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.
Highlights
Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents
To realize the cyclization of chiral tertiary alcohols via dynamic kinetic resolution, we propose a process involving reversible addition of a carbon nucleophile to ketones followed by cyclization[10], leading to the efficient simultaneous construction of two stereogenic centres, including a tetrasubstituted chiral carbon (Fig. 1b)
The diverse chemistry of the cyano group expands the utility of the resulting products as synthetic intermediates[36, 37]
Summary
Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents. 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. To accomplish the stereoselective construction of a tetrasubstituted chiral centre, which has been a long-standing challenge in organic synthesis[11,12,13], we aimed to use a small electronegative carbon nucleophile These features favour the introduction of the substituent adjacent to the heteroatom in an axial position in a six-membered oxacycle, enabling weaker 1,3-diaxial interactions as well as a favourable orbital interaction with the oxygen atom (anomeric effect)[14]
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