Synthesis of optically active phenylglycine derivatives from Ss-(+)-N-(benzylidene)-p-toluenesulfinamide by using Lewis acids and tert-amines

Article abstract of DOI:10.1016/S0022-328X(00)00478-2

Stereoselective synthesis of L- and D-phenylglycine derivatives was accomplished by the reaction of Ss-(+)-N-(benzylidene)-p-toluenesulfinamide with 2-(tert-butyldimethylsiloxy)malononitrile (H-MAC-TBS) in the presence of Lewis acids and tert -amines.

Full text of DOI:10.1016/S0022-328X(00)00478-2

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 611 (2000) 445–448
Synthesis of optically active phenylglycine derivatives from
Ss-(+)-N-(benzylidene)-p-toluenesulfinamide by using Lewis acids
and tert-amines
Hisao Nemoto *, Rujian Ma, Hideki Moriguchi, Ichiro Suzuki, Masayuki Shibuya
Faculty of Pharmaceutical Sciences, The Uni6ersity of Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan
Received 3 March 2000; accepted 26 March 2000
Abstract
Stereoselective synthesis of L- and D-phenylglycine derivatives was accomplished by the reaction of Ss-(+)-N-(benzylidene)-p-
toluenesulfinamide with 2-(tert-butyldimethylsiloxy)malononitrile (H-MAC-TBS) in the presence of Lewis acids and tert-amines.
© 2000 Published by Elsevier Science S.A. All rights reserved.
Keywords: Acyl cyanides; Asymmetric synthesis; Phenylglycine; Amino acids and peptides; Peptides; Sulfinimines; Lewis acids
We have applied this method to the asymmetric
synthesis of a-amino acid derivatives by, respectively,
using MAC reagent bearing asymmetric centers [5],
optically active alkoxycarbonylated imines, and so on
[6]. Typically, a mixture of diastereomers with low
1. Introduction
Chemical synthesis of a-amino acids is one of the
essential means for the supply of artificial, unnatural or
rare a-amino acids and the peptides containing them.
diastereoselectivity has been obtained. In this paper,
Based on the fact that N-protected-C-activated a-
however, we report a highly stereoselective synthesis of
amino acids are useful synthetic intermediates for the
optically active phenylglycine derivatives 4 starting
synthesis of peptides, we have recently developed a
from the sulfinimine 5 [7] by using a MAC reagent 1a
method for the synthesis of the masked form of a-(N-
(Scheme 2).
sulfonylamino)acyl cyanide 3 [1] by the reaction of
N-sulfonylimines 2 with MAC reagents 1 [2] (Scheme
1). The reaction proceeds within a short period at
ambient temperature under mild conditions including,
2. Results and discussions
for example, a catalytic amount of triethylamine [1],
palladium complex [3], or no catalyst under high-pres-
sure [4].
2.1. Preliminary examinations of the reaction of sulfin-
imine with H-MAC-TBS
In the presence of various tert-amines such as pyri-
dine, 2,6-lutidine, triethylamine, and diisopropylethyl-
amine, the desired carbon-carbon bond formation reac-
tion between 5 and 1a was not observed. In the reac-
tion, unidentified polar compounds were obtained
probably because of self-condensation of the MAC
Scheme 1.
reagent 1a, but the sulfinimine 5 was quantitatively
recovered. Therefore, trimethylsilyl triflate (TMSOTf)
was added for the sake of the activation of 5. In the
presence of both TMSOTf and 2,6-lutidine [8], forma-
* Corresponding author. Tel.: +81-88-6337284; fax: +81-88-
6339549.
E-mail address: nem@ph2.tokushima-u.ac.jp (H. Nemoto).
0022-328X/00/$ - see front matter © 2000 Publisehd by Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00478-2

446
H. Nemoto et al. / Journal of Organometallic Chemistry 611 (2000) 445–448
Scheme 2.
tion of the desired compounds 4 was observed. There-
fore, we decided to carry out further optimization by
the use of both Lewis acids and tert-amines.
7–9). In all cases shown in entries 1–9, the 2R-isomer
4a was selectively produced and the best diastereoselec-
tivity was observed when BF3 · OEt2 was used (entry
7). In contrast, Sn(OTf)2 gave the 2S-isomer 4b with
comparatively high stereoselectivity (entries 10 and 11).
2.2. The reactions of sulfinimine with H-MAC-TBS
under 6arious combinations of tert-amines and Lewis
acids
2.3. The determination of the absolute configuration
As shown in entries 1–3 in Table 1, we first carried
out the reaction in the presence of trimethylsilyl triflate
(TMSOTf) with 2,6-lutidine in CH2Cl2 at room temper-
ature. A catalytic amount of the promoters gave a trace
amount of the desired product 4, and the sulfinimine 5
and 1a were recovered in more than 90% yields (entry
1). By using two equivalents of TMSOTf and three
equivalents of 2,6-lutidine, the desired compound 4 was
obtained in 91% yield (entry 3). By using diisopropyl-
ethylamine (DIEA) instead of 2,6-lutidine, 4 was ob-
tained in 86% isolated yield within 30 min (entry 4). We
also examined several other Lewis acids (entries 5–9).
No reaction occurred when Sc(OTf)3 was used (entry
5). With titanium tetrachloride, the desired product 4
was not obtained and 5 was not recovered (entry 6).
The desired product 4 was obtained in moderate yields
with BF3·OEt2, ZnCl2, and SnCl4, respectively (entries
A diastereomer 4a, purified by using HPLC, was
transformed at −40°C in THF with butylamine in the
presence of tetrabutylammonium fluoride to the corre-
sponding N-butyl amide 6a in 92% yield along with a
trace amount of the diastereomer 6b (6a:6b= \98:2)
(Scheme 3). After purification by recrystallization, 6a
was converted to the sulfonylamine 7 with 3-chloroper-
benzoic acid in 99% yield. The authentic sample of
2R-7 was prepared from commercially available 2R-
phenylglycine 6ia sulfonylation and amide bond forma-
tion reactions with butylamine, according to the known
procedure [9]. Measurement of the [a]2D2 proved that the
synthetic 7 was a R-isomer (synthetic: [a]2D2= −109.7°;
authentic sample: [a]2D2= −109.4°). The absolute
configuration of the benzylic position of 4a, 4b, and 6a
is therefore determined to be R, S, and R, respectively.
Table 1
The reaction of 1a and 5 with Lewis acids and tert-amines
Entry
Lewis acid (equiv.)
Amine (equiv.)
Reaction period
Assumption of 5
Yield of 4
Ratio 4a:4b
1
2
3
4
5
6
7
8
9
TMSOTf (0.1)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
Sc(OTf)3 (2.0)
TiCl4 (2.0)
BF3·OEt2 (2.0)
Zn(OTf)2 (2.0)
SnCl4 (2.0)
2,6-Lutidine (2.0)
2,6-Lutidine (2.0)
2,6-Lutidine (3.0)
DIEA (3.0)
2,6-Lutidine (3.0)
DIEA (3.0)
DIEA (3.0)
DIEA (3.0)
DIEA (3.0)
DIEA (3.0)
2 h
2 h
1 h
30 min
5 h
8 h
2 h
2 h
2 h
5 min
5 min
trace
30
94
100
0
100
82
57
71
63
68
30
91
86
0
78:22
78:22
74:26
0
74
56
41
81
69
82:18
56:44
61:39
5:95
10
11
Sn(OTf)2 (2.0)
Sn(OTf)2 (3.0)
DIEA (3.0)
5:95
Scheme 3.

H. Nemoto et al. / Journal of Organometallic Chemistry 611 (2000) 445–448
447
3. Conclusion
4.2.1. (Ss,3R)-2-[(tert-Butyldimethylsilyl)oxy]-
2-cyano-3-[(4-methylphenyl)sulfinyl]amino -3-
phenylpropionitrile (4a)
In conclusion, we have developed a method for the
synthesis of an N-protected-C-activated phenylglycine
in good to excellent yields. Each enantiomer can be
selectively synthesized if the appropriate Lewis acid is
used.
White powder, m.p. 63–65°C; [a]2D2 +118.6° (c 2.5,
CHCl3); FT-IR (KBr): 3173, 2934, 2244, 1596, 1463,
1
1262, 1151, 1050, 848 cm−1; H-NMR (300 MHz): 7.65
(d, J=8.1 Hz, 2H), 7.41–7.32 (m, 5H), 7.29 (d, J=8.1
Hz, 2H), 4.96 (d, J=7.5 Hz, 1H), 4.83 (brd, J=7.5 Hz,
−SONH, 1H), 2.4 (s, 3H), 0.83 (s, 9H), 0.31 (s, 3H),
0.20 (s, 3H); 13C-NMR (75 MHz): 142.2, 141.3, 133.6,
129.9, 129.7, 128.8, 128.2, 125.4, 114.5, 113.9, 69.1,
66.0, 25.1, 21.4, 18.0, −4.6, −4.9; Anal. Calc. for
C23H29N3O2SSi: C, 62.84; H, 6.65; N, 9.56. Found: C,
63.32; H, 7.01; N, 9.21%; EI-HRMS for M+: 439.1750,
Found: 439.1735.
4. Experimental
4.1. General procedures
Melting points were determined using a Yanagimoto
Micro Melting Point Apparatus and are uncorrected.
IR spectra were measured on a JASCO FT-IR/420
4.2.2. (Ss,3S)-2-[(tert-Butyldimethylsilyl)oxy]-
2-cyano-3-[(4-methylphenyl)sulfinyl]amino-3-
phenylpropionitrile (4b)
1
Infrared Fourier Transfer Spectrometer. H- and 13C-
NMR spectra were recorded on a JEOL JMN-AL300
Spectrometer operating at 300 MHz for 1H and 75
MHz for 13C in CDCl3. Chemical shifts are described
by l value in ppm relative to tetramethylsilane as an
internal standard. High Resolution Mass Spectra
(HRMS) were measured on a JEOL JMS-SX102A.
Elementary analyses were performed on a Yanagimoto
CHN-Corder MT-3. 2,6-Lutidine and diisopropylethyl-
amine were distilled over potassium hydroxide.
Dichloromethane (CH2Cl2) was distilled over phospho-
rous pentoxide. All reactions were carried out under
argon atmosphere unless otherwise noted. Preparation
of (S)-(+)-N-Benzylidene-p-toluenesulfinamide (5)
([a]2D2= +118.1° (c 1.73, CHCl3)) was carried out by
the known method [7] ([a]2D2= +117.3° (c, 1.77,
CHCl3).
Colorless crystals, m.p. 174–176°C; [a]2D2 +119.4° (c
1.6, CHCl3); FT-IR (KBr): 3182, 2938, 2240, 1596,
1462, 1261, 1153, 1056, 849 cm−1 1H-NMR (300
;
MHz): 7.64 (d, J=8.0Hz, 2H), 7.60–7.52 (m, 2H),
7.52–7.42 (m, 3H), 7.36 (d, J=8.0 Hz, 2H), 4.83 (brd,
J=5.3 Hz, −SONH, 1H), 4.71 (d, J=5.3 Hz, 1H),
2.45 (s, 3H), 0.84 (s, 9H), 0.27 (s, 3H), 0.26 (s, 3H);
13C-NMR (75 MHz): 142.3, 140.6, 131.6, 130.4, 129.9,
129.4, 128.8, 125.4, 113.5, 113.4, 68.1, 64.5, 25.1, 21.4,
18.0, −4.7, −4.8; Anal. Calc. for C23H29N3O2SSi: C,
62.84; H, 6.65; N, 9.56. Found: C, 62.58; H, 6.68; N,
9.45%.
4.2.3. (Ss,2R)-(−)-N-Butyl-2-[(4-methylphenyl)-
sulfinyl]amino-2-phenylacetamide
To a solution of 4a (32.8 mg, 0.075 mmol) and
n-butylamine (11.2 mg, 15.1 ml, 0.153 mmol) in THF (1
ml) was added TBAF (1.0 M solution in THF) (90 ml,
0.09 mmol) at −40°C. The resultant mixture was
stirred for an additional 1 h at −40°C, quenched with
a saturated NH4Cl solution (5 ml), and extracted with
CH2Cl2 (3×10 ml). The combined organic layers were
dried over MgSO4 and concentrated in 6acuo. The
residue was purified with silica gel column chromatog-
raphy using hexane-ethyl acetate (1:1) as an eluent to
give a mixture of 6a along with a trace amount of 6b
(less than 2%) as a white solid (23.6 mg, 0.069 mmol,
92% yield), which was further purified by recrystalliza-
tion from ethyl acetate-hexane.
4.2. General procedure for the addition of
H-MAC-TBS to
(S)-(+)-N-benzylidene-p-toluenesulfinamide (5)
To a solution of 5 (243 mg, 1.0 mmol), and Lewis
acid (0.1–2.0 eq.) in CH2Cl2 (5 ml) was added H-MAC-
TBS (1a) (1.5–3.0 eq.), then tert-amine (1.0–3.0 eq.)
was added in turn at room temperature. After being
stirred for 5 min–8 h at room temperature, the reaction
mixture was poured into saturated NH4Claq, and ex-
tracted with three portions of CH2Cl2 (10 ml). The
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified with
silica gel column chromatography using hexane-ethyl
acetate (6:1) as an eluent to give a mixture of 4a and 4b
as a white solid. Each diastereomer was purified with
HPLC [Rt=34.8 min (4a), Rt=31.2 min (4b), 7 ml
min−1, hexane/ethyl acetate=10:1, Hibar column RT
c250–10, LiChorsorb Si60, 10 mm id×250 mm, Cica-
Merck].
Colorless crystals, m.p. 170–171°C; [a]2D2 −59.0° (c
2.3, CHCl3); FT-IR (KBr): 3377, 3242, 2956, 2929,
1669, 1534, 1088, 1063, 809 cm−1 1H-NMR (300
;
MHz): 7.38 (d, J=8.1 Hz, 2H), 7.21–7.09 (m, 3H),
7.05 (d, J=8.1 Hz, 2H), 6.99–6.88 (m, 2H), 5.82 (brd,
J=4.5Hz, −SONH, 1H), 5.74 (br, −CONH, 1H),
4.80 (d, J=4.5 Hz, 1H), 3.21 (dt, J=6.6, 6.6 Hz, 2H),
2.30 (s, 3H), 1.46–1.33 (m, 2H), 1.30–1.15 (m, 2H),

448
H. Nemoto et al. / Journal of Organometallic Chemistry 611 (2000) 445–448
0.85 (t, J=7.3 Hz, 3H); 13C-NMR (75 MHz): 170.4,
141.0, 139.8, 138.9, 129.0, 128.2, 127.4, 127.3, 126.0,
55.5, 39.5, 31.1, 21.1, 19.7, 13.5; Anal. Calc. for
C19H24N2O2S: C, 66.25; H, 7.02; N, 8.13. Found: C,
66.07; H, 7.08; N, 8.03%.
SOCl2 (0.5 ml). The mixture was refluxed with stirring
for 1 h then evaporated to dryness in 6acuo. The
resultant acid chloride was dissolved in CH2Cl2 (6 ml),
and butylamine (146 mg, 0.2 ml, 2.0 mmol) was added
at 0°C. After being stirred for 10 min at 0°C, the
reaction mixture was concentrated and the residue was
purified with silica gel column chromatography using
chloroform-ethyl acetate (3:1) as an eluent to give 7 as
a white solid (204 mg, 0.57 mmol, 86% yield, [a]D22
−102.1° (c 1.4, CHCl3)), which was further purified by
recrystallization from ethyl acetate (m.p. 159–160°C;
[a]2D2 −109.4° (c 1.4, CHCl3)).
4.3. The preparation of (R)-(−)-N-n-Butyl-2-
[(4-methylphenyl)sulfonyl]amino-2-phenylacetamide (7)
from 6a
A mixture of 6a (42.0 mg, 0.12 mmol) and m-
chloroperbenzoic acid (33.0 mg, 70% purity, 0.13
mmol) in CH2Cl2 (1.5 ml) was stirred for 30 min at
room temperature. The resulting mixture was purified
with silica gel column chromatography using chloro-
form-ethyl acetate (3:1) as an eluent to give 7 as a white
solid (43.7 mg, 0.12 mmol, 99% yield).
References
[1] (a) H. Nemoto, Y. Kubota and Y. Yamamoto, J. Org. Chem. 55
(1990), 4515. (b) H. Nemoto, J. Syn. Org. Chem. Jpn. (Yuki Gosei
Kagaku Kyokaishi) 52 (1994) 1044.
[2] MAC is an abbreviation of ꢀ[C(CN)2O]ꢀ. ‘MAC reagent’ means
‘Hꢀ[C(CN)2O]ꢀR’. H. Nemoto, T. Ibaragi, M. Kido, M. Bando,
M. Shibuya, Tetrahedron Lett. 40 (1999) 1319.
White powder, m.p. 158–159°C; [a]2D2 −109.7° (c 1.4,
CHCl3); FT-IR (KBr): 3326, 3264, 2957, 1648, 1554,
1453, 1344, 1327, 1162, 1093 cm−1 1H-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 (brd,
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,
143.5, 136.8, 136.6, 129.5, 128.9, 128.5, 127.4, 127.2,
60.5, 39.7, 31.2, 21.5, 19.8, 13.6; Anal. Calc. for
C19H24N2O3S: C, 63.31; H, 6.71; N, 7.77. Found: C,
63.28; H, 6.89; N, 7.67%.
[3] H. Nemoto, Y. Kubota, Y. Yamamoto, J. Chem. Soc. Chem.
Commun. (1994) 1665.
[4] H. Nemoto, Y. Kubota, N. Sasaki, Y. Yamamoto, Synlett (1993)
465.
[5] H. Nemoto, Tetrahedron Lett. 35 (1994) 7855.
[6] H. Nemoto, T. Takagaki, Y. Kubota, Y. Yamamoto (1993) un-
published results.
[7] F.A. Davis, R.E. Reddy, J.M. Szewczyk, G.V. Reddy, P.S. Por-
tonovo, H. Zhang, D. Fanelli, R.T. Reddy, P. Zhou, P.J. Carroll,
J. Org. Chem. 62 (1997) 2555.
[8] Recently, by the use of the combination of Lewis acids and bases,
efficient carbon-carbon bond formation reactions have been re-
ported. (a) M. Yamaguchi, A. Hayashi, T. Minami, J. Org. Chem.
56 (1991) 4091. (b) S. Sano, T. Miwa, X. Liu, T. Ishii, T. Takehisa,
M. Shiro, Y. Nagao, Tetrahedron Asymmetry 9 (1998) 3615. (c)
M. Shibasaki, H. Sasai, T. Arai, Angew. Chem. Int. Ed. Engl. 36
(1997) 1236. (d) D.E. Frantz, R. Fa¨ssler and E.M. Carreira J. Am.
Chem. Soc. 121 (1999) 11245.
4.4. (R)-(−)-N-n-Butyl-2-[(4-methylphenyl)-
sulfonyl]amino-2-phenylacetamide (7) from
(R)-N-toluenesulfonyl-phenylglycine
A suspension of (R)-N-toluenesulfonyl-phenylglycine
9 (202 mg, 0.66 mmol) in CH2Cl2 was treated with
[9] J. DeRuiter, R.F. Borne, C.A. Mayfield, J. Med. Chem. 32 (1989)
145.
.