Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst

Various optically active 2-hydroxyamide derivatives are produced based on the kinetic resolution of racemic 2-hydroxyamides with a diphenylacetyl component and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst, via asymmetric esterification and acylation. It was revealed that a tertiary amide can be used with this novel protocol to achieve high selectivity (22 examples; s-value reaching over 250). The resulting chiral compounds could be transformed into other useful structures while maintaining their chirality.

To assess the generality of this novel method, various racemic 2-hydroxy-N,N-dimethylamides (±)-3a-3k with different substituted forms ( Table 2) were subjected to asymmetric esterification (condition A1) and asymmetric acylation (condition B1). When the KR of 3a-3c, 3e, and 3h, bearing normal aliphatic alkyl chains at the C-2 positions, was performed under the conditions A1 and B1, Scheme 1. Our previous result (i) and working hypothesis for the present study (ii).

Results and Discussion
To determine suitable structures for the amide moiety, the KR reactions of a variety of racemic 2-hydroxyamides were initially examined using diphenylacetyl sources derived from Ph 2 CHCO 2 H or (Ph 2 CHCO) 2 O (DPHAA) [29], catalyzed by (R)-BTM in Et 2 O at room temperature for 12 h, which were reaction conditions similar to those established in the previous study (Table 1). We first performed the KR of the secondary N-alkyl amide with methyl (±)-1a or benzyl (±)-1b and N-phenyl amide (±)-1c via asymmetric esterification. These substrates were found to be unsuitable for the reaction (Entries 1-3). Conversely, it was found that the tertiary amide yielded high s-values under the reaction conditions [30]. The KR of (±)-1d smoothly proceeded, affording the corresponding ester (R)-2d (48%; 92% ee) and the recovered alcohol (S)-1d (46%; >99% ee) with a high s-value (Entry 4; s = 254). It is noteworthy that N-methoxy-N-methylamide (±)-1e (known as Weinreb amide) [31][32][33] was successfully applied to this protocol with high synthetic utility (Entry 5; s = 156). As the tertiary amide was recognized as a suitable structure for attaining high selectivity, we subsequently performed the KR via asymmetric acylation and not via asymmetric esterification for the same reaction. As expected, high selectivity was also achieved by the reaction of (±)-1d and 1e using the asymmetric acylation protocol (Entries 6 and 7).
To assess the generality of this novel method, various racemic 2-hydroxy-N,N-dimethylamides (±)-3a-3k with different substituted forms (Table 2) were subjected to asymmetric esterification (condition A1) and asymmetric acylation (condition B1). When the KR of 3a-3c, 3e, and 3h, bearing normal aliphatic alkyl chains at the C-2 positions, was performed under the conditions A1 and B1, To assess the generality of this novel method, various racemic 2-hydroxy-N,N-dimethylamides (±)-3a-3k with different substituted forms (Table 2) were subjected to asymmetric esterification (condition A1) and asymmetric acylation (condition B1). When the KR of 3a-3c, 3e, and 3h, bearing normal aliphatic alkyl chains at the C-2 positions, was performed under the conditions A1 and B1, the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,N-dimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries [19][20][21][22]. the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries [19][20][21][22]. the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries [19][20][21][22].  the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries [19][20][21][22]. the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries 19-22). the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries 19-22). the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries 19-22). the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries 19-22). the reaction successfully proceeded with high s-values in all cases. Asymmetric esterification (condition A1) tended to show better results than asymmetric acylation (condition B1); however, it was revealed that the chiral acylation protocol was also useful for obtaining good s-values. In contrast, the reaction of (±)-3d and 3g, bearing branched aliphatic alkyl chains (R = i-Pr and c-Hex) at the C-2 positions, showed a slight decrease in selectivity, while the reaction of 3f (R = i-Bu) yielded a good s-value. We also examined several racemic ω-(tert-butyldimethylsiloxy)-2-hydroxy-N,Ndimethylamide derivatives (±)-3i-3k, having different methylene lengths, as shown in  It was found that the selectivity of the KR of (±)-3i was somewhat lowered by the influence of the siloxy group at the C-3 position (Entries 17 and 18). Other reactions yielded high s-values, regardless of the length of the alkyl chains possessing tert-butyldimethylsiloxy groups under the conditions A1 and B1 (Entries 19-22). Furthermore, we performed the KR of various racemic 2-hydroxy-Weinreb amides (±)-5a-5k with substitution patterns corresponding to the N,N-dimethylamides (±)-3a-3k using a similar protocol (Table 3). Consequently, the same tendency was observed. The KR of 2-hydroxy-Weinreb amides 5a-5c, 5e, 5f, 5h, 5j, and 5k, bearing normal aliphatic alkyl chains at the C-2 positions, exhibited high s-values in all cases under the conditions A1 and B2. Conversely, the reactions of 2- Furthermore, we performed the KR of various racemic 2-hydroxy-Weinreb amides (±)-5a-5k with substitution patterns corresponding to the N,N-dimethylamides (±)-3a-3k using a similar protocol (Table 3). Consequently, the same tendency was observed. The KR of 2-hydroxy-Weinreb amides 5a-5c, 5e, 5f, 5h, 5j, and 5k, bearing normal aliphatic alkyl chains at the C-2 positions, exhibited high s-values in all cases under the conditions A1 and B2. Conversely, the reactions of 2-hydroxy-Weinreb amides (±)-5d, 5g, and 5i, bearing branched aliphatic alkyl chains at the C-2 positions or a siloxy group at the C-3 position, exhibited decreased selectivity. Table 3. KR of 2-hydroxy-Weinreb amide ((±)-5a-5k).
To support the results of the experimental data, we calculated the transition state of each enantiomer in the KR. This was performed using density functional theory (DFT) calculations at the B3LYP/6-31G*//B3LYP/6-31G* level according to a previously reported method [23,27,28]. Initially, we conducted a theoretical study on the KR of 2-hydroxy dimethylamides (Scheme 2) [34]. Scheme 2. Calculated transition states with a kinetic resolution (KR) of (±)-3.
The most stable transition state that affords (R)-or (S)-2-acyloxy-dimethylamides is shown in Figure 1. It was found that the high selectivity attained in the present KR can be explained by the rapid transformation of (R)-3 into (R)-4 through the stabilized transition state (R)-3-TS, which consists of (R)-3 and the isothiouronium salt derived from the mixed anhydride and (R)-BTM. The formation of a C-O bond (between carbonyl carbon of the acid component and oxygen of the hydroxy group) at a distance of 2.086 Å is accompanied by the coordination of oxygen in the carbonyl moiety to hydrogen at the C-2 position of the 2-hydroxydimethylamide at a distance of 2.342 Å, as shown in Figure 1. It was further observed that the length of the cleaved O-H bond (between oxygen and Scheme 2. Calculated transition states with a kinetic resolution (KR) of (±)-3.
The most stable transition state that affords (R)-or (S)-2-acyloxy-dimethylamides is shown in Figure 1. It was found that the high selectivity attained in the present KR can be explained by the rapid transformation of (R)-3 into (R)-4 through the stabilized transition state (R)-3-TS, which consists of (R)-3 and the isothiouronium salt derived from the mixed anhydride and (R)-BTM. The formation of a C-O bond (between carbonyl carbon of the acid component and oxygen of the hydroxy group) at a distance of 2.086 Å is accompanied by the coordination of oxygen in the carbonyl moiety to hydrogen at the C-2 position of the 2-hydroxydimethylamide at a distance of 2.342 Å, as shown in Figure 1. It was further observed that the length of the cleaved O-H bond (between oxygen and hydrogen in the hydroxyl group) was 1.356 Å. A frequency analysis of (R)-3-TS revealed that the nucleophilic attack of the alcohol to the carbonyl group and the deprotonation of the hydroxyl group with the pivalate anion proceeded via a concerted reaction mechanism because the C-O bond-forming step and the O-H bond-cleaving process occurred simultaneously.
An attractive interaction occurred between oxygen in the amide carbonyl group and the positive electronic charge on the surface of the thiouronium salt, together with coordination of oxygen in the pivalate anion to hydrogen in the hydroxyl group (1.109 Å) and hydrogen at the C-2 position of the dihydroimidazolium salt (2.964 Å). However, complexation of the thiouronium salt with (R)-2-hydroxydimethylamide ((R)-3a), an enantiomer of (S)-2-hydroxydimethylamide ((S)-3a), produced an unstable structure, i.e., (S)-3a-TS; thus, the formation of (S)-3a-TS proceeded slowly due to an energy gap of 4.02 kcal/mol.

Preferable transition structure ((R)-3a-TS)
Erel = 0.00 kcal/mol Unfavorable transition state structure ((S)-3a-TS) Erel = 4.02 kcal/mol We performed further calculations on the KR of 2-hydroxy-Weinreb amides (Scheme 3). The most stable transition state that affords (R)-or (S)-2-acyloxy-Weinreb amides is shown in Figure 2 [34]. It was found that the high selectivity attained in the present KR can be explained by the rapid transformation of (R)-5 to (R)-6 through the stabilized transition state (R)-5-TS, which consists of (R)-5 and the isothiouronium salt derived from the mixed anhydride and (R)-BTM. The formation of a C-O bond (between carbonyl carbon of the acid component and oxygen of the hydroxy group) at a distance of 2.080 Å is accompanied by the coordination of oxygen in the carbonyl moiety to hydrogen at the C-2 position of the 2-hydroxy-Weinreb amide at a distance of 2.311 Å, as shown in Figure 2. It was further observed that the length of the cleaved O-H bond (between oxygen and hydrogen in the hydroxy group) was 1.396 Å. A frequency analysis of (R)-5-TS revealed that the nucleophilic attack of the alcohol to the carbonyl group and the deprotonation of the hydroxyl group with the pivalate anion proceeded via a concerted reaction mechanism as for the reaction with the 2-hydroxy dimethylamide. electronic charge on the surface of the thiouronium salt, together with coordination of oxygen in the pivalate anion to hydrogen in the hydroxyl group (1.088 Å) and hydrogen at the C-2 position of the dihydroimidazolium salt (2.928 Å). However, complexation of the thiouronium salt with (R)-2hydroxy-Weinreb amide ((R)-5a), an enantiomer of (S)-2-hydroxy-Weinreb amide [(S)-5a], produced an unstable structure, i.e., (S)-5a-TS; thus, the formation of (S)-5a-TS proceeded slowly due to an energy gap of 3.24 kcal/mol. Scheme 3. Calculated transition states with a KR of (±)-5. Scheme 3. Calculated transition states with a KR of (±)-5.

General Information
Optical rotations were determined using a Jasco P-1020 polarimeter. Infrared (IR) spectra were obtained using a Jasco FT/IR-4600 Fourier transform infrared spectrometer. Proton and carbon

General Information
Optical rotations were determined using a Jasco P-1020 polarimeter. Infrared (IR) spectra were obtained using a Jasco FT/IR-4600 Fourier transform infrared spectrometer. Proton and carbon nuclear magnetic resonance ( 1 H and 13 C NMR) spectra were recorded with chloroform (in CDCl 3 ) on the following instruments: JEOL JNM-AL500 ( 1 H at 500 MHz and 13 C at 125 MHz). Mass spectra were determined by a Bruker Daltonics micrOTOF focus (ESI-TOF) mass spectrometer. Thin layer chromatography was performed on Wakogel B5F. HPLC was performed with a Hitachi LaChrom Elite system composed of the Organizer, L-2400 UV Detector, and L-2130 Pump.