Asymmetric synthesis of α-amino acids by reduction of N-tert-butanesulfinyl ketimine esters

Article abstract of DOI:10.1021/jo200401a

A highly regio- and diastereoselective reduction of various N-tert-butanesulfinyl ketimine esters with L-Selectride resulting in the formation of α-amino acids is reported. This method is quite general and also practical for the preparation of both enantiomers of aryl or aliphatic α-amino acids in high yields.

Full text of DOI:10.1021/jo200401a

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of r-Amino Acids by Reduction of
N-tert-Butanesulfinyl Ketimine Esters
Leleti Rajender Reddy,* Aditya P. Gupta,r and Yugang Liu
Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States
S Supporting Information
b
ABSTRACT: A highly regio- and diastereoselective reduction of various N-
tert-butanesulfinyl ketimine esters with L-Selectride resulting in the formation
of R-amino acids is reported. This method is quite general and also practical
for the preparation of both enantiomers of aryl or aliphatic R-amino acids in
high yields.
Scheme 1. Approaches to R-Amino Acids
’ INTRODUCTION
Natural and unnatural R-amino acids are components of a
number of significant drugs, including glycopeptide antibiotics,
β-lactam antibiotics such as vancomycin,1 cefprozil,2 amoxicillin,3
ampicillin,4 antihypertensive drugs such as enalapril,5 a GnRH
hormone such as nafarelin,6 and the cardiovascular agent Plavix.7
The asymmetric synthesis of unnatural R-amino acids is a funda-
mental challenge in organic chemistry.8 Therefore, intense re-
search has been focused on the preparation of enantiomerically
enriched R-amino acids.9
The classical approach to obtain enantiomerically pure R-amino
acids is by resolution of the racemate via diastereoselective salt
formation and also enzyme-catalyzed kinetic resolution even used
on an industrial scale.10a However, the maximum theoretical yield
for resolution is only 50%.10 The commercially available N-tert-
butanesulfinamides have been widely used as highly efficient chiral
auxiliaries in the synthesis of a variety of optically active amines by
virtue of their excellent diastereocontrol and mild conditions for
their cleavage.11 Recently, Ellman has reported12 an elegant
method for the asymmetric synthesis of R-amino acids by the
rhodium-catalyzed addition of arylboronic acids to N-tert-butane-
sulfinyl aldimine esters (1), which proceeds in high yield with high
diastereoselectivity for both electron-rich and electron-poor aryl-
boronic acids (2); but this method has some limitations: it is limited
to the synthesis of only arylglycine derivatives. We reasoned that a
direct method to access enantioenriched R-amino acids would be
an asymmetric reduction of N-tert-butanesulfinyl ketimine esters
(4), which has not been described to the best of our knowledge.10
Herein, we report a versatile and practical method for highly regio-
and diastereoselective reduction of N-tert-butanesulfinyl ketimine
esters (4) to give R-amino acids (5) with high yields (Scheme 1).
The tert-butanesulfinyl group not only induces excellent diaster-
eoselectivity but also serves as an efficient low molecular weight
protecting group for the nitrogen for future modifications of the
carboxylic acid of the R-amino acids, if needed.
’ RESULTS AND DISCUSSION
N-tert-Butanesulfinyl ketimine esters (RS)-4aꢀk13 were
synthesized in high yield via condensation of readily available
corresponding R-ketoesters (1.0 equiv)14 with (RS)-N-tert-buta-
nesulfinamide (1.1 equiv)15 in the presence of 1.5 equiv of
16
Ti(OEt)4 in THF at reflux temperature for 6 h. In the same
way, the N-tert-butanesulfinyl ketimine esters (SS)-4a,g were
synthesized via condensation of corresponding R-ketoesters with
(SS)-N-tert-butanesulfinamide.
Treatment of N-tert-butanesulfinyl ketimine esters (RS)-4a
(1 equiv) with L-Selectride (1.05 equiv, slow addition by syringe
pump for 1 h) at ꢀ78 °C in THF for 6 h afforded R-amino acid
derivative 5a (Table 1, entry 1) in high yield (93%) and with a
high diastereomeric ratio (dr g98:2). The diastereoselectivity of
the reaction was determined to be g98:2 by 1H NMR analysis of
the crude product.17 The structure and absolute configuration of
Received: February 22, 2011
Published: April 04, 2011
r
2011 American Chemical Society
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|

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Table 1. Asymmtric Reduction of N-tert-Butanesulfinyl
Ketimine Esters with L-Selectride
Table 2. Asymmtric Reduction of N-tert-Butanesulfinyl
Ketimine Esters 4a with Various Metal Hydrides
entry
reducing agent
conversion (%)
dra,c
1
2
3b
L-Selectride
LiBHEt3
NaBH4
100
100
60
g98:2
95:5
45:55
40:60
39:61
38:62
4
NaBH3CN
LiBH4
82
75d
5
6
9-BBN
90
a All reactions were performed with 1.1 equiv of reducing agent at ꢀ78
°C for 12 h in THF, unless stated otherwise indicated. b 10 equiv of
MeOH is used. c The diastereoselectivity was determined by 1H NMR
analysis. The “g 98:2” dr denotes that signals for only one diastereomer
were observed. d 5% alcohol was formed.
Table 3. Asymmtric Reduction of N-tert-Butanesulfinyl
Ketimine Ester 4a with L-Selectride at Different Temperatures
entry
temp (°C)
conversion (%)
dra,b
1
2
3
4
ꢀ78
ꢀ50
ꢀ20
0
100
100
100c
100d
g98:2
96:4
88:12
85:15
a All reactions were performed with 1.1 equiv of reducing agent for 6 h in
THF, unless otherwise indicated. b The diastereoselectivity was deter-
mined by 1H NMR analysis. The “g 98:2” dr denotes that signals for
only one diastereomer were observed. c 11% alcohol was formed. d 18%
alcohol was formed.
a Isolated yield. b The diastereoselectivity was determined by 1H NMR
analysis. The “g 98:2” dr denotes that signals for only one diastereomer
were observed.
Scheme 3. Selective Fuctional Group Tranformations
Scheme 2. Reduction of Various N-tert-Butanesulfinyl
Ketimine Esters with L-Selectride
best results in terms of diastereo- and regioselectivities. We also
investigated this readuction at different temparatures (Table 3),
and the best results were obtained at ꢀ78 °C in THF.
Encouraged by these results, we turned our attention to other
substituted aromatic N-tert-butanesulfinyl ketimine esters. Inter-
estingly, a large number of substituted aromatic N-tert-butane-
sulfinyl ketimine esters, such as p-chloro, p-methoxy, p-tert-butyl,
p-n-butyl, and 3,5-difluoro derivatives, reacted cleanly with
L-Selectride at ꢀ78 °C in THF for 6 h, leading to the correspond-
ing R-amino acid derivatives 5bꢀf (Table 1, entries 2ꢀ6) in
excellent yields (85ꢀ90%) and with high diastereometric ratios
(dr g98:2).
1
(Rs,R)-5a were confirmed by comparing the H NMR, 13C
NMR, and specific rotation with literature data.12 The reduction
of N-tert-butanesulfinyl ketimine ester (SS)-ent-4a (Table 1,
entry 12) with L-Selectride at ꢀ78 °C in THF for 6 h afforded
the other enantiomer of the R-amino acid derivative (ent-5a) in
high yield (90%) and with high diastereomeric ratio (dr g98:2)
(Scheme 2). A series of other metal hydrides (Table 2) were
screened to further elaborate this reduction, L-selectride gave the
Similarly, polyaromatic N-tert-butanesulfinyl ketimine esters,
such as naphthyl derivative 4j and anthracenyl N-tert-butanesul-
finyl ketimine esters 4k, were smoothly reduced with L-Selectride
at ꢀ78 °C in THF for 6 h, affording the correspending R-amino
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The Journal of Organic Chemistry
ARTICLE
acid derivative 5j and 5k (Table 1, entries 10 and 11) in 90% and
91% yield, respectively, with high diastereomeric ratio (dr
g98:2). In the same way, reduction of aliphatic N-tert-butane-
sulfinyl ketimine esters, such as methyl ketimine ester 4g and
isopropyl ketimine ester 4h, with L-Seletride in THF at ꢀ78 °C
for 6 h afforded 5g and 5h in high yields (88% and 86%,
respectively) and with high diastereomeric ratio (dr g98:2).
Similarly, the long chain aliphatic N-tert-butanesulfinyl ketimine
ester 4i was also reduced with L-Selectride in THF at ꢀ78 °C for
6 h to afford 5i (Table 1, entry 9) in high yield (94%) and with
high diastereoselectivity (dr g98:2). Referring to the literature,18
a possible mechanistic model explains the achieved stereoselec-
tivity (RS,R-5), which involves a cyclic chair transition state.
A key feature of this R-amino acid synthesis method is the
versatility of N-sulfinyl-R-amino ester products 5a,h in subse-
quent transformations. Selective cleavage of the sulfinyl group
with 4.0 M HCl in methanol at 0 °C for 30 min,12 or ester group
with LiOH in THF/water at 0 °C for 1 h,19 can be accom-
plished in high yields without loss of stereochemical purity
(Scheme 3).
(84%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-phenylacetate
(4a) as a viscous liquid. [R]25D ꢀ114.3 (c 0.89, CHCl3). FTIR (ATR) ν
2981, 1736, 1571, 1287, 1203, 1180, 1090, 1018, 689 cmꢀ1. 1H NMR
(500 MHz, CDCl3) δ (ppm) 1.34 (s, 9 H), 1.41 (t, J = 7.09 Hz, 3 H),
4.45 (dd, J = 12.45, 7.09 Hz, 2 H), 7.45 (t, J = 7.57 Hz, 2 H), 7.52 (d, J =
7.25 Hz, 1 H), 7.73ꢀ7.82 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ
(ppm) 14.0, 23.0, 59.5, 62.2, 127.8, 128.8, 132.6, 133.1, 163.3, 165.8.
HRMS (EI) calcd for C14H20NO3S [M þ H] 282.1164, found
282.1169.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-chlorophenyl)
acetate, 4b: Following the general procedure (GP1), the reaction of
ethyl 2-(4-chlorophenyl)-2-oxoacetate (12.1 g, 100.0 mmol) with (RS)-
tert-butanesulfinamide (13.3 g, 110.0 mmol) and Ti(OEt)4 (34.5 g,
150.0 mmol) gave 25.2 g (80%) of pure (R,E)-ethyl 2-[(tert-
butylsulfinyl)imino]-2-(4-chlorophenyl)acetate (4b) as a viscous liquid.
[R]25D ꢀ57.0 (c 1.31, CHCl3). FTIR (ATR) ν 2979, 1733, 1586, 1564,
1
1258, 1207, 1168, 1086, 877 cmꢀ1. H NMR (501 MHz, CDCl3) δ
(ppm) 1.34 (s, 9 H), 1.41 (t, J = 7.25 Hz, 3 H), 4.34ꢀ4.52 (m, 2 H), 7.42
(d, J = 8.51 Hz, 2 H), 7.71 (d, J = 8.51 Hz, 2 H). 13C NMR (125 MHz,
CDCl3) δ (ppm) 13.9, 23.0, 59.6, 62.3, 129.1, 129.2, 131.6, 138.9, 162.2,
165.4. HRMS (EI) calcd for C14H19NO3SCl [M þ H] 316.0774, found
316.0778.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(3,5-difluorophenyl)
acetate, 4c: Following the general procedure (GP1), the reaction of
ethyl 2-(3, 5-difluorophenyl)-2-oxoacetate (2.14 g, 10.0 mmol) with
(RS)-tert-butanesulfinamide (1.33 g, 11.0 mmol) and Ti(OEt)4 (3.45 g,
15.0 mmol) gave 2.45 g (78%) of pure (R,E)-ethyl 2-[(tert-
butylsulfinyl)imino]-2-(3,5-difluorophenyl)acetate (4c) as a viscous
’ CONCLUSION
In conclusion, we have described a practical, highly distereo-
selective reduction of various N-tert-butanesulfinyl ketimine
esters with L-Selectride affording chiral R-amino acids. This
method is quite general for the preparation of both enantiomers
of aromatic and aliphatic R-amino acids. Extension of this work is
currently under way in our laboratory.
liquid. [R]25 ꢀ120.1 (c 1.10, CHCl3). FTIR (ATR) ν 2982, 1736,
D
1
1586, 1331, 1255, 1150, 1095, 991, 854 cmꢀ1. H NMR (501 MHz,
CDCl3) δ (ppm) 1.35 (s, 9 H), 1.42 (t, J = 7.09 Hz, 3 H), 4.39ꢀ4.55 (m,
2 H), 6.94ꢀ7.02 (m, 1 H), 7.29 (dd, J = 7.88, 2.21 Hz, 2 H). 13C NMR
(125 MHz, CDCl3) δ (ppm) 13.8, 22.9, 60.0, 62.6, 107.7 (t, J = 25.20
Hz), 107.7, 110.6, 110.8, 136.1, 162.0 (d, J = 11.91 Hz), 164. 0 (d, J =
11.91 Hz), 164.8. HRMS (EI) calcd for C14H18NO3SF2 [M þ H]
318.975, found 318.970.
’ EXPERIMENTAL SECTION
General Information. All the reactions were performed under dry
nitrogen gas in glassware that was flame-dried and equipped with a
magnetic stirring bar. Tetrahydrofuran (THF) was freshly distilled from
the sodium complex of benzophenone before use. Thin-layer chroma-
tography (TLC) was performed with silica gel 60 F254 precoated plates
(0.25 mm). Flash chromatography was performed with silica gel (40 μm
particle size). All compounds were judged pure by TLC analysis (single
spot/two solvent systems), using a UV lamp or PMA for detection
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-methoxyphe-
nyl)acetate, 4d: Following the general procedure (GP1), the reaction
of ethyl 2-(4-methoxyphenyl)-2-oxoacetate (2.08 g, 10.0 mmol) with
(RS)-tert-butanesulfinamide (1.33 g, 11.0 mmol) and Ti(OEt)4 (3.45 g,
15.0 mmol) gave 2.23 g (72%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-2-(4-methoxyphenyl)acetate (4d) as a viscous liquid. [R]25
1
purposes. H and 13C NMR spectra were recorded on a FT-NMR
D
ꢀ98.2 (c 1.02, CHCl3). FTIR (ATR) ν 2981, 1731, 1599, 1577, 1229,
1157, 1075, 842 cmꢀ1. 1H NMR (501 MHz, CDCl3) δ (ppm) 1.32 (s, 9
H), 1.40 (t, J = 7.25 Hz, 3 H), 3.85 (s, 3 H), 4.33ꢀ4.55 (m, 2 H), 6.93 (d,
J = 8.83 Hz, 2 H), 7.73 (d, J = 8.83 Hz, 2 H). 13C NMR (125 MHz,
CDCl3) δ (ppm) 13.9, 22.9, 55.5, 59.1, 62.1, 114.2, 125.9, 129.9,162.7,
163.2, 165.9. HRMS (EI) calcd for C15H22NO4S [M þ H] 312.1270,
found 312.1273.
spectrometer at 500 and 125 MHz, respectively. High-resolution mass
spectroscopy (HRMS) was carried out in electrospray mode. All the
reagents were purchased from commercial suppliers and used without
further purification. Unless indicated otherwise, the reaction tempera-
tures refer to internal reaction temperatures.
General Procedure (GP1) for the Synthesis of N-tert-
Butanesulfinyl Ketimine Esters 4. A 500 mL, three-necked,
round-bottomed flask was charged with R-ketoesters (40.0 mmol),
THF (100 mL), tert-butanesulfinamide (44.0 mmol), and Ti(OEt)4
(60.0 mmol) under nitrogen atm. The reaction mixture was then heated
at reflux at 65 °C for 6 h. After completion, the reaction was allowed to
cool to rt. Isopropyl acetate (100 mL) and saturated NaCl solution
(100 mL) were then added and the mixture was stirred for 1 h. The solids
were removed by filtration, and the filtrate was washed with water (2 ꢁ
50 mL). The organic phase was evaporated under vacuum to dryness to
obtain the crude product. The crude product was purified by flash
column chromatography (silica gel, 10% ethyl acetate in heptanes) to
afford the pure N-tert-butanesulfinyl ketimine esters 4.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-tert-butylphenyl)
acetate, 4e: Following the general procedure (GP1), the reaction of
ethyl 2-(4-tert-butylphenyl)-2-oxoacetate (2.34 g, 10.0 mmol) with
(RS)-tert-butanesulfinamide (1.33 g, 11.0 mmol) and Ti(OEt)4 (3.45 g,
15.0 mmol) gave 2.72 g (81%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-2-(4-tert-butylphenyl)acetate (4e) as a viscous liquid. [R]25D ꢀ60.4
(c 0.9, CHCl3). FTIR (ATR) ν 2962, 1739, 1590, 1558, 1211, 1188,
1091, 832 cmꢀ1. 1H NMR (501 MHz, CDCl3) δ (ppm) 1.33 (s, 18 H),
1.40 (t, J = 7.25 Hz, 3 H), 4.36ꢀ4.53 (m, 2 H), 7.42ꢀ7.51 (m, 2 H), 7.71
(d, J = 8.83 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.9,
31.0, 35.1, 62.1, 125.8, 127.7, 130.5, 156.4, 163.2, 165.9. HRMS (EI)
calcd for C18H28NO3S [M þ H] 338.1790, found 338.1795.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-phenylacetate, 4a:
Following the general procedure (GP1), the reaction of ethyl 2-oxo-2-
phenylacetate (17.8 g, 100.0 mmol) with (RS)-tert-butanesulfinamide
(13.3 g, 110.0 mmol) and Ti(OEt)4 (34.5 g, 150.0 mmol) gave 23.6 g
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-butylphenyl)
acetate, 4f: Following the general procedure (GP1), the reaction of
ethyl 2-(4-butylphenyl)-2-oxoacetate (2.33 g, 10.0 mmol) with (RS)-
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tert-butanesulfinamide (1.35 g, 11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0
mmol) gave 2.91 g (92%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-2-(4-butylphenyl)acetate (4f) as a viscous liquid. [R]25D ꢀ66.5
(c 0.94, CHCl3). FTIR (ATR) ν 2958, 2930, 1738, 1590, 1562, 1208,
1179, 1091, 838, 754 cmꢀ1. 1H NMR (501 MHz, CDCl3) δ (ppm) 0.93
(t, J = 7.25 Hz, 3 H), 1.27ꢀ1.37 (m and s, 11 H), 1.40 (t, J = 7.25 Hz,
3 H), 1.55ꢀ1.65 (m, 2 H), 2.66 (t, J = 7.57 Hz, 2 H), 4.44 (dd, J = 12.61,
7.25 Hz, 2 H), 7.19ꢀ7.29 (m, 2 H), 7.68 (d, J = 8.51 Hz, 2 H). 13C NMR
(125 MHz, CDCl3) δ (ppm) 13.8, 13.9, 22.2, 22.9, 33.2, 35.6, 59.3, 62.1,
127.9, 128.9, 130.7, 148.4, 163.3, 165.9. HRMS (EI) calcd for
C18H28NO3S [M þ H] 338.1790, found 338.1793.
of ethyl 2-(phenanthren-9-yl)-2-oxoacetate (2.78 g, 10.0 mmol) with
(RS)-tert-butanesulfinamide (1.35 g, 11.0 mmol) and Ti(OEt)4 (3.45 g,
15.0 mmol) gave 3.42 g (90%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-2-(phenanthren-9-yl)acetate (4k) as a viscous liquid. [R]25D ꢀ124.8
(c 1.10, CHCl3). FTIR (ATR) ν 2982, 1729, 1597, 1261, 1204, 1115,
1087, 728 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.28ꢀ1.47 (m,
12 H), 4.45 (q, J = 6.94 Hz, 2 H), 7.56 (t, J = 7.41 Hz, 1 H), 7.59ꢀ7.69
(m, 3 H), 7.88 (d, J = 7.57 Hz, 1 H), 8.09 (s, 1 H), 8.57 (d, J = 8.20 Hz,
1 H), 8.61ꢀ8.68 (m, 1 H), 8.77 (d, J = 7.57 Hz, 1 H). 13C NMR
(125 MHz, CDCl3) δ (ppm) 14.0, 23.0, 59.1, 62.5, 122.6, 123.1, 126.4,
127.2, 127.2, 128.7, 128.9, 129.9, 130.1, 130.4, 130.9, 131.6, 165.6.
HRMS (EI) calcd for C22H24NO3S [M þ H] 382.1477, found
382.1481.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]propanoate, 4g:
Following the general procedure (GP1), the reaction of ethyl 2-oxo-
propanoate (1.16 g, 10.0 mmol) with (RS)-tert-butanesulfinamide (1.35 g,
11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0 mmol) gave 1.86 g (85%) of
pure (R,E)-ethyl 2-[(tert-butylsulfinyl)imino)propanoate (4g) as a
(S,E)-Ethyl2-[(tert-butylsulfinyl)imino]-2-phenylacetate, ent-4a:
Following the general procedure (GP1), the reaction of ethyl 2-oxo-2-
phenylacetate (8.9 g, 50.0 mmol) with (RS)-tert-butanesulfinamide
(6.65 g, 55.0 mmol) and Ti(OEt)4 (17.25 g, 75.0 mmol) gave 12.3 g
(89%) of pure (S,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-phenylacetate
viscous liquid. [R]25 ꢀ125.8 (c 1.79, CHCl3). FTIR (ATR) ν 2981,
D
1778, 1734, 1253, 1129, 1019, 859 cmꢀ1. 1H NMR (501 MHz, CDCl3)
δ (ppm) 1.32 (t and m, 12 H), 2.46 (s, 3 H), 4.19ꢀ4.41 (m, 2 H). 13C
NMR (125 MHz, CDCl3) δ (ppm) 13.9, 18.2, 22.7, 25.1, 59.1, 62.2,
163.3, 166.7, 167.6. HRMS (EI) calcd for C9H18NO3S [M þ H]
220.1007, found 220.1011.
(ent-4a) as a viscous liquid. [R]25 þ110.2 (c 1.08, CHCl3). FTIR
D
(ATR) ν 2980, 1736, 1571, 1287, 1203, 1190, 1018, 689 cmꢀ1. 1H NMR
(500 MHz, CDCl3) δ (ppm) 1.35 (s, 9 H), 1.41 (t, J = 7.25 Hz, 3 H),
4.38ꢀ4.53 (m, 2 H), 7.45 (t, J = 7.57 Hz, 2 H), 7.53 (d, J = 7.25 Hz, 1 H),
7.73ꢀ7.84 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 14.0, 23.0,
59.5, 62.3, 127.8, 128.8, 132.6, 133.1, 163.3, 165.8. HRMS (EI) calcd for
C14H20NO3S [M þ H] 282.1164, found 282.1169.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-3-methylbutano-
ate, 4h: Following the general procedure (GP1), the reaction of ethyl
3-methyl-2-oxobutanoate (1.16 g, 10.0 mmol) with (RS)-tert-butanesul-
finamide (1.35 g, 11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0 mmol) gave
1.86 g (85%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-3-methyl-
(S,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-3-methylbutano-
ate, ent-4h: Following the general procedure (GP1), the reaction of
ethyl 3-methyl-2-oxobutanoate (1.18 g, 10.0 mmol) with (SS)-tert-
butanesulfinamide (1.35 g, 11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0
mmol) gave 1.75 g (80%) of pure (S,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-3-methylbutanoate (ent-4h) as a viscous liquid. [R]25D þ152.2
(c 1.10, CHCl3). FTIR (ATR) ν 2981, 1733, 1624, 1250, 1180, 1088,
848 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.20 (t, J = 6.15 Hz, 6
H), 1.25 (s, 9 H), 1.36 (t, J = 7.09 Hz, 3 H), 2.75ꢀ2.89 (m, 1 H),
4.21ꢀ4.41 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 16.3, 21.2,
21.7, 24.9, 39.4, 60.4, 64.1, 168.9, 176.6. HRMS (EI) calcd for
C11H22NO3S [M þ H] 248.1313, found 248.1315.
butanoate (4h) as a viscous liquid. [R]25 ꢀ154.2 (c 1.64, CHCl3).
D
FTIR (ATR) ν 2975, 1734, 1626, 1251, 1178, 1089, 847 cmꢀ1. 1H NMR
(500 MHz, CDCl3) δ (ppm) 1.20 (t, J = 6.15 Hz, 6 H), 1.25 (s, 9 H),
1.36 (t, J = 7.09 Hz, 3 H), 2.79ꢀ2.90 (m, 1 H), 4.24ꢀ4.39 (m, 2 H). 13C
NMR (125 MHz, CDCl3) δ (ppm) 13.9, 18.9, 19.3, 22.5, 37.1, 58.1,
61.7, 166.5, 174.2. HRMS (EI) calcd for C11H22NO3S [M þ H]
248.1313, found 248.1317.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]icosanoate, 4i:
Following the general procedure (GP1), the reaction of ethyl
2-oxoicosanoate (3.54 g, 10.0 mmol) with (RS)-tert-butanesulfina-
mide (1.35 g, 11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0 mmol) gave
4.34 g (95%) of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]
icosanoate (4i) as a viscous liquid. [R]25D ꢀ127.7 (c 1.22, CHCl3).
General Procedure (GP2) for the Synthesis of r-Amino
Acids 5. L-Selectride (5.25 mL, 5.5 mmol, 1.0 M solution in THF
solution) was added to a solution of ketimine ester 4 (5 mmol) in THF
(20 mL) at ꢀ78 °C under nitrogen (by syringe pump for 1 h). After
being stirred for 6 h at ꢀ78 °C, the reaction mixture was quenched with
saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (2 ꢁ
25 mL). The combined organic layer was washed with water and dried
under vacuum to give crude product. The crude product was purified by
column chromatography (silica gel, ethyl acetate/hexanes) to afford the
pure R-amino acid 5.
FTIR (ATR) ν 2916, 2849, 1737, 1631, 1471, 1253, 1091, 717 cmꢀ1
.
1H NMR (500 MHz, CDCl3) δ (ppm) 0.88 (m, 3 H), 1.18ꢀ1.32 (m, 36
H), 1.35 (q, J = 7.04 Hz, 6 H), 1.50ꢀ1.75 (m, 2 H), 2.46ꢀ2.71 (m, 2 H),
4.18ꢀ4.39 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 14.1,
22.6, 22.7, 25.0, 26.9, 29.4, 29.5, 29.7, 31.9, 38.4, 58.0, 61.3, 166.9, 170.3.
HRMS (EI) calcd for C26H52NO3S [M þ H] 458.3668, found 458.3666.
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(1,2-dihydroa-
cenaphthylen-5-yl)acetate, 4j: Following the general procedure
(GP1), the reaction of ethyl 2-(1,2-dihydroacenaphthylen-5-yl)-2-ox-
oacetate (2.54 g, 10.0 mmol) with (RS)-tert-butanesulfinamide (1.35 g,
11.0 mmol) and Ti(OEt)4 (3.45 g, 15.0 mmol) gave 3.24 g (91%)
of pure (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(1,2-dihydroace-
(R)-Ethyl 2-[(R)-1,1-dimethylethylsulfinamido]-2-pheny-
lacetate, 5a: Following the general procedure (GP2), the reaction
of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-phenylacetate (4a) (1.40
g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in THF)
afforded R-amino acid 5a (1.31 g, 93%) as a viscous liquid. [R]25
D
naphthylen-5-yl)acetate (4j) as a viscous liquid. [R]25 ꢀ116.1
ꢀ186.4 (c 0.98, CHCl3). FTIR (ATR) ν 2980, 1733, 1247, 1175, 1066,
847, 697 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.20 (t, J = 7.09
Hz, 3 H), 1.24 (s, 9 H), 4.09ꢀ4.18 (m, 1 H), 4.23 (dd, J = 10.72, 7.25 Hz,
1 H), 4.59 (d, J = 4.41 Hz, 1 H), 5.06 (d, J = 4.41 Hz, 1 H), 7.26ꢀ7.43
(m, 5 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.5, 55.9, 60.4,
62.1, 127.6, 128.6, 137.2, 171.3. HRMS (EI) calcd for C14H22NO3S [M
þ H] 284.1320, found 284.1318.
D
(c 0.88, CHCl3). FTIR (ATR) ν 2955, 1733, 1576, 1248, 1177, 1085,
832 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.39 (s, 9 H), 1.41 (t,
J = 7.09 Hz, 3 H), 3.25ꢀ3.40 (m, 4 H), 4.41ꢀ4.53 (m, 2 H), 7.25 (d, J =
7.25 Hz, 1 H), 7.33 (d, J = 6.62 Hz, 1 H), 7.55 (dd, J = 8.51, 6.94 Hz,
1 H), 7.75 (d, J = 7.25 Hz, 1 H), 8.72 (d, J = 8.83 Hz, 1 H). 13C NMR
(125 MHz, CDCl3) δ (ppm) 14.0, 22.9, 30.3, 30.4, 53.4, 58.8, 62.2,
118.6, 120.5, 121.9, 125.0, 129.3, 130.2, 132.6, 139.7, 146.7, 153.1, 165.1,
165.9. HRMS (EI) calcd for C20H24NO3S [M þ H] 358.3477, found
358.3479.
(R)-Ethyl 2-(4-chlorophenyl)-2-[(R)-1,1-dimethylethylsul-
finamido]acetate, 5b: Following the general procedure (GP2), the
reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-chlorophe-
nyl)acetate (4b) (1.57 g, 5.0 mmol) with L-Selectride (5.25 mL,
5.25 mmol, 1.0 M in THF) afforded R-amino acid 5b (1.39 g, 88%)
(R,E)-Ethyl 2-[(tert-butylsulfinyl)imino]-2-(phenanthren-
9-yl)acetate, 4k: Following the general procedure (GP1), the reaction
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ARTICLE
as a viscous liquid. [R]25D ꢀ66.1 (c 1.02, CHCl3). FTIR (ATR) ν 2960,
mmol) with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in THF) afforded
1
1735, 1491, 1366, 1174, 1073, 1014, 824 cmꢀ1. H NMR (500 MHz,
R-amino acid 5g (0.96 g, 88%) as a viscous liquid. [R]25D ꢀ60.2 (c 1.04,
CDCl3) δ (ppm) 1.20 (t, J = 7.25 Hz, 3 H), 1.23 (s, 9 H), 4.06ꢀ4.28 (m,
2 H), 4.62 (d, J = 4.10 Hz) 1 H), 5.04 (d, J = 4.10 Hz, 1 H), 7.27ꢀ7.37
(m, 4 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.5, 55.9, 59.7,
62.3, 128.6, 129.1, 134.3, 135.8, 170.8. HRMS (EI) calcd for
C14H21NO3SCl [M þ H] 318.0931, found 318.0928.
CDCl3). FTIR (ATR) ν 2981, 1733, 1286, 1194, 1131, 1053, 853 cmꢀ1
.
1H NMR (500 MHz, CDCl3) δ (ppm) 1.24 (s, 9 H), 1.27ꢀ1.32 (m,
3 H), 1.41 (d, J = 6.94 Hz, 3 H), 3.96ꢀ4.06 (m, 1 H), 4.16 (br s, 1 H),
4.22 (q, J = 7.25 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 14.1,
19.7, 22.5, 52.6, 55.7, 61.7, 173.4. HRMS (EI) calcd for C9H20NO3S [M
þ H] 222.1164, found 222.1156.
(R)-Ethyl 2-(2,5-difluorophenyl)-2-[(R)-1,1-dimethylethyl-
sulfinamido]acetate, 5c: Following the general procedure (GP2),
the reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(2,5-fluoro-
phenyl)acetate (4c) (1.58 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25
mmol, 1.0 M in THF) afforded R-amino acid 5c (1.35 g, 85%) as a
(R)-Ethyl 2-[(R)-1,1-dimethylethylsulfinamido]-3-methyl-
butanoate, 5h: Following the general procedure (GP2), the reaction
of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-3-methylbutanoate (4h)
(1.2 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in
viscous liquid. [R]25 ꢀ86.4 (c 1.12, CHCl3). FTIR (ATR) ν 2981,
THF) afforded R-amino acid 5h (1.07 g, 86%) as a viscous liquid. [R]25
D
D
1
1736, 1624, 1598, 1459, 1183, 1119, 1071, 849, 673 cmꢀ1. H NMR
ꢀ100.8 (c 0.98, CDCl3). FTIR (ATR) ν 2969, 1732, 1467, 1198, 1064,
724 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 0.90 (d, J = 6.94 Hz,
3 H), 0.97 (d, J = 6.94 Hz, 3 H), 1.27 (s, 9 H), 1.29 (t, J = 7.09 Hz, 3 H),
2.00ꢀ2.18 (m, 1 H), 3.71 (dd, J = 7.88, 5.04 Hz, 1 H), 4.10 (d, J = 7.88
Hz, 1 H), 4.15ꢀ4.29 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ
ppm 14.1, 17.3, 19.1, 22.7, 32.3, 56.2, 61.5, 63.1, 173.0. HRMS (EI) calcd
for C11H24NO3S [M þ H] 250.1477, found 250.1479.
(500 MHz, CDCl3) δ (ppm) 1.23 (t, J = 7.09 Hz, 3 H), 1.27 (s, 9 H),
4.11ꢀ4.29 (m, 2 H), 4.60 (d, J = 3.78 Hz, 1 H), 5.03 (d, J = 4.10 Hz, 1
H), 6.72ꢀ6.81 (m, 1 H), 6.94 (d, J = 5.67 Hz, 2 H). 13C NMR (125
MHz, CDCl3) δ (ppm) 13.9, 22.5, 56.2, 59.5, 62.7, 103.9, (t, J = 25.20
Hz) 104.1, 110.6, 110.6, 141.0, 162.0 (d, J = 11.91 Hz), 164.0 (d, J =
12.81 Hz), 170.2. HRMS (EI) calcd for C14H20NO3SF2 [M þ H]
320.1132, found 320.1125.
(R)-Ethyl 2-[(R)-1,1-dimethylethylsulfinamido]icosanoate, 5i:
Following the general procedure (GP2), the reaction of (R,E)-ethyl
2-[(tert-butylsulfinyl)imino]icosanoate (4i) (2.28 g, 5.0 mmol) with L-
Selectride (5.25 mL, 5.25 mmol, 1.0 M in THF) afforded R-amino acid
(R)-Ethyl 2-(4-methoxyphenyl)-2-[(R)-1,1-dimethylethyl-
sulfinamido]actate, 5d: Following the general procedure (GP2),
the reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-methoxy-
phenyl)acetate (4d) (1.55 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25
mmol, 1.0 M in THF) afforded R-amino acid 5d (1.34 g, 86%) as a
viscous liquid. [R]25D ꢀ161.1 (c 1., CHCl3). FTIR (ATR) ν 2959, 1733,
5i (2.15 g, 94%) as a viscous liquid. [R]25 ꢀ134.2 (c 1.14, CHCl3).
D
FTIR (ATR) ν 2915, 2850, 1740, 1470, 1180, 1072, 716 cmꢀ1. 1H NMR
(500 MHz, CDCl3) δ (ppm) 0.88 (t, J = 6.94 Hz, 3 H), 1.12ꢀ1.45 (m,
44 H), 1.62ꢀ1.86 (m, 2 H), 3.84ꢀ3.95 (m, 1 H), 4.08 (d, J = 7.25 Hz,
1 H), 4.22 (q, J = 7.25 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ (ppm)
14.1, 22.6, 24.9, 29.1, 29.3, 29.6, 29.7, 31.9, 33.9, 55.9, 57.4, 61.5, 173.4.
HRMS (EI) calcd for C26H54NO3S [M þ H] 460.3824, found
460.3820.
1
1512, 1245, 1175, 1071, 831 cmꢀ1. H NMR (500 MHz, CDCl3) δ
(ppm) 1.20 (t, J = 7.09 Hz, 3 H), 1.23 (s, 9 H), 3.81 (s, 3 H), 4.04ꢀ4.30
(m, 2 H), 4.54 (d, J = 3.78 Hz, 1 H), 5.01 (d, J = 4.10 Hz, 1 H), 6.88 (d,
J = 8.83 Hz, 2 H), 7.28 (d, J = 8.83 Hz, 2 H). 13C NMR (125 MHz,
CDCl3) δ (ppm) 13.9, 22.5, 55.2, 55.8, 59.8, 62.0, 114.0, 128.9, 129.2,
159.8, 171.5. HRMS (EI) calcd for C15H24NO4S [M þ H] 314.1426,
found 314.1420.
(R)-Ethyl 2-(1,2-dihydroacenaphthylen-5-yl)-2-[(R)-1,1-
dimethylethylsulfinamido]acetate 5j. Following the general
procedure (GP2), the reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)
imino]-(1,2-dihydroacenaphthylen-5-yl)acetate (4j) (1.75 g, 5.0 mmol)
with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in THF) afforded
(R)-Ethyl 2-(4-tert-butylphenyl)-2-[(R)-1,1-dimethylethyl-
sulfinamido]acetate, 5e: Following the general procedure (GP2),
the reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-tert-butyl-
phenyl)acetate (4e) (1.68 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25
mmol, 1.0 M in THF) afforded R-amino acid 5e (1.52 g, 90%) as a
R-amino acid 5j (1.61 g, 90%) as a viscous liquid. [R]25 ꢀ124.8
D
(c 1.10, CHCl3). FTIR (ATR) ν 2959, 1729, 1215, 1178, 1068,
viscous liquid. [R]25 ꢀ145.9 (c 0.98, CHCl3). FTIR (ATR) ν 2959,
838 cmꢀ1. H NMR (500 MHz, CDCl3) δ (ppm) 1.10 (t, J = 7.09
1
D
299, 1735, 1246, 1175, 1074, 849 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ
(ppm) 1.22 (t, J = 7.09 Hz, 3 H), 1.24 (s, 9 H), 1.30ꢀ1.32 (m, 9 H),
4.07ꢀ4.17 (m, 1 H), 4.24 (dd, J = 10.72, 7.25 Hz, 1 H), 4.56 (d, J = 5.04
Hz, 1 H), 5.03 (d, J = 5.04 Hz, 1 H), 7.26ꢀ7.31 (m, 2 H), 7.33ꢀ7.39 (m,
2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.5, 31.2, 34.5, 55.9,
60.2, 62.0, 125.5, 127.1, 134.1, 151.2, 171.5. HRMS (EI) calcd for
C18H30NO3S [M þ H] 340.1946, found 340.1941.
Hz, 3 H), 1.15 (s, 9 H), 3.27ꢀ3.43 (m, 4 H), 4.08 (dd, J = 10.88, 7.09 Hz,
1 H), 4.21 (dd, J = 10.88, 7.09 Hz, 1 H), 4.71 (d, J = 3.47 Hz, 1 H), 5.56
(d, J = 3.78 Hz, 1 H), 7.25 (dd, J = 21.75, 6.94 Hz, 2 H), 7.40ꢀ7.50 (m, 2
H), 7.76 (d, J = 8.51 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ (ppm)
13.9, 22.5, 30.0, 30.5, 55.7, 58.5, 62.1, 118.7, 119.5, 128.1, 129.5, 138.8,
146.4, 147.3, 172.0. HRMS (EI) calcd for C20H26NO3S [M þ H]
360.1633, found 360.1630.
(R)-Ethyl 2-(4-butylphenyl)-2-[(R)-1,1-dimethylethylsulfi-
namido]acetate, 5f: Following the general procedure (GP2), the
reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(4-butylphe-
nyl)acetate (4f) (1.66 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25
mmol, 1.0 M in THF) afforded R-amino acid 5f (1.50 g, 89%) as a
(R)-Ethyl 2-(phenanthren-9-yl)-2-[(R)-1,1-dimethylethyl-
sulfinamido]acetate 5k. Following the general procedure (GP2),
the reaction of (R,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-(phenanthren-
9-yl)acetate (4k) (1.90 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25
mmol, 1.0 M in THF) afforded R-amino acid 5k (1.74 g, 91%) as a
viscous liquid. [R]25 ꢀ128.2 (c 1.16, CDCl3). FTIR (ATR) ν 2960,
viscous liquid. [R]25 ꢀ134.4 (c 1.19, CHCl3). FTIR (ATR) ν 2959,
D
D
1734, 1249, 1174, 1077, 1018, 825 cmꢀ1. 1H NMR (500 MHz, CDCl3)
δ (ppm) 0.92 (t, J = 7.41 Hz, 3 H), 1.20 (t, J = 7.09 Hz, 3 H), 1.23 (s,
9 H), 1.32ꢀ1.41 (m, 2 H), 1.50ꢀ1.64 (m, 2 H), 2.54ꢀ2.64 (m, 2 H),
4.07ꢀ4.17 (m, 1 H), 4.17ꢀ4.28 (m, 1 H), 4.58 (d, J = 4.73 Hz, 1 H),
5.02 (d, J = 4.73 Hz, 1 H), 7.15 (d, J = 8.20 Hz, 2 H), 7.26 (d, J = 7.88 Hz,
2 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.3, 22.5, 33.3, 35.2,
55.9, 60.3, 62.0, 127.4, 128.6, 134.4, 143.1, 171.5. HRMS (EI) calcd for
C18H30NO3S [M þ H] 340.1930, found 340.1921.
1728, 1219, 1115, 1068, 728 cmꢀ1. H NMR (500 MHz, CDCl3) δ
1
(ppm) 1.04 (t, J = 7.09 Hz, 3 H), 1.12 (s, 9 H), 4.05ꢀ4.23 (m, 2 H), 5.64
(d, J = 3.15 Hz, 1 H), 7.50ꢀ7.65 (m, 4 H), 7.82 (s, 1 H), 7.86 (d, J = 7.57
Hz, 1 H), 8.09ꢀ8.16 (m, 1 H), 8.60 (d, J = 8.20 Hz, 1 H), 8.67 (d, J =
7.88 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.5, 55.7,
60.0, 62.3, 122.5, 123.3, 124.8, 126.6, 126.9, 127.4, 128.9, 129.6, 130.7,
130.7, 131.0, 131.2, 171.9. HRMS (EI) calcd for C22H26NO3S [M þ H]
384.1633, found 384.1638.
(S)-Ethyl 2-[(S)-1,1-dimethylethylsulfinamido]-2-phenyla-
cetate, ent-5a: Following the general procedure (GP2), the reaction
of (S,E)-ethyl 2-[(tert-butylsulfinyl)imino]-2-phenylacetate (ent-4a)
(R)-Ethyl 2-[(R)-1,1-dimethylethylsulfinamido]propano-
ate, 5g: Following the general procedure (GP2), the reaction of
(R,E)-ethyl 2-[(tert-butylsulfinyl)imino]propanoate (4g) (1.1 g, 5.0
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ARTICLE
(1.38 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in
THF) afforded R-amino acid ent-5a (1.26 g, 90%) as a viscous liquid.
[R]25D þ184.2 (c 1.06, CHCl3). FTIR (ATR) ν 2981, 1737, 1585, 1292,
1178, 1090, 834 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.13 (t,
J = 7.09 Hz, 3 H), 1.19 (s, 9 H), 4.00ꢀ4.12 (m, 1 H), 4.12ꢀ4.22 (m,
1 H), 4.62 (d, J = 4.10 Hz, 1 H), 5.02 (d, J = 4.41 Hz, 1 H), 7.21ꢀ7.37
(m, 5 H). 13C NMR (125 MHz, CDCl3) δ (ppm) 13.9, 22.5, 55.9, 60.4,
62.0, 127.6, 128.6, 137.1, 171.3. HRMS (EI) calcd for C14H22NO3S [M
þ H] 284.1320, found 284.1317.
(R)-2-Phenylglycine ethyl ester hydrochloride, 7a: Follow-
ing the general procedure (GP4), the reaction of 5a (565 mg, 2.0 mmol)
with a 4 M HCl solution (in dioxane, 2 mL) gives the (R)-2-phenylgly-
cine ethyl ester hydrochloride (7a) (418 mg, 97%) as a white solid. Mp
189ꢀ190 °C. [R]25 ꢀ98.2 (c 1.22, CHCl3). FTIR (ATR) ν 2842,
D
1737, 1494, 1232, 1185, 1044, 857 cmꢀ1. 1H NMR (500 MHz, DMSO-
d6) δ (ppm) 1.13 (t, J = 7.09 Hz, 3 H), 4.04ꢀ4.28 (m, 2 H), 5.19 (s,
1 H), 7.35ꢀ7.49 (m, 3 H), 7.54 (dd, J = 7.57, 1.89 Hz, 2 H), 9.28 (br s,
3 H). 13C NMR (125 MHz, DMSO-d6) δ (ppm) 13.7, 55.2, 61.9, 128.2,
128.8, 129.3, 132.6, 168.2. HRMS (EI) calcd for C10H14NO2 [M þ H]
180.1025, found 180.1027.
(S)-Ethyl 2-[(S)-1,1-dimethylethylsulfinamido]-3-methyl-
butanoate, ent-5h: Following the general procedure (GP2), the
reaction of (S,E)-ethyl 2-[(tert-butylsulfinyl)imino]propanoate (ent-4h)
(1.15 g, 5.0 mmol) with L-Selectride (5.25 mL, 5.25 mmol, 1.0 M in
THF) afforded R-amino acid ent-5h (0.91 g, 85%) as a viscous liquid.
[R]25D þ104.2 (c 1.10, CHCl3). FTIR (ATR) ν 2969, 1732, 1467, 1198,
1063, 724 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 0.90 (d, J = 6.94
Hz, 3 H), 0.97 (d, J = 6.94 Hz, 3 H), 1.27 (s, 9 H), 1.29 (t, J = 7.09 Hz, 3
H), 1.97ꢀ2.15 (m, 1 H), 3.71 (dd, J = 7.88, 5.04 Hz, 1 H), 4.10 (d, J =
7.88 Hz, 1 H), 4.17ꢀ4.32 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ
(ppm) 14.0, 17.2, 19.1, 22.6, 32.2, 56.1, 61.4, 63.0, 172.9. HRMS (EI)
calcd for C9H20NO3S [M þ H] 222.1164, found 222.1160.
(R)-Valine ethyl ester hydrochloride, 7h: Following the gen-
eral procedure (GP4), the reaction of 5h (498 mg, 2.0 mmol) with a 4 M
HCl solution (in dioxane, 2 mL) gives the (R)-valine ethyl ester
hydrochloride (7h) (360 mg, 98%) as a white solid. Mp 98ꢀ100 °C.
[R]25D ꢀ38.2 (c 1.10, CHCl3). FTIR (ATR) ν 2863, 1742, 1522, 1263,
1097, 701 cmꢀ1. 1H NMR (500 MHz, CDCl3) δ (ppm) 1 1.15 (t, J =
7.41 Hz, 6 H), 1.32 (t, J = 7.09 Hz, 3 H), 2.37ꢀ2.57 (m, 1 H), 3.93 (d, J =
3.47 Hz, 1 H), 4.19ꢀ4.41 (m, 2 H), 8.85 (br s, 3 H). 13C NMR (125
MHz, CDCL3) δ (ppm) 14.1, 18.2, 18.3, 29.9, 58.5, 62.3, 168.1. HRMS
(EI) calcd for C7H16NO2 [M þ H] 146.1181, found 146.1184.
General Procedure (GP3) for the Hydrolysis of Ester 5. To a
round-bottomed flask containing LiOH (1.2 g, 50 mmol, 10 equiv) was
added distilled H2O (50.0 mL), and the resulting solution was cooled to
0 °C. A solution of 5 (5.0 mmol, 1.0 equiv) in THF (50.0 mL) was added
into the reaction flask. The resulting solution was stirred at 0 °C for 1 h.
The reaction mixture was then concentrated to remove the THF, and
the remaining material was diluted with distilled H2O (50 mL) and
EtOAc (50 mL). The reaction mixture was neutralized with saturated
NaHSO4 solution to pH ∼2 and the organic layer was separated and
washed with water (2 ꢁ 50 mL). The organic layer were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The pro-
duct 6 was isolated as a white solid with no further purification.
(R)-2-[(R)-1,1-Dimethylsulfinamido]-2-phenylacetic acid, 6a:
Following the general procedure (GP3), hydrolysis of (R)-ethyl 2-[(R)-
1, 1-dimethylethylsulfinamido]-2-phenylacetate (5a) (1.41 g, 5.0 mmol)
with LiOH (1.2 g, 50 mmol) afforded compound (R)-2-[(R)-1,1-
dimethylsulfinamido]-2-phenylacetic acid (6a) (1.16 g, 96%) as a white
solid. Mp 141ꢀ142 °C. [R]25D ꢀ86.2 (c 1.08, CHCl3). FTIR (ATR) ν
2967, 1715, 1184, 1060, 1013, 722 cmꢀ1. 1H NMR (500 MHz, CDCl3)
δ (ppm) 1.27 (s, 9 H), 5.10 (br s, 2 H), 7.25ꢀ7.55 (m, 5 H). 13C NMR
(125 MHz, CDCl3) δ (ppm) 22.6, 56.6, 61.3, 127.4, 128.4, 128.7, 137.1,
172.5. HRMS (EI) calcd for C12H16NO3S [M ꢀ H] 254.0851, found
254.0853.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra all the
b
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rajender.leleti@novartis.com.
Notes
rSummer Intern (2010): Undergraduate Student from New York
University, New York 10012, United States.
’ REFERENCES
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(R)-2-[(R)-1,1-Dimethylsulfinamido]-3-methylbutanoic acid,
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2-[(R)-1,1-dimethylethylsulfinamido]-3-methylbutanoate (5h) (1.24 g,
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(s, 9 H), 1.99ꢀ2.12 (m, 1 H), 3.71 (dd, J = 7.88, 5.04 Hz, 1 H), 4.42 (d, J =
7.57 Hz, 1 H), 11.36 (br s, 1 H). 13C NMR (125 MHz, CDCl3) δ (ppm)
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General Procedure (GP4) for Deprotection of the tert-
Butanesulfinyl Group from 5. To a solution of 5 (2 mmol) in
MeOH (10 mL) was added a 4 M HCl solution (in dioxane, 2 mL). After
the mixture was stirred at room temperature for 30 min, it was
concentrated to dryness and diethyl ether (40 mL) was added. The
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The Journal of Organic Chemistry
ARTICLE
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(16) Titanium(IV) ethoxide (purum) was purchased from Aldrich,
and it contains ∼3% of tetraisopropyl orthotitanate.
1
(17) We have seen less than 1% of amino alcohol in the H NMR
analysis of the crude product.
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3415
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