Lipase-catalyzed resolution of (2R*,3S*)- and (2R*,3R*)-3-methyl-3-phenyl-2-aziridinemethanol at low temperatures and determination of the absolute configurations of the four stereoisomers

Article abstract of DOI:10.1021/jo048243n

(Chemical Equation Presented) Lipase-catalyzed resolution of (2R*,3S*)-3-methyl-3-phenyl-2-aziridinemethanol, (±)-2, at low temperatures gave synthetically useful (2R,3S)-2 and its acetate (2S,3R)-2a with (2S)-selectivity (E = 55 at -40 °C), while a simil

Full text of DOI:10.1021/jo048243n

Lipase-Catalyzed Resolution of (2R*,3S*)- and
(2R*,3R*)-3-Methyl-3-phenyl-2-aziridinemethanol at Low
Temperatures and Determination of the Absolute Configurations
of the Four Stereoisomers
Takashi Sakai,* Yu Liu, Hiroshi Ohta, Toshinobu Korenaga, and Tadashi Ema
Department of Applied Chemistry, Faculty of Engineering, Okayama University,
3-1-1 Tsushima-naka, Okayama 700-8530, Japan
tsakai@cc.okayama-u.ac.jp
Received October 6, 2004
Lipase-catalyzed resolution of (2R*,3S*)-3-methyl-3-phenyl-2-aziridinemethanol, (()-2, at low
temperatures gave synthetically useful (2R,3S)-2 and its acetate (2S,3R)-2a with (2S)-selectivity
(E ) 55 at -40 °C), while a similar reaction of (2R*,3R*)-3-methyl-3-phenyl-2-aziridinemethanol,
(()-3, gave (2S,3S)-3 and its acetate (2R,3R)-3a with (2R)-selectivity (E ) 73 at -20 °C). Compound
(()-2 was prepared conveniently via diastereoselective addition of MeMgBr to tert-butyl 3-phenyl-
2H-azirine-2-carboxylate, (()-1a, which was successfully prepared by the Neber reaction of oxime
tosylate of tert-butyl benzoyl acetate 7a. The tert-butyl ester was requisite to promote this reaction.
For determination of the absolute configuration of (2S,3R)-2a, enantiopure (2S,3R)-2 was
independently prepared in three steps involving diastereoselective methylation of 3-phenyl-2H-
azirine-2-methanol, (S)-10, with MeMgBr. The absolute configuration of (2S,3S)-3 was deter-
mined by X-ray analysis of the corresponding N-(S)-2-(6-methoxy-2-naphthyl)propanoyl derivative
(S,S,S)-13.
Introduction
ment of a convenient synthetic method for optically active
aziridine derivatives is an important subject. We have
recently reported the “low-temperature method”3 in the
lipase-catalyzed reaction of primary alcohols including
azirine derivatives.3a,e The method was practically per-
formed with porous ceramic (Toyonite)-immobilized lip-
ase (PS-C II).3d,e In this paper, we report (1) new synthetic
methods for four stereoisomers of 3-methyl-3-
phenyl-2-aziridinemethanol (()-2 (2R*,3S*) and (()-3
Recently, optically active aziridine derivatives have
attracted considerable attention because of their versatile
synthetic utilities, and a variety of methods for asym-
metric syntheses have been reported.1 Methods for the
regio- and stereoselective ring cleavage of the aziridines
have been well studied, and are still under active
investigation for the syntheses of chiral amines, amino
alcohols, amino acids, and so on.2 Therefore, the develop-
(3) (a) Sakai, T.; Kawabata, I.; Kishimoto, T.; Ema, T.; Utaka, M.
J. Org. Chem. 1997, 62, 4906-4907. (b) Sakai, T.; Kishimoto, T.;
Tanaka, Y.; Ema, T.; Utaka, M. Tetrahedron Lett. 1998, 39, 7881-
7884. (c) Sakai, T.; Miki, Y.; Tsuboi, M.; Takeuchi, H.; Ema, T.;
Uneyama, K.; Utaka, M. J. Org. Chem. 2000, 65, 2740-2747. (d) Sakai,
T.; Hayashi, K.; Yano, F.; Takami, M.; Ino, M.; Korenaga, T.; Ema, T.
Bull. Chem. Soc. Jpn. 2003, 76, 1441-1446. (e) Sakai, T.; Matsuda,
A.; Korenaga, T.; Ema, T. Bull. Chem. Soc. Jpn. 2003, 76, 1819-1821.
(f) Sakai, T.; Matsuda, A.; Tanaka, Y.; Korenaga, T.; Ema, T.
Tetrahedron: Asymmetry 2004, 15, 1929-1932. (g) Review: Sakai, T.
Tetrahedron: Asymmetry 2004, 15, 2749-2756.
(1) For recent reviews on the synthesis of aziridines, see: (a) Tanner,
D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (b) Osborn, H. M.
I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693-1715. (c)
Atkinson, R. S. Tetrahedron 1999, 55, 1519-1559. (d) Rai, K. M. L.;
Hassner, A. Adv. Strained Interesting Org. Mol. 2000, 8, 187-257.
(2) For recent reviews on the reaction of aziridines, see: (a) McCoull,
M.; Davis, F. A. Synthesis 2000, 1347-1365. (b) Zwanenburg, B.; ten
Holte, P. Top. Curr. Chem. 2001, 216, 93-124. (c) Cardillo, G.;
Gentilucci, L.; Tolomelli, A. Aldrichim. Acta 2003, 36, 39-50. (d) Hu,
X. E. Tetrahedron 2004, 60, 2701-2743.
10.1021/jo048243n CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/25/2005
J. Org. Chem. 2005, 70, 1369-1375
1369

Sakai et al.
SCHEME 1. Outline of the Lipase-Catalyzed
Resolution of 2-Aziridinemethanols
FIGURE 1. Calculated relative energy for 4a, 4b, and 6a (syn/
anti against ester moiety).
readily cyclize to the corresponding isoxazolone,7 probably
because of the preferential syn-hydroxyimino group. In
fact, the ab initio calculations at the B3LYP/6-31G*//
B3LYP/6-31G* level with ZPE correction by using Gauss-
ian 03W8,9 performed to study the stability of syn and
anti configurations for methyl 3-phenyl-3-(hydroxyimino)-
propanoate (4a) and methyl 3-(hydroxyimino)butanoate
(4b) showed that syn-4a is more stable (3.06 kcal/mol)
than anti-4a, while anti-4b is more stable (0.89 kcal/mol)
than syn-4b (Figure 1). These results prompted us to
reexamine the applicability of the Neber reaction by
changing the ester moiety of 4a to tert-butyl ester, which
might prevent the intramolecular cyclization. Although
(2R*,3R*) via the lipase-catalyzed resolution using the
low-temperature method and porous ceramic-immobilized
lipase PS-C II and (2) an improved method for prepara-
tion of tert-butyl (()-3-phenyl-2H-azirine-2-carboxylate,
(()-1a,4 an important intermediate for (()-2 (Scheme 1).
As far as we know, a few examples of the lipase-catalyzed
reaction for such 2-aziridinemethanols having two stereo-
genic centers at â- and γ-carbons are known,5 and none
of the reaction with aziridine derivatives without N-
protection have been reported. Here, we report that the
low-temperature method was effective for the resolutions
of (()-2 and (()-3, and that the lipase showed the
opposite stereochemical preferences at the C-2 position
of them. The observed temperature effect is also interest-
ing and practically useful for enhancing the enantio-
selectivity.
(7) (a) Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf,
T. I. J. Org. Chem. 1986, 51, 4037-4042. (b) Jacobsen, N.; Kolind-
Andersen, H.; Christensen, J. Can. J. Chem. 1984, 62, 1940-1944.
Results and Discussion
Preparation of 2-Aziridinemethanols (()-2 and
(()-3. First, we required a convenient synthetic method
for (()-1a, the precursor for (()-2. The synthetic method
for the analogous compound, ethyl (()-3-methyl-2H-
azirine-2-carboxylate, had been reported via the Neber
reaction of ethyl 3-N-hydroxyiminobutanoate.6 However,
the corresponding 3-phenyl-substituted derivative could
not be prepared by the method, because the precursor,
ethyl 3-phenyl-3-(hydroxyimino)propanoate, is known to
(8) Frequency calculation performed on optimized structures at the
same level produced no imaginary frequencies.
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03, Revision B.04; Gaussian, Inc.:
Pittsburgh, PA, 2003.
(4) Optically active 3-phenyl-2H-azirine-2-carboxylic esters were
synthesized by asymmetric syntheses either from N-sulfinylaziridine-
2-carboxylic ester4a-c or from 1H-aziridine-2-carboxylic esters:4d (a)
Davis, F. A.; Liu, H.; Liang, C.-H.; Reddy, G. V.; Zhang, Y.; Fang, T.;
Titus, D. D. J. Org. Chem. 1999, 64, 8929-8935. (b) Davis, F. A.; Liang,
C.-H.; Liu, H. J. Org. Chem. 1997, 62, 3796-3797. (c) Davis, F. A.;
Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117, 3651-3652. (d)
Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett.
1995, 36, 4665-4668.
(5) (a) Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y. Tetrahedron
Lett. 1990, 31, 6663-6666. (b) Davoli, P.; Prati, F. Heterocycles 2000,
53, 2379-2389. (c) Davoli, P.; Caselli, E.; Bucciarelli, M.; Forni, A.;
Torre, G.; Prati, F. J. Chem. Soc., Perkin Trans. 1 2002, 1948-1953.
(6) Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am.
Chem. Soc. 1996, 118, 8491-8492.
1370 J. Org. Chem., Vol. 70, No. 4, 2005

3-Methyl-3-phenyl-2-aziridinemethanol
SCHEME 2. Synthetic Pathways for (()-2 and
(()-3a
trans stereochemistry and the N-substituent moiety on
the aziridine ring highly influence the resolution ef-
ficiency.
We first examined the resolution of (()-2 with lipase
PS (immobilized on Celite) and vinyl acetate (1 equiv) in
ether at 30 °C; however, the E value10 was only 7.2, and
it took as long as 3 h to reach 26% conversion. The slow
reaction rate suggested that further lowering the tem-
perature seemed to be impractical. We then examined
lipase PS-C II [lipase PS immobilized on a porous ceramic
support (Toyonite)], whose high acceleration ability has
been demonstrated by our recent studies.3c-e,11 Results
for the resolution of (()-2 are summarized in Table 1 and
Figure 2. The reaction with lipase PS-C II at 25 °C in
ether (entry 2) gave a higher conversion of 0.52 in only
0.4 h together with a slightly increased E value of 9.3 as
compared with those obtained with lipase PS on Celite
(entry 1). To further improve the E value in ether,
temperature modulation was then attempted. The results
in Table 1 show that the E value was found to increase
up to 19 by lowering the temperature to -20 °C (entry
4). However, further lowering the temperature rather
decreased it to 7.3 (entry 6). Figure 2 shows that a linear
correlation was observed between ln E vs 1/T, obeying
Eyring’s equation.12 The temperature (-20 °C) is called
the inversion temperature (Tinv), at which the two lines
intersect.13 The reaction in acetone gave higher enantio-
selectivity, and the best result (E ) 55) was obtained at
-40 °C (entry 9). However, further lowering the temper-
ature to -50 °C did not increase the E value. Replacing
the acylating agent with vinyl butyrate was not effective
to improve the E value (entry 10), although the enantio-
selectivity for 3-phenyl-2H-azirine-2-methanol3e had been
improved by changing the acylating agent (vinyl buty-
rate). In contrast, the temperature modulation in THF
increased the E value continuously to -60 °C (entries
12-15). These results show that lipase PS-C II made it
possible to carry out the low-temperature reaction practi-
cally for obtaining high enantioselectivity.
a Reagents: (a) NH2OH; (b) TsCl, pyridine; (c) Et3N; (d)
MeMgBr or PhMgBr; (e) LiAlH4.
the calculations for the tert-butyl esters anti-6a and syn-
6a also showed the preference for syn-6a, compound 6a
was actually converted to tosylate 7a (Scheme 2). These
results suggest that the bulkiness of the tert-butyl group
in 6a retarded the cyclization as expected.
A reaction of tert-butyl benzoyl acetate (5a) with 2
equiv of NH2OH‚HCl and pyridine gave ketoxime 6a,
which was immediately tosylated (TsCl in pyridine) to
afford oxime tosylate 7a as a single isomer (Scheme 2).
The results were quite different from the case with the
corresponding ethyl ester.7 Subsequent treatment of 7a
with 1.1 equiv of Et3N gave azirine ester (()-1a success-
fully. The sequential reactions can be carried out in a
one-pot procedure in 70% overall yield from 5a. This is a
convenient pathway for the synthesis of (()-1a, which
can accept a variety of nucleophiles to its CdN double
bond.
We initially intended to perform the enzymatic resolu-
tion of 1a; however, all attempts for its chemical and
enzymatic hydrolysis failed. Therefore, (()-1a was trans-
formed into (()-2 by diastereoselective methylation4b
(MeMgBr, g94% de) followed by reduction with LiAlH4
in 75% yield, without affecting the aziridine ring. The
The resolution of compound (()-3 was carried out in a
similar way in acetone, the best solvent for (()-2. As
shown in Table 2, the resolution was first examined with
lipase PS (immobilized on Celite) and vinyl acetate at
30 °C and gave the E value of 9.4 (entry 1) with a slow
reaction rate (24 h for 11% conversion). The enantio-
selectivity was also optimized by using lipase PS-C II and
lowering the reaction temperature. The plot of ln E vs
1/T for this reaction is shown in Figure 3. The E value
was increased up to 73 by lowering the temperature to
-20 °C, which is the Tinv value. Noteworthy is that the
(2R)-enantiomer for compound 3 reacted faster than the
(2S)-3, while the (2R)-enantiomer for compound 2 reacted
slower than the (2S)-2. In general, the stereopreference
relative stereochemistry of (()-2 was determined by 13
C
NMR. Diastereomeric compound (()-3 was prepared from
5b through 7b (a syn/anti (32:68) mixture), (()-1b,6 and
(()-9 in a similar way (overall 18% yield). However, the
step for addition of PhMgBr to (()-1b gave reduced
selectivity (76:24) as shown in Scheme 2.
Lipase-Catalyzed Resolution of (()-2 and (()-3.
We next examined the lipase-catalyzed resolution of (()-2
and (()-3 without the N-protecting group, which is
usually essential. For example, the resolution of cis-3-
phenyl-2-aziridinemethanol with lipase PS (vinyl acetate,
at 37 °C) was reported to give only racemic acetate and
alcohol, while the resolution of its N-benzyl-protected
derivative gave high enantioselectivity (E > 200) in a
shorter reaction time.5c On the other hand, trans-N-
benzyl-3-phenyl-2-aziridinemethanol gave an E value of
less than 2.5c These results suggested that both the cis/
(10) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 104, 7294-7299.
(11) We have recently reported that lipase PS-C II is also usable at
high temperature up to 120 °C and that it is effectively applicable to
a bulky substrate: Ema, T.; Kageyama, M.; Korenaga, T.; Sakai, T.
Tetrahedron: Asymmetry 2003, 14, 3943-3947.
(12) Phillips, R. S. Trends Biotechnol. 1996, 14, 13-16.
(13) Cainelli, G.; de Mattesis, V.; Galleti, P.; Giacomini, D. Chem.
Commun. 2000, 2351-2352.
J. Org. Chem, Vol. 70, No. 4, 2005 1371

Sakai et al.
TABLE 1. Lipase PS-C II-Catalyzed Resolution of 2-Aziridinemethanol (()-2 at Low Temperatures
solvent
(5 mL)
lipase
(mg)
vinyl
temp
(°C)
alcohol
% eec
ester
% eec
time
(h)
entrya
acetateb
convd,e
Ee
1
2
Et2O
50f
50
1
1
1
1
1
2
1
2
2
2g
2
1
1
2
2
30
25
25
70
72
55
25
49
70
84
77
87h
53
69
89
85
78
70
66
72
84
78
64
83
85
92
90i
94
82
77
83
87
3.0
0.4
0.8
2.5
3.5
5.0
3.0
3.5
15
0.26
0.52
0.50
0.40
0.24
0.43
0.46
0.50
0.46
0.49
0.36
0.46
0.54
0.51
0.47
7.2
9.3
13
19
10
7.3
22
32
55
53
54
20
22
28
33
Et2O
3
Et2O
50
0
4
Et2O
50
50
200
50
200
300
300
300
50
50
300
300
-20
-30
-40
0
-20
-40
-40
-50
0
5
Et2O
6
Et2O
7
acetone
acetone
acetone
acetone
acetone
THF
8
9
10
11
12
13
14
15
17
17
2.0
7.8
5.0
24
THF
-20
-40
-60
THF
THF
a In all entries, (()-2 (50 mg, 0.31 mmol) was used. b Molar equivalent. c Determined by GC analysis. d Conversion calculated from c
) ee (substrate)/(ee (product) + ee (substrate)). e Reference 10. f Lipase PS on Celite. g Vinyl butyrate. h [R]21 -31.3 (c 0.75, CHCl3).
D
i Butanoate (2S,3R)-2b.
FIGURE 3. Temperature effect in the lipase-catalyzed resolu-
tion of (()-3 in acetone.
FIGURE 2. Temperature effect in the lipase-catalyzed resolu-
tion of (()-2: [, in acetone; b, in THF; 2, in Et2O.
has the priority in the stereorecognition, whereas the C-2
stereogenic center is not critical. Similar results are
reported in the resolution of (2-fluoro-2-phenylcyclo-
propyl)methanol,16 in which (2S)-enantiomers reacted
faster than (2R)-ones, while the C-1 stereogenic center,
adjacent to the alcohol moiety, does not affect the
enantiopreference. Accumulation of these examples would
be useful for prediction of the enantioselectivity.
TABLE 2. Lipase PS-C II-Catalyzed Resolution of
2-Aziridinemethanol (()-3 in Acetone
lipase vinyl temp alcohol ester time
entrya (mg) acetateb (°C) % eec % eed (h) conve, f Ef
1
2
3
4
5
6
50g
50
1
1
1
1
5
5
30
25
10
38
65
41
54
23
79
91
93
96
95
96
24
3.0
12
29
15
24
0.11 9.4
0.29 30
0.41 54
0.30 73
0.36 67
0.19 61
50
0
50
300
300
-20
-40
-50
Absolute Configurations of (2S,3R)-2a and (2S,3S)-
3. Compound (2S,3R)-2a in Scheme 1 was converted to
the corresponding alcohol (2S,3R)-2, the absolute config-
uration of which was determined by comparison of its
a In all entries, (()-3 (50 mg, 0.31 mmol) was used. b Molar
equivalent. c Determined by HPLC analysis. d Determined by GC
analysis. e Conversion calculated from c ) ee (substrate)/(ee
(product) + ee (substrate)). f Reference 10. g Lipase PS on Celite.
specific rotation [[R]26 +49.9 (c 1.1, CHCl3)] with that
D
prepared from optically pure azirine-2-methanol (S)-103a
as shown in Scheme 3. The starting compound (S)-10 was
prepared by the previous method in five steps from
cinnamyl alcohol involving the lipase-catalyzed resolution
at low temperatures (-40 °C) in the final step.3a,e Addi-
tion of MeMgBr to (S)-10 at room temperature in THF
gave a 93:7 inseparable mixture of (2S,3R)-2 and (2S,3S)-3
as a result of coordination control. The minor compound
(2S,3S)-3 could not be removed at this stage. The dias-
tereoselectivity was much improved here by the temper-
in the lipase-catalyzed resolution of primary alcohols3,14
is not clear in contrast with that for secondary ones.15
The present results suggest that the C-3 position (3R)
(14) For recent examples: (a) Itoh, T.; Kawai, K.; Hayase, S.; Ohara,
H. Tetrahedron Lett. 2003, 44, 4081-4084. (b) Kurokawa, M.; Shindo,
T.; Suzuki, M.; Nakajima, N.; Ishihara, K.; Sugai, T. Tetrahedron:
Asymmetry 2003, 14, 1323-1333. (c) Murakami, M.; Kamaya, H.;
Kaneko, C.; Sato, M. Tetrahedron: Asymmetry 2003, 14, 201-215. (d)
de Gonzalo, G.; Brieva, R.; Sa´nchez, V. M.; Bayod, M.; Gotor, V. J.
Org. Chem. 2003, 68, 3333-3336.
(16) Rosen, T. C.; Haufe, G. Tetrahedron: Asymmetry 2002, 13,
1397-1405.
(15) Review: Ema, T. Curr. Org. Chem. 2004, 8, 1009-1025.
1372 J. Org. Chem., Vol. 70, No. 4, 2005

3-Methyl-3-phenyl-2-aziridinemethanol
SCHEME 3. Preparation of 2-Aziridinemethanol
(2S,3R)-2 as Reference
methanol, which were prepared by the Neber reaction
followed by the lipase-catalyzed resolution at low tem-
peratures. Use of lipase PS-C II enabled us to carry out
the acylation reaction of the aziridine derivatives without
N-protection. The low-temperature method in the lipase-
catalyzed reaction was proved to be effective for primary
aziridine alcohols 2 and 3. Although (2S,3R)-2 was
prepared independently from (S)-10 for assignment of the
absolute configuration, the method via the Neber reaction
is a shorter and more convenient synthetic pathway with
high diastereoselectivity. The regio- and stereoselective
cleavage of the aziridine skeleton is also under investiga-
tion.
Experimental Section
SCHEME 4. Preparation of (S,S,S)-13
tert-Butyl 3-Phenyl-2H-azirine-2-carboxylate [(()-1a].
To a solution of NH2OH‚HCl (0.28 g, 4.0 mmol) in pyridine
(2 mL) was added tert-butyl benzoyl acetate (5a) (0.44 g, 2.0
mmol) dropwise. After the solution was stirred for 14 h, a usual
workup gave tert-butyl 3-phenyl-3-(hydroxyimino)propanoate
(6a) as a crude product, to which was added TsCl (0.45 g, 2.4
mmol) and pyridine (2 mL). After the solution was stirred for
3 h, toluene was added, and the mixture was filtered under
nitrogen atmosphere to give oxime tosylate 7a as a single
isomer: colorless solid, mp 80-81 °C. IR (KBr) 1724 (CdO),
1303, 1120 (SdO) cm-1. 1H NMR (CDCl3) δ 7.93-7.89 (d, 2H,
J ) 8.2 Hz), 7.56-7.52 (m, 2H), 7.43-7.32 (m, 5H), 3.76
(s, 2H), 2.43 (s, 3H), 1.35 (s, 9H). 13C NMR (CDCl3) δ 165.9,
159.9, 145.0, 132.9, 132.4, 130.9, 129.5, 128.8, 128.6, 127.0,
82.3, 35.6, 27.7, 21.7. Anal. Calcd for C20H23NO5S: C, 61.68;
H, 5.95; N, 3.60. Found: C, 61.44; H, 6.02; N, 3.21. To the
obtained 7a was added Et3N (0.40 g, 4.0 mmol) dropwise at
0 °C, and the mixture was stirred at room temperature for
6.5 h. The usual workup gave a crude product (()-1a, which
was purified by column chromatography (hexane/EtOAc ) 4/1)
to afford 0.31 g of 1a (70% yield from keto ester 5a): colorless
ature control and choice of solvent as compared with the
results reported by Laurent et al.,17 who observed a low
diastereoselectivity of 56:44 in 70% yield in a similar
reaction but at a reflux temperature in toluene. The
mixture of (2S,3R)-2 and (2S,3S)-3 was once transformed
into the corresponding TBS ethers (2S,3R)-11 and (2S,3S)-
12, which were separated by a preparative HPLC, and
deprotected (TBAF) to give pure (2S,3R)-2 [[R]21 +49.7
(c 1.86, CHCl3)]. The absolute configuration of (2S,3R)-
2a was thus determined by comparison of the specific
rotation after conversion to (2S,3R)-2.
D
solid, mp 71-72 °C. IR (KBr) 1770 (CdN), 1724 (CdO) cm-1
.
1H NMR (CDCl3) δ 7.90-7.85 (m, 2H), 7.63-7.56 (m, 3H), 2.75
(s, 1H), 1.46 (s, 9H). 13C NMR (CDCl3) δ 170.8, 158.8, 133.6,
130.2, 129.4, 129.2, 122.5, 81.6, 30.6, 28.1. These spectral data
are consistent with those reported.4b
On the other hand, the absolute configuration of
(2S,3S)-3 was determined by X-ray analysis18 of the
corresponding N-(S)-2-(6-methoxy-2-naphthyl)propanoyl
derivative (S,S,S)-13, which was prepared by the reaction
of (2S,3S)-3 with (S)-2-(6-methoxy-2-naphthyl)propanoic
acid in the presence of DCC (Scheme 4). X-ray structure
shows that the reaction occurred exclusively at the
aziridine nitrogen atom, while the hydroxyl group and
the aziridine three-membered ring remained intact. The
bulky naphthyl moiety is fixed anti to the phenyl and
methyl groups on the aziridine ring. The hydroxyl group
is weakly hydrogen bonded with the oxygen atom of the
carbonyl group of the adjacent 13 intermolecularly.
tert-Butyl 3-Methyl-3-phenylaziridine-2-carboxylate
[(()-8] was prepared by the diastereoselective methylation of
azirine-2-carboxylate 1a with MeMgBr in a similar way to the
reported procedure.4b A solution of azirine ester (()-1a (0.22
g, 1.0 mmol) in THF (5 mL) was cooled to -78 °C and MeMgBr
(3.8 mL, 3.45 mmol, 0.93 M in THF) was added dropwise. The
mixture was stirred at -78 °C for 1.5 h, warmed to -15 °C,
and then stirred for an additional 20 min. The reaction was
quenched with H2O (1 mL) at -78 °C, diluted with EtOAc (50
mL), warmed to room temperature, and then filtered. The
filtrate was evaporated under reduced pressure to give a crude
product, which was purified by column chromatography (hex-
ane/EtOAc ) 4/1) to give 0.15 g of (()-8 (65%). The percent de
value was determined to be higher than 94% by the 1H NMR
analysis of the aziridine ring proton. Compound (()-8: IR
Conclusions
1
(film) 3274 (N-H), 1720 (CdO), 1602 (N-H) cm-1. H NMR
We obtained and assigned the absolute configurations
of four stereoisomers of 3-methyl-3-phenyl-2-aziridine-
(CDCl3) δ 7.46-7.28 (m, 5H), 2.59 (s, 1H), 1.69 (s, 3H), 1.53
(s, 9H). 13C NMR (CDCl3) δ 169.3, 142.9, 128.2, 127.0, 126.0,
82.0, 45.0, 43.1, 28.2, 18.4.
(17) Laurent, A.; Marsura, A.; Pierre, J.-L. J. Heterocycl. Chem.
1980, 17, 1009-1017.
3-Methyl-3-phenyl-2-aziridinemethanol [(()-2]. A solu-
tion of tert-butyl ester of aziridine carboxylate (()-8 (0.93 g,
4.0 mmol) in Et2O (10 mL) was added dropwise to a suspension
of LiAlH4 (0.30 g, 8.0 mmol) in Et2O (5 mL) at 0 °C. The
mixture was stirred at 0 °C for 0.5 h and then at room
temperature for 9 h. The usual workup gave a crude product,
which was purified by recrystallization from Et2O to give
0.49 g of (()-2 as a white solid in 75% yield. The percent de
value was higher than 99% as determined by 1H NMR
analysis. The relative stereochemistry was determined by
(18) The single-crystal growth for (S,S,S)-13 was carried out in
i-Pr2O at room temperature. C24H25NO3, Fw ) 375.47, orthorhombic,
space group P212121, a ) 6.102(2) Å, b ) 9.911(4) Å, c ) 30.75(1) Å, V
) 1859(1) Å3, T ) 150.2 K, Z ) 4, Dcalc ) 1.341 g cm-3, R ) 0.069 for
2615 observed reflections [I > 2.00σ(I)] and 329 variable parameters.
All measurements were made on a Rigaku RAXIS-IV imaging plate
area detector with Mo KR radiation. Crystallographic data for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication
no. CCDC-255492.
J. Org. Chem, Vol. 70, No. 4, 2005 1373

Sakai et al.
comparison of the 13C NMR data with those reported.17
(2R*,3S*)-(()-2: mp 72-73 °C (lit.17 mp 74-76 °C). IR (KBr)
3240 (N-H), 2818 (O-H) cm-1. 1H NMR (CDCl3) δ 7.34-7.24
(m, 5H), 3.92 (dd, 1H, J ) 5.5, 11.7 Hz), 3.74 (dd, 1H, J ) 6.6,
11.7 Hz), 2.52 (dd, 1H, J ) 5.5, 6.6 Hz), 1.85 (br s, 2H), 1.54
(s, 3H). 13C NMR (CDCl3) δ 144.5, 128.5, 127.1, 125.9, 61.3,
44.0, 42.3, 20.1.
was monitored by TLC. The lipase was removed by filtration
through Celite pad quickly, and the filtrate was concentrated
under reduced pressure. The products were separated by
column chromatography (EtOAc), and the enantiomeric puri-
ties of both 2 and 2a were determined by capillary GC, using
a CP-cyclodextrin-â-2,3,6-M-19 column (Chrompack, Φ 0.25
mm × 25 m, oven temperature 130 °C): retention time ) 56.9
min for (2S,3R)-2, 59.1 min for (2R,3S)-2, 61.3 min for (2R,3S)-
2a, and 63.8 min for (2S,3R)-2a.
tert-Butyl 3-Methyl-2H-azirine-2-carboxylate [(()-1b]
was prepared from tert-butyl acetoacetate (5b) in a similar way
to the reported procedure.6 â-Keto ester 5b (3.16 g, 20 mmol)
was added to a solution of NH2OH‚HCl (1.53 g, 22 mmol) and
NaHCO3 (1.85 g, 22 mmol) in aqueous MeOH. After the
mixture was stirred at room temperature for 1 h, a usual
workup gave an oily crude product 6b, which was dissolved
in CH2Cl2 (10 mL). A solution of TsCl (3.81 g, 20 mmol) and
pyridine (1.58 g, 20 mmol) in CH2Cl2 (10 mL) was added, and
the mixture was stirred for 3 h. Usual workup and purification
by column chromatography (EtOAc/hexane ) 4/1) gave 7b
(5.06 g, 77%) as a mixture of syn/anti isomers (32/68 by NMR).
The stereochemistry of syn and anti isomers was not assigned
spectroscopically.6 The major isomer was isolated by recrys-
tallization from Et2O for analysis. Oxime tosylate 7b: major,
white solid, mp 93-95 °C. IR (KBr) 1720 (CdO), 1355, 1157
(SdO) cm-1. 1H NMR (CDCl3) δ 7.84 (d, 2H, J ) 8.2 Hz), 7.32
(d, J ) 8.2 Hz), 3.16 (s, 2H), 2.43 (s, 3H), 2.03 (s, 3H), 1.39 (s,
9H). 13C NMR (CDCl3) δ 166.7, 162.0, 144.8, 132.4, 129.4,
128.5, 82.0, 41.8, 27.7, 21.5, 15.8. Minor: 1H NMR (CDCl3) δ
7.84 (d, 2H, J ) 8.2 Hz), 7.32 (d, J ) 8.2 Hz), 3.34 (s, 2H),
2.43 (s, 3H), 2.00 (s, 3H), 1.43 (s, 9H).
To a solution of tosylate 7b (2.94 g, 8.98 mmol) in CH2Cl2
(20 mL) was added Et3N (1.00 g, 9.87 mmol) dropwise with
ice cooling. After the mixture was stirred at room temperature
for 6.5 h, the usual workup gave an oily crude product,
which was purified by bulb-to-bulb distillation (100-110 °C
(4 mmHg); lit.6 110 °C (0.5 mmHg)) to give 0.92 g (66%) of
(()-1b as a colorless oil. Azirine ester 1b: IR (film): 1801 (Cd
N), 1732 (CdO) cm-1. 1H NMR (CDCl3) δ 2.50 (s, 3H), 2.34 (s,
1H), 1.45 (s, 9H). 13C NMR (CDCl3) δ 171.1, 159.3, 81.4, 29.7,
28.1, 12.6.
(2S,3R)-2a: colorless oil. IR (film) 3295 (N-H), 1731 (Cd
1
O), 1603 (N-H) cm-1. H NMR (CDCl3) δ 7.33-7.24 (m, 5H),
4.26 (d, 2H, J ) 6.6 Hz), 2.48 (t, 1H, J ) 6.6 Hz), 2.11 (s, 3H),
1.55 (s, 3H). 13C NMR (CDCl3) δ 170.9, 144.3, 128.5, 127.1,
125.9, 64.5, 41.6, 40.7, 20.9, 20.3. [R]29D +23.8 (c 0.33, CHCl3),
70% ee. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82.
Found: C, 70.08; H, 7.36; N, 7.08.
(2R,3S)-2: colorless oil. [R]21D -31.3 (c 0.75, CHCl3), 87% ee.
Butanoate of 3-Methyl-3-phenyl-2-aziridinemethanol
(2S,3R)-2b (Table 1, entry 10): colorless oil. IR (film) 3242
(N-H), 1735 (CdO), 1602 (N-H) cm-1 1H NMR (CDCl3) δ
.
7.34-7.22 (m, 5H), 4.32 (dd, 1H, J ) 6.6, 11.8 Hz), 4.24 (dd,
1H, J ) 6.6, 11.8 Hz), 3.47 (br s, 1H), 2.50 (t, 1H, J ) 6.6 Hz),
2.36 (t, 2H, J ) 7.4 Hz), 1.78-1.60 (m, 2H), 1.56 (s, 3H), 0.93
(t, 3H, J ) 7.4 Hz). 13C NMR (CDCl3) δ 173.6, 144.4, 128.5,
127.1, 126.0, 64.3, 41.7, 40.8, 36.2, 20.4, 18.5, 13.7. Anal. Calcd
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.32;
H, 8.26; N, 5.65. GC analysis (oven temperature 150 °C,
retention time of the butanoate: 69.2 min for (2R,3S) and 71.3
min for (2S,3R). [R]21 +31.8 (c 0.75, CHCl3), 90% ee.
D
General Procedure for the Lipase-Catalyzed Resolu-
tion of (()-3. To a mixture of (()-3 (50 mg, 0.30 mmol) and
lipase PS or PS-C II in acetone (5 mL) was added vinyl acetate
at the temperature indicated in Table 2. The resulting suspen-
sion was vigorously stirred, and the reaction progress was
monitored by TLC. After workup in a usual manner, the
percent ee value of (2R,3R)-3a was determined by capillary
GC using a CP-cyclodextrin-â-2,3,6-M-19 column (Chrompack,
Φ 0.25 mm × 25 m, oven temperature 130 °C): retention time
) 47.6 min for (2S,3S)-3a and 49.4 min for (2R,3R)-3a. The
enantiomeric purity of (2S,3S)-3 was determined by HPLC
using a Chiralpak AD-H column (hexane/i-PrOH ) 9/1, flow
rate 1.0 mL/min, detection 254 nm), 8.3 min for (2S,3S)-3 and
9.7 min for (2R,3R)-3).
tert-Butyl (2R*,3R*)-3-Methyl-3-phenylaziridine-2-car-
boxylate [(()-9]. A solution of azirine ester 1b (1.29 g, 8.31
mmol) in THF (30 mL) was cooled to -80 °C, and a THF
solution of PhMgBr [magnesium turning (0.81 g, 33.25 mmol),
bromobenzene (5.22 g, 33.25 mmol), and 50 mL of THF] was
added dropwise through a dropping funnel. After the mixture
was stirred at -80 °C for 1 h, the reaction was quenched with
H2O (2 mL) at -80 °C. A usual workup gave crude products
(isomeric ratio of 76/24 by 1H NMR), which were separated
by column chromatography (hexane/EtOAc ) 4/1) to give the
major (0.93 g, 48%) and minor products (0.32 g, 17%).
Major product: (()-9, colorless oil, Rf 0.30 (hexane/EtOAc
(2S,3S)-3: white solid, mp 107-108 °C. [R]26D +89.8 (c 1.10,
CHCl3), 99% ee.
(2R,3R)-3a: colorless oil. IR (film) 3305 (N-H), 1732 (Cd
1
O), 1604 (N-H) cm-1. H NMR (CDCl3) δ 7.41-7.23 (m, 5H),
3.86 (dd, 1H, J ) 5.4, 11.8 Hz), 3.49 (dd, 1H, J ) 7.4, 11.8
Hz), 2.49 (dd, 1H, J ) 5.4, 7.4 Hz), 2.03 (s, 3H), 1.64 (s, 3H).
13C NMR (CDCl3) δ 170.9, 140.1, 128.3, 127.5, 127.1, 65.4, 42.5,
41.0, 28.0, 20.9. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37;
N, 6.82. Found: C, 70.06; H, 7.51; N, 6.82. [R]26D -31.5 (c 0.98,
CHCl3), 94% ee.
) 2/1). IR (film) 3240 (N-H), 1716 (CdO), 1610 (N-H) cm-1
.
1H NMR (CDCl3) δ 7.32-7.23 (m, 5H), 2.67 (s, 1H), 1.70 (br s,
1H), 1.56 (s, 3H), 1.19 (s, 9H). 13C NMR (CDCl3) δ 167.7, 139.5,
127.6, 126.8, 126.7, 80.9, 45.5, 43.2, 27.2, 27.0. Anal. Calcd
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.35;
H, 8.12; N, 6.11.
(2S,3R)-3-Methyl-3-phenyl-2-aziridinemethanol [(2S,3R)-
2] from 3-Phenyl-2H-azirine-2-methanol [(S)-10]. To a
solution of (S)-103a (150 mg, 1.0 mmol) in THF (15 mL) was
added MeMgBr [4.6 mL (4.0 mmol, 0.87 M in THF)] dropwise
at room temperature and the mixture was stirred at room
temperature for 3 h. A usual workup and purification by
column chromatography (EtOAc) gave a 93:7 (1H NMR)
inseparable diastereomeric mixture of (2S,3R)-2 and (2S,3S)-3
(126 mg, 71% yield). Thus, the mixture (93 mg, 0.57 mmol)
was dissolved in THF (3 mL), and a THF (2 mL) solution of
imidazole (82 mg, 1.2 mmol) and a THF (3 mL) solution of
TBS-Cl (181 mg, 1.2 mmol) were added subsequently. After
being stirred at room temperature for 4.5 h, the mixture was
treated in a usual manner to give products, which were
purified by column chromatography (hexane/EtOAc ) 5/1) to
afford a mixture of TBS ethers (2S,3R)-11 and (2S,3S)-12 (132
mg, 84% yield) as oily products. The mixture was separated
by preparative HPLC on a YMC-Pack SIL column (Φ 6 mm ×
Minor product: (()-8,4b Rf 0.60 (hexane/EtOAc ) 2/1).
3-Methyl-3-phenyl-2-aziridinemethanol [(()-3] was pre-
pared in 72% yield and >99% de (1H NMR) by a similar
procedure to that for (()-2. (()-3: mp 102-103 °C. IR (KBr)
3251 (N-H), 2821 (O-H), 1603 (N-H) cm-1. 1H NMR (CDCl3)
δ 7.42-7.23 (m, 5H), 3.38 (dd, 1H, J ) 5.6, 11.7 Hz), 3.11 (1H,
dd, J ) 7.0, 11.7 Hz), 2.47 (dd, J ) 5.6, 7.0 Hz), 1.64 (s, 3H),
1.47 (br s, 2H). 13C NMR (CDCl3) δ 140.4, 128.2, 127.4, 126.9,
62.5, 44.6, 43.0, 28.0. The 13C NMR spectral data are consistent
with those reported.17
General Procedure for the Lipase-Catalyzed Resolu-
tion of (()-2. To a mixture of (()-2 (50 mg, 0.30 mmol) and
lipase PS or PS-C II in an organic solvent (5 mL) was added
vinyl acetate at the temperature indicated in Table 1. The
suspension was vigorously stirred, and the reaction progress
1374 J. Org. Chem., Vol. 70, No. 4, 2005

3-Methyl-3-phenyl-2-aziridinemethanol
250 mm, hexane/EtOAc ) 3/1) to afford a major product of
95 mg (72%) and a minor product of 5 mg.
tion of (2S,3S)-3 [73 mg, 0.45 mmol, 90% ee, obtained by lipase-
catalyzed resolution of (()-3] in CH3CN (10 mL) was added to
a mixture of (S)-naproxen (154 mg, 0.67 mmol) and DCC (185
mg, 0.90 mmol) in CH3CN (10 mL). The mixture was stirred
for 3.5 h at room temperature, and a usual workup gave a
crude product, which was purified by column chromatography
(hexane/Et2O ) 1/5) and then recrystallized from i-Pr2O to give
a crystalline product (85 mg, 50%): mp 132-133 °C. IR (KBr)
Major product: (2S,3R)-11, retention time ) 12.0 min, g
99% de. IR (film) 3285 (N-H), 1064 (Si-O) cm-1 1H NMR
.
(CDCl3) δ 7.34-7.25 (m, 5H), 3.91 (dd, 1H, J ) 5.4, 11.2 Hz),
3.76 (dd, 1H, J ) 6.6, 11.2 Hz), 2.35 (t, 1H, J ) 6.6 Hz), 1.53
(s, 3H), 0.92 (s, 9H), 0.10 (s, 6H). 13C NMR (CDCl3) δ 145.4,
128.5, 126.9, 126.2, 62.8, 44.3, 41.4, 26.0, 20.1, 18.4, -5.1, -5.2.
Anal. Calcd for C16H27NOSi: C, 69.26; H, 9.81; N, 5.05.
Found: C, 69.61; H, 9.91; N, 5.09. [R]26D +22.7 (c 1.40, CHCl3).
Minor product: (2S,3S)-12, retention time ) 10.8 min, g99%
de. IR (film) 3260 (N-H), 1078 (Si-O) cm-1. 1H NMR (CDCl3)
δ 7.43-7.21 (m, 5H), 3.40 (dd, 1H, J ) 5.4, 10.8 Hz), 3.09 (dd,
1H, J ) 7.0, 10.8 Hz), 2.36 (dd, 1H, J ) 5.4, 7.0 Hz), 1.61 (s,
3H), 1.37 (br s, 1H), 0.82 (s, 9H), -0.11 (s, 6H). 13C NMR
(CDCl3) δ 140.8, 128.0, 127.8, 126.7, 63.5, 44.6, 42.7, 28.2, 25.9,
18.3, -5.5. Anal. Calcd for C16H27NOSi: C, 69.26; H, 9.81; N,
1
3327 (O-H), 1651 (CdO) cm-1. H NMR (600 MHz, acetone-
d6) δ 7.83 (d, 1H, J ) 1.8 Hz), 7.82 (d, 1H, J ) 9.6 Hz), 7.79
(d, 1H, J ) 9.6 Hz), 7.53 (dd, 1H, J ) 1.8, 8.4 Hz), 7.35-7.30
(m, 3H), 7.28-7.22 (m, 3H), 7.16 (dd, 1H, J ) 3.0, 8.4 Hz),
4.16 (q, 1H, J ) 7.2 Hz), 3.16-3.14 (m, 2H), 2.68 (t, 1H, J )
6.0 Hz), 1.52 (s, 3H), 1.51 (d, 3H, J ) 7.2 Hz). 13C NMR
(acetone-d6) δ 183.9, 158.6, 140.2, 137.4, 134.8, 129.9, 128.8,
128.1, 128.0, 127.2, 119.7, 106.5, 61.5, 55.6, 50.1, 49.4, 48.5,
23.5, 20.2. Anal. Calcd for C24H25NO3: C, 76.77; H, 6.71; N,
3.73. Found: C, 76.52; H, 6.69; N, 3.42. [R]25D +133.0 (c 0.20,
Et2O), 99% ee.
5.05. Found: C, 69.46; H, 9.78; N, 5.08. [R]26 +19.5 (c 0.20,
D
CHCl3).
A THF solution of TBAF [0.41 mL, 0.41 mmol (1 M in THF)]
was added to a THF (1 mL) solution of (2S,3R)-11 (94 mg, 0.34
mmol) at room temperature. After being stirred at room
temperature for 2 h, the mixture was treated in a usual
manner to give a product, which was purified by column
chromatography (EtOAc) to afford (2S,3R)-2 quantitatively as
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology
of Japan. We thank the SC-NMR Laboratory of Oka-
a colorless oil. [R]21 +49.7 (c 1.86, CHCl3).
1
yama University for H and 13C NMR measurements
D
Transformation of (2S,3R)-2a to (2S,3R)-2. A solution
of (2S,3R)-2a [98 mg, 0.48 mmol, 94% ee, obtained by the
lipase-catalyzed resolution of (()-2] in Et2O (5 mL) was added
dropwise to a suspension of LiAlH4 (36 mg, 0.95 mmol) in Et2O
(5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and
then at room temperature for 2.5 h. The usual workup gave a
crude product which was purified by column chromatography
(EtOAc) to afford 45 mg (58%) of (2S,3R)-2 as a colorless oil.
[R]26D +49.9 (c 1.10, CHCl3), the same sign (+) as that obtained
from (S)-10.
and the Venture Business Laboratory of Okayama
University for X-ray analysis.
Supporting Information Available: Copies of 1H and 13
C
NMR spectra of all new compounds (2a, 2b, 3a, 7a, 9, 11, 12,
and 13), computational data for 4a, 4b, and 6a, and X-ray
crystallographic analytical data for (S,S,S)-13 (CIF file). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(2S,3S)-N-[(S)-2-(6-Methoxy-2-naphthyl)propionyl]-3-
methyl-3-phenyl-2-aziridinemethanol (S,S,S)-13. A solu-
JO048243N
J. Org. Chem, Vol. 70, No. 4, 2005 1375