Diastereoselective aziridination of chiral electron-deficient olefins with N-chloro-N-sodiocarbamates catalyzed by chiral quaternary ammonium salts

Article abstract of DOI:10.1021/jo2010632

Chiral quaternary ammonium salt-catalyzed diastereoselective aziridination of electron-deficient olefins that possess a chiral auxiliary with N-chloro-N-sodiocarbamates was developed. The key to high stereoselectivity was found to be the employment of the

Full text of DOI:10.1021/jo2010632

ARTICLE
pubs.acs.org/joc
Diastereoselective Aziridination of Chiral Electron-Deficient Olefins
with N-Chloro-N-sodiocarbamates Catalyzed by Chiral Quaternary
Ammonium Salts
Yuta Murakami,† Youhei Takeda,‡ and Satoshi Minakata*,†
†Department of Applied Chemistry and ‡Frontier Research Base for Global Young Researchers, Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
S Supporting Information
b
ABSTRACT: Chiral quaternary ammonium salt-catalyzed diaster-
eoselective aziridination of electron-deficient olefins that possess a
chiral auxiliary with N-chloro-N-sodiocarbamates was developed.
The key to high stereoselectivity was found to be the employment
of the “matching” stereochemical combination of chiral auxiliary/
ammonium salt. For example, when 3-phenyl-(4R,7S)-4-methyl-7-
isopropyl-4,5,6,7-tetrahydroindazole (L-menthopyrazole) as a chir-
al auxiliary and a cinchonidine-derived chiral ammonium salt as a
catalyst were applied to the reaction system, perfect diastereoselec-
tivity was realized. Furthermore, the preparation of enantiomerically pure aziridines by removal of the chiral auxiliary was demonstrated.
Scheme 1. Enantioselective Aziridination of Electron-Defi-
cient Olefins with N-Chloro-N-sodiocarbamate
’ INTRODUCTION
Aziridines, three-membered aza-heterocycles, constitute an im-
portant class of biologically active compounds, such as azinomycin,
porfiromycin, and mitomycin, which are potent antitumor or
antibiotic agents.1 Not only are aziridines biologically interesting
components but they also serve as versatile building blocks in
organic synthesis. For example, aziridines can be ring-opened with
various nucleophiles to afford 1,2-difunctionalized products.2 Some
types of aziridines can also be transformed into useful products by
rearrangement,3 cycloaddition,4 and carbonylative ring expansion
reactions.5 Therefore, tremendous effort has been devoted to the
development of efficient and stereoselective synthetic methods for
aziridines.1,6 Among the myriad methods available, aziridination of
olefins represents one of the most efficient approaches,7 because
aziridines are obtained in only a single step from readily available
starting materials. Especially, aziridination of electron-deficient
olefins such as R,β-unsaturated carbonyl compounds8 should be
useful, because the aziridinated products can be further derivatized.
For example, ring-opening reaction of ester-substituted aziridines
gives amino acid derivatives.9 Hence, the developments of catalytic
asymmetric variants have led to a breakthrough in this area. Evans
and co-workers reported the first catalytic asymmetric nitrene
transfer to R,β-unsaturated esters using a bis(oxazoline)ꢀcopper
complex as a catalyst.10 Although sufficient chemical yields and
enantioselectivities were obtained by the reaction, the scope of the
substrates were limited to cinnamate esters. Prabhakar and co-
workers developed chiral ammonium salt-catalyzed enantioselec-
tive aziridination of R,β-unsaturated esters, sulfones, and sulfines.11
Asymmetric aziridination of chalcones using a tertiary amine
(Tr€oger’s base or quinine) was reported by the Shi7 and Armstrong
groups.12 The methods given above have shown great promise;
however, they require transition-metal catalysts or strong bases for
the generation of the active nitrogen species. In this regard,
organocatalytic asymmetric protocols have recently been reported,
whereas the substrates were yet limited to R,β-unsaturated
aldehydes13 and ketones.14 We have developed a new aziridination
reaction of electron-deficient olefins such as R,β-unsaturated
ketones, esters, sulfones, and amides with a chloramine salt, N-
chloro-N-sodiocarbamate, in the presence of a phase-transfer
catalyst.15 Our preliminary investigation also showed that the
reaction could be extended to the enantioselective version with
the aid of a chiral ammonium salt, providing enantioenriched
aziridines with good enantiomeric excess (ee) values up to 87% ee
(Scheme 1). Nevertheless, the results do not meet the require-
ments of modern asymmetric synthesis in terms of enantioselec-
tivity. We envisaged that introduction of chiral auxiliaries16 to
substrates should allow for more highly diastereoselective aziridi-
nation, and thus that literally enantiopure aziridines would be
obtained by the removal of the auxiliaries (Scheme 2). Tardella and
co-workers have reported chiral auxiliary-assisted diastereoselective
aziridination using the combination of nosyloxycarbamates as a
Received: May 25, 2011
Published: June 15, 2011
r
2011 American Chemical Society
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Scheme 2. Strategy for the Diastereoselective Aziridination of Chiral Electron-Deficient Olefins
Table 1. Influence of Quaternary Ammonium Catalysts on the Aziridination Reaction of Chiral Electron-Deficient Olefin 1a-(S)
with 2aa
entry
*cat. (10 mol %)
yield of 3a (%)b
drc
1
2
3
4
5
6
7
Et3(PhCH2)N+Clꢀ
83
90
80
88
87
89
94
57:43
41:59
42:58
76:24
81:19
79:21
80:20
CD1
CD2
CN1
CN2
CN3
CN4
a Reaction conditions: 1a-(S) (0.15 mmol), 2a (0.15 mmol), and *cat. (0.015 mmol) in CH2Cl2 (0.5 mL) at room temperature for 6 h. b Combined
isolated yield. c Diastereomeric ratio of 3a-(S,R):3a-(S,S) determined by 1H NMR of the crude product.
nitrogen source and an inorganic base (CaO).8k,17 Although their
protocols were promising for production of highly enatioenriched
azirizines, olefinic substrates were limited to alkenes bearing two
geminal electron-withdrawing groups. Similarly, some types of N-
amino heterocycles such as N-aminophthalimide, N-aminobenzi-
midazole, and 3-aminoquinazolinone have been applied to diaster-
eoselective aziridination of chiral auxiliary-connected enone
derivatives or utilized as a chiral nitrogen source.18 However, the
use of toxic Pb(OAc)4 is indispensible for the reaction. Herein, we
report a highly diastereoselective aziridination reaction of electron-
deficient olefins having a chiral auxiliary, in which the concomitant
use of a chiral ammonium catalyst is the key to achieving the high
diastereoselectivity. Furthermore, the preparation of enantiopure
aziridines was demonstrated.
experiments.15 The chiral auxiliaries used in this study were easily
prepared from natural amino acids or readily available chiral amino
alcohols. An acryloyl moiety was then introduced to the auxiliaries
according to the procedure described in the literature.20 With the
enone derivatives bearing a chiral auxiliary in hand, we investigated
the reaction of enone 1a-(S) with chloramine salt 2a in the
presence of a quaternary ammonium salt at room temperature
(Table 1). Although the reaction using an achiral phase-transfer
catalyst Et3(PhCH2)N+Clꢀ proceeded smoothly to give the
corresponding aziridine 3a in good yield, the diastereoselectivity
was found to be very poor(entry 1). To improve stereoselectivity, a
series of chiral ammonium salts, which were derived from cinch-
onidine or cinchonine, were examined as a catalyst. The reactions
using chiral catalyst CD1 or CD2 yet resulted in very low
diastereoselectivity in both cases (entries 2 and 3). The use of
catalyst CN1 was found to invert the sense of diastereoselectivity
and resulted in higher stereoisomeric ratio, compared with the
results of entries 2 and 3 (entry 4). The introduction of a bulkier
substituent of an anthracenylmethyl group (CN2) on the quinu-
clidine nitrogen of the catalyst, instead of a benzyl group, improved
’ RESULTS AND DISCUSSION
Oxazolidinone-type chiral auxiliaries19 were initially chosen
because R,β-unsaturated carbonyl compounds bearing an oxazoli-
dinone auxiliary were smoothly aziridinated in our preliminary
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the diastereomeric ratio to 81:19 (entry 5). When the allyloxy
group of CN2 was replaced with benzyloxy (CN3) or propargyloxy
(CN4) groups, the selectivities turned out to be almost the same
with that obtained with catalyst CN2 (entries 6 and 7).
Because the combination of a chiral auxiliary and chiral
ammonium salt CN2 was found to be the most effective in terms
of the diastereomeric ratio of the product, solvent influence on
the selectivity of the reaction was then investigated (Table 2).
Among the solvents examined, nonpolar solvents proved to be
effective for the reaction with respect to dr of the product;
especially CH2Cl2 provided the best result (entries 1 and 2).
Polar solvents such as THF and MeCN were ineffective, giving
lower selectivities (entries 3 and 4).
Table 2. Solvent Effect on Diastereoselectivity of the Aziri-
dination of 1a-(S)a
In order to improve stereoselectivities, various enones bearing
various chiral auxiliaries were examined (Table 3). When an
enone having (S)-4-phenyl oxazolidinone moiety 1b-(S) was
employed as an auxiliary in place of the (S)-4-benzyl counterpart
1a-(S), diastereoselectivity was slightly improved (entry 1).
Chiral olefin 1b-(R) was aziridinated with good diastereoselec-
tivity when catalyst CD2 (entry 2), which is a diastereomer of
CN2, was employed, whereas the combination of chiral olefin
1b-(S) and chiral catalyst CN2 was necessary to induce higher
diastereoselectivity. Both of the major diastereomers formed in
entry
solvent
time (h)
yield (%)b
drc
1
2
3
4
CH2Cl2
toluene
THF
6
6
6
3
87
91
84
83
81:19
78:22
69:31
58:42
MeCN
a Reaction conditions: 1a-(S) (0.15 mmol), 2a (0.15 mmol), and CN2
(0.015 mmol) in the corresponding solvent (0.5 mL) at room tempera-
ture. b Combinedisolatedyield.c Diastereomeric ratio of 3a-(S,R):3a-(S,S)
determined by 1H NMR of the crude product.
Table 3. Diastereoselective Aziridination of Electron-Deficient Olefins Possessing a Chiral Auxiliary with Chloramine Salta
a Reaction conditions: 1 (0.15 mmol), 2a or 2b (0.15 mmol), and *cat. (0.015 mmol) in CH2Cl2 (0.5 mL) at room temperature. b Major diastereomer is
indicated. c Combined isolated yield. d Diastereomeric ratios determined by 1H NMR of the crude product.
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Table 4. Effect of Temperature on Diastereoselective Aziridination of 1g-(R,S)a
entry
R
temperature
time (h)
3b
yield (%)c
drd
1
2
3
4
CH2Ph
t-Bu
ꢀ20 °C
rt
36
9
3g-(R,S,S)
3h-(R,S,S)
3h-(R,S,S)
3h-(R,S,S)
75
90
81
77
95:5
94:6
t-Bu
ꢀ20 °C
ꢀ40 °C
36
80
98:2
t-Bu
>99:<1
a Reaction conditions: 1g-(R,S) (0.15 mmol), 2a or 2b (0.15 mmol), and CD2 (0.015 mmol) in CH2Cl2 (0.5 mL) at room temperature. b Major
diastereomer is indicated. c Combined isolated yield. d Diastereomeric ratios determined by 1H NMR of the crude product.
Because the best result was obtained with the L-menthopyrazole
auxiliary among the chiral auxiliaries surveyed, the influence of
reaction temperature on the reaction of 1g-(R,S) was then inves-
tigated (Table 4). At a lower temperature, higher stereoselectivity
(95:5) was observed (entry 1). Notably, reaction efficiency was
improved by employing N-Boc chloramine salt 2b instead of N-Cbz
chloramine salt 2a (entry 2).23 Furthermore, as the reaction
temperature was lowered, diastereomeric ratio increased (entries
2ꢀ4), and perfect selectivity was achieved at ꢀ40 °C (entry 4).
Diastereoselective aziridination of enone 1g-(S,R), which is
the enantiomer of 1g-(R,S), also successfully proceeded to give
the corresponding aziridine 3h-(S,R,R) in good yield (eq 1).
Excellent diastereoselectivity was attained with the combination
of chiral olefin 1g-(S,R) and catalyst CN2. In this case, the
product 3h-(S,R,R) was the enantiomer of 3h-(R,S,S).
Scheme 3. Proposed Ion-Pairs for Diastereoselective
Aziridination of 1b-(S)
the reaction of 1b-(S) and 1b-(R) were found to be the
enantiomers of each other. Substitution of the phenyl moiety
with a more sterically demanding substituent such as a tert-butyl
group lowered both the reaction efficiency and dr (entry 3).
Chiral enone 1d possessing two phenyl groups and 1e, which is
the conformationally constrained analogue of 1b-(S), reacted
with chloramine salt 2a to afford the corresponding aziridines 3d
and 3e in high yield, while diastereomeric ratios were not
improved (entries 4 and 5) compared with that obtained with
1b-(S). Trans-disubstituted chiral enone 1f was also converted to
the desired aziridine 3f with retention of the configuration
around the olefinic bond by the reaction with tert-butyloxycar-
bonyl N-chloro-N-sodiocarbamate (2b) (entry 6).21 In our
previous study, we found that a series of pyrazole auxiliaries
were effective to obtain high enantioselectivity in a similar
reaction system. Therefore, a pyrazole-containing chiral auxiliary,
L-menthopyrazole,22 was also examined. Chiral enone 1g was
aziridinated by 2a with good diastereoselectivity (entry 7).
In the reaction of (S)-configured chiral olefin 1b-(S) with
chloramine salt 2a catalyzed by CN2, major diastereomer was
found to be (S,R)-aziridine. To account for the observed
stereochemical outcome, it could be reasonable to assume that
a chiral ammonium salt/enolate ion pair is involved in this
reaction (Scheme 3). According to the X-ray crystallographic
data of CD2 and modeling studies,24 N-anthracenylmethylated
quaternary ammonium salts would likely take a conformation
where one of the tetrahedron faces formed by the ammonium
group is blocked by the 9-anthracenylmethyl substituent, whose
spatial position is fixed for steric reason. In addition, a bicyclic
ring system and an allyloxy group would shield the two other
faces of the tetrahedron, leaving the space above the remaining
face open. Thus, the enolate approaches from the open face to
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form the two possible ion pairs (IP1 and IP2). The π-conjuga-
tion of the enolate could adopt a face to face πꢀπ interaction
with the quinoline ring.25 Cyclization from the opposite side of
the quinoline moiety starting from IP1 and IP2 should give
3a-(S,R) and 3a-(S,S), respectively. In pathway A, the phenyl
group at the C4 position of the oxazolidinone auxiliary is pointing
up to avoid steric interactions with the rest of the substituents of
the enolate and the ammonium catalyst. In pathway B, formation
of the ion-pair IP2 would be less favorable because of steric
repulsion between the phenyl group of the chiral oxazolidinone
and the ammonium catalyst.
In all cases, each of the diastereomers of aziridines 3 was
readily separated by silica gel column chromatography. More-
over, the versatility of the method was demonstrated by prepara-
tion of enantiopure methyl ester-substituted aziridine 3h-(S)
from 3g-(R,S,S) (eq 2). When 3g-(R,S,S) was treated with
MeOH in the presence of a catalytic amount of DMAP,26
methanolysis of the acyl auxiliary proceeded smoothly to give
enantiopure 3i-(S) in 78% yield along with recovery of the chiral
auxiliary in 86% yield.
(GPC) was performed withanLCsystemequippedwith twopolystyrene-
gel columns using chloroform as an eluent. Analytical thin layer chroma-
tography (TLC) was performed using silica gel plates. Visualization was
accomplished with UV light (254 nm) and spraying with an ethanolic
phosphomolybdic acid solution followed by heating.
Typical Procedure for Diastereoselective Aziridination. A
suspension of chiral olefin 1 (0.15 mmol), chloramine salt 2 (0.15 mmol),
and ammonium catalyst (0.015 mmol) was stirred inCH2Cl2 (0.5 mL) for
the durations indicated. The solution was then diluted with Et2O (20 mL)
and filtered, and the solvent was evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica gel (eluent:
hexane/AcOEt) to give the corresponding aziridines 3.
Removal of the Chiral Auxiliary of 3g-(R,S,S). A solution of
aziridine 3g-(R,S,S) (35.5 mg, 0.09 mmol) and 4-(N,N-dimethylami-
no)pyridine (3.3 mg, 0.03 mmol) was stirred in MeOH (0.5 mL) at
room temperature for 5 h. The solvent was then evaporated under
reduced pressure, and the resulting residue was immediately purified
using silica gel column chromatography (eluent: hexane/AcOEt) to give
the methyl ester-substituted aziridine 3i-(S).
(4S)-3-Acryloyl-4-benzyl-2-oxazolidinone [1a-(S)]. Spectroscopic
data of compounds were in agreement with those for the previously
reported material.27 1H NMR (270 MHz, CDCl3) δ 2.81 (dd, 1H, J =
9.5, 13.5 Hz), 3.32 (dd, 1H, J = 3.2, 13.5 Hz), 4.16ꢀ4.26 (m, 2H),
4.69ꢀ4.78 (m, 1H), 5.93 (dd, 1H, J = 1.6, 10.5 Hz), 6.60 (dd, 1H, J = 1.6,
17.0 Hz), 7.20ꢀ7.36 (m, 5H), 7.51 (dd, 1H, J = 10.5, 17.0 Hz); 13C
NMR (68 MHz, CDCl3) δ 37.7, 55.2, 66.2, 127.2, 128.8, 129.2, 131.7,
135.0, 153.1, 164.6
(4S)-3-Acryloyl-4-phenyl-2-oxazolidinone [1b-(S)]. Spectroscopic
data of compounds were in agreement with those for the previously
reported material.28 1H NMR (270 MHz, CDCl3) δ 4.31 (dd, 1H, J =
3.8, 8.9 Hz), 4.72 (dd, 1H, J = 8.9, 8.9 Hz), 5.49 (dd, 1H, J = 3.8, 8.9 Hz),
5.88 (dd, 1H, J = 1.6, 10.5 Hz), 6.48 (dd, 1H, J = 1.6, 16.7 Hz),
7.30ꢀ7.43 (m, 5H), 7.52 (dd, 1H, J = 10.5, 16.7 Hz); 13C NMR (68
MHz, CDCl3) δ 57.7, 70.1, 125.9, 127.0, 128.6, 129.1, 132.1, 138.6,
153.4, 164.2.
(4R)-3-Acryloyl-4-phenyl-2-oxazolidinone [1b-(R)]. Spectroscopic
data of compounds were in agreement with those for the previously
reported material.29 1H NMR (270 MHz, CDCl3) δ 4.30 (dd, 1H, J =
3.8, 8.9 Hz), 4.72 (dd, 1H, J = 8.9, 8.9 Hz), 5.49 (dd, 1H, J = 3.8, 8.9 Hz),
5.88 (dd, 1H, J = 1.6, 10.3 Hz), 6.48 (dd, 1H, J = 1.6, 17.0 Hz),
7.31ꢀ7.42 (m, 5H), 7.52 (dd, 1H, J = 10.3, 17.0 Hz); 13C NMR (68
MHz, CDCl3) δ 57.7, 70.0, 125.8, 127.0, 128.6, 129.1, 132.1, 138.6,
153.4, 164.2.
(4S)-3-Acryloyl-4-tert-butyl-2-oxazolidinone [1c-(S)]. Spectroscopic
data of compounds were in agreement with those for the previously reported
material.30 1H NMR (270 MHz, CDCl3) δ 0.95 (s, 9H), 4.24ꢀ4.33 (m,
2H), 4.52 (dd, 1H, J = 2.4, 6.8 Hz), 5.91 (dd, 1H, J = 1.9, 10.5 Hz), 6.54 (dd,
1H, J = 1.9, 17.0 Hz), 7.53 (dd, 1H, J = 10.5, 17.0 Hz); 13C NMR (68 MHz,
CDCl3) δ 25.6, 35.9, 60.8, 65.2, 127.2, 131.6, 154.3, 164.9.
’ CONCLUSION
Chiral auxiliary-assisted diastereoselective aziridination of
enones with N-chloro-N-sodiocarbamates has been developed.
The aziridination was accelerated by a catalytic amount of a
quaternary ammonium salt. The combination of a chiral auxiliary
and a chiral ammonium salt with appropriate stereochemistry
was crucial in terms of the diastereomeric ratio. The chiral
auxiliary derived from menthol was found to be the most
effective. This efficient and convenient method for diastereose-
lective aziridination could be a general method for the synthesis
of enantiomerically pure aziridines. Further research is currently
underway to synthesize natural or highly functionalized com-
pounds using enantiopure aziridines.
(4S,5R)-3-Acryloyl-4,5-diphenyl-2-oxazolidinone [1d-(S,R)]. Color-
less solid; mp 117ꢀ119 °C; Rf = 0.33 (hexane/EtOAc, 7:3, v/v, silica
’ EXPERIMENTAL SECTION
1
gel plate); IR (KBr) 1695, 1768 cmꢀ1; H NMR (270 MHz, CDCl3)
General Experimental Methods. All reactions were carried out
under a nitrogen atmosphere. Melting points were determined on a
melting point apparatus and are uncorrected. Infrared (IR) spectra were
obtained on an infrared spectrophotometer. The 1H and 13C NMR
δ 5.73 (dd, 1H, J = 1.9, 10.5 Hz), 5.93(d, 1H, J = 10.3 Hz), 5.94 (d, 1H,
J = 10.3 Hz), 6.53 (dd, 1H, J = 1.9, 17.0 Hz), 6.86ꢀ6.90 (m, 2H),
6.96ꢀ7.00 (m, 2H), 7.08ꢀ7.14 (m, 6H), 7.63 (dd, 1H, J = 10.5, 17.0
Hz); 13C NMR (68 MHz, CDCl3) δ 62.9, 80.4, 126.0, 126.5,
127.0, 127.9, 128.1, 128.2, 128.3, 132.3, 132.6, 134.1, 153.5, 164.0;
MS (EI) m/z (relative intensity, %) 293 (M+, 9), 249 (15), 132 (100),
77 (16), 55 (50); HRMS (EI) calcd for C18H15NO3 (M)+ 293.1053,
found 293.1052; [R]16D ꢀ39.7 (c 0.95, CHCl3).
spectra were recorded on a NMR spectrometer (1H NMR, 270 MHz; 13
C
NMR, 68 MHz) using tetramethylsilane as an internal standard. Mass
spectra were measured with a mass spectrometer. High resolution mass
spectral data were obtained on a mass spectrometer. High performance
liquid chromatography (HPLC) was performed using an LC system
equipped with a chiral column and UV detector. Optical rotations were
measured on a digital polarimeter. Flash column chromatography (FCC)
was performed on silica gel. Preparative gel permeation chromatography
(3aS,8aR)-3-Acryloyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-
2-one [1e-(S,R)]. Colorless solid; mp 142ꢀ143 °C; Rf = 0.35 (hexane/
EtOAc, 7:3, v/v, silica gel plate); IR (KBr) 1689, 1782 cmꢀ1; 1H NMR
(270 MHz, CDCl3) δ 3.40ꢀ3.42 (m, 2H), 5.32 (ddd, 1H, J = 3.2, 4.1,
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7.0 Hz), 5.93 (dd, 1H, J = 1.6, 10.5 Hz), 6.01 (d, 1H, J = 7.0 Hz), 6.63 (dd,
1H, J = 1.6, 16.7Hz), 7.26ꢀ7.36 (m, 3H), 7.51 (dd, 1H, J = 10.5, 16.7 Hz),
7.67 (d, 1H, J = 7.3 Hz); 13C NMR (68 MHz, CDCl3) δ 37.9, 63.1, 78.1,
125.0, 127.1, 127.2, 127.9, 129.7, 131.7, 138.7, 139.2, 152.6, 165.0; MS
(EI) m/z (relative intensity, %) 229 (M+, 3), 185 (22), 157 (46), 130
(21), 77 (13), 55 (100); HRMS (EI) calcd for C13H11N1O3 (M)+
229.0739, found 229.0740; [R]16D +441.4 (c 0.99, CHCl3).
intensity, %) 380 (M+, 5), 245 (6), 91 (100); HRMS (EI) calcd for
C21H20N2O5 (M)+ 380.1373, found 380.1374; [R]15 +23.8 (c 1.06,
D
CHCl3).
(4S)-3-[{(20R)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-phen-
yl-2-oxazolidinone [3b-(S,R)] (major isomer). Colorless oil (45.7 mg,
83%, 87:13); Rf = 0.35 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (neat)
1732, 1784 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 2.51ꢀ2.53 (m, 2H),
4.27 (dd, 1H, J = 3.5, 8.9 Hz), 4.55 (dd, 1H, J = 3.5, 4.9 Hz), 4.60 (dd, 1H,
J = 8.9, 8.9 Hz), 5.07 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H, J = 12.2 Hz), 5.22
(dd, 1H, J = 3.5, 8.9 Hz), 7.23ꢀ7.26 (m, 2H), 7.32ꢀ7.36 (m, 8H); 13C
NMR (68 MHz, CDCl3) δ 32.5, 34.0, 57.7, 68.4, 70.4, 125.8, 128.2, 128.3,
128.4, 128.7, 129.0, 135.3, 138.0, 153.3, 160.5, 166.5; MS (EI) m/z (relative
intensity, %) 366 (M+, 9), 231 (3), 91 (100); HRMS (EI) calcd for
(4S)-3-{(E)-3-(Ethoxycarbonyl)propenyl}-4-phenyl-2-oxazolidinone
[1f-(S)]. Colorless solid; mp 101ꢀ102 °C; Rf = 0.30 (hexane/EtOAc,
7:3, v/v, silica gel plate); IR (KBr) 1632, 1689, 1724, 1788 cmꢀ1
;
1H NMR (270 MHz, CDCl3) δ 1.31 (t, 3H, J = 7.0 Hz), 4.26 (q, 2H,
J = 7.0 Hz), 4.34 (dd, 1H, J = 3.8, 8.9 Hz), 4.76 (dd, 1H, J = 8.9, 8.9 Hz),
5.49 (dd, 1H, J = 3.8, 8.9 Hz), 6.86 (d, 1H, J = 15.5 Hz), 7.30ꢀ7.40
(m, 5H), 8.16 (d, 1H, J = 15.5 Hz); 13C NMR (68 MHz, CDCl3) δ 14.2,
57.8, 61.4, 70.2, 125.9, 128.9, 129.2, 131.9, 134.5, 138.1, 153.1, 163.1,
164.6; MS (EI) m/z (relative intensity, %) 289 (M+, 7), 244 (9), 216
(82), 200 (7), 172 (17), 162 (100), 127 (43), 99 (48); HRMS (EI) calcd
for C15H15N1O5 (M)+ 289.0950, found 289.0952; [R]16D +81.8 (c 1.03,
CHCl3).
C20H18N2O5 (M)+ 366.1216, found 366.1219; [R]15 +139.6 (c 1.46,
D
CHCl3).
(4S)-3-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-phen-
yl-2-oxazolidinone [3b-(S,S)] (minor isomer). Colorless solid (45.7 mg,
83%, 87:13); mp 122ꢀ123 °C; Rf = 0.20 (hexane/EtOAc, 6:4, v/v, silica gel
1
plate); IR (KBr) 1720, 1794 cmꢀ1; H NMR (270 MHz, CDCl3) δ
(4R,7S)-1-Acryloyl-7-isopropyl-4-methyl-3-phenyl-4,5,6,7-tetrahydro-
1H-indazole [1g-(R,S)]. Colorless oil; Rf = 0.40 (hexane/EtOAc, 9:1, v/v,
silica gel plate); IR (neat) 1711 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ
0.89(d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J = 7.0 Hz), 1.00 (d, 3H, J = 7.0),
1.45ꢀ1.51 (m, 1H), 1.78ꢀ1.85 (m, 2H), 2.02ꢀ2.24 (m, 2H), 3.18ꢀ3.24
(m, 1H), 3.45ꢀ3.50 (m, 1H), 5.96 (dd, 1H, J = 1.9, 10.3 Hz), 6.63
(dd, 1H, J = 1.9, 17.3 Hz), 7.39ꢀ7.47 (m, 3H), 7.73 (dd, 1H, J = 10.3,
17.3 Hz), 7.78ꢀ7.81 (m, 2H); 13C NMR (68 MHz, CDCl3) δ 19.6, 19.8,
20.9, 21.3, 25.9, 27.3, 31.5, 38.1, 125.2, 127.5, 128.4, 128.5, 128.8, 131.1,
133.1, 146.1, 152.3, 164.7; MS (EI) m/z (relative intensity, %) 308
(M+, 6), 265 (23), 253 (28), 211 (100);HRMS (EI) calcdfor C20H24N2O
(M)+ 308.1890, found 308.1888; [R]15D ꢀ75.4 (c 1.44, CHCl3).
(4S,7R)-1-Acryloyl-7-isopropyl-4-methyl-3-phenyl-4,5,6,7-tetrahydro-
1H-indazole [1g-(S,R)]. Colorless oil; Rf = 0.40 (hexane/EtOAc, 9:1, v/v,
2.54ꢀ2.58 (m, 2H), 4.34 (dd, 1H, J = 4.3, 8.9 Hz), 4.52 (dd, 1H, J = 3.2, 5.7
Hz), 4.69 (d, 1H, J = 12.2 Hz), 4.74 (dd, 1H, J = 8.9, 8.9 Hz), 5.09 (d, 1H,
J = 12.2 Hz), 5.44 (dd, 1H, J = 4.3, 8.9 Hz), 7.16ꢀ7.19 (m, 2H), 7.28ꢀ7.33
(m, 8H); 13C NMR (68 MHz, CDCl3) δ 32.7, 34.6, 57.8, 68.3, 70.5, 126.0,
128.0, 128.1, 128.3, 128.8, 129.1, 135.2, 137.8, 153.4, 160.7, 167.0; MS (EI)
m/z (relative intensity, %) 366 (M+, 13), 231 (2), 91 (100); HRMS (EI)
calcd for C20H18N2O5 (M)+ 366.1216, found 366.1214; [R]16D +60.4 (c
1.04, CHCl3).
(4R)-3-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-phen-
yl-2-oxazolidinone [3b-(R,S)] (major isomer). Colorless oil (46.1 mg,
84%, 85:15); Rf = 0.35 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (neat)
1731, 1780 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 2.52ꢀ2.55 (m, 2H),
4.30 (dd, 1H, J = 3.5, 8.9 Hz), 4.56 (dd, 1H, J = 3.5, 5.1 Hz), 4.62 (dd, 1H,
J = 8.9, 8.9 Hz), 5.08 (d, 1H, J = 11.9 Hz), 5.19 (d, 1H, J = 11.9 Hz), 5.22
(dd, 1H, J = 3.5, 8.9 Hz), 7.24ꢀ7.27 (m, 2H), 7.33ꢀ7.39 (m, 8H); 13C
NMR (68 MHz, CDCl3) δ 32.5, 33.9, 57.7, 68.4, 70.4, 76.4, 76.9, 77.4,
125.8, 128.2, 128.3, 128.7, 129.0, 135.2, 138.0, 153.2, 160.4, 166.5; MS (EI)
m/z (relative intensity, %) 366 (M+, 17), 260 (13), 218 (9), 104 (29), 91
(100); HRMS (EI) calcd for C20H18N2O5 (M)+ 366.1216, found
366.1208; [R]15D ꢀ140.6 (c 0.87, CHCl3).
1
silica gel plate); IR (neat) 1711 cmꢀ1; H NMR (270 MHz, CDCl3)
δ 0.89 (d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J = 7.0 Hz), 1.00 (d, 3H, J = 7.0),
1.45ꢀ1.52 (m, 1H), 1.79ꢀ1.85 (m, 2H), 2.02ꢀ2.24 (m, 2H), 3.18ꢀ3.24
(m, 1H), 3.45ꢀ3.50 (m, 1H), 5.96 (dd, 1H, J = 1.9, 10.3 Hz), 6.63
(dd, 1H, J = 1.9, 17.3 Hz), 7.39ꢀ7.48 (m, 3H), 7.73 (dd, 1H, J = 10.3,
17.3 Hz), 7.78ꢀ7.81 (m, 2H); 13C NMR (68 MHz, CDCl3) δ 19.5, 19.7,
20.8, 21.2, 25.8, 27.2, 31.4, 38.0, 125.1, 127.4, 128.3, 128.4, 128.7, 131.0,
133.0, 146.0, 152.2, 164.6; MS (EI) m/z (relative intensity, %) 308 (M+,
5), 265 (22), 253 (27), 211 (100); HRMS (EI) calcd for C20H24N2O
(M)+ 308.1890, found 308.1879; [R]15D +78.5 (c 0.92, CHCl3).
(4R)-3-[{(20R)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-phen-
yl-2-oxazolidinone [3b-(R,R)] (minor isomer). Colorless solid (46.1 mg,
84%, 85:15); mp 123ꢀ124 °C; Rf = 0.20 (hexane/EtOAc, 6:4, v/v, silica gel
1
plate); IR (KBr) 1720, 1792 cmꢀ1; H NMR (270 MHz, CDCl3) δ
(4S)-4-Benzyl-3-[{(20R)-(10-benzyloxycarbonyl)aziridin-20-yl}carbonyl]-
2-oxazolidinone [3a-(S,R)] (major isomer). Colorless oil (49.9 mg, 87%,
81:19); Rf = 0.35 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (neat) 1732,
1784 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 2.63 (dd, 1H, J = 1.6, 5.7 Hz),
2.68 (dd, 1H, J = 1.6, 3.2 Hz), 2.78 (dd, 1H, J = 9.7, 13.5 Hz), 3.25 (dd, 1H,
J = 3.2, 13.5 Hz), 4.15ꢀ4.20 (m, 2H), 4.50ꢀ4.53 (m, 2H), 5.12 (d, 1H,
J = 11.9 Hz), 5.26 (d, 1H, J = 11.9 Hz), 7.16ꢀ7.18 (m, 2H), 7.30ꢀ7.38 (m,
8H); 13C NMR (68 MHz, CDCl3) δ 32.6, 34.0, 37.5, 55.4, 66.7, 68.5, 127.3,
127.9, 128.2, 128.3, 128.8, 129.1, 134.5, 135.2, 153.0, 160.5, 167.0; MS (EI)
m/z (relative intensity, %) 380 (M+, 7), 91 (100); HRMS (EI) calcd for
2.54ꢀ2.58 (m, 2H), 4.32 (dd, 1H, J = 4.3, 8.9 Hz), 4.52 (dd, 1H, J = 3.2, 5.7
Hz), 4.68 (d, 1H, J = 12.2 Hz), 4.72 (dd, 1H, J = 8.9, 8.9 Hz), 5.09 (d, 1H,
J = 12.2 Hz), 5.43 (dd, 1H, J = 4.3, 8.9 Hz), 7.15ꢀ7.19 (m, 2H), 7.28ꢀ7.33
(m, 8H); 13C NMR (68 MHz, CDCl3) δ 32.6, 34.6, 57.8, 68.2, 70.5, 126.0,
128.0, 128.1, 128.3, 128.7, 129.0, 135.2, 137.8, 153.4, 160.7, 167.0; MS (EI)
m/z (relative intensity, %) 366 (M+, 16), 260 (16), 218 (11), 104 (33), 91
(100); HRMS (EI) calcd for C20H18N2O5 (M)+ 366.1216, found
366.1219; [R]16D = ꢀ59.9 (c 0.73, CHCl3).
(4S)-3-[{(20R)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-tert-
butyl-2-oxazolidinone[3c-(S,R)] (major isomer). Colorless oil (35.5mg,
68%, 76:24); Rf = 0.40 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (neat)
1734, 1780 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 0.91 (s, 9H), 2.60 (dd,
1H, J = 1.6, 5.4 Hz), 2.67 (dd, 1H, J = 1.6, 3.2 Hz), 4.09 (dd, 1H, J = 7.6, 9.2
Hz), 4.26 (dd, 1H, J = 1.4, 9.2 Hz), 4.29 (dd, 1H, J = 1.4, 7.6 Hz), 4.58 (dd,
1H, J = 3.2, 5.4 Hz), 5.09 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H,
J = 12.2 Hz), 7.34ꢀ7.38 (m, 5H); 13C NMR (68 MHz, CDCl3) δ 25.6,
32.8, 33.8, 35.8, 61.6, 65.8, 68.5, 128.2, 128.3, 128.4, 135.3, 154.3, 160.6,
167.2; MS (EI) m/z (relative intensity, %) 346 (M+, 7), 91 (100); HRMS
(EI) calcd for C18H22N2O5 (M)+ 346.1530, found 346.1524; [R]15D +85.2
(c 1.43, CHCl3).
C21H20N2O5 (M)+ 380.1373, found 380.1371; [R]15 +76.8 (c 1.15,
D
CHCl3).
(4S)-4-Benzyl-3-[{(20S)-(10-benzyloxycarbonyl)aziridin-20-yl}carbonyl]-
2-oxazolidinone [3a-(S,S)] (minor isomer). Colorless oil (49.9 mg, 87%,
81:19); Rf = 0.20 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (neat) 1732,
1782 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 2.61 (dd, 1H, J = 1.6, 5.7 Hz),
2.64 (dd, 1H, J = 1.6, 3.2 Hz), 2.70 (dd, 1H, J = 9.2, 13.5 Hz), 3.17 (dd, 1H,
J = 3.2, 13.5 Hz), 4.17ꢀ4.28 (m, 2H), 4.57 (dd, 1H, J = 3.2, 5.7 Hz),
4.64ꢀ4.70 (m, 1H), 5.18 (s, 2H), 7.14ꢀ7.17 (m, 2H), 7.26ꢀ7.40 (m, 8H);
13CNMR(68 MHz, CDCl3) δ32.7, 34.3, 37.5, 55.2, 66.6, 68.7, 127.3, 128.0,
128.3, 128.9, 129.3, 134.5, 135.1, 153.1, 160.7, 167.4; MS (EI) m/z (relative
6282
dx.doi.org/10.1021/jo2010632 |J. Org. Chem. 2011, 76, 6277–6285

The Journal of Organic Chemistry
ARTICLE
(4S)-3-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4-tert-
butyl-2-oxazolidinone [3c-(S,S)] (minor isomer). Colorless oil (35.5 mg,
68%, 76:24); Rf = 0.25 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR
(neat) 1732, 1780 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 0.92 (s, 9H),
2.54 (dd, 1H, J = 1.6, 3.0 Hz), 2.58 (dd, 1H, J = 1.6, 5.7 Hz), 4.25ꢀ4.36
(m, 2H), 4.43 (dd, 1H, J = 1.9, 7.3 Hz), 5.05 (d, 1H, J = 12.2 Hz), 5.24 (d,
1H, J = 12.2 Hz), 7.35ꢀ7.40 (m, 5H); 13C NMR (68 MHz, CDCl3) δ
25.5, 32.7, 34.8, 35.8, 61.2, 65.7, 68.5, 128.2, 128.4, 135.2, 154.2, 160.7,
167.7; MS (EI) m/z (relative intensity, %) 346 (M+, 6), 91 (100); HRMS
(EI) calcd for C18H22N2O5 (M)+ 346.1530, found 346.1526; [R]15D +9.4
(c 0.89, CHCl3).
1.31 (t, 3H, J = 7.0 Hz), 1.45 (s, 9H), 3.27 (d, 1H, J = 2.2 Hz), 4.17ꢀ4.32
(m, 2H), 4.37 (dd, 1H, J = 3.2, 8.9 Hz), 4.71 (d, 1H, J = 2.2 Hz), 4.78 (dd,
1H, J = 8.6, 8.9 Hz), 5.43 (dd, 1H, J = 3.2, 8.6 Hz), 7.27ꢀ7.40 (m, 5H);
13C NMR (68MHz, CDCl3) δ 14.1, 27.9, 39.7, 41.1, 57.8, 62.2, 70.6, 82.7,
125.9, 128.8, 129.1, 137.9, 153.1, 156.7, 164.7, 166.0; MS (CI, isobutane)
m/z (relative intensity, %) 405 (M+ + H, 1), 389 (2), 361 (2), 349 (12),
305 (100); HRMS (CI, isobutane) calcd for C20H25N2O7 (M + H)+
405.1662, found 405.1668; [R]15D = +39.2 (c 0.95, CHCl3).
(4S)-3-[{(20S)-(10-Benzyloxycarbonyl-30-ethoxycarbonyl)aziridin-
20-yl}carbonyl]-4-phenyl-2-oxazolidinone [3f-(S,S)] (minorisomer).Col-
orless solid (36.7 mg, 60%, 76:24); mp 50ꢀ51 °C; Rf = 0.20 (hexane/
1
EtOAc, 6:4, v/v, silica gel plate); IR (KBr) 1738, 1786 cmꢀ1; H NMR
(4S,5R)-3-[{(20R)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-
4,5-diphenyl-2-oxazolidinone [3d-(S,R,R)] (majorisomer).Colorless solid
(60.1 mg, 91%, 87:13); mp 52ꢀ53 °C; Rf = 0.45 (hexane/EtOAc, 6:4, v/v,
silica gel plate); IR (KBr) 1730, 1784 cmꢀ1;1H NMR (270 MHz, CDCl3) δ
2.59ꢀ2.62 (m, 2H), 4.65 (dd, 1H, J= 3.5, 4.9 Hz), 5.10 (d, 1H, J=12.2Hz),
5.22 (d, 1H, J = 12.2 Hz), 5.44 (d, 1H, J = 7.6 Hz), 5.81 (d, 1H, 7.6 Hz),
6.80ꢀ6.84 (m, 2H), 6.92ꢀ6.96 (m, 2H), 7.08ꢀ7.14 (m, 6H), 7.32ꢀ7.41
(m, 5H); 13C NMR (68 MHz, CDCl3) δ 32.7, 34.1, 63.1, 68.5, 80.9, 125.9,
126.3, 128.0, 128.3, 128.4, 128.5, 128.6, 132.1, 133.5, 135.4, 153.4, 160.5,
166.4; MS (EI) m/z (relative intensity, %) 442(M+, 1), 180 (98), 91(100);
HRMS (EI) calcd for C26H22N2O5 (M)+ 442.1530, found 442.1528;
[R]15D +53.6 (c 1.42, CHCl3).
(270 MHz, CDCl3) δ 1.22 (s, 9H), 1.31 (t, 3H, J = 7.0 Hz), 3.30 (d, 1H,
J = 2.2 Hz), 4.19ꢀ4.32 (m, 2H), 4.39 (dd, 1H, J = 4.1, 8.9 Hz), 4.66 (d, 1H,
J = 2.2 Hz), 4.77 (dd, 1H, J = 8.9, 8.9 Hz), 5.42 (dd, 1H, J = 4.1, 8.9 Hz),
7.30ꢀ7.39 (m, 5H); 13C NMR (68 MHz, CDCl3) δ 14.1, 27.5, 39.9, 41.3,
57.8, 62.1, 70.4, 82.5, 126.2, 128.8, 129.1, 137.7, 153.0, 156.7, 165.0, 166.0;
MS (CI, isobutane) m/z (relative intensity, %) 405 (M+ + H, 1), 389 (1),
361 (2), 349 (9), 305 (100); HRMS (CI, isobutane) calcd for C20H25N2O7
(M + H)+ 405.1662, found 405.1656; [R]15D +107.5 (c 0.73, CHCl3).
(4R,7S)-1-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-7-
isopropyl-4-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazole [3g-(R,
S,S)]. Colorless oil (33.4 mg, 75%, 95:5); Rf = 0.55 (hexane/EtOAc, 7:3,
v/v, silica gel plate); IR (neat) 1734 cmꢀ1; 1H NMR (270 MHz, CDCl3)
δ 0.87ꢀ0.97 (m, 9H), 1.45ꢀ1.51 (m, 1H), 1.70ꢀ1.80 (m, 2H), 2.03ꢀ2.12
(m, 2H), 2.63 (dd, 1H, J = 1.6, 5.7 Hz), 2.72 (dd, 1H, J = 1.6, 3.2 Hz),
3.15ꢀ3.25 (m, 1H), 3.27ꢀ3.35 (m, 1H), 4.78 (dd, 1H, J = 3.2, 5.7 Hz),
5.20 (s, 2H), 7.31ꢀ7.46 (m, 8H), 7.77ꢀ7.80 (m, 2H); 13C NMR (68
MHz, CDCl3) δ 19.7, 19.9, 20.7, 21.1, 25.8, 26.9, 31.5, 32.7, 35.1, 37.8,
68.5, 125.4, 127.5, 128.2, 128.4, 128.5, 128.8, 132.6, 135.4, 146.3, 153.6,
161.1, 166.6; MS (EI) m/z (relative intensity, %) 457 (M+, 3), 429 (4),
414 (1), 366 (13), 338 (15), 301 (19), 294 (13), 253 (21), 211 (25), 91
(100); HRMS (EI) calcd for C28H31N3O3 (M)+ 457.2367, found
457.2373; [R]15D ꢀ14.6 (c 1.42, CHCl3) (90% de).
(4S,5R)-3-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-4,
5-diphenyl-2-oxazolidinone [3d-(S,R,S)] (minor isomer). Colorless
solid (60.1 mg, 91%, 87:13); mp 198ꢀ199 °C; Rf = 0.20 (hexane/
EtOAc, 6:4, v/v, silica gel plate); IR (KBr) 1714, 1788 cmꢀ1; 1H NMR
(270 MHz, CDCl3) δ 2.61ꢀ2.63 (m, 2H), 4.68 (dd, 1H, J = 3.2, 5.1 Hz),
4.73 (d, 1H, J = 12.2 Hz), 5.10 (d, 1H, J = 12.2 Hz), 5.70 (d, 1H, J =
7.6 Hz), 5.96 (d, 1H, 7.6 Hz), 6.87ꢀ6.90 (m, 2H), 6.96ꢀ6.98 (m, 2H),
7.01ꢀ7.29 (m, 11H); 13C NMR (68 MHz, CDCl3) δ 32.7, 34.6, 62.9,
68.3, 80.8, 126.0, 126.5, 127.9, 128.0, 128.1, 128.2, 128.3, 128.5, 132.2,
133.4, 135.2, 153.4, 160.7, 166.8; MS (EI) m/z (relative intensity, %)
442 (M+, 1), 180 (100), 91 (81); HRMS (EI) calcd for C26H22N2O5
(M)+ 442.1530, found 442.1527; [R]16D ꢀ22.2 (c 1.32, CHCl3).
(3aS-cis)-3-[{(20R)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-
3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-2-oxazolidinone [3e-(S,R,R)]
(major isomer). Colorless solid (48.7 mg, 86%, 88:12); mp 45ꢀ46 °C;
Rf = 0.35 (hexane/EtOAc, 6:4, v/v, silica gel plate); IR (KBr) 1732,
1782 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ 2.60 (dd, 1H, J = 1.9, 5.7 Hz),
2.67 (dd, 1H, J = 1.9, 3.2 Hz), 3.38ꢀ3.40 (m, 2H), 4.52 (dd, 1H, J = 3.2, 5.7
Hz), 5.15 (d, 1H, J = 11.9 Hz), 5.21 (d, 1H, J = 11.9 Hz), 5.27 (ddd, 1H, J =
3.8, 3.8, 7.0 Hz), 5.81 (d, 1H, J = 7.0 Hz), 7.23ꢀ7.41 (m, 8H), 7.56 (d, 1H,
J = 7.0 Hz); 13C NMR (68 MHz, CDCl3) δ 32.8, 34.2, 37.8, 63.4, 68.6, 78.9,
125.1, 127.1, 128.1, 128.2, 128.3, 128.4, 129.9, 135.3, 138.2, 139.2, 152.6,
160.7, 167.5; MS (EI) m/z (relative intensity, %) 378 (M+, 10), 116 (39),
91 (100); HRMS (EI) calcd for C21H18N2O5 (M)+ 378.1216, found
378.1213; [R]15D +260.3 (c 0.93, CHCl3).
(4R,7S)-1-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-7-
isopropyl-4-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazole [3h-(R,
S,S)]. Colorless oil (32.6 mg, 77%, >99:<1); Rf = 0.43 (hexane/EtOAc,
7:3, v/v, silica gel plate); IR (neat) 1732 cmꢀ1; 1H NMR (270 MHz, CD-
Cl3) δ 0.85ꢀ1.02 (m, 9H), 1.46 (s, 9H), 1.75ꢀ1.83 (m, 2H), 2.02ꢀ2.20
(m, 2H), 2.56 (dd, 1H, J = 1.6, 5.7 Hz), 2.67 (dd, 1H, J = 1.6, 3.2 Hz),
3.20ꢀ3.30 (m, 1H), 3.34ꢀ3.39 (m, 1H), 4.67 (dd, 1H, J = 3.2, 5.7 Hz),
7.41ꢀ7.49 (m, 3H), 7.80ꢀ7.84 (m, 2H); 13C NMR (68 MHz, CDCl3) δ
19.7, 19.9, 20.8, 21.1, 25.8, 27.0, 28.0, 31.5, 32.5, 35.2, 37.9, 81.9, 125.2, 127.5,
128.5, 128.7, 132.8, 146.2, 153.4, 159.9, 166.9; MS (EI) m/z (relative
intensity, %) 423 (M+, 3), 253 (58), 211 (100); HRMS (EI) calcd for
C25H33N3O3 (M)+ 423.2522, found 423.2524; [R]15 ꢀ24.2 (c 1.33,
D
CHCl3).
(4S,7R)-1-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-7-iso-
propyl-4-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazole [3h-(S,R,R)].
Colorless oil (30.7 mg, 72%, >99:<1); Rf = 0.43 (hexane/EtOAc, 7:3, v/v,
(3aS-cis)-3-[{(20S)-(10-Benzyloxycarbonyl)aziridin-20-yl}carbonyl]-3,3a,
8,8a-tetrahydro-2H-indeno[1,2-d]-2-oxazolidinone [3e-(S,R,S)] (major
isomer). Colorless solid (48.7 mg, 86%, 88:12); mp 46ꢀ47 °C; Rf = 0.20
1
silica gel plate); IR (neat) 1730 cmꢀ1; H NMR (270 MHz, CDCl3) δ
(hexane/EtOAc, 6:4, v/v, silica gel plate); IR (KBr) 1701, 1734, 1776 cmꢀ1
;
0.85ꢀ1.02 (m, 9H), 1.46 (s, 9H), 1.75ꢀ1.83 (m, 2H), 2.02ꢀ2.20 (m, 2H),
2.56 (dd, 1H, J = 1.6, 5.7 Hz), 2.67 (dd, 1H, J = 1.6, 3.2 Hz), 3.20ꢀ3.30 (m,
1H), 3.34ꢀ3.39 (m, 1H), 4.67 (dd, 1H, J = 3.2, 5.7 Hz), 7.41ꢀ7.49 (m,
3H), 7.80ꢀ7.84 (m, 2H); 13C NMR (68 MHz, CDCl3) δ 19.6, 19.8, 20.7,
21.0, 25.7, 26.9, 27.9, 31.4, 32.4, 35.1, 37.8, 81.8, 125.1, 127.4, 128.4, 128.6,
132.6, 146.1, 153.3, 159.8, 166.8; MS (EI) m/z (relative intensity, %) 423
(M+, 3), 253 (56), 211 (100); HRMS (EI) calcd for C25H33N3O3 (M)+
423.2522, found 423.2519; [R]15D +23.9 (c 1.43, CHCl3).
1H NMR (270 MHz, CDCl3) δ 2.61ꢀ2.63 (m, 2H), 3.40ꢀ3.42 (m, 2H),
4.53ꢀ4.56 (m, 1H), 5.12 (d, 1H, J= 12.3 Hz), 5.24 (d, 1H, J= 12.3 Hz), 5.35
(ddd, 1H, J = 3.0, 4.6, 7.3 Hz), 5.94 (d, 1H, J = 7.3 Hz), 7.13ꢀ7.38 (m, 8H),
7.52 (d, 1H, J = 7.8 Hz); 13C NMR (68 MHz, CDCl3) δ 32.7, 34.5, 38.0,
63.1, 68.5, 78.6, 124.9, 127.2, 128.1, 128.2, 128.3, 129.9, 135.1, 138.0, 139.0,
152.6, 160.7, 167.7; MS (EI) m/z (relative intensity, %) 378 (M+, 9), 116
(50), 91 (100); HRMS (EI) calcd for C21H18N2O5 (M)+ 378.1216, found
378.1213; [R]15D = +162.3 (c 1.00, CHCl3).
(2S)-1-Benzyloxycarbonylaziridine-2-carboxylic Acid Methyl Ester
[3i-(S)]. Colorless oil (16.1 mg, 78%); Rf = 0.49 (hexane/EtOAc, 1:1, v/
v, silica gel plate); HPLC (Daicel Chiralcel OD, hexane/2-propanol, 9:1,
0.2 mL/min, 254 nm, 30 °C) t = 56.8 and 66.0 min.; IR (neat) 1732,
(4S)-3-[{(20R)-(10-Benzyloxycarbonyl-30-ethoxycarbonyl)aziridin-20-
yl}carbonyl]-4-phenyl-2-oxazolidinone [3f-(S,R)] (major isomer). Col-
orless oil (36.7 mg, 60%, 76:24); Rf = 0.30 (hexane/EtOAc, 6:4, v/v, silica
gel plate); IR (neat) 1738, 1786 cmꢀ1; 1H NMR (270 MHz, CDCl3) δ
1
1743 cmꢀ1; H NMR (270 MHz, CDCl3) δ 2.49 (dd, 1H, J = 1.2,
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ARTICLE
5.4 Hz), 2.60 (dd, 1H, J = 1.2, 3.2 Hz), 3.11 (dd, 1H, J = 3.2, 5.4 Hz), 3.71
(s, 3H), 5.13 (d, 1H, J = 10.5 Hz), 5.17 (d, 1H, J = 10.5 Hz), 7.36 (m,
5H); 13C NMR (68 MHz, CDCl3) δ 31.4, 34.9, 52.7, 68.6, 128.3, 128.4,
135.2, 160.5, 168.4; MS (CI, isobutane) m/z (relative intensity, %) 236
(M+ + H, 20), 192 (M+ + H ꢀ CO2, 100), 91 (CH2Ph, 39); HRMS (CI,
isobutane) calcd for C12H14NO4 (M + H)+ 236.0923, found 236.0917;
[R]15D ꢀ48.5 (c 1.00, CHCl3).
thendriedoveranhydrous magnesiumsulfate and concentrated to give the
crude product. The residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate) to give product (2.38 g, 94%). Spectroscopic
data were in agreement with those of previously published material. 1H
NMR (270 MHz, CDCl3) δ 0.88 (d, 3H, J = 7.0), 1.00 (d, 3H, J = 7.0),
1.06 (d, 3H, J = 7.0), 1.25ꢀ1.38 (m, 1H), 1.52ꢀ1.65 (m, 1H), 1.81ꢀ1.90
(m, 1H), 2.00ꢀ2.10 (m, 1H), 2.18ꢀ2.32 (m, 1H), 2.62ꢀ2.69 (m, 1H),
3.05ꢀ3.12 (m, 1H), 7.30ꢀ7.44 (m, 3H), 7.58ꢀ7.61 (m, 2H).
Typical Procedure for the Preparation of Chiral 3-Acry-
loyl-2-oxazolidinones.31 To the solution of acrylic acid (8.1 mmol)
and triethylamine (16.5 mmol) in THF (23 mL) was added acryloyl
chloride (7.2 mmol) at ꢀ20 °C. After the mixture was stirred at ꢀ20 °C
for 1 h, lithium chloride (12.0 mmol) and chiral oxazolidinone (3 mmol)
was added. The mixture was allowed to warm to room temperature and
stirred for 2 h. The reaction was quenched by addition of 0.2 M HCl aq
(20 mL), and THF was removed in vacuo. The residue was extracted
with ethyl acetate (30 mL ꢁ 3). The organic layer was washed
subsequently with saturated sodium bicarbonate (20 mL) and brine
(20 mL). The organic solution was then dried over anhydrous magne-
sium sulfate and concentrated to give the crude product. The residue was
purified by flash column chromatography on silica gel (hexane/ethyl
acetate) to give the corresponding olefins.
(4R,7S)-1-Acryloyl-7-isopropyl-4-methyl-3-phenyl-4,5,6,7-tetrahy-
dro-1H-indazole.34 To the solution of 3-phenyl-L-menthopyrazole (251 mg,
0.98 mmol) in toluene (3 mL) were added triethylamine (297 mg,
2.9 mmol) and acryloyl chloride (270 mg, 2.9 mmol), and the mixture
was stirred at room temperature for 2 h. The reaction was quenched with
water and extracted with ether (20 mL x 4). The combined organic layer was
washed subsequently with 1 M hydrochloric acid (20 mL) and brine
(20 mL). The organic solution was then dried over anhydrous magnesium
sulfate and concentrated to give the crude product. Regioisomers (1g-(R,
S):1g0-(R,S) = 43:57) were separated by flash column chromatography on
silica gel (hexane/toluene) to give the corresponding olefins (111 mg, 37%).
Preparation of Catalysts. Ammonium catalysts CD1 and CD2
are commercially available, and CN1,35 CN2,36 CN3,37 and CN438 were
prepared by following the procedures described in the literature.
Typical Procedure for the Preparation of N-Acryloyl-L-
menthopyrazole.32 (2S,5R)-2-Isopropyl-5-methylcyclohexanone.33
Pyridinium chlorochromate (2.04 g, 10.5 mmol) and silica gel 60 (2.04 g,
purchased from Nacalai Tesque Co., average diameter: 75 μm) was
ground to a fine powder using a mortar and pestle. The light orange
mixture was added to a round-bottom flask containing dichloromethane
(21 mL). To the resulting suspension was added a solution of L-menthol
(990 mg, 6.3 mmol) in dichloromethane (5 mL). After the mixture was
stirred at room temperature for 5 h, the resulting suspension was diluted
with diethyl ether (60 mL) and filtered at reduced pressure through a
B€uchner funnel layered with Celite and silica gel. The filtrate was
concentrated and purified by Kugelrohr distillation to give the corre-
sponding ketone (2.98 g, 92%). Spectroscopic data were in agreement
with those of previously published material. 1H NMR (270 MHz, CDCl3)
δ 0.85 (d, 3H, J = 6.6 Hz), 0.91 (d, 3H, J = 6.6 Hz), 1.01 (d, 3H, J = 5.9
Hz), 1.32ꢀ1.42 (m, 2H), 1.77ꢀ1.93 (m, 2H), 1.95ꢀ2.18 (m, 4H), 2.36
(ddd, 1H, J = 2.2, 3.6, 12.7 Hz).
’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
b
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: minakata@chem.eng.osaka-u.ac.jp.
’ ACKNOWLEDGMENT
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion
of Science. One of the authors (Y.M.) would like to express his
special thanks to The Global COE (center of excellence)
Program “Global Education and Research Center for Bio-En-
vironmental Chemistry” of Osaka University.
(3R, 6S)-2-Benzoyl-6-isopropyl-3-methylcyclohexanone.34 L-Menthone
(3.01 g, 19.5 mmol) was added to THF solution (21 mL) of lithium
diisopropylamine (LDA) which was prepared in situ from diisopropylamine
(2.90 g, 28.6 mmol) and n-butyllithium (20 mL, 1.65 M in hexane) at
ꢀ78 °C. After the mixture was stirred for 30 min at ꢀ78 °C, it was treated
with benzoyl chloride (3.30 g, 23.5 mmol) in THF (11 mL) and then
warmed up to room temperature. After the mixture was stirred for 2 h at
room temperature, it was quenched with 1 M hydrochloric acid and
extracted with ether (20 mL ꢁ 5). The combined organic layer was washed
subsequently with saturated sodium bicarbonate (20 mL) and brine
(20 mL). The organic solution was then dried over anhydrous magnesium
sulfate and concentrated to give the crude product. The residue was purified
by recrystallization from hexane to give product (2.67 g, 89%). Spectro-
scopic data were in agreement with those of previously published material.
1H NMR (270 MHz, CDCl3) δ0.86 (d, 3H, J=6.8Hz), 0.92(d, 3H, J=6.8
Hz), 0.98 (d, 3H, J = 6.5 Hz), 1.45ꢀ1.60 (m, 2H), 2.02ꢀ2.17 (m, 2H),
1.95ꢀ2.20 (m, 4H), 2.19ꢀ2.30 (m, 1H), 2.49ꢀ2.62 (m, 1H), 4.03 (d, 1H,
J = 11.6 Hz), 7.41ꢀ7.57 (m, 3H), 7.81ꢀ7.84 (m, 2H).
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