Kinetic resolution of racemic 2-hydroxyamides using a diphenylacetyl component as an acyl source and a chiral acyl-transfer catalyst

Article abstract of DOI:10.3390/molecules23082003

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.

Full text of DOI:10.3390/molecules23082003

molecules
Article
Kinetic Resolution of Racemic 2-Hydroxyamides
Using a Diphenylacetyl Component as an Acyl Source
and a Chiral Acyl-Transfer Catalyst
Takatsugu Murata 1, Tatsuya Kawanishi 1, Akihiro Sekiguchi 1, Ryo Ishikawa 1, Keisuke Ono 1,
Kenya Nakata 2,
*
and Isamu Shiina 1,
*
ID
ID
1
Department of Appliaed Chemistry, Faculty of Science, Tokyo University of Science, Tokyo 162-8601, Japan;
b116707@ed.tus.ac.jp (T.M.); tatsuya.kawanishi@tcichemicals.com (T.K.);
akihiro.sekiguchi@nipponkayaku.co.jp (A.S.); 12ishikawa25@gmail.com (R.I.); ki_ono@jp.daicel.com (K.O.)
Graduate School of Natural Science and Technology, Shimane University, Shimane 690-8504, Japan
Correspondence: nakata@riko.shimane-u.ac.jp (K.N.); shiina@rs.kagu.tus.ac.jp (I.S.);
Tel.: +81-852-32-6424 (K.N.); +81-3-3260-4271 (I.S.)
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 23 July 2018; Accepted: 7 August 2018; Published: 10 August 2018
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.
Keywords: kinetic resolution; 2-hydroxyamide; organocatalysis; Weinreb amide; esterification;
carboxylic anhydride
1. Introduction
Optically active 2-hydroxyamide derivatives are frequently utilized as chiral building blocks
not only for synthesizing biologically active compounds [
catalysts and chiral auxiliaries [ ]. Consequently, considerable effort has been devoted toward
developing efficient methods for synthesizing these compounds, including enzymatic [ ] and chemical
transformations [ 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 13]. However, to the best of our knowledge, a general method for the
1–4], but also for preparing asymmetric
5,6
7
8–
–
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 [14–27] 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.
Molecules 2018, 23, 2003; doi:10.3390/molecules23082003
www.mdpi.com/journal/molecules

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Scheme 1. Our previous result (i) and working hypothesis for the present study (ii).
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 (
)-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 33] was
±
)-1a or benzyl (
±
)-1b and N-phenyl amide
(
±
±
±
–
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 (
protocol (Entries 6 and 7).
±
)-1d and 1e using the asymmetric acylation
Table 1. Kinetic resolution (KR) of various racemic 2-hydroxyamides ((±)-1a–1e).
Entry
R1, R2
Yield (2; 1) [%]
ee (2; 1) [%]
s
1
2
3
Me, H (a)
Bn, H (b)
Ph, H (c)
Me, Me (d)
Me, OMe (e)
Me, Me (f)
Me, OMe (g)
42; 52
50; 50
55; 45
48; 46
50; 50
47; 50
47; 42
12; 14
17; 15
79; 73
92; >99
94; 99
91; 98
94; 98
1
2
18
254
156
95
4 a
5 a
6 b
7 c
157
a
b
Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.) were used. (Ph2CHCO)2O (DPHAA; 0.60 eq.) and
c
i-Pr2NEt (0.60 eq.) were used. (Ph2CHCO)2O (DPHAA; 0.75 eq.) and i-Pr2NEt (0.75 eq.) were used.
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

Molecules 2018, 23, 2003
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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 -(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
(
±
ω
(
±
–
±
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).
Table 2. KR of 2-hydroxy dimethylamide ((±)-3a–3k).
Entry
Substrate
Conditions a,b
Yield (4; 3) [%]
ee (4; 3) [%]
s
1
2
A1
B1
52; 46
37; 56
89; 82
88; 57
42
27
3
4
A1
B1
40; 53
37; 54
93; 54
88; 62
45
29
5
6
A1
B1
41; 57
45; 47
94; 65
93; 74
65
63
7
8
A1
B1
13; 76
25; 75
82; 14
63; 21
12
5
9
A1
B1
41; 56
36; 60
95; 69
95; 74
75
63
10
11
12
A1
B1
47; 52
48; 45
95; 78
97; 94
92
208
13
14
A1
B1
7; 83
66; 6
5
43; 49
74; 68
13
15
16
A1
B1
58; 46
47; 50
92; >99
91; 98
254
95
17
18
A1
B1
34; 66
45; 49
82; 41
80; 69
15
18
19
20
A1
B1
46; 50
44; 51
93; 95
94; 79
103
81
21
22
A1
B1
48; 51
47; 46
b
94; 99
96; 92
151
176
a
Conditions A1; Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.). Conditions B1; (Ph2CHCO)2O
(DPHAA; 0.60 eq.) and i-Pr2NEt (0.60 eq.).

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Furthermore, we performed the KR of various racemic 2-hydroxy-Weinreb amides (
substitution patterns corresponding to the N,N-dimethylamides ( )-3a
(Table 3). Consequently, the same tendency was observed. The KR of 2-hydroxy-Weinreb amides 5a
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.
±
)-5a
–
5k with
±
–
3k using a similar protocol
5c
–
,
,
,
,
(
±
,
Table 3. KR of 2-hydroxy-Weinreb amide ((±)-5a–5k).
Entry
Substrate
Conditions a,b
Yield (6; 5) [%]
ee (6; 5) [%]
s
1
2
A1
B2
51; 44
50; 50
93; 99
85; 98
130
57
3
4
A1
B2
46; 51
46; 49
96; 85
90; 89
118
57
5
6
A1
B2
45; 55
45; 42
96; 94
94; 96
176
118
7
8
A1
B2
9; 91
66; 7
5
7
27; 65
67; 31
9
A1
B2
43; 56
49; 50
96; 69
91; 97
113
89
10
11
12
A1
B2
46; 49
46; 44
97; 89
94; 99
168
168
13
14
A1
B2
4; 91
59; 5
4
3
35; 61
42; 24
15
16
A1
B2
50; 50
47; 42
94; 99
94; 98
156
157
17
18
A1
B2
40; 60
50; 46
86; 51
73; 84
22
16
19
20
A1
B2
47; 50
49; 48
95; 91
90; 99
115
106
21
22
A1
B2
54; 46
48; 41
b
94; 99
87; 99
118
76
a
Conditions A1; Ph2CHCO2H (0.75 eq.), Piv2O (0.9 eq.), and i-Pr2NEt (1.2 eq.). Conditions B2; (Ph2CHCO)2O
(DPHAA; 0.75 eq.) and i-Pr2NEt (0.75 eq.).

Molecules 2018, 23, 2003
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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)- and the isothiouronium salt derived from the mixed anhydride and (R)-BTM. The formation of a
3
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

Molecules 2018, 23, 2003
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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
Figure 1. Three-dimensional structures of the calculated transition states ((R)-3a-TS and (S)-3a-TS).
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.

Molecules 2018, 23, 2003
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Scheme 3. Calculated transition states with a KR of (±)-5.
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.

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Preferable transition structure ((R)-5a-TS)
Erel = 0.00 kcal/mol
Unfavorable transition structure [(S)-5a-TS]
Erel = 3.24 kcal/mol
Figure 2. Three-dimensional structures of the calculated transition states ((R)-5a-TS and (S)-5a-TS).
Scheme 4. Transformation of chiral 2-hydroxyamides and their esters.

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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 ((
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 L, 0.18 mmol), i-Pr2NEt (62.7 L, 0.36 mmol) and (R)-BTM (2.5 mg, 0.01 mmol). The reaction
±
)-1d) with
±
µ
µ
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 ((
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 L,
±
)-1d) with
±
µ
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,
1
1550 cm–1; H 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.

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(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
1
cm–1; H 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):
1
3424, 3309, 1743, 1673, 1542, 748, 709 cm–1; H 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):
170.7,
δ
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, 20-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,
0
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,

Molecules 2018, 23, 2003
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1H, 20-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, 20-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):
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):
174.2, 68.9, 36,3, 35,7, 27,5, 9.1; HR MS: calcd for C6H13NO2Na [M + Na]+ 154.0838, found
154.0845.
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,
δ
(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):
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):
174.4, 67.6, 36.7, 36.2, 35.7, 18.2, 13.6; HR MS: calcd for C7H15NO2Na [M + Na]+
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,
δ
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):
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); 13
NMR (125 MHz, CDCl3): 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.
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),
C
δ
(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

Molecules 2018, 23, 2003
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(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); 13
NMR (125 MHz, CDCl3): 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.
C
δ
(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):
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,
;
δ
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):
1
3278, 1635 cm−1; H 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,
0
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, 20-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):
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.
δ

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(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, 20-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):
172.4, 169.5,
δ
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, 20-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, 20-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):
172.4,
δ
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, 20-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).
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):
7.29–7.13 (m, 10H, Ph),
5.06 (s, 1H, 20-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):
172.5, 169.1, 138.6,
HPLC (CHIRALPAK IC,
δ
δ
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, 20-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):
172.2, 168.1, 138.4,
δ
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

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(neat): 1743, 1666, 1496, 1466, 748, 717 cm−1; 01H 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),
0
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); 13
C
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); 13
NMR (CDCl3):
174.6, 72.8, 32.3, 31.3, 19.6, 15.2; HR MS: calcd for C7H15NO3Na [M + Na]+ 184.0944,
found 184.0949.
C
δ
(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.

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(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, 20-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, 20-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):
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.
δ

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(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, 20-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):
172.7, 170.2, 138.6, 138.5, 128.8,
δ
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).
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): 7.42–7.21 (m, 10H, Ph), 5.17 (s, 1H, 20-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):
172.6, 169.5, 138.6,
HPLC (CHIRALPAK IC,
δ
δ
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):
172.6, 170.2, 138.6, 138.5, 128.8, 128.8,
δ
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, 20-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,
0
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):
(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
δ 7.36–7.21 (m, 10H, Ph), 5.48
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):
61.3, 56.7, 32.1, 25.7, 18.2,
480.2174.
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,
5.5,
5.6; HR MS: calcd for C25H35NO5SiNa [M + Na]+ 480.2177, found
−
−

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(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, 20-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, 735,0701 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); 13
NMR (CDCl3): 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.
C
δ
−
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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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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