Enantioselective synthesis of 2-alkylidenetetrahydrofurans based on a ‘cyclization/enzymatic resolution’ strategy

Enantiomerically pure 2-alkylidenetetrahydrofurans have been prepared by TiCl4 mediated enantiospecific reactions of 1,3-bis-silyl enol ethers with enantiomerically pure epichlorohydrin. In addition, the enzymatic kinetic resolution of 2-alkylidenetetrahydrofurans, using Candida antarctica lipase B (CAL-B), was studied. Enzymatic kinetic resolution of monocyclic 5-vinyl-2-alkylidenetetrahydrofuran with CAL-B afforded the enantiomerically pure ester with 97% ee. For a bicyclic 2-alkylidenetetrahydrofuran, this proceeded with excellent enantioselectivity (E >100) affording the enantiomerically pure acid with 98% ee. 2-Alkylidenetetrahydrofurans were prepared by [3+2] cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol ethers (‘masked dianions’).

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(−)-(E)-Methyl 2-((R)-5-(chloromethyl)-dihydrofuran-2(3H)-ylidene)acetateC8H11ClO3Ee = 98%[α]D20=-66 (c 1, CHCl3)Source of chirality: enantiospecific reaction

(−)-Ethyl 2,3,3a,4,5,6-hexahydrobenzofuran-7-carboxylateC11H16O3Ee = 97%[α]D20=-110 (c 1, CDCl3)Source of chirality: enzymatic resolution

(+)-2,3,3a,4,5,6-Hexahydrobenzofuran-7-carboxylic acidC9H12O3Ee = 53%[α]D20=+29 (c 1, CDCl3)Source of chirality: enzymatic resolution

(−)-(E)-Ethyl 2-(dihydro-5-vinylfuran-2(3H)-ylidene)acetateC10H14O3Ee = 97%[α]D20=-94 (c 1, CDCl3)Source of chirality: enzymatic resolution

(−)-(E)-2-(Dihydro-5-vinylfuran-2(3H)-ylidene)acetic acidC8H10O3Ee = not detected[α]D20=-16 (c 1, CDCl3)Source of chirality: enzymatic resolution