Stereodivergent Synthesis of Highly Substituted Tetrahydropyrans

Biocatalysts from Biosynthetic Pathways: Enabling Stereoselective, Enzymatic Cycloether Formation on a Gram Scale

“…Chemical IMOMA, often integrated into efficient tandem processes, gained growing attention for the stereoselective synthesis of tetrahydropyrans (THPs) during recent years. − It has been shown that the cis - or trans -THP selectivity of IMOMA can be influenced by kinetic or thermodynamic reaction control, by the type of activation (acid, base, or metal catalysis), by the configuration of the double bond, and by the nature of the acceptor moiety. − Although the reaction outcome is predictable for some systems (tandem-cross metathesis-IMOMA with vinylketone intermediates for example reliably leads to cis -THPs with diastereomeric excess > 5:1), low to moderate d.e. s are rather common and have only occasionally been improved by extensive reaction optimization or product re-equilibration (see, e.g., refs − ).…”

The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization

“… 12 The origin of this moderate 2,6- trans -selectivity is generally accepted as arising from better orbital overlap in the transition state of the kinetic cyclization leading to the 2,6- trans -THP compared to the 2,6- cis -THP. 8 Although there is no generally accepted mechanism for the acid-mediated cyclization, it has been proposed that the formation of the 2,6- cis -THP is favored due to greater stereoelectronic stabilization of the transition state from both the FMO coefficients of the allylic cation and orbital overlap with the oxygen lone pair, compared to the transition state leading to the 2,6- trans -THP. 9 …”

Biosynthesis-Inspired Intramolecular Oxa-Conjugate Cyclization of α,β-Unsaturated Thioesters: Stereoselective Synthesis of 2,6-cis-Substituted Tetrahydropyrans

“…Accordingly, numerous methodologies have been developed for the synthesis of tetrahydropyran derivatives. Intramolecular oxa-conjugate cyclization (IOCC), often referred to as oxa-Michael cyclization, of α,β-unsaturated esters stands as one of the renowned methodologies for tetrahydropyran synthesis, and the products of this reaction have served as important intermediates in the total synthesis of complex natural products. , In general, the stereoselectivity of base-catalyzed IOCC of α,β-unsaturated esters depends on the reaction conditions. , It is known that the reaction provides 2,6- trans -substituted tetrahydropyrans under kinetic control, while 2,6- cis -substituted tetrahydropyrans are formed only when 2,6- trans and 2,6- cis isomers are in thermodynamic equilibrium . Unfortunately, despite the fact that the majority of tetrahydropyran-containing natural products have 2,6- cis stereochemistry, the reaction sometimes results in poor diastereoselectivity under thermodynamic conditions .…”