Synthesis of B-keto esters

Details Synthesis of B-keto esters Synthesis of B-keto esters

2001-01-26

2003-11-04

Weber, Jon P. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C435S041000, C435S043000

Reexamination Certificate

active

06642035

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the synthesis of &bgr;-keto esters. More particularly, the invention relates to a highly chemo- and stereoselective synthesis of &bgr;-keto esters via a polymer-supported lipase catalyzed transesterfication.
BACKGROUND
&bgr;-keto esters are noteworthy in that they represent an important class of organic building blocks used in the synthesis of complex natural products (S. Benetti, et al.,
Chem Rev.
1995, 95, 1065). A seemingly straight-forward method to prepare these molecules is through an alcohol based transesterification (J. G. Gilbert, et al.,
J. Org. Chem.
1988, 53, 449; D. F. Taber, et al.,
J. Org. Chem.
1985, 50, 3618). Yet the synthesis of allylic and propargylic &bgr;-keto esters is not trivial by this route due to their acid/base lability and sigmatropic rearrangement of the &bgr;-keto ester. To circumvent these problems a report has appeared describing the heating of alcohols with &bgr;-keto esters in toluene (C. Mottet, et al.,
J. Org. Chem.
1999, 64, 138;). However, the reaction times were lengthy and yields variable for many of the substrates. Another mild method uses crystalline microporous nanosilicates (zeolites) as the catalyst for the transesterification in refluxing toluene to avoid potential side reactions, but here the yields were even lower compared to the former case (B. S. Balaji, et al.,
J. Chem. Soc. Chem. Commun.
1996, 707). Furthermore, none of these or any of the conventional methods display stereoselectivity or chemoselectivity between aliphatic alcohols or phenols. What is required is a general method of synthesizing &bgr;-ketoesters either as racemates or as single enantiomers. What is required is a general method for resolving alcohol racemates.
SUMMARY OF INVENTION
Candida antarctica
lipase B (CALB) immobilized on a macroporous poly(propylene) resin (Novozym 435) catalyzed the transesterification of &bgr;-keto esters under environmentally safe conditions. The reactions were performed by simply solubilizing the alcohols in methyl or ethyl &bgr;-keto esters and then treating the reaction mixture with the lipase under reduced pressure. The &bgr;-keto ester products were obtained in high yields (>90%) and CALB was chemoselective in the acylation of aliphatic alcohols in the presence of phenols. In addition, CALB was able to resolve sec-alcohols with high enantioselectivity. This is a general route to prepare &bgr;-keto esters by lipase-catalyzed transesterification and it can be of ample use due to its mild, solvent-free conditions. Moreover, it also provides a simple protocol to produce optically active &bgr;-keto esters that are useful building blocks and starting materials for natural product synthesis.
One aspect of the invention is directed to a process for synthesizing chiral &bgr;-keto ester products by way of a lipase catalyzed transesterification. In the first step of the process, an acyl donor &bgr;-keto ester, a racemic alcohol, and a catalytic concentration of a lipase are admixed under catalytic contitions. In the second step of this aspect of the invention, a transesterification of the acyl donor &bgr;-keto ester with the racemic alcohol is catalyzed by means of the lipase for producing the chiral &bgr;-keto ester product. Preferred racemic alcohols include allylic, propargylic, benzylic, allenic, and aliphatic alcohols. A preferred lipase is
Candida antartica
lipase B (CALB). Preferred acyl donor &bgr;-keto esters include a methyl ester or an ethyl ester. A preferred solvent is the acyl donor &bgr;-keto ester.
Another aspect of the invention is directed to a process for resolving a racemic alcohol. In the first step of the process the racemic alcohol is admixed with a catalytic concentration of a lipase in the presence of an excess of acyl donor &bgr;-keto ester under catalytic contitions. In the second step of the process, a transesterification of the acyl donor &bgr;-keto ester with the racemic alcohol is catalyzed by means of lipase for resolving the racemic alcohol. producing the chiral &bgr;-keto ester product. Preferred racemic alcohols include allylic, propargylic, benzylic, allenic, and aliphatic alcohols. A preferred lipase is
Candida antartica
lipase B (CALB). Preferred acyl donor &bgr;-keto esters include a methyl ester or an ethyl ester. A preferred solvent is the acyl donor &bgr;-keto ester.


REFERENCES:
patent: 5817490 (1998-10-01), Hubbs
patent: 6365398 (2002-04-01), Bornscheuer et al.
Oikawa, et al., “Meldrum's Acid in Organic Synthesis. 2. A General and Versatile Synthesis of &bgr;-Keto Esters”,J. Org. Chem. 43: 2087-2088 (1978).
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Gilbert, et al., “Transesterification of 3-Oxo Esters with Allylic Alcohols”,J. Org. Chem. 53: 449-450 (1988).
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Suginaka, et al., “Highly Selective Resolution of Secondary Alcohols and Acetoacetates with Lipases and Diketene in Organic Media”,Tetrahedron: Asymmetry 7: 1153-1158 (1996).
Balaji, et al., “A Facile and Selective Synthesis of &bgr;-Keto Esters via Zeolite Catalysed Transesterification”,J. Chem. Soc., Chem. Commun.: 707-708 (1996).
Mottet, et al., “A Simple and Efficient Preparation of Propargylic &bgr;-Keto Esters through Transesterification”,J. Org. Chem. 64: 1380-1382 (1999).

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