Spiro‐ and Bicycloannulation of Sulfoximine‐Substituted 2‐Hydroxy‐dihydropyrans: Enantioselective Synthesis of Spiroketals, Spiroethers, and Oxabicycles and Structure of Dihydropyran Oxocarbenium Ions

Abstract

AbstractA modular enantioselective synthesis of spiroketals, spiroethers, and oxabicycles, each containing a dihydropyran subunit, is described. It is based on the 2,2‐spiro‐ and 2,6‐bicycloannulation of sulfoximine‐substituted 2‐hydroxy‐dihydropyrans. Key steps of the spiroannulations are the ring‐closing metathesis of the corresponding 2,2‐oxadienyl and 2,6‐dienyl dihydropyrans and Prins cyclization of 2‐alkenyl 2‐hydroxy‐dihydropyrans. Ring‐closing metathesis of the corresponding 2,6‐dienyl dihydropyrans gave oxabicycles with oxabicyclo[4.3.1]decane skeletons. These routes were extended to the synthesis of spiroketals and spiroethers incorporating additional annulated six‐membered rings. Diastereoselective Prins cyclization of mono‐ and bicyclic 2‐alkenyl‐2‐hydroxy‐dihydropyrans was highly selective and afforded chloro‐substituted spirocycles. Substituted 2‐hydroxy‐dihydropyrans were obtained through cyclization of δ‐hydroxy ketones, which were synthesized from enantiomerically pure sulfoximine‐substituted homoallylic alcohols through lithiation and trapping of the α‐lithioalkenylsulfoximines with unsaturated aldehydes, followed by allylic oxidation. Inter‐ and intramolecular glycosidations of the 2‐hydroxy‐dihydropyrans with O‐ and C‐nucleophiles proceeded with high stereoselectivities and furnished 2,6‐trans‐configured glycosides. Dihydropyran oxocarbenium ions are most likely intermediates in the glycosidations. According to ab initio calculations, sulfoximine‐ and trimethyl‐substituted dihydropyran oxocarbenium ions adopt a half‐chair‐like conformation. The energy difference between the oxocarbenium ion with pseudoaxial and the one with pseudoequatorial methyl groups is very small. A transition state model for their reactions with nucleophiles is proposed. It features a half‐chair‐like conformation, a pseudoequatorial C6 substituent, and an anti‐addition of the nucleophile along an axial trajectory to C2 that produces an anti‐periplanar lone pair at the O atom. A similar transition state model allows a general explanation for the trans stereoselectivity of the reactions between C6‐substituted dihydropyran oxocarbenium ions and nucleophiles.