An efficient synthesis of enantiomerically pure unnatural aryl glycinols and aryl glycines

Article abstract of DOI:10.1016/j.tetasy.2006.03.031

A quick route to enantiomerically pure unnatural aryl glycinols and aryl glycines has been established based on an asymmetric azidation reaction using a chiral benzosultam auxiliary. The synthesis of aryl glycinols involves three steps starting from aryla

Full text of DOI:10.1016/j.tetasy.2006.03.031

Tetrahedron: Asymmetry 17 (2006) 1111–1115
An efficient synthesis of enantiomerically pure unnatural aryl
glycinols and aryl glycines
Hui-Young Ku,a Junyang Jung,a Soo-Hyun Kim,a Hee Yeon Kim,a
Kyo Han Ahna,* and Sung-Gon Kimb,*
aDepartment of Chemistry and Center for Integrated Molecular Systems, Division of Molecular and Life Sciences,
Pohang University of Science and Technology, San 31 Hyoja-dong, Pohang 790-784, Republic of Korea
bMedicinal Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu,
Daejeon 305-600, Republic of Korea
Received 8 March 2006; accepted 30 March 2006
Abstract—A quick route to enantiomerically pure unnatural aryl glycinols and aryl glycines has been established based on an asymmetric
azidation reaction using a chiral benzosultam auxiliary. The synthesis of aryl glycinols involves three steps starting from arylacetic acids,
and the chiral auxiliary can be readily recovered.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
recognition of organoammonium ions,7 gram-quantities
of (m-hydroxyphenyl)glycinol 1 and a-naphthylglycinol 28
(Scheme 1) were required for the construction of new oxaz-
oline receptors. We found that the corresponding enantio-
merically pure amino acids were either not readily
available or were very expensive.9 Therefore, it was neces-
sary for us to develop an efficient synthetic route. Herein,
we report an efficient route to the aryl glycinols and the cor-
responding aryl glycines in gram quantities with high enan-
tiomeric purities, which involves an asymmetric azidation
reaction using a benzosultam chiral auxiliary10 that can
be readily recovered and reused. The established procedure
can also be applied as an expeditious route to other enantio-
merically pure b-amino alcohols and a-amino acids.
An efficient synthesis of enantiomerically pure a-amino
acids has drawn a considerable research interest. A diversity
of methodology1 has been developed for the stereoselective
construction of naturally occurring amino acids as well as
optically active nonproteinogenic amino acids, of which
aryl glycine derivatives constitute an important class.2
Highly functionalized aryl glycines can be found in numer-
ous peptide and glycopeptide antibiotics, such as the vanco-
mycins.3 Several substituted phenylglycine derivatives,
including 3-hydroxyphenylglycine, have been described as
potent and selective agonists or antagonists of glutamate
receptors of the central nervous system (CNS).4 Aryl glyci-
nols constitute a class of b-amino alcohols, which are also
valuable structural units in synthetic and natural com-
pounds.5 The enantiomerically pure aryl glycinols can be
directly synthesized from the corresponding a-amino acids
by reduction of the acid function.6 This route is, however,
only amenable to the case when an enantiopure amino
acid is readily available, either from a natural source or
by a short synthesis. Otherwise, other synthetic routes can
be used. Over the course of our study on the development
of oxazoline-based artificial receptors for the molecular
Me
HO
HO
O Si t-Bu
NH2
NH2
Me
1
2
Scheme 1. Selected aryl glycinols.
2. Results and discussion
*
Corresponding authors. Tel.: +82 42 860 7115; fax: +82 42 861 1291
(S.-G.K.); tel.: +82 54 279 2105; fax: +82 54 279 3399 (K.H.A.);
e-mail addresses: ahn@postech.ac.kr; sgkim@krict.re.kr
Among various plausible routes, we investigated two chem-
ical synthesis routes to enantiomerically pure aryl glycinols:
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.031

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H.-Y. Ku et al. / Tetrahedron: Asymmetry 17 (2006) 1111–1115
the Sharpless asymmetric aminohydroxylation (AA) of aryl
olefins11 and the chiral auxiliary-based asymmetric synthe-
sis.12 Although the Sharpless’ AA route seemed to be con-
cise, it has a drawback of low regioselectivity (about 7:3)
in the case of most substituted styrene derivatives. Further-
more, the chromatographic separation of the regioisomers
was problematic due to their similar Rf values. In addition
to the regioselectivity problem, we had difficulty in repro-
ducing the Sharpless AA reaction in cases where benzyl
carbamate or tert-butyl carbamate was used as the amine
source, even though we followed the reaction conditions
described in the literature. When we used N-bromoaceta-
mide as the amine source, this problem did not occur; how-
ever, this route was unsuitable for our purpose because an
additional protection step raised a selectivity problem.
Therefore, we turned our attention to the chiral auxiliary-
based route, which involves readily available starting
materials, gives high enantioselectivity, and, above all,
the auxiliary can be recovered and reused.
7a with LiAlH4 in THF at 0–25 °C, followed by quenching
with water, afforded the desired amino alcohol 1.
This one-step reduction of the azido-sulfonamide to the
amino alcohol is possible, because the chiral auxiliary is
robust under the reaction conditions. After a standard extr-
active work-up and column chromatography on silica gel,
amino alcohol 1 was then isolated in 89% yield as oil,
together with recovered benzosultam 4 in quantitative
yield. The enantiopurity of amino alcohol 1 was deter-
mined to be 91% ee by NMR analyses for its Mosher’s
amide, which in turn was synthesized from an unpurified
sample. The value is a little lower than the diastereoselec-
tivities observed in the cases of other azido compounds
(>98:2). In previous cases,10 acyl sultam intermediates were
derived from 1-pentenoic acid and 3-phenylpropanoic acid,
which are less prone to epimerization at the stereogenic
center, compared to the present case of aryl acetic acid.
We suspected that a certain degree of racemization
occurred during the conversion of azido compound 7a to
the amino alcohol.16 Following a similar route as above,
(1-naphthyl)glycinol 2 can be synthesized, starting from
commercially available (1-naphthyl)acetic acid. The whole
sequence was efficiently carried out in 68% overall yield,
while the enantiopurity was found to be 95% ee before
recrystallization.
To synthesize amino alcohol 1, arylacetic acid 3a was cou-
pled with benzosultam 413 using a mixed anhydride method
(t-BuCOCl, LiCl, Et3N)14 to afford acyl sultam 5a in 75%
yield (Scheme 2). The next azidation reaction was carried
out as following the Evans protocol:15 enolization of acyl
sultam 5a with sodium hexamethyldisilazide (NaHMDS)
in THF at ꢀ78 °C, and subsequent reaction with trisyl
azide provided intermediate 6a, which was then decom-
posed to azido compound 7a by treatment with sodium
acetate at 25 °C overnight. The azidation step proceeded
in good yield (92%) and with near complete stereoselectiv-
ity, as judged by 1H NMR spectrum analysis for the crude
product (de > 98:2). Finally, treatment of azido compound
Aryl glycines 9a and 9b can be readily synthesized from azo
compounds 7a and 7b. Hydrolysis of azido compound 7a
with lithium hydroxide and hydrogen peroxide, followed
by catalytic hydrogenation provided amino acid 9a in
95% overall yield (Scheme 3). Similarly, (1-naphthyl)gly-
cine 9b could also be obtained in 62% overall yield starting
from azo compound 7b.
t-Bu
t-Bu
O
O
NaHMDS, Trisyl-N3, AcOH
THF
t-BuCOCl, Et3N, LiCl
R
+
R
N
NH
O
HO
S
THF
S
O
O
O
3a, R = (m-TBSO)phenyl
3b, R = 1-naphthyl
4
5a, R = (m-TBSO)phenyl, 75%
5b, R = 1-naphthyl, 81%
t-Bu
t-Bu
O
O
H
N3
R
N
N
LiAlH4, THF
NaOAc, THF
N
N
N
S
OH
O2
S
S
R
H2N
R
O
O
O
O
1, R = (m-TBSO)phenyl, 89%
2, R = 1-naphthyl, 87%
7a, R = (m-TBSO)phenyl, 92%
7b, R = 1-naphthyl, 96%
6a, R = (m-TBSO)phenyl
6b, R = 1-naphthyl
Scheme 2. Asymmetric synthesis of aryl glycinols 1 and 2 using chiral auxiliary benzosultam 4.
t-Bu
O
R
O
LiOH, H2O2
THF, H2O
H2, Pd/C
N3
OH
N3
N
H2N
HO
AcOH, H2O
S
R
O
R
O
O
8a, R = (m-TBSO)phenyl, 97%
8b, R = 1-naphthyl, 65%
9a, R = (m-OH)phenyl, 98%
9b, R = 1-naphthyl, 96%
7a, R = (m-TBSO)phenyl
7b, R = 1-naphthyl
Scheme 3. Asymmetric synthesis of aryl glycine derivative 9a and 9b.

H.-Y. Ku et al. / Tetrahedron: Asymmetry 17 (2006) 1111–1115
1113
3. Conclusion
(1.42 g, 33.4 mmol), followed by 3-(S)-tert-butyl-1.2-benz-
isothiazoline 1,1-dioxide 4 (6.95 g, 30.4 mmol) dissolved
in THF (30 mL). The reaction mixture was allowed to
warm to room temperature and stirred for 1 h, and then
treated with additional triethylamine (4.2 mL, 30.4 mmol).
After being stirred for 12 h, the reaction mixture was
quenched with water and THF was removed in vacuo.
The residue was extracted with EtOAc, and the combined
organic layers were washed with 1 M NaHCO3 followed
by brine, dried over anhydrous MgSO4, and concentrated
in vacuo. The crude product was purified by flash column
chromatography (5% EtOAc/hexane, then 10% EtOAc/
hexane) to afford 5a (10.7 g, 75%) and the sultam auxiliary
In conclusion, we have developed an efficient route for the
synthesis of enantiomerically pure aryl glycinols 1 and 2,
as well as corresponding aryl glycines 9a and 9b. The proce-
dure utilizes readily available starting materials and estab-
lished reactions. Of particular note is that the chiral
auxiliary can be readily recovered and reused. The estab-
lished synthesis can be used as an expeditious route to other
enantiomerically pure b-amino alcohols and a-amino acids.
4. Experimental
(2.21 g):
Rf = 0.62
(EtOAc/hexanes = 1:4,
v/v);
27
4.1. General methods
½aꢁD ¼ ꢀ12:1 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.82 (d, J = 7.7, 1H), 7.57–7.65 (m, 2H), 7.50
(d, J = 7.8, 1H), 7.19 (dd, J = 8.1, 7.6, 1H), 6.92 (s, 1H),
6.75 (d, J = 8.1, 1H), 5.60 (s, 1H), 4.18 (dd, J = 39.8,
15.1, 2H), 0.96 (s, 9H), 0.88 (s, 9H), 0.17 (s, 6H). 13C
NMR (75 MHz, CDCl3) d 171.0, 156.1, 136.1, 135.5,
135.3, 133.4, 129.9, 129.8, 126.4, 123.4, 122.3, 122.1,
119.5, 66.4, 53.8, 44.6, 38.8, 27.4, 26.1, 18.6, ꢀ4.0; MS
(EI): m/z (rel intensity) 473 (M+, 3), 458 (5), 416 (100),
221 (35) 191 (36), 164 (78).
1H NMR spectra are reported as follows: chemical shift in
parts per million from internal tetramethylsilane on the
delta scale, multiplicity (s = singlet, d = doublet, br
s = broad singlet), integration, and coupling constant (in
hertz). Elemental analyses were performed by Center for
Integrated Molecular Systems. Melting points are uncor-
rected ones. Chromatography means flash column chroma-
tography, which was carried out on Merck silica gel 60
(230–400 mesh). Analytical thin layer chromatography
was carried out on Merck silica gel F254 plates. All reac-
tions were run under an inert atmosphere of dry argon.
4.4. 1-(3(S)-tert-Butyl-1,1-dioxo-1,3-dihydro-1k6-benzo-
[d]isothiazol-2-yl)-2-(naphthalen-1-yl)ethanone 5b
4.2. 3-(tert-Butyldimethylsilanyloxy)phenylacetic acid 3a
This material was prepared following the same procedure
used for 5a, starting from 1-naphthaleneacetic acid 3b
(3.65 g, 42.6 mmol). Purification by column chromatogra-
phy (10–20% EtOAc/hexane) afforded 5b (5.68 g, 81%) as
To a suspension of sodium hydride (60% dispersion in oil,
0.88 g, 22 mmol) in THF (30 mL) was added a solution of
3-hydroxyphenylacetic acid (1.52 g, 10.0 mmol) in THF
(10 mL), dropwise at 0 °C, and the resulting mixture was
stirred for 30 min. To this mixture was added tert-butyl-
dimethylsilyl chloride (1.81 g, 12 mmol) in THF (10 mL)
dropwise, and then stirred at room temperature for 18 h.
The reaction mixture was quenched with 0.5 M aqueous
HCl solution. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over anhy-
drous MgSO4, and concentrated in vacuo. The crude resi-
due was purified by flash column chromatography (20%
EtOAc/hexane) to afford 3a (2.21 g, 83%): Rf = 0.53
a solid: Rf = 0.56 (EtOAc/hexanes = 3:7, v/v); mp 121–
26
122 °C; ½aꢁD ¼ ꢀ32:7 (c 1.54, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.25–7.87 (m, 11H), 5.63 (s, 1H),
4.72 (dd, J = 41.6, 16.6, 2H), 0.92 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 170.9, 136.5, 135.7, 134.5, 133.8,
13.9, 130.9, 130.4, 129.4, 129.3, 129.0, 127.0, 126.7, 126.4,
126.1, 124.8, 122.6, 66.9, 42.4, 39.1, 27.8; MS (FAB): m/z
(rel intensity) 394 (M+1, 100), 226 (40), 168 (29).
4.5. 2(S)-Azido-2-[3-(tert-butyl-dimethylsilanyloxy)phenyl]-
1-(3(S)-tert-butyl-1,1-dioxo-1,3-dihydro-1k6-benzo[d]iso-
thiazol-2-yl)ethanone 7a
1
(EtOAc/hexanes = 2:3, v/v); H NMR (300 MHz, CDCl3)
d 10.13 (s, 1H), 7.17 (dd, J = 7.7, 7.5, 1H), 6.65 (d, J=
7.5, 1H), 6.76 (s, 1H), 6.74 (d, J = 7.7, 1H), 3.58 (s, 2H),
0.97 (s, 9H), 0.21 (s, 6H); 13C NMR (75 MHz, CDCl3) d
178.3, 156.2, 135.1, 129.9, 122.7, 121.7, 119.4, 41.4, 26.1,
18.6, ꢀ3.4; MS (EI): m/z (rel intensity) 266 (M+, 9), 209
(13), 181 (100), 107 (21).
To a solution of sodium bis(trimethylsilyl)amide (NaH-
MDS, 1.0 M in THF, 5.90 mL, 5.90 mmol) in THF
(20 mL) at ꢀ78 °C was added a pre-cooled (ꢀ78 °C) solu-
tion of starting material 5a (2.54 g, 5.36 mmol) in THF
(15 mL) via a cannula, and the resulting solution was
stirred for 30 min. This sodium enolate solution was
treated with a pre-cooled (ꢀ78 °C) solution of trisyl azide
(1.82 g, 6.97 mmol) in THF (7 mL) via a cannula, and then
stirred for 2 min before being quenched with glacial acetic
acid (1.47 mL, 25.7 mmol). After being stirred for 10 min,
the cooling bath was removed, and the solution partitioned
between EtOAc and water. The aqueous phase was extr-
acted twice with EtOAc, and the combined organic phase
was washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo to afford crude compound 6a as a
light yellow solid, which was immediately used for the next
reaction without further purification. To a solution of
4.3. 2-[3-(tert-Butyldimethylsilanyloxy)phenyl]-1-(3(S)-tert-
butyl-1,1-dioxo-1,3-dihydro-1k6-benzo[d]isothiazol-2-yl)-
ethanone 5a
To a solution of 3-(tert-butyldimethylsilanyloxy)phenylace-
tic acid 3a (8.50 g, 31.9 mmol) and triethylamine (10.1 mL,
73.0 mmol) in THF (170 mL) was added pivaloyl chloride
(4.5 mL, 36.5 mmol) at ꢀ20 °C. A white solid was formed
instantaneously. The mixture was stirred at the same tem-
perature for 2 h, and then treated with lithium chloride

1114
H.-Y. Ku et al. / Tetrahedron: Asymmetry 17 (2006) 1111–1115
crude compound 6a in THF (54 mL) was added sodium
acetate (880 mg, 10.7 mmol) at room temperature. After
being stirred for 12 h, the solution was partitioned between
EtOAc and water. The aqueous phase was extracted with
EtOAc twice, and the combined organic phase was washed
with brine, dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was purified by flash column chroma-
tography (2–10% EtOAc/hexane) to afford 7a (2.54 g, 92%)
as a white solid. The diastereomeric ratio of the product
auxiliary was also recovered (1.14 g, 87%). The enantio-
purity of the resulting product was determined to be 91%
ee by 19F NMR analysis of the corresponding N-acylated
derivative obtained by treatment with (R)-Mosher’s chlo-
ride and triethylamine: Rf = 0.31 (MeOH/EtOAc = 1:9,
v/v); ½aꢁD ¼ þ21:8 (c 1.00, CHCl3); H NMR (300 MHz,
CDCl3) d 6.74–7.24 (m, 4H), 4.44 (br s, 1H), 3.81 (br s,
2H), 0.98 (s, 9H), 0.20 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 156.8, 136.9, 130.9, 121.4, 120.0, 64.8, 58.2, 26.3,
18.8, ꢀ3.7; MS (EI): m/z (rel intensity) 267 (M+, 100).
HRMS (EI) calcd for C14H25NO2Si 267.1655, found
267.1647.
23
1
1
(de > 98:2) was determined by H NMR analysis. The dia-
stereoselectivity increased to >99% de by recrystallizing the
product from hexane–CH2CH2 (white crystals, 2.08 g,
78%). 7a: Rf = 0.65 (EtOAc/hexanes = 1:4, v/v); mp 163–
28
165 °C; ½aꢁD ¼ þ41:1 (c 1.0, CHCl3) before crystallization,
25
½aꢁD ¼ þ47:7 (c 0.52, CHCl3) after crystallization; 1H
4.8. 2(S)-Amino-2-(naphthalen-1-yl)ethanol 2
NMR (300 MHz, CDCl3) d 7.53–7.75 (m, 4H), 7.02–7.26
(m, 4H), 5.66 (s, 1H), 5.55 (s, 1H), 1.09 (s, 9H), 0.97 (s,
9H), 0.20 (s, 6H); 13C NMR (75 MHz, CDCl3) d 169.4,
156.2, 135.4, 135.3, 133.9, 133.3, 130.3, 126.7, 122.5,
122.4, 121.6, 121.0, 67.1, 66.8, 39.0, 27.8, 26.3, 18.8,
ꢀ3.8; MS (FAB): m/z (rel intensity) 514 (M+1, 10), 487
(50), 472 (100), 457 (43), 444 (55), 401 (63). Anal. Calcd
for C25H34N4O4SSiÆ1/2H2O: C, 57.66; H, 6.71; N, 10.76.
Found: C, 57.85; H, 6.82; N, 10.95.
This compound was prepared, as above, starting from 7b
(0.40 g, 1.00 mmol) in 87% yield (0.16 g, 95%
ee) as a white solid: Rf = 0.17 (MeOH/EtOAc = 1:9,
26
v/v); mp 130–132 °C; ½aꢁD ¼ þ82:7 (c 0.51, MeOH)
25
[lit.8b ½aꢁD ¼ þ83 (c 0.5, MeOH), lit.8a for (R)-2
1
[a]D = ꢀ85 (c 0.5, MeOH)]; H NMR (300 MHz, CDCl3)
d 7.26–8.13 (m, 7H), 4.92 (dd, J = 8.0, 3.9, 1H), 3.95 (dd,
J = 10.8, 3.9, 1H), 3.67 (dd, J = 10.8, 8.0, 1H), 2.03 (br s,
3H); 13C NMR (75 MHz, CDCl3) d 138.7, 134.5, 131.5,
129.7, 128.6, 127.0, 126.4, 126.1, 123.5, 123.2, 67.9, 53.4;
MS (EI): m/z (rel intensity) 187 (M+, 28), 156 (100), 128
(38). Anal. Calcd for C12H12NO: C 76.98; H 7.00; N
7.48. Found: C, 77.32; H, 7.02; N, 7.40.
4.6. 2(S)-Azido-1-(3(S)-tert-butyl-1,1-dioxo-1,3-dihydro-
1k6-benzo[d]isothiazol-2-yl)-2(naphthalen-1-yl)ethanone 7b
This compound was prepared, as above, starting from
5b (4.00 g, 10.2 mmol). Purification by column
chromatography (10% EtOAc/hexane) afforded 7b
4.9. (S)-Azido[3-(tert-butyldimethylsilanyloxy)phenyl]-
acetic acid 8a
(4.48 g, 96%; de > 98:2) as a solid: Rf = 0.33 (EtOAc/
22
hexanes = 1:4, v/v); mp 70–71 °C; ½aꢁD ¼ ꢀ102:2 (c
25
1.04, CHCl3) before crystallization, ½aꢁD ¼ ꢀ94:4
To a solution of 7a (770 mg, 1.5 mmol) in THF (24 mL)
and H2O (6 mL) at 0 °C was added H2O2 (35 wt %,
0.50 mL, 6.0 mmol) followed by LiOH (72 mg, 3.0 mmol).
The mixture was allowed to warm to room temperature
and stirred for a further 30 min, after which it was treated
with 4 mL of 1 M Na2SO3 followed by 5 mL of 1 N NaOH.
After being stirred for 30 min, most of the THF was
removed in vacuo, and the residue diluted with water and
extracted three times with CH2Cl2 to recover chiral auxil-
iary 4 after drying and concentration (315 mg). The aque-
ous layer was acidified to pH 1–2 with 4 M aqueous HCl
and then extracted three times with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo to afford nearly pure azido acid 8a
1
(c 0.52, CHCl3) after crystallization; H NMR (300 MHz,
CDCl3) d 7.44–7.89 (m, 11H), 6.30 (s, 1H), 5.71 (s, 1H),
1.10 (s, 9H); 13C NMR (75 MHz, CDCl3) d 169.5, 136.3,
135.4, 134.4, 134.8, 133.9, 131.8, 130.7, 130.3, 129.9,
129.6, 127.6, 126.9, 126.8, 126.7, 125.6, 124.2, 122.5, 67.2,
64.8, 39.1, 27.9; MS (FAB): m/z (rel intensity) 435 (M+1,
9), 407 (17), 392 (100), 226 (29), 165 (19). Anal. Calcd for
C23H22N4O3S: C 63.58; H 5.10; N 12.89. Found: C,
63.82; H, 5.01; N, 12.82.
4.7. 2(S)-Amino-2-[3-(tert-butyldimethylsilanyloxy)-
phenyl]ethanol 1
To a solution of LiAlH4 (1.0 M in THF, 14.0 mL,
14.0 mmol) in THF (30 mL) was added a solution of com-
pound 7a (3.00 g, 5.83 mmol) in THF (10 mL) dropwise at
0 °C. The mixture was allowed to warm to room tempera-
ture and stirred for a further 1 h. The reaction mixture was
cooled by using an ice-water bath, and then was quenched
with water carefully. The mixture was diluted with EtOAc
(8 mL) and treated with 20% aqueous Rochelle’s salt
(10 mL). After being vigorously stirred for 12 h at room
temperature, the mixture was extracted with EtOAc. The
combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The
crude residue was purified by column chromatography
(30% EtOAc in hexane; then 20% MeOH in EtOAc) to
afford the desired compound 1 (1.39 g, 89%). The sultam
(280 mg, 97% yield) as a white solid: mp 142–143 °C;
22
½aꢁD ¼ þ122 (c 0.5, acetone); 1H NMR (300 MHz,
CD3COCD3) d 6.84–7.51 (m, 4H), 5.09 (s, 1H); 13C
NMR (75 MHz, CD3COCD3) d 170.2, 158.2, 136.5,
130.4, 119.3, 116.4, 114.9, 64.9. HRMS (EI) calcd for
C14H21N3O3Si 307.1352, found 307.1354.
4.10. (S)-Azido(naphthalen-1-yl)acetic acid 8b
This compound was prepared, as above, starting from 7b
(625 mg, 1.5 mmol) in 65% yield (220 mg) as a white solid:
22
mp 152–153 °C; ½aꢁD ¼ þ142 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3) d 10.08 (br s, 1H), 7.41–8.09 (m, 7H),
5.69 (s, 1H); 13C NMR (75 MHz, CDCl3) d 175.4, 134.5,

H.-Y. Ku et al. / Tetrahedron: Asymmetry 17 (2006) 1111–1115
1115
2. For review, see: Williams, R. M. The Synthesis of Optically
Active a-Amino Acids. In Organic Chemistry Series; Baldwin,
J. E., Ed.; Pergamon Press: Oxford, 1989.
131.2, 130.9, 129.5, 127.7, 127.1, 126.8, 125.5, 123.5, 63.5.
MS (EI): m/z (rel intensity) 227 (M+, 100).
3. For reviews, see: (a) Williams, D. H.; Raganada, V.;
Williamson, M. P.; Bojesen, G. In Topics in Antibiotics
Chemistry; Sammes, P., Ed.; Ellid Harwood: Chichester,
1980; Vol. 5, p 123; (b) Williams, D. H. Acc. Chem. Res. 1984,
17, 364–369.
4. For recent reviews, see: (a) Watkins, J.; Collingridge, G.
TIPS 1994, 15, 333–342; (b) Pin, J.-P.; Duvoisin, R. Neuro-
pharmacology 1995, 34, 1–26; (c) Roberts, P. J. Neurophar-
macology 1995, 34, 813–819.
5. (a) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359–
1472; (b) Craig, P. N. In Medicinal Chemistry; Drayton,
C. J., Ed.; Pergamon: Oxford, 1990; Vol. 6, pp 237–991.
6. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835–876.
7. (a) Kim, S.-G.; Ahn, K. H. Chem. Eur. J. 2000, 6, 3399–3403;
(b) Kim, S.-G.; Kim, K.-H.; Jung, J.; Shin, S. K.; Ahn, K. H.
J. Am. Chem. Soc. 2002, 124, 591–596; (c) Ahn, K. H.; Ku,
H.-Y.; Kim, Y.; Kim, S.-G.; Kim, Y. K.; Son, H. S.; Ku, J. K.
Org. Lett. 2003, 5, 1419–1422; (d) Kim, S.-G.; Kim, K.-H.;
Kim, Y. K.; Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2003,
125, 13819–13824; (e) Kim, J.; Kim, S.-G.; Seong, H. R.;
Ahn, K. H. J. Org. Chem. 2005, 70, 7227–7231; (f) Kim, J.;
Raman, B.; Ahn, K. H. J. Org. Chem. 2006, 71, 38–45; (g)
Kim, J.; Ryu, D.; Sei, Y.; Yamaguchi, K.; Ahn, K. H. Chem.
Commun. 2006, 1136–1138.
4.11. (S)-Amino-(3-hydroxyphenyl)acetic acid 9a
A solution of compound 8a (62 mg, 0.20 mmol) in H2O
(0.9 mL) and acetic acid (0.3 mL) was treated with Pd/C
(10 wt %, 12 mg), and the mixture stirred for 18 h under
a hydrogen atmosphere. The reaction mixture was filtered
through Celite 545, and the filtrate was concentrated in va-
cuo to give a white solid. This amino acid was first dried by
azeotropic removal of water and acetic acid with benzene,
and then it was further dried over P2O5 under vacuum for
12 h to afford pure 9a (34 mg, 98% yield). The enantio-
purity of the resulting product was determined to be 99%
ee by 19F NMR analysis of the derived Mosher amide:
22
1
mp 198–199 °C; ½aꢁ ¼ þ128 (c 0.2, 1 M HCl); H NMR
(300 MHz, D2O) dD6.77–7.21 (m, 4H), 4.56 (s, 1H); 13C
NMR (75 MHz, D2O) d 173.4, 156.4, 136.0, 131.2, 120.3,
116.8, 115.0, 58.6. Anal. Calcd for C8H9NO3Æ1/2H2O: C
54.54, H 5.72, N 7.95. Found: C 54.65, H 5.83, N 7.73.
4.12. (S)-Amino(naphthalen-1-yl)acetic acid 9b
Reduction of compound 8b (52 mg, 0.22 mmol) afforded 9b
in 96% yield (42 mg, 99% ee) as a white solid: mp 167–
8. (a) Takacs, J. M.; Jaber, M. R.; Vellekoop, A. S. J. Org.
Chem. 1998, 63, 2742; (b) van Lingen, H. L.; van de Mortel,
J. K. W.; Hekking, K. F. W.; van Delft, F. L.; Sonke, T.;
Rutjes, F. P. J. T. Eur. J. Org. Chem. 2003, 317–324.
9. (S)-3-Hydroxyphenylglycine is commercially available from
Sigma.
22
168 °C (decomp.); ½aꢁD ¼ þ141 (c 0.2, 1 M HCl) {lit.17
22
½aꢁD ¼ þ164:7 (c 0.71 M HCl)}; 1H NMR (300 MHz,
D2O) d 7.39–8.01 (m, 4H), 5.31 (s, 1H); 13C NMR
(75 MHz, D2O) d 170.8, 132.2, 130.1, 129.2, 128.1, 127.5,
125.7, 125.0, 124.9, 124.2, 121.6, 53.3.
10. Ahn, K. H.; Kim, S.-K.; Ham, C. Tetrahedron Lett. 1998, 39,
6321–6322.
11. (a) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int.
Ed. 1996, 35, 2813–2817; (b) Reddy, K. L.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 1207–1217.
12. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmet-
ric Synthesis; John Wiley: New York, 1995.
13. For a practical two-step synthesis of chiral auxiliary 4 from
saccharine that does not require chromatographic separation,
see: Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho, C.-W. J. Org.
Chem. 1997, 62, 7047–7048.
14. Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–
2273.
Acknowledgments
This work was supported by the Korea Science & Engi-
neering Foundation (Basic Research Program, Grant No.
R02-2002-000-00103-0) and the Center for Integrated
Molecular Systems. We are also grateful to the Ministry
of Commerce, Industry, and Energy (TS-052-03) for the
financial support.
15. (a) Evans, D. A.; Britton, T. C. J. Am. Chem. Soc. 1987, 109,
6881–6883; (b) Evans, D. A.; Britton, T. C.; Ellman, J. A.;
Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030.
16. A similar level of enantiopurity was obtained when we used
recrystallized azido compound 7a, which suggests that the
loss of enantiopurity results at the subsequent reduction
stage.
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