Enantioselective Total Synthesis of (−)-Chlorothricolide via the Tandem Inter- and Intramolecular Diels−Alder Reaction of a Hexaenoate Intermediate

Abstract

An enantioselective total synthesis of (−)-chlorothricolide (1) has been completed via a route involving the tandem inter- and intramolecular Diels−Alder (IMDA) reaction of hexaenoate 19 and the chiral dienophile (R)-12. This reaction, which establishes seven asymmetric centers in a single operation, is feasible only by virtue of the high diastereofacial and exo selectivity of dienophile 12. The C(9)-trimethylsilyl steric directing group of 19 also plays a key role by controlling the stereochemical course of the IMDA reaction leading to the bottom half octahydronaphthalene unit. Hexaenoate 19 was prepared in 32% overall yield by a 10-step sequence starting from the known acetylenic ketone 33. Key steps include the asymmetric reduction of 33 using Alpine Borane (up to 94% ee), the Suzuki cross coupling of α-iodo vinylsilane 20 with vinylboronic acid 21, and the Horner-type olefination of aldehyde 41 with dienylic phosphonate 22. The key tandem inter-intramolecular Diels−Alder reaction was performed by heat...