Robert B. Morin

Approaches to the chemical synthesis of the prostaglandins

This is a detailed report of efforts to synthesize compounds related to PGE1 (prostaglandin E1). Basically the approach involved attaching 1 or both of the side chains to an appropriately substituted benzene ring and subsequently converting the aromatic nucleus to the cyclopentane system. The chemical structure in each step of the process is diagrammed.

The iodination of azetidinone thio compounds a convenient synthesis of 3-iodo-3-methylcephams and 3-alkoxy-3-methylcephams

3-Jod-cepham (VI) wird aus den Ausgangsverbindungen (I)-(IV) uber die Zwischenstufe (V) erhalten.

Rearrangement of benzothiazine sulphoxides

The reaction of substituted benzothiazine sulphoxides with Ac2O under reflux leads by an elimination reaction to a sulphenic acid derivative which undergoes subsequent addition to the generated double bond if the nitrogen is tertiary but is trapped as a cyclic sulphenamide by a secondary nitrogen.

THE SYNTHESIS OF 2,2-DIMETHYLTHIOCHROMAN BY CATALYTIC HYDROGENATION

2,2-Dimethylthiochroman (XI) has been prepared by the Clemmensen reduction of 2,2-dimethylthiochroman-4-one (I) (Reaction 1 ) . The reaction is characterized by low yields due to pinacol (111) and polymer formation. In some cases in order to obtain pure XI, column chromatography is necessary, followed by distillation. Variations of the conditions under which the Clemmensen reduction was run produced yields from 36-64%. A reaction time of three hours in vigorously stirred, refluxing toluene yielded, after chromatography and distillation, 53% pure I1 (36% by distillation without chromatography). If the reaction is refluxed 96 hours without stirring, 64% of I1 can be obtained by distillation. Surprisingly, the Wolff-Kishner reaction on I failed to yield any 11. Needing large amount of 11 in our laboratories, we sought a more practical preparation which would give high yields of pure material. About four years ago, we were successful in developing a simple method for preparing the chroman (V) from the chromanone (IV) (Reaction 2). Using method C1 on the thiochromanone (I) first led to a mixture of starting material and 11. However, when the catalyst load was increased to 25% by weight of substrate, and the H,SO, concentration was kept at 1.0 ml per 0.1 mole of substrate, pure I1 was isolated in 82% yield or better. Isolation of I1 consisted of removal of the catalyst by filtration, a water wash of the filtrate to remove the acid, evaporation under reduced pressure, and distillation of the residual oil. Purification of the pot residue produced a dimer (VI) which proved to be the hydrogenolysis product of 111 (Reaction 3) . 11 was identified by tlc, ir, nmr, and elemental analysis. Using benzene or ethyl acetate as the solvent system, tlc showed one-spot material. In the infrared spectrum, the carbonyl band of I appears at 6.03 mp, and is absent in the spectrum of 11. In the nmr spectrum of I, two sharp single peaks are seen: for the gem dimethyl, the signal is at 1.43 ppm, and that for the 3position protons at 2.85 ppm. For the product 11, the gem dimethyl proton signal appears at 1.38 ppm, the 3-position methylene signal at 1.86 ppm, and the signal for the new protons at the 4-position at 2.90 ppm. The elemental analysis was calculated for C,,H,,S: C, 74.13; H, 7.92; found: C, 73.96; H, 8.08. Thus, it is our conclusion that the catalytic hydrogenation method is superior to the chemical preparation in reaction time, isolation procedure, and yield of pure material. Other workers,2 using conditions similar to those in the catalytic reduction of I-but with acetic acid as the solvent and omitting the H,SO,-have reported the successful hydrogenolysis of cyclic ketones in compounds not containing the sulfur atom structurally arranged as in I. Duplication of the