Wolfgang Schwede

Synthesis of 14β-H antiprogestins

Abstract An efficient approach to 14β-H antiprogestins is described. The key step of the synthesis is a cleavage of 17-silyl dienol ethers 7 respectively 12, which are generated from the corresponding Δ 14 -17-ketones, with hydrogen fluoride-pyridine complex. This method gave access to 14β-H analogs of the 11β,19-bridged series (type A) as well as of the 10β-H,11β-aryl series (type B).

11β-Aryl Steroids in the Androstene Series. The Role of the 11β-Region in Steroid Progesterone Receptor Interaction

Abstract The syntheses of 11β-arylandrost-4-en-3-one 24 and the corresponding 9β,19-cyclo derivative 8 are described. Steric interaction between C-19 and the aryl residue effects conformational changes of the steroid ring system that result in reduced affinity for the progesterone receptor. The conformation of 11β-arylandrostenes is discussed in comparison with known antiprogestational steroids.

Synthesis of 11α-methyl-11β-(arylethynyl)substituted steroids of the estrane series

The synthesis of 11α-methyl-11β-(arylethynyl) substituted 19-norsteroids of 13, 14, and 15 is described. The preparation of these compounds opens for the first time an approach to 11-disubstituted antiprogestins.

Synthesis of 11β-(alkynyl)substituted 19-norsteroids

Abstract A new access to 11β-(alkynyl)estranes I is described. The synthesis of key intermediate 11β-ethynylestr-4-ene-3,17-dione 8 can be achieved by stereoselective thermodynamically controlled formation of 11β-aldehyde 1 , its conversion to vinyl bromide 7 by Wittig reaction and subsequent dehydrobromination. Broad variation of the acetylenic 11β-substitution is possible by nucleophilic substitution as well as transition metal mediated coupling reactions.

7α,15α-Ethano bridged steroids. Synthesis and progesterone receptor interaction

Abstract The synthesis of 7α,15α-ethano bridged steroids is described. Diels-Alder reaction of 3-methoxyestra-1,3,5(10),7,14-pentaen-17-one 4 with ethylene under high pressure provides efficient synthetic access to this class of steroids. Compounds 15 and 17 were tested for their binding affinities to the progesterone receptor (PR). Two low energy conformations 17a and 17b could be identified by force field calculations of compound 17. Both conformations were analysed in complex with the ligand binding domain of the human progesterone receptor (hPR LBD).

Synthesis and biological activity of 17-chloro-16(17) unsaturated D-homo antiprogestins

An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.

A facile construction of the 17α-fluoroprogesterone side chain

Abstract The ambident functionality of a 21-hydroxy-20-methoxy-17(20)-unsaturated pregnane side chain is used for a new access to 17α-fluoroprogesterone derivatives by reaction with diethylaminosulfur trifluoride.

Synthesis and Biological Activity of 11,19-Bridged Progestins

A synthetic approach to 11,19-bridged progestins is described. The key step in the synthesis is a 6-endo-trig radical cyclisation. The new progestins were tested for their biological activities in vitro and in vivo and compared to those of known progestins.