A new synthesis of enantiomerically pure α- and β-amino acid derivatives using aziridinyl anions

Article abstract of DOI:10.1016/j.tet.2003.09.025

Optically active sulfinylaziridines having a 4-methoxyphenyl group on their nitrogen atom were synthesized from optically active 1-chloroalkyl p-tolyl sulfoxide and an imine derived from benzaldehyde and p-anisidine stereoselectively in good overall yield

Full text of DOI:10.1016/j.tet.2003.09.025

Tetrahedron 59 (2003) 9803–9810
A new synthesis of enantiomerically pure a- and b-amino acid
derivatives using aziridinyl anions
*
Tsuyoshi Satoh and Yuta Fukuda
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku Tokyo 162-8601, Japan
Received 22 July 2003; revised 29 August 2003; accepted 5 September 2003
Abstract—Optically active sulfinylaziridines having a 4-methoxyphenyl group on their nitrogen atom were synthesized from optically
active 1-chloroalkyl p-tolyl sulfoxide and an imine derived from benzaldehyde and p-anisidine stereoselectively in good overall yields. The
sulfinylaziridines were treated with ethylmagnesium bromide or tert-butyllithium to afford aziridinylmagnesiums or aziridinyllithiums,
respectively, in quantitative yields. Cross-coupling of the aziridinylmagnesiums with iodoalkanes in the presence of Cu(I) iodide gave
tri-substituted aziridines in high yields from which enantiomerically pure b,b-disubstituted b-amino acid derivatives were synthesized.
A b-amino acid derivative having deuterium at the stereogenic center was also realized by this method. On the other hand, from the
aziridinyllithium, enantiomerically pure quaternary phenylalanine and quaternary aspartic acid derivatives were synthesized.
q 2003 Elsevier Ltd. All rights reserved.
a-Amino acids and b-amino acids are fundamental
compounds in the area of biology, medicine, biochemistry,
material science, and synthetic organic chemistry. For this
reason, the stereoselective synthesis of natural and unnatural
a-amino acids1 and b-amino acids2 is of much interest these
days. In addition, quaternary amino acids (a,a-disubstituted
a-amino acids and b,b-disubstituted b-amino acids) have
received considerable recent attention in the area of
bioorganic chemistry. In synthetic organic chemistry, the
asymmetric synthesis of a stereogenic quaternary carbon
center is an interesting and challenging target in its own
right.3
generation of aziridinyl anions 44 from sulfinylaziridines
3, which were synthesized stereoselectively from 1-chloro-
alkyl p-tolyl sulfoxide 2 and benzalaniline in high yields, by
a sulfoxide–metal exchange reaction.5 We also investigated
this chemistry of the aziridinyl anions 4 to develop a new
method for synthesis of optically active amines 6 by the
use of optically active chloromethyl p-tolyl sulfoxide 1
(Scheme 1).6
In continuation of our interest in the use of the generated
aziridinyl anions in organic synthesis, we planned to
develop the above-mentioned chemistry to a new synthesis
of optically active a- and b-amino acid derivatives starting
from the optically active sulfoxide 2 (Scheme 2). The key
Over the last few years, we have been studying the
Scheme 1.
Keywords: aziridinyllithium; aziridinylmagnesium; a-amino acid; b-amino acid; sulfoxide–metal exchange; chiral synthesis.
*
Corresponding author. Tel.: þ81-352-288-272; fax: þ81-332-352-214; e-mail: tsatoh@ch.kagu.sut.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.025

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T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
Scheme 2.
improvement step is the use of a p-methoxyphenyl group
instead of the phenyl group in order to remove the aromatic
ring on the nitrogen at a later stage. We also utilized the
phenyl group on the aziridine ring as a masked carboxyl
group. Herein we report a novel synthesis of both
enantiomers of the b,b-disubstituted b-amino acid deriva-
tives 11 and b-amino acid derivatives bearing a deuterium at
the stereogenic center 11 (R2¼D), from the aziridinyl-
magnesium 9 (Metal¼MgBr) through the enantiomerically
pure tri-substituted aziridine 10. A synthesis of a quaternary
phenylalanine derivative and quaternary aspartic acid
derivative 13 through the ethoxycarbonylation of the
aziridinyllithium 9 (Metal¼Li) is also described.
aziridine 8b was synthesized from 2b6d and the imine 7
through the adduct 14b in good overall yield (Scheme 3).
A solution of the sulfinylaziridine 8a in THF was added to a
solution of EtMgBr (3.5 equiv.) at 2788C and the reaction
mixture was slowly allowed to warm to room temperature to
give aziridinylmagnesium 9a. The aziridinylmagnesium 9a
was found to be stable at room temperature for several hours
without decomposition and structural isomerization.
To the solution of 9a, Cu(I) iodide (10 mol%) was added
and after 10 min, iodomethane (3.5 equiv.) was added and
the reaction mixture was stirred at room temperature for
30 min to afford the desired tri-substituted aziridine 10a
([a]D¼287.0, c 0.5 in acetone) in 94% yield as a single
product. Similar treatment of 8b with EtMgBr followed
by iododecane gave the tri-substituted aziridine 10b
([a]D¼292.8, c 0.5 in acetone) in 89% yield. It is worth
noting that 10a and 10b are diastereomers of each other.
1. Results and discussion
1.1. Synthesis of both enantiomers of b,b-disubstituted
b-amino acid derivatives
Next, the synthesized aziridine 10a was regioselectively
cleaved at the benzylic position by catalytic hydrogenation
using palladium hydroxide as a catalyst7 under hydrogen
atmosphere to give cleanly the amine 15a. The amine 15a
was found to be easily adsorbed on silica gel, so without
further purification, the amine was treated with ceric (IV)
ammonium nitrate (CAN)8 to afford the free amine 16a. The
produced 16a was again presumed to be unstable on silica
gel; it was successively acetylated to give the acetamide 17a
in 47% overall yield from 10a. The amide 17a was a stable
compound and showed specific rotation [a]D¼þ28.9 (c 0.5
in acetone). The same treatment of 10b afforded 17b in
First, the optically pure 1-chloroundecyl p-tolyl sulfoxide
2a6d was treated with LDA at 2788C followed by the imine
7 to give the adduct 14a in 78% yield as colorless crystals.
As already observed in the previous study, the product was a
single diastereo isomer even though the adduct has three
chiral centers.5b The absolute configuration of the adduct
14a was determined to be as shown in Scheme 3 by
comparison of the spectral data with those in the previous
studies.5b,6d The adduct 14a was treated with tert-BuOK in
THF to afford the optically active sulfinylaziridine 8a in
94% yield. By similar treatment, optically active sulfinyl-

T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
9805
Scheme 3.
somewhat lower yield. The produced amide 17b showed the
same IR and NMR spectra as those of 17a; however, the
value for the specific rotation was 230.9. These data clearly
indicated that 17a and 17b are enantiomers to each other.
The enantiomeric purity of both 17a and 17b was
determined to be over 99% by HPLC using chiral column
(Daicel, CHIRALCEL OD; hexane–2-propanol¼9:1).
11b was successful, in enantiomerically pure form, through
the aziridinylmagnesium as the key intermediate.
1.2. A synthesis of a chiral b-amino acid having
deuterium at the stereogenic center
As described above, the aziridinylmagnesium 9a is configu-
rationally highly stable; protonation of 9a gave diastereo-
merically pure aziridine 20a in quantitative yield. In
addition, reaction of 9a with methyl-d3 alcohol-d
(CD3OD) gave deuterated aziridine 20b. This reaction is
quite interesting for a synthesis of deuterium-labeled
optically active compounds at the stereogenic center
(Scheme 4).
Finally, oxidative degradation of the benzene ring in 17a
and 17b was carried out under the Sharpless conditions9 to
give the desired quaternary b-amino acids 11a and 11b.
Interestingly, both 11a and 11b showed no specific rotation;
however, racemization was quite unlikely in this oxidation
step. We determined the enantiomeric purity by using
racemic 11 and its methyl ester. Several trials to separate the
enantiomers with HPLC and GC (using chiral column) were
not successful. Finally, the racemic 11 was derived into
its (S)-(2)-1-(1-naphthyl)ethylamide 18.10 1H NMR spec-
troscopy of the produced mixture of two diastereomers
was measured and the methylene proton underlined (see
Scheme 3) was clearly separated. By this technique, the
enantiomeric purity of both 11a and 11b was found to be
over 99%.
The aziridine 20 was hydrogenated under H2 atmosphere
with Pd(OH)2 as a catalyst to give 21 in good yield. The
p-methoxyphenyl group of 21 was eliminated with CAN
and the produced amine 22 was acetylated without further
purification to afford the amide 23, but the overall yield of
the amide 23 was somewhat low. Taking into account the
instability of the amine 22, we conducted the one-pot
conversion of the p-methoxyphenyl group of 21 to the acetyl
group of the amide 23, which resulted in good overall yield
of the amide 23 (53% from 20a).11 The enantiomeric purity
of this amide 23 could be determined by using HPLC and
it was found to be over 99%. Finally, the phenyl ring in
23 was oxidatively converted into a carboxylic acid to
give b-amino acid derivative 24a in moderate yield.
The deuterium-labeled enantiomerically pure b-amino
acid derivative 24b was also successfully synthesized.
In a detailed inspection of the products for the oxidative
degradation of the benzene ring, we found a small amount
of a-amino acids 19a and 19b. Treatment of 11 with the
oxidation conditions (RuCl2–NaIO4) did not give a-amino
acid 19. We are not sure of the mechanism for the formation
of the a-amino acids at present. In any event, a synthesis of
both enantiomers of the quaternary b-amino acids 11a and

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T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
Scheme 4.
Interestingly, deuterated 24b showed low value for the
specific rotation ([a]D¼þ0.76, c 1.4 in MeOH) although
24a has specific rotation [a]D¼þ2.0 (c 1.0 in MeOH).
This method is found to be useful for the labeled
b-amino acid derivatives having deuterium at the stereo-
genic center.
derivative 26 and quaternary aspartic acid derivative 13a in
enantiomerically pure form; herein we report in detail the
results (Scheme 5).
First, a solution of 8a in THF at 2788C was treated with
methylmagnesium bromide followed by tert-butyllithium to
afford the aziridinyllithium 9b. After 1 min, ethyl chloro-
formate was added to give the desired optically active
ethoxycarbonylated aziridine 12a in moderate yield. The
aziridine 12a was hydrogenated with Pd(OH)2 to give a
quaternary phenylalanine derivative 25 in good yield. The
p-methoxyphenyl group of 25 was eliminated with CAN to
give quaternary phenylalanine ethyl ester 26 in enantio-
merically pure form.
1.3. Synthesis of enantiomerically pure quaternary
phenylalanine derivative and quaternary aspartic acid
derivative via aziridinyllithium as the key intermediate
As has been already reported from our research group6a,b the
sulfinylaziridine 8a gave the aziridinyllithium 9b on
treatment with tert-butyllithium at lower than 2308C. The
aziridinyllithum 9b was found to be reactive with ethyl
chloroformate in a stereospecific manner to give ethoxy-
carbonylated aziridine 12a without any other diastereomers.
Recently, we investigated this reaction in the development
of a new synthetic method for quaternary phenylalanine
Finally, the amino group of 26 was acetylated and the
produced amide 27 was oxidized with RuCl3–NaIO4 to give
optically pure quaternary aspartic acid derivative 13a in
good yield.
Scheme 5.

T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
9807
In conclusion, we have successfully synthesized several a-
and b-amino acid derivatives in enantiomerically pure form
from optically active 1-chloroalkyl p-tolyl sulfoxides 2 and
imine 7 via the enantiomerically pure sulfinylaziridine 8 and
the aziridinylmagnesium and aziridinyllithium 9 as the
key intermediates. At the same time, we were able to
demonstrate that the aziridinyl anions are quite important
and versatile intermediates in organic synthesis.
Compound Racemic-14b. Colorless crystals; mp 165–
1688C (AcOEt–hexane); IR (KBr) 3302 (NH), 1509,
1252, 1037 (SO) cm21; MS m/z (%) 413 (Mþ, 9), 361 (4),
273 (74), 238 (78), 212 (84), 122 (100). Anal. calcd for
C23H24ClNO2S: C, 66.74; H, 5.84; Cl, 8.56; N, 3.38; S, 7.75.
Found: C, 66.49; H, 5.72; Cl, 8.72; N, 3.18; S, 7.80.
2.1.3. (2R,3R,RS)-2-Decyl-1-(4-methoxyphenyl)-3-phenyl-
2-(p-tolylsulfinyl)aziridine (8a). To a solution of 14a
(550 mg; 1.02 mmol) in THF (25 mL) at 708C was added a
suspension of t-BuOK (285 mg; 2.55 mmol) in 5 mL of
t-BuOH. The reaction mixture was stirred at 708C for
40 min. After cooling the reaction mixture to room
temperature, the reaction was quenched by sat. aq. NH4Cl.
The whole was extracted with CHCl3. The product was
purified by silica gel column chromatography to give 8a
(482 mg; 94%) as a colorless oil; IR (neat) 2926, 2854,
1507, 1242, 1084, 1056 (SO) cm21; 1H NMR d 0.88 (3H, t,
J¼7 Hz), 1.0–1.3 (16H, m), 1.6–1.8 (2H, m), 2.41 (3H, s),
3.78 (3H, s), 4.62 (1H, s), 6.87, 7.05 (each 2H, d, J¼9 Hz),
7.2–7.7 (9H, m). MS m/z (%) 503 (Mþ, trace), 478 (1.4),
364 (28), 274 (100). Calcd for C32H41NO2S: M, 503.2858.
Found: m/z 503.2869. [a]2D5¼2307.1 (c 0.5 acetone).
2. Experimental
2.1. General
Melting points were measured with a Yanagimoto micro
melting point apparatus and are uncorrected. 1H NMR
spectra were measured in a CDCl3 solution with JEOL
JNM-LA 400 and 500 spectrometer. Electron-impact mass
spectra (MS) were obtained at 70 eV by direct insertion.
Silical gel 60 (MERCK) containing 0.5% fluorescence
reagent 254 and a quartz column were used for column
chromatography and the products having UV absorption
were detected by UV irradiation. In experiments requiring a
dry solvent, dichloromethane, diisopropylamine, pyridine,
and toluene were distilled from CaH2 and THF was distilled
from diphenylketyl. Methanol and liquid N2 were used for
the cooling bath at 21008C.
2.1.4. (2R,3R,RS)-2-Methyl-1-(4-methoxyphenyl)-3-phenyl-
2-(p-tolylsulfinyl)aziridine (8b). Colorless oil (98%); IR
(neat) 3034, 2997, 2833, 1597, 1505, 1452, 1399, 1241,
1
1040, 909, 811, 759, 702 cm21; H NMR d 1.03 (3H, s),
2.41 (3H, s), 3.78 (3H, s), 4.51 (1H, s), 6.86, 6.98 (each 2H,
d, J¼9 Hz), 7.2–7.7 (9H, m). [a]3D0¼2348.4 (c 0.5
acetone).
2.1.1. (1R,2R,RS)-2-Chloro-1-(4-methoxyphenylamino)-
1-phenyl-2-(p-tolylsulfinyl)dodecane (14a). To a solution
of LDA (3.6 mmol) in 10 mL of THF at 2788C was added a
solution of 2a (1 g; 3 mmol) in 4 mL of THF dropwise with
stirring. After 10 min, a solution of imine 7 (0.76 g;
3.6 mmol) in 2 mL of THF was added to the reaction
mixture and the reaction mixture was stirred at 2788C for
30 min. The reaction was quenched by sat. aq. NH4Cl and
the whole was extracted with CHCl3. The organic layer was
washed once with sat. aq. NH4Cl and dried over MgSO4.
The solvent was evaporated to give colorless crystals, which
were collected on a glass filter and washed with a mixture
of AcOEt–hexane (10:1) to give pure 14a (1.26 g; 78%).
Colorless crystals; mp 132–1338C (AcOEt–hexane).
IR (KBr) 3295 (NH), 2920, 2852, 1510, 1251, 1039
Compound Racemic-8b. Colorless crystals; mp 88–918C
(AcOEt–hexane). IR (KBr) 1505, 1238, 1228, 1046
(SO) cm21; MS m/z (%) 377 (Mþ, 7), 361 (25), 238 (52),
212 (63), 148 (100). Anal. calcd for C23H23NO2S: C, 73.18;
H, 6.14; N, 3.71; S, 8.49. Found: C, 73.31; H, 6.01; N, 3.52;
S, 8.51.
2.1.5. (2S,3R)-2-Decyl-2-methyl-1-(4-methoxyphenyl)-3-
phenylaziridine (10a). To
a solution of EtMgBr
(15.43 mmol) in 20 mL of THF at 2788C was added a
solution of 8a (2.22 g; 4.41 mmol) in 4 mL of THF
dropwise with stirring. After 10 min, the cooling bath was
removed and the reaction mixture was allowed to warm up
to room temperature at once and was stirred at room
temperature for 30 min. Cu(I) iodide (209 mg; 1.1 mmol)
was then added to the reaction mixture and after 10 min,
iodomethane (1.09 mL; 17.63 mmol) was added success-
ively and the reaction mixture was stirred at room
temperature for 30 min. The reaction was quenched by
sat. aq. NH4Cl and the whole was extracted with CHCl3.
The organic layer was washed once with sat. aq. NH4Cl and
dried over MgSO4. The product was purified by silica gel
flash chromatography to afford 10a (1.57 g; 94%) as
colorless oil; IR (neat) 2925, 2854, 1507, 1465,
1239 cm21; 1H NMR d 0.87 (3H, t, J¼7 Hz), 1.10 (3H, s),
1.16–1.28 (18H, m), 3.10 (1H, s), 3.77 (3H, s), 6.79, 6.84
(each 2H, d, J¼9 Hz), 7.24–7.43 (5H, m). MS m/z (%) 379
(Mþ, 40), 365 (10), 322 (4), 308 (3), 280 (21), 266 (82), 253
(29), 238 (14), 197 (100), 148 (74), 134 (24), 121 (17), 91
(80). Calcd for C26H37NO: M, 379.2875. Found: m/z
379.2860. [a]2D9¼287.0 (c 0.5 acetone).
1
(SO) cm21; H NMR d 0.88 (3H, t, J¼6.4 Hz), 1.2–2.0
(18H, m), 2.36 (3H, s), 3.68 (3H, s), 4.06 (1H, s), 6.23,
6.60 (each 2H, d, J¼9 Hz), 7.1–7.7 (9H, m). [a]2D7¼2194.6
(c 1.0 acetone).
Compound Racemic-14a. Colorless crystals; mp 127–
1308C (AcOEt–hexane). IR (KBr) 3293 (NH), 1514,
1251, 1039 (SO) cm21; MS m/z (%) 539 (Mþ, 0.6), 399
(100), 272 (82). Anal. calcd for C32H42ClNO2S: C, 71.15;
H, 7.84; Cl, 6.56, N, 2.59; S, 5.94. Found: C, 71.36; H, 7.82;
Cl, 6.67; N, 2.41; S, 5.99.
2.1.2. (1R,2R,RS)-2-Chloro-1-(4-methoxyphenylamino)-
1-phenyl-2-(p-tolylsulfinyl)propane (14b). Colorless crys-
tals (69%); mp 170–1728C (AcOEt–hexane). IR (KBr)
1
3304 (NH), 1511, 1251, 1038 (SO) cm21; H NMR d 1.84
(3H, s), 2.39 (3H, s), 3.68 (3H, s), 4.36 (1H, d, J¼3 Hz),
5.57 (1H, d, J¼3 Hz, NH), 6.39, 6.63 (each 2H, d, J¼9 Hz),
7.2–7.6 (9H, m). [a]D30¼2184.3 (c 0.5 acetone).

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T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
2.1.6. (2R,3R)-2-Decyl-2-methyl-1-(4-methoxyphenyl)-3-
phenylaziridine (10b). Colorless oil (89%); IR (neat) 2926,
J¼14.5 Hz), 5.80 (1H, s). MS m/z (%) 285 (Mþ, 0.4), 271
(8), 226 (54), 184 (100), 131 (24), 88 (62), 60 (78). Calcd for
C16H31NO3: M, 285.2304. Found: m/z 285.2319.
1
2855, 1506, 1464, 1238 cm21; H NMR d 0.87 (3H, t, J¼
7 Hz), 1.07 (3H, s), 1.24–1.46 (18H, m), 3.09 (1H, s), 3.77
(3H, s), 6.79, 6.85 (each 2H, d, J¼9 Hz), 7.27–7.41 (5H,
m). MS m/z (%) 379 (Mþ, 73), 364 (4), 336 (3), 280 (22),
266 (87), 197 (100), 148 (62), 91 (76). Calcd for C26H37NO:
M, 379.2875. Found: m/z 379.2881. [a]2D9¼292.8 (c 0.5
acetone).
2.1.9. (S)-3-Acetamino-3-methyltridecanoic acid N-{1-
(1-naphthyl)ethyl}amide (18a). To a solution of 11a
(28.5 mg; 0.1 mmol) in CH2Cl2 (4 mL), EDC (23 mg;
0.12 mmol) and HOBt (16.4 mg; 0.12 mmol) were added
at 08C with stirring. After stirring for 1 h at 08C, (S)-(2)-1-
(1-naphthyl)ethylamine (32 mL; 0.2 mmol) was added to
the reaction mixture and stirred for 3 h. The reaction
mixture was washed with 5% aq. HCl twice and sat. aq.
NaHCO3 then dried over MgSO4. The solvent was
evaporated under vacuum to afford 43 mg (98%) of pure
18a as colorless oil; IR (neat) 3298, 3053, 2926, 2854, 1652,
2.1.7. N-(1-Benzyl-1-methylundecyl)acetamide (17a,b).
Palladium hydroxide (20 wt% Pd (dry basis) on carbon;
3.05 g, 300 wt%) was added to a solution of 10a (1.05 g;
2.77 mmol) in 50 mL of a mixture of MeOH and AcOEt.
The reaction mixture was stirred for 30–60 min under
hydrogen atmosphere. The catalyst was filtered off and
the solvent was evaporated under vacuum to afford the
secondary amine 15a. Without further purification, a
solution of CAN (6.07 g; 11.1 mmol) in 13 mL of water
was added to a solution of 15a in 25 mL of CH3CN at 08C
with stirring. The reaction mixture was stirred at 08C for
30 min, then the solution was neutralized with 5% aq.
NaHCO3. Na2SO3 (1.4 g) was added to the reaction mixture
with stirring and after 10 min, the reaction mixture was
filtered through a celite pad. The aqueous layer was
extracted with AcOEt. The combined organic layers were
washed with sat. aq. NaHCO3, 10% aq. Na2SO3, and brine,
and then dried over MgSO4. After concentration, obtained
crude 16a was successively added pyridine (11 mL), acetic
anhydride (5.2 mL) and 4-(dimethylamino)pyridine (67 mg;
0.55 mmol). The reaction mixture was stirred at room
temperature for 1 h. The acetic anhydride and pyridine were
evaporated under vacuum and the residue was purified by
silica gel column chromatography to give (S)-(þ)-17a
(412 mg; 47% from 10a) as colorless oil; IR (neat) 3298,
2925, 2855, 1652, 1558, 1465, 1371, 1031 cm21; [a]D29¼
þ28.9 (c 0.5 acetone).
1
1525, 1449, 1372, 799, 778, 756 cm21; H NMR d 0.87
(3H, t, J¼7 Hz), 1.15 (3H, s), 1.10–1.31 (18H, m), 1.34
(3H, s), 1.65 (3H, d, J¼6.7 Hz), 2.28, 2.89 (each 1H, d,
J¼12.8 Hz), 5.41 (1H, s), 5.95–6.01 (1H, m), 6.09 (1H, d,
J¼8.9 Hz), 7.12–8.17 (7H, m). MS m/z (%) 438 (Mþ, 28),
268 (35), 209 (11), 170 (100), 155 (54). Calcd for
C28H42N2O2: M, 438.3246. Found: m/z 438. 3249.
[a]2D5¼22.4 (c 0.73 acetone).
2.1.10. (R)-3-Acetamino-3-methyltridecanoic acid N-{1-
(1-naphthyl)ethyl}amide (18b). Colorless oil (94%); IR
(neat) 3299, 3053, 2927, 2855, 1645, 1525, 1449, 1372,
1239, 799, 777, 756 cm21; 1H NMR d 0.88 (3H, t, J¼7 Hz),
1.26–1.40 (18H, m), 1.32 (3H, s), 1.46 (3H, s), 1.63 (3H, d,
J¼6.7 Hz), 2.55, 2.60 (each 1H, d, J¼13 Hz), 5.68 (1H, s),
5.92–5.98 (1H, m), 6.11 (1H, d, J¼8.6 Hz), 7.43–8.13 (7H,
m). MS m/z (%) 438 (Mþ, 26), 268 (34), 209 (11), 170
(100), 155 (54). Calcd for C28H42N2O2: M, 438.3246.
Found: m/z 438.3250. [a]2D1¼21.6 (c 0.7 acetone).
2.1.11. (dl)-2-Acetamino-2-methyldodecanoic acid
(19a,b). Colorless crystals (14%); IR (KBr) 3339, 2921,
2851, 2604, 1701, 1631, 1555, 1469, 1372, 1326, 1254,
1
Compound (R)-(2)-17b. Colorless oil (31% yield);
[a]3D0¼230.9 (c 0.5 acetone). Racemic-17: Colorless
crystals; mp 82–838C (AcOEt–hexane). IR (KBr) 3277,
3088, 2918, 2848, 1643, 1568, 1470, 1371 cm21; 1H NMR d
0.88 (3H, t, J¼7 Hz), 1.19 (3H, s), 1.26–1.55 (17H, m), 1.51
(1H, m), 1.91 (3H, s), 2.89, 3.19 (each 1H, d, J¼13 Hz),
4.86 (1H,s), 7.12–7.29 (5H, m). MS m/z (%) 317 (Mþ, 3),
302 (5), 274 (0.5), 258 (6), 226 (60), 184 (100), 176 (6), 134
(6), 91 (11), 70 (7). Calcd for C21H35NO: M, 317.2719.
Found: m/z 317.2715. Anal. calcd for C21H35NO: C, 79.43;
H, 11.12; N, 4.41. Found: C, 79.27; H, 11.08; N, 4.35.
1238, 1143 cm21; H NMR d 0.88 (3H, t, J¼7 Hz), 1.10–
1.32 (16H, m), 1.58 (3H, s), 1.84 (1H, m), 2.04 (3H, s), 2.14
(1H, m), 6.07 (1H, s). MS m/z (%) 271 (Mþ, 5), 226 (52),
184 (100), 144 (22), 130 (19), 113 (15), 102 (30), 88 (50), 60
(71). Calcd for C15H29NO3: M, 271.2147. Found: m/z
271.2141.
2.1.12. (2S,3R)-2-Decyl-1-(4-methoxyphenyl)-3-phenyl-
aziridine (20a). To a solution of EtMgBr (2.07 mmol) in
20 mL of THF at 2788C was added a solution of 8a
(300 mg; 0.59 mmol) in 4 mL of THF dropwise with
stirring. After 10 min, the cooling bath was removed and
the reaction mixture was allowed to warm up to room
temperature at once and was stirred at room temperature for
30 min. The reaction was quenched by sat. aq. NH4Cl and
the whole was extracted with CHCl3. The organic layer was
washed once with sat. aq. NH4Cl and dried over MgSO4.
The product was purified by silica gel flash chromatography
to afford 20a (210 mg; 97%) as colorless oil; IR (neat) 2924,
2854, 1506, 1464, 1455, 1241, 1180, 1041 cm21; 1H NMR d
0.87 (3H, t, J¼7 Hz), 1.21–1.53 (18H, m), 1.56 (3H, s), 2.35
(1H, dt, J¼6.4, 6.7 Hz), 3.24 (1H, d, J¼6.4 Hz), 3.76 (3H,
s), 6.79, 6.96 (each 2H, d, J¼8.8 Hz), 7.27–7.42 (5H, m).
MS m/z (%) 365 (Mþ, 100), 308 (7), 294 (11), 274 (25), 252
(94), 238 (40), 224 (22), 211 (31), 197 (21), 162 (5), 134
2.1.8. 3-Acetamino-3-methyltridecanoic acid (11a,b). A
mixture of 17a (50 mg; 0.16 mmol), ruthenium trichloride
hydrate (1.6 mg; 0.00785 mmol) and sodium periodate
(600 mg; 2.82 mmol) in a mixture of CCl4 (1.5 mL),
CH3CN (1.5 mL) and water (1 mL) was stirred at room
temperature for 2 days. The mixture was extracted with
AcOEt and the organic layer was washed with brine and
then dried over MgSO4. After concentration, the residue
was purified by silica gel column chromatography to give
11a (16.6 mg; 37%) as colorless oil; IR (neat) 3335, 2926,
2855, 1714, 1659, 1549, 1466, 1376, 1221 cm21; 1H NMR d
0.88 (3H, t, J¼7 Hz), 1.25–1.29 (16H, m), 1.38 (3H, s),
1.70, 1.85 (each 1H, m), 1.95 (3H, s), 2.65, 2.91 (each 1H, d,

T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
9809
(82), 91 (38). Calcd for C25H35NO: M, 365.2719. Found:
m/z 365.2728. [a]2D5¼2170.7 (c 0.5 acetone).
(3H, s), 2.48–2.63 (2H, m), 4.22 (1H, m), 6.16 (1H, d, J¼
8.8 Hz). [a]2D3¼þ2.0 (c 1.0 MeOH).
2.1.13. (2S,3R)-2-Decyl-2-deuterio-1-(4-methoxyphenyl)-
3-phenylaziridine (20b). Colorless oil (97%); IR (neat)
2924, 2853, 1604, 1506, 1464, 1454, 1239, 1180, 1106,
Compound Racemic-24a. Colorless crystals; mp 109–
1108C (AcOEt–hexane); IR (KBr) 3326, 2919, 2851,
1730, 1651, 1605, 1559, 1412, 1375 cm21. MS m/z (%)
271 (Mþ, 11), 256 (4), 228 (42), 212 (14), 170 (25), 130
(67), 88 (100), 60 (28). Calcd for C15H29NO3: M, 271.2147.
Found: m/z 271.2153. Anal. calcd for C15H29NO3: C, 66.38;
H, 10.77; N, 5.16. Found: C, 65.48; H, 10.49; N, 4.94.
1
1141 cm21; H NMR d 0.87 (3H, t, J¼6.8 Hz), 1.21–1.56
(18H, m), 3.23 (1H, s), 3.76 (3H, s), 6.79, 6.96 (each 2H, d,
J¼8.8 Hz), 7.26–7.42 (5H, m). MS m/z (%) 366 (Mþ, 100),
323 (4), 309 (7), 295 (12), 274 (18), 253 (80), 239 (39), 211
(36), 197 (21), 135 (67), 91 (33), 77 (13). Calcd for
C25H34DNO: M, 366.2780. Found: m/z 366.2784.
[a]2D6¼2151.8 (c 1.05 acetone).
2.1.17. (S)-3-Acetamino-3-deuteriotridecanoic acid
(24b). Colorless crystals (54%); mp 71–738C (AcOEt–
hexane). IR (KBr) 3286, 2918, 2851, 1703, 1648, 1544,
1
2.1.14. (S)-N-(1-Benzylundecyl)acetamide (23a). Palla-
dium hydroxide (20 wt% Pd (dry basis) on carbon; 1.2 g,
300 wt%) was added to a solution of 20a (400 mg;
1.1 mmol) in 20 mL of a mixture of MeOH and AcOEt.
The reaction mixture was stirred for 30–60 min under
hydrogen atmosphere. The catalyst was filtered off and
the solvent was evaporated under vacuum to afford the
secondary amine 21a. Without further purification, a
solution of CAN (1.21 g; 2.2 mmol) in 5 mL of water was
added to a solution of 21a in 10 mL of CH3CN at 08C with
stirring. The reaction mixture was stirred at 08C for 30 min
and at room temperature for 2 h, and then was added
successively 10% aq. NaOH (1 mL) and acetic anhydride
(2.6 mL; 28 mmol) at 08C. After stirring overnight, the
reaction mixture was filtered through a celite pad. The
aqueous layer was extracted with AcOEt. The combined
organic layers were washed with sat. aq. NaHCO3, 10% aq.
Na2SO3, and brine, and then dried over MgSO4. Concen-
tration of the solution followed by purification by silica gel
column chromatography gave 23a (176 mg; 53% from 20a)
as colorless crystals; mp 94–968C (AcOEt–hexane). IR
(KBr) 3295, 2917, 2850, 1646, 1555, 1372 cm21; 1H NMR
d 0.87 (3H, t, J¼7 Hz), 1.15–1.55 (18H, m), 1.92 (3H, s),
2.78 (2H, m), 4.18 (1H, m), 5.14 (1H, d, J¼8.9 Hz), 7.15–
7.30 (5H, m). [a]D22¼26.6 (c 0.5 acetone).
1466, 1435, 1373, 1051 cm21; H NMR d 0.87 (3H, t, J¼
6.9 Hz), 1.25–1.55 (18H, m), 2.00 (3H, s), 2.50, 2.60 (each
1H, d, J¼15.9 Hz), 6.23 (1H, s). MS m/z (%) 272 (Mþ, 4),
257 (3), 229 (24), 213 (17), 171 (32), 131 (61), 89 (100), 71
(13), 60 (35). Calcd for C15H28DNO3: M, 272.2209. Found:
m/z 272.2216. Anal. calcd for C15H28DNO3·0.8H2O: C,
62.82; H, 10.75; N, 4.88. Found: C, 62.81; H, 10.39; N, 4.78.
[a]2D7¼þ0.76 (c 1.4 MeOH).
2.1.18. (2R,3R)-2-Decyl-2-ethoxycarbonyl-1-(4-methoxy-
phenyl)-3-phenylaziridine (12a). To a solution of 8a
(300 mg; 0.59 mmol) in 25 mL of dry THF in a flame-
dried flask was added MeMgBr (0.77 mmol) at 2508C with
stirring. The reaction mixture was stirred at 2508C for
15 min, then the solution was cooled to 2808C. t-BuLi
(1.2 mmol) was added to the reaction mixture dropwise with
stirring and after 1 min, ethyl chloroformate (0.23 mL;
2.4 mmol) was added. The reaction mixture was stirred for
1 min, then the reaction was quenched by adding sat. aq.
NH4Cl. The whole was extracted with ether–benzene. The
product was purified by silica gel flash chromatography to
afford 12a (165 mg; 64%) as a colorless oil. IR (neat) 1724
1
(CO), 1507, 1241, 1177 cm21. H NMR d 0.88 (3H, t, J¼
7 Hz), 1.02 (3H, t, J¼7 Hz), 1.08–1.70 (18H, m), 3.76 (3H,
s), 3.93–4.02 (2H, m), 4.13 (1H, s), 6.77, 6.82 (each 2H, d,
J¼8.8 Hz), 7.28–7.44 (5H, m). MS m/z (%) 437 (Mþ, 52),
408 (31), 364 (45), 276 (100), 274 (58). Calcd for
C28H39NO3: M, 437.2929. Found: m/z 437.2924. [a]2D7¼
244.4 (c 1.1 acetone).
Compound Racemic-23. Colorless crystals; mp 100–1028C
(AcOEt–hexane); IR (KBr) 3300, 2917, 2850, 1646, 1550,
1466, 1370 cm21. MS m/z (%) 303 (Mþ, 0.5), 244 (8), 212
(56), 170 (100), 120 (6), 91 (14). Calcd for C20H33NO: M,
303.2562. Found: m/z 303.2571. Anal. calcd for C20H33NO:
C, 79.15; H, 10.96; N, 4.62. Found: C, 79.22; H, 11.18; N,
4.64.
2.1.19. (S)-Ethyl 2-amino-2-benzyldodecanoate (26). To a
solution of 12a (0.24 g; 0.54 mmol) in distilled methanol
(15 mL) was added 60 mg of Pd(OH)2 (10% on carbon).
The reaction mixture was stirred under hydrogen atmos-
phere for 1 h. The catalyst was filtered off and the methanol
was evaporated to give crude 25. A solution of CAN (1.48 g;
2.7 mmol) in 10 mL of water was added to a crude solution
of 25 in 15 mL of CH3CN at 08C with stirring. The reaction
mixture was stirred at 08C for 30 min, then the solution was
neutralized with 5% aq. NaHCO3. Na2SO3 (340 mg) was
added to the reaction mixture with stirring and after 10 min,
the reaction mixture was filtered through a celite pad and the
whole was extracted with ethyl acetate. The product was
purified by silica gel column chromatography to afford
99 mg (54% from 12a) of 26 as colorless oil. IR (neat) 3388
(NH), 1732 (CO), 1182, 1031 cm21; 1H NMR d 0.88 (3H, t,
J¼7 Hz), 1.10–1.70 (22H, m), 1.85–1.95 (1H, m), 2.76,
3.18 (each 1H, d, J¼13 Hz), 4.09–4.23 (2H, m), 7.10–7.40
(5H, m). MS (FAB) m/z (%) 334 ([MþH]þ, 100), 260 (51),
2.1.15. (S)-N-(1-Benzyl-1-deuterioundecyl)acetamide
(23b). Colorless crystals (43% from 20b); mp 94–958C
(AcOEt–hexane). IR (KBr), 3293, 2917, 2850, 1644,
1
1547 cm21; H NMR d 0.87 (3H, t, J¼7 Hz), 1.15–1.55
(18H, m), 1.92 (3H, s), 2.73 (2H, m), 5.24 (1H, s), 7.15–
7.30 (5H, m). MS m/z (%) 304 (Mþ, 0.5), 245 (10), 213 (72),
171 (100), 91 (13). Calcd for C20H32DNO: M, 304.2624.
Found: m/z 304.2622. Anal. calcd for C20H32DNO: C,
78.89; H, 10.92; N, 4.60. Found: C, 78.99; H, 11.20; N, 4.52.
[a]2D5¼27.3 (c 0.5 acetone).
2.1.16. (S)-3-Acetaminotridecanoic acid (24a). Colorless
crystals (54%); mp 84–868C (AcOEt–hexane). IR (KBr)
3286, 2919, 2850, 1721, 1649, 1552, 1376, 1238 cm21; 1H
NMR d 0.87 (3H, t, J¼7 Hz), 1.15–1.60 (18H, m), 2.00

9810
T. Satoh, Y. Fukuda / Tetrahedron 59 (2003) 9803–9810
Y. J. Synth. Org. Chem. Jpn 2000, 58, 756. (g) Cativiela, C.;
Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
645. (h) Beller, M.; Eckert, M. Angew. Chem. Int. Ed. 2000,
39, 1010.
242 (21), 91 (15). Calcd for C21H36NO2: M, 334.2746.
Found: m/z 334.2734. [a]2D4¼215.4 (c 1.0 acetone).
2.1.20. (S)-Ethyl 2-acetamino-2-benzyldodecanoate (27).
Colorless oil (97%); IR (neat) 3410, 3299, 2926, 2855,
1737, 1680, 1658, 1497, 1455, 1374, 1201 cm21; 1H NMR d
0.88 (3H, t, J¼7 Hz), 0.98 (1H, m), 1.24–1.31 (15H, m),
1.33 (3H, t, J¼7.2 Hz), 1.83 (1H, m), 1.96 (3H, s), 2.63 (1H,
m), 3.07, 3.75 (each 1H, d, J¼13.4 Hz), 4.16–4.29 (2H, m),
6.18 (1H, s), 7.01–7.24 (5H, m). MS m/z (%) 375 (Mþ, 4),
316 (24), 302 (5), 284 (76), 242 (100), 168 (12), 91 (20).
Calcd for C23H37NO3: M, 375.2773. Found: m/z 375.2770.
[a]2D5¼þ7.88 (c 1.0 acetone).
2. Recent monograph and reviews for the chemistry and
synthesis of b-amino acids: (a) Cole, D. C. Tetrahedron
1994, 50, 9517. (b) Juaristi, E.; Quintana, D.; Escalante, J.
Aldrichim. Acta 1994, 27, 3. (c) Enantioselective Synthesis of
b-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York,
1997. (d) Davies, S. G.; Ichihara, O. J. Synth. Org. Chem. Jpn
1997, 55, 26. (e) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Oiarbide, M. Synlett 2001, 1813. (f) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991.
3. (a) Martin, S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem.
Rev. 1993, 93, 2037. (c) Corey, E. J.; Guzman-Perez, A.
Angew Chem. Int. Ed. 1998, 37, 388.
2.1.21. (S)-2-Acetamino-2-decylsuccinic acid-1-ethyl
ester (13a). Colorless crystals (60%); mp 65–668C
(Hexane); IR (KBr) 3361, 2959, 2923, 2853, 2490, 1740,
1720, 1620, 1536, 1377, 1206, 1016 cm21; 1H NMR d 0.87
(3H, t, J¼6.9 Hz), 1.00 (1H, m), 1.15–1.24 (15H, m), 1.27
(3H, t, J¼7.2 Hz), 1.63 (1H, m), 1.99 (3H, s), 2.45 (1H, m),
2.92, 3.66 (each 1H, d, J¼16.6 Hz), 4.24 (2H, m), 6.73 (1H,
s). Anal. calcd for C18H33NO5: C, 62.95; H, 9.68; N, 4.08.
Found: C, 62.63; H, 9.62; N, 4.08.. [a]2D9¼211.0 (c 0.5
MeOH).
4. Satoh, T. Chem. Rev. 1996, 96, 3303.
5. (a) Satoh, T.; Oohara, T.; Yamakawa, K. Tetrahedron Lett.
1988, 29, 4093. (b) Satoh, T.; Sato, T.; Oohara, T.; Yamakawa,
K. J. Org. Chem. 1989, 54, 3973. (c) Satoh, T. J. Synth. Org.
Chem. Jpn 1996, 54, 481. (d) Satoh, T. J. Synth. Org. Chem.
Jpn 2003, 61, 98.
6. (a) Satoh, T.; Ozawa, M.; Takano, K.; Kudo, M. Tetrahedron
Lett. 1998, 39, 2345. (b) Satoh, T.; Ozawa, M.; Takano, K.;
Chyouma, T.; Okawa, A. Tetrahedron 2000, 56, 4415. (c)
Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S. Tetrahedron
Lett. 2000, 41, 6495. (d) Satoh, T.; Matsue, R.; Fujii, T.;
Morikawa, S. Tetrahedron 2001, 57, 3891.
Compound Racemic-13a. Colorless oil; IR (neat) 3360,
2926, 2855, 1739, 1659, 1526, 1466, 1374, 1211,
1024 cm21; MS m/z (%) 343 (Mþ, 4), 300 (10), 284 (6),
270 (84), 228 (100), 203 (25), 160 (29), 142 (8), 114 (10), 99
(8), 60 (9). Calcd for C18H33NO5: M, 343.2359. Found: m/z
343.2367.
7. (a) Atkinson, R. S.; Coogan, M. P.; Lochrie, I. S. T.
Tetrahedron Lett. 1996, 37, 5179. (b) Davis, F. A.; Liu, H.;
Reddy, G. V. Tetrahedron Lett. 1996, 37, 5473. (c) Choi,
S.-K.; Lee, J.-S.; Kim, J.-H.; Lee, W. K. J. Org. Chem. 1997,
62, 743. (d) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem.
1997, 62, 3796. (e) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997,
53, 13603. (f) Chang, J-W.; Bae, J.-H.; Shin, S.-H.; Park, C. S.;
Choi, D.; Lee, W. K. Tetrahedron Lett. 1998, 39, 9193.
8. (a) Bravo, P.; Guidetti, M.; Viani, F.; Zanda, M.; Markovsky,
A. L.; Sorochinsky, A. E.; Soloshonok, I. V.; Soloshonok,
V. A. Tetrahedron 1998, 54, 12789. (b) Bravo, P.; Capelli, S.;
Crucianelli, M.; Guidetti, M.; Markovsky, A. L.; Meille, S. V.;
Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.
Tetrahedron 1999, 55, 3025. (c) Fustero, S.; Pina, B.; Garcia
de la Torre, M.; Navarro, A.; Ramirez de Arellano, C.; Simon,
A. Org. Lett. 1999, 977.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research No. 11640545 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, which is
gratefully acknowledged.
References
1. Recent monographs and reviews for the chemistry and
synthesis of a-amino acids: (a). In Chemistry and Bio-
chemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman &
Hall: London, 1985. (b) Williams, R. M. Synthesis of Optically
Active a-Amino Acids; Pergamon: Oxford, 1989. (c) Duthaler,
R. O. Tetrahedron 1994, 50, 1539. (d) Cativiela, C.; Diaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517. (e)
Sano, S. Yakugaku Zasshi 2000, 120, 28. (f) Sano, S.; Nagao,
9. (a) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936. (b) Mander, L. N.; Willliams,
C. M. Tetrahedron 2003, 59, 1105.
10. Konig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
11. Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000,
56, 10153.