Kinetic Resolution of Racemic 1-Heteroarylalkanols by Asymmetric Esterification Using Diphenylacetic Acid with Pivalic Anhydride and a Chiral Acyl-transfer Catalyst

Abstract

A variety of optically active 1-heteroarylalkanols and their esters, which include heteroaromatic moieties, such as 2-furyl, 2-thienyl, 3-thienyl, 2-thiazoyl, 2-benzothiazoyl, and 2-benzoxazoyl groups, are efficiently produced by a novel asymmetric esterification. The transition states that form the desired (R)-esters from the (R)-1-heteroarylalkanols are determined by DFT calculations, and the structural features of these transition states are systematically discussed.Optically active 1-heteroarylalkanols are commonly utilized as chiral building blocks in pharmaceutical and agrochemical industries to provide valuable drugs via asymmetric synthesis. Several useful enzymatic methods for preparing chiral 1-heteroarylalkanols are available today for these purposes.1 To the best of our knowledge, however, a general nonenzymatic method for the kinetic resolution (KR) of the racemic 1-heteroarylalkanols has not yet appeared until now. In order to expand the synthetic utilities of the chiral 1-heteroarylalkanol derivatives, we planned to develop a nonenzymatic method for the production of the chiral molecules starting from racemic substrates using the KR of (R)-and (S)-1-heteroarylalkanols.We have reported the first asymmetric esterification 2,3 of racemic benzylic alcohols with free carboxylic acids via the formation of the mixed anhydrides in situ using carboxylic anhydrides as coupling reagents and chiral acyl-transfer catalysts, such as (S)-tetramisole and (R)-benzotetramisole ((R)-BTM), which were introduced by Birman et al. 4 Recently, we also achieved the KR of racemic 2-hydroxyalkanoates 5 with diphenylacetic acid using pivalic anhydride in the presence of (R)-BTM. During our examination of solvent effects, it became apparent that diethyl ether is a suitable media for the KR of racemic alcohols to improve both the reactivity and the selectivity.Furthermore, we successfully determined several preferable transition states to form the desired chiral (R)-diesters from (R)-2-hydroxyesters using (R)-BTM, 5 and the optically active bis-(1-naphthyl)methyl (R)-esters from (R)-2-arylpropanoic acids 3b using (R)-BTM based on theoretical calculations from density functional theory (DFT). 6 The transition state ts-(R)-A in Figure 1 presents the most stable structure forming methyl (R)-2-acetyloxypropanoate from methyl (R)-lactate by reaction with acetic anhydride and (R)-BTM. It was revealed that this transition state is strongly stabilized by the attractive interaction between oxygen in the ester carbonyl group and the positive electronic charge on the face of the dihydroimidazolium salt during the bond-forming step. Based on our investigation of the reaction mechanism during the BTM-mediated acyl-transfer catalysis, we also disclosed the preferable transition state ts-(R)-B to provide (R)-1-phenylethyl acetate from (R)-1-phenylethanol by the reaction with acetic anhydride and (R)-BTM. It is apparently observed that the aromatic ring in (R)-1-phenylethanol is almost parallel to the horizontal plane of the conjugated aroma...

Kinetic Resolution of Secondary Alcohols Using Amidine-Based Catalysts

“…The results obtained with Cl-PIQ 2 and BTM 3 were rather modest (entries 8 and 9). While we have made no attempt at optimization in these cases, a recent study by Shiina et al 7c has demonstrated that good to excellent enantioselectivities can be obtained in BTM-catalyzed KR of similar substrates using mixed diphenylacetic-pivalic anhydride as the acylating agent.…”

“…More elaborate acylating agents have not been studied systematically in our group due to their higher cost. However, recent studies by Shiina 7b,c indicate that the use of diphenylacetic-pivalic anhydride often results in dramatically increased selectivity factors. Overall, BTM 3 is the most enantioselective of all ABCs developed to date in the KR of benzylic and propargylic alcohols, as well as several other applications described elsewhere.…”

Isothiourea‐Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols

“…The optimal conversion and high selectivity obtained using diphenylacetic anhydride 7 o , and the lack of reactivity using pivalic anhydride 7 c , presented the possibility of using the mixed anhydride 2,2‐diphenylacetic pivalic anhydride 7 r . Mixed anhydrides have been reported to be advantageous in some cases for the KR of point chiral secondary alcohols ,,,,,,,. Generating the mixed anhydride in situ from diphenylacetic acid and pivalic anhydride provided a KR protocol that gave excellent selectivity ( s =50–60) but inconsistent reaction conversion in our hands ( c =8–42 %) .…”

An Enantiodivergent Synthesis of (+)‐ and (−)‐Centrolobines by Asymmetric Esterification Catalyzed by (R)‐(+)‐N‐Methylbenzoguanidine ((R)‐NMBG)

“…In a different approach, we recently reported the kinetic resolution of racemic alcohols with achiral carboxylic acids by asymmetric esterification. [3] This reaction proceeded by the formation of a mixed anhydride using carboxylic anhydrides in situ as coupling reagents in the presence of chiral acyltransfer catalysts. As the desired chiral carboxylic esters (R)-iv (R 3 = any alkyl group) were obtained directly in one step from the condensation of alcohols rac-i with free carboxylic acids, it was anticipated that the protocol could be an alternative means by which to achieve asymmetric acylation for the synthesis of natural product derivatives (Scheme 1).…”