Frank H. Lincoln

NOVEL PROSTAGLANDIN SYNTHESES

Syntheses of 2 different classes of prostaglandin (PG) analogs are described that of the 3-oxa-PGs and that of the 15-methyl PGs the former of which inhibit beta-oxidative degradation and the latter of which prevent degradation by the C-15 dehydrogenase. 7 sterochemical figures accompany the descriptions of the synthesis procedures. The analogs though inert to 2 of the recognized modes of enzymatic catabolism maintain appreciable smooth muscle activity. Furthermore as an alternative to totally synthetic routes a partially synthetic route by which the 15-methyl analogs of PGE and PGF types as well as the partially synthetic route by which the types as well as the parent PGs may be derived from the non-mammalian marine source Plexaura Homomall is described.

Development of a GC-MS method for quantitation of 2, 3-dinor-TXB2 and determinations of the daily urinary excretion rates in healthy humans

Tetradeuterated 2,3-dinor-thromboxane B2 (2,3-dinor-TxB2) of high isotopic purity was prepared. This compound was used as internal standard in the development of a method for quantitation of 2,3-dinor-TxB2 in human urine based on gas chromatography--mass spectrometry with multiple ion detection. The accuracy of the method is about +/- 5% at the levels encountered when urine from normal healthy individuals was analyzed. The daily urinary excretion of 2,3-dinor-TxB2 in twenty normal healthy males and females was 457 +/- 210 (mean +/- SD) and 444 +/- 160 (mean +/- SD) ng/24 hrs respectively. The diurnal and day-to-day variations were found to be relatively small.

Gas Liquid Chromatographic—Mass Spectrometric Methods for Quantitation of Prostaglandin Analogs

Abstract The synthesis of tetradeuterated 15-methyl-PGF2α and 17-phenyl-18, 19, 20-trinor-PGF2α, is described. Gas chromatographic -mass spectrometric methods, using the deuterated compounds as internal standards and carriers, for quantitation of corresponding unlabeled prostaglandin analogues is described. With acceptable accuracy and precision the sensitivity is in the subpicomole range.

PGF2α 15-methyl ether methyl ester

Abstract The isolation, structure elucidation, total synthesis, and biological activity of PGF 2 α 15-methyl ether methyl ester are described.

A new approach to 16α-halo corticoids. I. The synthesis of 16-hydroxy steroids

Abstract Reaction of cis -17(20)-pregnen-21-oic acid methyl esters with selenium dioxide gives two 16-hydroxy steroids, a 16α-hydroxy- cis -unsaturated ester and a 16β-hydroxy- trans derivative. Reaction of the trans isomer produces mainly the 16α-hydroxy trans derivative. The application of the hydroxylation reaction to a variety of steroids is described. The stereochemical significance of these findings is discussed as well as the intended use of these 16-hydroxy steroids as intermediates for the synthesis of 16α-halo-corticoids.

A new approach to 16α-halo corticoids. II The synthesis of 16α-fluoro and 16α-chloro corticoids

Abstract Reaction of 16-hydroxy-17(20)-pregnen-21-oic acid methyl esters with N-(2-chloro-1,1,2-tri-fluorethyl)-diethylamine gives in high yield the corresponding 16-fluoro unsaturated esters, inversion accompanying the replacement at C-16. In a similar manner the 16-chloro-17(20)-pregnen-21-oic acid methyl esters are readily prepared in excellent yields using N,N-diethyl-1,2,2-trichlorovinylamine. Reduction of the 16α-fluoro derivatives with lithium aluminum hydride leads to the 16α-fluoro-17(20)-pregnene-21-hydroxy compounds, which on treatment (as the 21-acetates) with osmium tetroxide and Nmethylmorpholine oxide-hydrogen peroxide complex lead to the 16α-fluoro steroids with the cortical side chain. A similar reaction sequence is applicable to the 16α-chloro series except that it is necessary to reduce the unsaturated esters with diisobutyl aluminum hydride (Dibal-H) to avoid reductive removal of the 16α-chlorine substituent.

Preparation of prostaglandin E2 from Plexaura homomalla

An efficient method for enzymatic hydrolysis of esters of PGA2 contained in the sea whip, Plexaura homomalla(var.S) and subsequent conversion of the released PGA2 to PGE2via silylation, epoxidation, and reductive opening of the epoxide is described.