Kinetic Resolution of the Racemic 2‐Hydroxyalkanoates Using the Enantioselective Mixed‐Anhydride Method with Pivalic Anhydride and a Chiral Acyl‐Transfer Catalyst

Abstract

A variety of optically active 2-hydroxyalkanoates and the corresponding 2-acyloxyalkanoates are produced by the kinetic resolution of racemic 2-hydroxyalkanoates by using achiral 2,2-diarylacetic acid with hindered carboxylic anhydrides as the coupling reagents. The combined use of diphenylacetic acid, pivalic anhydride, and (+)-(R)-benzotetramisole ((R)-BTM) effectively produces (S)-2-hydroxyalkanoates and (R)-2-acyloxyalkanoates from the racemic 2-hydroxyalkanoates (s-values=47-202). This protocol directly provides the desired chiral 2-hydroxyalkanoate derivatives from achiral diarylacetic acid and racemic secondary alcohols that do not include the sec-phenethyl alcohol moiety by using the transacylation process to generate the mixed anhydrides from the acid components with bulky carboxylic anhydrides under the influence of the chiral acyl-transfer catalyst. The transition state that provides the desired (R)-2-acyloxyalkanoate from (R)-2-hydroxyalkanoate included in the racemic mixture is disclosed by DFT calculations, and the structural features of the transition form are also discussed.

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

“…The spontaneous formation of this stable stacking structure due to ³cation interaction is easily anticipated according to the pioneering theoretical analysis of the transition state to provide (R)-1-phenylethyl acetate using (R)-CF 3 -PIP, a chiral acyltransfer catalyst, reported by Houk, Birman, et al 8 The dihedral angle ª (O1C2C3C*cat) in ts-(R)-A is ¹12.5°and it clearly suggests that the C=O group in the ester moiety and the plane surface of the conjugated aromatics in the dihydroimidazolium salt nearly cross at right angles. 5 On the other hand, the dihedral angle ª (C1C2C3C*cat) in ts-(R)-B is 89.6°, so that the structure of ts-(R)-B includes the stacking correlation between the aromatic ring in (R)-1-phenylethanol and the plane surface of the conjugated aromatics in the dihydroimidazolium salt.In this communication, we report the novel KR of a variety of racemic 1-heteroarylalkanols using diphenylacetic acid by the promotion of pivalic anhydride and (R)-BTM, as an application of our mixed anhydride formation technology for enantioselective esterification. The peculiar transition structures of several 1-heteroarylalkanols that will be converted into the corresponding chiral esters in the stereo-discriminating reactions are also discussed.…”

“…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.…”

“…The spontaneous formation of this stable stacking structure due to ³cation interaction is easily anticipated according to the pioneering theoretical analysis of the transition state to provide (R)-1-phenylethyl acetate using (R)-CF 3 -PIP, a chiral acyltransfer catalyst, reported by Houk, Birman, et al 8 The dihedral angle ª (O1C2C3C*cat) in ts-(R)-A is ¹12.5°and it clearly suggests that the C=O group in the ester moiety and the plane surface of the conjugated aromatics in the dihydroimidazolium salt nearly cross at right angles. 5 On the other hand, the dihedral angle ª (C1C2C3C*cat) in ts-(R)-B is 89.6°, so that the structure of ts-(R)-B includes the stacking correlation between the aromatic ring in (R)-1-phenylethanol and the plane surface of the conjugated aromatics in the dihydroimidazolium salt.…”

“…We first examined the KR of racemic 1-(2-furyl)ethanol ((«)-1a) with diphenylacetic acid (3) using pivalic anhydride and a catalytic amount of (R)-BTM in diethyl ether at room temperature for 12 h, 5 which was the standard reaction conditions established in our preliminary study (Table 1, Entry 1). Fortunately, the reaction smoothly proceeded to afford the corresponding ester (R)-2a (42% yield, 90% ee) and the recovered alcohol (S)-1a (42% yield, 57% ee) with a good s-value 9 (s = 34).…”

“…5,10 Among the several calculated transition state models forming the desired ester from the alcohol (R)-1a with int-II, the most stable structure ts-(R)-1a is depicted in Scheme 1. All of the three-dimensional structures of the transition states in Scheme 1 and Figure 2 are shown in the SI.…”