Synthetic methodology for key intermediates in the total synthesis of reiswigin A: and, Improvement in the Semmler-Wolf aromatization of 19-nortestosterone oxime

Abstract

The MARSEIL/SOS program was used to generate a retrosynthetic scheme for a marine natural product reiswigin A. As written, the MARSEIL/SOS program can not cope with considerations of stereochemistry in the planning process. Therefore, PCMODEL was used as an aid in projecting the steric course of a variety of useful synthetic reactions. PCMODEL predictions were found to be correct for the simple case of the cyclization reaction of a 2,5,8-nonatrione (27). However, application to larger molecules gave more equivocal results. As a model study for the anticipated ring closure procedure, the previously unknown triketone 27 was prepared and studied. The same procedure was used successfully to carry out the cyclization of the diketone 22B. 3-Methyl-2-cyclopentenone (45) was used in a model study for the Michael addition of an acyl anion synthon to the $\alpha$,$\beta$-unsaturated ketone. While cyanide could be added to 3-methyl-2-cyclopentenone, the addition failed with 2-alkyl-3-methyl-2-cyclopentenone (20B). The hydrocyanation reaction on enone 20B using Et$\sb2$AlCN gave the mixture of two 1,4-addition products, which can be explained by the presence of syn and anti nitrile groups with respect to the substituent at carbon-2. The two products are formed in the ratio of 65:35 as indicated by the relative intensities in the $\sp{13}$C NMR spectrum. This major product was shown to be the syn isomer. 19-Nortestosterone oxime after refluxing in acetic anhydride has been reported to yield 3-acetamido-1,3,5(10)-estratien-17$\beta$-ol acetate in 45% yield. However, an NMR examination of the crude reaction product shows a nearly quantitative yield of a precursor substance which is converted to the acetamido product upon passage through an alumina column. This precursor material was shown to be the diacetamido analog of the reported product. This material could be produced in 91% yield by heating the oxime at 110$\sp\circ$C. The proton and carbon NMR spectra of these and related materials are recorded and assigned. The diacetamido compound was hydrolysed in an acidified 1:1 water-ethanol mixture at 80$\sp\circ$C overnight to give the reported compound in quantitative yield.