Margarita A. Lapitskaya

Synthesis of 3β-hydroxy-androsta-5,7-dien-17-one from 3β-hydroxyandrost-5-en-17-one via microbial 7α-hydroxylation

The synthesis of 3beta-hydroxy-androsta-5,7-dien-17-one from 3beta-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA) via microbial 7alpha-hydroxylation has been accomplished. At the first stage, 3beta,7alpha-dihydroxy-androst-5-en-17-one was obtained in high yield (71.2%) using a strain of Gibberella zeae VKM F-2600, which was first applied for DHEA conversion. The further route included the substitution of 7alpha-hydroxyl group with chlorine followed by a dehydrochlorination stage, and required minimal purifications of the intermediate products. The steroids obtained at every step were characterized by TLC,1H NMR, MS, UV- and IR-spectrometry. The combination of microbial and chemical steps ensured 54.6% yield of the target 3beta-hydroxy-androsta-5,7-dien-17-one from DHEA and can be applied for obtaining novel vitamin D derivatives.

Synthetic study of hepoxilins

Total synthesis of trioxilin (10S,11S,12S)-B3 was performed starting from a hepoxilin synthon, (2S,3S)-2,3-epoxyundec-5-yn-1-ol, available from the corresponding allylic alcohol by Sharpless enantiodirected epoxidation. The synthesis features stereoselective (7 ∶ 1)syn-addition of the acetylenide anion to the intermediate (2S,3S)-2,3-(isopropylidenedioxy)undec-5-yn-1-al and regioselective partial hydrogenation of a triacetylene trioxilin precursor, which allowed the preparation of 14,15-dehydro-(10S,11S,12S)-TrXB3.

Enantioselective synthesis of methyl (5Z,8S)-8,9-epoxynon-5-enoate, an eicosanoid synthon

A six-step synthesis of methyl (5Z,8S)-8,9-epoxynon-5-enoate, a known synthon of constanolactones and hepoxilins, from 5-hexynoic ester was developed. The enantiomeric purity of the synthon was attained by S-enantiodirected dihydroxylation of a double bond in the intermediate methyl non-8-en-5-ynoate with subsequent enantioselective hydrolysis of the epoxide group in the admixture of the minor R-enantiomer.

NEW SYNTHESIS OF ESTRADIOL FROM ANDROSTA-1,4-DIENE-3,17-DIONE

A new method for the aromatization of ring A in androsta-1,4-diene-3,17-dione, available from sterols by means of the microbiological degradation of the side chain, was developed. The method consists of the reduction of androsta-1,4-diene-3,17-dione to the corresponding dienediol followed by double C,O-deprotonation of ring A, accompanied by expulsion of the 19-methyl group and formation of estradiol in a high yield.

Solvolysis of allylic prostaglandin mesylates : moderate 1,3-syn-stereoselectivity

The stereochemistry of SN2 and SN2′ substitutions of the allylic mesyloxy group in mesylates of prostaglandin allylic epimeric 13- and 15-alcohols under the action of various nucleophiles (H2O, MeOH, AcOH, LiBr) was studied. The substitution accompanied by rearrangement occurs with moderate (1.4–1.6 : 1) syn-stereoselectivity with respect to the configuration of the mesyloxy group, which increases with decreasing temperature and depends only slightly on the nature of the nucleophile.

Transformation of steroidal cyclohexadienyl anion without fragmentation: Unexpected synthesis of methylenesteroid

In contrast with androsta-1,4-diene-3α/β, 17β-diol, its 3-O-methyl ether is transformed upon C(3)-deprotonation into the corresponding 3-methylene steroid with migration of theO-methyl group on the steroid skeleton (by the scheme of Wittig rearrangement) rather than eliminating the 19-methyl group.