Diastereoselective intermolecular coupling of chiral α-imino amides with ketones by electroreduction

Article abstract of DOI:10.1016/j.tetasy.2011.10.022

The electroreductive intermolecular coupling of chiral α-imino N,N-dialkylamides derived from (S)-α-amino N,N-dialkylamides and aromatic aldehydes with ketones in the presence of chlorotrimethylsilane and triethylamine gave β-amino alcohols with moderate to good (R)-stereoselectivity.

Full text of DOI:10.1016/j.tetasy.2011.10.022

Tetrahedron: Asymmetry 22 (2011) 1906–1917
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective intermolecular coupling of chiral a-imino amides with
ketones by electroreduction
⇑
Naoki Kise , Aiko Yamane, Shingo Nakao, Akiko Takebe, Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101, Koyama-cho Minami, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2011
Accepted 27 October 2011
The electroreductive intermolecular coupling of chiral
a-imino N,N-dialkylamides derived from (S)-a-
amino N,N-dialkylamides and aromatic aldehydes with ketones in the presence of chlorotrimethylsilane
and triethylamine gave b-amino alcohols with moderate to good (R)-stereoselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
triethylamine (TEA).8 However, the electroreduction of chiral
a-
imino esters prepared from (S)-a-amino acids with acetone only
The reductive coupling of imines with carbonyl compounds is a
promising method for the synthesis of b-amino alcohols. A number
of methods have been reported for this purpose using metal reduc-
ing agents such as NbCl3(DME),1 Cp2Zr,2 Li-naphthalene,3 TiCl3,4
and SmI2,5 and electroreduction.6 Several of these2,5c–f have accom-
plished the diastereoselective imino pinacol coupling of chiral imi-
nes with carbonyl compounds for the asymmetric synthesis of
optically active b-amino alcohols, which are useful as chiral ligands
and auxiliaries.7 On the other hand, we have reported the electrore-
gave intramolecularly coupled azetidines,8a while the desired
intermolecularly coupled products, b-amino alcohols, could not
be obtained (Eq. 1). Therefore, we investigated the other chiral imi-
nes derived from (S)-
coupling with carbonyl compounds. Herein we report that the
electroreductive intermolecular coupling of chiral (S)- -imino
a-amino acids as substrates for the reductive
a
N,N-dialkylamides with ketones gave the corresponding b-amino
alcohols with moderate to good (R)-stereoselectivity (Eq. 2). This
reaction provides a synthetic method for a new class of chiral b-
ductive intramolecular coupling of aromatic
ters in the presence of chlorotrimethylsilane (TMSCl) and
a
-, b-, and
c
-imino es-
amino alcohols from readily available optically active
acids.
a-amino
Ph
TMSO
Ph
OR
1) +2e
TMSCl/Et3N
O
(S)
N
CO2R
+
ð1Þ
2) BzCl/Et3N
N
Bz
60%
R3
R3
(R)
Ar
Ar
1) +2e
OH
CONR2
O
TMSCl/Et3N
ð2Þ
N
CONR2
+
2
(S)
HN
(S)
2
R3
R3
2) TBAF
R1
R1
⇑
Corresponding author.
E-mail address: kise@bio.tottori-u.ac.jp (N. Kise).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.022

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1907
Table 1
Electroreductive coupling of (S)-
a
-benzylideneamino N,N-dimethylamides with acetone
(R)
Ph
Ph
1) +2e
O
OH
TMSCl/Et3N
HN
CONMe2
N
CONMe2
+
2) TBAF
R1
R1
(5 equiv)
Run
Imines
R1
Products
% yielda
(R):(S)b
1
2
3
4
5
1a
3a
5
7
9
i-Pr
sec-Bu
i-Bu
Bn
2a
4a
6
8
10
68
62
65
55
57
72:28
72:28
60:40
54:46
63:37
CH2CH2CO2Me
a
Isolated yields.
Determined by separation.
b
Ph
SiMe3
CONMe2
Ph
HN
CONMe2
HN
R1
R1
I
II
THF to give the corresponding chiral b-amino alcohols as mixtures
2. Results and discussion
of two diastereomers. The results of the electroreductive coupling
of (S)-
several (S)-
a
-benzylideneamino N,N-dimethylamides, prepared from
Chiral imines were prepared by the condensation of (S)-
a-ami-
a
-amino acids with acetone and subsequent desilyla-
no N,N-dialkylamides, derived from readily available (S)- -amino
a
tion of the resulting trimethylsilyl ethers, are summarized in Ta-
ble 1. From chiral imines 1a (R1 = i-Pr) and 3a (R1 = sec-Bu), b-
amino alcohols 2a and 4a were obtained with the same (R):(S) ratio
of 72:28 and in 68% and 62% yields, respectively (runs 1 and 2).
acids, with aromatic aldehydes. The electroreduction of the chiral
aromatic imines with acetone (5 equiv) was carried out in 0.3 M
Bu4NClO4 in THF containing TMSCl (5 equiv) and Et3N (5 equiv)
at a constant current of 100 mA (300 C) employing a divided cell
and platinum electrodes, according to our previously reported
method.8 The resulting silyl ethers were desilylated with TBAF in
Other chiral imines
5
(R1 = i-Bu),
7
(R1 = Bn), and
9
(R1 = CH2CH2CO2Me) afforded b-amino alcohols 6, 8, and 10 in low-
Figure 1. X-ray crystal structures of (R)-2a, (R)-4a, and (R)-6.

1908
N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
Figure 2. X-ray crystal structures of (R)-2c and (S)-2c.
er diastereomeric ratios than for 1a and 3a (runs 3–5). The diaste-
reomers of the resulting b-amino alcohols could be separated by
column chromatography and the absolute configuration of the
newly-formed stereogenic center in the major isomers of 2a, 4a,
and 6 was determined to be (R) by X-ray crystallographic analysis
(Fig. 1). Therefore, it was likely that the sense of the newly-formed
stereogenic center in the major isomers of 8 and 10 was also (R).
The by-products of the electroreductive intermolecular coupling
Next, several aromatic imines derived from (S)-valine N,N-
diethylamide were subjected to reductive coupling with acetone
to study the effect of the aromatic substituent on the diastereose-
lectivity in the cross coupling (Table 2). Substitution of the elec-
tron donating para-methoxy group slightly decreased the (R):(S)
ratio in b-amino alcohol 12 (run 1), whereas electron withdraw-
ing meta-methoxy and para-cyano substituents increased the (R)-
selectivity in 14 and 16 (runs 2 and 3). 1- and 2-Naphthyl imines
17 and 19 also gave b-amino alcohols 18 and 20, respectively,
with increased (R):(S) ratios (runs 4 and 5). Of these coupling
products shown in Table 2, the stereostructures of (R)-12,
(S)-14, and (R)-20 were confirmed by X-ray crystallography
(Fig. 3).
The electroreduction of 1a,b with cyclopentanone and cyclo-
hexanone also gave the corresponding b-amino alcohols 21a,b
and 22a,b, respectively (Eqs. 5 and 6). Although the diastereoselec-
tivities in 21a,b and 22a,b were higher than those in the cross cou-
pled products with acetone 2a,b, the yields, especially of 22a,b,
were much lower than those of 2a,b. Incidentally, the electroreduc-
tive coupling of 1b with n-butyraldehyde afforded b-amino alcohol
23 in good yield (Eq. 7). However, 23 was obtained as a mixture of
four possible diastereomers (ca. 1:1:1:1). In addition, the
electroreduction of 1b with benzaldehyde gave a homo-coupled
product of benzaldehyde (pinacol) as the only product and no
cross-coupled product was detected.
were simply reduced amines I (10–15%) and N-a-trimethylsilylat-
ed products II (5–10%). Similar to previous reports for the elect-
roreductive intramolecular coupling,8 the presence of TMSCl was
essential for the present intermolecular coupling. Although the
presence of Et3N was not absolutely necessary, the absence of
Et3N brought about a slight decrease of the yields of the coupled
products; the electroreduction of 1a with acetone in the absence
of Et3N gave 2a in a 55% yield [(R):(S) = 72:28].
(S)-a
-Benzylideneamino N,N-diethylamides 1b (R1 = i-Pr) and
3b (R1 = sec-Bu) and piperidine amide 1c were employed for the
electroreductive coupling with acetone (Eqs. 3 and 4). Cross cou-
pled products 2b,c and 4b were obtained in 60–65% yields with
the same (R):(S) ratio of 75:25, which was slightly higher than with
N,N-dimethylamides 2a and 4a [(R):(S) = 72:28]. The diastereomers
of 2b,c and 4b could be separated by column chromatography and
the stereostructures of both diastereomers of 2c were assigned by
X-ray crystallographic analysis (Fig. 2).
Ph
(R)
Ph
1) +2e
TMSCl/Et3N
O
OH
N
CONEt2
+
HN
CONEt2
2) TBAF
ð3Þ
R1
R1
(5 equiv)
1b (R1 = i-Pr)
2b
4b
65% (R):(S) = 75:25
62% (R):(S) = 75:25
3b (R1 = sec-Bu)
(R)
Ph
Ph
1) +2e
TMSCl/Et3N
OH
O
HN
CON
N
CON
+
ð4Þ
2) TBAF
(5 equiv)
2c 60% (R):(S) = 75:25
1c

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1909
Table 2
Electroreductive coupling of (S)-
a
-arylideneamino N,N-diethylamides with acetone
(R)
Ar
Ar
1) +2e
TMSCl/Et3N
OH
O
HN
CONEt2
N
CONEt2
+
2) TBAF
(5 equiv)
Run
Imines
Ar
Products
% Yielda
R:Sb
1
2
3
4
5
11
13
15
17
19
p-MeOC6H4
m-MeOC6H4
p-NCC6H4
1-Naphthyl
2-Naphthyl
12
14
16
18
20
68
64
50
55
58
72:28
80:20
89:11
88:12
84:16
a
Isolated yields.
Determined by separation.
b
Ph
Ph (R)
O
1) +2e
TMSCl/Et3N
OH
CONR2
N
CONR2
2
+
HN
2
2) TBAF
ð5Þ
1a (R2 = Me)
(5 equiv)
21a
21b
48% (R):(S) = 82:18
39% (R):(S) = 90:10
2
1b
(R = Et)
Ph
O
1) +2e
TMSCl/Et3N
(R)
Ph
OH
N
CONR2
2
+
HN
CONR2
2
2) TBAF
ð6Þ
ð7Þ
1a (R2 = Me)
(5 equiv)
2
22a
22b
1b
32% (R):(S) = 88:12
25% (R):(S) = >99:1
(R = Et)
OH
Ph
Ph
1) +2e
TMSCl/Et3N
CHO
+
N
CONEt2
HN
CONEt2
2) TBAF
(5 equiv)
1b
23
76% (ca. 1:1:1:1)
A plausible mechanism for the electroreductive coupling of
TBAF affords b-amino alcohol 2a. Substitution of the electron
withdrawing group on the phenyl group stabilizes anion B and
therefore increases the stereoselectivity in the nucleophilic
addition of B to acetone (Table 1, runs 2 and 3). The naphthyl
groups stabilize anion B more strongly by a resonance effect than
a phenyl group and thus the stereoselectivity increases (Table 1,
runs 4 and 5). In order to study the (R)-stereoselectivity in the
imine 1a with acetone is shown in Scheme 1. As previously repor-
ted,8a 1a forms complex A with TMSCl. Anion B generated by the
two-electron transfer to A attacks acetone through transition state
TS; this is followed by the O-silylation of the resulting adduct C to
give N,O-disilylated D. The TMS ether E is obtained by N-desilyla-
tion of D during workup and subsequent O-desilylation of E with

1910
N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
Figure 3. X-ray crystal structures of (R)-12, (S)-14, and (R)-20.
Cl
Ph
Ph
Ph
H
+TMSCl
-TMSCl
Ph
O
+2e
O
N
TMSN
TMSN
N
TMS
CONMe2
1a
CONMe2
CONMe2
CONMe2
A
B
(R)-TS
OH
OTMS
OTMS
O
Ph
Ph
Ph
Ph
H
TBAF
H
H
work-up
+TMSCl
H
HN
HN
TMSN
TMSN
CONMe2
(R)-2a
CONMe2
CONMe2
CONMe2
E
D
C
Scheme 1. Reaction mechanism of electroreductive coupling of 1a with acetone.
addition of B to acetone, the energetically lowest transition states
leading to the (R)- and (S)-adducts were optimized by the DFT
method at the B3LYP/6-311+G(d,p) level and their energies were
calculated using the PCM model for the THF solvent at the same
level (Fig. 4). The results of the calculations show that (R)-TS is
lower in energy than (S)-TS (0.81 kcal/mol corresponding to
R:S = 80:20); this is in good agreement with the experimental
results [(R):(S) = 72:28].

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1911
2.194 A
2.200 A
(R)-TS
(S)-TS
0 kcal/mol
0.81 kcal/mol
Figure 4. Optimized structures and relative energies at the B3LYP/6-311+G(d,p) level using the IEFPCM model (THF) of transition states (R)-TS and (S)-TS for the addition of B
to acetone.
128.4 (d), 130.7 (d), 135.8 (s), 161.7 (d), 171.1 (s). Anal. Calcd for
14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.34; H, 8.73;
3. Conclusion
C
N, 11.96.
The electroreduction of chiral aromatic (S)-a-imino N,N-dial-
kylamides derived from (S)-a-amino acids with acetone in the
presence of TMSCl and TEA led to cross-coupled products, b-amino
alcohols has been reported, in moderate to good yields and (R)-ste-
reoselectivity. Electron withdrawing group substituted aromatic
imines and naphthyl imines afforded b-amino alcohols with rela-
tively high (R)-stereoselectivity. The electroreductive coupling
with cyclopentanone and cyclohexanone gave the corresponding
b-amino alcohols with good to high diastereoselectivity, although
the yields decreased.
4.2.2. (S,E)-2-(Benzylideneamino)-N,N-diethyl-3-methylbutana-
mide 1b
White solid. Rf 0.5 (hexanes–ethyl acetate, 2:1). Mp 51–52 °C
(hexanes–ethyl acetate, 5:1). ½a D23
ꢀ
¼ ꢁ15:0 (c 1.15, CHCl3). IR
(KBr) 1641, 1578, 937, 835, 812, 758, 698 cmꢁ1
.
1H NMR (CDCl3)
d 0.91 (d, 3H, J = 6.4 Hz), 1.02 (d, 3H, J = 6.9 Hz), 1.15 (t, 3H,
J = 6.9 Hz), 1.19 (t, 3H, J = 6.9 Hz), 2.37–2.46 (m, 1H), 3.30–3.39
(m, 1H), 3.41–3.51 (m, 2H), 3.65–3.74 (m, 1H), 3.93 (d, 1H,
J = 9.6 Hz), 7.40–7.47 (m, 3H), 7.76–7.82 (m, 2H), 8.32 (s, 1H). 13C
NMR (CDCl3) d 12.8 (q), 14.7 (q), 19.4 (q), 19.8 (q), 31.3 (d), 40.4
(t), 41.3 (t), 79.3 (d), 128.2 (d), 128.4 (d), 130.7 (d), 135.9 (s),
161.5 (d), 170.3 (s). Anal. Calcd for C16H24N2O: C, 73.81; H, 9.29;
N, 10.76. Found: C, 73.74; H, 9.33; N, 10.57.
4. Experimental
4.1. General
All 1H and 13C NMR spectra were measured on a JEOL GMX-500
spectrometer with tetramethylsilane (TMS) as an internal stan-
dard. IR spectra were recorded on a Shimadzu FTIR-8300 infrared
spectrometer. Optical rotations were obtained on a Jasco DIP-360
digital polarimeter. Melting points were uncorrected. Column
chromatography was performed on silica gel 60. THF was freshly
distilled from sodium benzophenone ketyl. TMSCl and TEA were
distilled from CaH2.
4.2.3. (S,E)-2-(Benzylideneamino)-3-methyl-1-(piperidin-1-
yl)butan-1-one 1c
Colorless paste. Rf 0.5 (hexanes–ethyl acetate, 2:1).
½
a 2D0
ꢀ
¼ þ12:7 (c 1.04, CHCl3). IR (neat) 1630, 1578, 996, 957, 853,
845, 806, 756, 743, 694 cmꢁ1 1H NMR (CDCl3) d 0.88 (d, 3H,
.
J = 6.4 Hz), 1.03 (d, 3H, J = 6.9 Hz), 1.47–1.67 (m, 6 H), 2.31–2.42
(m, 1H), 3.47–3.53 (m, 1H), 3.60–3.67 (m, 1H), 3.68–3.75 (m,
1H), 3.86–3.93 (m, 2H), 7.38–7.46 (m, 3H), 7.73–7.78 (m, 2H),
8.27 (s, 1H). 13C NMR (CDCl3) d 19.7 (q), 19.8 (q), 24.5 (t), 25.7
(t), 26.5 (t), 30.9 (d), 43.5 (t), 46.5 (t), 81.6 (d), 128.2 (d), 128.4
(d), 130.7 (d), 135.9 (s), 161.6 (d), 169.5 (s).
4.2. Chiral a-imino N,N-dialkylamides
Chiral
a-imino N,N-dialkylamides were synthesized by the
treatment of (S)-a-amino acid N,N-dialkylamides with aromatic
aldehydes in dichloromethane in the presence of magnesium sul-
fate at room temperature. Solid imines were purified by recrystal-
lization, whereas paste ones were used without purification.
4.2.4. (2S,3S,E)-2-(Benzylideneamino)-N,N,3-trimethylpentana-
mide 3a
White solid. Rf 0.25 (hexanes–ethyl acetate, 2:1). Mp 65–67 °C
(hexanes–ethyl acetate, 10:1). ½a D21
ꢀ
¼ ꢁ40:6 (c 1.02, CHCl3). IR
(KBr) 1630, 1580, 974, 810, 775, 760, 746, 698, 650 cmꢁ1
.
1H
4.2.1. (S,E)-2-(Benzylideneamino)-N,N,3-trimethylbutanamide
1a
NMR (CDCl3) d 0.87 (t, 3H, J = 7.6 Hz), 0.96 (d, 3H, J = 7.0 Hz),
0.91–1.06 (m, 1H), 1.46–1.58 (m, 1H), 2.15–2.28 (m, 1H), 2.96 (s,
3H), 3.24 (s, 3H), 4.03 (d, 1H, J = 9.6 Hz), 7.37–7.47 (m, 3H), 7.73–
7.80 (m, 2H), 8.28 (s, 1H). 13C NMR (CDCl3) d 10.7 (q), 15.7 (q),
25.4 (t), 36.1 (q), 36.99 (d), 37.09 (q), 79.0 (d), 128.3 (d), 128.5
(d), 130.8 (d), 135.9 (s), 161.8 (d), 171.3 (s). Anal. Calcd for
White solid. Rf 0.3 (hexanes–ethyl acetate, 2:1). Mp 115–117 °C
(hexanes–ethyl acetate, 2:1). ½a D22
ꢀ
¼ þ40:6 (c 1.02, CHCl3). IR (KBr)
1638, 1599, 1578, 845, 824, 764, 746, 700, 652 cmꢁ1
.
1H NMR
(CDCl3) d 0.89 (d, 3H, J = 6.9 Hz), 1.00 (d, 3 H, J = 6.9 Hz), 2.36–
2.47 (m, 1H), 2.97 (s, 3 H), 3.23 (s, 3 H), 3.93 (d, 1 H, J = 9.2 Hz),
7.39–7.46 (m, 3H), 7.76–7.79 (m, 2H), 8.28 (s, 1H). 13C NMR (CDCl3)
d 19.4 (q), 19.7 (q), 30.9 (d), 36.0 (q), 37.0 (q), 80.1 (d), 128.3 (d),
C15H22N2O: C, 73.13; H, 9.00; N, 11.37. Found: C, 73.05; H, 9.11;
N, 11.19.

1912
N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
4.2.5. (2S,3S,E)-2-(Benzylideneamino)-N,N-diethyl-3-methyl-
pentanamide 3b
3H, J = 7.1 Hz), 2.35–2.44 (m, 1H), 3.29–3.37 (m, 1H), 3.38–3.48
(m, 2H), 3.63–3.72 (m, 1H), 3.85 (s, 3H), 3.91 (d, 1H, J = 9.5 Hz),
6.96–7.00 (m, 1H), 7.27–7.34 (m, 2H), 7.37–7.39 (m, 1H), 8.27 (s,
1H). 13C NMR (CDCl3) d 12.8 (q), 14.8 (q), 19.4 (q), 19.8 (q), 31.3
(d), 40.4 (t), 41.3 (t), 55.2 (q), 79.2 (d), 111.8 (d), 117.3 (d), 121.6
(d), 129.3 (d), 137.4 (s), 159.7 (s), 161.4 (d), 170.3 (s).
Colorless paste. Rf 0.55 (hexanes–ethyl acetate, 2:1).
½
a 2D6
ꢀ
¼ þ7:0 (c 1.08, CHCl3). IR (neat) 1632, 1578, 804, 773, 756,
746, 696 cmꢁ1 1H NMR (CDCl3) d 0.88 (t, 3H, J = 7.6 Hz), 0.97 (d,
.
3H, J = 6.6 Hz), 0.98–1.07 (m, 1H), 1.13 (t, 3H, J = 7.3 Hz), 1.16 (t,
3H, J = 7.3 Hz), 1.49–1.58 (m, 1H), 2.16–2.25 (m, 1H), 3.27–3.35
(m, 1H), 3.40–3.49 (m, 2H), 3.66–3.74 (m, 1H), 4.01 (d, 1H,
J = 9.8 Hz), 7.38–7.45 (m, 3H), 7.75–7.80 (m, 2H), 8.30 (s, 1H). 13C
NMR (CDCl3) d 10.6 (q), 12.7 (q), 14.7 (q), 15.7 (q), 25.3 (t), 37.3
(d), 40.3 (t), 41.3 (t), 78.0 (d), 128.2 (d), 128.4 (d), 130.7 (d),
135.9 (s), 161.5 (d), 170.3 (s).
4.2.11. (S,E)-2-(4-Cyanobenzylideneamino)-N,N-diethyl-3-
methylbutanamide 15
Colorless paste. Rf 0.45 (hexanes–ethyl acetate, 1:1).
½
a 2D3
ꢀ
¼ þ3:7 (c 1.08, CHCl3). 1H NMR (CDCl3) d 0.90 (d, 3H,
J = 6.5 Hz), 1.01 (d, 3H, J = 6.6 Hz), 1.14 (t, 3H, J = 7.0 Hz), 1.17 (t,
3H, J = 7.1Hz), 2.34–2.46 (m, 1H), 3.31–3.51 (m, 3H), 3.56–3.66
(m, 1H), 4.01 (d, 1H, J = 9.5 Hz), 7.68–7.73 (m, 2H), 7.85–7.90 (m,
2H), 8.34 (s, 1H). 13C NMR (CDCl3) d 12.7 (q), 14.7 (q), 19.3 (q),
19.7 (q), 31.4 (d), 40.4 (t), 41.4 (t), 78.5 (d), 113.8 (s), 118.2 (s),
128.6 (d), 132.1 (d), 139.6 (s), 159.6 (d), 169.7 (s).
4.2.6. (S,E)-2-(Benzylideneamino)-N,N,4-trimethylpentanamide
5
White solid. Rf 0.3 (hexanes–ethyl acetate, 2:1). Mp 85–87 °C
(hexanes–ethyl acetate, 10:1). ½a D20
ꢀ
¼ ꢁ32:2 (c 1.01, CHCl3). IR
(KBr) 1630, 1580, 988, 802, 760, 743, 698 cmꢁ1
.
1H NMR (CDCl3)
d 0.94 (d, 3H, J = 6.9 Hz), 0.95 (d, 3H, J = 6.4 Hz), 1.56–1.87 (m,
3H), 2.97 (s, 3H), 3.18 (s, 3H), 4.53 (t, 1H, J = 6.9 Hz), 7.38–7.45
(m, 3H), 7.74–7.78 (m, 2H), 8.30 (s, 1H). 13C NMR (CDCl3) d 22.2
(q), 23.0 (q), 24.8 (d), 36.0 (q), 37.0 (q), 42.0 (t), 68.9 (d), 128.3
(d), 128.5 (d), 130.8 (d),136.0 (s), 161.6 (d), 171.6 (s). Anal. Calcd
for C15H22N2O: C, 73.13; H, 9.00; N, 11.37. Found: C, 72.94; H,
9.08; N, 11.23.
4.2.12. (S,E)-N,N-Diethyl-3-methyl-2-(naphthalen-1-ylmethyl-
eneamino)butanamide 17
White solid. Rf 0.4 (hexanes–ethyl acetate, 2:1). Mp 54–56 °C.
½
a 2D2
ꢀ
¼ ꢁ1:1 (c 1.01, CHCl3). IR (KBr) 1620, 1574, 939, 818, 802,
773, 737, 723 cmꢁ1 1H NMR (CDCl3) d 0.98 (d, 3H, J = 6.5 Hz),
.
1.06 (d, 3H, J = 6.2Hz), 1.15 (t, 3H, J = 7.0 Hz), 1.18 (t, 3H,
J = 7.0 Hz), 2.44–2.54 (m, 1H), 3.31–3.40 (m, 1H), 3.43–3.57 (m,
2H), 3.68–3.76 (m, 1H), 4.03 (d, 1H, J = 9.3Hz), 7.50–7.55 (m,
2H), 7.56–7.60 (m, 1H), 7.87–7.95 (m, 3H), 8.90 (d, 1H,
J = 8.3Hz), 8.96 (s, 1H). 13C NMR (CDCl3) d 12.8 (q), 14.8 (q),
19.6 (q), 20.0 (q), 31.5 (d), 40.4 (t), 41.3 (t), 80.3 (d), 124.2 (d),
125.1 (d), 125.9 (d), 127.1 (d), 128.5 (d), 129.1 (d), 131.1 (d),
131.2 (s), 131.3 (s), 133.7 (s), 161.4 (d), 170.4 (s). Anal. Calcd
for C20H26N2O: C, 77.38; H, 8.44; N, 9.02. Found: C, 77.42; H,
8.43; N, 8.93.
4.2.7. (S,E)-2-(Benzylideneamino)-N,N-dimethyl-3-phenylpro-
panamide 7
White solid. Rf 0.7 (hexanes–ethyl acetate, 5:1). Mp 117.5–
119 °C (hexanes–ethyl acetate, 2:1). ½a D22
¼ ꢁ183 (c 1.02, CHCl3).
ꢀ
IR (KBr) 1634, 1578, 966, 839, 795, 756, 741, 708, 692, 669 cmꢁ1
.
1H NMR (CDCl3) d 2.95 (s, 3H), 2.99 (s, 3H), 3.08 (dd, 1H, J = 7.5,
13.6 Hz), 3.35 (dd, 1H, J = 6.1, 13.6 Hz), 4.62 (dd, 1H, J = 6.1,
7.5 Hz), 7.15–7.27 (m, 5 H), 7.36–7.44 (m, 3H), 7.68–7.72 (m,
2H), 8.03 (s, 1H). 13C NMR (CDCl3) d 35.9 (q), 36.8 (q), 39.4 (t),
71.5 (d), 126.2 (d), 128.1 (d), 128.2 (d), 128.3 (d), 129.6 (d), 130.8
(d), 135.7 (s), 138.1 (s), 162.3 (d), 170.6 (s). Anal. Calcd for
4.2.13. (S,E)-N,N-Diethyl-3-methyl-2-(naphthalen-2-ylmethyl-
eneamino)butanamide 19
Colorless paste. Rf 0.4 (hexanes–ethyl acetate, 2:1).
C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found: C, 77.08; H, 7.20; N,
½
a 2D2
ꢀ
¼ ꢁ22:4 (c 1.05, CHCl3). 1H NMR (CDCl3) d 0.93 (d, 3H,
9.93.
J = 6.7 Hz), 1.03 (d, 3H, J = 6.6 Hz), 1.14 (t, 3H, J = 7.0 Hz), 1.19 (t,
3H, J = 7.0 Hz), 2.40–2.48 (m, 1H), 3.31–3.39 (m, 1H), 3.41–3.51
(m, 2H), 3.67–3.75 (m, 1H), 3.98 (d, 1H, J = 9.6 Hz), 7.48–7.55 (m,
2H), 7.83–7.91 (m, 3H), 8.03–8.05 (m, 1H), 8.06 (br s, 1H), 8.46
(s, 1H). 13C NMR (CDCl3) d 12.8 (q), 14.8 (q), 19.5 (q), 19.9 (q),
31.5 (d), 40.4 (t), 41.4 (t), 79.3 (d), 123.8 (d), 126.3 (d), 127.1 (d),
127.7 (d), 128.2 (d), 128.5 (d), 130.3 (d), 132.9 (s), 133.6 (s),
134.7 (s), 161.6 (d), 170.4 (s).
4.2.8. (S,E)-Methyl 4-(benzylideneamino)-5-(dimethylamino)-5-
oxopentanoate 9
Pale yellow paste. ½a D22
ꢀ
¼ ꢁ44:3 (c 1.20, CHCl3). IR (neat) 1733,
1H NMR (CDCl3) d 2.12–
1699, 1647, 1579, 1497, 758, 696 cmꢁ1
.
2.20 (m, 1H), 2.26–2.34 (m, 1H), 2.38–2.44 (m, 2H), 2.98 (s, 3H),
3.13 (s, 3H), 3.65 (s, 3H), 4.50–4.53 (m, 1H), 7.38–7.47 (m, 3H),
7.73–7.78 (m, 2H), 8.30 (s, 1H). 13C NMR (CDCl3) d 28.1 (t), 30.2
(t), 35.8 (q), 36.8 (q), 51.4 (q), 68.8 (d), 128.2 (d), 128.4 (d), 130.9
(d), 135.5 (s), 162.5 (d), 170.5 (s), 173.4 (s).
4.3. Typical procedure for electroreductive coupling and
desilylation
4.2.9. (S,E)-N,N-Diethyl-2-(4-methoxybenzylideneamino)-3-
A 0.3 M solution of Bu4NClO4 in THF (15 mL) was placed in the
cathodic chamber of a divided cell (40 mL beaker, 3 cm diameter,
6 cm height) equipped with a platinum cathode (5 ꢂ 5 cm2), a plat-
inum anode (2 ꢂ 1 cm2), and a ceramic cylindrical diaphragm
(1.5 cm diameter). A 0.3 M solution of Bu4NClO4 in DMF (4 mL)
was placed in the anodic chamber (inside the diaphragm). Imine
1a (232 mg, 1 mmol), acetone (348 mg, 5 mmol), TMSCl (0.64 mL,
5 mmol), and triethylamine (0.70 mL, 5 mmol) were added to the
cathodic chamber. After 300 C of electricity was passed at a con-
stant current of 100 mA at room temperature, the catholyte was
evaporated in vacuo. The residue was diluted with Et2O (30 mL)
and the insoluble Bu4NClO4 was filtered off. The filtrate was evap-
orated in vacuo. The residue was dissolved in THF (10 mL). To the
solution was added 1 M TBAF in THF (1.0 mL, 1.0 mmol) in an ice
bath, and then the mixture was stirred at this temperature for
15 min. After the addition of acetic acid (60 mg, 1.0 mmol), the
methylbutanamide 11
Colorless paste. Rf 0.6 (hexanes–ethyl acetate, 1:1). ½a D23
¼ ꢁ5:0
ꢀ
(c 1.05, CHCl3). 1H NMR (CDCl3) d 0.86 (d, 3H, J = 6.6 Hz), 0.99 (d,
3H, J = 6.6 Hz), 1.12 (t, 3H, J = 7.1Hz), 1.16 (t, 3H, J = 7.2 Hz), 2.32–
2.43 (m, 1H), 3.28–3.37 (m, 1H), 3.38–3.48 (m, 2H), 3.62–3.72
(m, 1H), 3.84 (s, 3H), 3.86 (d, 1H, J = 10.3Hz), 6.90–6.95 (m, 2H),
7.69–7.74 (m, 2H), 8.22 (s, 1H). 13C NMR (CDCl3) d 12.7 (q), 14.6
(q), 19.4 (q), 19.7 (q), 31.2 (d), 40.2 (t), 41.2 (t), 55.0 (q), 79.1 (d),
113.7 (d), 128.8 (s), 129.7 (d), 160.6 (d), 161.6 (s), 170.4 (s).
4.2.10. (S,E)-N,N-Diethyl-2-(3-methoxybenzylideneamino)-3-
methylbutanamide 13
Colorless paste. Rf 0.6 (hexanes–ethyl acetate, 1:1).
½
a 2D0
ꢀ
¼ ꢁ13:4 (c 1.07, CHCl3). 1H NMR (CDCl3) d 0.89 (d, 3H,
J = 6.7 Hz), 1.00 (d, 3H, J = 6.5 Hz), 1.13 (t, 3H, J = 7.1Hz), 1.17 (t,

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1913
solvent was removed in vacuo. The crude mixture was purified by
column chromatography on silica gel to give 2a in a 68% yield with
a (R):(S) = 72:28 diastereomeric ratio.
1H NMR (CDCl3) d 0.89 (d, 3H, J = 6.9 Hz), 0.99 (d, 3H, J = 6.9 Hz),
1.05 (s, 3H), 1.18 (s, 3H), 1.22–1.38 (m, 3H), 1.50–1.63 (m, 2H),
1.70–1.78 (m, 1H), 2.63 (br s, 1H), 2.80 (s, 1H), 2.96 (t, 2H,
J = 5.5 Hz), 3.03 (d, 1H, J = 6.4 Hz), 3.33 (s, 1H), 3.45–3.52 (m, 1H),
3.65–3.72 (m, 1H), 7.23–7.37 (m, 5 H). 13C NMR (CDCl3) d 18.1
(q), 20.1 (q), 24.0 (q), 24.4 (t), 25.9 (t), 26.2 (t), 28.4 (q), 31.7 (d),
42.9 (t), 46.0 (t), 59.8 (d), 70.2 (d), 72.7 (s), 127.2 (d), 127.6 (d),
129.3 (d), 140.2 (s), 173.2 (s). Anal. Calcd for C20H32N2O2: C,
72.25; H, 9.70; N, 8.43. Found: C, 72.21; H, 9.73; N, 8.40.
4.3.1. (S)-2-((R)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,3-trimethylbutanamide (R)-2a
White solid. Rf 0.25 (hexanes–ethyl acetate, 1:5). Mp 175 °C
(hexanes–ethyl acetate, 1:2). ½a D24
ꢀ
¼ ꢁ76:0 (c 1.05, CHCl3). IR
(KBr) 3479, 1634, 1493, 895, 791, 746, 710 cmꢁ1
.
1H NMR (CDCl3)
d 0.87 (d, 3H, J = 6.9 Hz), 1.01 (d, 3 H, J = 6.9 Hz), 1.05 (s, 3H), 1.19
(s, 3H), 1.72–1.80 (m, 1H), 2.53 (s, 3H), 2.57 (br s, 1H), 2.68 (br s,
1H), 2.96 (s, 3H), 3.02 (d, 1H, J = 6.4 Hz), 3.31 (s, 1H), 7.24–7.37
(m, 5 H). 13C NMR (CDCl3) d 18.4 (q), 19.6 (q), 23.6 (q), 28.2 (q),
31.6 (d), 35.3 (q), 36.4 (q), 59.9 (d), 70.0 (d), 72.5 (s), 127.1 (d),
127.5 (d), 129.2 (d), 140.1 (s), 175.2 (s). Anal. Calcd for
4.3.6. (S)-2-((S)-2-Hydroxy-2-methyl-1-phenylpropylamino)-3-
methyl-1-(piperidin-1-yl)butan-1-one (S)-2c
White solid. Rf 0.6 (hexanes–ethyl acetate, 1:2). Mp 104.5–
106 °C (hexane). ½a D21
ꢀ
¼ þ57:7 (c 0.92, CHCl3). 1H NMR (CDCl3) d
0.73–0.82 (m, 1H), 0.92 (d, 3H, J = 6.9 Hz), 0.98 (d, 3H, J = 6.9 Hz),
1.09 (s, 3H), 1.11 (s, 3H), 1.10–1.16 (m, 1H), 1.21–1.44 (m, 4 H),
1.65 (br s, 1H), 1.72–1.80 (m, 1H), 2.89–2.95 (m, 1H), 2.97–3.10
(m, 3H), 3.37–3.44 (m, 2H), 4.19 (br s, 1H), 7.17–7.28 (m, 5 H).
13C NMR (CDCl3) d 18.1 (q), 19.9 (q), 23.8 (q), 24.3 (t), 25.2 (t),
25.7 (t), 27.1 (q), 32.9 (d), 42.9 (t), 46.4 (t), 61.9 (d), 72.3 (s), 75.3
(d), 127.1 (d), 127.7 (d), 128.8 (d), 139.8 (s), 173.0 (s). Anal. Calcd
for C20H32N2O2: C, 72.25; H, 9.70; N, 8.43. Found: C, 72.26; H,
9.68; N, 8.41.
C17H28N2O2: C, 69.83; H, 9.85; N, 9.58. Found: C, 69.84; H, 9.88;
N, 9.51.
4.3.2. (S)-2-((S)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,3-trimethylbutanamide (S)-2a
Colorless paste. Rf 0.5 (hexanes–ethyl acetate, 1:5). ½a D23
¼
ꢀ
þ44:3 (c 1.40, CHCl3). IR (neat) 3431, 1636, 737, 702 cmꢁ1
.
1H
NMR (CDCl3) d 0.86 (d, 3H, J = 6.9 Hz), 1.04 (d, 3H, J = 6.9 Hz),
1.09 (s, 3H), 1.10 (s, 3H), 1.78–1.85 (m, 1H), 2.49 (s, 3H), 2.53 (s,
3H), 2.77 (br s, 1H), 2.98 (d, 1H, J = 7.3Hz), 3.43 (s, 1H), 4.06 (br
s, 1H), 7.15–7.29 (m, 5 H). 13C NMR (CDCl3) d 18.7 (q), 19.3 (q),
23.8 (q), 27.0 (q), 32.8 (d), 35.0 (q), 36.6 (q), 62.6 (d), 72.2 (s),
74.9 (d), 127.2 (d), 127.5 (d), 128.5 (d), 139.6 (s), 175.1 (s). Anal.
Calcd for C17H28N2O2: C, 69.83; H, 9.85; N, 9.58. Found: C, 69.72;
H, 9.83; N, 9.46.
4.3.7. (2S,3S)-2-((R)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,3-trimethylpentanamide (R)-4a
White solid. Rf 0.35 (hexanes–ethyl acetate, 1:2). Mp 148–
149 °C (hexanes–ethyl acetate, 1:1). ½a D23
¼ ꢁ72:0 (c 1.00, CHCl3).
ꢀ
1H NMR (CDCl3) d 0.81 (d, 3H, J = 7.1 Hz), 0.86 (t, 3H, J = 7.8 Hz),
1.06 (s, 3H), 1.18 (s, 3H), 1.19–1.28 (m, 1H), 1.49–1.61 (m, 1H),
1.78–1.90 (m, 1H), 2.50 (s, 3H), 2.57 (br s, 1H), 2.87 (br s, 1H),
2.96 (s, 3H), 3.07 (d, 1H, J = 7.4 Hz), 3.33 (s, 1H), 7.22–7.38 (m, 5
H). 13C NMR (CDCl3) d 11.0 (q), 15.6 (q), 23.6 (q), 24.6 (t), 28.2
(q), 35.3 (q), 36.5 (q), 38.2 (d), 58.9 (d), 70.0 (d), 72.5 (s), 127.1
(d), 127.5 (d), 129.2 (d), 140.1 (s), 175.4 (s). Anal. Calcd for
4.3.3. (S)-N,N-Diethyl-2-((R)-2-hydroxy-2-methyl-1-phenyl-
propylamino)-3-methylbutanamide (R)-2b
White solid. Rf 0.3 (hexanes–ethyl acetate, 1:1). Mp 106–
107 °C (hexanes–ethyl acetate, 2:1). ½a D24
ꢀ
¼ ꢁ84:8 (c 1.09, CHCl3).
IR (KBr) 3422, 1620, 880, 772, 741, 704 cmꢁ1
.
1H NMR (CDCl3) d
C18H30N2O2: C, 70.55; H, 9.87; N, 9.14. Found: C, 70.52; H, 9.87;
N, 9.08.
0.81 (t, 3H, J = 6.9 Hz), 0.94 (d, 3H, J = 6.9 Hz), 0.99 (d, 3H,
J = 6.9 Hz), 1.07 (s, 3H), 1.12 (t, 3H, J = 6.9 Hz), 1.18 (s, 3H),
1.70–1.80 (m, 1H), 2.67 (br s, 1H), 2.78 (br s, 1H), 2.78–2.87 (m,
1H), 2.98 (d, 1H, J = 5.5 Hz), 3.01–3.16 (m, 2H), 3.32 (s, 1H),
3.60–3.68 (m, 1H), 7.23–7.31 (m, 3H), 7.34–7.39 (m, 2H). 13C
NMR (CDCl3) d 12.7 (q), 13.8 (q), 17.5 (q), 20.0 (q), 23.4 (q),
28.0 (q), 31.6 (d), 39.7 (t), 40.7 (t), 59.6 (d), 69.9 (d), 72.4 (s),
126.9 (d), 127.3 (d), 129.2 (d), 140.1 (s), 173.7 (s). Anal. Calcd
for C19H32N2O2: C, 71.21; H, 10.06; N, 8.74. Found: C, 71.25; H,
10.09; N, 8.69.
4.3.8. (2S,3S)-2-((S)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,3-trimethylpentanamide (S)-4a
Colorless paste. Rf 0.6 (hexanes–ethyl acetate, 1:2).
½
a 2D3
ꢀ
¼ ꢁ40:4 (c 1.05, CHCl3). 1H NMR (CDCl3) d 0.80 (d, 3H,
J = 7.1Hz), 0.90 (t, 3H, J = 7.5 Hz), 1.09 (s, 6 H), 1.17–1.30 (m, 1H),
1.56–1.67 (m, 1H), 1.76–1.87 (m, 1H), 2.47 (s, 3H), 2.51 (s, 3H),
3.05 (d, 1H, J = 8.1Hz), 3.42 (s, 1H), 4.03 (br s, 1H), 7.15–7.31 (m,
5 H). 13C NMR (CDCl3) d 11.1 (q), 15.2 (q), 23.8 (q), 25.0 (t), 27.0
(q), 35.0 (q), 36.6 (q), 39.3 (d), 61.3 (d), 72.2 (s), 74.8 (d), 127.2
(d), 127.5 (d), 128.5 (d), 139.6 (s), 175.2 (s). Anal. Calcd for
4.3.4. (S)-N,N-Diethyl-2-((S)-2-hydroxy-2-methyl-1-phenyl-
propylamino)-3-methylbutanamide (S)-2b
C18H30N2O2: C, 70.55; H, 9.87; N, 9.14. Found: C, 70.66; H, 9.95;
N, 9.02.
Colorless paste. Rf 0.55 (hexanes–ethyl acetate, 1:1).
½
a 2D3
ꢀ
¼ þ35:6 (c 1.26, CHCl3). IR (neat) 3437, 1632, 737,
702 cmꢁ1 1H NMR (CDCl3) d 0.65 (t, 3H, J = 6.9 Hz), 0.87 (t, 3H,
.
4.3.9. (2S,3S)-N,N-Diethyl-2-((R)-2-hydroxy-2-methyl-1-phenyl-
propylamino)-3-methylpentanamide (R)-4b
J = 7.3 Hz), 0.96 (d, 3H, J = 6.4 Hz), 0.98 (d, 3H, J = 6.9 Hz), 1.09 (s,
3H), 1.10 (s, 3H), 1.72–1.81 (m, 1H), 2.85–3.02 (m, 4 H), 3.07–
3.25 (m, 2H), 3.44 (s, 1H), 4.23 (br s, 1H), 7.16–7.25 (m, 5 H). 13C
NMR (CDCl3) d 12.6 (q), 13.5 (q), 17.5 (q), 20.0 (q), 23.6 (q), 26.9
(q), 32.8 (d), 40.2 (t), 41.4 (t), 62.0 (d), 72.2 (s), 74.8 (d), 127.5
(d), 128.0 (d), 128.6 (d), 139.6 (s), 173.6 (s). Anal. Calcd for
Colorless paste. Rf 0.55 (hexanes–ethyl acetate, 1:1).
½
a 2D4
ꢀ
¼ ꢁ73:1 (c 1.50, CHCl3). 1H NMR (CDCl3) d 0.81 (t, 3H,
J = 7.1 Hz), 0.87 (t, 3H, J = 7.5 Hz), 0.89 (d, 3H, J = 7.1 Hz), 1.06 (s,
3H), 1.12 (t, 3H, J = 7.2 Hz), 1.17 (s, 3H), 1.15–1.24 (m, 1H), 1.45–
1.54 (m, 1H), 1.74–1.82 (m, 1H), 2.72 (br s, 1H), 2.77–2.85 (m,
1H), 2.99–3.07 (m, 1H), 3.01 (d, 1H, J = 6.4 Hz), 3.11–3.19 (m,
1H), 3.31 (s, 1H), 3.58–3.66 (m, 1H), 7.23–7.31 (m, 3H), 7.33–
7.38 (m, 2H). 13C NMR (CDCl3) d 11.4 (q), 12.8 (q), 13.8 (q), 16.2
(q), 23.6 (q), 24.2 (t), 28.2 (q), 38.6 (d), 39.9 (t), 40.9 (t), 59.3 (d),
70.0 (d), 72.6 (s), 127.1 (d), 127.5 (d), 129.3 (d), 140.1 (s), 174.1
(s). Anal. Calcd for C20H34N2O2: C, 71.81; H, 10.25; N, 8.37. Found:
C, 71.93; H, 10.38; N, 8.20.
C19H32N2O2: C, 71.21; H, 10.06; N, 8.74. Found: C, 71.40; H,
10.14; N, 8.58%.
4.3.5. (S)-2-((R)-2-Hydroxy-2-methyl-1-phenylpropylamino)-3-
methyl-1-(piperidin-1-yl)butan-1-one (R)-2c
White solid. Rf 0.4 (hexanes–ethyl acetate, 1:2). Mp 154.5–
156 °C (hexanes–ethyl acetate, 2:1). ½a D22
¼ ꢁ73:7 (c 1.00, CHCl3).
ꢀ

1914
N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
4.3.10. (2S,3S)-N,N-Diethyl-2-((S)-2-hydroxy-2-methyl-1-phenyl-
propylamino)-3-methylpentanamide (S)-4b
4.3.15. (S)-Methyl 5-(dimethylamino)-4-((R)-2-hydroxy-2-
methyl-1-phenylpropylamino)-5-oxopentanoate (R)-10
Colorless paste. Rf 0.2 (hexanes–ethyl acetate, 1:5).
Colorless paste. Rf 0.7 (hexanes–ethyl acetate, 1:1).
½
a 2D4
ꢀ
¼ þ27:6 (c 1.14, CHCl3). 1H NMR (CDCl3) d 0.67 (t, 3H,
½
a 2D3
ꢀ
¼ þ58:7 (c 1.73, CHCl3). IR (neat) 3433, 1734, 1636, 1493,
J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz), 0.89 (t, 3H, J = 7.5 Hz), 0.90 (d,
3H, J = 6.8 Hz), 1.07 (s, 3H), 1.09 (s, 3H), 1.20–1.30 (m, 1H), 1.50–
1.59 (m, 1H), 1.66–1.75 (m, 1H), 2.87–2.98 (m, 3H), 3.01 (d, 1H,
J = 6.1 Hz), 3.12–3.20 (m, 1H), 3.44 (s, 1H), 4.23 (br s, 1H), 7.15–
7.25 (m, 5 H). 13C NMR (CDCl3) d 11.4 (q), 12.5 (q), 13.6 (q), 16.1
(q), 23.6 (q), 24.3 (t), 26.9 (q), 39.8 (d), 40.1 (t), 41.5 (t), 61.6 (d),
72.3 (s), 74.7 (d), 127.0 (d), 127.5 (d), 128.6 (d), 139.6 (s), 173.8
(s). Anal. Calcd for C20H34N2O2: C, 71.81; H, 10.25; N, 8.37. Found:
C, 72.02; H, 10.34; N, 8.18.
885, 739, 706 cmꢁ1 1H NMR (CDCl3) d 1.06 (s, 3H), 1.15 (s, 3H),
.
1.56–1.66 (m, 1H), 1.75–1.84 (m, 1H), 2.43–2.50 (m, 1H), 2.67 (s,
3H), 2.68–2.76 (m, 1H), 2.95 (s, 3H), 3.25 (dd, 1H, J = 3.7,
11.0 Hz), 3.33 (s, 1H), 3.61 (s, 3H), 3.69 (br s, 2H), 7.21–7.32 (m,
5 H). 13C NMR (CDCl3) d 23.0 (q), 27.6 (t), 28.1 (q), 29.7 (t), 35.5
(q), 36.1 (q), 51.2 (q), 53.7 (d), 70.1 (d), 72.6 (s), 127.1 (d), 127.5
(d), 128.9 (d), 139.8 (s), 173.6 (s), 175.0 (s). Anal. Calcd for
C19H30N2O4: C, 65.12; H, 8.63; N, 7.99. Found: C, 65.37; H, 8.81;
N, 7.84.
4.3.16. (S)-Methyl 5-(dimethylamino)-4-((S)-2-hydroxy-2-
methyl-1-phenylpropylamino)-5-oxopentanoate (S)-10
Colorless paste. Rf 0.3 (hexanes–ethyl acetate, 1:5).
4.3.11. (S)-2-((R)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,4-trimethylpentanamide (R)-6
White solid. Rf 0.4 (hexanes–ethyl acetate, 1:2). Mp 99.5–
½
a 2D3
ꢀ
¼ þ31:4 (c 1.14, CHCl3). IR (neat) 3433, 1734, 1638, 1493,
101.5 °C (hexane). ½a D21
ꢀ
¼ ꢁ78:7 (c 1.01, CHCl3). 1H NMR (CDCl3)
737, 704 cmꢁ1 1H NMR (CDCl3) d 1.10 (s, 3H), 1.11 (s, 3H), 1.73–
.
d 0.74 (d, 3H, J = 6.5 Hz), 0.90 (d, 3H, J = 6.6 Hz), 1.05 (s, 3H),
1.08–1.15 (m, 1H), 1.19 (s, 3H), 1.40–1.48 (m, 1H), 1.98–2.08 (m,
1H), 2.55 (s, 3H), 2.68 (br s, 2H), 2.94 (s, 3H), 3.27 (dd, 1H, J = 3.3,
10.7 Hz), 3.37 (s, 1H), 7.23–7.38 (m, 5 H). 13C NMR (CDCl3) d 21.3
(q), 23.6 (q), 24.0 (q), 24.4 (d), 28.5 (q), 35.6 (q), 36.1 (q), 42.8 (t),
53.3 (d), 70.1 (d), 72.5 (s), 127.3 (d), 127.7 (d), 129.2 (d), 140.2
(s), 175.8 (s). Anal. Calcd for C18H30N2O2: C, 70.55; H, 9.87; N,
9.14. Found: C, 70.57; H, 9.90; N, 9.08.
1.85 (m, 2H), 2.38–2.45 (m, 2H), 2.57 (s, 3H), 2.61 (s, 3H), 3.42 (s,
1H), 3.41–3.45 (m, 1H), 3.69 (s, 3H), 7.17–7.29 (m, 5 H). 13C NMR
(CDCl3) d 24.1 (q), 27.2 (q), 29.0 (t), 29.6 (t), 35.2 (q), 36.5 (q),
51.5 (q), 55.4 (d), 72.2 (s), 73.8 (d), 127.2 (d), 127.6 (d), 128.5 (d),
139.4 (s), 174.1 (s), 174.6 (s). Anal. Calcd for C19H30N2O4: C,
65.12; H, 8.63; N, 7.99. Found: C, 65.39; H, 8.79; N, 7.75.
4.3.17. (S)-N,N-Diethyl-2-((R)-2-hydroxy-1-(4-methoxyphenyl)-
2-methylpropylamino)-3-methylbutanamide (R)-12
4.3.12. (S)-2-((S)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N,4-trimethylpentanamide (S)-6
White solid. Rf 0.55 (hexanes–ethyl acetate, 1:2). Mp 139–
140.5 °C (hexanes–ethyl acetate, 1:1). ½a D24
¼ þ90:0 (c 1.03, CHCl3).
ꢀ
1H NMR (CDCl3) d 0.85 (t, 3H, J = 6.9 Hz), 0.93 (d, 3H, J = 6.9 Hz),
0.98 (d, 3H, J = 6.9 Hz), 1.05 (s, 3H), 1.12 (t, 3H, J = 6.9 Hz), 1.16
(s, 3H), 1.71–1.78 (m, 1H), 2.62 (br s, 2H), 2.81–2.90 (m, 1H),
2.97 (d, 1H, J = 5.5 Hz), 3.03–3.16 (m, 4 H), 3.25 (s, 1H), 3.61–3.69
(m, 1H), 3.81 (s, 3H), 6.81–6.86 (m, 2H), 7.24–7.30 (m, 2H). 13C
NMR (CDCl3) d 12.9 (q), 14.1 (q), 17.6 (q), 20.2 (q), 23.9 (q), 28.1
(q), 31.7 (d), 39.9 (t), 40.9 (t), 55.0 (q), 59.9 (d), 69.4 (d), 72.7 (s),
112.9 (d), 130.2 (d), 132.1 (s), 158.7 (s), 173.9 (s). Anal. Calcd for
Colorless paste. Rf 0.45 (hexanes–ethyl acetate, 1:2).
½
a 2D4
ꢀ
¼ þ21:1 (c 0.90, CHCl3). 1H NMR (CDCl3) d 0.90 (d, 3H,
J = 6.9 Hz), 0.92 (d, 3H, J = 6.9 Hz), 1.10 (s, 6 H), 1.21–1.28 (m,
1H), 1.51–1.58 (m, 1H), 1.78–1.87 (m, 1H), 2.09 (br s, 1H), 2.55
(s, 3H), 2.57 (s, 3H), 3.36 (dd, 1H, J = 4.9, 9.1 Hz), 3.45 (s, 1H),
3.57 (br s, 1H), 7.19–7.29 (m, 5 H). 13C NMR (CDCl3) d 22.1 (q),
23.3 (q), 23.8 (q), 24.5 (d), 27.2 (q), 35.3 (q), 36.5 (q), 43.9 (t),
54.9 (d), 72.2 (s), 74.1 (d), 127.3 (d), 127.6 (d), 128.6 (d), 139.5
(s), 175.6 (s). Anal. Calcd for C18H30N2O2: C, 70.55; H, 9.87; N,
9.14. Found: C, 70.72; H, 10.04; N, 8.96.
C20H34N2O3: C, 68.54; H, 9.78; N, 7.99. Found: C, 68.57; H, 9.78;
N, 7.91.
4.3.18. (S)-N,N-Diethyl-2-((S)-2-hydroxy-1-(4-methoxyphenyl)-
2-methylpropylamino)-3-methylbutanamide (S)-12
4.3.13. (S)-2-((R)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N-dimethyl-3-phenylpropanamide (R)-8
Colorless paste. Rf 0.6 (hexanes–ethyl acetate, 1:2).
Colorless paste. Rf 0.4 (hexanes–ethyl acetate, 1:5).
a 2D2
ꢀ
¼ þ56:0 (c 1.04, CHCl3). 1H NMR (CDCl3) d 0.72 (t, 3H,
½ ꢀ
a 2D3
¼ þ12:0 (c 1.07, CHCl3). 1H NMR (CDCl3) d 1.04 (s, 3H), 1.17
½
J = 7.3Hz), 0.88 (t, 3H, J = 7.3Hz), 0.95 (d, 3H, J = 6.6 Hz), 0.98 (d,
3H, J = 6.5 Hz), 1.08 (s, 6 H), 1.74–1.81 (m, 1H), 2.89–3.05 (m, 4
H), 3.14–3.23 (m, 1H), 3.39 (s, 1H), 3.56 (br s, 2H), 6.76–6.80 (m,
2H), 7.07–7.11 (m, 2H). 13C NMR (CDCl3) d 12.6 (q), 13.7 (q), 17.6
(q), 20.0 (q), 23.6 (q), 26.9 (q), 32.8 (d), 40.2 (t), 41.5 (t), 55.1 (q),
62.2 (d), 72.4 (s), 74.1 (d), 113.0 (d), 129.6 (d), 131.6 (s), 158.7
(s), 173.8 (s). Anal. Calcd for C20H34N2O3: C, 68.54; H, 9.78; N,
7.99. Found: C, 68.68; H, 9.87; N, 7.72.
(s, 3H), 2.11 (s, 3H), 2.74–2.87 (m, 2H), 2.84 (s, 3H), 3.03 (br s,
2H), 3.39 (s, 1H), 3.47 (t, 1H, J = 7.2 Hz), 7.08–7.25 (m, 10 H). 13C
NMR (CDCl3) d 24.0 (q), 28.2 (q), 35.4 (q), 35.9 (q), 40.6 (t), 56.8
(d), 69.9 (d), 72.4 (s), 126.3 (d), 127.2 (d), 127.7 (d), 128.0 (d),
129.0 (d), 129.2 (d), 137.9 (s), 139.7 (s), 174.5 (s). Anal. Calcd for
C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found: C, 74.18; H, 8.34;
N, 8.02.
4.3.14. (S)-2-((S)-2-Hydroxy-2-methyl-1-phenylpropylamino)-
N,N-dimethyl-3-phenylpropanamide (S)-8
4.3.19. (S)-N,N-Diethyl-2-((R)-2-hydroxy-1-(3-methoxyphenyl)-
2-methylpropylamino)-3-methylbutanamide (R)-14
White solid. Rf 0.5 (hexanes–ethyl acetate, 1:5). Mp 133–135 °C
Colorless paste. Rf 0.2 (hexanes–ethyl acetate, 1:1).
(hexanes–ethyl acetate, 5:1). ½a D25
ꢀ
¼ þ109 (c 1.03, CHCl3). 1H NMR
½
a 2D5
ꢀ
¼ þ85:0 (c 1.01, CHCl3). 1H NMR (CDCl3) d 0.85 (t, 3H,
(CDCl3) d 1.04 (s, 3H), 1.07 (s, 3H), 2.23 (s, 3H), 2.48 (s, 3H), 2.83
(dd, 1H, J = 7.9, 13.1 Hz), 2.91 (dd, 1H, J = 7.0, 13.1 Hz), 3.38 (s,
1H), 3.52 (dd, 1H, J = 7.0, 7.9 Hz), 3.54 (br s, 2H), 7.11–7.28 (m,
10 H). 13C NMR (CDCl3) d 23.9 (q), 27.1 (q), 35.0 (q), 36.2 (q),
41.1 (t), 58.7 (d), 72.0 (s), 73.3 (d), 126.4 (d), 127.2 (d), 127.6 (d),
128.2 (d), 128.5 (d), 129.1 (d), 138.0 (s), 139.4 (s), 174.3 (s). Anal.
Calcd for C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found: C, 74.07;
H, 8.32; N, 8.19.
J = 6.9 Hz), 0.95 (d, 3H, J = 6.9 Hz), 1.00 (d, 3H, J = 6.6 Hz), 1.09
(s, 3H), 1.12 (t, 3H, J = 7.0 Hz), 1.18 (s, 3H), 1.72–1.80 (m, 1H),
2.55 (br s, 2H), 2.82–2.90 (m, 1H), 3.00 (d, 1H, J = 5.5 Hz),
3.04–3.16 (m, 2H), 3.29 (s, 1H), 3.61–3.69 (m, 1H), 3.79 (s,
3H), 6.78–6.83 (m, 1H), 6.90 (brd, 1H, J = 7.3 Hz), 7.00 (br s,
1H), 7.18 (t, 1H, J = 7.8 Hz). 13C NMR (CDCl3) d 12.7 (q), 13.8
(q), 17.7 (q), 20.1 (q), 23.5 (q), 28.2 (q), 31.7 (d), 39.9 (t), 41.0
(t), 54.8 (q), 59.8 (d), 69.9 (d), 72.6 (s), 112.8 (d), 114.2 (d),

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1915
122.0 (d), 128.3 (d), 141.9 (s), 159.0 (s), 174.0 (s). Anal. Calcd for
20H34N2O3: C, 68.54; H, 9.78; N, 7.99. Found: C, 68.72; H, 9.90;
N, 7.75.
J = 7.1 Hz), 0.68 (t, 3H, J = 7.1 Hz), 0.97 (d, 3H, J = 6.9 Hz), 1.02
(d, 3H, J = 6.8 Hz), 1.09 (s, 3H), 1.20 (s, 3H), 1.70–1.80 (m, 1H),
2.54–2.64 (m, 1H), 2.67–2.86 (m, 2H), 2.94 (d, 1H, J = 5.5 Hz),
2.94–3.03 (m, 1H), 4.51 (s, 1H), 7.39–7.56 (m, 4 H), 7.71 (br s,
1H, J = 8.1 Hz), 7.80–7.84 (m, 1H), 8.16 (brd, 1H, J = 8.6 Hz). 13C
NMR (CDCl3) d 12.5 (q), 13.2 (q), 17.8 (q), 20.1 (q), 24.3 (q),
27.2 (q), 32.9 (d), 40.0 (t), 41.1 (t), 62.5 (d), 66.8 (d), 73.5 (s),
123.1 (d), 125.0 (d), 125.76 (d), 125.80 (d), 127.5 (d), 128.9 (d),
132.9 (s), 133.5 (s), 136.1 (s), 173.5 (s). Anal. Calcd for
C
4.3.20. (S)-N,N-Diethyl-2-((S)-2-hydroxy-1-(3-methoxyphenyl)-
2-methylpropylamino)-3-methylbutanamide (S)-14
White solid. Rf 0.5 (hexanes–ethyl acetate, 1:1). Mp 94–96 °C.
½
a 1D9
ꢀ
¼ þ49:6 (c 1.02, CHCl3). IR (KBr) 3364, 1632, 1601, 1593,
945, 899, 833, 797, 777, 762, 702 cmꢁ1 1H NMR (CDCl3) d 0.69 (t,
.
3H, J = 7.3 Hz), 0.88 (t, 3H, J = 7.0 Hz), 0.95 (d, 3H, J = 6.9 Hz), 0.98
(d, 3H, J = 6.9 Hz), 1.11 (s, 3H), 1.12 (s, 3H), 1.74–1.81 (m, 1H),
2.89–3.04 (m, 4 H), 3.18–3.27 (m, 1H), 3.43 (s, 1H), 3.78 (s, 3H),
4.11 (br s, 2H), 6.71–6.78 (m, 3H), 7.11–7.16 (m, 1H). 13C NMR
(CDCl3) d 12.6 (q), 13.6 (q), 17.7 (q), 20.1 (q), 23.9 (q), 27.0 (q),
32.9 (d), 40.2 (t), 41.6 (t), 55.1 (q), 62.2 (d), 72.5 (s), 74.8 (d),
112.9 (d), 113.9 (d), 121.3 (d), 128.6 (d), 141.3 (s), 159.1 (s),
173.9 (s). Anal. Calcd for C20H34N2O3: C, 68.54; H, 9.78; N, 7.99.
Found: C, 68.59; H, 9.82; N, 7.88.
C23H34N2O2: C, 74.55; H, 9.25; N, 7.56. Found: C, 74.66; H, 9.32;
N, 7.38.
4.3.25. (S)-N,N-Diethyl-2-((R)-2-hydroxy-2-methyl-1-(naphtha-
len-2-yl)propylamino)-3-methylbutanamide (R)-20
White solid. Rf 0.3 (hexanes–ethyl acetate, 1:1). Mp 109.5–
110 °C (hexanes–ethyl acetate, 2:1). ½a D22
¼ þ95:8 (c 1.10, CHCl3).
ꢀ
1H NMR (CDCl3) d 0.75 (t, 3H, J = 7.3Hz), 0.94 (d, 3H, J = 6.8 Hz),
1.02 (d, 3H, J = 6.6 Hz), 1.12 (s, 3H), 1.13 (t, 3H, J = 7.0 Hz), 1.22
(s, 3H), 1.72–1.80 (m, 1H), 2.34–2.82 (m, 1H), 2.93–3.17 (m, 5 H),
3.48 (s, 1H), 3.62–3.70 (m, 1H), 7.44–7.49 (m, 2H), 7.55–7.61 (m,
1H), 7.76–7.85 (m, 4 H). 13C NMR (CDCl3) d 12.9 (q), 13.9 (q),
17.7 (q), 20.2 (q), 23.8 (q), 28.3 (q), 31.8 (d), 39.9 (t), 40.9 (t),
60.1 (d), 70.3 (d), 72.9 (s), 125.5 (d), 125.7 (d), 127.0 (d), 127.4
(d), 127.6 (d), 128.4 (d), 132.9 (s), 138.1 (s), 174.1 (s). Anal. Calcd
for C23H34N2O2: C, 74.55; H, 9.25; N, 7.56. Found: C, 74.54; H,
9.28; N, 7.52.
4.3.21. (S)-2-((R)-1-(4-Cyanophenyl)-2-hydroxy-2-methylpropyl-
amino)-N,N-diethyl-3-methylbutanamide (R)-16
Colorless paste. Rf 0.3 (hexanes–ethyl acetate, 1:2).
½
a 2D3
ꢀ
¼ ꢁ92:3 (c 1.11, CHCl3). 1H NMR (CDCl3) d 0.84 (t, 3H,
J = 7.3 Hz), 0.95 (d, 3H, J = 6.9 Hz), 0.97 (d, 3H, J = 6.9 Hz), 1.05 (s,
3H), 1.12 (t, 3H, J = 7.1 Hz), 1.17 (s, 3H), 1.72–1.80 (m, 1H), 2.77–
3.18 (m, 6 H), 3.36 (s, 1H), 3.65–3.73 (m, 1H), 7.50–7.55 (m, 2H),
7.58–7.62 (m, 2H). 13C NMR (CDCl3) d 12.8 (q), 14.0 (q), 17.4 (q),
20.1 (q), 23.6 (q), 27.9 (q), 31.6 (d), 40.0 (t), 40.9 (t), 60.1 (d),
70.0 (d), 72.4 (s), 110.8 (s), 118.6 (s), 130.0 (d), 131.2 (d), 146.5
(s), 173.4 (s). Anal. Calcd for C20H31N3O2: C, 69.53; H, 9.04; N,
12.16. Found: C, 69.74; H, 9.18; N, 12.03.
4.3.26. (S)-N,N-Diethyl-2-((S)-2-hydroxy-2-methyl-1-(naphtha-
len-2-yl)propylamino)-3-methylbutanamide (S)-20
Colorless paste. Rf 0.45 (hexanes–ethyl acetate, 1:1).
½
a 2D4
ꢀ
¼ þ57:6 (c 1.03, CHCl3). 1H NMR (CDCl3) d 0.50 (t, 3H,
J = 6.9 Hz), 0.64 (t, 3H, J = 6.9 Hz), 0.96 (d, 3H, J = 6.8 Hz), 1.01 (d,
3H, J = 6.8 Hz), 1.15 (s, 6 H), 1.76–1.84 (m, 1H), 2.09 (s, 1H),
2.74–2.89 (m, 3H), 2.98–3.06 (m, 2H), 3.62 (s, 1H), 4.31 (br s,
1H), 7.32–7.37 (m, 1H), 7.40–7.47 (m, 2H), 7.63 (br s, 1H), 7.72
(brd, 1H, J = 8.8 Hz), 7.75–7.80 (m, 2H). 13C NMR (CDCl3) d 12.4
(q), 13.5 (q), 17.9 (q), 20.0 (q), 23.9 (q), 27.1 (q), 32.9 (d), 40.2 (t),
41.5 (t), 62.4 (d), 72.7 (s), 74.9 (d), 125.6 (d), 125.9 (d), 126.6 (d),
127.2 (d), 127.4 (d), 127.6 (d), 127.7 (d), 132.7 (s), 132.8 (s),
137.3 (s), 173.8 (s). Anal. Calcd for C23H34N2O2: C, 74.55; H, 9.25;
N, 7.56. Found: C, 74.67; H, 9.38; N, 7.41.
4.3.22. (S)-2-((S)-1-(4-Cyanophenyl)-2-hydroxy-2-methylpropyl-
amino)-N,N-diethyl-3-methylbutanamide (S)-16
Colorless paste. Rf 0.65 (hexanes–ethyl acetate, 1:2).
½
a 2D1
ꢀ
¼ þ42:0 (c 1.05, CHCl3). 1H NMR (CDCl3) d 0.73 (t, 3H,
J = 7.6 Hz), 0.88 (t, 3H, J = 7.3 Hz), 0.96 (d, 3H, J = 6.7 Hz), 0.97 (d,
3H, J = 6.8 Hz), 1.06 (s, 3H), 1.12 (s, 3H), 1.73–1.82 (m, 1H), 2.90–
3.25 (m, 7 H), 3.47 (s, 1H), 7.32–7.37 (m, 2H), 7.53–7.58 (m, 2H).
13C NMR (CDCl3) d 12.6 (q), 13.9 (q), 17.4 (q), 20.1 (q), 24.1 (q),
27.0 (q), 32.8 (d), 40.3 (t), 41.5 (t), 62.4 (d), 72.3 (s), 74.4 (d),
110.9 (s), 118.6 (s), 129.5 (d), 131.3 (d), 146.0 (s), 173.2 (s). Anal.
Calcd for C20H31N3O2: C, 69.53; H, 9.04; N, 12.16. Found: C,
69.68; H, 9.22; N, 11.96.
4.3.27. (S)-2-((R)-(1-Hydroxycyclopentyl)(phenyl)methylamino)-
N,N,3-trimethylbutanamide (R)-21a
4.3.23. (S)-N,N-Diethyl-2-((R)-2-hydroxy-2-methyl-1-(naphtha-
len-1-yl)propylamino)-3-methylbutanamide (R)-18
White solid. Rf 0.45 (hexanes–ethyl acetate, 1:2). Mp 104–
105 °C (hexanes–ethyl acetate, 2:1). ½a D24
ꢀ
¼ ꢁ54:4 (c 1.04, CHCl3).
White solid. Rf 0.25 (hexanes–ethyl acetate, 1:1). Mp 76.5–
IR (KBr) 3454, 1632, 856, 760, 706 cmꢁ1
.
1H NMR (CDCl3) d 0.86
78.5 °C. ½a 2D3
ꢀ
¼ ꢁ7:4 (c 1.12, CHCl3). 1H NMR (CDCl3) d 0.31 (t,
(d, 3H, J = 6.9 Hz), 1.01 (d, 3H, J = 6.9 Hz), 1.12–1.18 (m, 1H),
1.39–1.87 (m, 8 H), 2.48 (s, 3H), 2.91 (br s, 1H), 2.95 (s, 3H), 3.02
(d, 1H, J = 6.9 Hz), 3.40 (s, 1H), 7.20–7.37 (m, 5 H). 13C NMR (CDCl3)
d 18.5 (q), 19.6 (q), 23.5 (t), 23.7 (t), 31.8 (d), 35.4 (q), 36.4 (q), 36.5
(t), 38.8 (t), 59.7 (d), 68.6 (d), 83.9 (s), 127.3 (d), 127.8 (d), 129.1
(d), 139.9 (s), 174.8 (s). Anal. Calcd for C19H30N2O2: C, 71.66; H,
9.50; N, 8.80. Found: C, 71.70; H, 9.53; N, 8.75.
3H, J = 7.1 Hz), 0.90 (d, 3H, J = 6.8 Hz), 1.01 (d, 3H, J = 6.8 Hz),
1.09 (t, 3H, J = 7.3Hz), 1.10 (s, 3H), 1.24 (s, 3H), 1.67–1.78 (m,
1H), 2.48–2.65 (m, 2H), 2.89 (d, 1H, J = 5.5 Hz), 3.07–3.16 (m,
1H), 3.45–3.54 (m, 1H), 4.42 (s, 1H), 7.34–7.44 (m, 2H), 7.52 (t,
1H, J = 7.7 Hz), 7.77 (br s, 1H, J = 8.1 Hz), 7.82–7.85 (m, 1H), 7.92–
7.95 (m, 1H), 8.06–8.10 (m, 1H). 13C NMR (CDCl3) d 12.9 (q), 13.0
(q), 17.8 (q), 20.2 (q), 24.2 (q), 28.6 (q), 31.8 (d), 40.0 (t), 40.7 (t),
59.8 (d), 61.9 (d), 73.7 (s), 123.5 (d), 124.8 (d), 125.1 (d), 125.4
(d), 126.6 (d), 127.4 (d), 128.7 (d), 133.4 (s), 133.5 (s), 135.9 (s),
174.1 (s). Anal. Calcd for C23H34N2O2: C, 74.55; H, 9.25; N, 7.56.
Found: C, 74.50; H, 9.26; N, 7.58.
4.3.28. (S)-2-((S)-(1-Hydroxycyclopentyl)(phenyl)methylamino)-
N,N,3-trimethylbutanamide (S)-21a
Colorless paste. Rf 0.5 (hexanes–ethyl acetate, 1:2). IR (neat)
3422, 1628, 1493, 731, 704 cmꢁ1 1H NMR (CDCl3) d 0.87 (d, 3H,
.
J = 6.9 Hz), 1.02 (d, 3H, J = 6.9 Hz), 1.35–1.65 (m, 4 H), 1.67–1.86
(m, 5 H), 2.50 (s, 3H), 2.61 (s, 3H), 3.04 (d, 1H, J = 7.3 Hz), 3.60 (s,
1H), 7.19–7.32 (m, 5 H). 13C NMR (CDCl3) d 18.6 (q), 19.4 (q),
23.2 (t), 23.3 (t), 32.8 (q), 35.1 (t), 36.7 (q), 37.3 (t), 62.3 (d), 72.2
(d), 83.9 (s), 127.2 (d), 127.6 (d), 128.8 (d), 140.3 (s), 175.2 (s).
4.3.24. (S)-N,N-Diethyl-2-((S)-2-hydroxy-2-methyl-1-(naphtha-
len-1-yl)propylamino)-3-methylbutanamide (S)-18
Colorless paste. Rf 0.45 (hexanes–ethyl acetate, 1:1).
½
a 2D3
ꢀ
¼ ꢁ22:0 (c 0.95, CHCl3). 1H NMR (CDCl3) d 0.28 (t, 3H,

1916
N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
4.3.29. N,N-Diethyl-2-((1-hydroxycyclopentyl)(phenyl)-
methylamino)-3-methylbutanamide 21b (9:1 diastereomeric
mixture)
4.4. X-ray crystallographic analysis
All measurements were made on a Rigaku RAXIS imaging plate
Pale yellow paste. Rf 0.4 (hexanes–ethyl acetate, 2:1). 1H NMR
(CDCl3) d 0.67 (t, 0.3H, J = 7.3 Hz), 0.77 (t, 2.7 H, J = 7.3 Hz), 0.87–
1.21 (m, 9 H), 1.33–1.89 (m, 9 H), 2.70–3.05 (m, 4 H), 3.07–3.17
(m, 0.9 H), 3.21–3.30 (m, 0.1H), 3.41 (s, 0.9 H), 3.56–3.66 (m,
1.1H), 7.13–7.45 (m, 5 H). 13C NMR (CDCl3) major: d 12.8 (q),
13.8 (q), 17.5 (q), 20.2 (q), 23.5 (t), 23.6 (t), 31.7 (d), 36.3 (t), 38.4
(t), 39.8 (t), 40.8 (t), 59.4 (d), 68.4 (d), 83.9 (s), 127.58 (d), 127.60
(d), 129.1 (d), 139.9 (s), 173.4 (s); minor: d 12.6 (q), 13.5 (q),
17.4 (q), 20.0 (q), 23.0 (t), 23.1 (t), 32.7 (d), 34.7 (t), 36.9 (t), 40.1
(t), 41.4 (t), 61.7 (d), 72.1 (d), 83.8 (s), 126.9 (d), 127.2 (d), 128.8
(d), 140.2 (s), 173.6 (s).
area detector with graphite monochromated Mo Ka radiation. The
structure was solved by direct methods with SIR-97 and refined
with SHELXL-97. The non-hydrogen atoms were refined anisotrop-
ically. Hydrogen atoms were refined isotropically. All calculations
were performed using the Yadokari-XG software package. CCDC
846727–846734 contain the supplementary crystallographic data.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_re-
quest/cif.
4.4.1. Crystal data for (R)-2a (CCDC 846729)
C17H28N2O2,
FW = 292.41,
mp
175 °C,
orthorhombic,
4.3.30. (S)-2-((R)-(1-Hydroxycyclohexyl)(phenyl)methylamino)-
N,N,3-trimethylbutanamide (R)-22a
P2(1)2(1)2(1) (no. 19), colorless block, a = 9.3264(11) Å, b =
11.7753(14) Å, c = 15.943(2) Å, V = 1750.9(4) Å3, T = 223 K, Z = 4,
White solid. Rf 0.55 (hexanes–ethyl acetate, 1:1). Mp 103–
Dcalcd = 1.109 g/cm3, = 0.72 cmꢁ1, GOF = 1.031.
l
105 °C. ½a 2D2
ꢀ
¼ þ35:1 (c 1.15, CHCl3). IR (KBr) 3383, 1630, 1559,
974, 883, 797, 704 cmꢁ1
.
1H NMR (CDCl3)
d
0.84 (d, 3H,
4.4.2. Crystal data for (R)-2c (CCDC 846730)
20H32N2O2, FW = 332.48, mp 154.5–156 °C, monoclinic, C2 (no.
J = 7.1 Hz), 1.00 (d, 3H, J = 6.8 Hz), 1.02–1.12 (m, 2H), 1.32–1.79
(m, 9 H), 2.47 (s, 3H), 2.87 (br s, 2H), 2.94 (s, 3H), 3.00 (d, 1H,
J = 6.8 Hz), 3.32 (s, 1H), 7.23–7.34 (m, 5 H). 13C NMR (CDCl3) d
18.5 (q), 19.6 (q), 21.5 (t), 21.7 (t), 25.8 (t), 31.8 (d), 32.9 (t), 35.4
(q), 36.0 (t), 36.5 (q), 59.9 (d), 69.7 (d), 72.8 (s), 127.2 (d), 127.7
(d), 129.6 (d), 139.5 (s), 175.1 (s). Anal. Calcd for C20H32N2O2: C,
72.25; H, 9.70; N, 8.43. Found: C, 72.35; H, 9.77; N, 8.38.
C
5), colorless block, a = 23.771(4) Å, b = 8.4539(14) Å, c = 9.9533
(15) Å,
b = 95.403(9),
V = 1991.3(5) Å3,
T = 298 K,
Z = 4,
Dcalcd = 1.109 g/cm3,
l
= 0.71 cmꢁ1, GOF = 1.023.
4.4.3. Crystal data for (S)-2c (CCDC 846734)
20H32N2O2, FW = 332.48, mp 104.5–106 °C, orthorhombic,
P2(1)2(1)2(1) (no. 19), colorless block, a = 9.094(3) Å, b = 11.307
(3) Å, c = 19.527(6) Å, V = 2008.1(10) Å3, T = 298 K, Z = 4, Dcalcd
1.100 g/cm3, = 0.71 cmꢁ1, GOF = 1.037.
C
4.3.31. (S)-2-((S)-(1-Hydroxycyclohexyl)(phenyl)methylamino)-
N,N,3-trimethylbutanamide (S)-22a
=
l
Colorless paste. Rf 0.6 (hexanes–ethyl acetate, 1:1).
½
a 2D3
ꢀ
¼ þ15:8 (c 1.05, CHCl3). 1H NMR (CDCl3) d 0.85 (d, 3H,
4.4.4. Crystal data for (R)-4a (CCDC 846731)
18H30N2O2, FW = 306.44, mp 148–149 °C, orthorhombic,
J = 6.8 Hz), 1.03 (d, 3H, J = 6.7 Hz), 0.89–1.85 (m, 11H), 2.48 (S,
3H), 2.52 (s, 3H), 2.84 (br s, 2H), 2.97 (d, 1H, J = 7.5 Hz), 3.36 (s,
1H), 7.14–7.32 (m, 5 H). 13C NMR (CDCl3) d 18.8 (q), 19.4 (q),
21.5 (t), 21.9 (t), 25.8 (t), 31.7 (t), 32.9 (d), 35.1 (q), 35.3 (t), 36.7
(q), 62.8 (d), 73.0 (s), 75.1 (d), 127.1 (d), 127.5 (d), 128.9 (d),
139.6 (s), 175.2 (s). Anal. Calcd for C20H32N2O2: C, 72.25; H, 9.70;
N, 8.43. Found: C, 72.44; H, 9.80; N, 8.21.
C
P2(1)2(1)2(1) (no 19), colorless block, a = 9.2602(8) Å, b =
12.6526(9) Å, c = 15.8514(9) Å, V = 1857.2(2) Å3, T = 298 K, Z = 4,
Dcalcd = 1.096 g/cm3,
l
= 0.71 cmꢁ1, GOF = 1.016.
4.4.5. Crystal data for (R)-6 (CCDC 846732)
18H30N2O2, FW = 306.44, mp 99.5–101.5 °C, orthorhombic,
C
P2(1)2(1)2(1) (no 19), colorless block, a = 8.9519(8) Å, b =
4.3.32. (S)-N,N-Diethyl-2-((R)-(1-hydroxycyclohexyl)(phenyl)-
methylamino)-3-methylbutanamide (R)-22b
12.5092(9) Å, c = 16.8022(14) Å, V = 1881.5(3) Å3, T = 203 K, Z = 4,
Dcalcd = 1.082 g/cm3,
l
= 0.70 cmꢁ1, GOF = 1.030.
Pale yellow paste. Rf 0.3 (hexanes–ethyl acetate, 2:1). 1H NMR
(CDCl3) d 0.79 (t, 3H, J = 7.1 Hz), 0.82–1.83 (m, 20 H), 2.62–2.84
(m, 2H), 2.91–3.04 (m, 2H), 3.31 (s, 1H), 3.55–3.65 (m, 1H), 7.19–
7.40 (m, 5 H). 13C NMR (CDCl3) d 12.9 (q), 13.9 (q), 17.6 (q), 20.2
(q), 21.5 (t), 21.7 (t), 25.8 (t), 31.8 (d), 33.0 (t), 35.9 (t), 39.9 (t),
40.9 (t), 59.7 (d), 69.6 (d), 72.8 (s), 127.2 (d), 127.5 (d), 129.6 (d),
139.5 (s), 173.6 (s).
4.4.6. Crystal data for (R)-12 (CCDC 846727)
20H34N2O3, FW = 350.49, mp 139–140.5 °C, orthorhombic,
C
P2(1)2(1)2(1) (no 19), colorless block, a = 9.6712(11) Å, b =
11.6120(10) Å, c = 18.4141(19) Å, V = 2067.9(4) Å3, T = 298 K,
Z = 4, Dcalcd = 1.126 g/cm3,
l
= 0.75 cmꢁ1, GOF = 1.033.
4.4.7. Crystal data for (S)-14 (CCDC 846728)
20H34N2O3, FW = 350.49, mp 94–96 °C, monoclinic, P21 (no 4),
4.3.33. (2S)-N,N-Diethyl-2-(2-hydroxy-1-phenylpentylamino)-3-
methylbutanamide 23 (ca. 1:1:1:1 diastereomeric mixture)
Colorless paste. Rf 0.35 (hexanes–ethyl acetate, 1:1). 1H NMR
(CDCl3) d 0.74–1.34 (m, 18 H), 1.42–1.56 (m, 1H), 1.70–1.87 (m,
1H), 2.77–3.38 (m, 5 H), 3.43–3.82 (m, 2H), 4.17 (br s, 2H), 7.12–
7.38 (m, 5 H). 13C NMR (CDCl3) d 12.5 (q), 12.65 (q), 12.70 (q),
12.72 (q), 13.66 (q), 13.69 (q), 13.75 (q), 13.80 (q), 13.84 (q), 13.9
(q), 14.0 (q), 17.3 (q), 17.5 (q), 17.6 (q), 17.7 (q), 18.6 (t), 18.7 (t),
19.0 (t), 19.2 (t), 19.7 (q), 19.9 (q), 20.0 (q) 21.5 (q), 31.4 (d), 31.7
(d), 32.1 (d), 32.3 (d), 34.1 (t), 34.6 (t), 35.1 (t), 35.8 (t), 39.95 (t),
40.04(t), 40.1 (t), 40.96 (t), 41.03 (t), 41.3 (t), 41.4 (t), 59.5 (d),
59.8 (d), 60.6 (d), 61.6 (d), 65.4 (d), 66.9 (d), 67.1 (d), 71.1 (d),
71.7 (d), 74.2 (d), 74.5 (d), 74.7 (d), 127.10 (d), 127.14 (d), 127.3
(d), 127.5 (d), 127.7 (d), 127.8 (d), 127.9 (d), 128.0 (d), 128.16
(d), 128.22 (d), 128.4 (d), 128.7 (d), 139.0 (s), 139.8 (s), 140.0 (s),
140.2 (s), 172.7 (s), 172.8 (s), 173.3 (s), 173.8 (s).
C
colorless block, a = 9.533(3) Å, b = 9.3432(18) Å, c = 12.252(4) Å,
b = 109.943(11), V = 1025.8(5) Å3, T = 298 K, Z = 2, Dcalcd = 1.135 g/
cm3,
l
= 0.76 cmꢁ1, GOF = 1.016.
4.4.8. Crystal data for (R)-20 (CCDC 846733)
23H34N2O2, FW = 370.52, mp 109.5–110 °C, orthorhombic,
C
P2(1)2(1)2(1) (no 19), colorless block, a = 9.9694(19) Å, b =
11.601(2) Å, c = 19.281(3) Å, V = 2229.8(7) Å3, T = 298 K, Z = 4,
Dcalcd = 1.104 g/cm3,
l
= 0.70 cmꢁ1, GOF = 1.005.
4.5. Computational methodology
All calculations were carried out with the Gaussian 03 pro-
gram.9 Geometry optimization was performed at the B3LYP/6-
311+G(d,p) level throughout (in gas phase at 298 K). All optimized

N. Kise et al. / Tetrahedron: Asymmetry 22 (2011) 1906–1917
1917
Chem. Soc. 2005, 127, 11956; (f) Lin, X.; Bentley, P. A.; Xie, H. Tetrahedron Lett.
2005, 46, 7849.
6. Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett. 1991, 2191.
7. For reviews, see: (a) Ager, D. J.; Prakash, L.; Schaad, D. R. Chem. Rev. 1996, 96,
835; (b) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
8. (a) Kise, N.; Ozaki, H.; Moriyama, N.; Kitagishi, Y.; Ueda, N. J. Am. Chem. Soc.
2003, 125, 11591; (b) Kise, N.; Ohya, K.; Arimoto, K.; Yamashita, Y.; Hirano, Y.;
Ono, T.; Ueda, N. J. Org. Chem. 2004, 69, 7710; (c) Kise, N.; Hirano, Y.; Tanaka, Y.
Org. Lett. 2006, 8, 1323.
9. The calculations were carried out using the Gaussian 03 program: Frisch, M. J.;
Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega,
N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.
W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc.: Pittsburgh, PA, 2003.
geometries were verified by the vibrational analysis. As for the
transition states, it was confirmed that these structures had only
one imaginary frequency. The imaginary frequency was ascer-
tained to be consistent with the addition of B to acetone by dis-
playing the vibrational mode using the Gauss View program.
Single point calculations were carried out for the optimized transi-
tion states using the IEFPCM model for the THF solvent at the same
level as the geometry optimization to take the solvent effect into
consideration.
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