New synthesis and ring opening of cis-3-alkylaziridine-2-carboxylates

Article abstract of DOI:10.1016/S0040-4020(01)00823-7

Syntheses of cis-3-alkylaziridine-2-carboxylates including cis-3-benzyl- and cis-3-phenylaziridine-2-carboxylates were achieved from the reaction of α-aminonitrile and alkyldiazoacetate in the presence of a Lewis acid. Asymmetric version of this reaction with the chiral α-methylbenzylamine was also successful for the preparation of chiral aziridines that were used for the synthesis of various amino acids including homophenylalanine, β-amino-α-hydroxy acid, α,β-diamino acid, and α-amino-β-hydroxy acid via regioselective aziridine ring openings.

Full text of DOI:10.1016/S0040-4020(01)00823-7

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 8267±8276
New synthesis and ring opening
of cis-3-alkylaziridine-2-carboxylatesq
Kwang-Deuk Lee,a Jang-Min Suh,a Jae-Hoon Park,a Hyun-Joon Ha,a,p Hwan Gun Choi,b
Chan Sun Park,b Jae Won Chang,b Won Koo Lee,b,p Yongkwan Dongc and Hoseop Yunc
aDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-791, South Korea
bDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
cDepartment of Molecular Science and Technology, Ajou University, Suwon 442-749, South Korea
Received 13 June 2001; accepted 30 July 2001
AbstractÐSyntheses of cis-3-alkylaziridine-2-carboxylates including cis-3-benzyl- and cis-3-phenylaziridine-2-carboxylates were
achieved from the reaction of a-aminonitrile and alkyldiazoacetate in the presence of a Lewis acid. Asymmetric version of this reaction
with the chiral a-methylbenzylamine was also successful for the preparation of chiral aziridines that were used for the synthesis of various
amino acids including homophenylalanine, b-amino-a-hydroxy acid, a,b-diamino acid, and a-amino-b-hydroxy acid via regioselective
aziridine ring openings. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
possible with phenylacetaldimines so far. Phenylacetal-
dimine is an unstable and non-isolable imine due to its
possible conversion to more stable enamine, 2-phenyl-
ethenamine, under the reaction condition for its prepa-
ration.6 Therefore, no direct synthesis of 3-benzylaziridine-
2-carboxylate was available up to now. However, we found
the synthetic possibility from our recent success utilizing
phenylacetaldimine equivalent7 generated in situ from
2-amino-3-phenylpropanenitrile in the presence of a Lewis
acid.
Aziridine-2-carboxylates and their derivatives are useful
intermediates for the synthesis of various amine-containing
molecules by stereospeci®c ring opening reactions with
several different nucleophiles.1 Nucleophiles for the ring
opening reactions include not only heteroatoms such as
halide, oxygen, nitrogen but also carbanions as alkyl-
cuprates and phosphorus ylides.1,2 Aziridine ring could
also be transformed into ®ve-membered heterocycles such
as oxazoline-2-ones and imidazolidin-2-ones.3
In this paper we would like to describe the ®rst direct syn-
thesis of cis-3-benzylaziridine-2-carboxylates and its
expanded version for a general synthesis of cis-3-alkylaziri-
dine-2-carboxylates, including cis-3-phenylaziridine-2-
carboxylate, from the reaction of a-aminonitriles for the
synthetic precursors of the corresponding imines and alkyl-
diazoacetate in the presence of a Lewis acid.
Ample examples of their synthesis were reported in the
literature based on three different approaches as shown in
Scheme 1, 3i) nucleophilic displacement by nitrogen with
removal of the leaving group at the a-position, 3ii) 1,2-
addition of a nitrene to ole®ns, and 3iii) 1,2-addition of a
carbene to imines.
Among the methods 3iii) was most extensively investigated
with success of its catalytic versions with various imines.4 A
new version of three-components reactions with aldehydes,
amines, and diazoacetates were also achieved by Kobayashi
group with lathanide tri¯ate as a catalyst.5 However, one
great limitation in the method 3iii) is that no reaction is
2. Results and discussion
Though several synthetic methods are available for the
q This paper is part 16 in the series of `Lewis acid induced synthetic
equivalents of imines and iminum ions'. For part 15 see Ref. 26.
Keywords: aziridine-2-carboxylate; homophenylalanine; b-amino-a-hy-
droxy acid; a,b-diamino acid; a-amino-b-hydroxy acid.
Corresponding authors. Tel.: 182-335-30-4369; fax: 182-335-333-1696.
p
Scheme 1.
Fax: 182-2-7010967; e-mail: hjha@hufs.ac.kr; wonkoo@sogang.ac.kr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00823-7

8268
K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
The reactions starting form 2-benzylamino-3-phenyl-
propanenitrile 31, R1ˆR2ˆBn) and ethyl diazoacetate 33)
were not successful with several different Lewis acids8
including TiCl4, AlCl3, MgBr2, TMSOTf, BF3´OEt2, TiF4,
AgBF4, and Yb3OTf)3 until ZnCl2 and SnCl4 were found to
be effective 3entries 1±10) 3Table 1).
With one mole equivalent of SnCl4, reactions with either
ethyl- or methyl diazoacetate 33, 4) proceed smoothly in
CH2Cl2 at room temperature to afford the expected product
3-benzylaziridine-2-carboxylate 35, 6) in 51 and 48 %
yields, respectively, with the only cis stereochemistry
between benzyl at C-3 and carboxylate at C-2 3entry 10
and 12).9 Cutting the mole ratio of SnCl4 to the half of
a-aminonitrile, lowered the reaction yield to 42% 3entry
11). Neither changing the solvent nor the reaction tempera-
ture could improve the reaction yield.
Once the reaction condition was established we carried out
the reaction with a chiral substrate, 3-phenyl-2-[3S)-1-
phenylethylamino]propanenitrile 31, R1ˆBn, R2ˆ3S)-Ph-
3CH3)CH), considering the additional factor of diastereo-
facial selectivity. The standard Strecker synthesis10 from
phenylacetaldehyde and 3S)-1-phenylethylamine provides
3-phenyl-2-[3S)-1-phenylethylamino]propanenitrile as a dia-
stereomeric mixture of 2S and 2R with 4:1 ratio.7,10 This
diastereomeric mixture was used for the next coupling reac-
tion without further puri®cation or isolation because each
isolated isomer yielded the same stereochemical outcome
possibly due to the same iminium ion intermediate. With
one mole equiv. of SnCl4 the expected product ethyl cis-
3-benzyl-1-[3S)-1-phenylethyl]aziridine-2-carboxylate was
obtained as a diastereomeric mixture 37 and 70) with the
ratio of 58:42 in 47% yield after chromatography 3Scheme
3).
Scheme 2.
preparation of 3-alkylaziridine-2-carboxylates from imines
and alkyl diazoacetates in high yields, no direct synthesis of
3-benzylaziridine-2-carboxylates was reported due to the
instability of the corresponding phenylacetaldimine.
Therefore, 3-benzylaziridine-2-carboxylate 35) was the
®rst synthetic target based on the possible reaction of the
phenylacetaldimine generated in situ from its precursor with
ethyl diazoacetate. We generated the phenylacetaldimine
equivalent 32, R1ˆBn) in situ from 2-amino-3-phenyl-
propanenitrile 31, R1ˆBn) in the presence of a Lewis acid,
TMSOTf, and subsequently utilized it for the aldimine
coupling reaction with 3Z)-a-methoxy trimethylsilyl ketene
acetal to afford 3-amino-2-hydroxy-4-phenylbutanoate.7
This observation suggested us the possible direct synthetic
method toward 3-benzylaziridine-2-carboxylate 35) from
2-amino-3-phenylpropanenitrile 31) and alkyldiazoacetate
33, 4) with the assistance of a proper Lewis acid 3Scheme 2).
The major isomer 3-benzyl-1-[3S)-1-phenylethyl]aziridine-
2-carboxylate 37) was reduced by LiAlH4 to give hydroxy-
methylaziridine 14. Hydrogenolysis of 14 with a catalyst
Pd3OH)2 in the presence of 3Boc)2O gave the ring-opened
Table 1. Reactions of a-aminonitriles 31) and alkyldiazoacetate 33, 4) in CH2Cl2 at room temperature in the presence of Lewis acids 3LA)
Entry
R1
R2
R3
LA 3equiv.)
Yielda 3%)
32S,3S)/32R,3R)
1
2
3
4
5
6
7
8
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
3CH3)2CHCH2
Ph
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
3S)-Ph3CH3)CH
3R)-Ph3CH3)CH
3S)-Ph3CH3)CH
3R)-Ph3CH3)CH
3S)-Ph3CH3)CH
3R)-Ph3CH3)CH
3S)-Ph3CH3)CH
3S)-Ph3CH3)CH
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
TiCl4 31.0)
AlCl3 31.0)
MgBr2 31.0)
TMSOTf 31.0)
TiF4 31.0)
No rxn
No rxn
No rxn
No rxn
No rxn
No rxn
No rxn
No rxn
5 321)
5 351)
5 342)
6 348)
7 347)
AgBF4 31.0)
Yb3OTf)3 31.0)
BF3´OEt2 31.0)
ZnCl2 31.0)
SnCl4 31.0)
SnCl4 30.5)
SnCl4 31.0)
SnCl4 31.0)
SnCl4 31.0)
SnCl4 31.0)
SnCl4 30.5)
SnCl4 30.5)
SnCl4 30.5)
SnCl4 31.0)
ZnCl2 31.0)
9
10
11
12
13
14
15
16
17
18
19
20
58/42
61/39
73/27
75/25
66/34
63/37
71/29b
53/47b
8 342)
9 371)
10 339)
11 350)
12 354)
13 325)
13 363)
CH3
CH3
PhCH2OCH2
PhCH2OCH2
a
More than .98% of cis was observed.
The absolute stereochemistry was not con®rmed.
b

K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
8269
Scheme 4.
synthetic method with diverse a-cyanoalkylamines as
substrates prepared from the Strecker reaction of aldehydes
and amines at ease. cis-3-Isobutyl-, 3-phenyl-, and 3-methyl-
aziridine-2-carboxylates 39, 10, 11 and 12) bearing either
3S)-1-phenylethyl or 3R)-1-phenylethyl as a chiral auxiliary
were elaborated in 71, 39, 50 and 54% yield with the dia-
stereomeric ratio of 73:27, 75:25, 66:34, and 63:37, respec-
tively 3entries 15, 16, 17 and 18). For all of these reactions
SnCl4 was effective as a Lewis acid. However, SnCl4 was
not a very effective Lewis acid for the same reaction with
the substrate 31, R1ˆCH2OCH2Ph) to attain the aziridine in
better yield than 25% with the diastereomeric ratio 71:29
3entry 19). In this case ZnCl2 was effective to yield the
corresponding aziridine 313) in much better yield of 63%.
However, the diastereomeric ratio was poor as 53:47
3entries 19 and 20).
Scheme 3.
product 4-phenyl-2-t-butyloxycarbonylaminobutanol 315)
exclusively without formation of its regioisomer. Selective
ring opening between N-1 and C-3 of 3-benzyl-2-hydroxy-
methyl-1-[3S)-1-phenylethyl]aziridines can be explained by
possible coordinated association of amine and oxygen
pended in aziridine via hydrogen bond or metal-mediated
coordination to result for the bond between N-1 and C-3 of
the aziridine ring to be weak. Oxidation of the aminobutanol
315) by RuCl3 and NaIO4 followed by methylation with
CH3I with K2CO3 to afford N-Boc-homophenylalanine
methyl ester 316) with [a]D24 as 214.2 that is corresponding
to 2S isomer.11 Therefore, the major isomer of the aziridine
was assigned as 32S,3S)-3-benzyl-2-hydroxymethyl-1-[3S)-
1-phenylethyl]aziridines 37). The same reaction with
3-phenyl-2-[3R)-1-phenylethylamino]propanenitrile [1, R1ˆ
Bn, R2ˆ3R)-Ph3CH3)CH] yielded a set of diastereomers of
3-benzyl-1-[3S)-1-phenylethyl]aziridine-2-carboxylates 38)
in 42% yield. Those were reduced by LiAlH4 to give
32S,3S)- and 32R,3R)-3-benzyl-2-hydroxymethyl-1-[3S)-1-
phenylethyl]aziridines in 88% yield. X-ray structure of its
major isomer 32R,3R)-3-benzyl-2-hydroxymethyl-1-[3R)-1-
phenylethyl]aziridine 3ent-14) was determined as shown in
Fig. 1.12 An intramolecular hydrogen bond was observed
between the hydrogen of the hydroxy group and the nitrogen
The major isomer 39) from the entry 15 was reduced by
LiAlH4 in quantitative yield to give 3-iso-butyl-2-hydroxy-
methyl-1-[3S)-1-phenylethyl]aziridines 317) whose con®g-
urations were con®rmed as 2S and 3S by comparison of
the authentic compound synthesized from 32R)-1-[3S)-1-
phenylethyl]aziridine-2-carboxaldehyde.13 3Scheme 4)
32R,3R)-3-Benzyl-1-[3R)-1-phenylethyl]aziridine-2-carb-
oxylate 38) was reduced by DIBAL and reacted with a
phosphorus ylide in one pot to give 32R,3R)-2-benzyl-3-
vinyl-1-[3R)-1-phenylethyl]aziridine 319) in 64% yield.
Ring opening was carried out with AcOH in CH2Cl2 to
afford 3-acetyloxy-4-[3R)-1-phenylethyl]amino-5-phenyl-
pent-1-ene 320) exclusively due to the allylic activation.
The ring opening product 20 was transformed by the
Ê
of aziridine with the length of 2.808 A and the dihedral
angle of 1748.
The values of chiral aziridines prompted us to expand this
Figure 1. X-ray structure of 32R,3R)-3-benzyl-2-hydroxymethyl-1-[3R)-1-phenylethyl]aziridine 3ent-14).

8270
K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
Scheme 7.
aziridine is not big enough to discriminate for the reaction
to proceed in one direction. Electronic characteristics in the
aziridin-2-carboxylate governs the ring opening reaction
with breakage between N-1 and C-3 selectively.16 Coordi-
nation of the Lewis acid to the nitrogen of the aziridine
develops positive charge that is dispersed through the aziri-
dine ring with concomitant weakening the C±N bonds. The
bond accommodating positive charge better becomes
weaker. Between two carbon±nitrogen bonds of the aziri-
dine ring, the bond between N-1 and C-3 gets weaker with
better accommodation of the developing positive charge
with concomitant bond-breakage toward the coming nucleo-
phile. This observation is consistent with the early report.
Ring opening reaction of aziridine-2-carboxylates with
simple halide such as NaBr occurred with breakage of the
bond between N-1 and C-2 while the reaction with a Lewis
acid MgBr2 resulted the bond breaking at N-1 and C-3 of the
aziridine ring.18
Scheme 5.
known method14 to 32S,3R)-3-amino-2-hydroxy-4-phenyl-
butanoic acid 321) as a key component of natural product
bestatin15 3Scheme 5).
Ring opening of aziridine-2-carboxylates with azide would
produce a,b-diamino acids which can be used widely as a
synthetic precursors and chiral ligands.1a When TMSN3 was
added to the solution of ethyl 32S,3S)-3-methyl-1-[3S)-1-
phenylethyl]aziridine-2-carboxylate 310) in CH2Cl2, no
reaction occurred even under re¯ux. This was contrasted
to the early observation that the substrate ethyl 32R)-1-
[3S)-1-phenylethyl]aziridine-2-carboxylate 3ent-25) was
known to be reacted.16 Addition of the Lewis acid
BF3´OEt2 promoted the reaction to proceed at room
temperature to give ethyl 32S,3R)-3-azido-2-[3S)-1-
phenylethyl]aminopropionate 322) in 67% yield as shown
in Scheme 6. The absolute stereochemistry and the exact
location of the azide in the product 22 could not be
con®rmed by spectral data. If the ring opening by the
azide occurs at C-2 of the aziridine, 32R,3S)-2-azido-3-
[3S)-1-phenylethyl]amino-propionate would have been
produced with the similar spectral data. The ring-opened
product was further transformed to 2,3-diaminobutanoic
acid by sequential reaction of hydrogenation with Pd/C in
the presence of 3.0 mol equiv. 3Boc)2O and the subsequent
acid hydrolysis to yield 32S,3R)-2,3-diaminobutanoatic acid
The same regiochemical outcome was observed in the ring
opening reaction of ethyl 32S)-1-[3R)-1-phenylethyl]aziri-
dine-2-carboxylate 325) by AcCl in the presence of TiCl4
as a Lewis acid to afford 32R)-2-{N-acetyl-N-[3R)-1-phenyl-
ethyl]amino}-3-chloro-propionic acid methyl ester 326) in
64% yield 3Scheme 7), whose X-ray structure19 is in Fig. 2.
Note that the apparent inversion 32S) to 32R) is only due to a
switch in the CIP-priority.
In the same manner 32R,3R)-3-benzyl-1-[3R)-1-phenylethyl]-
aziridine-2-carboxylate 38) and 32R,3R)-3-methyl-1-[3R)-1-
phenylethyl]aziridine-2-carboxylate 312) were reacted with
AcCl and TiCl4 to produce 32R,3R)-3-acetoxy-4-phenyl-2-
[3S)-1-phenylethyl]aminobutanoate 327) and 32R,3R)-3-
acetoxy-2-[3S)-1-phenylethyl]aminobutanoate 328) in 54
and 75% respectively. Their con®gurations were deter-
mined by the corresponding 2-amino-3-hydroxy-4-phenyl-
324){HCl disalt, [a]D ˆ134.7 3c 0.2, 6N HCl); lit.17
22
20
[a]D ˆ133.4 3c 1.0, 6N HCl)}. Retrospectively the stereo-
chemical course of aziridine ring opening by TMSN3 in the
presence of BF3´OEt2 occurred with breakage of the bond
between N-1 and C-3.
22
22
butanoic acid {[a]D ˆ25.5 3c 5.0, 1N HCl); lit.20, [a]D
ˆ
The origin of the regioselectivity in the ring opening stems
from the electronic effect because the size difference
between methyl at C-3 and ethoxycarbonyl at C-2 in the
19.1 3c 1.0, 1N HCl) for its enantiomer} and d-allo-threo-
22
nine {[a]D ˆ28.7 3c 0.9, H2O); lit.21, [a]Dˆ19.7 3c 1.0,
H2O) for its enantiomer}that were obtained by the
sequential reactions of hydrogenolysis with 3Boc)2O toward
29 and 30 and the subsequent hydrolysis.
These streochemical results of the ring opening reactions
with retention of con®guration at b-position bearing
acetoxy could be explained by double displacements by
chloride and by oxygen to replace chlorine with formation
of oxazoline ring that was subsequently hydrolyzed to the
products 27 and 28 as shown in Scheme 8. All of these
observations make it possible to predict that most Lewis
acid mediated nucleophilic ring opening reactions of cis-
3-alkylaziridine-2-carboxylates occur with concomitant
breakage of the bond between N-1 and C-3 of the aziridine
ring.
Scheme 6.

K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
8271
Figure 2. X-Ray structure of 32R)-2-{N-acetyl-N-[3R)-1-phenylethyl]amino}-3-chloro-propionic acid methyl ester 326).
Scheme 8.
1
3. Conclusion
or 400 3200 and 400 MHz for H and 50.3 and 100.6 MHz
for 13C). Chemical shifts were given in ppm using TMS as
the internal standard. Mass spectra were obtained using a
Hewlett Packard Model 5985B spectrometer or a Kratos
Concept 1-S double focusing mass spectrometer. Elemental
analysis was taken on a Perkin±Elmer 240 DS elemental
analyzer. Melting point was measured by Mel-II capillary
melting point apparatus. Optical rotation was measured with
Rudolph Research Autopole 3 polarimeter. The silica gel
used for column chromatography was Merck 200±230
mesh. Thin layer chromatography was carried out with
Merck 60F-254 plates with 0.25 mm thickness.
This work describes a new synthesis of cis-3-alkylaziridine-
2-carboxylates from the reaction between a-aminonitrile
and alkyldiazoacetate in the presence of a Lewis acid includ-
ing the ®rst direct preparation of cis-3-benzylaziridine-2-
carboxylate. Asymmetric version of this reaction with the
chiral a-methylbenzylamine was also successful for the
preparation of chiral aziridines that were used for the syn-
thesis of various amino acids including homophenylalanine,
b-amino-a-hydroxy acid, a,b-diamino acid and a-amino-
b-hydroxy acid via regioselective aziridine ring openings.
We also have found that Lewis acid mediated nucleophilic
ring opening reactions occur with concomitant breakage of
the bond between N-1 and C-3 of the aziridine ring.
4.1. General synthesis of cis-3-alkylaziridine-2-carboxyl-
ates .2±10)
Anhydrous SnCl4 31.2 mmol) and alkyldiazoacetate
31.8 mmol) was added at room temperature under nitrogen
atmosphere to the solution of the a-aminonitrile 31) 31.2
mmol) that was prepared from the corresponding aldehyde
4. Experimental
1H NMRand 13C NMRspectra were recorded on Varian 200

8272
K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
and amine in CH2Cl2 330 mL). The resultant solution was
stirred for 8 h until all the starting nitrile was consumed on
TLC. The reaction mixture was poured into ice±water and
the resulting solution was neutralized with cold sat.
NaHCO3 solution. The reaction product was extracted
with EtOAc 350 mL£3) and the organic layer was washed
with 100 mL of water and brine, dried over anhydrous
MgSO4, ®ltered and concentrated under reduced pressure.
The crude product was puri®ed by ¯ash column chroma-
tography to give product. Product for chemical analysis was
obtained as colorless oil by short path vacuum distillation
except 10 and 100.
9.15; N, 5.09. Found: C, 73.7; H, 8.96; N, 5.32. For 90
24
1
[a]D ˆ9.1 3cˆ5.0 in CH2Cl2) H NMR d 1.11 33H, t,
Jˆ7.0 Hz), 1.20 33H, d, Jˆ6.2 Hz), 2.02±2.13 32H, m),
2.54 31H, q, Jˆ6.6 Hz), 2.75±3.02 32H, m), 3.96±4.13
32H, m), 7.03±7.29 310H, m); 13C NMR d 14.1, 23.6,
34.4, 42.2, 48.3, 60.7, 69.4, 126.3, 126.4, 126.9, 128.2,
128.4, 128.8, 138.8, 143.5, 169.4. [HREIms. Found:
275.1891. C17H25NO23M1) requires: 275.1885].
4.1.5. Ethyl .2R,3R)-3-phenyl-1-[.R)-1-phenylethyl]aziri-
dine-2-carboxylate .10) and ethyl .2S,3S)-3-phenyl-1-
[.R)-1-phenylethyl]aziridine-2-carboxylate .100). Rf 3n-
Hex/Ether, 2:1) 0.40 for 10 and 0.52 for 100. For 10, solid,
mp 87±898C, [a]D ˆ251.0 3cˆ5.0 in CH2Cl2), 1H NMR d
24
4.1.1. Ethyl cis-3-benzyl-1-benzylaziridine-2-carboxyl-
1
ate .5). H NMR d 1.28 33H, t, Jˆ7.2 Hz), 2.21 31H, q,
1.00 33H, t, Jˆ7.0 Hz), 1.57 33H, d, Jˆ6.6 Hz), 2.64 31H, d,
Jˆ7.0 Hz), 2.86 31H, q, Jˆ6.6 Hz), 3.01 31H, d, Jˆ6.6 Hz),
3.99 32H, q Jˆ7.0 Hz), 7.17±7.50 310H, m); 13C NMR d
13.9, 22.9, 46.0, 47.3, 60.6, 69.7, 126.9, 127.1, 127.2, 127.6,
127.7, 128.3, 135.1, 143.2, 168.2. Anal. Calcd for
C19H21NO2: C, 77.3; H, 7.17; N, 4.74. Found: C, 77.6; H,
7.41; N, 4.69. For 100, solid, mp 64±668C, 1H NMR d 1.13
33H, t, Jˆ7.0 Hz), 1.52 33H, d, Jˆ6.5 Hz), 2.55 31H, d,
Jˆ6.9 Hz), 2.93 31H, q, Jˆ6.6 Hz), 3.13 31H, d, Jˆ
6.9 Hz), 3.87±4.15 32H, m), 7.03±7.29 310H, m). Anal.
Calcd for C19H21NO2: C, 77.3; H, 7.17; N, 4.74. Found:
C, 77.4; H, 7.37; N, 4.66.
Jˆ6.4 Hz), 2.33 31H, d, Jˆ7.0 Hz), 2.87 31H, dd Jˆ4.6,
5.7 Hz), 3.18 31H, dd, Jˆ6.6, 14.4 Hz), 3.63 32H, dd, Jˆ
13.6, 20.0 Hz), 4.24 32H, q, Jˆ7.2 Hz), 7.15±7.42 310H, m);
13C NMR d 14.2, 33.9, 42.3, 47.3, 60.9, 63.5, 126.2, 127.1,
127.9, 128.2, 128.3, 128.6, 137.6, 138.6, 169.6. Anal. Calcd
for C19H21NO2: C, 77.3; H, 7.17; N, 4.74. Found: C, 77.6; H,
7.24; N, 4.89.
4.1.2. Methyl cis-3-benzyl-1-benzylaziridine-2-carboxy-
1
late .6). H NMR d 2.09 31H, q, Jˆ6.2 Hz), 2.26 31H, d,
Jˆ7.0 Hz), 2.72 31H, dd Jˆ4.8, 5.4 Hz), 2.95 31H, dd,
Jˆ6.2, 14.2 Hz), 3.55 32H, dd, Jˆ13.6, 20.0 Hz), 3.70
33H, s), 7.05±7.24 310H, m); 13C NMR d 34.0, 42.2, 47.3,
52.1, 63.6, 126.3, 127.2, 128.0, 128.3, 128.4, 128.6, 137.5,
138.6, 170.1. Anal. Calcd for C18H19NO2: C, 76.8; H, 6.81;
N, 4.98. Found: C, 76.6; H, 6.77; N, 4.79.
4.1.6. Ethyl .2S,3S)-3-methyl-1-[.S)-1-phenylethyl]aziri-
dine-2-carboxylate .12) and ethyl .2R,3R)-3-methyl-1-
[.S)-1-phenylethyl]aziridine-2-carboxylate .120). Rf 3n-
Hex/Ether, 1:2) 0.64 for 120 and 0.54 for 12. For 12,
24
1
[a]D ˆ256.8 3cˆ5.0 in CH2Cl2), H NMR d 1.15 33H, t,
Jˆ5.4 Hz), 1.27 33H, t, Jˆ7.0 Hz), 1.42 33H, d, Jˆ6.6 Hz),
1.85 31H, q, Jˆ6.6 Hz), 2.21 31H, d, Jˆ6.6 Hz), 2.61 31H, q,
Jˆ6.6 Hz), 4.14 32H, q, Jˆ6.6 Hz), 7.18±7.39 35H, m); 13C
NMR d 13.0, 14.2, 22.8, 40.9, 42.9, 60.6, 69.6, 126.5, 126.8,
128.1, 143.6, 169.6. [HREIms. Found: 233.1421.
C14H19NO23M1) requires: 233.1416]. Anal. Calcd for
C14H19NO2: C, 72.1; H, 8.21; N, 6.00. Found: C, 72.4; H,
4.1.3. Ethyl .2S,3S)-3-benzyl-1-[.S)-1-phenylethyl]aziri-
dine-2-carboxylate .7) and ethyl .2R,3R)-3-benzyl-1-
[.S)-1-phenylethyl]aziridine-2-carboxylate .70). Rf 3n-
Hex/Ether, 3:1) 0.56 for 7 and 0.63 for 70. For 7,
24
[a]D ˆ236.8 3cˆ5.0 in CH2Cl2), 1.30 33H, t, Jˆ7.0 Hz),
1.48 33H, d, Jˆ6.6 Hz), 2.11 31H, q, Jˆ6.6 Hz), 2.32 31H, d,
Jˆ6.6 Hz), 2.68 31H, q, Jˆ6.6 Hz), 2.89 32H, m), 4.26 32H,
q, Jˆ7.0 Hz), 6.95±7.37 310H, m); 13C NMR d 14.10,
22.45, 33.75, 42.42, 46.71, 60.77, 69.50, 125.88, 126.79,
127.01, 128.05, 128.09, 128.34, 138.40, 142.98, 169.63.
Anal. Calcd for C20H23NO2: C, 77.6; H, 7.49; N, 4.53.
8.38; N, 5.84. For 120 [a]D ˆ121.1 3cˆ5.0 in CH2Cl2) 1H
24
NMR d 1.18 33H, t, Jˆ7.0 Hz), 1.33 33H, d, Jˆ7.0 Hz),
1.42 33H, d, Jˆ6.6 Hz), 1.95±2.09 32H, m), 2.62 31H, q,
Jˆ6.6 Hz), 4.04±4.20 32H, m), 7.18±7.39 35H, m); 13C
NMR d 13.4, 14.1, 23.5, 42.0, 42.3, 60.5, 69.4, 126.3,
126.8, 128.1, 143.5, 169.3. [HREIms. Found: 233.1427.
C14H19NO23M1) requires: 233.1416]. Anal. Calcd for
C14H19NO2: C, 72.1; H, 8.21; N, 6.00. Found: C, 72.2; H,
8.25; N, 5.72.
24
Found: C, 77.4; H, 7.44; N, 4.59. For 70 [a]D ˆ19.1 3cˆ
5.0 in CH2Cl2) 1H NMR d 1.11 33H, t, Jˆ7.0 Hz), 1.20 33H,
d, Jˆ6.2 Hz), 2.02±2.13 32H, m), 2.54 31H, q, Jˆ6.6 Hz),
2.75±3.02 32H, m), 3.96±4.13 32H, m), 7.03±7.29 310H,
m); 13C NMR d 14.1, 23.6, 34.4, 42.2, 48.3, 60.7, 69.4,
126.3, 126.4, 126.9, 128.2, 128.4, 128.8, 138.8, 143.5,
169.4. Anal. Calcd for C20H23NO2: C, 77.6; H, 7.49; N,
4.53. Found: C, 77.3; H, 7.56; N, 4.32.
4.1.7. Ethyl .2S,3S)-3-benzyloxymethyl-1-[.S)-1-phenyl-
ethyl]aziridine-2-carboxylate .13) and ethyl .2R,3R)-3-
methoxymethyl-1-[.S)-1-phenylethyl]-aziridine-2-carb-
oxylate .130). Rf 3n-Hex/Ether, 1:2) 0.63 for 13 and 0.56 for
130. For 13, 1H NMR d 1.30 33H, t, Jˆ7.0 Hz), 1.48 33H, d,
Jˆ6.6 Hz), 2.11 31H, q, Jˆ6.6 Hz), 2.32 31H, d, Jˆ6.6 Hz),
2.68 31H, q, Jˆ6.6 Hz), 2.89±2.95 32H, m), 4.26 32H, q,
Jˆ7.0 Hz), 6.95±7.37 312H, m); 13C NMR d 14.1, 22.5,
33.8, 42.4, 46.7, 60.8, 69.5, 125.9, 126.8, 127.0, 128.1,
128.1, 128.3, 138.4, 143.0, 169.6. Anal. Calcd for
C21H25NO3: C, 74.3; H, 7.42; N, 4.13. Found: C, 74.1; H,
4.1.4. Ethyl .2S,3S)-3-iso-butyl-1-[.S)-1-phenylethyl]-
aziridine-2-carboxylate .9) and ethyl .2R,3R)-3-iso-
butyl-1-[.S)-1-phenylethyl]aziridine-2-carboxylate .90).
Rf 3n-Hex/Ether, 1:2) 0.56 for 9 and 0.65 for 90. For 9
24
[a]D ˆ236.8 3cˆ5.0 in CH2Cl2), 1.30 33H, t, Jˆ7.0 Hz),
1.48 33H, d, Jˆ6.6 Hz), 2.11 31H, q, Jˆ6.6 Hz), 2.32 31H, d,
Jˆ6.6 Hz), 2.68 31H, q, Jˆ6.6 Hz), 2.89 32H, m), 4.26 32H,
q, Jˆ7.0 Hz), 6.95±7.37 310H, m); 13C NMR d 14.1, 21.4,
22.7, 28.4, 36.0, 42.7, 44.8, 60.5, 69.5, 126.8, 127.0, 128.0,
143.3, 170.0. [HREIms. Found: 275.1889. C17H25NO23M1)
requires: 275.1885]. Anal. Calcd for C17H25NO2: C, 74.1; H,
1
7.52; N, 4.29. For 130, H NMR d 1.11 33H, t, Jˆ7.0 Hz),
1.20 33H, d, Jˆ6.2 Hz), 2.02±2.13 32H, m,), 2.54 31H, q,
Jˆ6.6 Hz), 2.75±3.02 32H, m), 3.96±4.13 32H, m), 7.03±

K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
8273
7.29 312H, m); 13C NMR d 14.1, 23.6, 34.4, 42.2, 48.3, 60.7,
69.4, 126.3, 126.4, 126.9, 128.2, 128.4, 128.8, 138.8, 143.5,
169.4. Anal. Calcd for C21H25NO3: C, 74.3; H, 7.42; N, 4.13.
Found: C, 74.6; H, 7.29; N, 4.14.
6 h and quenched by adding water. The reaction product
was extracted with CH2Cl2 310 mL£3) and the organic
layer was washed with 20 mL each of water and brine,
dried over anhydrous MgSO4, ®ltered and concentrated
under reduced pressure. The crude product was puri®ed
by ¯ash column chromatography to give 130 mg of the
4.1.8. .2S,3S)-3-Benzyl-2-hydroxymethyl-1-[.S)-1-phenyl-
ethyl]aziridine .14). To a suspension of LiAlH4 3228 mg,
6 mmol) in 30 mL of Et2O at 08C was added slowly ethyl 3-
benzyl-1-[3S)-1-phenylethyl]aziridine-2-carboxylate 37, 464
mg, 1.5 mmol) in 15 mL of Et2O. The mixture was stirred at
08C and then quenched with sat. KHSO4 solution. The
mixture was dried over anhydrous MgSO4, ®ltered and
concentrated under reduced pressure. The crude product
as a diastereomeric mixture was puri®ed and each isomers
was separated by ¯ash column chromatography to give
353 mg of the product in 88% yield. Rf 3n-Hex/Ether, 1:1)
0.30 for 14 and 0.59 for its diastereomer as white solid. The
same products were formed from the separated isomers
of aziridine-2-carboxylates. 32S,3S)-3-Benzyl-2-hydroxy-
methyl-1-[3S)-1-phenylethyl]aziridine 314) Mp 79±818C,
1H NMR d 1.47 33H, d, Jˆ6.6 Hz), 1.38±1.94 3m, 2H),
2.53±2.80 33H, m), 3.80±3.88 32H, m), 4.25 31H, br s),
6.91±7.30 310H, m); 13C NMR d 22.8, 34.3, 44.2, 45.1,
59.7, 69.6, 125.8, 126.7, 126.9, 128.1, 128.1, 128.2, 138.9,
24
product 16 in 62% yield. [a]D ˆ214.2 3c 2.0, MeOH);
20
lit.11, [a]D ˆ214.7 3c 1.2, MeOH).
4.1.11.
.2S,3S)-2-hydroxymethyl-3-isobutyl-1-[.S)-1-
phenylethyl]aziridine .17). To a suspension of LiAlH4
3152 mg, 4 mmol) in 25 mL of Et2O at 08C was added
slowly ethyl 32S,3S)-3-iso-butyl-1-[3S)-1-phenylethyl]aziri-
dine-2-carboxylate 36, 275 mg, 1.0 mmol) in 15 mL of
Et2O. The mixture was stirred at 08C and then quenched
with sat. KHSO4 solution. The mixture was dried over
anhydrous MgSO4, ®ltered and concentrated under reduced
pressure. The crude product was puri®ed by ¯ash column
chromatography to give 228 mg of the product in 98% yield.
1H NMR d 1.18±1.30 33H, m), 1.33±1.40 33H, m), 2.01
31H, br s), 2.96 31H, d, Jˆ4.0 Hz), 3.50±3.78 35H, m),
7.23±7.33 35H, m); 13C NMR d 16.2, 25.2, 51.2, 56.7,
22
59.1, 62.7, 127.0, 128.3, 128.3, 144.5, 173.6. [a]D
275.5 3c 6.0, CHCl3). Anal. Calcd for C15H23NO: C, 77.2;
ˆ
20
143.7. [a]D ˆ20.15 3cˆ6.0 in CH2Cl2). [HREIms. Found:
H, 9.93; N, 6.00. Found: C, 77.1; H, 9.77; N, 5.89.
267.1626. C18H21NO23M1) requires: 267.1623]. Anal.
Calcd for C18H21NO2: C, 80.9; H, 7.92; N, 5.24. Found:
C, 80.7; H, 7.74; N, 5.36. For 32R,3R)-3-benzyl-2-hydroxy-
methyl-1-[3S)-1-phenylethyl]aziridine, 1H NMR d 1.19
33H, d, Jˆ6.6 Hz), 1.74 31H, q, Jˆ6.2 Hz), 1.88 31H, q,
Jˆ6.1 Hz), 2.53 31H, q, Jˆ6.6 Hz), 2.68 31H, br s), 2.83
32H, d, Jˆ6.6 Hz), 3.58 32H, d, Jˆ5.6 Hz), 7.15±5.38 310H,
m); 13C NMR d 22.6, 34.5, 43.6, 45.9, 59.6, 69.2, 126.0,
4.1.12. .2S,3R)-2-Benzyl-1-[.S)-1-phenylethylamino]-3-
vinylaziridine .19). To a stirred solution of methyltri-
phenylphosphonium bromide 3502 mg, 1.40 mmol) was
added dropwisely n-BuLi in hexane 31.12 mmol). After
stirring the solution for 30 min was added ethyl 32S,3S)-3-
benzyl-1-[3S)-1-phenylethyl]aziridine-2-carboxylate 38, 290
mg, 93.8 mmol) in THF and then a solution of DIBAL
31.03 mmol) in toluene. The resulting solution was stirred
for 6 h at 2788C prior to warming to room temperature. The
reaction mixture was poured into water and the resulting
solution was extracted with EtOAc 3100 mL£3). The
organic layer was washed with 100 mL each of water and
brine, dried over anhydrous MgSO4, ®ltered and concen-
trated under reduced pressure. The crude product was
puri®ed by ¯ash column chromatography to give 158 mg
20
126.4, 126.9, 128.2, 128.6, 139.4, 144.0. [a]D ˆ226.5 3cˆ
2.5 in CH2Cl2).
4.1.9. .2S)-2-N-t-Butyloxycarbonylamino-4-phenylbuta-
nol .15). To a solution of 14 3780 mg, 2.92 mmol) was
added 3Boc)2O 3956 mg, 4.39 mmol) with 180 mg
Pd3OH)2 on carbon. This solution was charged with H2
gas in a balloon and the mixture was stirred at room
temperature until all the starting material was consumed
on TLC for 8 h. The mixture was ®ltered and concentrated
under reduced pressure. This crude reaction product was
puri®ed by ¯ash chromatography to give 564 mg 373%) of
1
of the product in 64% yield. H NMR d 0.67 33H, d,
Jˆ6.3 Hz), 0.76 33H, d, Jˆ6.3 Hz), 1.15±1.79 31H, m),
1.32±1.38 31H, m), 1.49 33H, d, Jˆ6.59 Hz), 1.66 31H, q,
Jˆ6.6 Hz), 1.84±1.94 31H, m), 2.61 31H, q, Jˆ6.59 Hz),
3.02 31H, br), 3.61 31H, dd, Jˆ7, 11.54 Hz), 3.85 31H, dd,
1
the product. H NMR d 1.49 39H, s), 1.9531H, m), 1.81±
22
1.86 32H, m), 2.69 31H, bs), 2.71±2.88 32H, m), 3.62±3.74
32H, m), 4.75 31H, bs), 7.21±7.34 35H, m). Anal. Calcd for
C15H23NO3: C, 67.9; H, 8.74; N, 5.28. Found: C, 67.7; H,
8.46; N, 5.03.
Jˆ4.81, 11.54 Hz), 7.34±7.44 31H, m). [a]D ˆ223.9 3c
1.1, CHCl3). Anal. Calcd for C19H21N: C, 86.7; H, 8.04;
N, 5.32. Found: C, 86.6; H, 8.17; N, 5.09.
4.1.13.
ethylamino]pentene .20). To
.3S,4R)-3-Acetyloxy-5-benzyl-4-[.S)-1-phenyl-
stirred solution of
4.1.10. .2S)-N-Boc-homophenylalanine methyl ester .16).
To a vigorously stirred solution of the aminoalcohol 15
3190 mg, 0.72 mmol) in 1.1 mL of a mixed solvent 3CCl4,/
CH3CN/H2O, 2:2:3) were added sodium periodate 3192 mg,
0.90 mmol) and ruthenium chloride 39 mg, 0.02 mmol). The
reaction mixture was stirred for 8 h, the acidic material was
carefully extracted into diethyl ether. The ethereal solution
was brie¯y dried over anhydrous MgSO4, ®ltered and
concentrated under reduced pressure. To a solution of the
crude acid in N,N-dimethylformamide were added K2CO3
361 mg, 0.22 mmol) and methyl iodide 327 mL, 0.44 mmol).
The resultant mixture was stirred at room temperature for
a
32S,3R)-2-Benzyl-1-[3S)-1-phenylethylamino]-3-vinylaziri-
dine 319, 138 mg, 0.52 mmol) in CH2Cl2 33 mL) was added
acetic acid 30.15 mL, 2.6 mmol). The reaction mixture was
stirred at room temperature and quenched with sat. NaHCO3
solution. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 320 mL£3). The organic
layer was washed with 20 mL each of water and brine, dried
over anhydrous MgSO4, ®ltered and concentrated under
reduced pressure. The crude product was puri®ed by ¯ash
column chromatography to give 138 mg of the product in
82% yield. 1H NMR d 1.16 33H, d, Jˆ6.6 Hz), 1.95 33H, s),

8274
K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
2.71 32H, m), 3.79 31H, q, Jˆ6.6 Hz), 5.24±5.39 33H, m),
5.93±6.01 31H, m), 6.78±7.12 311H, m). Anal. Calcd for
C21H25NO2: C, 78.0; H, 7.79; N, 4.33. Found: C, 77.7; H,
7.64; N, 4.42.
3150 mL) with EtOAc 3150 mL). The aqueous layer was
extracted with EtOAc 360 mL£2) and the combined organic
layer was washed with brine 3200 mL), dried by anhydrous
MgSO4, ®ltered and concentrated under reduced pressure.
The crude product was puri®ed by ¯ash column chroma-
tography to give 1.60 g of the target product in 69% yield.
[a]D ˆ167.5 3c 4.6, CHCl3). H NMR d 1.64 31H, dd,
Jˆ6.6 Hz), 2.26 33H, s), 2.86±2.94 31H, m), 3.63±3.71
31H, m), 3.71 33H, s), 4.08±4.19 31H, m), 5.14 31H, q, Jˆ
6.6 Hz), 7.17±7.38 35H, m); 13C NMR d 17.1, 21.9, 42.8,
52.4, 57.0, 58.8, 127.4, 128.4, 128.8, 138.7, 169.5, 170.2.
Anal. Calcd for C15H20ClNO3: C, 60.5; H, 6.77; N, 4.70.
Found: C, 60.6; H, 6.69; N, 4.84.
4.1.14. Ethyl .2S,3R)-3-azido-2-[.S)-1-phenylethylamino]-
butanoate .22). BF3´OEt2 3298 mg, 2.10 mmol) was added
at room temperature to ethyl 32S,3S)-3-methyl-1-[3S)-1-
phenylethyl]aziridine-2-carboxylate 310) 3976 mg, 4.19
mmol) dissolved in CH2Cl2 330 mL). This solution was
stirred for 10 min before adding TMSN3 32.42 g, 21.0
mmol). The resultant reaction mixture was stirred for 18 h
and the reaction mixture was poured into water with EtOAc.
The resulting solution was extracted with EtOAc 350 mL£3)
and the organic layer was washed with 100 mL each of
water and brine, dried over anhydrous MgSO4, ®ltered and
concentrated under reduced pressure. The crude product
was puri®ed by ¯ash column chromatography to give
22
1
4.1.18. Ethyl .2R,3R)-3-acetyloxy-4-phenyl-2-[.R)-1-
phenylethylamino]butanoate .27). TiCl4 3131 mg,
0.69 mmol) was added at room temperature to ethyl
32R,3R)-3-benzyl-1-[3R)-1-phenylethyl]aziridine-2-carb-
oxylate 38) 3534 mg, 1.73 mmol) dissolved in CH2Cl2
330 mL). This solution was stirred for 10 min before adding
acetyl chloride 30.33 mL, 4.58 mmol). The resultant
reaction mixture was stirred for 8 h and the reaction mixture
was poured into water 360 mL) with EtOAc 390 mL). The
resulting solution was neutralized by adding NaHCO3. This
solution was stirred for two days until no change was
observed based on TLC. The aqueous layer was extracted
with EtOAc 330 mL£2) and the combined organic layer was
washed with brine 3100 mL), dried over anhydrous MgSO4,
®ltered and concentrated under reduced pressure. The crude
product was puri®ed by ¯ash column chromatography to
1
1.01 g of the product in 87% yield. H NMR d 1.06±1.17
39H, m), 2.04 31H, s), 2.94 31H, d, Jˆ4.0 Hz), 3.12±3.72
32H, m), 4.12 32H, q, Jˆ7.4 Hz), 7.09±7.29 35H, m); 13C
NMR d 14.2, 16.4, 25.3, 56.8, 59.2, 61.1, 62.9, 127.1, 127.2,
22
128.4, 144.7, 173.2. [a]D ˆ290.8 3c 6.0, CHCl3). Anal.
Calcd for C14H20N4O2: C, 60.9; H, 7.30; N, 20.3. Found:
C, 60.7; H, 7.42; N, 20.1.
4.1.15. Ethyl .2S,3R)-2,3-bis-N-tert-butoxycarbonyl-
amino butanoate .23). Ethyl 32S,3R)-3-azido-2-[3S)-1-
phenylethylamino]butanoate 322) 3474 mg, 1.72 mmol)
and 3Boc)2O 3788 mg, 3.61 mmol) were dissolved in
EtOH 320 mL). Into this solution was added Pd/C
3150 mg) and the solution was charged with H2 gas in a
balloon and the mixture was stirred at room temperature
until all the starting material was consumed on TLC for
20 h. The mixture was ®ltered and concentrated under
reduced pressure and the crude product was puri®ed by
¯ash chromatography to give 357 mg of the product in
1
give 338 mg of the product in 53% yield. H NMR d 1.29
33H, t, Jˆ7.0 Hz), 1.39 33H, d, Jˆ5.4 Hz), 1.88 33H, s), 2.11
31H, br s), 2.84 31H, dd, Jˆ13.8, 8.2 Hz), 3.07 31H, dd,
Jˆ13.8, 5.2 Hz), 3.24 31H, d, Jˆ5.8 Hz), 3.72 31H, q, Jˆ
6.2 Hz), 4.19 32H, q, Jˆ7.0 Hz), 5.15±5.24 31H, m), 7.18±
7.35 310H, m); 13C NMR d 14.2, 20.7, 22.5, 36.7, 56.8, 61.0,
61.1, 75.1, 126.4, 127.0, 127.1, 128.1, 128.2, 129.2, 136.8,
1
22
60% yield. H NMR d 1.11 33H, d, Jˆ5.4 Hz), 1.28±1.52
144.2, 169.7, 172.7. [a]D ˆ267.5 3c 6.0, CHCl3). Anal.
318H, br s), 3.66 33H, s), 4.02±4.30 32H, br s), 4.85 31H, br
s), 5.52 31H, br s); 13C NMR d 18.2, 28.1, 48.3, 57.8, 79.3,
Calcd for C22H27NO4: C, 71.5; H, 7.37; N, 3.79. Found:
C, 71.4; H, 7.16; N, 3.63.
22
79.7, 155.1, 155.7, 171.4. [a]D ˆ145.2 3c 4.6, CHCl3).
Anal. Calcd for C16H30N2O6: C, 55.5; H, 8.73; N, 8.09.
Found: C, 55.8; H, 8.59; N, 8.13.
4.1.19. Ethyl .2R,3R)-3-acetyloxy-2-[.R)-1-phenylethyl-
amino]butanoate .28). The same reaction as for 25 with
the different substrate 32R,3R)-3-methyl-1-[3R)-1-phenyl-
ethyl]aziridine-2-carboxylate 311) 3919 mg, 3.94 mmol)
was carried out to obtained 1.06 g of the target product in
4.1.16. .2S,3R)-2,3-Diaminobutanoic acid 2HCl .24). The
substrate 23 3195 mg, 0.56 mmol) in 6N HCl solution
310 mL) was re¯uxed for 6 h for the reaction to be
completed. The reaction mixture was concentrated under
reduced pressure to give yellowish crude product that was
recrystallized from acetone to give 123 mg of white solid in
79% yield. [a]D ˆ110.2 3c 4.6, CHCl3). 1H NMR d 1.13±
22
1.38 39H, m), 1.93 33H, s), 3.08 31H, d, Jˆ6.0 Hz), 3.66
31H, q, Jˆ6.6 Hz), 4.17 32H, q, Jˆ6.6 Hz), 4.94 31H, quin,
Jˆ6.2 Hz), 7.16±7.31 35H, m); 13C NMR d 14.2, 16.3, 20.8,
25.2, 56.7, 60.8, 62.5, 71.2, 126.9, 127.0, 128.2, 144.5,
169.9, 173.0. Anal. Calcd for C16H23NO4: C, 65.5; H,
7.90; N, 4.77. Found: C, 65.4; H, 7.83; N, 4.62.
22
22
95% yield. [a]D ˆ134.7 3c 0.2, 6N HCl); lit.17, [a]D
ˆ
1
133.4 3c 1.0, 6N HCl). H NMR d 1.15±1.22 33H, m),
3.60±3.77 31H, m), 3.85±3.90 31H, m); 13C NMR d 10.3,
43.8, 51.6, 167.9.
4.1.20. Ethyl .2R,3R)-3-acetyloxy-2-N-tert-butoxycarbo-
nylamino-4-phenylbutanoate .29). Methyl 32R,3R)-3-
aceryloxy-4-phenyl-2-[3S)-1-phenylethylamino]butanoate
327) 3194 mg, 0.53 mmol) and 3Boc)2O 3194 mg,
0.89 mmol) were dissolved in MeOH 310 mL). Into this
solution was added Pd/C 380 mg) and the mixture was
charged with H2 in a balloon and stirred at room temperature
until all the starting material was consumed on TLC for
20 h. The mixture was ®ltered and concentrated under
4.1.17. Ethyl .2R)-2-[N-acetyl-N-.R)-1-phenylethyl-
amino]-3-chloropropionate .26). TiCl4 3588 mg, 3.1
mmol) was added at room temperature to 32S)-1-[3R)-10-
phenylethyl]aziridine-2-carboxylate 325) 31.70 g, 7.76
mmol) dissolved in CH2Cl2 350 mL). This solution was
stirred for 10 min before adding acetyl chloride 31.5 mL,
20 mmol). The resultant reaction mixture was stirred for
8 h and the reaction mixture was poured into water

K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
8275
2. 3a) Baldwin, J. E.; Adlington, R. M.; Robinson, N. G. J. Chem.
Soc., Chem. Commun. 1987, 153. 3b) Baldwin, J. E.;
Adlington, R. M.; O'Neil, I. A.; Scho®eld, C.; Spivey, A. C.;
Sweeney, J. B. J. Chem. Soc., Chem. Commun. 1989, 1852. 3c)
Tanner, D.; Birgersson, C.; Dhaliwal, N. K. Tetrahedron Lett.
1990, 31, 1903.
reduced pressure. This crude product was puri®ed by ¯ash
chromatography to give 145 mg of the product in 75% yield.
22
1
[a]D ˆ226.8 3c 2.0, CH2Cl3). H NMR d 1.28 33H, t,
Jˆ6.8 Hz), 1.42 39H, s), 1.94 33H, s), 2.90±3.00 32H, m),
4.17 32H, q, Jˆ7.0 Hz), 4.61±4.66 31H, m), 5.26±5.34 31H,
m), 5.40 31H, d, Jˆ8.6 Hz), 7.18±7.29 35H, m); 13C NMR d
14.4, 20.8, 28.2, 36.5, 55.3, 61.7, 74.6, 80.0, 126.7, 128.4,
129.3, 136.4, 155.2, 169.4, 170.4. Anal. Calcd for
C19H27NO6: C, 62.5; H, 7.45; N, 3.83. Found: C, 62.4; H,
7.31; N, 3.72.
3. 3a) Baeg, J.-O.; Bensimon, C.; Alper, H. J. Am. Chem. Soc.
1995, 117, 4700. 3b) Maas, H.; Bensimon, C.; Alper, H. J. Org.
Chem. 1998, 63, 17. 3c) Cardillo, G.; Gentilucci, L.; Gianotti,
M.; Tolomelli, A. J. Org. Chem. 2000, 2489.
4. 3a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. Engl. 1995, 34, 676. 3b) Rasmussen, K. G.;
Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1997, 1287.
3c) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.; Standen,
M. C. H. J. Org. Chem. 1996, 61, 1838. 3d) Ha, H.-J.; Kang,
K.-H.; Suh, J.-M.; Ahn, Y.-G.; Han, O. Tetrahedron 1998, 54,
851. 3e) Antilla, J.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121,
5099.
4.1.21. Ethyl .2R,3R)-3-acetyloxy-2-N-tert-butoxycarbo-
nylaminobutanoate .30). The same reaction as for 29 with
the different substrate methyl 32R,3R)-3-acetyloxy-2-[3S)-1-
phenylethylamino]butanoate 328) 3530 mg, 1.81 mmol) was
carried out to obtained 439 mg of the target product in 84%
yield. [a]D ˆ110.2 3c 5.0, CHCl3). 1H NMR d 1.09±1.24
22
36H, m), 1.34 39H, s), 1.93 33H, s), 4.13 32H, q, Jˆ7.2 Hz),
4.45±4.51 31H, m), 5.01±5.12 31H, m), 5.31 31H, d,
Jˆ8.8 Hz); 13C NMR d 14.0, 15.5, 20.8, 28.0, 56.2, 61.5,
70.2, 79.8, 155.1, 169.4, 170.2. Anal. Calcd for C13H23NO6:
C, 54.0; H, 8.01; N, 4.84. Found: C, 53.8; H, 7.89; N, 4.67.
5. Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685.
6. Pure form of N-benzylphenylacetaldimine could not be
obtained for the synthetic purpose. In the literature there is
one report using this imine for the reaction with 2,2,6-
trimethyl-4H-1,3-dioxin-4-one to give a product in less than
10% yield as an inseparable mixture. D'Annibale, A.; Pesce,
A.; Resta, S.; Trogolo, C. Tetrahedron Lett. 1996, 37, 7429.
7. Ha, H.-J.; Ahn, Y.-G.; Lee, G.-S. Tetrahedron: Asymmetry
1999, 10, 2327.
4.1.22. .2R,3R)-2-Amino-3-hydroxy-4-phenylbutanoic
acid .31). Methyl 32R,3R)-3-acetyloxy-2-N-tert-butyloxya-
mino-4-phenylbutanoate 329, 99 mg, 0.27 mmol) in 6N HCl
solution 310 mL) was re¯uxed for 6 h for the reaction to be
completed. The reaction mixture was concentrated under
reduced pressure to give yellowish crude product that was
recrystallized from acetone to give 58 mg of a white solid in
8. Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in
Organic Synthesis; CRC: Boca Raton, FL, 1995.
9. 3a) Casarrubios, L.; Perez, J. A.; Brookhart, M. J. Org. Chem.
1996, 61, 8358. 3b) Aggarwal, V. K.; Ferrara, M. Org. Lett.
2000, 2, 4107. 3c) Hori, R.; Aoyama, T.; Shioiri, T.
Tetrahedron Lett. 2000, 41, 9455.
95% yield. [a]D ˆ25.5 3c 5.0, 1N HCl); lit.14,
22
22
1
[a]D ˆ19.1 3c 1.0, 1N HCl) for its enantiomer. H NMR
d 2.72±2.94 32H, m), 3.94±4.02 31H, m), 4.08±4.22 31H,
m), 7.02±7.38 35H, m); 13C NMR d 36.4, 54.5, 68.9, 124.8,
126.6, 127.2, 135.0, 167.0.
10. 3a) Weinges, K.; Gries, K.; Stemmle, B.; Schrank, W. Chem.
Ber. 1977, 110, 2098. 3b) Shafran, Y. M.; Bakulev, V. A.;
Mokrushin, V. S. Russ. Chem. Rev. 1989, 58, 148.
4.1.23. .d)-allo-Threonine .32). The same reaction as for
31 with the different substrate methyl 32R,3R)-3-acetyloxy-
2-N-tert-butyloxyaminobutanoate 330) 336 mg, 0.12 mmol)
was carried out to obtained 16 mg of the target product as
11. Fraser, J. L.; Jackson, R. F. W.; Porter, B. Synlett 1994, 379.
12. Crystallographic data for C18H21NO: Mwˆ267.37, triclinic,
Ê
Ê
space group P1, aˆ6.28632) A, bˆ10.66433) A, cˆ
Ê
11.93533) A, aˆ85.4332), bˆ86.2432), gˆ79.0332)8, Vˆ
22
Ê 3
781.834) A , F3000)ˆ288, Zˆ2, Dcˆ1.136 g/cm3, mˆ
cystalline solid in 84% yield. [a]D ˆ28.7 3c 0.9, H2O);
lit.21, [a]Dˆ19.7 3c 1.0, H2O) for its enantiomer. 1H
NMR d 1.12 33H, d, Jˆ4.6 Hz), 3.84 31H, d, Jˆ4.4 Hz),
4.12±4.26 31H, m), 4.66 34H, bs); 13C NMR d 15.3, 55.4,
63.2, 167.5. Mp 2758C 3decomp.).
0.070 mm21. Preliminary examination and data collection
were performed on an MXC3 diffractometer 3Mac Science)
equipped with graphite monochromatized MoKa radiation
Ê
3lˆ0.7107 A). The cell parameters and an orientation matrix
were determined from least-squares analysis, using the setting
angles of 18 re¯ections in the range of 20.08#2u#28.08. For
the single crystal studies the transparent rectangular crystal of
dimension 0.64£0.56£0.32 mm3 was chosen. Intensity data
were collected by the v-2u scan techniques. Diffraction data
2h, ^k, ^l were collected from the inner sphere 33.08#
2u3MoKa)#55.08) at room temperature329332) K). The
initial positions for all non-hydrogen atoms were obtained
by using direct methods of the SHELXS-86 program.22 The
structure was re®ned with the use of the SHELXL-97
program.23 Positional and thermal parameters for non-
hydrogen atoms were re®ned using a full-matrix least-squares
re®nement procedure. Atomic positions of hydrogen atoms
were generated with riding model technique of SHELXL-
Acknowledgements
This work was supported by Korea Science and Engineering
Foundation 32000-1-12300-002-5 to H. J. H. and 2000-1-
123-001-5 to W. K. L.) and the Korea Research Foundation
Grant 3KRF-99-042-D00079-D3004). H. Yun is also grate-
ful for the use of the X-ray facility supported by the Korea
Basic Science Institute 3Research Infrastructure Program
2000).
References
97.23 The ®nal cycle of re®nement showed that wR23Fo .0)
2
1. For reviews, see. 3a) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. 3b) Pearson, W. H.; Lian, B. W.; Bergmeier,
S. C. Comprehensive Heterocyclic Chemistry II; Padwa, A.,
Ed.; Pergamon: New York, 1996; Vol. 1A, p. 1.
with 3273 unique re¯ections afforded residuals 0.1241 and the
conventional R index based on the re¯ections, 2612, having
2
3Fo .2s3Fo )) was 0.0452. The MISSYM algorithm in the
2

8276
K.-D. Lee et al. / Tetrahedron 57 -2001) 8267±8276
PLATON suite of programs indicates no additional potential
symmetry in this structure.24,25
plate-like crystal of dimension 0.86£0.60£0.22 mm3 was
chosen for the single crystal studies. Intensity data were
collected by the v-2u scan techniques. Diffraction data 1h,
2k, 1l were collected form the inner sphere 33.08#
2u3MoKa)#55.08) at 19031) K. The initial positions for all
non-hydrogen atoms were obtained by using direct methods of
the SHELXS-86 program.22 The structure was re®ned with the
use of the SHELXL-97 program.23 Positional and thermal
parameters for non-hydrogen atoms were re®ned using a
full-matrix least-squares re®nement procedure. Atomic
positions of hydrogen atoms were generated with riding
model technique of SHELXL-97.23 The ®nal cycle of re®ne-
13. More detailed procedure and the general method for the
preparation of 3-alkyl-2-hydrolymethylaziridine from 18
will be published in due course. The similar transformation
could be found in our early publication. Park, C. S.; Choi,
H. G.; Lee, H.; Lee, W. K.; Ha, H.-J. Tetrahedron: Asymmetry
2000, 11, 3283.
14. Okamoto, S.; Fukuhara, K.; Sata, F. Tetrahedron Lett. 2000,
41, 5561 and references cited therein.
15. 3a) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1976, 29, 97. 3b) Suda, H.; Takita,
T.; Aoyagi, T.; Umezawa, H. J. Antibiot. 1976, 29, 100.
3c) Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.;
Ito, Y.; Terashima, S. Tetrahedron 1992, 48, 1853.
2
ment showed that wR23Fo .0) with 1910 unique re¯ections
afforded residuals 0.1191 and the conventional R index based
2
2
on the re¯ections, 1682, having 3Fo .2s3Fo )) was 0.0436.
The MISSYM algorithm in the PLATON suite of programs
indicates no additional potential symmetry in this struc-
ture.24,25
16. Shin, S.-H.; Han, E. Y.; Park, C. S.; Lee, W. K.; Ha, H.-J.
Tetrahedron: Asymmetry 2000, 11, 3293.
17. Han, H.; Yoon, J.; Janda, K. J. Org. Chem. 1998, 63, 2045.
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19. Crystallographic data for C14H16ClNO3: Mwˆ281.74, orthor-
20. Blank, S.; Seebach, D. Liebigs Ann. Chem. 1993, 889.
21. Cardillo, G.; Gentilucei, L.; Tolomelli, A.; Tomasini, C.
J. Org. Chem. 1998, 63, 3458.
Ê
hombic, space group P212121, aˆ10.67233) A, bˆ
Ê
Ê
Ê 3
22. Shedrick, G. M. Acta Crystallogr. 1990, A46, 467±473.
23. Shedrick, G.M. SHELXL-97: Program for the Re®nement of
È È
Crystal Structure, University of Gottingen: Gottingen,
17.04734) A, cˆ8.25433) A, Vˆ1501.637) A , F3000)ˆ592,
Zˆ4, Dcˆ1.246 g/cm3, mˆ0.257 mm21. Preliminary exami-
nation and data collection were performed on an MXC3
diffractometer 3Mac Science) equipped with graphite mono-
Germany, 1997.
Ê
24. Le Page, Y. J. Appl. Crystallogr. 1987, 20, 264.
25. Spek, A. L. Acta Crystallogr. 1990, A46, C34.
26. Ha, H.-J.; Choi, C.-J.; Lee, W. K. Synth. Commun., In press.
chromatized MoKa radiation 3lˆ0.7107 A). The cell
parameters and an orientation matrix were determined from
least-squares analysis, using the setting angles of 27
re¯ections in the range of 20.08#2u#28.08. The transparent