Lipase-catalyzed resolutions

Temperature control of the enantioselectivity in the lipase-catalyzed resolutions... 

In the lipase-catalyzed resolution, temperature control of enantioselectivity has been generally accepted for its simplicity and theoretical reliability. Lowering the reaction temperature usually enhances the enantioselectivity. Here, the historical and theoretical backgrounds of the temperature control of enantioselectivity and its applicability to the method are described. Recent literatures for the lipase-catalyzed resolutions to which the low-temperature method seems to be promising to enhance the enantioselectivity are also summarized. 

We first examined the lipase-catalyzed resolution of azirine-2-methanol I, which we expected to have a versatile synthetic utility. As expected for primary alcohols, the enantioselectivity obtained in the transesterification with lipase PS in ether was low (E = 17 at best) at room temperature despite considerable efforts such as screening of lipases, solvents, additives, and acylating agents. 

Scheme 1 Low-temperature method in the lipase-catalyzed resolution of 3-phenyl-27f-azirine-2-methanol (1) for enhancement of the enantioselectivity.

Lowering the temperature in the lipase-catalyzed resolution usually enhances the enantioselectivity. The phenomenon does not come from the temperature-induced conformational change of lipase, but it is understandable on the basis of the theory of physical organic chemistry as explained below. ... 

The low-temperature method has been applied to some primary and secondary alcohols (Fig. 1) For example, solketal, 2,2-dimethyl-1,3-dioxolane-4-methanol (3) had been known to show low enantioselectivity in the lipase-catalyzed resolution (lipase AK, Pseudomonas fluorescens, E = 16 at 23°C, 27 at 0oc) 2ia however, the E value was successfully raised up to 55 by lowering the temperature to —40°C (Table 1). Further lowering the temperature rather decreased the E value and the rate was markedly retarded. Interestingly, the loss of the enantioselectivity below —40°C is not caused by the irreversible structural damage of lipase because the lipase once cooled below —40°C could be reused by allowing it to warm higher than -40°C, showing that the lipase does not lose conformational flexibility at such low temperatures. 

Figure 7 Substrates for the lipase-catalyzed resolutions at low temperatures.

Figure 8 Correlation between In E and 1/T for the lipase-catalyzed resolution...

Tbyonife-immobilized lipase-catalyzed resolution of solketal ( )-3 (vinyl butylate)... 

Figure 10 Temperature effect on the rojonite-immobilized lipase-catalyzed resolution of ( )-4 by varying the organic bridges.

The lipase-catalyzed resolution of (2/ , 35 )-3-methyl-3-phenyl-2-aziridine-methanol ( )-H by using the low-temperature method gave synthetically useful (2/ ,35 )-ll and its acetate (2S, iR)- a with (25 )-selectivity E = 55 at —40°C), while a similar reaction of (2/ , 3f )-3-methyl-3-phenyl-2-aziridinemethanol ( )-12 gave (25,35 )-12 and its acetate (2/ ,3/ )-12a with (2/ )-selectivity E = 73 at —20°C) (Scheme 2). Compound ( )-ll was prepared conveniently via diastereos-elective addition of MeMgBr to t-butyl 3-phenyl-2//-azirine-2-carboxylate, which was successfully prepared by the Neber reaction of oxime tosylate of t-butyl... 

LIPASE-CATALYZED RESOLUTION OF PRIMARY ALCOHOLS PROMISING CANDIDATES FOR THE LOW-TEMPERATURE METHOD ... 

Examples of the lipase-catalyzed resolution of primary alcohols are listed in Fig. 17,63-126 TTigy usually give low enantioselectivity because of mechanistic reasons, and no effective method for improving the enantioselectivity is available. One of the purposes of this book is to create new ideas and possibilities in this field. The low-temperature method is a promising one to improve the enantioselectivity of these alcohols. 

Figure 17 Example of lipase-catalyzed resolution of primary alcohols [lit.].

Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of l,l-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee... 

Scheme 6.7 Lipase-catalyzed resolution of cyanohydrin library DCL-D, yielding ester (35) as the major product.

The lipase-catalyzed resolutions usually are performed with racemic secondary alcohols in the presence of an acyl donor in hydrophobic organic solvents such as toluene and tert-butyl methyl ether (Scheme 1.3). In case the enzyme is highly enantioselective E = 200 or greater), the resolution reaction in general is stopped at nearly 50% conversion to obtain both unreacted enantiomers and acylated enantiomers in enantiomerically enriched forms. With a moderately enantioselective enzyme E = 20-50), the reaction carries to well over 50% conversion to get unreacted enantiomer of high optical purity at the cost of acylated enantiomer of lower optical purity. The enantioselectivity of lipase is largely dependent on the structure of substrate as formulated by Kazlauskas [6] most lipases show... 

Scheme 1.3 Lipase-catalyzed resolution of secondary alcohols.

Table 4.1 Lipase-catalyzed resolution of 2-methylalkanols (2) with vinyl acetate in dichloromethane or chloroform at room temperature.

Scheme 4.27 Lipase-catalyzed resolution of some octahydronaphthalenols.

Lipase-Catalyzed Resolution of Racemic Menthol Esters... 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

A practical resolution of 3-phenyl-2H-azirine-2-methanol 15 at a very low temperature (-40 °C) was reported by Sakai et al64 to enhance the enantioselectivity in immobilized lipase-catalyzed resolution of 15 using vinyl butanoate as acyl donor in ether as organic solvent. The method was found to be effective in enhancing the enantioselectivity E and affords the primary alcohol (S)-15 with 99% ee and the ester (A)-16 with 91% ee. 

Figure 13 Toyonit-immobilized lipase-catalyzed resolution of 1 at -40...

Secondary alcohols are by far the most frequently used targets in lipase-catalyzed resolutions. This is due to their importance in organic synthesis but also that lipases usually show much higher enantioselectivity in resolutions compared to primary and tertiary alcohols. 

A practical method for the synthesis of chiral pyridazinone bearing a pyrazolopyridine ring via lipase-catalyzed resolution of 2-(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-one derivatives 113 was reported by Yoshida et al.95... 

Figure 55 Lipase-catalyzed resolution of 2-(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-one...

Henke, E. Schuster, S. Yang, H. Bomscheuer, W. T. Lipase-catalyzed resolution of ibuprofen. Monatshefte fur chemie 2000, 131, 633-638. 

Figure 10. Lipase catalyzed resolution coupled with a chemical inversion...

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