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Article

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

by
Takatsugu Murata
1,
Tatsuya Kawanishi
1,
Akihiro Sekiguchi
1,
Ryo Ishikawa
1,
Keisuke Ono
1,
Kenya Nakata
2,* and
Isamu Shiina
1,*
1
Department of Appliaed Chemistry, Faculty of Science, Tokyo University of Science, Tokyo 162-8601, Japan
2
Graduate School of Natural Science and Technology, Shimane University, Shimane 690-8504, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(8), 2003; https://doi.org/10.3390/molecules23082003
Submission received: 23 July 2018 / Revised: 6 August 2018 / Accepted: 7 August 2018 / Published: 10 August 2018
(This article belongs to the Special Issue Stereogenic Centers)
Browse Figures
Versions Notes

Abstract

:
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.

1. Introduction

Optically active 2-hydroxyamide derivatives are frequently utilized as chiral building blocks not only for synthesizing biologically active compounds [1,2,3,4], but also for preparing asymmetric catalysts and chiral auxiliaries [5,6]. Consequently, considerable effort has been devoted toward developing efficient methods for synthesizing these compounds, including enzymatic [7] and chemical transformations [8,9,10]. For the purpose of providing chiral alcohols, the kinetic resolution (KR) of racemic alcohols by asymmetric acylation using organocatalysis is widely used as one of the most effective methods [11,12,13]. However, to the best of our knowledge, a general method for the kinetic resolution of racemic 2-hydroxyamide derivatives has not been reported to date. We recently accomplished the first KR of racemic alcohols with achiral carboxylic acids and of racemic carboxylic acids with achiral alcohols by asymmetric esterification [14,15,16,17,18,19,20,21,22,23,24,25,26,27] via the in situ formation of a mixed anhydride using carboxylic anhydrides as coupling reagents combined with chiral acyl-transfer catalysts. Furthermore, KR of racemic 2-hydroxyalkanoates with diphenylacetic acid was achieved using pivalic anhydride in the presence of (R)-benzotetramisole [27,28] ((R)-BTM; Scheme 1; (i)). Therefore, it was hypothesized that this KR protocol could be similarly applied to 2-hydroxyamide derivatives (Scheme 1; (ii)). In this article, we report the novel KR of various racemic 2-hydroxyamide derivatives using a diphenylacetyl component as an acyl source, catalyzed by (R)-BTM.

2. 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 Ph2CHCO2H or (Ph2CHCO)2O (DPHAA) [29], catalyzed by (R)-BTM in Et2O 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, 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 Entries 17–22. 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-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.
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].
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.
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.
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 (1.088 Å) and hydrogen at the C-2 position of the dihydroimidazolium salt (2.928 Å). However, complexation of the thiouronium salt with (R)-2-hydroxy-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.
Finally, we attempted to transform the obtained chiral 2-hydroxyamides and their esters based on the KR to demonstrate the synthetic utility of this method (Scheme 4). Reduction of chiral 2-hydroxy-N,N-dimethylamide (S)-1d with BH3·SMe2 in THF afforded amino alcohol (S)-7 in good yield with no loss of chirality (i). When 2-acyloxy-N,N-dimethylamide (R)-2d was subjected to solvolysis with K2CO3 in MeOH, 2-hydroxyamide (R)-1d was produced in good yield (ii). Treatment of 2-hydroxy-Weinreb amide (S)-5a and 2-ayloxy-Weinreb amide (R)-6a with PhMgBr afforded the corresponding 2-hydroxyketone 8 with opposite stereochemistry (iii) and (iv), respectively.

3. Materials and Methods

3.1. 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 (1H and 13C NMR) spectra were recorded with chloroform (in CDCl3) on the following instruments: JEOL JNM-AL500 (1H at 500 MHz and 13C 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.

3.2. Typical Procedure for the Preparation of Optically Active 2-Hydroxy-dimethylamides 2d and 4a–4k

Condition A; Asymmetric esterification of racemic 2-hydroxy-dimethylamide ((±)-1d) with diphenylacetic acid by using Piv2O in the presence of (R)-BTM was described (Table 1, entry 4): To a solution of racemic 2-hyroxy-dimethylamide ((±)-1d) (41.5 mg, 0.20 mmol) in Et2O (1.0 mL, 0.20 M) at room temperature were successively added diphenylacetic acid (31.8 mg, 0.15 mmol), Piv2O (36.5 μL, 0.18 mmol), i-Pr2NEt (62.7 μL, 0.36 mmol) and (R)-BTM (2.5 mg, 0.01 mmol). The reaction mixture was stirred for 24 h at the same temperature and then it was quenched with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4. After filtration of the mixture and evaporation of the solvent, the crude product was purified by preparative thin layer chromatography on silica to afford the corresponding optically active ester (R)-2d (38.2 mg, 48% yield, 92% ee) and the recovered optically active alcohol (S)-1d (19.1 mg, 46% yield, 99% ee) [s = 254, Table 1, Entry 4].
Condition B; Asymmetric esterification of racemic 2-hydroxy-dimethylamide ((±)-1d) with diphenylacetic anhydride in the presence of (R)-BTM was described (Table 1, entry 6): To a solution of racemic 2-hydroxy-dimethylamide ((±)-1d) (41.5 mg, 0.20 mmol) in Et2O (1.0 mL, 0.2 M) at room temperature were successively added diphenylacetic anhydride (48.8 mg, 0.12 mmol), i-Pr2NEt (20.9 μL, 0.12 mmol) and (R)-BTM (2.5 mg, 0.011 mmol). The reaction mixture was stirred for 24 h at the same temperature and then it was quenched with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4. After filtration of the mixture and evaporation of the solvent, the crude product was purified by preparative thin layer chromatography on silica to afford the corresponding optically active ester (R)-2d (37.4 mg, 47% yield, 91% ee) and the recovered optically active alcohol (S)-1d (20.7 mg, 50% yield, 98% ee) [s = 95, Table 1, Entry 6].
(S)-2-Hydroxy-N-methyl-4-phenylbutanamide ((S)-1a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/20, flow rate = 1.0 mL/min): tR = 47.2 min (57.2%), tR = 54.5 min (42.8%); IR (neat): 3309, 1643, 1619, 1550 cm–1; 1H NMR (CDCl3): δ 7.33–7.22 (m, 5H, Ph), 6.85 (brs, 1H, NH), 4.15 (m, 1H, 2-H), 3.92 (d, J = 5.5 Hz, 1H, OH), 2.86 (s, 3H, NMe), 2.86–2.79 (m, 2H, 4-H), 2.24–2.12 (m, 1H, 3-H), 2.02–1.95 (m, 1H, 3-H); 13C NMR (CDCl3): δ 174.8, 141.2, 128.4, 126.0, 71.4, 36.3, 31.2, 25.7; HR MS: calcd for C12H17NO2Na [M + Na]+ 216.0995, found 216.1004.
(S)-N-Benzyl-2-hydroxy-4-phenylbutanamide ((S)-1b). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 12.3 min (42.8%), tR = 14.6 min (57.2%); IR (KBr): 3366, 3252, 1621, 1538, 1496, 1454, 732, 699 cm–1; 1H NMR (CDCl3): δ 7.37–7.18 (m, 10H, Ph), 7.02 (brs, 1H, NH), 4.46 (dd, J = 15.0, 6.0 Hz, 1H, Bn), 4.42 (dd, J = 15.0, 6.0 Hz, 1H, Bn), 4.16 (ddd, J = 8.0, 5.0, 3.5 Hz, 1H, 2-H), 3.47 (brs, 1H, OH), 2.83–2.73 (m, 2H, 4-H), 2.25–2.15 (m, 1H, 3-H), 2.04–1.94 (m, 1H, 3-H); 13C NMR (CDCl3): δ 173.8, 141.1, 137.8, 128.7, 128.4, 127.6, 127.5, 126.0, 71.5, 43.1, 36.4, 31.2; HR MS: calcd for C17H19NO2Na [M + Na]+ 292.1308, found 292.1312.
(S)-2-Hydroxy-N,4-diphenylbutanamide ((S)-1c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 8.2 min (86.6%), tR = 11.4 min (13.4%); IR (KBr): 3332, 3230, 1656, 1496, 1445, 755, 702 cm–1; 1H NMR (CDCl3): δ 8.42 (s, 1H, NH), 7.57–7.48 (m, 2H, Ph), 7.31–7.09 (m, 8H, Ph), 4.24 (ddd, J = 8.3, 4.8, 4.0 Hz, 1H, 2-H), 2.89 (brd, J = 4.0 Hz, 1H, OH), 2.82 (d, J = 8.0 Hz, 1H, 4-H), 2.81 (d, J = 9.5 Hz, 1H, 4-H) 2.32–2.22 (m, 1H, 3-H), 2.11–2.01 (m, 1H, 3-H); 13C NMR (CDCl3): δ 171.6, 140.9, 137.1, 129.1, 128.6, 128.5, 126.2, 124.6, 119.8, 72.1, 36.2, 31.3; HR MS: calcd for C16H17NO2Na [M + Na]+ 278.1151, found 278.1153.
(S)-2-Hydroxy-N,N-dimethyl-4-phenylbutanamide ((S)-1d). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 29.2 min (100.0%); IR (neat): 3457, 1738, 1498, 1456, 1045, 752, 698 cm–1; 1H NMR (CDCl3): δ 7.31–7.16 (m, 5H, Ph), 4.30 (ddd, J = 9.0, 7.5, 3.0 Hz, 1H, 2-H), 3.78 (dd, J = 7.5, 1.5 Hz, 1H, OH), 2.96 (s, 3H, OMe), 2.87–2.75 (m, 2H, 4-H), 2.80 (s, 3H, NMe), 1.91 (dddd, J = 13.5, 9.0, 8.0, 3.0 Hz, 1H, 3-H), 1.78 (dddd, J = 13.5, 9.0, 8.5, 5.0 Hz, 1H, 3-H); 13C NMR (CDCl3): δ 174.2, 141.3, 128.6, 128.4, 126.0, 66.9, 36.4, 36.1, 35.8, 31.2; HR MS: calcd for C12H17NO2Na [M + Na]+ 230.1151, found 230.1150.
(S)-2-Hydroxy-N-methoxy-N-methyl-4-phenylbutanamide ((S)-1e) (=(S)-5h). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 26.7 min (0.8%), tR = 29.6 min (99.2%); IR (neat): 3439, 1657, 1487, 1450, 753, 707 cm–1; 1H NMR (CDCl3): δ 7.36–7.19 (m, 5H, Ph), 4.38 (dd, J = 7.0, 7.0 Hz, 1H, 2-H), 3.59 (s, 3H, OMe), 3.40 (d, J = 7.0 Hz, 1H, OH), 3.24 (s, 3H, NMe), 2.88 (ddd, J = 14.0, 9.0, 5.0 Hz, 1H, 4-H), 2.83 (ddd, J = 14.0, 8.5, 8.5 Hz, 1H, 4-H), 2.16–2.05 (m, 1H, 3-H), 1.90–1.83 (m, 1H, 3-H); 13C NMR (CDCl3): δ 175.0, 141.4, 128.6, 128.3, 125.8, 67.7, 61.1, 36.1, 32.4, 31.2; HR MS: calcd for C12H17NO3Na [M + Na]+ 246.1101, found 246.1106.
(R)-2-(Diphenylacetyloxy)-N-methyl-4-phenylbutanamide ((R)-2a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 2/3, flow rate = 0.5 mL/min): tR = 23.6 min (55.9%), tR = 39.3 min (44.1%); IR (neat): 3424, 3309, 1743, 1673, 1542, 748, 709 cm–1; 1H NMR (CDCl3): δ 7.32–7.20 (m, 10H, Ph), 7.17–7.07 (m, 3H, Ph), 6.99–6.97 (m, 2H, Ph), 5.41 (brs, 1H, NH), 5.23 (dd, J = 7.0, 4.0 Hz, 1H, 2-H), 4.99 (s, 1H, CHPh2), 2.52–2.45 (m, 2H, 3-H), 2.49 (s, 3H, NMe), 2.18–2.00 (m, 1H, 4-H); 13C NMR (CDCl3): δ 170.7, 169.8, 140.6, 137.8, 137.6, 128.9, 128.7, 128.6, 128.6, 128.4, 128.3, 127.7, 127.6, 126.0, 73.9, 57.1, 33.3, 31.0, 25.7; HR MS: calcd for C26H27NO3Na [M + Na]+ 410.1727, found 410.1717.
(R)-N-Benzyl-2-(diphenylacetyloxy)-4-phenylbutanamide ((R)-2b). HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 23.1 min (58.6%), tR = 25.7 min (41.4%); IR (neat): 3308, 1744, 1677, 1496, 1451, 747, 697 cm−1; 1H NMR (CDCl3): δ 7.36–7.18 (m, 16H, Ph), 7.14–7.07 (m, 4H, Ph), 5.88 (t, J = 5.5 Hz, 1H, NH), 5.40 (dd, J = 7.3, 4.3 Hz, 1H, 2-H), 5.05 (s, 1H, 2′-H), 4.32 (dd, J = 14.8, 5.5 Hz, 1H, Bn), 4.24 (dd, J = 14.8, 5.5 Hz, 1H, Bn), 2.62 (t, J = 8.3 Hz, 2H, 4-H), 2.32–2.17 (m, 2H, 3-H); 13C NMR (CDCl3): δ 170.7, 169.2, 140.6, 137.7, 137.6, 137.6, 128.9, 128.7, 128.6, 128.6, 128.4, 128.4, 128.3, 127.7, 127.6, 127.6, 127.5, 126.1, 73.9, 57.1, 43.0, 33.4, 31.0; HR MS: calcd for C31H29NO3Na [M + Na]+ 486.2040, found 486.2031.
(R)-2-(Diphenylacetyloxy)-N,4-diphenylbutanamide ((R)-2c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 11.5 min (10.7%), tR = 25.6 min (89.3%); IR (neat): 3312, 1750, 1670, 1494, 1447, 754, 695 cm–1; 1H NMR (CDCl3): δ 7.34–7.00 (m, 21H, Ph, NH), 5.40 (dd, J = 6.8, 4.5 Hz, 1H, 2-H), 5.03 (s, 1H, 2′-H), 2.60 (t, J = 8.0 Hz, 2H, 4-H), 2.23 (m, 2H, 3-H); 13C NMR (CDCl3): δ 170.6, 167.3, 140.5, 137.7, 137.7, 136.6, 129.2, 128.8, 128.8, 128.7, 128.5, 128.5, 128.3, 127.8, 127.7, 126.1, 124.7, 119.9, 73.9, 57.2, 33.3, 31.0; HR MS: calcd for C30H27NO3Na [M + Na]+ 472.1883, found 472.1874.
(R)-2-(Diphenylacetyloxy)-N,N-dimethyl-4-phenylbutanamide ((R)-2d). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 17.9 min (4.3%), tR = 40.2 min (95.7%); IR (neat): 1737, 1663, 1496, 744, 697 cm–1; 1H NMR (CDCl3): δ 7.38–7.07 (m, 13H, Ph), 6.92–6.85 (m, 2H, Ph), 5.13 (s, 1H, 2′-H), 5.08 (dd, J = 10.0, 3.5 Hz, 1H, 2-H), 2.84 (s, 3H, OMe), 2.73 (s, 3H, NMe), 2.59 (ddd, J = 14.0, 8.5, 5.0 Hz, 1H, 4-H), 2.41 (ddd, J = 14.0, 8.5, 8.5 Hz, 1H, 4-H), 2.11 (dddd, J = 14.5, 10.0, 8.5, 5.0 Hz, 1H, 3-H), 1.88 (dddd, J = 14.5, 8.5, 8.5, 3.5 Hz, 1H, 3-H); 13C NMR (CDCl3): δ 172.3, 169.4, 140.3, 138.5, 138.4, 128.8, 128.7, 128.5, 128.4, 128.3, 127.4, 127.2, 126.2, 70.1, 56.7, 36.5, 35.9, 32.4, 31.0; HR MS: calcd for C26H27NO3Na [M + Na]+ 424.1883, found 424.1901.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N-methyl-4-phenylbutanamide ((R)-2e) (=(R)-6h). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 14.8 min (3.0%), tR = 41.3 min (97.0%); IR (neat): 1736, 1674, 1496, 1450, 741, 702 cm–1; 1H NMR (CDCl3): δ 7.51–7.19 (m, J = 13H, Ph), 7.05–6.99 (m, 2H, Ph), 5.27 (s, 1H, 2′-H), 5.19 (dd, J = 9.5, 3.5 Hz, 1H, 2-H), 3.61 (s, 3H, OMe), 3.21 (s, 3H, NMe), 2.74 (ddd, J = 14.0, 8.0, 5.0 Hz, 1H, 4-H), 2.53 (ddd, J = 14.0, 8.5, 8.5 Hz, 1H, 4-H), 2.22–2.07 (m, 2H, 3-H); 13C NMR (CDCl3): δ 172.5, 170.0, 140.3, 138.5, 138.4, 128.8, 128.8, 128.6, 128.4, 128.4, 128.3, 127.3, 127.1, 126.0, 70.8, 61.1, 56.8, 32.1, 31.7, 31.1; HR MS: calcd for C26H27NO4Na [M + Na]+ 440.1832, found 440.1852.
(S)-2-Hydroxy-N,N-dimethylpropanamide ((S)-3a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 17.3 min (5.7%), tR = 26.6 min (93.3%); IR (neat): 3417, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.41 (q, J = 6.5 Hz, 1H, 2-H), 3.82 (br s, 1H, OH) 2.95 (s, 3H, NMe), 2.94 (s, 3H, NMe), 1.27 (d, J = 6.5 Hz, 3H, 3-H); 13C NMR (125 MHz, CDCl3): δ 174.9, 64.0, 36.2, 35.8, 20.8; HR MS: calcd for C5H11NO2Na [M + Na]+ 140.0682, found 140.0684.
(S)-2-Hydroxy-N,N-dimethylbutanamide ((S)-3b). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 15.6 min (3.7%), tR = 28.2 min (96.3%); IR (neat): 3425, 1642 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.27 (m, 1H, 2-H), 3.68 (d, J = 7.5 Hz, 1H, OH), 2.96 (s, 3H, NMe), 2.94 (s, 3H, NMe), 1.67 (m, 1H, 3-H), 1.46 (m, 1H, 3-H), 0.94 (dd, J = 7.0, 7.0 Hz, 3H, 4-H); 13C NMR (125 MHz, CDCl3): δ 174.2, 68.9, 36,3, 35,7, 27,5, 9.1; HR MS: calcd for C6H13NO2Na [M + Na]+ 154.0838, found 154.0845.
(S)-2-Hydroxy-N,N-dimethylpentanamide ((S)-3c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 17.4 min (82.5%), tR = 36.2 min (17.5%); IR (neat): 3425, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.26 (m, 1H, 2-H), 3.64 (d, J = 7.0 Hz, 1H, OH), 2.90 (s, 3H, NMe), 2.89 (s, 3H, NMe), 1.52–1.47 (m, 1H, 3-H), 1.43–1.32 (m, 3H, 3-H, 4-H), 0.84 (dd, J = 7.5, 7.5 Hz, 3H, 5-H); 13C NMR (125 MHz, CDCl3): δ 174.4, 67.6, 36.7, 36.2, 35.7, 18.2, 13.6; HR MS: calcd for C7H15NO2Na [M + Na]+ 168.0995, found 168.1000.
(S)-2-Hydroxy-N,N,3-trimethylbutanamide ((S)-3d). HPLC (CHIRALPAK ID, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 8.7 min (42.8%), tR = 17.4 min (57.2%); IR (neat): 3425, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.23 (dd, J = 7.5, 2.5 Hz, 1H, 2-H), 3.56 (d, J = 7.0 Hz, 1H, OH), 2.98 (s, 3H, NMe), 2.97 (s, 3H, NMe), 1.91–1.82 (m, 1H, 3-H), 1.04 (d, J = 7.5 Hz, 3H, 4-H), 0.77 (d, J = 7.5 Hz, 3H, 4-H); 13C NMR (125 MHz, CDCl3): δ 173.9, 72.1, 36.5, 35.8, 31.2, 19.7, 15.0; HR MS: calcd for C7H15NO2Na [M + Na]+ 168.0995, found 168.0994.
(S)-2-Hydroxy-N,N-dimethylhexanamide ((S)-3e). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 13.7 min (84.7%), tR = 31.2 min (15.3%); IR (neat): 3425, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.32 (ddd, J = 7.5, 7.5, 3.5 Hz, 1H, 2-H), 3.67 (d, J = 7.5 Hz, 1H, OH), 2.98 (s, 3H, NMe), 2.96 (s, 3H, NMe), 1.64–1.56 (m, 1H, 3-H), 1.48–1.24 (m, 5H, 3-H, 4-H, 5-H), 0.88 (dd, J = 7.5, 7.0 Hz, 3H, 6-H); 13C NMR (125 MHz, CDCl3): δ 174.5, 67.9, 36.3, 35.8, 34.3, 27.1, 22.4, 13.9; HR MS: calcd for C8H17NO2Na [M + Na]+ 182.1151, found 182.1149.
(S)-2-Hydroxy-N,N,4-trimethylpentanamide ((S)-3f). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 14.6 min (89.2%), tR = 31.2 min (10.8%); IR (neat): 3425, 1642 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.35 (ddd, J = 7.0, 2.5 Hz, 1H, 2-H), 3.59 (d, J = 7.0 Hz, 1H, OH), 2.96 (s, 3H, NMe), 2.93 (s, 3H, NMe), 1.94 (ddqq, J = 2.5, 4.0, 6.0, 7.0 Hz, 1H, 4-H), 1.38 (ddd, J = 14.0, 10.0, 4.0 Hz, 1H, 3-H), 1.27 (ddd, J = 14.0, 10.0, 2.5 Hz, 1H, 3-H), 0.95 (d, J = 6.0 Hz, 3H, 5-H), 0.91 (d, J = 7.0 Hz, 3H, 5-H); 13C NMR (125 MHz, CDCl3): δ 174.9, 66.4, 43.9, 36.2, 35.8, 24.5, 23.5, 21.2; HR MS: calcd for C8H17NO2Na [M + Na]+ 182.1151, found 182.1152.
(S)-2-Cyclohexyl-2-Hydroxy-N,N-dimethylacetamide ((S)-3g). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 11.0 min (53.2%), tR = 32.8 min (46.8%); IR (KBr): 3363, 1628 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.19 (d, J = 1.5 Hz, 1H, 2-H), 3.54 (br s, 1H, OH), 2.98 (s, 3H, NMe), 2.97 (s, 3H, NMe), 1.77–1.72 (m, 2H, c-Hex), 1.62–1.60 (m, 2H, c-Hex), 1.50–1.37 (m, 3H, c-Hex), 1.26–1.05 (m, 4H, c-Hex); 13C NMR (125 MHz, CDCl3): δ 173.8, 72.0, 41.4, 36.6, 35.8, 29.8, 26.4, 26.0, 25.9, 25.5; HR MS: calcd for C10H19NO2Na [M + Na]+ 208.1308, found 208.1311.
(S)-3-(tert-Butyldimethylsiloxy)-2-hydroxy-N,N-dimethylpropanamide ((S)-3i). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 9.0 min (70.6%), tR = 13.3 min (29.4%); IR (neat): 3278, 1635 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.49 (ddd, J = 9.5, 6.0, 2.0 Hz, 1H, 2-H), 3.78 (dd, J = 10.0, 5.0 Hz, 1H, 3-H), 3.65 (d, J = 7.5 Hz, 1H, OH), 3.63 (dd, J = 10.0, 7.5 Hz, 1H, 3-H), 3.05 (s, 3H, NMe), 2.99 (s, 3H, NMe), 0.86 (s, 9H, TBS), 0.04 (s, 3H, TBS), 0.03 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3): δ 172.8, 68.7, 66.3, 36.8, 35.9, 25.8, 18.3, –5.5; HR MS: calcd for C11H25NO3SiNa [M + Na]+ 270.1496, found 270.1509.
(S)-4-(tert-Butyldimethylsiloxy)-2-hydroxy-N,N-dimethylbutanamide ((S)-3j). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 11.4 min (3.5%), tR = 25.0 min (96.5%); IR (neat): 3363, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.55–4.51 (m, 1H, 2-H), 3.85 (ddd, J = 10.0, 10.0, 3.5 Hz, 1H, 4-H), 3.75 (ddd, J = 10.0, 10.0, 3.5 Hz, 1H, 4-H), 3.65 (d, J = 7.5 Hz, 1H, OH), 2.98 (s, 6H, NMe), 1.85–1.80 (m, 1H, 3-H), 1.58–1.51 (m, 1H, 3-H), 0.88 (s, 9H, TBS), 0.06 (s, 3H, TBS), 0.05 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3): δ 174.6, 64.9, 59.2, 38.3, 36.1, 35.8, 25.8, 18.2, –5.5; HR MS: calcd for C12H27NO3SiNa [M + Na]+ 284.1652, found 284.1645.
(S)-5-(tert-Butyldimethylsiloxy)-2-hydroxy-N,N-dimethylpentanamide ((S)-3k). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 12.2 min (97.2%), tR = 30.3 min (2.8%); IR (neat): 3425, 1643 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.36 (m, 1H, 2-H), 3.71 (d, J = 7.0 Hz, 1H, OH), 3.69–3.59 (m, 2H, 5-H), 2.98 (s, 3H, NMe), 2.96 (s, 3H. NMe), 1.80–1.73 (m, 1H, 3-H), 1.68–1.62 (m, 2H, 4-H), 1.52–1.44 (m, 1H, 3-H), 0.86 (s, 9H, TBS), 0.01 (s, 6H, TBS); 13C NMR (125 MHz, CDCl3): δ 174.4, 67.6, 62.3, 36.3, 35.8, 30.9, 28.0, 25.8, 18.2, –5.4; HR MS: calcd for C13H29NO3SiNa [M + Na]+ 298.1809 found 298.1805.
(R)-2-(Diphenylaceloxy)-N,N-dimethylpropanamide ((R)-4a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 17.3 min (5.7%), tR = 24.0 min (94.3%); IR (neat): 1736, 1666, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.35–7.21 (m, 10H, Ph), 5.43 (q, J = 6.0 Hz, 1H, 2-H), 5.12 (s, 1H, 2′-H), 2.93 (s, 6H, NMe2), 1.41 (d, J = 6.0 Hz, 3H, 3-H); 13C NMR (125 MHz, CDCl3): δ 172.1, 169.7, 138.4, 138.3, 128.7, 128.6, 128.5, 128.4, 127.2, 127.1, 67.7, 56.6, 36.6, 35.6, 16.5; HR MS: calcd for C19H21NO3Na [M + Na]+ 334.1414, found 334.1407.
(R)-2-(Diphenylacetyloxy)-N,N-dimethylbutanamide ((R)-4b). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 15.6 min (3.7%), tR = 28.2 min (96.3%); IR (neat): 1736, 1658, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.34–7.18 (m, 10H, Ph), 5.21 (dd, J = 7.5, 5.5 Hz, 1H, 2-H), 5.11 (s, 1H, 2′-H), 2.96 (s, 3H, NMe), 2.91 (s, 3H, NMe) 1.79–1.71 (m, 2H, 3-H), 0.84 (t, J = 7.5 Hz, 3H, 4-H); 13C NMR (125 MHz, CDCl3): δ 172.4, 169.3, 138.5, 128.7, 128.6, 128.5, 128.4, 127.2, 127.1, 72.5, 56.7, 36.7, 35.8, 24.3, 9.6; HR MS: calcd for C20H23NO3Na [M + Na]+ 348.1570, found 348.1577.
(R)-2-(Diphenylacetyloxy)-N,N-dimethylpentanamide ((R)-4c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 13.8 min (2.9%), tR = 27.6 min (97.1%); IR (neat): 1736, 1666, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.36–7.21 (m, 10H, Ph), 5.31 (dd, J = 8.5, 4.5 Hz, 1H, 2-H), 5.14 (s, 1H, 2′-H), 3.00 (s, 3H, NMe), 2.94 (s, 3H, NMe), 1.82–1.76 (m, 1H, 3-H), 1.70–1.64 (m, 1H, 3-H), 1.38–1.22 (m, 2H, 4-H), 0.85 (t, J = 7.5 Hz, 3H, 5-H); 13C NMR (125 MHz, CDCl3): δ 172.4, 169.5, 138.5, 138.5, 128.7, 128.6, 128.5, 128.4, 127.2, 127.1, 71.0, 56.6, 36.7, 35.9, 32.9, 18.4, 13.5; HR MS: calcd for C21H25NO3Na [M + Na]+ 362.1727, found 362.1733.
(R)-2-(Diphenylacetyloxy)-N,N,3-trimethylbutanamide ((R)-4d). HPLC (CHIRALPAK ID, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 8.7 min (90.9%), tR = 18.4 min (9.1%); IR (neat): 1736, 1658, 1496, 1458, 748, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.31–7.14 (m, 10H, Ph), 5.08 (s, 1H, 2′-H), 4.99 (d, J = 7.5 Hz, 1H, 2-H), 3.00 (s, 3H, NMe), 2.89 (s, 3H, NMe), 2.08 (m, 1H, 3-H), 0.80 (d, J = 7.5 Hz, 3H, 4-H), 0.78 (d, J = 6.0 Hz, 3H, 4-H); 13C NMR (125 MHz, CDCl3): δ 172.5, 169.1, 138.5, 138.5, 128.7, 128.7, 128.5, 128.3, 127.2, 127.1, 75.6, 56.8, 37.0, 35.9, 30.1, 18.4, 17.7; HR MS: calcd for C21H25NO3Na [M + Na]+ 362.1727, found 362.1710.
(R)-2-(Diphenylacetyloxy)-N,N-dimethylhexanamide ((R)-4e). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 13.4 min (2.7%), tR = 30.0 min (97.3%); IR (neat): 1736, 1666, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.37–7.21 (m, 10H, Ph), 5.30 (dd, J = 5.0, 5.0 Hz, 1H, 2-H), 5.14 (s, 1H, 2′-H), 3.00 (s, 3H, NMe), 2.94 (s, 3H, NMe), 1.80 (m, 1H, 3-H), 1.70 (m, 1H, 3-H), 1.27–1.20 (m, 4H, 4-H, 5-H), 0.77 (t, J = 6.5, 6.0 Hz, 3H, 3-H); 13C NMR (125 MHz, CDCl3): δ 172.4, 169.6, 138.5, 138.5, 128.7, 128.7, 128.6, 128.4, 127.2, 127.1, 71.2, 56.7, 36.7, 35.9, 30.6, 27.2, 22.1, 13.7; HR MS: calcd for C22H27NO3Na [M + Na]+ 376.1883, found 376.1898.
(R)-2-(Diphenylacetyloxy)-N,N,4-trimethylpentanamide ((R)-4f). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 14.8 min (2.5%), tR = 31.3 min (97.5%); IR (neat): 1736, 1666, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.33–7.18 (m, 10H, Ph), 5.32 (dd, J = 10.4, 3.4 Hz, 1H, 2-H), 5.12 (s, 1H, 2′-H), 2.98 (s, 3H, NMe), 2.91 (s, 3H, NMe), 1.79 (ddd, J = 14.6, 10.4, 4.6, 1H, 3-H), 1.54–1.51 (m, 1H, 4-H), 1.38 (ddd, J = 14.0, 9.2, 3.4 Hz, 1H, 3-H), 0.81 (d, J = 6.7 Hz, 3H, 5-H), 0.79 (d, J = 6.4 Hz, 3H, 5-H); 13C NMR (125 MHz, CDCl3): δ 172.5, 169.8, 138.5, 138.4, 128.7, 128.7, 128.5, 128.4, 127.2, 127.1, 69.9, 56.7, 39.6, 36.6, 35.9, 24.4, 23.0, 21.3; HR MS: calcd for C22H27NO3Na [M + Na]+ 376.1883, found 376.1873.
(R)-2-Cyclohexyl-2-(diphenylacetyloxy)-N,N-dimethylacetamide ((R)-4g). HPLC (CHIRALPAK IC, i-PrOH/hexane = 40/60, flow rate = 0.75 mL/min): tR = 11.2 min (16.8%), tR = 31.3 min (83.2%); IR (neat): 1736, 1658, 1496, 1450, 748, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.29–7.13 (m, 10H, Ph), 5.06 (s, 1H, 2′-H), 5.00 (d, J = 7.3 Hz, 1H, 2-H), 3.00 (s, 3H, NMe), 2.88 (s, 3H, NMe), 1.77 (m, 1H, 3-H), 1.58–1.45 (m, 5H, c-Hex), 1.17–0.80 (m, 5H, c-Hex); 13C NMR (125 MHz, CDCl3): δ 172.5, 169.1, 138.6, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 75.0, 56.7, 39.5, 37.1, 35.9, 28.5, 28.2, 26.0, 25.8, 25.5; HR MS: calcd for C24H29NO3Na [M + Na]+ 402.2040, found 402.2047.
(R)-3-(tert-Butyldimethylsiloxy)-2-(diphenylacetyloxy)-N,N-dimethylpropanamide ((R)-4i). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 11.4 min (9.0%), tR = 13.3 min (91.0%); IR (neat): 1743, 1658, 1496, 1458, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.36–7.23 (m, 10H, Ph), 5.49 (t, J = 6.0 Hz, 1H, 2-H), 5.15 (s, 1H, 2′-H), 3.90 (m, 2H, 3-H), 3.10 (s, 3H, NMe), 2.97 (s, 3H, NMe), 0.85 (s, 9H, TBS), 0.02 (s, 3H, TBS), 0.00 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3): δ 172.2, 168.1, 138.4, 138.4, 128.7, 128.6, 128.5, 127.3, 127.2, 71.6, 62.9, 56.6, 37.0, 36.0, 25.7, 18.1, 5.6, 5.7; HR MS: calcd for C25H35NO4SiNa [M + Na]+ 464.2228, found 464.2222.
(R)-4-(tert-Butyldimethylsiloxy)-2-(diphenylacetyloxy)-N,N-dimethylbutanamide ((R)-4j). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 11.4 min (3.5%), tR = 25.0 min (96.5%); IR (neat): 1743, 1666, 1496, 1466, 748, 717 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.38–7.22 (m, 10H, Ph), 5.54 (dd, J = 9.5, 3.0 Hz, 1H, 2-H), 5.17 (s, 1H, 2′-H), 3.60 (dt, J = 10.0, 5.0 Hz, 1H, 4-H), 3.48 (dt, J = 10.0, 3.5 Hz, 1H, 4-H), 3.08 (s, 3H, NMe), 2.98 (s, 3H, NMe), 1.98 (m, 1H, 3-H), 1.89 (m, 1H, 3-H) 0.86 (s, 9H, TBS), 0.02 (s, 3H, TBS), 0.06 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3): δ 172.3, 169.8, 138.6, 138.5, 128.8, 128.7, 128.6, 128.4, 127.2, 127.1, 68.0, 58.4, 56.7, 36.6, 35.8, 34.2, 25.8, 18.1, 5.6, 5.7; HR MS: calcd for C26H37NO4SiNa [M + Na]+ 478.2384, found 478.2386.
(R)-5-(tert-Butyldimethylsiloxy)-2-(Diphenylacetyloxy)-N,N-dimethylpentanamide ((R)-4k). HPLC (CHIRALPAK IC, i-PrOH/hexane = 20/80, flow rate = 1.0 mL/min): tR = 12.2 min (2.4%), tR = 29.7 min (97.6%); IR (neat): 1751, 1666, 1496, 1458, 748, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.37–7.22 (m, 10H, Ph), 5.35 (t, J = 6.5 Hz, 1H, 2-H), 5.15 (s, 1H, 2′-H), 3.54 (t, J = 6.0 Hz, 2H, 5-H), 3.02 (s, 3H, NMe), 2.95 (s, 3H, NMe), 1.84 (dt, J = 6.5, 6.5 Hz, 2H, 3-H), 1.55–1.39 (m, 2H, 4-H), 0.87 (s, 9H, TBS), 0.01 (s, 6H, TBS); 13C NMR (125 MHz, CDCl3): δ 172.4, 169.5, 138.5, 138.5, 128.8, 128.7, 128.6, 128.4, 127.2, 127.1, 71.1, 62.0, 56.7, 36.7, 35.9, 28.0, 27.3, 25.9, 18.2, 5.4; HR MS: calcd for C27H39NO4SiNa [M + Na]+ 492.2541, found 492.2554.
(S)-2-Hydroxy-N-methoxy-N-methylpropanamide ((S)-5a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min): tR = 16.6 min (99.2%), tR = 27.3 min (0.8%); IR (neat): 3443, 1662 cm–1; 1H NMR (CDCl3): δ 4.42 (dq, J = 7.0, 7.0 Hz, 1H, 2-H), 3.65 (s, 3H, OMe), 3.42 (d, J = 7.0 Hz, 1H, OH), 2.81 (s, 3H, NMe), 1.29 (d, J = 7.0 Hz, 3H, 3-H); 13C NMR (CDCl3): δ 175.6, 64.8, 61.1, 32.2, 20.8; HR MS: calcd for C5H11NO3Na [M + Na]+ 156.0631, found 156.0634.
(S)-2-Hydroxy-N-methoxy-N-methylbutanamide ((S)-5b). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 13.6 min (92.4%), tR = 41.3 min (7.6%); IR (neat): 3448, 1658 cm–1; 1H NMR (CDCl3): δ 4.33 (ddd, J = 7.5, 7.5, 3.5 Hz, 1H, 2-H), 3.69 (s, 3H, OMe), 3.24 (d, J = 7.5 Hz, 1H, OH), 3.22 (s, 3H, NMe), 1.76 (dqd, J = 14.5, 7.5, 3.5 Hz, 1H, 3-H), 1.55 (ddq, J = 14.5, 7.5, 7.5 Hz, 1H, 3-H), 0.95 (dd, J = 7.5, 7.5 Hz, 3H, 4-H); 13C NMR (CDCl3): δ 175.0, 69.6, 61.2, 32.3, 27.6, 9.1; HR MS: calcd for C6H13NO3Na [M + Na]+ 170.0788, found 170.0793.
(S)-2-Hydroxy-N-methoxy-N-methylpentanamide ((S)-5c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 13.1 min (96.8%), tR = 33.4 min (3.2%); IR (neat): 3464, 1658 cm–1; 1H NMR (CDCl3): δ 4.43–4.24 (m, 1H, 2-H), 3.66 (dd, J = 14.0, 14.0 Hz, 3H, OMe), 3.28–3.20 (m, 1H, OH), 3.19 (dd, J = 14.0, 14.0 Hz, 3H, NMe), 1.71–1.57 (m, 1H, 3-H), 1.53–1.35 (m, 3H, 3-H, 4-H), 0.89 (dddd, J = 15.0, 15.0, 7.5, 7.5 Hz, 3H, 5-H); 13C NMR (CDCl3): δ 175.2, 68.3, 61.1, 36.8, 36.7, 32.3, 18.2, 18.1, 13.6; HR MS: calcd for C7H15NO3Na [M + Na]+ 184.0944, found 184.0941.
(S)-2-Hydroxy-N-methoxy-N,3-dimethylbutanamide ((S)-5d). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 11.1 min (53.4%), tR = 31.8 min (46.6%); IR (neat): 3455, 1656 cm–1; 1H NMR (CDCl3): δ 4.23 (dd, J = 8.0, 2.5 Hz, 1H, 2-H), 3.67 (s, 3H, OMe), 3.21 (s, 3H, NMe), 3.13 (d, J = 8.0 Hz, 1H, OH), 2.05–1.93 (m, 1H, 3-H), 1.00 (d, J = 7.0 Hz, 3H, 4-H), 0.78 (d, J = 7.0 Hz, 3H, 4-H); 13C NMR (CDCl3): δ 174.6, 72.8, 32.3, 31.3, 19.6, 15.2; HR MS: calcd for C7H15NO3Na [M + Na]+ 184.0944, found 184.0949.
(S)-2-Hydroxy-N-methoxy-N-methylhexanamide ((S)-5e). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 10.3 min (84.3%), tR = 26.1 min (15.7%); IR (neat): 3449, 1658 cm–1; 1H NMR (CDCl3): δ 4.37–4.34 (m, 1H, 2-H), 3.68 (s, 3H, OMe), 3.23 (s, 1H, OH), 3.21 (s, 3H, NMe), 1.75–1.64 (m, 1H, 3-H), 1.55–1.21 (m, 3H, 3-H, 4-H), 0.88 (dd, J = 7.5, 7.5 Hz, 3H, 5-H); 13C NMR (CDCl3): δ 175.3, 68.6, 61.2, 34.3, 32.3, 27.0, 22.3, 13.8; HR MS: calcd for C8H17NO3Na [M + Na]+ 198.1101, found 198.1110.
(S)-2-Hydroxy-N-methoxy-N,4-dimethylpentanamide ((S)-5f). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min): tR = 20.0 min (82.3%), tR = 50.9 min (4.8%); IR (neat): 3447, 1660 cm–1; 1H NMR (CDCl3): δ 4.39 (dd, J = 8.0, 8.0 Hz, 1H, 2-H), 3.68 (s, 3H, OMe), 3.20 (s, 3H, NMe), 3.15 (d, J = 8.0 Hz, 1H, OH), 1.95–1.84 (m, 1H, 4-H), 1.48–1.33 (m, 2H, 3-H), 0.93 (d, J = 7.0 Hz, 3H, 5-H), 0.91 (d, J = 6.5 Hz, 3H, 5-H); 13C NMR (CDCl3): δ 175.7, 67.2, 61.1, 43.9, 32.4, 24.5, 23.5, 21.2; HR MS: calcd for C8H17NO3Na [M + Na]+ 198.1101, found 198.1097.
(S)-2-Cyclohexyl-2-hydroxy-N-methoxy-N-methylacetamide ((S)-5h). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 10.2 min (52.5%), tR = 40.4 min (47.5%); IR (neat): 3451, 1656 cm–1; 1H NMR (CDCl3): δ 4.20 (d, J = 4.0 Hz, 1H, 2-H), 3.67 (s, 3H, OMe), 3.21 (s, 3H, NMe), 3.13 (d, J = 8.0 Hz, 1H, OH), 1.76–1.53 (m, 5H, c-Hex), 1.47–1.30 (m, 2H, c-Hex), 1.26–1.03 (m, 4H, c-Hex); 13C NMR (CDCl3): δ 174.4, 72.6, 61.1, 41.4, 32.2, 29.6, 26.3, 26.0, 25.9; HR MS: calcd for C10H19NO3Na [M + Na]+ 224.1257, found 224.1248.
(S)-3-(tert-Butyldimethylsiloxy)-2-hydroxy-N-methoxy-N-methylpropanamide ((S)-5i). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min): tR = 13.7 min (75.4%), tR = 20.2 min (24.6%); IR (neat): 3447, 1665 cm–1; 1H NMR (CDCl3): δ 4.52–4.35 (m, 1H, 2-H), 3.86 (dd, J = 10.0, 3.5 Hz, 1H, 3-H), 3.81 (dd, J = 10.0, 3.5 Hz, 1H, 3-H), 3.70 (dd, J = 15.0, 15.0 Hz, 3H, OMe), 3.48 (ddd, J = 15.0, 15.0, 8.5 Hz, 1H, OH), 3.23 (dd, J = 15.0, 15.0 Hz, 3H, NMe), 0.86 (dd, J = 15.0, 15.0 Hz, 9H, TBS), 0.04 (dd, J = 15.0, 15.0 Hz, 3H, TBS), 0.03 (s, 3H, TBS); 13C NMR (CDCl3): δ 172.3, 70.2, 65.2, 61.2, 32.4, 25.8, 18.3, −5.4, −5.5; HR MS: calcd for C11H25NO4SiNa [M + Na]+ 286.1445, found 286.1431.
(S)-4-(tert-Butyldimethylsiloxy)-2-hydroxy-N-methoxy-N-methylbutanamide ((S)-5j). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 9.6 min (95.2%), tR = 23.1 min (4.8%); IR (neat): 3451, 1662, cm–1; 1H NMR (CDCl3): δ 4.62–4.48 (m, 1H, 2-H), 3.90–3.74 (m, 2H, 4-H), 3.70 (dd, J = 15.0, 15.0 Hz, 3H, OMe), 3.28 (d, J = 7.0 Hz, 1H, OH), 3.23 (ddd, J = 14.5, 14.5, 5.0 Hz, 3H, NMe), 2.05–1.88 (m, 1H, 3-H), 1.68–1.55 (m, 1H, 3-H), 0.89 (dd, J = 15.0, 15.0 Hz, 9H, TBS), 0.06 (ddd, J = 14.5, 14.5, 5.0 Hz, 3H, TBS), 0.05 (s, 3H, TBS); 13C NMR (CDCl3): δ 175.3, 65.9, 61.3, 59.2, 37.6, 32.5, 25.9, 18.2, −5.4, −5.5; HR MS: calcd for C12H27NO4SiNa [M + Na]+ 300.1602, found 300.1607.
(S)-4-(tert-Butyldimethylsiloxy)-2-hydroxy-N-methoxy-N-methylpentanamide ((S)-5k). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 8.7 min (99.6%), tR = 21.7 min (0.4%); IR (neat): 3464, 1658 cm–1; 1H NMR (CDCl3): δ 4.47–4.33 (m, 1H, 2-H), 3.70 (s, 3H, OMe), 3.64 (td, J = 6.0, 2.5 Hz, 1H, 5-H), 3.30 (d, J = 8.0 Hz, 1H, OH), 3.23 (s, 3H, NMe), 1.87–1.78 (m, 1H, 3-H), 1.70–1.51 (m, 3H, 3-H, 4-H), 0.87 (s, 9H, TBS), 0.03 (s, 6H, TBS); 13C NMR (CDCl3): δ 175.1, 68.5, 62.7, 61.2, 32.4, 31.2, 28.3, 25.9, 18.3, –5.3; HR MS: calcd for C13H29NO4SiNa [M + Na]+ 314.1758, found 314.1748.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N-methylpropanamide ((R)-6a). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 18.9 min (26.5%), tR = 26.5 in (96.4%); IR (neat): 1736, 1673, 1489, 1458, 741, 702 cm–1; 1H NMR (CDCl3): δ 7.36–7.19 (m, 10H, Ph), 5.39 (q, J = 6.8 Hz, 1H, 2-H), 5.13 (s, 1H, 2′-H), 3.73 (s, 3H, OMe), 3.18 (s, 3H, NMe), 1.41 (d, J = 6.8 Hz, 3H, 3-H); 13C NMR (CDCl3): δ 172.5, 170.6, 138.6, 138.5, 128.8, 128.7, 128.6, 128.4, 127.2, 127.1, 68.3, 56.6, 32.1, 16.3; HR MS: calcd for C19H21NO4Na [M + Na]+ 350.1363, found 350.1350.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N-methylbutanamide ((R)-6b). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/min): tR = 13.6 min (2.2%), tR = 30.8 min (97.8%); IR (neat): 1736, 1676, 1486, 1454, 749, 699 cm–1; 1H NMR (CDCl3): δ 7.39–7.19 (m, 10H, Ph), 5.25 (t, J = 7.0 Hz, 1H, 2-H), 5.16 (s, 1H, 2′-H), 3.76 (s, 3H, OMe), 3.20 (s, 3H, NMe), 1.85–1.76 (m, 2H, 3-H), 0.88 (t, J = 7.0 Hz, 3H, 4-H); 13C NMR (CDCl3): δ 172.7, 170.0, 138.6, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 73.0, 61.2, 56.7, 32.0, 24.1, 9.7; HR MS: calcd for C20H23NO4Na [M + Na]+ 364.1519, found 364.1537.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N-methylpentanamide ((R)-6c). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 13.2 min (1.9%), tR = 32.7 min (98.1%); IR (neat): 1736, 1678, 1602, 1497, 1459, 740, 698 cm–1; 1H NMR (CDCl3): δ 7.35–7.16 (m, 10H, Ph), 5.28 (dd, J = 9.0, 3.5 Hz, 1H, 2-H), 5.12 (s, 1H, 2′-H), 3.73 (s, 3H, OMe), 3.16 (s, 3H, NMe), 1.80–1.61 (m, 2H, 3-H), 1.39–1.16 (m, 2H, 4-H), 0.81 (dd, J = 7.5, 7.5 Hz, 3H, 5-H); 13C NMR (CDCl3): δ 172.7, 170.2, 138.6, 138.5, 128.8, 128.8, 128.5, 128.4, 127.2, 127.1, 71.6, 61.2, 56.7, 32.6, 32.1, 18.5, 13.4; HR MS: calcd for C21H25NO4Na [M + Na]+ 378.1676, found 378.1689.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N,3-dimethylbutanamide ((R)-6d). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 11.3 min (17.1%), tR = 32.5 min (82.9%); IR (neat): 1735, 1674, 1496, 750, 700 cm–1; 1H NMR (CDCl3): δ 7.42–7.21 (m, 10H, Ph), 5.17 (s, 1H, 2′-H), 5.17 (d, J = 6.5 Hz, 1H, 2-H), 3.79 (s, 3H, OMe), 3.22 (s, 3H, NMe), 2.17 (dqq, J = 7.0, 6.5, 6.5 Hz, 1H, 3-H), 0.88 (d, J = 6.5 Hz, 3H, 4-H), 0.87 (d, J = 6.5 Hz, 3H, 4-H); 13C NMR (CDCl3): δ 172.6, 169.5, 138.6, 138.5, 128.8, 128.8, 128.6, 128.3, 127.2, 127.0, 75.8, 61.1, 56.9, 32.0, 29.9, 18.7, 17.3; HR MS: calcd for C21H25NO4Na [M + Na]+ 378.1676, found 378.1686.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N-methylhexanamide ((R)-6e). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 10.4 min (1.8%), tR = 25.4 min (98.2%); IR (neat): 1736, 1678, 1498, 1445, 743, 704 cm–1; 1H NMR (CDCl3): δ 7.35–7.17 (m, 10H, Ph), 5.27 (dd, J = 8.5, 4.0 Hz, 1H, 2-H), 5.13 (s, 1H, 2-H), 3.73 (s, 3H, OMe), 3.16 (s, 3H, NMe), 1.80–1.67 (m, 2H, 3-H), 1.29–1.13 (m, 4H, 4-H, 5-H), 0.79 (ddd, J = 7.0, 7.0, 2.5 Hz, 3H, 6-H); 13C NMR (CDCl3): δ 172.6, 170.2, 138.6, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 71.7, 61.2, 56.7, 21.1, 30.2, 27.2, 22.0, 13.7; HR MS: calcd for C22H27NO4Na [M + Na]+ 392.1832, found 392.1848.
(R)-2-(Diphenylacetyloxy)-N-methoxy-N,4-dimethylpentanamide ((R)-6f). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 10.1 min (1.8%), tR = 24.7 min (98.2%); IR (neat): 1733, 1678, 1491, 752, 702 cm–1; 1H NMR (CDCl3): δ 7.34–7.17 (m, 10H, Ph), 5.31 (dd, J = 10.3, 3.0 Hz, 1H, 2-H), 5.12 (s, 1H, 2′-H), 3.74 (s, 3H, OMe), 3.15 (s, 3H, NMe), 1.73 (ddd, J = 14.0, 10.0, 4.0 Hz, 1H, 3-H), 1.58–1.48 (m, 1H, 4-H), 1.45 (ddd, J = 14.0, 9.5, 3.5 Hz, 1H, 3-H), 0.80 (d, J = 6.0 Hz, 3H, 5-H), 0.76 (d, J = 6.5 Hz, 5-H); 13C NMR (CDCl3): δ 172.7, 170.6, 138.5, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 70.6, 61.2, 56.7, 39.2, 32.2, 24.5, 23.1, 21.1; HR MS: calcd for C22H27NO4Na [M + Na]+ 392.1832, found 392.1847.
(R)-2-Cyclohexyl-2-(diphenylacetyloxy)-N-methoxy-N-methylacetamide ((R)-6g). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 10.3 min (20.4%), tR = 40.0 min (79.6%); IR (neat): 1736, 1672, 1495, 1451, 752, 700 cm–1; 1H NMR (CDCl3): δ 7.35–7.16 (m, 10H, Ph), 5.13 (d, J = 6.5 Hz, 1H, 2-H), 5.11 (s, 1H, 2′-H), 3.75 (s, 3H, OMe), 3.17 (s, 3H, NMe), 1.84–1.75 (m, 1H, c-Hex), 1.68–1.41 (m, 5H, c-Hex), 1.24–0.92 (m, 5H, c-Hex); 13C NMR (CDCl3): δ 172.6, 169.5, 138.6, 138.5, 128.8, 128.6, 128.3, 127.2, 127.0, 75.4, 61.1, 56.9, 39.3, 31.9, 28.7, 27.8, 26.0, 25.7; HR MS: calcd for C24H29NO4Na [M + Na]+ 418.1989, found 418.2003.
(R)-3-(tert-Butyldimethylsiloxy)-2-(diphenylacetyloxy)-N-methoxy-N-methylpropanamide ((R)-6i). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min): tR = 13.7 min (93.0%), tR = 21.2 min (7.0%); IR (neat): 1741, 1670, 1496, 1469, 737, 699 cm–1; 1H NMR (CDCl3): δ 7.36–7.21 (m, 10H, Ph), 5.48 (dd, J = 7.0, 4.0 Hz, 1H, 2-H), 5.17 (s, 1H, 2′-H), 3.91 (dd, J = 11.0, 4.0 Hz, 1H, 3-H), 3.88 (dd, J = 11.0, 7.0 Hz, 1H, 3-H), 3.80 (s, 3H, OMe), 3.20 (s, 3H, NMe), 0.83 (s, 9H, TBS), –0.00 (s, 3H, TBS), –0.03 (s, 3H, TBS); 13C NMR (CDCl3): δ 172.6, 167.7, 138.5, 138.4, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 73.3, 62.0, 61.3, 56.7, 32.1, 25.7, 18.2, −5.5, −5.6; HR MS: calcd for C25H35NO5SiNa [M + Na]+ 480.2177, found 480.2174.
(R)-4-(tert-Butyldimethylsiloxy)-2-(diphenylacetyloxy)-N-methoxy-N-methylbutanamide ((R)-6j). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 9.8 min (2.7%), tR = 23.4 min (97.3%); IR (neat): 1738, 1673, 1496, 1469, 762, 701 cm–1; 1H NMR (CDCl3): δ 7.38–7.21 (m, 10H, Ph), 5.25 (d, J = 8.5 Hz, 1H, 2-H), 5.16 (s, 1H, 2′-H), 3.78 (s, 3H, OMe), 3.59 (ddd, J = 10.0, 6.0, 4.0 Hz, 1H, 4-H), 3.50 (ddd, 10.0, 10.0, 5.0 Hz, 1H, 4’-H), 3.21 (s, 3H, NMe), 2.04–1.84 (m, 2H, 3-H), 0.85 (s, 9H, TBS), –0.03 (s, 3H, TBS), –0.07 (s, 3H, TBS); 13C NMR (CDCl3): δ 172.5, 170.4, 138.6, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 68.7, 61.2, 58.3, 56.8, 33.6, 32.2, 25.8, 18.1, −5.5, −5.6; HR MS: calcd for C26H37NO5SiNa (M + Na+) 494.2333, found 494.2321.
(R)-4-(tert-Butyldimethylsiloxy)-2-(diphenylacetyloxy)-N-methoxy-N-methylpentanamide ((R)-6k). HPLC (CHIRALPAK IC, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min): tR = 8.8 min (3.0%), tR = 21.4 min (97.0%); IR (neat): 1739, 1680, 1496, 1469, 735, 701 cm–1; 1H NMR (CDCl3): δ 7.39–7.20 (m, 10H, Ph), 5.34 (dd, J = 8.5, 4.5 Hz, 1H, 2-H), 5.16 (s, 1H, 2′-H), 3.77 (s, 3H, OMe), 3.54 (t, J = 6.0 Hz, 2H, 5-H), 3.20 (s, 3H, NMe), 1.93–1.77 (m, 2H, 3-H), 1.58–1.42 (m, 2H, 4-H), 0.87 (s, 9H, TBS), 0.01 (s, 6H, TBS); 13C NMR (CDCl3): δ 172.6, 170.1, 138.6, 138.5, 128.8, 128.8, 128.6, 128.4, 127.2, 127.1, 71.8, 62.3, 61.2, 56.7, 32.1, 28.4, 27.2, 25.9, 18.2, −5.4; HR MS: calcd for C27H39NO5SiNa [M + Na]+ 508.2490, found 508.2514.
The 1H and 13C-NMR spectra of the compounds are available in Supplementary Materials.

4. Conclusions

In summary, we developed an efficient method for producing optically active 2-hydroxyamides based on the KR of racemic 2-hydroxyamides with diphenylacetyl components using (R)-BTM as a nucleophilic chiral acyl-transfer catalyst. The resulting chiral compounds could be converted into the other useful chiral compounds without erosion of the chirality. The transition states were determined by DFT calculations to support the observations in their process. Further research on the present method, including the application of this novel protocol to the production of other chiral materials, is currently underway in our laboratory.

Supplementary Materials

The Supplementary Materials containing 1H and 13C NMR spectroscopic data are available online, Figure S1: Preferable transition structure ((R)-3a-TS), Table S1: Cartesian Coordinates (Angstroms), Figure S2: Unfavorable transition structure ((S)-3a-TS), Table S2: Cartesian Coordinates (Angstroms), Figure S3: Preferable transition structure ((R)-5a-TS), Table S3: Cartesian Coordinates (Angstroms), Figure S4: Unfavorable transition structure ((S)-5a-TS), Table S4: Cartesian Coordinates (Angstroms).

Author Contributions

K.N. and I.S. conceived and designed the experiments; T.M., T.K., A.S., R.I., K.O., K.N. and I.S. carried out the synthesis and characterization of all compounds; All authors discussed the results of the experiments.

Funding

This research was funded by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Available.
Molecules 23 02003 sch001 550
Scheme 1. Our previous result (i) and working hypothesis for the present study (ii).
Scheme 1. Our previous result (i) and working hypothesis for the present study (ii).
Molecules 23 02003 sch001
Molecules 23 02003 sch002 550
Scheme 2. Calculated transition states with a kinetic resolution (KR) of (±)-3.
Scheme 2. Calculated transition states with a kinetic resolution (KR) of (±)-3.
Molecules 23 02003 sch002
Molecules 23 02003 g001 550
Figure 1. Three-dimensional structures of the calculated transition states ((R)-3a-TS and (S)-3a-TS).
Figure 1. Three-dimensional structures of the calculated transition states ((R)-3a-TS and (S)-3a-TS).
Molecules 23 02003 g001
Molecules 23 02003 sch003 550
Scheme 3. Calculated transition states with a KR of (±)-5.
Scheme 3. Calculated transition states with a KR of (±)-5.
Molecules 23 02003 sch003
Molecules 23 02003 g002 550
Figure 2. Three-dimensional structures of the calculated transition states ((R)-5a-TS and (S)-5a-TS).
Figure 2. Three-dimensional structures of the calculated transition states ((R)-5a-TS and (S)-5a-TS).
Molecules 23 02003 g002
Molecules 23 02003 sch004 550
Scheme 4. Transformation of chiral 2-hydroxyamides and their esters.
Scheme 4. Transformation of chiral 2-hydroxyamides and their esters.
Molecules 23 02003 sch004
Table
Table 1. Kinetic resolution (KR) of various racemic 2-hydroxyamides ((±)-1a–1e).
Table 1. Kinetic resolution (KR) of various racemic 2-hydroxyamides ((±)-1a–1e).
Molecules 23 02003 i001
EntryR1, R2Yield (2; 1) [%]ee (2; 1) [%]s
1Me, H (a)42; 5212; 141
2Bn, H (b)50; 5017; 152
3Ph, H (c)55; 4579; 7318
4 aMe, Me (d)48; 4692; >99254
5 aMe, OMe (e)50; 5094; 99156
6 bMe, Me (f)47; 5091; 9895
7 cMe, OMe (g)47; 4294; 98157
a Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.) were used. b (Ph2CHCO)2O (DPHAA; 0.60 eq.) and i-Pr2NEt (0.60 eq.) were used. c (Ph2CHCO)2O (DPHAA; 0.75 eq.) and i-Pr2NEt (0.75 eq.) were used.
Table
Table 2. KR of 2-hydroxy dimethylamide ((±)-3a–3k).
Table 2. KR of 2-hydroxy dimethylamide ((±)-3a–3k).
Molecules 23 02003 i002
EntrySubstrateConditions a,bYield (4; 3) [%]ee (4; 3) [%]s
1 Molecules 23 02003 i003A152; 4689; 8242
2B137; 5688; 5727
3 Molecules 23 02003 i004A140; 5393; 5445
4B137; 5488; 6229
5 Molecules 23 02003 i005A141; 5794; 6565
6B145; 4793; 7463
7 Molecules 23 02003 i006A113; 7682; 1412
8B125; 7563; 215
9 Molecules 23 02003 i007A141; 5695; 6975
10B136; 6095; 7463
11 Molecules 23 02003 i008A147; 5295; 7892
12B148; 4597; 94208
13 Molecules 23 02003 i009A17; 8366; 65
14B143; 4974; 6813
15 Molecules 23 02003 i010A158; 4692; >99254
16B147; 5091; 9895
17 Molecules 23 02003 i011A134; 6682; 4115
18B145; 4980; 6918
19 Molecules 23 02003 i012A146; 5093; 95103
20B144; 5194; 7981
21 Molecules 23 02003 i013A148; 5194; 99151
22B147; 4696; 92176
a Conditions A1; Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.). b Conditions B1; (Ph2CHCO)2O (DPHAA; 0.60 eq.) and i-Pr2NEt (0.60 eq.).
Table
Table 3. KR of 2-hydroxy-Weinreb amide ((±)-5a–5k).
Table 3. KR of 2-hydroxy-Weinreb amide ((±)-5a–5k).
Molecules 23 02003 i014
EntrySubstrateConditions a,bYield (6; 5) [%]ee (6; 5) [%]s
1 Molecules 23 02003 i015A151; 4493; 99130
2B250; 5085; 9857
3 Molecules 23 02003 i016A146; 5196; 85118
4B246; 4990; 8957
5 Molecules 23 02003 i017A145; 5596; 94176
6B245; 4294; 96118
7 Molecules 23 02003 i018A19; 9166; 75
8B227; 6567; 317
9 Molecules 23 02003 i019A143; 5696; 69113
10B249; 5091; 9789
11 Molecules 23 02003 i020A146; 4997; 89168
12B246; 4494; 99168
13 Molecules 23 02003 i021A14; 9159; 54
14B235; 6142; 243
15 Molecules 23 02003 i022A150; 5094; 99156
16B247; 4294; 98157
17 Molecules 23 02003 i023A140; 6086; 5122
18B250; 4673; 8416
19 Molecules 23 02003 i024A147; 5095; 91115
20B249; 4890; 99106
21 Molecules 23 02003 i025A154; 4694; 99118
22B248; 4187; 9976
a Conditions A1; Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.). b Conditions B2; (Ph2CHCO)2O (DPHAA; 0.75 eq.) and i-Pr2NEt (0.75 eq.).

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MDPI and ACS Style

Murata, T.; Kawanishi, T.; Sekiguchi, A.; Ishikawa, R.; Ono, K.; Nakata, K.; Shiina, I. Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst. Molecules 2018, 23, 2003. https://doi.org/10.3390/molecules23082003

AMA Style

Murata T, Kawanishi T, Sekiguchi A, Ishikawa R, Ono K, Nakata K, Shiina I. Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst. Molecules. 2018; 23(8):2003. https://doi.org/10.3390/molecules23082003

Chicago/Turabian Style

Murata, Takatsugu, Tatsuya Kawanishi, Akihiro Sekiguchi, Ryo Ishikawa, Keisuke Ono, Kenya Nakata, and Isamu Shiina. 2018. "Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst" Molecules 23, no. 8: 2003. https://doi.org/10.3390/molecules23082003

APA Style

Murata, T., Kawanishi, T., Sekiguchi, A., Ishikawa, R., Ono, K., Nakata, K., & Shiina, I. (2018). Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst. Molecules, 23(8), 2003. https://doi.org/10.3390/molecules23082003

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