The Preparation of 9-Oxo-10-Oxaprostanoids by the Conjugate Addition of (E)-1-(Phenylthio)Oct-2-Enyllithium to γ-Crotonolactone and the Direct Alkylation of the Derived Enolate With Methyl 7-Bromohept-5-ynoate and Related Electrophiles

Abstract

The conjugate addition of (E)-1-(pheny1thio)oct-2-enyllithium in tetrahydrofuran containing hexamethylphosphoric triamide to γ-crotonolactone (but-2-en-4-olide) followed by treatment of the resulting lactone enolate with either methyl 7-bromohept-5-ynoate or 7-bromohept-5-ynenitrile gave the corresponding enolate trapped products in yields of 50-55% from the octenyllithium reagent. Use of 7-iodohept-5-ynoate gave a slightly higher yield than the first electrophile. Treatment of the enolate with triphenyltin chloride prior to addition of the electrophiles resulted in approximately 5-10% enhancement of the yields of the products. The products obtained from the methyl 7-halohept-5-ynoates were converted into the 9-oxo-l0-oxaprostanoids through the corresponding sulfoxides and the allylically transposed alcohols by a standard sequence of reactions. In an attempt to convert the lactone ring of the enolate-trapped products into the fully carbocyclic nucleus of primary prostaglandins, the nucleophilic ring opening of the lactone nucleus with the lithiated carbanion derived from t-butyl methyl sulfone in the presence of N, N, N', N'- tetramethylethylenediamine was carried out. However, attempts to oxidize the resulting hemiacetals to the requisite diketone precursors of the carbocyclic prostaglandins were unsuccessful.