Chemoenzymatic Preparation of 1‐Heteroarylethanamines of Low Solubility

Abstract

Both enantiomers of biologically and pharmaceutically interesting benzofuran‐, benzothiophen‐, and phenylfuran‐based 1‐heteroarylethanamines were prepared at close to theoretical yields by using Candida antarctica lipase B (Novozym 435) catalyzed (R)‐selective N‐acylation with isopropyl butanoate (enantiomeric ratio E > 200). The use of N‐methyl‐2‐pyrrolidinone (NMP) as a cosolvent (1:30) in isopropyl butanoate solved the problem of low solubility of the compounds. Instability of the heterocyclic ring systems against traditional acid‐ and base‐catalyzed hydrolysis was solved by using Candida antarctica lipase A as a commercial CAL‐A‐CLEA preparation for deprotection of the N‐acylated (R) enantiomers in water. The slow, highly enantioselective (E > 200) hydrolyses of racemic butanamides was also observed in the presence of Novozym 435.

Lipase-Catalyzed Kinetic Resolution of 1-(2-Hydroxycyclohexyl)Indoles in Batch and Continuous-Flow Systems

“…The high enantiomer selectivity of CaLA with rac-2a (E »200) is also noteworthy, because in other KRs of various secondary alcohols this lipase was not particularly selective. 36,69,70 With CaLB, adsorbed on acrylic resin (Entry 1) was much more active but similarly selective than when adsorbed onto phenyl silica (Entry 10). Surprisingly, the lipase from Burkholderia cepacia exhibited no activity as lyophilised powder (Amano PS) or when adsorbed on octyl-grafted silica gel (data not shown in Table 1), whereas excellent enantiomeric excess values and conversions were observed when it was covalently attached to acrylic resin (Entry 2).…”

“…Alcohols and amines are the most thoroughly investigated substrates in KR and DKR. [29][30][31][32][33][34][35][36][37][38] The production of chiral alcohols brought in 2002 more than 7 billion dollars in revenues worldwide and this was forecasted to be 14.9 billion dollars by the year 2009. 39 Although a tremendous number of biocatalytic reactions have been studied, [16][17][18][20][21][22][23][24][25][26] the operational parameters reported for most of them seem to be rather suboptimal.…”

How the mode of Candida antarctica lipase B immobilization affects the continuous-flow kinetic resolution of racemic amines at various temperatures

“…As an important tool for enantioselective syntheses, biocatalysis has become a widely used technology [4][5][6]. Recently attention turned to the kinetic resolution of racemic amines [7][8][9][10][11][12]. Hydrolases have long been used for the kinetic resolution of racemic alcohols and carboxylic acids.…”

Acylation of β‐Amino Esters and Hydrolysis of β‐Amido Esters: Candida antarctica Lipase A as a Chemoselective Deprotection Catalyst

“…Apart from the different functions of serine hydrolase enzymes, their catalytic triad, consisting of Ser, His and Asp (or Glu) residues, provides them with the potential to catalyse reactions by the formation and cleavage of both ester and amide bonds through similar reaction mechanisms. However, only restricted number of lipases (lipases from Candida rugosa , Aspergillus niger, Rhizomucor miehei and Pseudomonas stutzeri , Pseudomonas aerigunosa , and lipases A (CAL‐A), and B (CAL‐B)– from Candida antarctica ) have been reported to cleave amide bonds, although usually very slowly. The mechanistic difference between the two enzyme types was previously proposed to reside in the transition‐state‐stabilising hydrogen bond at the amide hydrogen of endopeptidases, which is lacking in lipases…”

“…CAL‐A is a chemoselective N‐acylation catalyst, for instance, for the acylation of ethyl 3‐aminobutanoate with carboxylic acid esters, whereas many other lipases tend to form multiple products through both N‐acylation and interesterification . As CAL‐A has already shown interesting amidase activity,, the present paper focuses on attaining a deeper insight into the utility of CAL‐A on this activity. CAL‐A was previously shown to contain two active forms, the native enzyme and the one possibly lacking the active site flap that usually restricts access to the active site.…”