Lipase Catalysed Synthesis of Optically Enriched -Haloamides Abul Azim, a Sunil K. Sharma, a Carl E. Olsen b and Virinder S. Parmar a, * a Department of Chemistry, University of Delhi, Delhi-110 007, India b Chemistry Department, Royal Veterinary and Agricultural University, DK-1871 Frederiksberg C, Copenhagen, Denmark Received 2 August 2000; accepted 6 January 2001 AbstractÐAn ecient lipase catalysed synthesis of optically enriched a-halogenated amides with concomitant optical enrichment of the starting a-haloesters is described. Candida antarctica lipase (CAL) was found to be a better catalyst over porcine pancreatic lipase (PPL) and Candida cylindracea lipase (CCL). The eect of dierent organic solvents was also studied. # 2001 Elsevier Science Ltd. All rights reserved. Introduction The synthesis of optically active amides is an area of growing interest in synthetic organic chemistry, 1 since amide bonds are present in a large number of com- pounds exhibiting dierent biological activities. 2 5 Synthesis of these compounds have mainly been achieved by classical chemical reactions which generally involve the generation of reactive carboxy derivative, either an acid chloride or anhydride, followed by ami- nolysis with amine. 6 However, the conversion of esters to amides has some limitations as the commonly used reagents, that is sodium methoxide, sodium hydride, sodium metal, butyl lithium, and so forth, often inter- fere with other functional groups present in the reacting species. 7 12 Besides these, the growing environmental consciousness and increasing demand of the chiral amides and acids led us to employ the biocatalytic procedures for carrying the amidation. Due to their low cost and tolerance towards a variety of organic molecules, we explored the possibility of using lipases for carrying the aminolysis of esters. The use of lipases to catalyse amide bond formation is a mild and an interesting alternative to conventional methods using proteases, because lipases can act as catalysts in low hydrated (dry) organic solvents exhibiting wide sub- strate preference, high enantioselectivity and very low amidase activity. a-Haloamides constitute an important class of com- pounds, they are used as starting materials for a wide variety of compounds, such as a-lactams, dioxopiper- azines, oxazolidines and depsipeptides. 13 16 Halogen- ated amides in optically pure form are also being used as herbicides. These observations encouraged us to synthesise a- haloamides using lipases as catalysts. Gotor et al. 17 have earlier reported the Candida cylindracea lipase (CCL) catalysed enantioselective aminolysis of the esters of ( )-2-chloropropanoic acid with aliphatic as well as aromatic amines, but the reactions were carried out at 2 and 60 C with aliphatic and aromatic amines, respec- tively. In order to overcome this problem, we attempted aminolysis at a relatively more standard temperature (40 C) using porcine pancreatic lipase (PPL) and Can- dida antarctica lipase (CAL) in dierent organic sol- vents, that is DMF, tetrahydrofuran, acetonitrile, hexane, cyclohexane and diisopropyl ether. Of these, CAL in diisopropyl ether (DIPE) was found to be a better choice over PPL as no signi®cant reaction was observed with PPL. Results and Discussion We carried out the aminolysis of racemic a-haloesters, namely ( )-ethyl 2-bromopropanoate (1), ( )-ethyl 2- chloropropanoate (2) and ( )-ethyl 2-bromoheptanoate (3) with benzylamine and cyclohexylamine to obtain the corresponding enantiomerically enriched a-halogenated amides, that is ()-N-benzyl 2-bromopropanamide (4), ()-N-cyclohexyl 2-bromopropanamide (5), ()-N-ben- zyl 2-chloropropanamide (6), ()-N-cyclohexyl 2- chloropropanamide (7), ()-N-benzyl 2-bromoheptana- mide (8) and ()-N-cyclohexyl 2-bromoheptanamide (9) (Scheme 1). It has been observed that the amide synthesis was faster with benzylamine as compared to that with cyclohexylamine (Table 1). 0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(01)00006-2 Bioorganic & Medicinal Chemistry 9 (2001) 1345±1348 *Corresponding author. Tel.: +91-11-725-6555; fax: +91-11-725- 7206; e-mail: vsparmar@bol.net.in