Studies directed towards total synthesis of the unusual marine alkaloid sarain A

In work directed towards a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 238, containing all the key elements and the seven stereogenic centers of sarain A, was successfully synthesized from commercially available dihydroanisole (91) in 41 steps.; Bicyclic compound 80, prepared via an intramolecular stereospecific [3+2]-azomethine ylide dipolar cycloaddition, could be converted to N-Boc derivative 146 on a hundred gram scale. Introduction of C-7' and its attendant stereochemistry into lactam 146 was then achieved by C-acylation of the corresponding enolate and a subsequent stereoselective ketone reduction with Zn(BH4)2. Intermediate 148 has the incorrect C-7' stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7' center via an intramolecular cyclization of the corresponding silyl carbamate 175 (Scheme 46). It was then possible to convert allylsilane 180 to the alkaloid tricyclic core 129 via an allylsilane/N-sulfonyliminium ion cyclization without any serious adverse effects by the C-7' substituent (Scheme 47).; Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3' and N-1' on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs' ruthenium catalyst.; A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 234 afforded a single diastereomeric adduct 236 which was tentatively assigned to have correct C-7 ',8' syn diol stereochemistry (see Scheme 64). It was then possible to effect a reductive amination protocol between secondary amine 237 and aldehyde 222 to afford vinyl iodide alkyne 238 to set the stage for the "eastern" ring macrocyclization. We have attempted to construct eastern macrocycle 239 by means of an intramolecular Sonogashira coupling, but unfortunately were not able to detect any of the desired product. Work is currently in progress on alternative strategy to build the eastern macrocycle 239 to complete a total synthesis of sarain A.