A lipase‐catalyzed process for green synthesis of temsirolimus

Abstract

Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma that can be prepared using enol acyl donors, which is not favorable in process development. An improved enzymatic process to prepare temsirolimus has been developed employing lipase‐catalyzed regioselective acylation of rapamycin with environmentally friendly acyl donors. After screening of common commercial lipases and none‐enol acyl donors, it was found that p‐nitrophenyl 2,2,5‐trimethyl‐1,3‐dioxane‐5‐carboxylate reacted as efficient acyl donor when catalyzed by immobilized Thermomyces lanuginose lipase. By optimizing the process conditions (i.e., reaction temperature, solvents, and additives), the reaction time was significantly shortened while the reaction conversion reached 95.4% in methyl tert‐butyl ether after 48 h at 50°C using the new acyl donors. This work demonstrated a cost‐effective, efficient, and scalable process to synthesize temsirolimus.

Late-stage diversification of bacterial natural products through biocatalysis

“… Enzymatic esterification of rapamycin at 42-hydroxyl position in the presence of one of the following lipases: Novozym 435, lipase PS-C “Amano” II, lipase PS-D “Amano” I and (A) vinyl acetate, vinyl propionate, vinyl 1-chloroacetate, vinyl crotonate, vinyl benzoate and vinyl decanoate ( Gu et al, 2005 ) (B) succinic anhydride in toluene ( Gu et al, 2005 ), (C) divinyl adipate in TBME in the first step and acetonitrile in the second step ( Gu et al, 2005 ). Biocatalytic synthesis of temsirolimus using (D) cyclic methylborate protected vinyl ester in the first step, and alcoholic solvents such as MeOH, EtOH, 2-methylpentane-2 or -5-diol for the deprotection in the second step ( Gu et al, 2005 ), (E) ketal-protected vinyl esters in the first step, and a subsequent acid-catalyzed deprotection ( Ju et al, 2015 ). (F) Glycosylation of rapamycin using glycosyltransferases BsGT-1 and UDP-Glc as the sugar donor with three possible products ( Zhang et al, 2020 ).…”

“…In another chemo-enzymatic strategy for obtaining temsirolimus ( Figure 4E ), 1 g of rapamycin was reacted with ketal-protected vinyl esters as acyl donors using Thermomyces lanuginose lipase (Immozyme Tll) in TBME for 48 h at 50°C ( Ju et al, 2015 ). Through the optimization of the reaction conditions, including temperature, solvent and additives, the reaction of 6 acyl donors was optimized to achieve yields up to 95.4%.…”

Expanding the Substrate Scope of Acyltransferase LovD9 for the Biosynthesis of Statin Analogues

“…[14] On the other hand, pnitrophenyl (pNP) esters are also normally cheaper than classical enzyme acyl donors such as acyl-CoA derivatives, and they can be easily generated from commercially available carboxylic acids through a very efficient procedure using p-nitrophenyl chloroformate. [15,16] pNP esters have been used as acyl donors for the lipase-catalyzed synthesis of anticancer drug temsirolimus [17] as well as for the synthesis of ethyl acetate catalyzed by acyltransferases. [18] In this study we have selected both vinyl and pNP esters with different substitution patterns as potential substrates for the acyl-transfer reaction catalyzed by LovD9.…”