Organocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins

Abstract

Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents. Here we present a concise organocatalytic cycloetherification for the highly enantio- and diastereoselective synthesis of tetrahydropyrans involving simultaneous construction of two chiral centres, one of which is fully substituted. This method involves dynamic kinetic resolution of reversibly generated chiral cyanohydrins. A chiral bifunctional organocatalyst selectively recognizes a specific chair-like conformation of the intermediate, in which the small steric effect of the linear cyano group as well as its anomeric effect play important roles in controlling stereoselectivity. The products offer additional utility as synthetic intermediates because the cyano group can be further transformed into a variety of important functional groups. This strategy provides a platform to design efficient approaches to obtain a wide range of optically active tetrahydropyrans, which are otherwise synthetically challenging materials.

Fig. 1

Simultaneous construction of two stereogenic centres in tetrahydropyrans. a Cycloetherification via kinetic resolution of racemic alcohols. b Cycloetherification via dynamic kinetic resolution involving reversible addition of a carbon nucleophile to ketones

Fig. 2

Reaction design for cycloetherification via dynamic kinetic resolution. a Intramolecular oxy-Michael addition via dynamic kinetic resolution through reversible generation of chiral cyanohydrins. b Rationale for the proposed strategy

Fig. 3

Substrate scope. Reactions were run using 1 (0.15 mmol), 2 (0.30 mmol), and 4a (0.015 mmol) in CH₂Cl₂ (0.30 ml). Yields represent material isolated after silica gel column chromatography. Diastereomeric ratios (dr) were determined by ¹H NMR spectroscopy. *Reaction was run for 72 h

Fig. 4

Cyanohydrin formation under the optimized conditions. Reactions were run using 5 (0.15 mmol), 2 or trimethylsilylcyanide (0.30 mmol), and 4a (0.015 mmol) in CH₂Cl₂ (0.30 ml)

Fig. 5

Transformations of the cyano group in product 3a. Synthesis of 8: 3a (0.10 mmol) was treated with lithium aluminium hydride (0.50 mmol) in Et₂O (1.0 ml). Synthesis of 9: 8 (0.10 mmol) was treated with manganese dioxide (1.0 mmol) in CH₂Cl₂ (2.0 ml). Synthesis of 10: 3a (0.10 mmol) was treated with diisobutylaluminium hydride (0.40 mmol) in CH₂Cl₂ (1.0 ml). Synthesis of 11: 10 (0.056 mmol) was treated with pyridinium chlorochromate (0.17 mmol) in CH₂Cl₂ (2.0 ml)