylation of the tert-butyl ether with the known m-methoxy-phenacyl bromide 6 [4] gave the mono-alkylated product 7 in good yield which was further converted into the furan 8 by treatment with acid. The hydrogenation of 8 at a pressure of 40-6Oatm yielded the secoalcohol 9 possessing the ctconfiguration at C-8, C-9 and C-14. The configuration assignments could be clearly defined on the basis of the NMR-spectra and by subsequent transformations of the secoalcohcjl 9.
Oxidation of the hydroxy group and subsequent equilibration of the side chain at C-8 into the more stable equatorial position yielded the seco ketone 10 which after treatment with ION hydrochloric acid in methanol, was converted into the ~i~~olefin 11 in 93% yield. Subsequent hydrogenation of the 9(11double bond (Pd/carbon in ethyl acetate) did not yield a pure product. Instead, a mixture was obtained containing approximately 85% of the 9a-derivative and 12-15x of the unwanted 9/3epimer which could be removed by crystallization. Simultaneous removal of both protecting groups gave oestradiol 13 in an overall yield of 42% (based on the CD-synthon 3) [5]. When propiophenone bromide 14 is used to alkylate 3 (Fig. 3), it is possible to prepare 7#&methyl steroids following a similar reaction sequence as was described above for the synthesis of oestradiol. The alkylation of the a,&unsaturated ketone 3 with the bromide 14 yielded the mono-alkylated product 15 in 60% yield as a mixture of epimers in which the 7/I-methyl derivative predominates. After ring closure to the furane 16 and subsequent catalytic hydrogenation, the seco alcohol 17 obtained in this manner proved to be the product derived from an all cis, a-hydrogenation. The 7&configurated methyl group can therefore be securely introduced by this procedure.
SIPhenylalanine (H “1 CH,O
CH,O Fig. 1. 55
56
ULRICH
EDER
HO
c
Fig. 2. After oxidation of the alcohol 17 followed by equilibration of the side chain at C-8 and subsequent cyclization of 18, there was formed the tetracyclic product 19 in good yield. The hydrogenation of the ill)-double bond is obviously influenced by the 7~-methyl group as the triene 20 with the 9a-configuration was obtained in 95% yield. By manipulation of the protecting groups, 20 can be transformed into the ketodiacetate 21 [6]. Following this reaction sequence, it is therefore possible to prepare 78-methyl substituted steroids. However, it is known from the work of Anner et a/.[71 that the oestrogens which are pharmacologically more interesting are those possessing a 7a-configurated methyl group. For the synthesis of these derivatives, we began by alkylating the CD-partial structure 3 with the optically-active tosylate S-22 (Fig. 4). In this manner, it was possible to obtain the 7u-methyl derivative in 72% yield. The reaction proceeds with complete inversion at the chiral center of the tosylate 22 to yield the product expected from a clean Sn, displacement.
The subsequent hydrogenation of 23 proceeded stereoselectively to give the trans perhydroindane 24 in more than 90% yield. After equilibration of the side chain at C-8 and treatment with 10N hydrochloric acid in methanol, there was obtained the tetracyclic 7~-methy product 25. The yield over these last three steps amounts to 75%. Catalytic hydrogenation on the 9( 1l)-doubfe bond in the compound 25 results in exclusive formation of the non-natural product containing the 98-H configuration. The 7oconfigurated, axial methyl group shields the underside of the steroid molecule to such an extent that the reduction of the double bond occurs from the less hindered /I-face. This problem could be avoided by subjecting the olefin 25 to a partial Birch reduction (lithium/liquid ammonia/aniline) and there was isolated exclusively the product containing the natural 9a-H configuration. Therefore, the preparation of 7~-methyl substituted steroids is also possible folluw~ng this synthetic scheme. Two other syntheses which have been completed starting from the CD-system 3 shah also be men-
Total synthesis of natural and non-natural steroid hormones
==ah I
AC
CH Fig. 3,
+
w
C
3
Fig, 4.
57
ULRICH EDER
58
CHj
islR_
27
1. H,(86%)
c
2. HBr-HOAc
(7%)
RO Fig. 5.
Fig. 6.
a) R&H, b) R=C-CH,
t;
Total synthesis of natural and non-natural tioned. The first of these is the preparation of l-acetoxy oestradiol derivative 30b in the 8a-oestrone series (Fig. 5). This compound is of pharmacological interest because of its use as an “impeded oestrogen”. The partial synthesis of 30b proceeds with difficulty and in such low yields that a total synthesis was viewed as a possible alternative method for the economic preparation of this substance. The reaction of 3 with the tosylate 27 gave the monoalkylated product 28 which was further transformed into the pentaene acetate 29 by treatment with catalytic amounts of perchloric acid in acetic acid/acetic anhydride. The tertbutyl ether is first converted into the 17-acetate followed by cyclization of the secosteroid to form the pentaene 29. Hydrogenation of the diene system in 29 gives the 8a-product 30a which is subjected to ether cleavage and acetylation to yield the triacetate 30b [S]. The next project undertaken was the synthesis of A. 19-dinorsteroids as little was known of the biological properties of these compounds [9]. For the preparation of such derivatives, a different synthetic plan was developed such as was normally used for the synthesis of the usual steroid structures (Fig. 6). The reaction of the CD-structural unit 3 with paraformaldehyde and benzenesulfinic acid leads to the monosulfomethylated product 31 in good yield. Hydrogenation of this product gives the keto sulfone 32 which can be isolated as a stable, crystalline solid in 76!/” yield. This substrate functions as the synthetic equivalent of the corresponding vinyl ketone which undergoes Michael addition with the /?-keto ester 33 (easily prepared from hexane-2.5dione) to yield the initial adduct 34. Cyclization followed by saponifica-
59
steroid hormones
tion and decarboxylation results in the formation of the secosteroid 35 in 78% yield. By cleavage of the ketal, the diketone 36 is obtained which is hydrogenated in ethanolltriethylamine to yield the product with the natural 9a, lo/?-configuration in over 90% yield. After cyclization followed by acid cleavage of the tert-butyl ether and oxidation. there is obtained a nearly 1: 1 mixture of isomeric diketones 38 and 39 in 86% yield from which 38 can be selectively crystallized. Treatment of 39 with acid or base results in isomerization to a 1: 1 mixture of 38 and 39. The last synthesis which shall be described concerns the preparation of C-nor-D-homosteroids (Fig. 7). It was initially planned to perform this conversion using a rat. trans-indanedione carboxylic acid ester 45 as the CD-structural unit. Methyl cyclohexane-1,3-dione 41 and bromocrotonic ester 40 were chosen as starting materials for the synthesis of 45. The condensation of these substrates produced the C-alkylation product 42 in over 609,; yield which is then hydrolysed and cyclized to 43 in 79”o yield. This approach however, was not successful because the diketo ester 43 was hydroxygenated exclusively from the p-side to yield the product 44 containing the cisring junction. The trans-diketo ester 45 was then prepared following another route starting from the [runs-decalin derivative 46 (Fig. 8). Oxidative ring cleavage gave the dicarboxylic acid which was treated with diazomethane to yield the diester 47. By Dieckmann condensation followed by oxidation, there was obtained the Iruns-diketo ester 45 in 40”/, overall yield. From 45 there was prepared the bis-ethylene ketal
C-Nor-D-hcmo
0
COOCH3
40
41 0
0
4) ’
tOOC H3
43
0
o--
0
c&a :
Y 0
: +
H
H
coot H-J Fig. 7.
1
44
H
dooc Ii3 45
52
v
Fig. derivative 48 which was reduced to the alcohol, subjected to selective hydrolysis to yield the ~-hydroxy ketone and reacted with methanesuifonyi chloride to give the mesylate 49 in 78% overall yield (based on 45). This product, a protected vinyl ketone equivalent, was condensed with the known .$-keto-ester 50[3] to yield the initial Michael adduct 51 which after cycIization of ring B, saponification and decarboxyiatio~ yields the secosteroid 52. After removal of both ketais, ring A was then closed to give the C-nor-Dhomo-ketone 53a in 50% yield (based on the keto mesylate 49). The subsequent aromatization of 53a with acetyl bromide following a procedure developed by DanishevskytlO] resulted in exclusive formation of the 9&H (B/C-cis ring junction) product 54 which exhibited weak oestrogenic activity. Selective ethinylation of 53a yielded 53b, a substance with marked progestational activity. REFERENCES I.
Eder &I.. Sauer G. and Wiechert R.: Total synthesis of optically active steroids VI. New type of asymmetric
cyclization to optically active steroid CD partial structures. Anycw. Chem. Inter. Ed. En&. 10, (1971) 496-497. 2. Fa. Hoffmann-La Roche II. Co., Nutley, NJ U.S.A. (Inv. 2. C. Hajos and D. R. Parrish), D.O.S. 2102623
[CA. 76 59072X (1972)]. Asymmetric synthesis of optically active polycychc organic compounds. Micheii R. A., Hajos Z. G., Cohen N.. Parrish D. R.. Portland L. A., Sciamanna W., Scott M. A. and Wehrli P. A.: Total synthesis of optically active f9-norsteroids. (i~-Estr~~ene-3~17-dion~ and (+)-1 Ia-ethylgon-4ene-3,17-dione. J. Org. Chem. 40 (1975) 675-68 1. France D. J.. Hand J. J. and Los M.: Total synthesis of modified steroids II. 8/&Methyl-D-homoestranes. J*. Org. Chem. 35 (1970) 468472. Eder U., Gibian H., Hager G., Neef G.. Sauer 6. and Wiechert R.: Total synthesis of optically active steroids, XIV. Synthesis of estradiol. Chenz. Ber. 109 (1976) 2948-2953. Eder U., Haffer G.. Neef G., Sauer G., Seeger A. and Wiechert R.: Total synthesis of optically active steroids, XV. Synthesis of (+)-1,3-dimethoxy-7/?methyl- 1,3,5(IO)-estratrien- 17.one. Chum. &r. 110 (1977) 3161-3167. Kalvoda J.. Kriihenbiihl C.. Dessaufes P. A. and Anner G.: 7~-~ethyl~strogene. Nefv. Chim. Acta 50 (1967) 281-288.
Eder U., Haffer G., Neef G., Prezewowsky K., Sauer G. and Wiechert R.: Total synthesis of optically active steroids, XVI. Preparation of 1,3,17~-triacet~xy-8~estra- 1,3,5(IO)-triene. an “impeded” estrogen. Chrtn. Ber. 111 (19%) 939-943. Roffey P., Grant P. K. and Sondheimer F.: The synthesis of A-nor-19-nort~stosterone. Tet. Lrtt. I%7 1773--t775.
Danishefsky S. and Cain P.: Optically specific synthesis of estrone and 19-norsteroids from 2.6~lutidine. .I. Am. Chem. Sot. 98 (1976) 4975-4983.
1. Advances in Steroid Chemistry TOTAL
SYNTHESIS OF NATURAL AND NON-NATURAL STEROID HORMONES ULRICH EDER
Schering AG Research Laboratories, Berlin~3ergkamen. Federal Republic of Germany SUMMARY A number of steroid total syntheses. such as the synthesis of oestradiol, a 7/?- and 7cr-methyt oestrogen, an Sa-oestradiol analogue and a total synthesis of A, 19-dinorsteroids, are described starting from the optically-active, CD-synthon 3. In addition, a preparation of C-nor-D-homosteroids is also discussed. During the course of our work concerned with steroid total synthesis, we found that prochiral ketones of the type I or 4 could be cyclized to optically active CD-partial structures 2 or 5 (Fig. 1). Parallef to our studies, Hajos and Parrish of ~offmann-La Roche developed independently similar procedures for this transformation [l, 23. In this reaction, the triketones are cyclized in the presence of catalytic amounts (3-40 mol per cent) of S-aminoacids to give the corresponding, ring-closed ti, p-unsaturated ketones in chemical and optical yields of 85-97’4. Starting from the tert-butyl ether 3, which can be prepared from the optically-active diketone 2 by selective reduction and subsequent treatment of the resulting alcohol with isobutylene [3], we have completed a number of steroid total syntheses. The first of these which shaI1 be described is the preparation of oestradiol (Fig. 2). Alkylation of the tert-butyl ether with the known m-methoxy-phenacyl bromide 6 [4] gave the mono-alkylated product 7 in good yield which was further converted into the furan 8 by treatment with acid. The hydrogenation of 8 at a pressure of 40-6Oatm yielded the secoalcohol 9 possessing the ctconfiguration at C-8, C-9 and C-14. The configuration assignments could be clearly defined on the basis of the NMR-spectra and by subsequent transformations of the secoalcohcjl 9.
Oxidation of the hydroxy group and subsequent equilibration of the side chain at C-8 into the more stable equatorial position yielded the seco ketone 10 which after treatment with ION hydrochloric acid in methanol, was converted into the ~i~~olefin 11 in 93% yield. Subsequent hydrogenation of the 9(11double bond (Pd/carbon in ethyl acetate) did not yield a pure product. Instead, a mixture was obtained containing approximately 85% of the 9a-derivative and 12-15x of the unwanted 9/3epimer which could be removed by crystallization. Simultaneous removal of both protecting groups gave oestradiol 13 in an overall yield of 42% (based on the CD-synthon 3) [5]. When propiophenone bromide 14 is used to alkylate 3 (Fig. 3), it is possible to prepare 7#&methyl steroids following a similar reaction sequence as was described above for the synthesis of oestradiol. The alkylation of the a,&unsaturated ketone 3 with the bromide 14 yielded the mono-alkylated product 15 in 60% yield as a mixture of epimers in which the 7/I-methyl derivative predominates. After ring closure to the furane 16 and subsequent catalytic hydrogenation, the seco alcohol 17 obtained in this manner proved to be the product derived from an all cis, a-hydrogenation. The 7&configurated methyl group can therefore be securely introduced by this procedure.
SIPhenylalanine (H “1 CH,O
CH,O Fig. 1. 55
56
ULRICH
EDER
HO
c
Fig. 2. After oxidation of the alcohol 17 followed by equilibration of the side chain at C-8 and subsequent cyclization of 18, there was formed the tetracyclic product 19 in good yield. The hydrogenation of the ill)-double bond is obviously influenced by the 7~-methyl group as the triene 20 with the 9a-configuration was obtained in 95% yield. By manipulation of the protecting groups, 20 can be transformed into the ketodiacetate 21 [6]. Following this reaction sequence, it is therefore possible to prepare 78-methyl substituted steroids. However, it is known from the work of Anner et a/.[71 that the oestrogens which are pharmacologically more interesting are those possessing a 7a-configurated methyl group. For the synthesis of these derivatives, we began by alkylating the CD-partial structure 3 with the optically-active tosylate S-22 (Fig. 4). In this manner, it was possible to obtain the 7u-methyl derivative in 72% yield. The reaction proceeds with complete inversion at the chiral center of the tosylate 22 to yield the product expected from a clean Sn, displacement.
The subsequent hydrogenation of 23 proceeded stereoselectively to give the trans perhydroindane 24 in more than 90% yield. After equilibration of the side chain at C-8 and treatment with 10N hydrochloric acid in methanol, there was obtained the tetracyclic 7~-methy product 25. The yield over these last three steps amounts to 75%. Catalytic hydrogenation on the 9( 1l)-doubfe bond in the compound 25 results in exclusive formation of the non-natural product containing the 98-H configuration. The 7oconfigurated, axial methyl group shields the underside of the steroid molecule to such an extent that the reduction of the double bond occurs from the less hindered /I-face. This problem could be avoided by subjecting the olefin 25 to a partial Birch reduction (lithium/liquid ammonia/aniline) and there was isolated exclusively the product containing the natural 9a-H configuration. Therefore, the preparation of 7~-methyl substituted steroids is also possible folluw~ng this synthetic scheme. Two other syntheses which have been completed starting from the CD-system 3 shah also be men-
Total synthesis of natural and non-natural steroid hormones
==ah I
AC
CH Fig. 3,
+
w
C
3
Fig, 4.
57
ULRICH EDER
58
CHj
islR_
27
1. H,(86%)
c
2. HBr-HOAc
(7%)
RO Fig. 5.
Fig. 6.
a) R&H, b) R=C-CH,
t;
Total synthesis of natural and non-natural tioned. The first of these is the preparation of l-acetoxy oestradiol derivative 30b in the 8a-oestrone series (Fig. 5). This compound is of pharmacological interest because of its use as an “impeded oestrogen”. The partial synthesis of 30b proceeds with difficulty and in such low yields that a total synthesis was viewed as a possible alternative method for the economic preparation of this substance. The reaction of 3 with the tosylate 27 gave the monoalkylated product 28 which was further transformed into the pentaene acetate 29 by treatment with catalytic amounts of perchloric acid in acetic acid/acetic anhydride. The tertbutyl ether is first converted into the 17-acetate followed by cyclization of the secosteroid to form the pentaene 29. Hydrogenation of the diene system in 29 gives the 8a-product 30a which is subjected to ether cleavage and acetylation to yield the triacetate 30b [S]. The next project undertaken was the synthesis of A. 19-dinorsteroids as little was known of the biological properties of these compounds [9]. For the preparation of such derivatives, a different synthetic plan was developed such as was normally used for the synthesis of the usual steroid structures (Fig. 6). The reaction of the CD-structural unit 3 with paraformaldehyde and benzenesulfinic acid leads to the monosulfomethylated product 31 in good yield. Hydrogenation of this product gives the keto sulfone 32 which can be isolated as a stable, crystalline solid in 76!/” yield. This substrate functions as the synthetic equivalent of the corresponding vinyl ketone which undergoes Michael addition with the /?-keto ester 33 (easily prepared from hexane-2.5dione) to yield the initial adduct 34. Cyclization followed by saponifica-
59
steroid hormones
tion and decarboxylation results in the formation of the secosteroid 35 in 78% yield. By cleavage of the ketal, the diketone 36 is obtained which is hydrogenated in ethanolltriethylamine to yield the product with the natural 9a, lo/?-configuration in over 90% yield. After cyclization followed by acid cleavage of the tert-butyl ether and oxidation. there is obtained a nearly 1: 1 mixture of isomeric diketones 38 and 39 in 86% yield from which 38 can be selectively crystallized. Treatment of 39 with acid or base results in isomerization to a 1: 1 mixture of 38 and 39. The last synthesis which shall be described concerns the preparation of C-nor-D-homosteroids (Fig. 7). It was initially planned to perform this conversion using a rat. trans-indanedione carboxylic acid ester 45 as the CD-structural unit. Methyl cyclohexane-1,3-dione 41 and bromocrotonic ester 40 were chosen as starting materials for the synthesis of 45. The condensation of these substrates produced the C-alkylation product 42 in over 609,; yield which is then hydrolysed and cyclized to 43 in 79”o yield. This approach however, was not successful because the diketo ester 43 was hydroxygenated exclusively from the p-side to yield the product 44 containing the cisring junction. The trans-diketo ester 45 was then prepared following another route starting from the [runs-decalin derivative 46 (Fig. 8). Oxidative ring cleavage gave the dicarboxylic acid which was treated with diazomethane to yield the diester 47. By Dieckmann condensation followed by oxidation, there was obtained the Iruns-diketo ester 45 in 40”/, overall yield. From 45 there was prepared the bis-ethylene ketal
C-Nor-D-hcmo
0
COOCH3
40
41 0
0
4) ’
tOOC H3
43
0
o--
0
c&a :
Y 0
: +
H
H
coot H-J Fig. 7.
1
44
H
dooc Ii3 45
52
v
Fig. derivative 48 which was reduced to the alcohol, subjected to selective hydrolysis to yield the ~-hydroxy ketone and reacted with methanesuifonyi chloride to give the mesylate 49 in 78% overall yield (based on 45). This product, a protected vinyl ketone equivalent, was condensed with the known .$-keto-ester 50[3] to yield the initial Michael adduct 51 which after cycIization of ring B, saponification and decarboxyiatio~ yields the secosteroid 52. After removal of both ketais, ring A was then closed to give the C-nor-Dhomo-ketone 53a in 50% yield (based on the keto mesylate 49). The subsequent aromatization of 53a with acetyl bromide following a procedure developed by DanishevskytlO] resulted in exclusive formation of the 9&H (B/C-cis ring junction) product 54 which exhibited weak oestrogenic activity. Selective ethinylation of 53a yielded 53b, a substance with marked progestational activity. REFERENCES I.
Eder &I.. Sauer G. and Wiechert R.: Total synthesis of optically active steroids VI. New type of asymmetric
cyclization to optically active steroid CD partial structures. Anycw. Chem. Inter. Ed. En&. 10, (1971) 496-497. 2. Fa. Hoffmann-La Roche II. Co., Nutley, NJ U.S.A. (Inv. 2. C. Hajos and D. R. Parrish), D.O.S. 2102623
[CA. 76 59072X (1972)]. Asymmetric synthesis of optically active polycychc organic compounds. Micheii R. A., Hajos Z. G., Cohen N.. Parrish D. R.. Portland L. A., Sciamanna W., Scott M. A. and Wehrli P. A.: Total synthesis of optically active f9-norsteroids. (i~-Estr~~ene-3~17-dion~ and (+)-1 Ia-ethylgon-4ene-3,17-dione. J. Org. Chem. 40 (1975) 675-68 1. France D. J.. Hand J. J. and Los M.: Total synthesis of modified steroids II. 8/&Methyl-D-homoestranes. J*. Org. Chem. 35 (1970) 468472. Eder U., Gibian H., Hager G., Neef G.. Sauer 6. and Wiechert R.: Total synthesis of optically active steroids, XIV. Synthesis of estradiol. Chenz. Ber. 109 (1976) 2948-2953. Eder U., Haffer G.. Neef G., Sauer G., Seeger A. and Wiechert R.: Total synthesis of optically active steroids, XV. Synthesis of (+)-1,3-dimethoxy-7/?methyl- 1,3,5(IO)-estratrien- 17.one. Chum. &r. 110 (1977) 3161-3167. Kalvoda J.. Kriihenbiihl C.. Dessaufes P. A. and Anner G.: 7~-~ethyl~strogene. Nefv. Chim. Acta 50 (1967) 281-288.
Eder U., Haffer G., Neef G., Prezewowsky K., Sauer G. and Wiechert R.: Total synthesis of optically active steroids, XVI. Preparation of 1,3,17~-triacet~xy-8~estra- 1,3,5(IO)-triene. an “impeded” estrogen. Chrtn. Ber. 111 (19%) 939-943. Roffey P., Grant P. K. and Sondheimer F.: The synthesis of A-nor-19-nort~stosterone. Tet. Lrtt. I%7 1773--t775.
Danishefsky S. and Cain P.: Optically specific synthesis of estrone and 19-norsteroids from 2.6~lutidine. .I. Am. Chem. Sot. 98 (1976) 4975-4983.