Enantioselective Synthesis of 2,4,5-Trisubstituted Tetrahydropyrans via Peptide-Catalyzed Michael Addition Followed by Kishi’s Reductive Cyclization

An enantioselective synthesis of 2,4,5-trisubstituted tetrahydropyrans has been achieved in four steps from α,β-unsaturated ketones and dimethyl malonate by peptide-catalyzed asymmetric Michael addition and diastereoselective construction of tetrahydropyran rings by Kishi’s reductive cyclization as key steps. A variety of α,β-unsaturated ketones were converted to the 1,4-products with high enantioselectivities (83–98% ee). INTRODUCTION A number of isolations as well as syntheses of biologically active natural products possessing tetrahydropyran (THP) rings were reported, for example, laulimalides, bryostatins, halichondrins, and so on. Therefore, there are many efforts at developing enantioselective synthesis of THP ring motifs. We recently reported an enantioselective synthesis of 2,4,5-trisubstituted THP 5, which involves: (1) helical peptide 1-catalyzed enantioselective Michael addition reaction of dimethyl malonate to enone 2 with 94% ee; (2) ketal protection of 3 with neopentyl glycol and subsequent reduction of ester moiety to give diol 4; (3) Kishi’s reductive cyclization using unprecedented prochiral 1,3-diol as a precursor to afford the desired THP 5 as a single diastereomer without loss of the enantiomeric purity (Scheme 1). It is important to note that two hydroxy groups in prochiral diol 4 were completely differentiated to create new stereogenic centers at C2 and C5 positions. This high diastereoselectivity could be derived from phenyl substituent at C4 position. Since peptides are promising organocatalyst to construct new stereogenic center with a broad scope of substrates, this four-step protocol to construct 2,4,5-trisubstituted THP motif could be applicable to various substrates. Herein, we report an enantioselective synthesis of 2,4,5-trisubstituted THPs. This paper is dedicated to Professor Tohru Fukuyama on the occasion of his 70th birthday. HETEROCYCLES, Vol. 99, No. 2, 2019 989