Lipase-Catalyzed Enantioselective Synthesis of Methyl (R)- and (S)-2-Tetradecyloxiranecarboxylate through Sequential Kinetic Resolution

Abstract

Among a variety of lipases tested, Pseudomonas fluorescens lipase has been found to induce enantioselective acylation of methyl (R,S)-2-hydroxy-2-(hydroxymethyl)hexadecanoate (3), affording, through sequential kinetic resolution, both enantiomers in good optical yields. Efficiency of the process has been compared to the Sharpless asymmetric dihydroxylation of alkene 2 using (DHQD) 2 PHAL and (DHQ) 2 PHAL as chiral ligands. The (R)-and (S)-3 enantiomers have been cyclized to afford both enantiomers of methyl 2-tetradecyloxiranecarboxylate (1), a potent hypoglycemic agent and inhibitor of long-chain fatty acid oxidation.

Asymmetric catalysts

“…[345][346][347][348][349][350][351][352] In all the previous cases, the resolu-Scheme 63 tion was achieved through an acylation process which can also be applied to nonsymmetric diols. [353][354][355] Where there is a clear reactivity difference (i.e. tertiary versus primary) then the resolution process generally follows a sterically directed path.…”

“…tertiary versus primary) then the resolution process generally follows a sterically directed path. 353,354 The situation becomes a little more complex when two alcohols within a molecule are of similar reactivity, but may still be turned to the advantage of the synthetic chemist through careful planning. 355 Acetylation of prochiral diols is of course an excellent method for the synthesis of enantiomerically pure compounds in both high ee and conversion, since all of the starting material may theoretically be converted into product.…”

Fatty acids, fatty acid analogues and their derivatives

“…538 Pseudomonas fluorescens lipase has been found to induce enantioselective acylation of methyl (R,S)-2-hydroxy-2-(hydroxymethyl)hexadecanoate. 539 6-Hydroxy -lactones and 5,6-dihydroxy-20:0/ 22:0 were produced from meadowfoam (Limnanthes alba) fatty acids via a lipase-mediated self-epoxidation reaction. 540 Various C 18 and C 20 polyunsaturated fatty acids fed to the yeast Dipodascopsis uninucleata resulted in the production of 3(R)hydroxy polyenoic acids.…”

Asymmetric Epoxidation of α-Substituted Acroleins Catalyzed by Diphenylprolinol Silyl Ether

“…The present epoxidation was applied to enantioselective synthesis of ( R )-methyl palmoxirate (Scheme ), a potent oral hypoglycemic and antiketogenic agent in mammals including humans. , 2-Methylenehexadecanal was treated with H 2 O 2 in the presence of ( R )-diphenylprolinol silyl ether ent-4 , derived from unnatural d -proline, to afford the desired epoxide in 78% yield with excellent enantioselectivity (92% ee). Kraus oxidation followed by treatment with TMSCHN 2 gave ( R )-methyl palmoxirate in 81% yield over two steps.…”