Regioselective enzymatic acylation of complex natural products: expanding molecular diversity

Abstract

Enzymatic catalysis has become a common tool in both academia and industrial chemistry. The efforts of chemists over recent decades have led to the rationalization of the mechanism of action of biocatalysts, which have been routinely incorporated into many synthetic sequences. Nowadays, a further step consists in expanding the application of enzymes to the modification of complex molecular scaffolds common to many pharmaceutical leads isolated from nature. Regioselective enzymatic acylation is a process which has been profitably applied for this purpose in recent times, leading to new drugs with improved activity, stability and pharmacokinetic properties. This tutorial review provides an overview of this subject employing two classes of enzymes, hydrolases and acyltransferases, in the recently concluded decade although some representative older studies are commented upon, if required. We shall place special emphasis on those examples in which the novel acylated derivatives have improved the activity or properties of the parental molecules.

Biocatalysis of Cycloastragenol by Syncephalastrum racemosum and Alternaria alternata to Discover Anti‐Aging Derivatives

“…Thus,w ef ed 4.0 go fc ycloastragenol (CA, 1)i nto S. racemosum cultures and 1.9 gi nto A. alternata in this study, respectively.A fter 5-7 days of incubation, the culture supernatants were extracted with ethyla cetate.T he extractsw erec oncentrated, and were then separated by repeated column chromatographya nd semi-preparative HPLCt oy ield 27 compounds (2-28), including 16 products( 2 - 13 CNMR spectral data are given in Table S1 and TableS 2i nt he Supporting Information.…”

“…[18] In the 13 CNMR spectrum, ac arbonylr esonance appeared at d C = 210.9,a nd showedH MBC correlation with H-12( d H = 2.61) (Figure 2). Accordingly,t he signal of C-12 (d C = 51.2) was shifted downfield by 17.8 ppm compared to that of CA.…”

“…Four biotransformed products (9-12)s howed resonancesc orresponding to ac arbonyl group (d C =~170) and am ethyl group (d C =~21) in their 13 CNMR spectra.T heys hould contain an acetoxy group in the molecules.C ompounds 9 and 11 were identified as (20R,24S)-3b,16b,25-trihydroxy-6a-acetoxy-20,24-epoxy-cycloartane and (20R,24S)-6a,16b,25-trihydroxy-3b-acetoxy-20,24-epoxy-cycloartane,r espectively,byc omparison with the literature report. [19] Compound 10 had the molecular formula of C 32 H 50 O 6 on the basis of its HR-ESI-MSd ata( m/z = 553.3492, calcd.…”

“…[10] Biocatalysis is an alternative approach for structural modification,e specially for structurally complex natural products. [11][12][13] Particularly,m icrobial transformation has provedt ob ep owerful in the structural diversification of triterpenoids. [14,15] Af ew studies have been conducted to obtain CA derivatives by microbial transformation.K uban et al found that Cunninghamella blakesleeana NRRL1369c ould metabolize CA into an ew carbon skeleton through9,19-cyclopropane ring cleavage and methyl group migration.…”

Organocatalytic Site-Selective Acylation of 10-Deacetylbaccatin III

“…Treatment of 1 with acetic anhydride in the presence of catalyst 6 selectively provided baccatin III (2) in 89% yield (entry 1). Thus, one-step conversion of 1 into 2 was achieved by organocatalytic site-selective acylation.…”