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

Abstract

A simple chemoenzymatic method for the preparation of the enantiomers of 4-benzyl-b-lactam (4-benzylazetidin-2-one) from allylbenzene has been described. The enantiomers of this key intermediate have been used to produce the corresponding enantiomers of b-phenylalanine and N-Boc-protected bphenylalanine amide through the simple cleavage of the lactam ring by acid-catalyzed hydrolysis and by ammonolysis, respectively. Burkholderia cepacia lipase-catalyzed kinetic double resolution techniques were responsible for achieving enantiopurity in the products. This was performed through the acylation of N-hydroxymethylated b-lactam followed by the butanolysis of the obtained (S)-ester. Direct lipase-catalyzed cleavage of the b-lactam ring has also been studied.

Enantioselective acylation of alcohols with fluorinated β-phenyl-β-lactams in the presence of Burkholderia cepacia lipase

“…The observed opposite enantiopreference for the ring opening of the b-lactam and for the hydrolysis of the corresponding b-amino ester in the case of lipase PS-catalysis is in agreement with that which was observed earlier for 4-benzyl-2-azetidinone and CAL-B catalysis. 13 Interestingly, when rac-4 was incubated in the presence of methanol (5 equiv) and the lipase PS preparation, its hydrolysis in TBME was totally suppressed.…”

“…12 In our previous studies of the reaction of 4-benzyl-2-azetidinone in the presence of methanol and CAL-B in dry organic solvents, two important observations were evident: (1) the added methanol and the water in the enzyme preparation served as competitive nucleophiles for ring opening; (2) and the methyl ester produced by the action of methanol was further enzymatically hydrolyzed, the enantiopreference being opposite to that observed for the hydrolysis of the b-lactam ring. 13 Moreover, there was experimental evidence that the lipase PS preparation (lipase adsorbed on Celite in the presence of sucrose) 14 in dry organic solvents exposed the b-lactam to hydrolysis less than it did in the CAL-B preparation. This is in accordance with the observation that the lipophilic polymethacrylate carrier of Novozym 435 easily releases the attached water, giving hydrolysis of hydrolyzable compounds.…”

Chemoenzymatic preparation of fluorine-substituted β-lactam enantiomers exploiting Burkholderia cepacia lipase

“…14 N-Hydroxymethylation of the b-lactams with paraformaldehyde under ultrasound easily afforded racemic 2a-c as substrates for lipase-catalyzed O-acylation (Scheme 1). 14,15 There are two key steps in the chemoenzymatic synthesis of the b-lactam enantiomers 1a-c: lipase-catalyzed kinetic resolution of rac-2a-c through step 2 and N-deprotection of enantiomers 2a-c through step 3 (Scheme 1). When enzymatic enantioselectivity does not provide excellent results, a double resolution technique with the minimal number of reaction steps proved to be the best choice for the preparation of both enantiomers of a racemic alcohol.…”

“…12 Another widely used lipase-catalyzed kinetic resolution method exploits N-hydroxymethylated b-lactams as racemic alcohols for O-acylation, including the preparation of the enantiomers of rac-1c. 9,10,14,15 The benefit of the latter method is that the kinetic resolution leaves the b-lactam ring of both enantiomers untouched.…”

Enzymatic resolution of tetrahydroisoquinoline derivatives in batch and continuous-flow systems

“…More lipase PS-catalysed resolutions are to be found in the literature for Nhydroxymethylated β-lactams, with moderate E (< 94). [52][53][54][55] A lipase PS-catalysed dynamic kinetic resolution method for primary alcohols (±)-33 and (±)-49-56 was presented by Bäckvall and co-workers. 56 The reactions were performed under an argon atmosphere in the presence of 4-nitrophenyl 3-[4-trifluoromethyl-phenyl]propanoate and Shvo's ruthenium catalyst in toluene at 80 °C.…”