Facile asymmetric synthesis of α-amino acids employing chiral ligand-mediated asymmetric addition reactions of phenyllithium with imines

Article abstract of DOI:10.1016/S0040-4020(00)00860-7

A three-step methodology involving an external chiral ligand-mediated asymmetric addition of phenyllithium to an anisidine imine, oxidative removal of N-PMP group, and finally oxidative conversion of the phenyl group to a carboxyl group provides a facile synthesis of optically pure α-amino acid derivatives beating a bulky α-substituent. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00860-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10153±10158
Facile Asymmetric Synthesis of a-Amino Acids Employing Chiral
Ligand-Mediated Asymmetric Addition Reactions
of Phenyllithium with Imines
*
Masayoshi Hasegawa, Daisuke Taniyama and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
We dedicate this paper for the memory of the late Professor Toshiro Ibuka, Graduate School of Pharmaceutical Sciences, Kyoto University
Received 9 November 1999; accepted 27 January 2000
AbstractÐA three-step methodology involving an external chiral ligand-mediated asymmetric addition of phenyllithium to an anisidine
imine, oxidative removal of N-PMP group, and ®nally oxidative conversion of the phenyl group to a carboxyl group provides a facile
synthesis of optically pure a-amino acid derivatives bearing a bulky a-substituent. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
a-amino acids have been one of the targets for asymmetric
synthesis.10,11 Recently, North has disclosed an elegant
asymmetric synthesis of a-amino acids based on external
chiral ligand-mediated asymmetric addition of an organo-
lithium to N-trimethylsilylimine and subsequent oxidative
conversion of the ole®n moiety to a carboxyl group.
However, it was very disappointing for us to read that oxida-
tive removal of the N-PMP group was unsuccessful.12
We describe herein a three-step asymmetric synthesis of
a-amino acid derivatives 5 bearing a bulky a-substituent
by employing the asymmetric addition reaction of phenyl-
lithium with anisidine imines 2 and successful oxidative
removal of N-PMP group (Fig. 1).
We have been involved in an asymmetric addition reaction
of organolithium reagents with imines using an external
chiral ligand as a stereocontroller.1,2 Especially, 1,2-
addition reaction3 of phenyllithium with pivalaldehyde
anisidine imine 2a (Rˆt-Bu, PMPˆp-MeOPh) was
mediated by chiral dimethoxydiphenylethane 1 to give the
corresponding secondary amine 3a in high enantioselec-
tivity.4 Either enantiomer of 3 is available since both
enantiomers of 1 are readily available by asymmetric dihy-
droxylation of stilbene followed by methylation.3 Combined
with our related projects aimed at applications of asym-
metric reactions to the synthesis of biologically important
compounds,5 oxidative conversion of the phenyl group of 3a
to a carboxyl group without racemization provides a new
synthetic route to optically active tert-leucine.6,7 It is gener-
ally known that a bulky side chain of a-amino acid residue
around the active site of the peptide greatly in¯uences the
activity.8 It is also important to note that an optically pure
a-amino acid is a versatile chiral source for the synthesis of
a chiral auxiliary.9 Therefore, natural and unnatural
Asymmetric addition reactions of phenyllithium with
imine 2
The starting imines 2 were prepared in nearly quantitative
yields by condensation of the corresponding aldehydes with
p-anisidine in the presence of magnesium sulfate. The
addition reaction of 2 equiv. of phenyllithium with 2a
(Rˆt-Bu) was mediated by 2.6 equiv. (1.3 equiv. against
Figure 1. Three-step asymmetric synthesis of optically pure N-actyl a-amino acids.
Keywords: alkylation; asymmetric synthesis; oxidation; amino acid.
* Corresponding author. Tel.: 181-75-753-4553; fax: 181-75-753-4604; e-mail: tomioka@pharm.kyoto-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00860-7

10154
M. Hasegawa et al. / Tetrahedron 56 (2000) 10153±10158
Table 1. Asymmetric reactions of phenyllithium with imine 2 giving 3 mediated by the ligand 1 (2 equiv. of phenyllithium were used)
Entry
2
R
1 (equiv.)a
Temp (8C)
Time (h)
Yield (%)
ee (%)
R/S
1
2
3
4
a
b
c
t-Bu
c-C5H9
c-C6H11
1-adamantyl
1.3
1.3
1.3
1.3
245
245
245
245
0.7
1
1
95
84
77
98
90
76
80
89
S
S
S
S
d
1
a The equivalency against phenyllithium.
phenyllithium) of a chiral diether ligand (R,R)-1. The reac-
tion was conducted in toluene at 2458C for 0.7 h to afford
(S)-3a in 95% isolated yield after puri®cation by silica gel
column chromatography. The enantioselectivity was deter-
mined to be 90% by chiral stationary phase HPLC.13 The
speci®c rotation of 3a4 and its conversion to N-acetyl l-tert-
leucine determined (S)-absolute con®guration. The chiral
ligand 1 was recovered for reuse in nearly quantitative
yield. The asymmetric addition of phenyllithium was also
examined with 2b±d to afford (S)-3b±d in 76±89% ee and
77±98% yield (Table 1, entries 2±4).
nucleophilic phenyl group attacks the imine from the
re-face giving the product amine having the absolute con-
®guration identical with that observed. The presentation A0
indicates the positional relationship of the approaching
imine and chelated phenyllithium. On the other hand, the
structure B, giving the antipode, suffers from severe steric
repulsion between PMP and R groups of the imine and the
methyl groups of the ligand 1. The steric interaction
between PMP and methyl groups is the primary steric factor,
because the PMP group is nearer to the stereocontrolling
methyl group than the R group.
The sense of enantiofacial differentiation in the addition
reaction of phenyllithium with 2 under the control by 1
was same in all reactions examined here. Phenyllithium
attacks the imines from the re-face to give (S)-3. The degree
of enantioselectivity is related to the bulkiness of the
a-substituent (R) of the imine 2. The tertiary substituents,
t-butyl and 1-adamantyl groups (2a and 2d), induced 90%
ee and 89% ee, respectively (entries 1 and 4). Smaller
secondary c-pentyl and c-hexyl groups (2b and 2c) gave
76% ee and 80% ee, respectively (entries 2 and 3).
Analysis based on the structures A and B indicates that B is
much destabilized by the bulky R group of the imine, in
other words, A is much more favorable than B. Thus, the
observed higher selectivity of 3a (Rˆt-Bu) and 3d (Rˆ
1-adamantyl) having tertiary a-substituent than those of
3b (Rˆc-pentyl) and 3c (Rˆc-hexyl) having secondary
group is reasonably predictable.
One-¯ask conversion of N-PMP group to N-acetyl group
We have previously reported that oxidative removal of the
N-PMP group in 3 required a prior acylation of amine nitro-
gen (6) for ease of hydrolytic elimination of quinone 9 from
the oxidation product 7 (Fig. 3).4 However, attempted CAN
oxidation of 6a (Rˆt-Bu) gave 4a in only 29% yield. Since
CAN oxidation of the N-PMP group of 3 undergoes readily
to form quinone derivative 8, subsequent hydrolysis and
acylation should form 4. Without acylation, resulting
amine should attack to quinone 9 to form a 1,4-conjugate
addition product. The process from 3 to 4 via 8 can be
carried out in one-¯ask.
Catalytic addition reactions using 0.15 equiv. (against
phenyllithium) of 1 at 2458C did not proceed smoothly,
but proceeded at 08C for 1±1.5 h to give 3 in 69±97%
yield (Table 2). The enantioselectivity was maintained in
the range of 31±58% ee. The lower enantioselectivity is
attributable to the reaction of phenyllithium without
in¯uence of 1 at 08C.
Enantiofacial differentiation of imine 2
Enantiofacial differentiation of the imine 2 was reasonably
predictable by analyzing two coordinated structures A, A0
and B, B0 (Fig. 2). The chiral ligand 1 forms a chelated
complex with phenyllithium, in which two methyl groups
on the ether oxygen atoms are placed up and down faces of
the ®ve-membered chelate due to steric reason avoiding
repulsion between methyl groups and adjacent phenyl
groups. Coordination of imine nitrogen to the lithium is
the initial event for the reaction taking place. The structure
A represents a four-centered mechanism,14 in which the
Successive treatment of 3a (90% ee) with 2 equiv. of CAN
in aqueous acetonitrile at 08C for 0.5 h and at rt for further
2 h, and then with 10 equiv. of acetic anhydride and sodium
hydroxide at rt for 2 h provided N-acetylamine 4a in 78%
yield without detectable racemization. Enantioenrichment
by recrystallization of 4a of 90% ee from ethanol gave
optically pure 4a in 55% overall yield.
Under the same one-¯ask procedure, the removal of PMP
Table 2. Catalytic asymmetric reactions of phenyllithium with imine 2 mediated by 0.15 equiv. of 1 (2 equiv. of phenyllithium were used)
Entry
2
R
1 (equiv.)a
Temp (8C)
Time (h)
Yield (%)
ee (%)
R/S
1
2
3
4
a
b
c
t-Bu
c-C5H9
c-C6H11
1-adamantyl
0.15
0.15
0.15
0.15
0
0
0
0
1
85
79
69
97
58
31
53
43
S
S
S
S
1.5
1.5
1
d
a The equivalency against phenyllithium.

M. Hasegawa et al. / Tetrahedron 56 (2000) 10153±10158
10155
Figure 2. Models for favorable (A, A0) and disfavorable (B, B0) structures.
Figure 3. One-¯ask conversion of 3 to 4 by oxidative removal of N-PMP and acetylation.
group followed by acetylation of 3b±d obtained using
1.3 equiv. of 1 was carried out without any racemization
to give 4b±d in 64, 69, and 86% yields, respectively.
Enantioenrichment of N-acetylamines by recrystallization
gave optically pure N-acetylamines 4.
c-C5H9): A mixture of cyclopentanecarboxaldehyde (1.77 g,
18 mmol), 4-methoxyaniline (1.85 g, 15 mmol) and mag-
nesium sulfate (3.61 g) in ether ((30 mL) was stirred at
08C for 0.5 h. Filtration through a pad of potassium carbo-
nate followed by concentration gave 2b (3.03 g, quant) as a
pale yellow oil. 1H NMR (CDCl3, TMS) d: 1.6±1.8 (6H, m,
CH2), 1.9±2.0 (2H, m, CH2), 2.83 (1H, m, CH), 3.80 (3H, s,
OMe), 6.86 and 7.03 (each 2H, dd, Jˆ8.6, 2.8 Hz, ArH),
7.75 (1H, d, Jˆ6.1 Hz, vCH). 13C NMR (CDCl3, TMS) d:
25.7, 30.2, 46.0, 55.4, 114.1, 121.7, 145.1, 157.6, 168.2. IR
(neat): 1650 cm21. MS m/z: 203 (M1). HRMS Calcd for
C13H17NO: 203.1310. Found: 203.1315.
Synthesis of N-acetyl amino acids by conversion of a
phenyl group to a carboxyl group
Finally, conversion of the phenyl group of optically pure 4a
to a carboxyl group was conducted under modi®ed-Sharp-
less conditions,15 RuCl3±HIO4 in aqueous acetonitrile-CCl4
at rt for 48 h, to afford optically pure N-acetyl-tert-leucine
(S)-5a16 in 53% recrystallization yield. Optically pure tert-
leucine is easily available from 5a by acid hydrolysis.17
Likewise, conversion of 4b±d was carried out under the
same oxidative conditions for 4a to give optically pure
N-acetyl amino acids 5b±d in 40, 53, and 25% recrystalli-
zation yields. Optically pure (S)-1-adamantylglycine hydro-
chloride was obtained by acid hydrolysis of 5d in 34%
recystallization yield.
Cyclohexylmethylene-4-methoxyphenylamine (2c). (Rˆ
c-C6H11): A mixture of cyclohexanecarboxaldehyde (1.23 g,
10 mmol), 4-methoxyaniline (1.23 g, 10 mmol) and mag-
nesium sulfate (2.41 g) in chloroform (10 mL) was stirred
at rt for 2 h. Filtration through a pad of potassium carbonate
followed by concentration gave 2c (2.20 g, quant) as a pale
1
yellow oil. H NMR (CDCl3, TMS) d: 1.2±1.4 (5H, m,
CH2), 1.7±1.9 (5H, m, CH2), 2.34 (1H, m, CH), 3.80 (3H,
s, OMe), 6.86 and 7.01 (each 2H, dd, Jˆ8.6, 2.8 Hz, ArH),
7.71 (1H, d, Jˆ5.2 Hz, vCH). 13C NMR (CDCl3, TMS) d:
25.4, 25.9, 29.5, 44.0, 55.3, 114.1, 121.6, 145.3, 157.6,
168.4. IR (neat): 1650 cm21. MS m/z: 217 (M1). Anal.
Calcd for C14H19NO: C 77.38, H 8.81, N 6.45. Found: C
77.21, H 8.98, N 6.46.
Conclusion
The three-step methodology provided optically pure N-
acetyl a-amino acids 5 bearing bulky a-substituent from
the p-anisidine imines 2. The enantiofacial differentiation
is predictable by analyzing a coordination model. Since both
enantiomers of 1 are available by asymmetric dihydroxyl-
ation,3 the present synthesis provides either enantiomer of
optically pure a-amino acids.
1-Adamantylmethylene 4-methoxyphenylamine (2d).
(Rˆ1-adamantyl): A mixture of 1-adamantanecarbox-
aldehyde (12.1 g, 74 mmol), 4-methoxyaniline (8.24 g,
67 mmol) and magnesium sulfate (17.7 g) in ether
(150 mL) was stirred at 08C for 4 h. Filtration through a
pad of potassium carbonate followed by concentration and
recrystallization from EtOH gave 2d (9.80 g, 54%) as a pale
yellow powder of mp 89±908C. 1H NMR (CDCl3, TMS) d:
1.7±1.8 (12H, m, CH2), 2.0±2.1 (3H, m, CH), 3.79 (3H, s,
OMe), 6.85 and 6.99 (each 2H, dd, Jˆ8.6, 2.6 Hz, ArH),
7.54 (1H, s, vCH). 13C NMR (CDCl3, TMS) d: 28.0, 36.8,
38.7, 39.3, 55.4, 114.1, 121.7, 145.9, 157.5, 171.6. IR
Experimental18
2,2-Dimethylpropylidene-4-methoxyphenylamine (2a).
(Rˆt-Bu): Prepared as described before.4
Cyclopentylmethylene-4-methoxyphenylamine (2b). (Rˆ

10156
M. Hasegawa et al. / Tetrahedron 56 (2000) 10153±10158
(nujol): 1650 cm21. MS m/z: 269 (M1). Anal. Calcd for
C18H23NO: C 80.26, H 8.61, N 5.20. Found: C 79.97, H
8.49, N 5.11.
HPLC analysis (Daicel Chiralcel OJ, hexane±i-PrOH
(25:1), 254 nm, 1 mL/min, 14.7 min (minor enantiomer),
36.0 min (major enantiomer)).
Asymmetric addition reaction of phenyllithium with an
imine 2a. (2)-(S)-2,2-Dimethyl-1-phenylpropyl-4-meth-
oxyphenylamine (3a). (Rˆt-Bu): A solution of phenyl-
lithium (13.5 mL, 20 mmol) in a mixture of cyclohexane
and diethyl ether was added to a mixture of 2a (1.91 g,
10 mmol) and 1 (6.30 g, 26 mmol) in toluene (200 mL) at
2458C over a period of 10 min. The mixture was stirred at
2458C for 0.7 h and was quenched with water (100 mL).
The organic layer was separated. The aqueous layer was
extracted with AcOEt. The combined organic layers were
washed with brine, and then dried over K2CO3. Concen-
tration and column chromatography (ether±hexane) gave
(2)-(S)-N-[(1-Adamantyl)phenylmethyl]-4-methoxy-
phenylamine (3d). (Rˆ1-adamantyl): Puri®ed by column
chromatography (hexane±AcOEt) in 98% yield. A pale
20
435
yellow oil of [a] ˆ234.9 (c 1.72, EtOH). 1H NMR
(CDCl3, TMS) d: 1.4±1.7 (12H, m, CH2), 1.9±2.0 (3H, m,
CH), 3.65 (3H, s, OMe), 3.79 (1H, s, CH), 4.07 (1H, brs,
NH), 6.43 and 6.63 (each 2H, dd, Jˆ8.6, 3.1 Hz, ArH), 7.2±
7.3 (5H, m, ArH). 13C NMR (CDCl3, TMS) d: 28.4, 36.5,
36.9, 39.3, 55.7, 68.9, 114.2, 114.7, 126.6, 127.5, 128.7,
140.5, 142.3, 151.5. IR (neat): 3410 cm21. MS m/z: 347
(M1). Anal. Calcd for C24H29NO: C 82.95, H 8.41, N
4.03. Found: C 82.86, H 8.15, N 3.81.
(S)-3a (2.55 g, 95%) as a pale yellow solid of mp 67±
708C. [a]
20
435
252.7 (c 1.51, EtOH). 1H NMR (CDCl3,
One-¯ask procedure for CAN oxidation followed by
acetylation. (2)-(S)-N-(2,2-Dimethyl-1-phenylpropyl)-
acetamide (4a). (Rˆt-Bu): Cerium(IV) diammonium
nitrate (CAN) (18.4 g, 32 mmol) was added at once to a
solution of 3a (4.27 g, 16 mmol, 90% ee) in a mixture of
acetonitrile (64 mL) and water (32 mL) at 08C. The mixture
was stirred at 08C for 0.5 h and at rt for 2 h, and then was
added successively by 10% aqueous sodium hydroxide
(30 mL) and acetic anhydride (16.2 g, 160 mmol) at 08C.
After stirring for 1 h at 08C, the mixture was ®ltered through
a Celite pad. The aqueous layer was extracted with AcOEt.
The combined organic layers were washed with satd sodium
bicarbonate, 10% aqueous sodium sul®te, and brine, and
then dried over magnesium sulfate. Concentration and
column chromatography (hexane±AcOEt) gave 4a of 90%
ee (2.55 g, 78%) as a solid. Recrystallization from ethanol
gave optically pure 4a (1.82 g, 56%) as colorless cubes of
constant mp 177±177.58C. [a]2D8ˆ292.0 (c 2.05, EtOH). 1H
NMR (CDCl3, TMS) d: 0.92 (9H, s, 3£Me), 2.01 (3H, s,
CH3CO), 4.83 (1H, d, Jˆ9.5 Hz, CH), 6.04 (1H, brd, Jˆ
9.5 Hz, NH), 7.2±7.3 (5H, m, ArH). 13C NMR (CDCl3,
TMS) d: 23.5, 26.7, 34.8, 61.5, 127.0, 127.7, 128.1,
140.1, 169.2. IR (nujol): 3300, 1640 cm21. MS m/z: 205
(M1). Anal. Calcd for C13H19NO: C 76.06, H 9.33. Found:
C 75.83, H 9.44.
TMS) d: 0.98 (9H, s, 3 x Me), 3.66 (3H, s, OMe), 3.96
(1H, s, CH), 4.00 (1H, brs, NH), 6.43 and 6.64 (each 2H,
dd, Jˆ8.8, 3.1 Hz, ArH), 7.2±7.3 (5H, m, ArH). 13C NMR
(CDCl3, TMS) d: 27.1, 34.9, 55.7, 68.1, 114.3, 114.7, 126.7,
127.6, 128.5, 141.4, 142.2, 151.7. IR (nujol): 3400 cm21
.
MS m/z: 269 (M1). Anal. Calcd for C18H23NO: C 80.26,
H 8.61, N 5.20. Found: C 80.41, H 8.78, N 5.20.
Ee was determined to be 90% by chiral stationary phase
HPLC analysis (Daicel Chiralcel OJ, hexane±i-PrOH
(100:1), 254 nm, 0.5 mL/min, 33.6 min (minor enantiomer),
39.3 min (major enantiomer)).
(2)-(S)-Cyclopentylphenylmethyl-4-methoxyphenylamine
(3b). (Rˆc-C5H9): Puri®ed by column chromatography
(hexane±AcOEt) in 84% yield. A pale yellow oil of
20
435
1
[a] ˆ296.7 (c 1.54, EtOH). H NMR (CDCl3, TMS) d:
1.3 ±1.9 (8H, m, CH2), 2.11 (1H, m, CH), 3.63 (3H, s,
OMe), 3.92 (1H, brs, NH), 3.98 (1H, d, Jˆ8.0 Hz, CH),
6.44 and 6.64 (each 2H, dd, Jˆ8.7, 2.9 Hz, ArH), 7.1±7.3
(5H, m, ArH). 13C NMR (CDCl3, TMS) d: 25.27, 25.33,
30.1, 30.2, 47.9, 55.8, 64.1, 114.5, 114.8, 126.8, 127.1,
128.4, 142.1, 144.3, 151.8. IR (neat): 3400 cm21. MS m/z:
281 (M1). Anal. Calcd for C19H23NO: C 81.10, H 8.24, N
4.98. Found: C 80.85, H 8.26, N 4.80.
Ee was determined to be over 99% by chiral stationary
phase HPLC analysis (Daicel Chiralpak AS, hexane±i-
PrOH (19:1), 254 nm, 0.5 mL/min, 32.7 min (minor
enantiomer), 36.7 min (major enantiomer)).
Ee was determined to be 76% by chiral stationary phase
HPLC analysis (Daicel Chiralpak AS, hexane±i-PrOH
(30:1), 0.5 mL/min, 254 nm, 12.3 min (minor enantiomer),
18.0 min (major enantiomer)).
(2)-(S)-N-(Cyclopentylphenylmethyl)acetamide (4b). (Rˆ
c-C5H9): Puri®ed by column chromatography (hexane±
AcOEt) in 64% yield as a solid. Recrystallization from
AcOEt gave optically pure 4b as colorless cubes of constant
mp 145±145.58C in 27% overall yield. [a]2D5ˆ2118 (c 2.00,
(2)-(S)-Cyclohexylphenylmethyl-4-methoxyphenylamine
(3c). (Rˆc-C6H11): Puri®ed by column chromatography
(hexane±AcOEt) in 77% yield. A pale yellow oil of
20
1
[a] ˆ270.1 (c 1.59, EtOH). H NMR (CDCl3, TMS) d:
435
1
1.0±1.3 (5H, m, CH2), 1.5±1.9 (6H, m, CH2), 3.67 (3H, s,
OMe), 3.89 (1H, brs, NH), 4.03 (1H, d, Jˆ6.4 Hz, CH), 6.44
and 6.66 (each 2H, dd, Jˆ8.4, 3.1 Hz, ArH), 7.2±7.3 (5H,
m, ArH). 13C NMR (CDCl3, TMS) d: 26.30, 26.34, 26.4,
29.4, 30.1, 44.9, 55.6, 64.2, 114.2, 114.7, 126.6, 127.2,
128.1, 142.1, 142.8, 151.6. IR (neat): 3400 cm21. MS m/z:
295 (M1). Anal. Calcd for C20H25NO: C 81.31, H 8.53, N
4.74. Found: C 81.18, H 8.64, N 4.45.
EtOH). H NMR (CDCl3, TMS) d: 1.1±1.2 (1H, m, CH2),
1.4±1.8 (7H, m, CH2), 2.25 (1H, m, CH), 1.97 (3H, s,
CH3CO), 4.79 (1H, dd, Jˆ9.5, 9.5 Hz, CH), 5.82 (1H, brd,
Jˆ9.5 Hz, NH), 7.2±7.3 (5H, m, ArH). 13C NMR (CDCl3,
TMS) d: 23.4, 25.21, 25.25, 29.9, 30.2, 45.4, 57.9, 127.0,
127.1, 128.4, 142.6, 169.1. IR (nujol): 1650 cm21. MS m/z:
217 (M1). Anal. Calcd for C14H19NO: C 77.38, H 8.81, N
6.45. Found: C 77.44, H 8.70, N 6.41.
Ee was determined to be 80% by chiral stationary phase
Ee was determined to be over 99% by chiral stationary

M. Hasegawa et al. / Tetrahedron 56 (2000) 10153±10158
10157
phase HPLC analysis (Daicel Chiralpak AS, hexane±i-
PrOH (10:1), 254 nm, 1 mL/min, 18.3 min (major enan-
tiomer), 30.8 min (minor enantiomer)).
1.4 (2H, m, CH2), 1.5±1.7 (6H, m, CH2), 1.91 (3H, s,
CH3CO), 2.20 (1H, m, CH), 4.15 (1H, dd, Jˆ7.9, 7.9 Hz,
CH), 8.14 (1H, d, Jˆ7.9 Hz, NH), 12.5 (1H, s, CO2H). 13C
NMR (DMSO-d6) d: 22.3, 24.5, 24.8, 28.5, 28.7, 41.1, 55.4,
169.3, 173.5. IR (nujol): 1700, 1620 cm21. MS (CI) m/z:
186 (M111). HRMS Calcd for C9H16NO3 (M111):
186.1130. Found: 186.1135.
(2)-(S)-N-(Cyclohexylphenylmethyl)acetamide (4c). (Rˆ
c-C6H11):19 Puri®ed by column chromatography (hexane±
AcOEt) in 69% yield as a colorless powder of mp 1278C.
1
[a]2D1ˆ275.0 (c 2.14, MeOH). H NMR (CDCl3, TMS) d:
0.9±1.2 (4H, m, CH2), 1.4±1.5 (1H, m, CH2), 1.6±1.9 (6H,
m, CH2, CH), 1.99 (3H, s, CH3CO), 4.77 (1H, dd, Jˆ8.6,
8.6 Hz, CH), 5.69 (1H, brd, Jˆ8.6 Hz, NH), 7.2±7.3 (5H, m,
ArH). 13C NMR (CDCl3, TMS) d: 23.4, 25.95, 26.02, 26.2,
29.4, 30.1, 43.0, 58.4, 127.0, 128.4, 141.5, 169.2. IR (nujol):
1650 cm21. MS m/z: 231 (M1). HRMS Calcd for C15H22NO
(M111): 232.1701. Found: 232.1695.
(1)-(S)-Acetylaminocyclohexylacetic acid (5c). (Rˆ
c-C6H11):21 Puri®ed by recrystallization from EtOH in
53% yield as colorless needles of constant mp 208±
1
2108C. [a]2D0ˆ123.1 (c 1.09, MeOH). H NMR (DMSO-
d6) d: 1.0±1.3 (5H, m, CH2), 1.6±1.8 (6H, m, CH2, CH),
1.92 (3H, s, CH3CO), 4.17 (1H, dd, Jˆ6.4, 8.2 Hz, CH),
8.03 (1H, d, Jˆ8.2 Hz, NH), 12.5 (1H, brs, CO2H). 13C
NMR (DMSO-d6) d: 22.3, 25.5, 25.6, 28.0, 29.2, 56.7,
169.3, 173.1. IR (nujol): 1710, 1620 cm21. MS (CI) m/z:
200 (M111). Anal. Calcd for C10H17NO3: C 60.28, H
8.60. N 7.03. Found: C 60.02, H 8.33, N 6.79.
Ee was determined to be 80% by chiral stationary phase
HPLC analysis (Daicel Chiralpak AS, hexane±i-PrOH
(10:1), 254 nm, 1 mL/min, 15.9 min (major enantiomer),
38.3 min (minor enantiomer)).
(1)-(S)-Acetylaminotricyclo[3.3.1.10,0]dec-2-ylacetic acid
(5d). (Rˆ1-adamantyl): Puri®ed by recrystallization from
MeOH in 25% yield as colorless cubes of constant mp 234±
2408C. A mixture of 10:7 rotamers by PMR. [a]2D5ˆ138.3
(c 1.03, MeOH). 1H NMR (CD3OD) d: major rotamer: 1.6±
2.3 (15H, m, CH2), 2.012 (3H, s, Ac), 4.24 (1H, s, CH);
minor rotamer: 1.6±2.3 (15H, m, CH2), 2.006 (3H, s,
CH3CO), 4.14 (1H, s, CH). 13C NMR (CD3OD) d: 22.3,
22.4, 29.8, 32.7, 35.7, 36.7, 37.8, 38.0, 38.1, 39.8, 40.8,
62.0, 63.0, 68.7, 173.1, 173.3, 173.7. IR (nujol): 1710,
1655 cm21. MS (CI) m/z: 252 (M111). HRMS Calcd for
C14H22NO3 (M111): 252.1600. Found: 252.1596.
(2)-(S)-N-[(1-Adamantyl)phenylmethyl]acetamide (4d).
(Rˆ1-adamantyl): Puri®ed by column chromatography
(hexane±AcOEt) in 86% yield as a solid of mp 195±
2058C. Recrystallization from benzene gave optically pure
4d as colorless needles of constant mp 202±2038C in 51%
overall yield. [a]D25ˆ228.4 (c 1.60, EtOH). 1H NMR
(CDCl3, TMS) d: 1.4±1.5 (3H, m, CH2), 1.5±1.7 (9H, m,
CH2), 1.9±2.0 (3H, m, CH), 2.02 (3H, s, CH3CO), 4.66 (1H,
d, Jˆ9.5 Hz, CH), 6.02 (1H, brd, Jˆ9.5 Hz, NH), 7.1±7.2
(2H, m, ArH), 7.2±7.3 (3H, m, ArH). 13C NMR (CDCl3,
TMS) d: 23.4, 28.1, 36.2, 36.7, 38.8, 62.4, 126.8, 127.6,
128.3, 139.0, 169.5. IR (nujol): 1640 cm21. MS m/z: 283
(M1). Anal. Calcd for C19H25NO: C 80.52, H 8.89, N
4.94. Found: C 80.76, H 8.68, N 4.65.
(1)-(S)-1-Adamantylglycine hydrochloride.22 A suspen-
sion of 5d (80 mg, 0.32 mmol, .99% ee) in 7 M aqueous
HCl (3 mL) was re¯uxed for 1 h to give a pale yellow
solution. Concentration and recrystallization from MeOH±
AcOEt (1:10) gave (1)-(S)-1-adamantylglycine hydro-
chloride (27 mg) in 34% yield as colorless powder of mp
236±2418C. [a]2D5ˆ118.0 (c 0.50, MeOH). 1H NMR (D2O)
d: 1.4±2.2 (15H, m, CH2, CH), 3.57 (1H, s, CH). IR (nujol):
1740 cm21. MS (CI) m/z: 210 (M111). HRMS Calcd for
C12H20NO2 (M111): 210.1494. Found: 210.1501. Melting
point and speci®c rotation were identical with those
reported.
Ee was determined to be over 99% by chiral stationary
phase HPLC analysis (Daicel Chiralpak OD-H, hexane±i-
PrOH (20:1), 254 nm, 1 mL/min, 12.1 min (minor enan-
tiomer), 27.2 min (major enantiomer)).
Procedure for oxidation of phenyl group to carboxylic
group. (2)-(S)-N-Acetyl-tert-leucine (5a). (Rˆt-Bu)16: A
mixture of 4a (616 mg, 3.0 mmol, .99% ee), ruthenium
trichloride hydrate (38 mg, 0.15 mmol) and periodic acid
(13.7 g, 60 mmol) in a mixture of carbon tetrachloride
(6 mL), acetonitrile (6 mL) and water (9 mL) was stirred
at rt for 2 d. The mixture was extracted with AcOEt. The
organic layer was washed with brine and then dried over
magnesium sulfate. Concentration followed by recrystalli-
zation from aqueous EtOH gave 5a (276 mg, 53%) as color-
less cubes of dp 233±2348C. [a]2D6ˆ23.4 (c 2.00, EtOH).
1H NMR (CD3OD) d: 1.02 (9H, s, 3£Me), 2.00 (3H, s,
CH3CO), 4.28 (1H, s, CH). 13C NMR (CD3OD) d: 22.3,
27.1, 34.7, 62.2, 173.3, 174.2. IR (nujol): 3350, 1700,
1620 cm21. MS (CI) m/z: 174 (M111). Anal. Calcd for
C8H15NO3: C 55.47, H 8.73. N 8.09. Found: C 55.47, H
8.43, N 7.83.
Acknowledgements
We acknowledge ®nancial support from the Japan Society
for Promotion of Science (RFTF-96P00302) and the
Ministry of Education, Science, Sports and Culture, Japan.
References
1. For excellent reviews, see: (a) Denmark, S. E.; Nicaise, O. J.-C.
J. Chem. Soc., Chem. Commun. 1996, 999±1004. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895±1946.
(c) Bloch, R. Chem. Rev. 1998, 98, 1407±1438. For leading
references, see: (a) Itsuno, S.; Yanaka, H.; Hachisuka, C.; Ito, K.
J. Chem. Soc., Perkin Trans. 1 1991, 1341±1342. (b) Katritzky,
A. R.; Harris, P. A. Tetrahedron: Asymmetry 1992, 3, 437±442.
(2)-(S)-Acetylaminocyclopentylacetic acid (5b). (Rˆ
c-C5H9):20 Puri®ed by recrystallization from AcOEt in
40% yield as colorless needles of mp 173±1758C.
1
[a]2D5ˆ26.1 (c 0.38, EtOH). H NMR (DMSO-d6) d: 1.3±

10158
M. Hasegawa et al. / Tetrahedron 56 (2000) 10153±10158
(c) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem.
Commun. 1992, 1097±1098. (d) Ukaji, Y.; Hatanaka, T.; Ahmed,
A.; Inomata, K. Chemistry Lett. 1993, 1313±1316. (e) Denmark,
S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994, 116,
8797±8798. (f) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am.
Chem. Soc. 1996, 118, 8489±8490.
Soldevilla, N.; Borrego, M. A. Tetrahedron: Asymmetry 1999,
10, 493±509. (h) Jew, S.-S.; Cha, K.-H.; Kang, S.-D.; Woo,
Y.-H.; Kim, H.-O.; Park, H.-G. Heterocycles 1999, 50, 677±680.
(i) Cundy, D. J.; Donohue, A. C.; McCarthy, T. D. J. Chem. Soc.,
Perkin Trans. 1 1999, 559±568. (j) Chinchilla, R.; Galindo, N.;
Najera, C. Synthesis 1999, 704±717. (k) Lygo, B. Tetrahedron
Lett. 1999, 40, 1389±1392. Kim, B. J.; Park, Y. S.; Beak, P.
J. Org. Chem. 1999, 64, 1705±1708. (l) Muller, P.; Imogai, H.
Tetrahedron: Asymmetry 1999, 9, 4419±4428. (m) Guillena, G.;
Najera, C. Tetrahedron: Asymmetry 1999, 9, 3935±3938. (n) Tang,
T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12±13. (o) Seebach,
D.; Boog, A.; Schweizer, W. B. Eur. J. Org. Chem. 1999, 335±360.
(p) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999,
64, 336±337. (q) Bull, S. D.; Davies, S. G.; O'Shea, M. D. J. Chem.
Soc., Perkin Trans. 1 1998, 3657±3658. (r) O'Donnell, M. J.;
Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett.
1998, 39, 8775±8778. (s) Giraud, L.; Renaud, P. J. Org. Chem.
1998, 63, 9162±9163. (t) Meyer, L.; Poirier, J.-M.; Duhamel, P.;
Duhamel, L. J. Org. Chem. 1998, 63, 8094±8095.
2. (a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron
Lett. 1990, 31, 6681±6684. (b) Tomioka, K.; Inoue, I.; Shindo, M.;
Koga, K. Tetrahedron Lett. 1991, 32, 3095±3098. (c) Inoue, I.;
Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron: Asymmetry 1993,
4, 1603±1606. (d) Inoue, I.; Shindo, M.; Koga, K.; Kanai, M.;
Tomioka, K. Tetrahedron: Asymmetry 1995, 6, 2527±2533.
(e) Taniyama, D.; Kanai, M.; Iida, A.; Tomioka, K. Heterocycles
1997, 46, 165±168. (f) Taniyama, D.; Kanai, M.; Iida, A.;
Tomioka, K. Chem. Pharm. Bull. 1997, 45, 1705±1707.
3. For 1,4-conjugate addition reactions of organolithiums with
a,b-unsaturated imines, see: (a) Shindo, M.; Koga, K.; Tomioka,
K. J. Am. Chem. Soc. 1992, 114, 8732±8733. (b) Shindo, M.;
Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351±9357.
4. Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron
1994, 50, 4429±4438.
Â
12. Gittins (nee Jones), C. A.; North, M. Tetrahedron: Asymmetry
1997, 8, 3789±3799.
5. (a) Tomioka, K.; Satoh, M.; Taniyama, D.; Kanai, M.; Iida, A.
Heterocycles 1998, 47, 77±80. (b) Taniyama, D.; Hasegawa, M.;
Tomioka, K. Tetrahedron: Asymmetry 1999, 10, 221±223.
6. Ef®cient use of the phenyl group as the carboxyl synthon in the
total synthesis of mugineic acid has been reported. Matsuura, F.;
Hamada, Y.; Shioiri, T. Tetrahedron 1993, 49, 8211±8222.
7. tert-Leucine has been the target of chemical and enzymatic
asymmetric synthesis. (a) Corey, E. J.; Link, J. O. J. Am. Chem.
Soc. 1992, 114, 1906±1908. (b) Kunz, H.; Pfrengle, W. Tetrahedron
1988, 44, 5487±5494. (c) Grabley, S.; Keller, R.; Schlingmann, M.
EP 0141223, 1987. (d) Steglich, W.; Frauendorfer, E.; Weygand,
F. Chem. Ber. 1971, 104, 687±690.
13. Ee was accurately determined to be 90% by changing chiral
column described here instead of 87% reported previously (Ref.
[4]).
14. A six-membered mechanism is a possible alternative to the
four-centered one, because usually 2 equiv. of phenyllithium was
required for completion of the reaction. The six-membered
mechanism provides the same prediction of the enantiofacial
differentiation.
Â
15. NunÄez, M. T.; Martõn, V. S. J. Org. Chem. 1990, 55, 1928±
1932.
16. Barker, J.; Cook, S. L.; Lasterra-Sanchez, M. E.; Thomas, S. E.
J. Chem. Soc., Chem. Commun. 1992, 830±832.
Â
8. Josien, H.; Lavielle, S.; Brunissen, A.; Saffroy, M.; Torrens, Y.;
Beaujouan, J.-C.; Glowinski, J.; Chassaing, G. J. Med. Chem.
1994, 37, 1586±1601.
17. Bommarius, A. S.; Schwarm, M.; Stingl, K.; Kottenhahn, M.;
Huthmacher, K.; Drauz, K. Tetrahedron: Asymmetry 1995, 6,
2851±2888.
9. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis, Wiley: New York, 1995.
18. The reaction was monitored by tlc. Puri®cation was carried out
using silica gel column chromatography unless otherwise noted. 1H
NMR (500 MHz) and 13C NMR (126 MHz) were measured in
CDCl3 unless otherwise noted. Chemical shift (d) was presented
in ppm relative to internal tetramethylsilane. Coupling constant
value (J) was presented in Hz. Mass spectra were measured by
EI mode unless otherwise noted.
10. For excellent reviews, see: (a) Cativiela, C.; Diaz-De-Villegas,
M. D. Tetrahedron: Asymmetry 1998, 9, 3517±3599. (b) Williams,
R. M. Synthesis of Optically Active a-Amino Acids; Pergamon:
New York, 1989.
11. For recent impressive reports on asymmetric synthesis of
amino acids, see: (a) Ohtake, H.; Imada, Y.; Murahashi, S.
J. Org. Chem. 1999, 64, 3790±3791. (b) Moody, C. J.; Gallagher,
P. T.; Lightfoot, A. P.; Slawin, A. M. Z. J. Org. Chem. 1999, 64,
4419±4425. (c) Cardillo, G.; Gentilucci, L.; Tolomelli, A.;
Tomasini, C. Tetrahedron 1999, 55, 6231±6242. (d) Davis, F. A.;
McCoull, W. J. Org. Chem. 1999, 64, 3396±3397. (e) Tunge, J. A.;
Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520±
4521. (f) Fondekar, K. Pai; Volk, F.-J.; Frahm, A. W. Tetrahedron:
Asymmetry 1999, 10, 727±735. (g) Camps, P.; Perez, F.;
19. Ghislandi, V.; Vercesi, D. Il Farmaco-Ed. Sc. 1971, 26, 474±
486.
20. Eisler, K.; Rudinger, J.; Sorm, F. Coll. Czech. Chem. Commun.
1966, 31, 4563±4580.
21. Beller, M.; Eckert, M.; Geissler, H.; Napierski, B.;
Rebenstock, H.-P.; Holla, E. W. Chem. Eur. J. 1998, 4, 935±941.
Â
22. Galvez, N.; Morena-ManÄas, M.; Vallribera, A.; Molins, E.;
Cabrero, A. Tetrahedron Lett. 1996, 37, 6197±6200.