M. Thiel

A vinyl sulfone/vinyl sulfoxide based route to C(6)–;C(7) methylene-bridged derivatives of estradiol

Abstract Acceptor substituted 3-methoxyestra-1,3,5(10),6-tetraene derivatives 3 , 4 and 5 have been prepared and exploited in a synthesis of the title compounds 13 and 15 by key Michael-type addition reactions involving dimethylsulfoxonium methylide. α-Cyclopropanation was only slightly favored on the sulfone analogue 3 but strongly so on the (R)-sulfoxide 4 . On the contrary, the (S)-sulfoxide 5 displayed a weak preference for β-face attack.

A novel route to 3-alkylated estra-1,3,5(10)-trienes

Abstract Nucleophilic attack by the lithium anion of acetonitrile on the diastereomeric chromium tricarbonyl complexes of 17β-(tert-butyldimethylsilyloxy)-3-methoxyestra-1,3,5(10)-triene leads to the corresponding 3-cyanomethyl complexes, useful intermediates en route to 3-alkylated estra- 1,3,5(10)-trienes.

Regioselective functionalization of 3-oxygenated estra-1,3,5(10)-trienes at C-1 via (η6-arene)Cr(CO)3 complexes

Abstract The nucleophilic addition - oxidation reaction between the lithium anion of 1,3-dithiane and a mixture of complexes 3 and 4 installs the heterocycle predominantly at C-1 of the steroid to afford 5. This intermediate is converted into C-1 substituted steroids 6–12.

A new, stereoselective approach to C(7)-alkylated estra-1,3,5(10)-triene derivatives

Abstract 17β-Acetyloxy-3-methoxy-6-(phenylsulfonyl)estra- 1,3,5(10),6-tetraene ( 4 ) was prepared as a substrate for conjugate addition of organolithium reagents by a three-step sequence starting from 17β-acetyloxy-3-methoxyestra- 1,3,5(10)-trien-6-one ( 2 ). While methyllithium showed only poor face selectivity, higher alkyllithium species (n-BuLi, t-BuLi) preferred to add to the β-face of 4 . 7α-Substituted derivatives, on the other hand, were generated stereoselectively by utilizing alkynyllithium reagents in the addition step. Removal of the phenylsulfonyl group at C(6) from alkylated products was achieved by conventional reductive desulfonylation methods. A short synthesis of the estrogen receptor antagonist 1 exploiting these observations is presented.

A concise total synthesis of C(14)C(15) methylene-bridged equilenin derivatives

Abstract A five-step reaction sequence including hydroxyl group-assisted cyclopropanation, C(17)-oxidation, B-ring aromatization, C(17)-reduction, and methyl ether cleavage has been devised to convert 2 into 12 . The synthesis of 19 took advantage of a facile isomerization of vinyl(benzyl)cyclopropane derivatives 6–11 into the corresponding β-bridged analogues 13–18 over molecular sieves.

A highly stereocontrolled approach to 3-methoxyestra-1,3,5(10),14-tetraen-17α-ol, an important intermediate for the synthesis of C(14)-substituted steroid derivatives

Abstract A four-step reaction sequence including (1) hydroxyl group-assisted epoxidation, (2) Jones oxidation, (3) DIBAH-reduction, and (4) epoxide deoxygenation has been devised in order to effect epimerization of 4 to 1 , the overall yield approaching 65%.

A novel, stereocontrolled approach to ring B alkylated estratetraenes

Abstract A four-step reaction protocol, culminating in an oxy-Cope rearrangement, has been developed to transform 2 into 7 . 9α-Alkylated derivatives of equilin, e.g., 12 , as well as C(7)-C(9) propano-bridged 19-norsteroids, like 17 , demonstrate synthetic potential for 7 in estrogen receptor ligand synthesis.

Total synthesis and reactivity of c(8)–c(14) methylene-bridged derivatives in the 8α-estra-1,3,5(10)-triene series

Summary A stereoselective entry into a new class of pentacyclic estrogens is illustrated for the parent cycloprop[8,14]-8α-estra-1,3,5(10)-triene-3,17β-diol (3). Moreover, a high degree of regiocontrol in acidpromoted cyclopropane ring opening, 11→15 , offers an attractive, unprecedented access to 8-methyl 19-nor-8α-steroids.

Synthesis of 14,17α-ethano-bridged equilenin derivatives

Abstract Oxidation of 3,17β-diacetyloxy-14,17α-ethanoestra-1,3,5(10)-triene (2) by ceric ammonium nitrate furnished the equilenin derivative 3. This intermediate was subsequently converted into epimeric C(11)-alcohols 7 and 9, the C(11)-methylene derivative 11, and olefin 13.