Synthesis of optically active 2-alkyl-3,4-iminobutanoic acids. β-amino acids containing an aziridine heterocycle

Article abstract of DOI:10.1021/jo0014055

All four stereoisomers of 2-alkyl-3,4-iminobutanic acid, a novel class of β-amino acids bearing a chemically versatile aziridine ring, were synthesized starting with aspartic acid. The synthetic strategy involves the introduction of an alkyl group at the β-position of fully protected optically active aspartic acid followed by the construction of an aziridine ring making use of the α-carboxylate and α-amino groups. The α-carboxylate was reduced to the corresponding alcohol, which was then subjected to cyclization to form an aziridine ring with the N-protected amino group. Removal of the protection groups yielded the target compounds.

Full text of DOI:10.1021/jo0014055

3696
J . Org. Chem. 2001, 66, 3696-3703
Syn th esis of Op tica lly Active 2-Alk yl-3,4-im in obu ta n oic Acid s.
â-Am in o Acid s Con ta in in g a n Azir id in e Heter ocycle
J eong-il Park, Guan Rong Tian,† and Dong H. Kim*
Center for Biofunctional Molecules and Department of Chemistry, Pohang University of Science and
Technology, San 31 Hyoja-dong, Pohang 790-784, Korea
dhkim@postech.ac.kr
Received September 22, 2000 (Revised Manuscript Received February 27, 2001 )
All four stereoisomers of 2-alkyl-3,4-iminobutanoic acid, a novel class of â-amino acids bearing a
chemically versatile aziridine ring, were synthesized starting with aspartic acid. The synthetic
strategy involves the introduction of an alkyl group at the â-position of fully protected optically
active aspartic acid followed by the construction of an aziridine ring making use of the R-carboxylate
and R-amino groups. The R-carboxylate was reduced to the corresponding alcohol, which was then
subjected to cyclization to form an aziridine ring with the N-protected amino group. Removal of
the protection groups yielded the target compounds.
In tr od u ction
Three-membered heterocycles typified by oxirane dis-
play striking chemical property, which has its origin in
the relief of ring strain that occurs when the ring is
cleaved, and thus, they are extremely valuable chemical
entities industrially and synthetically. Aziridine, which
may be considered as a nitrogen analogue of oxirane, also
bears high ring-strain energy comparable to that of
oxirane.1 Due to the high ring strain of the heterocycle,
compounds having an aziridine ring would be valuable
as synthetic intermediates2 and are expected to exhibit
varied biological activities.3 The antineoplastic activity
of mitomycin C, an aziridine-containing antibiotic pro-
duced by Streptomyces caespitosus, is known to be as-
sociated with the high reactivity of the strained hetero-
cycle.4 In connection with other projects, we needed
2-alkyl-3,4-iminobutanoic acids (1) in which an aziridine
moiety is introduced in place of the amino group of
â-amino acid. We wish to report herein the synthesis of
all four diastereoisomers of 1 in an optically pure form.
Although aziridine-2-carboxylic acid, which may be con-
sidered as an R-amino acid, has been known since 19665
and has attracted much attention,6 its homologues such
as 1 have been scarcely reported7 despite their potential
utility as intermediates for the synthesis of biologically
active compounds.
Resu lts a n d Discu ssion
The initial strategy for the synthesis of 1 involved the
introduction of an alkyl group at the â-position of fully
protected aspartic acid by the protocol reported by
Baldwin et al.8 and subsequent construction of an aziri-
dine ring making use of the R-carboxylate and R-amino
groups of the aspartic acid as outlined in Scheme 1. The
R-ester moiety in 3 was preferentially hydrolyzed accord-
ing to the method described by Berger and Katchalski,9
and the carboxylate moiety was reduced to hydroxym-
ethyl via a mixed carboxylic-carbonic anhydride as
described by Rodriguez et al.10 The hydroxyl group thus
formed was tosylated and subjected to cyclization reaction
after the amino protection group was removed to obtain
7. Unexpectedly, however, the attempted removal of the
benzyl group in 7 to obtain the target compound under
the hydrogenolysis conditions using Pd/C catalyst met
with failure and resulted in the cleavage of the aziridine
ring as well as the obtainment of 3-amino-2-benzylbu-
tanoic acid, 8, a literature compound.11 It appears that
the cleavage of aziridine ring to give an amine may be a
* To whom correspondence should be addressed. Tel: +82-54-279-
2101. Fax: +82-54-279-5877.
(6) (a) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem.
Soc. J pn. 1978, 51, 1577-1578. (b) Morodor, L.; Musiol, H.-J .; Scharf,
R. FEBS Lett. 1992, 299, 51-53. (c) Korn, A.; Rudolph-Bo¨hnor, S.;
Morodor, L. Tetrahedron 1994, 50, 1717-1730. (d) Davis, F. A.; Zhou,
P.; Reddy, G. V. J . Org. Chem. 1994, 59, 3243-3245. (e) Church, N.
J .; Young, D. W. Tetrahedron Lett. 1995, 36, 151-154.
(7) (a) Kryczka, B.; Lourent, A.; Marquet, B. Tetrahedron 1978, 34,
3291-3298. (b) Blazoev, B.; Novkova, S. Tetrahedron 1982, 38, 1609-
1613.
† On leave from the Department of Chemistry, Yanbian University,
Yanji, People’s Republic of China.
(1) The ring strain energy of aziridine amounts to 26-27 kcal mol-1
.
Person, W. H.; Lian, S. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: Oxford: 1996; Vol. 1A, p 7.
(2) (a) Kump, J . E. G. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.7, p 469. (b) Tanner,
D. A. Angew. Chem., Intl. Ed. Engl. 1994, 33, 599-619. (c) Osborn, H.
M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8, 1693-1715.
(3) (a) Dermer, D. C.; Ham, G. E. Ethyleneimine and Other Aziri-
dines; Academic Press: New York, 1969; pp 425-441. (b) Reynolds,
R. C. Aziridines. In Cancer Chemotherapeutic Agents; Foye, W. O., Ed.;
American Chemical Society: Washington, DC, 1995; pp 186-197.
(4) Remers, W. A.; Iyengar, B. C. Antitumor Antibiobicts. In Cancer
Chemotherapeutic Agents; Foye, W. O. Ed.; American Chemical
Society: Washington, DC, 1995; pp 584-592.
(8) (a) Baldwin, J . E.; Moloney, M. G.; North, M. Tetrahedron 1989,
45, 6309-6318. (b) Baldwin, J . E.; Moloney, M. G.; North, M. J . Chem.
Soc., Perkin Trans. 1 1989, 833-834.
(9) Berger, A.; Katchalski, E. J . Am. Chem. Soc. 1951, 73, 4084-
4088.
(10) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
Tetrahedron Lett. 1991, 32, 923-926.
(11) (a) J uaristi, E.; Escalante, J .; Lamatsch, B.; Seebach, D. J . Org.
Chem. 1992, 57, 2396-2398. (b) Cardillo, G.; Tolomelli, A.; Tomasini,
C. J . Org. Chem. 1996, 61, 8651-8654.
(5) Clark, R. A. Ph.D. Thesis, University of Maryland, 1966.
10.1021/jo0014055 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/27/2001

Synthesis of Optically Active 2-Alkyl-3,4-iminobutanoic Acids
J . Org. Chem., Vol. 66, No. 11, 2001 3697
Sch em e 1a
Sch em e 2a
a
Reagents, conditions, and (yields): (a) BnBr, LHMDS, THF,
-78 °C (64%); (b) 0.1
N NaOH, dioxane/H2O (94%); (c) (i)
i-BuOCOCl, TEA, DME, (ii) NaBH4, H2O, -10 °C (75%); (d) TsCl,
pyr, CH2Cl2 (62%), (e) (i) TFA, CH2Cl2, (ii) TEA, CH2Cl2 (60%), (f)
H2, Pd/C, MeOH (63%).
a
Reagents and conditions: (a) RX, LHMDS, THF, -78 °C; (b)
HCl, MeOH; (c) CuCO3‚Cu(OH)2, EtOH/H2O, 70 °C; (d) CbzCl,
Na2CO3, H2O; (e) (i) N-hydroxysuccinimide, DCC, DME, (ii)
NaBH4, THF, 0 °C to rt, (f) Ph3P, DEAD, THF, (g) H2, Pd/C, MeOH;
(h) LiOH, MeOH/H2O.
reflection of the property of aziridine ring tending to
relieve its high strain energy through the ring opening.
As can be seen later in the preparation of 15, the
aziridine survives hydrogenolysis under neutral condi-
tions. Therefore, it appears that debenzylation of the
benzyl ester moiety in 7 precedes the ring cleavage and
the acid that generated facilitates the ring opening.12 It
was, therefore, thought that saponification of the ester
under mild hydrolysis conditions would be advantageous,
and we decided to make use of methyl ester, which is
known to be hydrolyzed much more readily than the
benzyl ester.
Sch em e 3a
The successful synthetic route for the preparation of
(2R,3S)-1 is outlined in Scheme 2. The synthesis was
started with fully protected (S)-aspartic acid 2, which was
prepared by treating the aspartic acid with methanol in
the presence of thionyl chloride followed by treatment
with (Boc)2O. The enolate dianion that was obtained by
treating (S)-9 with 2 molar equiv of lithium hexameth-
yldisilazane (LHMDS) at -78 °C was allowed to react
with alkyl halide to give 10.8 In the case of methylation,
two products in a diastereoisomeric relationship were
formed in about equal ratio. The mixture was readily
separated by column chromatography. The compound
having [R]D ) +15.5° was assigned to have the (2S,3R)-
configuration on the basis of the NMR NOESY spectrum
of 4-N-benzyloxycarbonylamino-3-methylbutyrolactone
(16) obtained by the acid-catalyzed cyclization of 13a (the
discussion of the NOESY spectrum will be presented
later). Furthermore, 18 that was obtained from 10a by
a
Reagents, conditions, and (yields): (a) (i) propylene oxide,
EtOH, (ii) TMSCI (1.05 equiv), TEA (2.1 equiv), Pb(NO3)2 (0.67
equiv), PhFlBr (1.3 equiv), ChCl3, 3 d, (iii) O-tert-butyl-N,N′-
diisopropylisourea (3 equiv), CH2Cl2, rt, 2 d (52%); (b) DIBAL (3
equiv), THF, -30 °C, 5 h (80%).
the sequence of reactions depicted in Scheme 3 was
identical with the compound prepared by the literature
method.13
In the â-methylation reaction of 9 under the conditions
reported by Baldwin et al., no stereoselectivity resulted,
giving a 1:1 mixture of diastereoisomers, but sterically
demanding alkylating reagents such as benzyl bromide
and tert-butyl bromoacetate provided diastereoselectivity
in the ratios of 4:1 and 7:1, respectively, in favor of the
trans alkylation with respect to the BocNH group, when
(12) Under the analogous conditions oxirane was reported to
undergo a similar ring cleavage reaction: Dragovich, P. S.; Prins, T.
J .; Zhou, R. J . Org. Chem. 1995, 60, 4922-4924.
(13) (a) Wolf, J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164-
3173. (b) Dunn, P. J .; Ha¨nner, R.; Rapoport, H. J . Org. Chem. 1990,
55, 5017-5025.

3698 J . Org. Chem., Vol. 66, No. 11, 2001
Park et al.
the product was examined by HPLC.14 Rapoport and
associates observed the similar trend that bulkier groups
prefer the anti-alkylation in the aspartate alkylation
reactions.13
Sch em e 4a
Treatment of 10 with methanolic hydrochloride solu-
tion provided the N-deprotected product, the R-methyl
ester that was then regioselectively hydrolyzed by the
method reported by Gmeiner et al.15 using CuCO3‚
Cu(OH)2 in an ethanol/water mixture to give 11 as a
hydrochloride salt. In the case of 10c, the tert-butyl ester
moiety was converted into methyl ester under the reac-
tion conditions. The amino group in the half-ester of (S)-
aspartic acid derivative thus obtained was then protected
to give 12. The conversion of the R-carboxylate in 12 into
the hydroxymethyl group to yield 13 was accomplished
in good yield by sodium borohydride reduction of the
active ester that was formed by treating 12 with N-
hydroxysuccinimide in the presence of DCC as reported
by Humphrey et al.16 The aziridine ring formation to yield
14, the key step in the present synthesis, was effected
in 82% yield (for 14b) under the Mitsunobu conditions
using triphenylphosphine in the presence of DEAD
following the procedure reported by Wipf and Miller.17
The remaining steps to the target compound (1) having
(2R,3S)-configuration involve removal of the Cbz group
from the aziridine nitrogen and hydrolysis of the methyl
ester moiety, which were effected by the hydrogenolysis
in the presence of Pd/C and treatment with methanolic
lithium hydroxide solution,18 respectively.16 In the case
of compound 1 having (2S,3R)-configuration we have
synthesized only 1b starting with (R)-aspartic acid in
overall yield of 13% by the synthetic path that is parallel
to that used for the preparation of (2R,3S)-1.
An alternative route had to be sought for the synthesis
of (2S,3S)- and (2R,3R)-1 because the precursor to the
key intermediate, namely, the compound that corre-
sponds to 13 in the synthesis of (2S,3R)-1, has a strong
tendency to cyclize to form a δ-lactone. Thus, instead of
methyl ester, the Weinreb amide that resists lactoniza-
tion but still can be readily converted to carboxylate via
aldehyde moiety was employed.19 The synthetic route for
the preparation of (2S,3S)-1 is outlined in Scheme 4.
Lactone 19 that was prepared from (S)-aspartic acid as
described in the literature20 was subjected to benzylation
in a solution of THF and HMPA using 2 equiv of lithium
diisopropylamide (LDA) to give a diastereoisomeric mix-
ture, from which 20 was obtained in 73% yield. Alkylation
of γ-lactone such as 19 via its dianion is known to give a
mixture of diastereoisomers, in which the anti-alkylated
product predominates, especially when the alkylating
reagent is bulky.21 Nevertheless, we have ascertained the
stereochemical assignment for 20 as well as 16 by 2D
1H NMR NOESY experiments: Thus, strong NOEs were
a
Reagents, conditions, and (yields): (a) BnBr, LDA, THF-
HMPA, -78 °C (73%); (b) HCl‚NHM(Me)OMe, AlMe3, CH2Cl2
(87%); (c) Ph3P, DEAD, THF (86%); (d) H2, Pd/C, MeOH; (e) TrCl,
TEA, CHCl3, (73% from 23); (f) LAH, THF, -78 °C; (g) LAH, THF,
0 °C to rt (72%); (h) TFA-CHCl3-MeOH; (i) FmocCl, Na2CO3, H2O
(80%); (j) RuCl3, NaIO4, CH3CN/CCl4/H2O (65%); (k) 10% piperi-
dine in DMF.
observed between Ha-Hc and Hb-Hd in the case of
20 but 16 showed strong NOEs between Ha-Hd and
Hb-Hc, which are in good agreement with the respective
stereochemical assignments. Accordingly, 10a from which
16 was derived is established to have the (2S,3R)-
configuration. The lactone obtained from 10b in a fashion
analogous to the preparation of 16 from 10a was found
to be a diastereoisomer of 20, indicating the 10b to have
the (2S,3R)-configuration. The assignments for the chemi-
cal shift of each proton in 16 and 20 were made from the
respective NMR COSY spectrum.
(14) Racemization at the 2-position of 9 does not appear to take place
to any appreciable extent under the reaction conditions: Thus, when
the crude products obtained from the methylation of (R)- and (S)-9
under the identical reaction conditions were analyzed using chiral
HPLC column (ChiraCel OD column), it was shown that each product
is a 1:1 binary mixture of optically pure diastereoisomers.
(15) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H.
J . Org. Chem. 1990, 55, 3068-3074.
The lactone 20 was readily converted into 21 by
treatment with N,O-dimethylhydroxylamine in the pres-
ence of trimethylaluminum.22 The aziridine ring forma-
tion was then effected by the intramolecular Mitsunobu-
(16) Humphrey, J . M.; Aggen, J . B.; Chamberlin, A. R. J . Am. Chem.
Soc. 1996, 118, 11759-11770.
(17) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267-6270.
(18) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem
Soc. J pn. 1978, 51, 1577-1578.
(21) Namikoshi, M.; Reinhart, K. L.; Dahlem, A. M.; Beasley, V. R.
Tetrahedron Lett. 1989, 30, 4349-4352. (b) Takahashi, Y.; Hasegawa,
S.; Izawa, T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, 34,
3020-3024.
(22) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171-4174.
(19) Nahm, S.; Weinreb, S, M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(20) J efford, C. W.; Wang, J . Tetrahedron Lett. 1993, 34, 1111-1114.

Synthesis of Optically Active 2-Alkyl-3,4-iminobutanoic Acids
J . Org. Chem., Vol. 66, No. 11, 2001 3699
type reaction to yield 22.17 Attempts at selective reduction
of the Weinreb amide moiety in 22 to aldehyde were
unsuccessful, so we converted the Cbz protecting group
into a bulkier trityl to obtain 24, which was then readily
reduced by lithium aluminum hydride to give aldehyde
25.19 The aldehyde 25 appeared unstable to observe a
change of color on the exposure to air, so it was not
isolated but directly reduced further to hydroxymethyl
again with lithium aluminum hydride to give 26. Fur-
thermore, there is a potential danger of the aldehyde
undergoing racemization during workup and purification.
Nonetheless, we tried direct conversion of the Weireb
amide in 24 to the hydroxymethyl with lithium alumi-
num hydride but met with failure, affording only the
aldehyde 25. It appears that the reduced amide carbonyl
forms an intramolecular complex with the lithium ion,
which resists further reduction.23 At this stage, the trityl
moiety on the aziridine nitrogen atom was replaced with
9-fluorenylmethyl carbamate (Fmoc), which bears excel-
lent acid stability because we thought that the trityl
group would not survive the oxidation conditions of
converting the primary alcohol group to carboxylate.24
Ruthenium tetraoxide catalyzed periodate oxidation25 of
27 followed by deprotection of the Fmoc group with
piperidine in DMF produced (2S,3S)-1b. (2R,3R)-1b was
similarly synthesized in an overall yield of 4% starting
with (R)-aspartic acid.
and then cooled to -78 °C. A solution of (S)-N-Boc-aspartic
acid dibenzyl ester 2 (31 g, 75 mmol) in THF (125 mL) was
added slowly to the mixture, and the reaction mixture was
allowed to stir for 2 h at the same temperature. After addition
of benzyl bromide (17 mL, 143 mmol), the reaction mixture
was stirred for an additional 12 h. The reaction mixture was
quenched by addition of 3 N HCl solution to pH ∼3. The
aqueous layer was saturated with sodium chloride and then
extracted with EtOAc (200 mL × 2). The combined organic
layer was dried over MgSO4 and evaporated under reduced
pressure to give an oily residue. Purification by column
chromatography (silica gel, EtOAc/hexane ) 1:10) gave the
product as a white solid. The product was recrystallized from
diethyl ether-petroleum ether to afford white crystalline 3b
(24 g, 64%): mp 78-80 °C; [R]D ) +1.0° (c ) 1.0, CHCl3); IR
1
(KBr) 3396 (NH), 1733, 1717 cm-1; H NMR (CDCl3) δ 7.35-
7.18 (m, 15H), 5.60 (d, J ) 9.9 Hz, 1H), 4.95-5.11 (m, 4H),
4.52 (dd, J ) 9.9, 3.7 Hz, 1H), 3.45 (t, J ) 8.3, 3.7 Hz, 1H),
3.12 (dd, J ) 13.8, 7.2 Hz, 1H), 2.86 (dd, J ) 13.8, 8.3 Hz,
1H), 1.48 (s, 9H); MS m/z (FAB) 504.21 (M + 1). Anal. Calcd
for C30H33NO6: C, 71.55; H, 6.61; N, 2.78. Found: C, 71.60;
H, 6.58; N, 2.72.
(2S,3R)-N-ter t-Bu tyloxycar bon yl-3-ben zylaspar tic Acid
4-Ben zyl Ester (4). To a stirred solution of 3 (16.1 g, 32 mmol)
in dioxane (600 mL) and water (204 mL) was added 1 N NaOH
solution (32 mL) over 2 h at room temperature. The mixture
was stirred for 24 h and evaporated under reduced pressure
to remove the dioxane. The resultant residue was acidified
with 3 N HCl solution to pH 2-3 and then extracted with
EtOAc (200 mL × 3). The organic layer was dried over MgSO4
and evaporated under reduced pressure to give an oily residue.
Purification by column chromatography (silica gel, EtOAc/
hexane ) 4:10-2:1) gave 4 (11 g, 94%) as a white solid that
was recrystallized from benzene-petroleum ether: mp 108-
110 °C; [R]D ) +14.2° (c ) 1.0, CHCl3); IR (KBr) 3400, 1741,
1701 cm-1; 1H NMR (CDCl3) δ 7.38-7.18 (m, 10H), 5.70 (d, J
) 8.4 Hz, 1H), 5.08 (s, 2H), 4.44 (m, 2H), 3.42 (m, J ) 8.8, 6.4,
3.6 Hz, 1H), 3.13 (dd, J ) 13.6, 6.4 Hz, 1H), 2.88 (dd, J ) 13.8,
8.8 Hz, 1H), 1.45 (s, 9H); MS m/z (FAB) 414.15 (M + 1). Anal.
Calcd for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C,
67.12; H, 6.55; N, 3.37.
Con clu sion
Stereospecific synthesis of all four stereoisomers of
2-alkyl-3,4-iminobutanoic acid (1) have been reported.
These compounds constitute a novel class of amino acids
bearing an aziridine ring. The aziridine moiety is highly
susceptible to ring cleavage reaction under a variety of
conditions because of the high strain energy the hetero-
cycle possesses and thus the 2-alkyl-3,4-iminobutanoic
acids are expected to bring about versatile chemical
transformations that can be useful for the synthesis of
biologically active compounds. The biological activity
shown by these compounds will be the subject of forth-
coming report.
(2R,3S)-2-Ben zyl-3-(ter t-bu tyloxyca r bon yla m in o)-4-h y-
d r oxybu ta n oic Acid Ben zyl Ester (5). To an ice-chilled
stirred solution of 4 (1.6 g, 3.9 mmol) in DME (20 mL) were
added dropwise triethylamine (0.54 mL, 3.9 mmol) and isobu-
tylchloroformate (0.5 mL, 3.9 mmol), and then the resulting
mixture was stirred for 30 min. To this mixture was added a
solution of NaBH4 in water (5 mL) within 2 min. After vigorous
gas evolution, an excess of water (150 mL) was added to
decompose the residual hydride. The mixture was acidified to
pH 3-4 with 3 N HCl solution and extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure to give a resin. Purification
by column chromatography (silica gel, EtOAc/hexane ) 4:10)
gave 5 (1.05 g, 75%) as a white solid that was recrystallized
in diethyl ether-petroleum ether: mp 78-80 °C; [R]D ) +24.5°
Exp er im en ta l Section
Melting points were measured on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. 1H and 13C
NMR spectra were recorded on a Bruker AM 300 (300 MHz)
instrument using tetramethylsilane as the internal standard.
IR spectra were recorded on a Bruker Equinox 55 FT-IR
spectrophotometer. Mass spectra were obtained with a Micro
Mass Platform II 8410E spectrometer. Flash chromatography
was performed on silica gel 60 (230-400 mesh) from Merck.
Elemental analyses were performed at the Center for Biofunc-
tional Molecules, Pohang University of Science and Technol-
ogy, Korea. Optical rotations were measured on a Rudolph
Research Autopol III digital polarimeter. All chemicals were
of reagent grade obtained from Aldrich Chemical Co., and
solvents were purified before use.
(c ) 1.0, CHCl3); IR (KBr) 3431, 3365, 1707, 1667 cm-1 1H
;
NMR (CDCl3) δ 7.34-7.15 (m, 10H), 5.65 (d, J ) 8.6 Hz, 1H),
5.03 (s, 2H), 3.87 (m, 1H), 3.61 (m, 2H), 3.12-2.88 (m, 3H),
2.25 (br, 1H), 1.48 (s, 9H); 13C NMR (CDCl3)_δ 174.8, 156.7,
138.7, 135.8, 129.2, 128.9, 128.6, 127.0, 125.7, 80.1, 67.0, 64.6,
53.7, 48.2, 36.4, 28.8; MS m/z (FAB) 400.29 (M + 1). Anal.
Calcd for C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C,
69.38; H, 7.18; N, 3.57.
(2R,3S)-2-Ben zyl-3-(ter t-bu tyloxyca r bon yla m in o)-4-p-
tolu en esu lfon yloxybu ta n oic Acid Ben zyl Ester (6). To a
stirred solution of 5 (1.27 g, 3.2 mmol) in CH2Cl2 (10 mL) were
added TsCl (1.2 g, 3.3 mmol) and pyridine (1.5 mL) over 30
min. The resultant mixture was stirred for 15 h, diluted with
CH2Cl2 (10 mL), and washed with 1 N HCl solution. The
organic layer was dried over Na2SO4 and evaporated under
reduced pressure to give an oil. Purification by column
chromatography (silica gel, EtOAc/hexane ) 1:4) gave 6 (1.1
g, 62%) as a white solid that was recrystallized in EtOAc-
petroleum ether: mp 82-83 °C; [R]D ) +1.2° (c ) 1.0, CHCl3);
IR (KBr) 3408, 1730, 1693 cm-1; 1H NMR (CDCl3) δ 7.74 (d, J
(2S,3R)-N-ter t-Bu tyloxycar bon yl-3-ben zylaspar tic Acid
Diben zyl Ester (3). To a solution of hexamethyldisilazane
(39.6 mL, 188 mmol) in THF (150 mL) was added 1.6 M of
n-butyllithium in hexane (109 mL, 175 mmol) at 0 °C under
nitrogen atmosphere, and the mixture was stirred for 20 min
(23) Fehrentz, J .-A.; Castro, B. Synthesis 1983, 676-678.
(24) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley: New York, 1999; pp 736-747.
(25) Calsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.

3700 J . Org. Chem., Vol. 66, No. 11, 2001
Park et al.
) 8.2 Hz, 2H), 7.35-7.18 (m, 10H), 7.11 (d, J ) 7.0 Hz, 2H),
5.63 (d, J ) 8.6 Hz, 1H), 5.00 (dd, J ) 40.2, 12.2 Hz, 2H), 4.04-
4.02 (m, 3H), 3.02-2.83 (m, 3H), 2.44 (s, 3H), 1.44 (s, 9H); MS
m/z (FAB) 554.17 (M + 1). Anal. Calcd for C30H35NO7S: C,
65.08; H, 6.37; N, 2.53. Found: C, 65.37; H, 6.43; N, 2.29.
156.4, 80.4, 55.7, 52.9, 52.5, 41.8, 28.5, 13.9; MS m/z (FAB)
276.12 (M + 1).
(2S,3S)-10a (oil, 245 mg, 29%): [R]D ) +36.0° (c ) 1.0,
CHCl3); 1H NMR (CDCl3) δ 5.26 (d, J ) 8.5 Hz, 1H), 4.65 (dd,
J ) 8.7, 4.1 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.98 (m, 1H),
1.44 (s, 9H), 1.25 (d, J ) 7.2 Hz, 3H).
(2S,3R)-N-Bu tyloxyca r bon yl-3-(ter t-bu tyloxyca r bon yl-
m eth yl)a sp a r tic Acid Dim eth yl Ester ((2S,3R)-10c). This
compound was obtained as an oil in 73% yield from (S)-9
following the procedure used for the preparation of (2S,3R)-
(2R,3S)-2-Ben zyl-3,4-im in obu ta n oic Acid Ben zyl Ester
(7). To an ice-chilled stirred solution of 6 (1.1 g, 2 mmol) in
CH2Cl2 (10 mL) was added TFA (2 mL) slowly, and then the
mixture was stirred overnight at 4 °C. The mixture was
evaporated to give a yellowish resin, which was dissolved in
CH2Cl2 (40 mL), and washed with 5% aqueous NaHCO3
solution (40 mL). To the organic layer was added triethylamine
(0.42 mL, 3 mmol) and the mixture stirred for 20 h. The solvent
and triethylamine was removed under reduced pressure, and
the resultant residue was purified by column chromatography
(silica gel, EtOAc/hexane ) 1:1) to give 7 (334 mg, 60%) as an
10b: [R]D ) +23.9° (c ) 1.0, CHCl3); IR (film) 3435, 1731 cm-1
;
1H NMR (CDCl3) δ 5.31 (d, J ) 9.3 Hz, 1H), 4.65 (dd, J ) 9.4,
3.5 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.65-3.59 (m, 1H), 2.71
(dd, J ) 16.9, 7.8 Hz, 1H), 2.52 (dd, J ) 16.9, 6.8 Hz, 1H),
1.46 (s, 18H); 13C NMR (CDCl3) δ 172.9, 171.6, 170.6, 156.0,
81.6, 80.6, 54.3, 53.0, 52.6, 43.9, 34.6, 28.6, 28.4; MS m/z (FAB)
376.19 (M + 1).
oil: [R]D ) -13° (c ) 1.0, CHCl3); IR (film) 3446, 1719 cm-1
;
1H NMR (CDCl3) δ 7.37-7.12 (m, 10H), 5.08 (m, 2H), 3.07 (m,
2H), 2.30 (m, 2H), 1.76 (m, 1H), 1.28 (s, 1H); 13C NMR (CDCl3)
δ 174.2, 139.0, 138.8, 136.2, 129.3 128.9, 128.8, 128.5, 126.9,
66.8, 52.4, 37.1, 31.9, 25.0; MS m/z (FAB) 282.01 (M + 1).
(2S,3R)-N-Ben zyloxyca r bon yl-3-ben zyla sp a r tic Acid
4-Meth yl Ester ((2S,3R)-12b). To an ice-chilled stirred
solution of (2S,3R)-10b (8 g, 23 mmol) in MeOH (30 mL) was
added acetyl chloride (3.2 g, 40 mmol) in MeOH (70 mL, both
components were premixed at 0 °C and stirred in an ice bath
for 30 min). The mixture was stirred for 3 h at the same
temperature and then evaporated under reduced pressure. The
residue was dissolved in water (70 mL), basic cupric carbonate
(CuCO3‚Cu(OH)2, 6.1 g, 27.6 mmol) was added, and the
mixture was stirred vigorously at 70 °C for 3 h. The mixture
was then filtered through a Celite pad, and the filter pad was
rinsed with copious water. Hydrogen sulfide was then bubbled
into the solution until an aliquot filtered through a Celite pad
was colorless. After the remaining black mixture was filtered
through a Celite pad, the resultant colorless solution was
concentrated under vacuum at 50 °C to provide (2S,3R)-11b:
(2R,3R)-2-Ben zyl-3-a m in obu ta n oic Acid (8). To a stirred
solution of 7 (140 mg, 0.5 mmol) in methanol (5 mL) was added
10% palladium on carbon (Pd/C, 20 mg). The mixture was
stirred under hydrogen atmosphere overnight, filtered, and
evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, EtOAc/MeOH ) 1:1) to
give 8 (60 mg, 63%) as a white solid: mp 232-234 °C dec;
1
[R]D ) +9.3° (c ) 1.0, MeOH); IR (KBr) 3396, 1701 cm-1; H
NMR (CD3OD) δ 7.29-7.17 (m, 5H), 3.24 (dt, J ) 11.7, 6.6
Hz, 1H), 3.03 (dd, J ) 13.8, 6.8 Hz, 1H), 2.92 (dd, J ) 13.8,
6.8 Hz, 1H), 2.56 (dd, J ) 11.9, 6.8 Hz, 1H), 1.32 (d, J ) 6.7
Hz, 3H); 13C NMR (CD3OD) δ 182.8, 143.3, 133.8, 133.4, 132.0,
131.4, 56.6, 39.9, 22.3, 20.6; MS m/z (FAB) 194.07 (M + 1).
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found:
C, 68.14; H, 7.98; N, 7.08.
1
IR (film) 3400-2400 1720, 1624 cm-1; H NMR (D2O) δ 8.83
(br, 1H), 7.27-7.40 (m, 5H), 4.33 (d, J ) 3.5 Hz, 1H), 3.66 (s,
3H), 3.16 (dd, J ) 14, 9.0 Hz, 1H), 3.04 (m, 1H), 2.97 (dd, J )
14, 7.8 Hz, 1H); MS m/z (FAB) 238.12 (M - Cl-).
(2S,3R)-N-ter t-Bu tyloxycar bon yl-3-ben zylaspar tic Acid
Dim eth yl Ester ((2S,3R)-10b). To a stirred solution of
hexamethyldisilazane (HMDS, 36 mL, 169 mmol) in THF (300
mL) was added 10 M of n-butyllithium in hexane (10 M, 17
mL, 170 mmol) at 0 °C under nitrogen atmosphere, and the
mixture was stirred for 20 min and then cooled to -78 °C. A
solution of (S)-9 (20 g, 76.6 mmol) in THF (100 mL) was added
slowly to the mixture, and the reaction mixture was allowed
to stir for 2 h at the same temperature. After the addition of
benzyl bromide (11.0 mL, 91.9 mmol), the reaction mixture
was stirred for an additional 6 h and quenched by addition of
3 N HCl solution to pH ∼3. The aqueous layer was saturated
with sodium chloride and then extracted with EtOAc (200 mL
× 2). The combined organic layer was dried over MgSO4 and
evaporated under reduced pressure to give an oily residue.
Purification by column chromatography (silica gel, EtOAc/
The crude (2S,3R)-11b was dissolved in water (30 mL), and
sodium carbonate (7.3 g, 69 mmol) and benzyl chloroformate
(3.6 mL, 27 mmol) were added at 0 °C. The mixture was stirred
for 4 h at room temperature and then extracted with diethyl
ether. The aqueous layer was acidified to pH 2-3, washed with
ether several times, dried over MgSO4, and evaporated to give
(2S,3R)-12b (5.8 g, 68%). The oily product was used in the next
step without further purification: IR (film) 3600-2400 (br),
1723 cm-1 1H NMR (CDCl3) δ 8.84 (br, 1H), 7.42-7.15 (m,
;
10H), 5.95 (d, J ) 9.8 Hz, 1H), 5.19 (d, J ) 9.2 Hz, 2H), 4.52
(dd, J ) 9.8, 3.3 Hz, 1H), 3.67 (s, 3H), 3.48-3.43 (m, 1H), 3.16
(dd, J ) 13.8, 5.9 Hz, 1H), 2.82 (dd, J ) 13.8, 9.3 Hz, 1H); MS
m/z (FAB) 372.12 (M + 1).
(2R,3S)-N-Ben zyloxyca r b on yl-3-b en zyla sp a r t ic a cid
4-m eth yl ester ((2R,3S)-12b) was obtained as an oil in 67%
yield from (2R,3S)-10b following the procedure used for the
preparation of (2S,3R)-12b and used in the next step without
further purification.
hexane ) 1:10) gave (2S,3R)-10b (15 g, 56%) as an oil: [R]D
)
1
+32.2° (c ) 1.0, CHCl3); IR (film) 3429, 1723 cm-1; H NMR
(CDCl3) δ 7.19-7.35 (m, 5H), 5.58 (d, J ) 9.9 Hz, 1H), 4.47
(dd, J ) 9.8, 3.7 Hz, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 3.42-3.35
(m, 1H), 3.11 (dd, J ) 13.7, 6.7 Hz, 1H), 2.85 (dd, J ) 13.7,
8.3 Hz, 1H), 1.50 (s, 9H); 13C NMR (CDCl3) δ 173.8, 172.2,
156.1, 138.4, 129.4, 129.0, 127.2, 53.9, 52.9, 52.5, 49.1, 35.1,
28.7, 22.1; MS m/z (FAB) 352.13 (M + 1).
(2S,3R)-N-Ben zyloxyca r bon yl-3-m eth yla sp a r tic a cid
4-m eth yl ester ((2S,3R)-12a ) was obtained as an oil in 74%
yield from (2S,3R)-10a following the procedure used for the
preparation of (2S,3R)-12b and used in the next step without
further purification. (2S,3R)-11a : IR (film) 3400-2400, 1717,
1
1618 cm-1; H NMR (D2O) δ 4.27 (d, J ) 3.6 Hz, 1H), 3.72 (s,
(2R,3S)-N-ter t-Bu tyloxycar bon yl-3-ben zylaspar tic acid
d im eth yl ester ((2R,3S)-10b) was obtained as an oil in 61%
yield from (R)-9 following the procedure used for the prepara-
tion of (2S,3R)-10b: [R]D ) -31.5 ° (c ) 0.9, CHCl3).
(2S,3R)-N-ter t-Bu tyloxycar bon yl-3-m eth ylaspar tic Acid
Dim eth yl Ester ((2S,3R)-10a ). (2S,3R)-10a was prepared
from (S)-9 following the procedure used for the preparation of
(2S,3R)-10b. The product was found to be a 1:1 mixture of
(2S,3R)- and (2S,3S)-10a . The mixture was separated by
column chromatography (silica gel, EtOAc/hexane ) 1:15).
3H), 3.36 (dq, J ) 11, 3.8 Hz, 1H), 1.30 (d, J ) 7.3 Hz, 3H);
MS m/z (FAB) 162.12 (M - Cl-). (2S,3R)-12a : IR (film) 3500-
2500 (br), 1730 cm-1; 1H NMR (CDCl3) δ 9.12 (br, 1H), 7.43-
7.16 (m, 5H), 5.47 (d, J ) 9.4 Hz, 1H), 5.06 (d, J ) 3.8 Hz,
2H), 4.53 (dd, J ) 9.4, 3.7 Hz, 1H), 3.26 (dq, J ) 7.2, 3.7 Hz,
1H), 1.26 (d, J ) 7.3 Hz, 3H); MS m/z (FAB) 296.12 (M + 1).
(2S,3R)-N-Ben zyloxyca r bon yl-3-(m eth yloxyca r bon yl-
m eth yl)a sp a r tic a cid 4-m eth yl ester ((2S,3R)-12c) was
obtained as an oil in 56% yield from (2S,3R)-10c following the
procedure used for the preparation of (2S,3R)-12b and used
in the next step without further purification. (2S,3R)-11c: IR
(2S,3R)-10a (320 mg, 38%) was eluted first as an oil: [R]D
)
1
+15.5° (c ) 1.0, CHCl3); IR (film) 3436, 1720 cm-1; H NMR
(CDCl3) δ 5.44 (d, J ) 9.4 Hz, 1H), 4.53 (dd, J ) 9.6, 3.8 Hz,
1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.27-3.23 (m, 1H), 1.47 (s, 9H),
1.26 (d, J ) 7.4 Hz, 3H); 13C NMR (CDCl3) δ 174.6, 171.9,
1
(film) 3400-2400, 1726, 1619 cm-1; H NMR (D2O) δ 4.37 (d,
J ) 3.9 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.51 (m, 1H), 2.87
(d. J ) 6.7 Hz, 2H); MS m/z (FAB) 220.12 (M - Cl-). (2S,3R)-
12c: IR (film) 3500-2500 (br), 1731 cm-1; 1H NMR (CDCl3) δ

Synthesis of Optically Active 2-Alkyl-3,4-iminobutanoic Acids
J . Org. Chem., Vol. 66, No. 11, 2001 3701
9.04 (br, 1H), 7.42-7.27 (m, 5H), 5.30 (d, J ) 11.2 Hz, 1H),
5.11 (d, J ) 3.9 Hz, 2H), 4.80 (dd, J ) 9.0, 2.9 Hz, 1H), 3.67
(s, 3H), 3.66 (s, 3H), 3.65-3.48 (m, 1H), 2.83 (dd, J ) 17.2, 6.9
Hz, 1H), 2.69-2.60 (dd, J ) 17.3, 7.3 Hz, 1H); MS m/z (FAB)
354.12 (M + 1).
1.17 (d, J ) 7.3 Hz, 3H); 13C NMR (CDCl3) δ 174.5, 163.3,
136.1, 128.9, 128.7, 128.5, 68.6, 52.3, 42.3, 39.8, 30.2, 13.8; MS
m/z (FAB) 264.15 (M + 1).
(2R,3S)-3,4-(Ben zyloxyca r b on ylim in o)-2-(m et h yloxy-
ca r bon ylm eth yl)bu ta n oic a cid m eth yl ester ((2R,3S)-
14c) was obtained as an oil in 76% yield from (2R,3S)-13c
following the procedure used for the preparation of (2R,3S)-
(2R,3S)-2-Ben zyl-3-(b en zyloxyca r b on yla m in o)-4-h y-
d r oxybu ta n oic Acid Meth yl Ester ((2R,3S)-13b). To an ice-
chilled stirred solution of (2S,3R)-12b (10.4 g, 28 mmol) and
N-hydroxysuccinimide (3.4 g, 29.4 mmol) in DME (50 mL) was
added DCC (6.1 g, 29.4 mmol). The mixture was stirred
overnight and then filtered through a Celite pad, and the
filtrate was concentrated to give the active ester as a white
solid. To an ice-chilled stirred solution of the crude active ester
in THF (26 mL) was added NaBH4 (3.40 g, 90 mmol). After 18
h, the mixture was poured into an ice-chilled, vigorously stirred
solution of 1 M citric acid buffer (600 mL, pH 4). The resultant
mixture was extracted twice with ether, and the combined
extracts were washed with water and and brine, dried over
MgSO4, and concentrated to give an oil. Purification by column
chromatography (silica gel, EtOAc/hexane ) 1:1) gave (2R,3S)-
13b (7.3 g, 73%) as an oil: [R]D ) -69.0° (c ) 0.5, CHCl3); IR
(film) 3304, 1712 cm-1; 1H NMR (CDCl3) δ 7.36-7.10 (m, 10H),
5.51 (d, J ) 9.0 Hz, 1H), 5.11 (d, J ) 7.8 Hz, 2H), 3.88 (m,
1H), 3.67-3.39 (m, 2H), 3.56 (s, 3H), 2.94 (m, 2H), 2.75(m,
1H); MS m/z (FAB) 358.15 (M + 1).
1
14b: [R]D ) +11.6° (c ) 1.0, CHCl3); IR (film) 1729 cm-1; H
NMR (CDCl3) δ 7.35-7.24 (m, 5H), 5.04 (s, 2H), 3.68 (s, 3H),
3.65 (s, 3H), 2.83 (m, 1H), 2.70 (m, 1H), 2.63 (m, 1H), 2.46 (m,
1H), 2.35 (d, J ) 6.1 Hz, 1H), 2.09 (d, J ) 3.6 Hz, 1H); 13C
NMR (CDCl3) δ 175.0, 172.6, 163.1, 135.6, 129.6, 128.5, 128.3,
68.7, 53.2, 50.8, 43.3, 39.4, 31.4, 27.9; MS m/z (FAB) 322.13
(M + 1).
(2R,3S)-2-Ben zyl-3,4-im in obu ta n oic Acid Meth yl Ester
((2R,3S)-15b). To a stirred solution of (2R,3S)-14b (2.8 g, 8.25
mmol) in methanol (60 mL) was added 10% Pd/C (200 mg).
Under hydrogen atmosphere the mixture was stirred for 2 h
and then filtered through a Celite pad, and the filtrate was
evaporated to give (2R,3S)-15b (1.6 g, 95%) as an oil: [R]D
)
1
-3.54° (c ) 0.5, CHCl3); IR (film) 3341, 1731 cm-1; H NMR
(CDCl3) δ 7.32-7.17 (m, 5H), 3.68 (s, 3H), 3.09 (dd, J ) 13.7,
7.3 Hz, 1H), 2.95 (dd, J ) 13.7, 6.6 Hz, 1H), 2.30-2.19 (m,
2H), 1.80 (d, J ) 5.3 Hz, 1H), 1.22 (d, J ) 2.8 Hz, 1H), 1.19
(m, 1H); MS m/z (FAB) 206.11 (M + 1).
(2S,3R)-2-Ben zyl-3-(b en zyloxyca r b on yla m in o)-4-h y-
d r oxybu ta n oic a cid m eth yl ester ((2S,3R)-13b) was ob-
tained as an oil in 75% yield from (2R,3S)-12b following the
(2S,3R)-2-Ben zyl-3,4-im in obu ta n oic a cid m eth yl ester
((2S,3R)-15b) was obtained in 97% yield from (2S,3R)-14b
following the procedure used for the preparation of (2R,3S)-
15b: [R]D ) +3.57° (c ) 0.5, CHCl3).
procedure used for the preparation of (2R,3S)-13b: [R]D
+67.2° (c ) 1.0, CHCl3).
)
(2R,3S)-2-Meth yl-3,4-im in obu ta n oic a cid m eth yl ester
((2R,3S)-15a ) was obtained in 94% yield from (2R,3S)-14a
following the procedure used for the preparation of (2R,3S)-
(2R,3S)-3-(Ben zyloxyca r bon yla m in o)-4-h yd r oxy-2-m e-
th ylbu ta n oic a cid m eth yl ester ((2R,3S)-13a ) was obtained
as an oil in 69% yield from (2S,3R)-12a following the procedure
used for the preparation of (2R,3S)-13b: [R]D ) +31.4° (c )
15b: [R]D ) -5.61° (c ) 0.6, CHCl3); IR (film) 3339, 1730 cm-1
;
1H NMR (CDCl3) δ 3.73 (s, 3H), 2.27-2.21 (m, 1H), 2.07-1.96
(m, 1H), 1.86 (d, J ) 5.9 Hz, 1H), 1.40 (d, J ) 3.5 Hz, 1H),
1.24 (d, J ) 7.2 Hz, 3H), 1.13 (dd, J ) 15.7, 7.1 Hz, 1H); MS
m/z (FAB) 130.12 (M + 1).
1
1.0, CHCl3); IR (thin film) 3329, 1715 cm-1; H NMR (CDCl3)
δ 7.46-7.25 (m, 5H), 5.41 (d, J ) 9.3 Hz, 1H), 5.07 (d, J ) 2.5
Hz, 2H), 3.75 (m, 1H), 3.70 (s, 3H), 3.64 (dd, J ) 11, 5.5 Hz,
1H), 3.60 (dd, J ) 11, 5.5 Hz, 1H), 2.86 (dq, J ) 6.4, 5.5 Hz,
1H), 1.22 (d, J ) 6.5 Hz, 3H); MS m/z (FAB) 282.12 (M + 1).
(2R,3S)-3-(Ben zyloxyca r bon yla m in o)-4-h ydr oxy-2-(m e-
t h yloxyca r b on ylm et h yl)b u t a n oic a cid m et h yl est er
((2R,3S)-13c) was obtained as an oil in 64% yield from
(2S,3R)-12c following the procedure used for the preparation
of (2R,3S)-13b: [R]D ) +42.7° (c ) 1.0, CHCl3); IR (film) 3331,
1721 cm-1; 1H NMR (CDCl3) δ 7.37-7.21 (m, 5H), 5.38 (d, J )
9.5 Hz, 1H), 5.02 (d, J ) 2.2 Hz, 2H), 3.81 (m, 1H), 3.73 (s,
3H), 3.67 (s, 3H), 3.59 (m, 1H), 3.54 (m, 1H), 2.77 (m, 2H),
2.64 (m, 1H); MS m/z (FAB) 340.14 (M + 1).
(2R,3S)-2-Ben zyl-3,4-(ben zyloxycar bon ylim in o)-bu tan o-
ic Acid Meth yl Ester ((2R,3S)-14b). To a stirred solution of
(2R,3S)-13b (3.84 g, 10.8 mmol) in dry THF (20 mL) was added
triphenylphosphine (5.64 g, 21.5 mmol). After the mixture was
cooled in an ice bath, DEAD (3.4 mL, 21.5 mmol) was added
dropwise over 20 min. The mixture was stirred for 3 h at 0 °C
and then concentrated to give an oil. Purification by column
chromatography (silica gel, EtOAc/hexane ) 1:4) gave (2R,3S)-
14b (3.0 g, 82%) as an oil: [R]D ) +14.7° (c ) 0.8, CHCl3); IR
(film) 1729, 1604 cm-1; 1H NMR (CDCl3) δ 7.35-7.12 (m, 10H),
5.08 (s, 2H), 3.57 (s, 3H), 3.04 (dd, J ) 13.7, 7.7 Hz, 1H), 2.88
(dd, J ) 13.7, 7.7 Hz, 1H), 2.74-2.68 (m, 1H), 2.44 (q, 1H),
2.28 (d, J ) 6.8 Hz, 1H), 1.80 (d, J ) 3.7 Hz, 1H); 13C NMR
(CDCl3) δ 173.4, 163.1, 138.4, 136.0, 129.3, 128.9, 128.8, 128.7,
128.5, 127.1, 68.7, 52.3, 50.6, 39.0, 36.1, 31.3; MS m/z (FAB)
340.17 (M + 1).
(2S,3R)-2-Ben zyl-3,4-(ben zyloxycar bon ylim in o)bu tan o-
ic a cid m eth yl ester ((2S,3R)-14b) was obtained as an oil
in 79% yield from (2S,3R)-13b following the procedure used
for the preparation of (2R,3S)-14b: [R]D ) -14.6° (c ) 0.7,
CHCl3).
(2R,3S)-3,4-(Ben zyloxycar bon ylim in o)-2-m eth ylbu tan o-
ic a cid m eth yl ester ((2R,3S)-14a ) was obtained as an oil
in 83% yield from (2R,3S)-13a following the procedure used
for the preparation of (2R,3S)-14b: [R]D ) +15.0° (c ) 1.0,
CHCl3); IR (film) 1730 cm-1; 1H NMR (CDCl3) δ 7.34-7.31 (m,
5H), 5.10 (s, 2H), 3.62 (s, 3H), 2.73-2.68 (m, 1H), 2.41-2.35
(m, 1H), 2.37 (d, J ) 6.2 Hz, 1H), 2.06 (d, J ) 3.8 Hz, 1H),
(2R,3S)-2-Meth yloxyca r bon ylm eth yl-3,4-im in obu ta n o-
ic a cid m eth yl ester ((2R,3S)-15c) was obtained in 85% yield
from (2R,3S)-14c following the procedure used for the prepa-
ration of (2R,3S)-15b: [R]D ) -4.76° (c ) 1.0, CHCl3); IR (film)
1
3340, 1735, 1730 cm-1; H NMR (CDCl3) δ 3.71 (s, 3H), 3.69
(s, 3H), 2.85 (m, 1H), 2.72 (m, 1H), 2.42 (m, 1H), 2.23 (m, 1H),
1.84 (d, J ) 5.4 Hz, 1H), 1.46 (d, J ) 3.4 Hz, 1H), 1.15 (m,
1H); MS m/z (FAB) 188.09 (M + 1).
(2R,3S)-2-Ben zyl-3,4-im in obu ta n oic Acid ((2R,3S)-1b).
To an ice-chilled stirred solution of (2R,3S)-15b (1.2 g, 5.85
mmol) in methanol (20 mL) and water (10 mL) was added
dropwise 1 N LiOH in water (6 mL), and the mixture was
stirred at the same temperature for 4 h and then evaporated
to give (2R,3S)-1b as a lithium salt (1.02 g, 85%). The lithium
salt was converted to the corresponding free acid by carefully
neutralizing its aqueous solution with a small amount of acetic
acid followed by addition of ethanol and ether: mp 237-239
°C dec; [R]D ) +5.9° (c ) 1.0, MeOH); IR (KBr) 3330-2300
1
(br), 1698 cm-1; H NMR (CD3OD) δ 7.31-7.13 (m, 5H), 2.87
(m, 2H), 2.09 (m, 1H), 1.89 (dd, J ) 15.6, 7.6 Hz, 1H), 1.65 (d,
J ) 5.9 Hz, 1H), 1.13 (d, J ) 3.4 Hz, 1H); 13C NMR (CD3OD)
δ 182, 140.6, 129.2, 128.2, 126.0, 54.6, 38.1, 32.4, 24.1; MS
m/z (FAB) 192.13 (M + 1). Anal. Calcd for C11H13NO2: C, 69.09;
H, 6.85; N, 7.32. Found: C, 68.85; H, 7.01; N, 7.12.
(2S,3R)-2-Ben zyl-3,4-im in obu ta n oic a cid ((2S,3R)-1b)
was obtained (80% yield as a lithium salt) from (2S,3R)-15b
following the procedure used for the preparation of (2R,3S)-
1b: [R]D ) -5.8° (c ) 1.0, MeOH).
(2R,3S)-2-Meth yl-3,4-im in obu ta n oic a cid ((2R,3S)-1a )
was obtained (83% yield as a lithium salt) from (2R,3S)-15a
following the procedure used for the preparation of (2R,3S)-
1b: mp 223-225 °C dec; [R]D ) +7.62 ° (c ) 0.5, CHCl3); IR
(KBr) 3356 (br), 1691 cm-1; 1H NMR (CD3OD) δ 2.27-2.21 (m,
1H), 2.07-1.96 (m, 1H), 1.76 (d, J ) 6.5 Hz, 1H), 1.30 (d, J )
6.0 Hz, 1H), 1.10 (d, J ) 7.1 Hz, 3H); MS m/z (FAB) 116.15
(M + 1). Anal. Calcd for C5H9NO2: C, 52.16; H, 7.88; N, 12.17.
Found: C, 52.04; H, 7.67; N, 12.05.
(2R,3S)-2-H yd r oxyca r b on ylm et h yl-3,4-im in ob u t a n o-
ic a cid ((2R,3S)-1c) was obtained (85% yield as a lithium salt)

3702 J . Org. Chem., Vol. 66, No. 11, 2001
Park et al.
from (2R,3S)-15c following the procedure used for the prepa-
ration of (2R,3S)-1b: mp 200-202 °C dec; [R]D ) +5.70° (c )
0.4, CHCl3); IR (KBr) 3238 (br), 1695 cm-1; 1H NMR (CD3OD)
δ 2.57 (m, 1H), 2.39 (m, 1H), 2.24 (m, 1H), 1.99 (m, 1H), 1.84
(d, J ) 5.7 Hz, 1H), 1.30 (d, J ) 3.3 Hz, 1H); MS m/z (FAB)
160.09 (M + 1). Anal. Calcd for C6H9NO4: C, 45.28; H, 5.70;
N, 8.80. Found: C, 45.01; H, 5.86; N, 8.52.
(CDCl3) δ 174.5, 148.9, 144.4, 141.5, 140.8, 128.9, 128.3, 127.7,
126.7, 126.2, 120.3, 81.8, 73.3, 68.3, 61.8, 40.3, 28.3, 14.7; MS
m/z (FAB) 430.3 (M + 1). The spectral data of this compound
were identical with those of reference compound prepared by
the literature method.13
(3S,4S)-3-Ben zyl-4-(N-ben zyloxyca r bon yla m in o)-bu ty-
r ola cton e ((3S,4S)-20). Ice-chilled stirred solution of LDA (50
mmol) and HMPA (40 mL) in THF (40 mL) was further cooled
to -78 °C. To the resulting mixture was added dropwise a
solution of (S)-19 (4.1 g, 20.4 mmol) in THF (50 mL). The
mixture was stirred for 2 h at -78 °C, and then was added
benzyl bromide (5.1 g, 30 mmol) over 30 min. The resulting
mixture was stirred for 3 h and acidified with 10% aqueous
citric acid to pH 3, and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (100 mL × 3).
The combined organic layer was washed with 10% aqueous
citric acid (100 mL × 3), brine (100 mL), dried over Na2SO4,
and concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, EtOAc/hexane
) 1:10 to 1:4) gave (3S,4S)-20 (4.33 g, 73%) as a white solid
which was recrystallized from ether/hexane: mp 89-90 °C;
[R]D ) -20.3° (c ) 0.62, CHCl3); IR (CHCl3) 3369, 1773, 1682
cm-1; 1H NMR (CDCl3) δ 7.32-7.19 (m, 10H), 5.13 (d, J ) 4.8
Hz, 1H), 5.02 (s, 2H), 4.24 (m, 2H), 3.90 (m, 1H), 3.19 (dd, J )
13.8, 4.5 Hz, 1H), 2.94 (dd, J ) 13.9, 7.4 Hz, 1H), 2.83 (dd, J
) 11.7, 6.5 Hz, 1H); 13C NMR (CDCl3) δ 176.7, 156.0, 137.3,
136.3, 129.6, 129.2, 129.0, 128.8, 128.6, 127.5, 71.1, 67.5, 52.5,
47.1, 34.7; MS (FAB) m/z 326.11 (M + 1). Anal. Calcd for
(3R,4S)-3-Met h yl-4-N-(b en zyloxyca r b on yla m in o)b u -
tyr ola cton e ((3R,4S)-16). To a stirred solution of 13a (300
mg, 1.0 mmol) in CH2Cl2 (20 mL) was added p-toluenesulfonic
acid monohydrate (100 mg, 0.5 mmol). The reaction mixture
was stirred for 2 h and then washed with saturated aqueous
NaHCO3 solution and with brine. The organic layer was dried
over MgSO4 and evaporated to give (3R,4S)-16 (252 mg, 95%)
as a white solid that was recrystallized from EtOAc-ether:
mp 116-118 °C; [R]D ) -57.2° (c ) 0.9, CHCl3); IR (film) 3331,
1
1756, 1684 cm-1; H NMR (CDCl3) δ 7.17-7.40 (m, 5H), 5.95
(d, J ) 8.5 Hz, 1H) 5.04 (s, 2H), 4.49 (m, 1H), 4.27 (dd, J ) 10,
8.5 Hz, 1H), 4.10 (m, H), 2.65 (m, 1H), 1.11 (d, J ) 7.3 Hz,
3H); 13C NMR (CDCl3) δ 178.2, 136.4, 128.9, 128.6, 126.3, 72.6,
67.7, 52.1, 38.5, 9.3; MS m/z (FAB) 250.16 (M + 1).
(2S,3R)-N-(9-P h en ylflu or en -9-yl)-3-m eth yl-aspar tic Acid
1-ter t-Bu tyl 4-Meth yl Diester ((2S,3R)-17). To a solution
of (2S,3R)-11a (0.9 g, 4.5 mmol) in dry EtOH (5 mL) was added
propylene oxide (1 mL), and then the solution was refluxed
for 6 h to liberate the free amino acid. The mixture was cooled,
and the precipitate was filtered and dried. The white solid was
suspended in dry CHCl3 (10 mL), and TMSCl (1.2 mL, 9.2
mmol) was added. After 2 h, triethylamine (2.7 mL, 9.2 mmol)
was added and the mixture stirred for 20 min. Pb(NO3)2 (1.0
g, 6 mmol) and 9-bromo-9-phenylfluorene (3.9 g, 12 mmol) in
dry CHCl3 (10 mL) were added separately. The mixture was
stirred for 3 days, and MeOH (4 mL) was added. After 20 min,
the reaction mixture was filtered and concentrated under
reduced pressure. The residue was dissolved in 10% aqueous
citric acid (30 mL) and extracted with ether (40 mL × 3). The
extract was washed with brine (30 mL), dried, and concen-
trated to 5 mL. The concentrated solution was chilled in an
ice bath, and the precipitate was filtered and washed with
diethyl ether (10 mL). Concentration of the filtrate yielded a
second crop to give 2.1 g of the product in total (67%): 1H NMR
(CDCl3) δ 7.70 (m, 2H), 7.19-7.44 (m, 11H), 3.65 (s, 3H), 3.21
(m, 1H), 2.96 (m, 1H), 2.47 (m, 1H), 1.09 (d, J ) 7.3 Hz, 3H).
The pale yellow solid (2.0 g, 5 mmol) was dissolved in CH2-
Cl2 (60 mL), and O-tert-butyl-N,N’-diisopropylisourea (3.0 g,
15 mmol) in CH2Cl2 (15 mL) was added at room temperature.
After the mixture was stirred for 2 days, water (10 mL) was
added, and the stirring was kept for 1 h. The reaction mixture
was filtered, and the filtrate was washed with saturated
aqueous NaHCO3 solution (10 mL) and with water (10 mL),
dried over MgSO4, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica
gel, EtOAc/hexane ) 1:10) gave (2S,3R)-17 (3.5 g, 73%): IR
(film) 3314, 1729 cm-1; 1H NMR (CDCl3) δ 7.66 (m, 2H), 7.17-
7.40 (m, 11H), 3.60 (s, 3H), 3.18 (m, 1H), 2.92 (m, 1H), 2.4 (m,
1H), 1.15 (s, 9H), 1.03 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3)
δ 174.4, 173.1, 149.5, 145.5, 141.5, 128.6, 128.5, 128.1, 127.5,
126.5, 126.3, 120.2, 81.7, 73.2, 58.9, 51.9, 45.5, 28.3, 12.8.
C
19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 69.87; H,
5.94; N, 4.08.
(3R,4R)-3-Ben zyl-4-N-ben zyloxyca r bon yla m in obu tyr o-
la cton e ((3R,4R)-20) was obtained from (R)-19 following the
procedure used for the preparation of (3S,4S)-20: [R]D
+21.0° (c ) 0.5, CHCl3).
)
(2S,3S)-N-Met h oxy-N-m et h yl-2-b en zyl-3-(b en zyloxy-
ca r bon yla m in o)-4-h yd r oxyb u t a n a m id e ((2S,3S)-21). To
an ice-chilled slurry of N,O-dimethylhydroxylamine hydro-
chloride (2.0 g, 20 mmol) in CH2Cl2 (20 mL) was added
dropwise 2 M trimethylaluminum in hexane (20 mL) over 20
min, and the resultant solution was stirred for 30 min. A
solution of (3S,4S)-20 (6.5 g, 20 mmol) in dry CH2Cl2 (20 mL)
was then added to the reaction mixture over 15 min. After
being stirred for 1 h at room temperature, the solution was
cooled to 0 ˚C, and then an ice-chilled 1 N HCl solution (100
mL) was slowly added. The resulting mixture was extracted
twice with EtOAc, and the combined organic layer was washed
once each with water and brine, dried over MgSO4, and
concentrated under reduced pressure to give a clear oil.
Purification by column chromatography (silica gel, EtOAc/
hexane ) 1:2) gave (2S,3S)-21 (6.7 g, 87%) as a white solid
that was recrystallized from EtOAc/hexane: mp 144-146 °C;
[R]D ) +9.69° (c ) 0.5, CHCl3); IR (film) 3304, 1704, 1620 cm-1
;
1H NMR (CDCl3) δ 7.35-7.16 (m, 10H), 5.70 (d, J ) 6.6 Hz,
1H), 5.11 (dd, J ) 33.3, 12.3 Hz, 2H), 4.17 (d, J ) 12.2 Hz,
1H), 3.81 (br, 1H), 3.85-3.76 (m, 1H), 3.63 (dd, J ) 12.1, 3.6
Hz, 1H), 3.13-2.98 (m, 2H), 2.85-2.78 (m, 1H), 2.77 (s, 3H),
2.34 (s, 3H); 13C NMR (CDCl3) δ 175.1, 156.5, 138.9, 137.0,
129.1, 128.9, 128.8, 128.5, 127.1, 126.3, 67.1, 60.8, 53.8, 46.1,
38.0, 37.3, 36.4; MS m/z (FAB) 369.25 (M - OH). Anal. Calcd
for C21H26N2O5: C, 65.27; H, 6.78; N, 7.25. Found: C, 64.99;
H, 6.84; N, 7.03.
(2S,3R)-2-[(9-P h en ylflu or en -9-yl)a m in o]-3-m et h yl-4-
h yd r oxyb u t a n oic Acid ter t-Bu t yl Εst er ((2S,3R)-18).
(2S,3R)-17 (411 mg, 0.9 mmol) was dissolved in dry THF (20
mL) and cooled to -30 °C. To the resulting mixture was added
1.0 M DIBAL in THF (2.8 mL, 2.8 mmol) and the mixture
stirred for 6 h. Acetone (130 µL) was added to the reaction
mixture and the mixture stirred for 10 min. Finally, MeOH
(810 µL) was added, and the resulting mixture was warmed
to room temperature. The mixture was diluted with ether (30
mL) and washed with 1 M K3PO4 solution (30 mL) and then
with brine. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, EtOAc/hexane
) 1:4) gave (2S,3S)-18 (300 mg, 80%): [R]D ) -217° (c ) 1.2,
(2R,3R)-N-Met h oxy-N-m et h yl-2-b en zyl-3-(b en zyloxy-
ca r bon yla m in o)-4-h yd r oxybu ta n a m id e ((2R,3R)-21) was
obtained from (3R,4R)-20 following the procedure used for the
preparation of (2S,3S)-21: [R]D ) -9.73° (c ) 0.5, CHCl3).
(2S,3S)-N-Meth oxy-N-m eth yl-2-ben zyl-3,4-(ben zyloxy-
ca r bon ylim in o)-bu ta n a m id e ((2S,3S)-22). To a stirred
solution of (2S,3S)-21 (4.28 g, 11.5 mmol) in dry THF (30 mL)
was added triphenylphosphine (6.03 g, 23.0 mmol). After the
mixture was cooled in an ice bath, DEAD (3.6 mL, 23 mmol)
was added dropwise over 20 min. The mixture was stirred for
3 h at 0 °C and then concentrated to give an oil. Purification
by column chromatography (silica gel, EtOAc/hexane ) 1:4)
gave (2S,3S)-22 (3.6 g, 86%) as a colorless oil: [R]D ) +31.1°
1
CHCl3); IR (film) 3440, 1720 cm-1; H NMR (CDCl3) δ 7.68-
7.70 (m, 2H), 7.17-7.35 (m, 11H), 3.54 (dd, J ) 11, 3.4 Hz,
1H), 3.40 (dd, J ) 11, 8.4 Hz, 1H), 2.44 (d, J ) 7.8 Hz, 1H),
1.85 (m, 1H), 1.15 (s, 9H), 0.64 (d, J ) 0.7.0 Hz, 3H); 13C NMR
1
(c ) 0.7, CHCl3); IR (film) 3455, 1633 cm-1; H NMR (CDCl3)
δ 7.38-7.18 (m, 10H), 5.17 (s, 2H), 3.16 (d, J ) 6.9 Hz, 2H),

Synthesis of Optically Active 2-Alkyl-3,4-iminobutanoic Acids
J . Org. Chem., Vol. 66, No. 11, 2001 3703
2.90-2.78 (m, 2H), 2.83 (s, 3H), 2.50 (s, 3H), 2.42 (d, J ) 5.9
Hz, 1H), 2.14 (d, J ) 3.4 Hz, 1H); MS m/z (FAB) 368.14 (M+).
(2R,3R)-N-Meth oxy-N-m eth yl-2-ben zyl-3,4-(ben zyloxy-
car bon ylim in o)bu tan am ide ((2R,3R)-22) was obtained from
(2R,3R)-21 following the procedure used for the preparation
of (2S,3S)-22: [R]D ) -30.6° (c ) 0.7, CHCl3).
(2S,3S)-N-Meth oxy-N-m eth yl-2-ben zyl-3,4-(tr ip h en yl-
m eth ylim in o)bu ta n a m id e ((2S,3S)-24). To a stirred solu-
tion of (2S,3S)-22 (3.1 g, 8.4 mmol) in methanol (70 mL) was
added 10% Pd/C (100 mg). Under hydrogen atmosphere the
mixture was stirred for 2 h, filtered through a Celite pad, and
the filtrate was concentrated to give (2S,3S)-23: IR (film) 3304,
1634 cm-1; 1H NMR (CDCl3) δ 7.28-7.17 (m, 5H), 3.11 (d, J )
7.9 Hz, 1H), 2.84 (m, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 2.51-2.42
(m, 2H), 1.90 (d, J ) 5.7 Hz, 1H), 1.42 (d, J ) 2.9 Hz, 1H),
1.09 (m, 1H); MS m/z (FAB) 235.27 (M + 1).
pressure to remove the excess TFA. The residue was diluted
with ether (10 mL) and washed with water, and then the
aqueous layer was basified by sodium carbonate to pH ∼10
and extracted with ether several times. The combined extracts
were dried over MgSO4 and evaporated to give a colorless oil:
1H NMR (CDCl3) δ 7.14-7.31 (m, 5H), 3.36-3.51 (m, 2H), 3.27
(br, 2H), 2.59-2.67 (m, 2H), 2.07-2.12 (m, 1H), 1.94-2.01 (m,
1H), 1.80 (d, J ) 6.1 Hz, 1H), 1.65 (d, J ) 3.7 Hz, 1H); 13C
NMR (CDCl3) δ 140.1, 129.5, 128.8, 126.5, 63.4, 43.7, 36.7, 32.7,
22.5.
The oily product was dissolved in a mixture of aqueous
sodium carbonate solution (2 M, 4 mL) and THF (1 mL), and
to this solution was added 9-fluorenylmethyl chloroformate
(270 mg, 1.0 mmol). The mixture was stirred at 0 °C for 3 h,
after which time it was diluted with EtOAc. The organic layer
was washed with water, dried over MgSO4, and evaporated to
give an oil. Purification by column chromatography (EtOAc/
hexane ) 1:2) gave product (2S,3S)-27 (160 mg, 80%) as an
oil: [R]D ) -28.3° (c ) 0.7, CHCl3); IR (film) 3347 (br), 1636
cm-1; 1H NMR (CDCl3) δ 7.78 (d, J ) 7.4 Hz, 2H), 7.63 (d, J )
7.4 Hz, 2H), 7.40-7.45 (t, 2H), 7.24-7.37 (m, 5H), 7.12-7.22
(m, 2H), 4.49-4.58 (m, 2H), 4.27 (t, J ) 6.3 Hz, 1H), 3.47-
3.56 (m, 2H), 2.75 (dd, J ) 5.6, 13.9 Hz, 1H), 2.57 (dd, J )
9.1, 13.9 Hz, 1H), 2.37-2.43 (m, 1H), 2.30 (d, J ) 6.3 Hz, 1H),
To an ice-chilled stirred solution of (2S,3S)-23 (1.04 g, 4.44
mmol) in chloroform (10 mL) were added triethylamine (700
µL, 5.0 mmol) and triphenylmethyl chloride (1.3 g, 4.4 mmol)
in chloroform (5 mL). The mixture was stirred at 4 °C
overnight and then diluted with chloroform and washed with
water and with brine. The organic layer was dried over MgSO4
and evaporated under reduced pressure to give a resin.
Purification by column chromatography (silica gel, EtOAc/
hexane ) 1:5) gave (2S,3S)-24 (1.5 g, 73%) as a white solid,
which was recrystallized form ether/petroleum ether: mp 182-
183 °C; [R]D ) +95.1° (c ) 1.0, CHCl3); IR (film) 3027, 1640
2.22 (d, J ) 3.8 Hz, 1H), 2.11 (br, 1H), 1.89-1.99 (m, 1H); 13
C
NMR (CDCl3) δ 164.0, 143.9, 141.8, 139.8, 129.4, 128.9, 128.3,
127.6, 126.3, 125.4, 120.4, 68.4, 63.2, 47.5, 43.7, 40.6, 34.8, 30.6;
MS m/z (FAB) 400.12 (M + 1).
cm-1 1H NMR (CDCl3) δ 7.55-7.51 (m, 5H), 7.29-7.12 (m,
;
15H), 3.04-2.81 (m, 3H), 2.76 (s, 3H), 2.49 (s, 3H), 1.73 (d, J
) 3.0 Hz, 1H), 1.60-1.55 (m, 1H), 1.16 (d, J ) 6.3 Hz, 1H);
13C NMR (CDCl3) δ 174.1, 144.9, 140.3, 130.0, 129.3, 128.7,
127.9, 127.1, 126.7, 74.6, 48.2, 39.5, 37.6, 37.1, 35.7, 26.4; MS
m/z (FAB) 461.20 (M - CH3). Anal. Calcd for C32H32N2O2: C,
80.64; H, 6.77; N, 5.88. Found: C, 80.62; H, 6.58; N, 5.79.
(2R,3R)-N-Meth oxy-N-m eth yl-2-ben zyl-3,4-(tr ip h en yl-
m eth ylim in o)bu ta n a m id e ((2R,3R)-24) was obtained from
(2R,3R)-22 following the procedure used for the preparation
of (2S,3S)-24: [R]D ) -95.9° (c ) 1.0, CHCl3).
(2R,3R)-2-Ben zyl-3,4-(flu or en ylm eth yloxyca r bon ylim i-
n o)bu ta n -1-ol ((2R,3R)-27) was obtained from (2R,3R)-26
following the procedure used for the preparation of (2S,3S)-
27: [R]D ) +27.9° (c ) 0.6, CHCl3).
(2S,3S)-2-Ben zyl-3,4-(flu or en ylm eth yloxyca r bon ylim i-
n o)bu ta n oic Acid ((2S,3S)-28). To a mixture of (2S,3S)-27
(200 mg, 0.64 mmol) and sodium periodate (560 mg, 2.6 mmol)
in acetonitrile (1.5 mL), carbon tetrachloride (1.5 mL), and
water (2 mL) was added ruthenium chloride hydrate (10 mg,
0.05 mmol) at room temperature. The resulting mixture was
stirred overnight and extracted with EtOAc. The combined
extracts were washed with water, dried over MgSO4, and
evaporated to give a resinous residue that was purified by
column chromatography (EtOAc/hexane ) 2:1) to give (2S,3S)-
28 in a resinous form (175 mg, 65%): [R]D ) -32.4° (c ) 0.5,
CHCl3); IR (film) 3402 (br), 1694, 1635 cm-1; 1H NMR (CDCl3)
δ 7.78 (d, J ) 7.4 Hz, 2H), 7.60 (t, J ) 7.5 Hz, 2H), 7.42-7.17
(m, 9H), 4.55 (d, J ) 6.8 Hz, 2H), 4.28 (t, J ) 6.6 Hz, 1H),
3.08 (dd, J ) 14.2, 7.3 Hz, 1H), 2.89 (dd, J ) 13.8, 7.5 Hz,
1H), 2.64 (m, 1H), 2.50 (dd, J ) 15.3, 7.5 Hz, 1H), 2.22 (d, J )
6.1 Hz, 1H), 1.81 (d, J ) 3.6 Hz, 1H); MS m/z (FAB) 414.17
(M + 1). Anal. Calcd for C26H23NO4: C, 75.53; H, 5.61; N, 3.39.
Found: C, 75.26; H, 5.52; N, 3.13.
(2S,3S)-2-Ben zyl-3,4-(t r ip h en ylm et h ylim in o)b u t a n -1-
ol ((2S,3S)-26). A solution of (2S,3S)-24 (1.0 g, 2.1 mmol) in
THF (30 mL) was cooled to -78 °C, and to this solution was
added lithium aluminum hydride (80 mg, 2.1 mmol). The
mixture was stirred at -78 °C for 4 h, and water (10 drops)
was added to decompose the residual hydride. The mixture
was dried over MgSO4 and evaporated under reduced pressure
to give (2S,3S)-25 as a resin: 1H NMR (CDCl3) δ 9.79 (s, 1H),
7.46-7.50 (m, 5H), 7.18-7.30 (m, 15H), 3.02-3.15 (m, 1H),
2.85-3.05 (m, 2H), 1.86 (d, J ) 3.1 Hz, 1H), 1.42-1.47 (m,
1H), 1.14 (d, J ) 6.2 Hz, 1H).
The resultant resinous product was dissolved in ether (20
mL) and to this solution was added lithium aluminum hydride
(60 mg, 1.5 mmol) at 0 °C. The mixture was stirred at the same
temperature for 3 h, after which time 6 drops of water was
added. The mixture was dried over MgSO4 and evaporated
under reduced pressure to give a resin. Purification by column
chromatography (silica gel, EtOAc/hexane ) 1:3) gave the
desired product (2S,3S)-26 (630 mg, 72%) as a solid which was
(2R,3R)-2-Ben zyl-3,4-(flu or en ylm eth yloxyca r bon ylim i-
n o)bu ta n oic a cid ((2R,3R)-28) was obtained from (2R,3R)-
27 following the procedure used for the preparation of (2S,3S)-
28: [R]D ) +33.1° (c ) 0.5, CHCl3).
(2S,3S)-2-Ben zyl-3,4-im in obu ta n oic Acid ((2S,3S)-1b).
To a solution of (2S,3S)-28 (300 mg, 0.73 mmol) in DMF (1
mL) was added piperidine (100 µL). The mixture was stirred
for 20 min, diluted with water, and washed with ether. The
aqueous layer was concentrated under vacuum to give (2S,3S)-
1b as a solid (83 mg, 57%) that was recrystallized from EtOH-
H2O (0.1% AcOH): mp 209-211 °C dec; [R]D ) -4.71° (c )
recrystallized from EtOAc/hexane: mp 51-53 °C; [R]D
)
-66.1° (c ) 0.6, CHCl3); IR (film) 3335, 1597 cm-1; H NMR
(CDCl3) δ 7.39 (dd, J ) 8.3, 1.7 Hz, 5H), 7.28-7.17 (m, 13H),
7.01 (dd, J ) 8.3, 1.7 Hz, 2H), 3.62-3.54 (m, 2H), 2.63 (m,
1H), 2.49-2.31 (m, 2H), 2.08 (d, J ) 3.5 Hz, 1H), 1.62-1.59
(m, 1H), 1.09 (d, J ) 6.3 Hz, 1H); 13C NMR (CDCl3) δ 144.1,
139.7, 129.9, 129.2, 128.7, 128.0, 127.3, 126.5, 75.5, 65.1, 39.4,
37.3, 36.9, 23.0; MS m/z (FAB) 420.15 (M + 1). Anal. Calcd
for C30H29NO: C, 85.88; H, 6.97; N, 3.34. Found: C, 85.74; H,
3.25; N, 3.76.
1
1
0.5, MeOH); IR (film) 3305 (br), 1697 cm-1; H NMR (D2O) δ
7.31-7.13 (m, 5H), 2.87 (m, 2H), 2.09 (m, 1H), 2.00 (m, 1H),
1.75 (d, J ) 5.7 Hz, 1H), 1.24 (d, J ) 3.4 Hz, 1H); MS m/z
(FAB) 192.13 (M + 1). Anal. Calcd for C11H13NO2: C, 69.09;
H, 6.85; N, 7.32. Found: C, 68.87; H, 7.03; N, 7.21.
(2R,3R)-2-Ben zyl-3,4-im in obu ta n oic Acid ((2R,3R)-1b)
was prepared from (2R,3R)-28 by the same method as the
preparation of (2S,3S)-1b: [R]D ) +4.65° (c ) 0.5, CHCl3).
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found:
C, 68.92; H, 6.91; N, 7.16.
(2R,3R)-2-Ben zyl-3,4-(tr ip h en ylm eth ylim in o)-bu ta n -1-
ol ((2R,3R)-26) was obtained from (2R,3R)-24 following the
procedure used for the preparation of (2S,3S)-26: [R]D
+65.6° (c ) 0.6, CHCl3).
(2S,3S)-2-Ben zyl-3,4-(flu or en ylm eth yloxyca r bon ylim i-
n o)bu ta n -1-ol ((2S,3S)-27). To an ice-chilled solution of
(2S,3S)-26 (400 mg, 0.95 mmol) in chloroform (2 mL) and
methanol (1 mL) was added dropwise TFA (3 mL). The mixture
was stirred for 4 h and then evaporated under reduced
)
J O0014055