Highly diastereoselective nucleophilic addition reactions of masked acyl cyanide reagents to tert-butanesulfiminides

Article abstract of DOI:10.1016/j.tetasy.2007.01.032

Addition reactions of dicyanomethyl tert-butyldimethylsilyl ether (H-MAC-TBS) to optically active tert-butanesulfinimides afforded α-amino acid precursors in excellent yields and with high diastereoselectivities.

Full text of DOI:10.1016/j.tetasy.2007.01.032

Tetrahedron: Asymmetry 18 (2007) 383–389
Highly diastereoselective nucleophilic addition reactions of
masked acyl cyanide reagents to tert-butanesulfiminides
Hisao Nemoto,* Hideki Moriguchi, Rujian Ma, Tomoyuki Kawamura,
Masaki Kamiya and Masayuki Shibuya
Division of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of The University of Tokushima,
1-78, Sho-machi, Tokushima 770-8505, Japan
Received 19 December 2006; accepted 31 January 2007
Available online 26 February 2007
Abstract—Addition reactions of dicyanomethyl tert-butyldimethylsilyl ether (H–MAC–TBS) to optically active tert-butanesulfinimides
afforded a-amino acid precursors in excellent yields and with high diastereoselectivities.
ꢀ 2007 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
O
R1
R2
R1
R2
OH
X
OH
7
2
NH
NH
Although the nucleophilic addition reaction of a naked car-
boxylate carbanion (ꢀCO2H) 1 to imines may appear as a
straightforward method for the synthesis of a-amino acids
2 (Scheme 1), the difficulty in the generation of 11 because
of the nature of carbonyl functionality has hindered the pro-
gress of this approach. Consequently, reagent 3, a synthetic
equivalent of 4, has been used until now. The traditional
methodology for preparing 2, known as the Strecker synthe-
sis,2 involves hydrogen cyanide as the synthetic equivalent 3.
Subsequently, several modified methodologies that involve
cyanides2 or nitromethane2a have been reported.
1
An α-Amino acid
A C-activated α-Amino acid
R1
H
R1
H
ref 2
ref 8
N
N
R2
R2
C
Z1
Z3
X = Cl, CN, SR3
O
C
O
C
Z1
C
Z1
C
Z2
Z2
X
OH
5
4
A Masked Activated
A Masked Carboxylate
Carbonyl Anion
Carbanion
3
Recently, a number of alternative reagents that can be clas-
sified as 3 have been reported; these include Seebach’s and
Manas’ orthothioester,3 Utimoto’s dimethoxyacetonitrile,4
Trost’s alkoxydisulfones,5 Dondoni’s silylthiazole,6 our
MAC (masked acyl cyanide)7 reagents 6,8 Katritzky’s
tris(benzotriazolyl)methane,9 Yamakawa’s a-chlorometh-
ylsulfoxides,10 Wasserman’s phosphoranylideneaceto-
nitrile,11 and Aggarwal’s cyclic sulfone.12 Nucleophilic
addition reactions between these carbanion reagents and
E+ have afforded various carbon–carbon bond formations.
Moreover, in addition to serving as masked carbanion 4,
some of the above reagents5,8,10–12 can also function as
ꢀCOX synthon 5 to afford C-activated species 7, which
E
E
ref 3,4,6,9
ref 5,8,9–12
ref 8
OR
CN
H
O
C
∈ 3
O
C
CN
6
E
OH
E
X
MAC reagents
Scheme 1.
would allow subsequent amide or ester bond formations
without condensation agents such as carbodiimides. To
the best of our knowledge, however, only MAC reagents
67,8,13–25 were successful in the formation of 7 via nucleo-
philic addition to the C@N double bond using 5.
We have previously reported8 on the reaction of MAC
*
Corresponding author. Tel./fax: +81 88 633 7284; e-mail: nem@ph.
tokushima-u.ac.jp
reagent 8 to N-sulfonylated imines 9 to afford the
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.032

384
H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
corresponding adduct 10, quantitatively. Due to the
reversible nature of the reaction (from 10 back to 8 and
9), adduct 10 was isolated as 11 by protection using chloro-
methyl methyl ether (MOM–Cl). Subsequently, as shown
in Scheme 2, adduct 11 was efficiently transformed to
dipeptide derivatives 13 via 12 (corresponding to 7) in
excellent yields under mild conditions and without the
use of any condensation reagents.8,14
O
O
H
HN
O
11
+
N
O
O
NC
50:50
18
CN
19
O
O
CN
In contrast, as shown in Scheme 3, alkoxycarbonylated
imine 1425 and phosphorous imine 1614 gave the corre-
sponding adducts 15 and 17, respectively, without the need
for MOM protection.
Et
H
CN
HN
O
O
CN
CN
O
O
14
+
O
O
O
20
21
Et
Et
50:50
HN
O
N
O
O
O
CN
H
CN
+
H
CN
CN
Scheme 4.
15
17
14
O
11
O
POPh2
POPh2
H
between the chiral auxiliary and the prochiral carbon is
significantly shorter than in the case of Scheme 4.
Additionally, the preparation of sulfinimides is well
established.29,30
HN
N
O
O
CN
CN
O
H
CN
CN
+
16
8
O
We have previously reported18 on the reaction of (SS)-p-
toluenesulfinimide 2229 with MAC reagent 23.8,21 As
shown in Scheme 5, our studies demonstrated the efficient
formation of 24 via the coexistence of a tertiary amine
and a Lewis acid. The Lewis acid affects the overall yield,
the diastereoselectivity, and the configuration of the domi-
nant diastereomer of the product.
Scheme 3.
Our first attempt to synthesize the optically active com-
pounds, as shown in Scheme 4, involved alkoxycarbonyl-
ated imines. Unfortunately, the reactions using optically
active imine 18 or a chiral MAC reagent 2026 did not exhi-
bit any diastereoselectivity.25 The lack of stereoselectivity
can be attributed to (1) the large distance between the ste-
reogenic center of the auxiliaries and the prochiral carbon
and (2) the flexible conformation of the entire molecule.
Furthermore, the preparation of N-alkoxycarbonylated
aliphatic imines requires delicate control of the reaction
temperature along with exhaustive removal of moisture,27
such stringent conditions discourage the general applicabil-
ity of this method for the synthesis of aliphatic a-amino
acids.
2. Results and discussion
Herein, we report on the highly diastereoselective reaction
of tert-butanesulfinimides using MAC reagents.30 First, as
shown in Scheme 6, we prepared 25 with an (R)-configura-
tion via the asymmetric oxidation of tert-butyl disulfide,
followed by treatment with ammonia and benzaldehyde.31
Next, we turned our attention to reactions involving an
optically active sulfinimide,18,28 in which the distance
The reaction of 25 was initially carried out in dichloro-
methane (CH2Cl2) at room temperature with 23
SO2R
N
triethylamine
benzene,
room temperature
RO2S
O
O
NH
H
O
O
H
CN
+
CN
MeO
CN
CN
silica gel
MeO
10
8
9
O
Cl
SO2R
CN
SO2R
O
N
O
N
H2N
COY
H
N
CN
COY
CN
O
O
O
MeO
O
MeO
12
11
13a: R= 4-MeC6H4–, Y=OMe
13b: R= Me3SiCH2CH2–, Y=N(CH2Ph)2
Scheme 2.

H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
385
O
O
O
TBS
CN
S
H
S
S
Tol
O
Tol
O
O
N
Tol
HN
HN
+
+
H
TBS
TBS
CN
NC
24a
NC
24b
CN
CN
22
23
Me3SiOSO2CF3+EtNiPr2 24a:24b = 78:22
Sn(OSO2CF3)2+EtNiPr2 24a:24b = 5:95
Scheme 5.
TBS
CN
O
Table 2. The reaction of various tert-butanesulfinimides 27 with 23
(3.0 equiv), 2,6-lutidine (2.0 equiv), and TMSOTf (3.0 equiv) in CH2Cl2 at
room temperature
O
O
O
H
S
H
S
S
tBu
tBu
N
tBu
HN
HN
23
CN
+
O
O
TBS
TBS
O
NC
26a
NC
26b
O
CN
CN
S
tBu
HN
23
S
H
25
N
tBu
O
TBS
R
R
Scheme 6.
NC
28
CN
27
(1.5 equiv), diisopropylethylamine (DIEA, 3.0 equiv)
as the base, and trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 2.0 equiv) as the Lewis acid (Table 1, entry 1).
It is worth noting that these conditions were based upon
the optimal conditions for the reaction of 22 to 24.18 After
1 h, 26a was obtained in 45% chemical yield and with 100%
diastereoselectivity. Our results also revealed the slow
decomposition of 26a along with the formation of uniden-
tified polar materials in the presence of DIEA. Further-
more, in the presence of strong organic bases, such as
triethylamine or DIEA, the MAC reagents were also slowly
converted into an unidentifiable polar compound. Accord-
ingly, by replacing DIEA (a strong base) with 2,6-lutidine
(a weak base) the yield of 26a increased to 67% (entry 2).
When the 3 equiv of 23 was used for the reaction, the yield
of 26a was further improved to 99% (entry 3). Since the
reaction of 22 in the presence of tin(II) trifluoromethane-
sulfonate (Sn(OTf)2) afforded 24a/24b with a ratio of
5:95,18 the reaction of 25 was similarly carried out using
Sn(OTf)2-surprisingly, the ratio of 26a:26b was 91:9 (entry
4). Presumably, the final diastereoselectivity was deter-
mined by the competing two transition states, the elec-
tronic interaction with Sn(OTf)2, and the steric influence
from either tert-butyl or 4-tolyl groups.
Entry sulfinimide 27
Time (h) Chemical yield (%) of 28
1
2
3a
27a (R = 4-MeOC6H4–)
27b (R = 4-F3C–C6H4–)
27c (R = (CH3)2CH–)
3
1
1
89 (28a)
88 (28b)
73 (28c)
a 2,6-Lutidine (5.0 equiv) was used.
The absolute configuration of 26a was determined by com-
paring its derivative 30 against a known compound,18 as
shown in Scheme 7. Deprotection of the TBS group of
26a, followed by in situ amide bond formation with butyl-
amine, gave 29 in 92% yield. Deprotection of the tert-but-
anesulfinyl group under acidic conditions,30 followed
by p-toluenesulfonylation, afforded 30 in 75% yield.
Comparison between the [a]D value of synthesized 30
22
{½aꢁD ¼ þ96:8 (c 1.0, CHCl3)} derived from 26a and that
22
of authentic (R)-30 {½aꢁD ¼ ꢀ109:4 (c 1.4, CHCl3)}18
revealed that the newly formed stereogenic center of 26a
had an (S)-configuration with an enantiomeric excess of
26a being 88%. Apparently, the original enantiomeric
excess of 25 (89% ee) was preserved in each chemical trans-
formation during the formation of 30.
The transformation of adduct 28a to 31a is illustrated in
Scheme 8. As shown in the H NMR data (Fig. 1), and
1
based on Kusumi’s PGME method,32 the Ha triplet signal
at lower field was assigned to 31a, whereas that at higher
field was assigned to 32a. The 85:15 ratio of 31a to 32a
indicates that the benzylic position of 28a has an (S)-con-
figuration with 70% ee. The benzylic position of 28b was
also determined to be (S) since 31b is favored over 32b.
In the case of 31b and 32b, however, the ratio of 70:30
was lower than expected. Simultaneous epimerization of
the sulfur center and benzylic position can be ignored since
As listed in Table 2, the optimized reaction conditions
(Table 1, entry 3) were applied to various tert-butane-
sulfinimides.31 Although the reaction of the electron rich
aromatic sulfinimide 27a (entry 1) was slower than that
of the electron deficient 27b (entry 2), in both cases, 28
was obtained in excellent yield with 100% diastereoselectiv-
ity. The desired adduct 28c was obtained from aliphatic
sulfinimide 27c in 73% yield with 100% diastereoselectivity
(entry 3).
Table 1. The reaction of 25 and 23 with Lewis acid (3 equiv) and base (2 equiv) in CH2Cl2 at room temperature
Entry
Lewis acid
Base
23
Time (min)
Chemical yield (%)
26a:26b
1
2
3
4
TMSOTf
TMSOTf
TMSOTf
Sn(OTf)2
DIEA
1.5
1.5
3.0
3.0
30
60
15
10
46
67
99
27
100:0
100:0
100:0
91:9
2,6-Lutidine
2,6-Lutidine
DIEA

386
H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
O
O
O
SO2Tol
S
S
tBu
Bu4NF
C4H9NH2
THF, -40 ºC
S
H
tBu
N
tBu
Entry 3
HN
HN
HN
H
N
H
N
1. HCl-MeOH-dioxane
2. TolSO2Cl, pyridine
75% yield
O
TBS
C4H9
C4H9
NC
26a
CN
in Table 1
99% yield
O
O
92% yield
25
29
30
single
diastereomer
single
diastereomer
(89% ee)
(88% ee)
Scheme 7.
O
O
O
a. Bu4NF, MeOH, THF, -40 ºC
S
tBu
NH
b. HCl, dioxane, room temperature
NH
+
O
S
HN
O
Ha
R
H
a
O
O
TBS
c. PyBop, Et3N, CH2Cl2
H2N
tBu
O
R
CO2Me
CO2Me
R
O
O
NC
CN
28
OH
70% ee
a: R=4-MeOC6H4
b: R=4-CF3C6H4
O
>
31
32
Ha
single
diastereomer
O
31a:32a = 85:15 (70% de)
31b:32b = 70:30 (40% de)
PyBop= (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
Scheme 8.
O
tBu
a. Bu4NF, H2NC4H9, THF, -40 ºC
O
HN
b. HCl, dioxane, room temperature
28c
CONHC4H9
c. Boc2O, CH2Cl2, Et3N
33
Scheme 9.
obtained from 4-toluenesulfinimides).18 The subsequent
synthesis of an a-amino acid derivative with an aliphatic
side chain was also successful. The results of our studies,
in tandem with those of a previous study,24 offer two
practical methodologies for the preparation of optically
active C-activated a-amino acid derivatives using MAC
reagents.
Figure 1. 1H NMR of Ha of a mixture of 31 and 32 derived from 28 (70%
ee).
4. Experimental
4.1. General
27a (70% ee) resulted in a 31a/32a ratio of 85:15. Epimer-
ization remains a possibility during the final condensation
(reaction step c) because the asymmetric center of 31b/
32b is triply activated by the 4-trifluoromethylphenyl,
methoxycarbonyl, and acylated amino groups.33
Melting points were measured with APPARATUS
MODEL MP-20 (Yamato Kagaku) and uncorrected. Opti-
cal rotations were measured with DIP-370 (JASCO). IR
spectra were recorded with 1720 Infrared Fourier Trans-
form Spectrometer (Perkin–Elmer) or FT/IR420 (JASCO),
As shown in Scheme 9, 28c was transformed to the
(S)-(ꢀ)-valine derivative 33 to assess the enantiomeric
and indicated with wavelength at cmꢀ1. H NMR spectra
1
excess; ca. 69% ee was determined by comparing thespecific
25
rotation of the synthesized derivative, ½aꢁD ¼ ꢀ15:6 (c 0.60,
25
were recorded with JMN-AL300, JMN-AL400, or
GSX400 spectrometers (JEOL) at 300, 400, 400 MHz,
respectively. 13C NMR spectra were recorded with JMN-
AL300, JMN-AL400, or GSX400 spectrometers (JEOL)
at 75, 100, 100 MHz, respectively. Chemical shifts were
indicated as a d value at ppm with tetramethylsilane as
an internal standard. Mass spectra were recorded with
JMS-DX303 or JMS-SX102A Mass Spectrometer (JEOL).
Unless noted, all the reactions were carried out under an
argon atmosphere. Tetrahydrofuran (THF) was distilled
over Na-benzophenone. Dichloromethane (CH2Cl2) was
distilled over phosphorous pentoxide. Methanol (MeOH)
was distilled over sodium methoxide.
MeOH), to that of the pure (S)-enantiomer,34 ½aꢁD ¼ ꢀ22:7
(c 2.2, MeOH). Thus, our results indicate that the chiral
auxiliary, tert-butanesulfinyl group, gives comparable dia-
stereoselectivities in all four cases, 25, 27a, 27b, and 27c.
3. Conclusion
The addition reaction of tert-butanesulfinimides with a
MAC reagent afforded a-amino acid precursors in excellent
yields, and with improved diastereoselectivities (over those

H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
387
4.2. Preparation of tert-butanesulfinimides
J = 11.5 Hz, 2H), 4.78 (d, J = 9.5 Hz, 1H), 4.06 (d,
J = 9.5 Hz, 1H), 3.81 (s, 3H), 1.31 (s, 9H), 0.85 (s, 9H),
0.28 (s, 3H), 0.22 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d 160.6 (C), 129.3 (CH · 2), 125.9 (C), 114.4 (C), 114.2
(CH · 2), 114.1 (C), 68.7 (C), 66.4 (CH), 57.2 (C), 55.2
(CH3), 25.0 (CH3 · 3), 22.4 (CH3 · 3), 17.9 (C), ꢀ4.7
(CH3), ꢀ5.0 (CH3); EI-HRMS calcd for C21H33N3O3SSi
(M+) 435.2012, found 435.2018.
Preparations of 25 and 27a–c were carried out using known
procedure.30 Since tert-butanesulfinimides 27a–c were
prepared from the same lot of (RS)-2-methylpropane-2-
sulfinamide (H2N–SOtBu) prepared from asymmetric
oxidation of 1,2-di-tert-butyldisulfane (tBu–S–S–tBu),30
(RS)-27b was determined to be 69–71% ee.
(RS)-2-Methyl-N-(4-benzylidene)propane-2-sulfinamide
4.6. (RS,2S)-N-(2-(tert-Butyldimethylsilyloxy)-2,2-dicyano-
1-(4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfin-
amide 28b
22
25: ½aꢁD ¼ ꢀ108:6 (c 1.0, CHCl3), 89% ee {lit.30
22
½aꢁD ¼ ꢀ122:0 (c 1.0, CHCl3)}.
(RS)-2-Methyl-N-(4-methoxybenzylidene)propane-2-sulfin-
Colorless oil; FT-IR (neat): 2934, 2863, 2380, 1472, 1328,
22
amide 27a: ½aꢁD ¼ ꢀ50:1 (c 1.0, CHCl3), 71% ee {lit.30
1
1132, 1070 cmꢀ1; H NMR (CDCl3, 400 MHz): d 7.69 (d,
22
½aꢁD ¼ ꢀ70:2 (c 1.0, CHCl3)}.
J = 10.5 Hz, 2H), 7.57 (d, J = 10.5 Hz, 2H), 4.86 (d,
J = 11.0 Hz, 1H), 4.11 (d, J = 11.0 Hz, 1H), 1.32 (s, 9H),
0.82 (s, 9H), 0.28 (s, 3H), 0.22 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 137.6 (C), 132.4 (q, JC–F = 33 Hz, C–CF3),
128.7 (CH · 2), 125.7 (q, JC–F = 4 Hz, CH · 2), 124.3 (q,
JC–F = 272 Hz, CF3), 114.0 (C), 113.7 (C), 68.2 (C), 66.7
(CH), 57.6 (C), 25.0 (CH3 · 3), 22.5 (CH3 · 3), 17.9
(C), ꢀ4.7 (CH3), ꢀ4.9 (CH3); EI-HRMS calcd for
C20H30F3N2O2SSi [(MꢀCN)+] 447.1749, found 447.1739.
(RS)-2-Methyl-N-(4-trifluoromethylbenzylidene)propane-2-
22
sulfinamide 27b: ½aꢁD ¼ ꢀ78:2 (c 1.0, CHCl3).
(RS)-2-Methyl-N-(2-methylpropylidene)propane-2-sulfin-
22
amide 27c ½aꢁD ¼ ꢀ179:2 (c 1.0, CHCl3), 69% ee {lit.30
22
½aꢁD ¼ ꢀ259:4 (c 1.0, CHCl3)}.
4.3. General procedure for the nucleophilic addition of 23 to
sulfinimides
4.7. (RS,2S)-N-(1-(tert-Butyldimethylsilyloxy)-1,1-dicyano-
3-methylbutan-2-yl)-2-methylpropane-2-sulfinamide 28c
To a solution of a tert-butanesulfinimide (0.50 mmol) and
23 (294 mg, 1.5 mmol) in CH2Cl2 (2.5 mL) were added
TMSOTf (0.18 mL, 1.0 mmol) and 2,6-lutidine (0.17 mL,
1.5 mmol), and the mixture was stirred at room tempera-
ture. After the disappearance of either tert-butanesulfini-
mide or 23 was monitored by thin layer chromatography,
the reaction mixture was poured into a saturated aqueous
solution of ammonium chloride (NH4Claq) and extracted
with CH2Cl2 (30 mL · 3). The combined organic layers
were washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography eluted with hexane/ethyl
acetate to afford the corresponding adduct.
Colorless oil; FT-IR (neat): 3348, 2960, 2932, 2862, 2360,
1472, 1261, 1086 cmꢀ1 1H NMR (CDCl3, 400 MHz): d
;
3.70 (d, J = 12.0 Hz, 1H), 3.59 (dd, J = 3.0, 12.0 Hz, 1H),
2.45 (dsept, J = 3.0, 9.0 Hz, 1H), 1.32 (s, 9H), 1.17 (d,
J = 9.0 Hz, 3H), 1.06 (d, J = 9.0 Hz, 3H), 0.95 (s, 9H),
0.41 (s, 3H), 0.38 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d 115.1 (C), 114.5 (C), 68.1, 59.2 (C), 57.3 (C), 27.6
(CH), 25.1 (CH3 · 3), 22.7 (CH3 · 3), 21.1 (CH3), 17.9
(C), 16.1 (CH3), ꢀ4.7 (CH3), ꢀ4.8 (CH3); EI-HRMS calcd
for C16H33N2O2SSi [(MꢀCN)+] 345.2032, found 345.2022.
4.8. (RS,2S)-N-Butyl-2-(1,1-dimethylethylsulfinamido)-2-
phenylacetamide 29
4.4. (RS,2S)-N-(2-(tert-Butyldimethylsilyloxy)-2,2-dicyano-
1-phenylethyl)-2-methylpropane-2-sulfinamide 26a
To a solution of 26a (480 mg, 1.19 mmol) in THF (15 mL)
cooled to ꢀ40 ꢁC was added butylamine (0.24 mL,
2.37 mmol). To the solution was added tetrabutylammo-
nium fluoride (Bu4NF) (1.0 M in THF, 1.3 mL, 1.3 mmol)
slowly at ꢀ40 ꢁC. The resulting mixture was stirred for 1 h
at ꢀ40 ꢁC, poured into NH4Claq and extracted with
CH2Cl2 (30 mL · 3). The combined organic layers were
washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo. The residue was purified by silica gel
column chromatography eluted with hexane/ethyl acetate
(3:1) to afford 29 as a colorless oil (338.0 mg, 92% yield).
FT-IR (CHCl3): 2932, 2861, 1472, 1261, 1146, 1076, 846,
Colorless oil; FT-IR (neat): 2932, 2861, 2240, 1472, 1261,
1146, 1453, 1076 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d 7.51–7.33 (m, 5H), 4.78 (d, J = 7.6 Hz, 1H), 4.06
(d, J = 7.6 Hz, 1H), 1.32 (s, 9H), 0.82 (s, 9H), 0.27 (s,
3H), 0.18 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 133.9
(C), 130.0 (CH), 128.9 (CH · 2), 128.2 (CH · 2), 114.5
(C), 114.0 (C), 68.7 (C), 67.0 (CH), 57.4 (C), 25.0
(CH3 · 3), 22.6 (CH3 · 3), 17.9 (C), ꢀ4.7 (CH3), ꢀ5.0
(CH3); EI-HRMS calcd for C20H31N3O2SSi (M+)
405.1906, found 405.1916.
1
4.5. (RS,2S)-N-(2-(tert-Butyldimethylsilyloxy)-2,2-dicyano-
1-(4-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide
28a
788 cmꢀ1; H NMR (CDCl3, 400 MHz): d 7.47–7.28 (m,
5H), 6.90 (br s, 1H), 5.06 (d, J = 4.4 Hz, 1H), 4.60 (d,
J = 4.4 Hz, 1H), 3.30–3.20 (m, 2H), 1.51–1.40 (m, 2H),
1.37–1.22 (m, 2H), 1.20 (s, 9H), 0.88 (t, J = 7.3 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 170.9 (C), 138.4 (C),
128.4 (CH2 · 2), 127.8 (CH), 127.4 (CH2 · 2), 58.4 (C),
56.6 (CH), 39.4 (CH2), 31.1 (CH2), 22.6 (CH3 · 3), 19.9
Colorless oil; FT-IR (neat): 3324, 2958, 2861, 2360, 1612,
1517, 1471, 1256, 1077 cmꢀ1
;
1H NMR (CDCl3,
400 MHz):
d 7.35 (d, J = 11.5 Hz, 2H), 6.92 (d,

388
H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
(CH2), 13.6 (CH3). Anal. Calcd for C16H26N2O2S: C,
61.90; H, 8.44; N, 9.02. Found: C, 61.55; H, 8.28; N, 8.88.
4.11. (S)-Methyl 2-(4-methoxyphenyl)-2-((S)-5-oxo-tetra-
hydrofuran-2-carboxamido)acetate 31a and (R)-methyl 2-(4-
methoxyphenyl)-2-((S)-5-oxo-tetrahydrofuran-2-carbox-
amido)acetate 32a (85:15)
4.9. (2S)-N-Butyl-2-(4-methylphenylsulfonamido)-2-phenyl-
acetamide 30
FT-IR (CHCl3): 3334, 2956, 1788, 1746, 1683, 1611, 1514,
1251, 1177, 1031 cmꢀ1 1H NMR (CDCl3, 400 MHz): d
;
A solution of 29 (140 mg, 0.452 mmol) in a mixed solvent
(3 M hydrochloric acid–MeOH–1,4-dioxane = 1:1:1 vol,
0.6 mL) was stirred for 15 min at room temperature. The
resulting mixture was concentrated in vacuo. The residue
was dissolved in pyridine (2 mL), and to the resulting
solution was added 4-toluenesulfonyl chloride (258 mg,
1.35 mmol) in portions at room temperature. The reaction
mixture was stirred for 2 h at room temperature, poured
into water and extracted with CH2Cl2 (50 mL · 3). The
combined organic layers were washed with brine, dried
over magnesium sulfate, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
eluted with chloroform/ethyl acetate (4:1) to afford 30 as
7.38–7.35 (m, 2H), 7.24–7.08 (m, 1H), 7.00–6.84 (m, 2H),
5.56–5.46 (m, 1H), 4.91 (t, J = 7.8 Hz, 1H · 0.85), 4.85 (t,
J = 7.6 Hz, 1H · 0.15), 3.81 (s, 3H · 0.15), 3.80 (s,
3H · 0.85), 3.74 (s, 3H · 0.85), 3.73 (s, 3H · 0.15), 2.75–
2.21 (m, 4H); EI-HRMS calcd for C15H17NO6 (M+)
307.1056, found 307.1043.
4.12. (S)-Methyl 2-((S)-5-oxo-tetrahydrofuran-2-carbox-
amido)-2-(4-(trifluoromethyl)phenyl)acetate 31b and (R)-
methyl 2-((S)-5-oxo-tetrahydrofuran-2-carboxamido)-2-(4-
(trifluoromethyl)phenyl)acetate 32b (70:30)
FT-IR (CHCl3): 3321, 2957, 1789, 1747, 1682, 1529, 1327,
a
colorless solid (97.5 mg, 0.271 mmol, 60% yield).
1170, 1125, 1067 cmꢀ1 1H NMR (CDCl3, 400 MHz): d
;
22
½aꢁD ¼ þ96:8 (c 1.0, CHCl3); FT-IR (KBr): 3326, 3264,
7.75–7.46 (m, 4H), 7.45–7.30 (m, 1H), 5.70–5.60 (m, 1H),
4.91 (t, J = 7.8 Hz, 1H · 0.70), 4.86 (t, J = 7.8 Hz,
1H · 0.30), 3.76 (s, 3H), 2.75–2.21 (m, 4H); EI-HRMS
calcd for C15H14F3NO5 (M+) 3345.0824, found 345.0838.
2957, 1648, 1554, 1453, 1344, 1327, 1162, 1093 cmꢀ1; H
1
NMR (300 MHz): 7.59 (d, J = 8.1 Hz, 2H), 7.30–7.22 (m,
2H), 7.19 (d, J = 8.1 Hz, 2H), 7.16–7.10 (m, 3H), 5.88 (br
d, J = 4.7 Hz, –SO2NH, 1H), 5.61 (br, –CONH, 1H),
4.70 (d, J = 4.7 Hz, 1H), 3.15 (dt, J = 6.7, 6.7 Hz, 2H),
2.39 (s, 3H), 1.41–1.27 (m, 2H), 1.27–1.11 (m, 2H), 0.84
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz): 168.9 (C), 143.5
(C), 136.8 (C), 136.6 (C), 129.5 (CH · 2), 128.9 (CH · 2),
128.5 (CH · 2), 127.4 (CH), 127.2 (CH · 2), 60.5 (CH),
39.7 (CH2), 31.2 (CH2), 21.5 (CH3), 19.8 (CH2), 13.6
(CH3). Anal. Calcd for C19H24N2O3S: C, 63.31; H, 6.71;
N, 7.77. Found: C, 63.28; H, 6.89; N, 7.67.
4.13. (S)-tert-Butyl 1-(butylamino)-3-methyl-1-oxobutan-2-
ylcarbamate 33
To a mixture of 28c (30.0 mg, 0.081 mmol) and MeOH
(0.016 mL, 0.16 mmol) in THF (1 mL) cooled to ꢀ40 ꢁC
was added Bu4NF (1.0 M in THF, 0.085 mL, 0.085 mmol),
and the mixture was stirred for 1 h at ꢀ40 ꢁC. The mixture
was poured into NH4Claq and extracted with CH2Cl2
(5 mL · 3). The combined organic layers were washed with
brine, dried over magnesium sulfate and concentrated in
vacuo. The residue was dissolved in a mixed solvent (3 M
hydrochloric acid–MeOH–1,4-dioxane = 1:1:1 vol, 0.3 mL),
and the mixture was stirred for 15 min at room tempera-
ture. The resulting mixture was concentrated in vacuo.
The residue was poured into an aqueous solution of
sodium hydroxide (10%), and extracted with CH2Cl2
(5 mL · 3). The combined organic layers were dried over
potassium carbonate, and concentrated in vacuo. To a
solution of the residue in THF (1 mL) were added triethyl-
amine (0.034 mL, 0.24 mmol) and tert-butyl pyrocarbonate
(Boc2O) (35.4 mg, 0.16 mmol), and the mixture stirred for
12 h at room temperature. The mixture was poured into
an aqueous solution of potassium hydrogen sulfate (5%),
and extracted with CH2Cl2 (5 mL · 3). The combined or-
ganic layers were washed with brine, dried over magnesium
sulfate, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography eluted with hex-
4.10. Determination of the absolute configuration of 28a and
28b by the PGME method
To a mixture of 28 (0.11 mmol) and MeOH (0.013 mL,
0.33 mmol) in THF (2 mL) cooled to ꢀ40 ꢁC was added
Bu4NF (1.0 M in THF, 0.11 mL, 0.11 mmol) slowly, and
the mixture stirred for 1 h at ꢀ40 ꢁC. The resulting solution
was poured into NH4Claq and extracted with CH2Cl2
(5 mL · 3). The combined organic layers were washed with
brine, dried over magnesium sulfate, and concentrated in
vacuo. The residue was dissolved in a mixed solvent (3 M
hydrochloric acid–MeOH–1,4-dioxane = 1:1:1 vol, 0.3 mL).
The solution was stirred for 15 min, and then concen-
trated in vacuo. To the residue dissolved in CH2Cl2 (1 mL)
were added triethylamine (0.077 mL, 0.55 mmol), (S)-tetra-
hydrofuran-2-carboxylic acid (42.9 mg, 0.33 mmol), PyBop
(172 mg, 0.33 mmol), and the mixture was stirred for 2 h at
room temperature. The mixture was poured into hydro-
chloric acid (1 M) and extracted with CH2Cl2 (5 mL · 3).
The combined organic layers were washed with brine, dried
over magnesium sulfate, and concentrated in vacuo. The
residue was purified roughly by silica gel column chroma-
tography eluted with hexane/ethyl acetate (1:1) to afford
a diastereomeric mixture of 31 and 32. (31a/32a: 24.3 mg,
0.079 mmol, 72% overall yield, 31b/32b: 26.5 mg, 0.077
mmol, 70% overall yield).
ane/ethyl acetate (2:1) to afford 33 (15.9 mg, 0.058 mmol,
25
72% yield). ½aꢁD ¼ ꢀ15:7 (c 0.60, MeOH) (69% ee) {lit. of
25
(S)-3333 ½aꢁD ¼ ꢀ22:7 (c 2.2, MeOH)}; FT-IR (CHCl3):
1
3326, 2932, 2855, 1705, 1648, 1381, 1255, 853 cmꢀ1; H
NMR (CDCl3, 400 MHz): d 5.95 (br, 1H, NH), 5.06 (br,
1H, NH), 3.83 (dd, J = 6.5, 8.8 Hz, 1H), 3.33–3.19 (m,
2H, NH–CH2), 2.18–2.06 (m, 1H), 1.55–1.23 (m, 4H),
0.95 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.91 (d,

H. Nemoto et al. / Tetrahedron: Asymmetry 18 (2007) 383–389
389
20. Nemoto, H.; Ma, R.; Li, X.; Suzuki, I.; Shibuya, M.
Tetrahedron Lett. 2001, 42, 2145–2147.
21. Nemoto, H.; Li, X.; Ma, R.; Suzuki, I.; Shibuya, M.
Tetrahedron Lett. 2002, 44, 73–75.
J = 6.6 Hz, 3H). Anal. Calcd for C14H28N2O3: C, 61.73; H,
10.36; N, 10.28. Found: C, 61.69; H, 10.34; N, 10.25.
22. Nemoto, H. Yuki Gosei Kagaku Kyokaishi 2004, 62, 347–
354.
Acknowledgement
23. Nemoto, H.; Kawamura, T.; Miyoshi, N. J. Am. Chem. Soc.
2005, 127, 14546–14547.
24. Nemoto, H.; Ma, R.; Kawamura, T.; Kamiya, M.; Shibuya,
M. J. Org. Chem. 2006, 71, 6038–6043.
25. Nemoto, H.; Takagaki, T.; Kubota, Y.; Yamamoto, Y. 1993,
Unpublished result.
This work was partly supported by a Grant-in-Aid for
Scientific Research of the Ministry of Education, Culture,
Sports, Science and Technology of Japan (Grant No.
18550094 in 2006–2007).
26. Bicyclic acetal moiety in 20 was prepared in an independent
project: Nemoto, H. Tetrahedron Lett. 1994, 35, 7785–7788;
Nemoto, H.; Tsutsumi, H.; Yuzawa, S.; Peng, X.; Zhong, W.;
Xie, J.; Miyoshi, N.; Suzuki, I.; Shibuya, M. Tetrahedron
Lett. 2004, 45, 1667–1670.
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34
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