K. K. Pivnitsky

Reduction of steroidal ketones with amine—boranes

Complexes of secondary amines with borane, R2NH·BH3, surpass sodium borohydride as reducing agents for saturated and unsaturated steroidal 3-, 12-, 17-, and 20-ketones as regards chemo- and regioselectivity and mildness of the reaction conditions. In the case of 12-ketones, stereoselectivity is also improved.

Hepoxilin A3 is Metabolized Into its ω-Hydroxy Metabolite by Human Neutrophils

Hepoxilins (Hx) elicit a variety of biological actions based on their ability to affect ion movements in the cell [Pace-Asciak 1994; Pace-Asciak et al., 1995a; Pace-Asciak et al., 1995b]. The most notable of these actions includes the release of insulin from pancreatic islets [Pace-Asciak and Martin 1984] as well as the regulation of cell volume in platelets [Margalit et al., 1993]. In the human neutrophil, HxA3 releases calcium from intracellular stores and this release is Hx-receptor mediated [Reynaud et al., 1996; Reynaud et al., 1995]. During the course of our investigations in neutrophils, we noted that radiolabeled HxA3 was metabolized into a single product which was identified as the corresponding ω-hydroxy product retaining the basic hydroxy-epoxide functional group of the parent hepoxilin intact [Reynaud et al., 1997]. Additional studies reported herein also indicate that the hepoxilin ω-hydroxylase is different from that which metabolizes LTB4.

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.

Synthesis of ω- and (ω – 1)-acetylenic acids from five-, six-, or seven-membered cycloalkanones

A convenient method for the synthesis of ω- and (ω – 1)-acetylenic acids involves free-radical oxidative scission of cycloalkanones containing five-, six, or seven-membered cycles to give the corresponding ω-olefinic acids followed by bromination of the latter and subsequent dehydrobromination under the action of alkalis.

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.

Non-selectivity in the reaction of levoglucosenone with the sulfinyl allyl carbanion

Condensation of levoglucosenone with the carbanion ofrac-allyl phenyl sulfoxide, in contrast with reactions of this anion with the majority of other unsaturated ketones, proceeds without regio- or enantioselectivity to give a (1.0–1.8): 1 mixture of products of both 1,2- and 1,4-γ-addition of the allylic residue. Each product is a (1.2–1.6): 1 mixture of epimers at the asymmetric sulfur atom.

Synthesis of tritium labelled 20-hydroxy-hepoxilin A3, the major hepoxilin metabolite in human neutrophils

Methyl (8S)-[20-3H]-8,20-dihydroxy-11,12-epoxy-5Z,9E,14Z-eicosatrienoate ((8S)-[20-3H]-20-hydroxy-HxA3 methyl ester), a radioactive analog of the HxA3 metabolite was prepared. The synthesis of the 20-hydroxy analog of HxA3 methyl ester was performed by the reduction of the corresponding 20-aldehydro-HxA3 with sodium [3H]-borohydride. The purified [20-3H]-20-hydroxy-HxA3 methyl ester had a specific activity of 2.5–2.7 Ci/mmol. Copyright