Preparation of Optically Active 1-O-Alkyl-3-O-arylsulfonyl-sn-glycerol Derivatives: Substrate Engineering in Enzyme-Mediated Enantioselective Hydrolysis

Abstract

Lipase PS catalyzes the enantioselective hydrolysis of various 2-acetyl compounds of the 1-O-alkyl-3-O-arylsulfonyl-sn-glycerol derivatives to afford the corresponding optically active compounds. Changing the structure of the 1-O-alkyl and 3-O-arylsulfonyl groups affects both the reactivity and enantioselectivity. Finally, the E value of the reaction for 2-acetyl-3-O-3,5-dimethylbenzenesulfonyl-1-O-4-methoxybenzyl-sn-glycerol is greater than 200.

Key words

enantioselective hydrolyses - enzymes - kinetic resolution - glycerol derivatives - tosylates

References and Notes

• For recent reviews, see:
• 1a Bornscheuer UT. Kazlauskas RJ. Hydrolases in Organic Synthesis   Wiley-VCH; Weinheim: 1999. 
• 1b Bommarius AS. Riebel BR. Biocatalysis   Wiley-VCH; Weinheim: 2004. 
• 1c Faber K. Biotransformations in Organic Chemistry: A Textbook   5th ed.:  Springer; Berlin: 2004. 
• 1d Ghanem A. Aboul-Enein HY. Chirality  2004,  17:  1 
• 1e Garcia-Uradiales E. Alfonso I. Gotor V. Chem. Rev.  2005,  105:  313 
• 1f Bornscheuer UT. Trends and Challenges in Enzyme Technology   Springer; Berlin: 2005. 
• 1g Fogassy E. Nógrádi M. Kozma D. Egri G. Pálovics E. Kiss V. Org. Biomol. Chem.  2006,  4:  3011 
• 1h Gadler P. Faber K. Trends Biotechnol.  2007,  25:  83 
• 1i Ghanem A. Tetrahedron  2007,  63:  1721 
• 1j Gotor V. Alfonso I. Garcia-Urdiales E. Asymmetric Organic Synthesis with Enzymes   Wiley-VCH; Weinheim: 2008. 
• For enzymatic hydrolysis of acyl derivatives of 1,2-diol monotosylates in an aqueous media, see:
• 2a Hamaguchi S. Ohashi T. Watanabe K. Agric. Biol. Chem.  1986,  50:  375 
• 2b Hamaguchi S. Ohashi T. Watanabe K. Agric. Biol. Chem.  1986,  50:  1629 
• 2c Hamaguchi S, Katayama K, Ohashi T, and Watanabe K. inventors; JP  62158250. 
• 2d Hamaguchi S, Kobayashi M, Katayama K, Ohashi T, and Watanabe K. inventors; JP  62209049. 
• 2e Kobayashi M, Hamaguchi S, Katayama K, Ohashi T, and Watanabe K. inventors; JP  62212382. 
• 2f Pederson RL. Liu KK.-C. Rutan JF. Chen L. Wong C.-H. J. Org. Chem.  1990,  55:  4897 
• 2g Chen C.-S. Liu Y.-C. Marsella M. J. Chem. Soc., Perkin Trans. 1  1990,  2559 
• For enzymatic esterification of 1,2-diol monotosylates in organic solvent, see:
• 3a Chen C.-S. Liu Y.-C. Tetrahedron Lett.  1989,  30:  7165 
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• 3f

  For enzymatic hydrolysis in organic solvent, see ref. 3c. For enzymatic alcoholysis in organic solvent, see refs. 3a and 2g.

• 4 Saito Y, and Nakamura T. inventors; JP  10057096. For enantioselective decomposition of 1,2-diol monotosylate by microorganisms, see:
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6

The racemic alcohols (±)-2, except for 2d, as the precursor of the substrates were prepared in three steps: 1) protection of the hydroxyl group of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 2) 2 M aq HCl-THF, 3) TsCl, Bu₂SnO, Et₃N-CH₂Cl₂.^¹² In all cases, the resulting (±)-2 contained the regioisomers, 3-acetyl-2-O-tosyl-sn-glycerol (±)-7, as the minor product. After the enzymatic acylation of the mixture using porcine pancreas lipase (PPL, Sigma), the pure (±)-2 was obtained. The details will be reported separately. On the other hand, (±)-2d was prepared from the coupling of (±)-glycidol with TsOH, followed by selective protection of the primary hydroxyl group with TBS.

7

The absolute configuration of 2a {[α]_D ^²5 -4.19 (c 2.49, C₆H₆) (59% ee)} was confirmed by comparing the obtained optical rotation value with the reported value: lit.^¹³ [α]_D ^²5
-6.70 (c 10, C₆H₆; R form).

9

The substrate with a mesyl group was quite unstable and decomposed under the enzymatic reaction conditions.

10

Compound (R)-5: [α]_D ^³0 +1.89 (c 0.90, CHCl₃; 93% ee).
Compound (S)-5: [α]_D ^²¹ -1.81 (c 0.83, CHCl₃; 95% ee); lit.^¹4 [α]_D ^²¹ +1.79 (c 5.02, CHCl₃; R form).

11

To a 200 mL Erlenmeyer flask containing (±)-6 (72.3 mg, 0.17 mmol; sub. concd, ca. 4 mM) were added of i-Pr₂O (4 mL), 0.1 M phosphate buffer (40 mL, pH 6.5), and lipase PS (30 mg). After the mixture was incubated for 24 h at 30 ˚C, the products were extracted with EtOAc and purified by flash column chromatography on SiO₂ (eluent: hexane-EtOAc, 4:1) to afford (S)-6 (26.4 mg, 37%, 99% ee) and (R)-7 (31.5 mg, 48%, 96% ee).