Molecular Basis for the Enantioselective Ring Opening of β‐Lactams Catalyzed by Candida antarctica Lipase B

Abstract

Lipase B from Candida antarctica (CAL-B) catalyzes the slow, but highly enantioselective (E >200), ring-opening alcoholysis of two bicyclic and two 4-aryl-substituted b-lactams. Surprisingly, the rate of the reaction varies with the nature of the alcohols and was fastest with either enantiomer of 2-octanol. A 0.5-g scale reaction with 2-octanol as the nucleophile in diisopropyl ether at 60 8C yielded the unreacted b-lactam in 39 ± 46% yield (maximum yield is 50%) with ! 96% ee. The product b-amino acid esters reacted further by polymerization (not isolated or characterized) or by hydrolysis due to small amounts of water in the reaction mixture yielding bamino acids (7 ± 11% yield, ! 96% ee). The favored enantiomer of all four b-lactams had similar 3-D orientation of substituents, as did most previously reported b-lactams and b-lactones in similar ringopening reactions. Computer modeling of the ring opening of 4-phenylazetidin-2-one suggests that the reaction proceeds via an unusual substrate-assisted transition state, where the substrate alcohol bridges between the catalytic histidine and the nitrogen of the b-lactam. Computer modeling also suggested that the molecular basis for the high enantioselectivity is a severe steric clash between Ile189 in CAL-B and the phenyl substituent on the slow-reacting enantiomer of the b-lactam.

A New Route to Enantiopure β‐Aryl‐Substituted β‐Amino Acids and 4‐Aryl‐Substituted β‐Lactams through Lipase‐Catalyzed Enantioselective Ring Cleavage of β‐Lactams

“…The absolute configurations in the cases of 21, 22, 23, 33 and 35 were assigned by comparing the [a] values with the literature data [9,11] (see Table 3 and Experimental Section), while for 17, 18 and 20 the analyzed chromatograms indicated the same enantiopreference for Lipolase.…”

“…96%) but in low yields (7 -11%). [9] We recently developed a very simple and efficient new enzymatic hydrolysis method for the enantioselective (E > 200) ring opening of alicyclic b-lactams (the synthesis of cispentacin, for instance). [10] A great advantage of this method is that the lactam ring does not necessarily need to be activated and the product b-amino acid and b-lactam are obtained in good chemical yields ( !…”

Enzyme‐Catalyzed Ring‐Opening Polymerization of Unsubstituted β‐Lactam

“…[14] In this communication, we present a new enzymatic route using Candida antarctica lipase B immobilized as novozyme 435 to produce unbranched poly(b-alanine) starting from unsubstituted 2-azetidinone. Ring-opening of substituted b-lactams with lipase was reported before [15] but not with the aim to polymerize. The synthesis of poly(b-alanine) by Candida antarctica lipase B immobilized as novozyme 435 catalyzed ring-opening of 2-azetidinone is reported.…”

Lipase‐Involved Strategy to the Enantiomers of 4‐Benzyl‐β‐Lactam as a Key Intermediate in the Preparation of β‐Phenylalanine Derivatives

“…[22] In the present paper, the chemoenzymatic preparation of the enantiomers of 4-benzyl-b-lactam [(R)-and (S)-1] is described. For this purpose, previously introduced lipase-catalyzed methods, lipase-catalyzed ringopening of the lactam ring in rac-1 (Scheme 2), [10,12] lipase-catalyzed asymmetric acylation of N-hydroxymethylated b-lactam rac-2 (Scheme 3) [16] and lipase-catalyzed asymmetric alcoholysis of the corresponding ester rac-3 (Scheme 4), [23] have been studied. The obtained (R)-and (S)-1 have been further used as key intermediates for the preparation of enantiopure b 3 -amino acids (R)-and (S)-4, N-Boc-protected b-lactam products (R)-and (S)-5 and N-Boc-protected amino amides (R)-and (S)-6 (Scheme 1).…”