Synthesis of enantiomerically pure aziridine-2-imides by cyclization of chiral 3-benzyloxyamino imide enolates

Article abstract of DOI:10.1021/jo971254e

Aziridine-2-imides are prepared both in high yield and high diastereoselectivity from chiral 3'-benzyloxyamino imides 2, 3, and 8 by treatment with triethylamine in the presence of either TiCl₄ or AlMe₂Cl. 2 and 3 are easily obtained

Full text of DOI:10.1021/jo971254e

9148
J . Org. Chem. 1997, 62, 9148-9153
Syn th esis of En a n tiom er ica lly P u r e Azir id in e-2-im id es by
Cycliza tion of Ch ir a l 3′-Ben zyloxya m in o Im id e En ola tes
Alessandro Bongini, Giuliana Cardillo,* Luca Gentilucci, and Claudia Tomasini
Dipartimento di Chimica “G. Ciamician”, Universita` di Bologna, via Selmi 2, 40126 Bologna, Italy
Received J uly 10, 1997X
Aziridine-2-imides are prepared both in high yield and high diastereoselectivity from chiral 3′-
benzyloxyamino imides 2, 3, and 8 by treatment with triethylamine in the presence of either TiCl4
or AlMe2Cl. 2 and 3 are easily obtained by a diastereoselective conjugate addition of O-
benzylhydroxylamine promoted by Lewis acids to R,â-unsaturated imides 1. The synthesis of 3′-
(benzyloxyamino)propanoyl 8 is performed by addition to the acryloyl compound 6 of N-BOC
O-benzylhydroxylamine followed by deprotection. The cyclization of 2 and 3 affords complete trans
selectivity and yields up to 97% of the corresponding 3′-alkyl aziridines 4 and 5, while the cyclization
of 8 affords a mixture of diasteroisomers 11, 12 in 86/14 ratio and a 95% yield. A mechanistic
study has been made to rationalize the trans selectivity observed in the cyclization of 2 and 3.
AM1 computations allow us to deduce that the reaction proceeds through cyclic titanium or
aluminum enolate formation, and they reveal that enolates leading to trans aziridines are more
stable than those leading to cis.
Aziridines1 are very interesting heterocyclic compounds
acids,7 hydroxy acids,8 or addition of ammonia to a
suitable 2-haloacrylic acid derivative.9
present in nature in unusual natural products that
display strong biological activity. Azinomycines A and
B2 for instance are potent antitumor antibiotics isolated
from the fermentation broth of Streptomyces griseofuscus
and (+)-FR9004823 from the culture broth of Streptomy-
ces sandaensis. They exhibit exceptionally potent anti-
tumor activity against various types of mammalian solid
tumors.
Since their discovery in 1888 by Gabriel, aziridines
have attracted much attention as starting material to
further transformations. The ring strain renders these
compounds susceptible to ring opening, and for this
aspect they have received great interest as precursors
for a variety of nitrogen-containing compounds. A num-
ber of synthetic approaches have been reported,1b most
of which start from easily available enantiomerically pure
compounds. Chiral nonracemic aziridines have been
prepared by enzymatic separation of racemic mixtures,4
from chiral oxiranes,5 chiral diols,6 â-hydroxy R-amino
Attention has recently been paid to the use of aziridine-
2-carboxylates as intermediates of substituted R- and
â-amino acids.10 We have described the preliminary
results in which enantiomerically pure trans-3-alkylaziri-
dine-2-carboxylates have been obtained from chiral 3′-
benzyloxyamino imides through a cyclization reaction.11
While a variety of methods for the preparation of 3-alkyl-
or 3-arylaziridines has been reported, the synthesis of
chiral 3-unsubstituted aziridine-2-carboxylates seems to
be limited to the use of natural serine from which (S)-
aziridine can be exclusively obtained.7a,12 Recently, 3-un-
substituted aziridine-2-carboxylates have been prepared
from the reaction of chiral 1,3,5-triazine with alkyldi-
azoacetates in the presence of a Lewis acid as catalyst.13
In this work we supply the data relative to the
preparation of 3-alkyl aziridine-2-carboxylates,11 and we
report the synthesis of 3-unsubstituted aziridine-2-car-
boxylates; furthermore we wish to give a rationale to the
mechanism of the cyclization reaction.
* Author to whom correspndence should be addressed. Tel.
0039.51.259570; FAX: 0039.51.259456; e-mail: cardillo@ciam.unibo.it.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) (a) Fanta, P. E. Heterocyclic Compounds with Three- and Four-
memberd Rings; Weissemberg, A., Ed.; Wiley Intrerscience: NewYork,
1964, Part 1, p 524. (b) For a recent review see: Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599.
(2) Armstrong, R. W.; Tellew, J . E.; Moran, E. J . Tetrahedron Lett.
1996, 37, 447.
(3) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron Lett.
1996, 37, 3471.
(4) Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y.; Taga, T.; Miwa,
Y. Tetrahedron Lett. 1990, 31, 6663.
(5) Legters, J .; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 1.
(6) Lohray, B. B.; Gao. Y.; Sharpless, K. B. Tetrahedron Lett. 1989,
30, 2623.
Resu lts
It has been reported14 that treatment of 3-meth-
oxyamino ketones with 2 equiv of sodium methoxide in
methanol give rise to 2-ketoaziridines in good yields and
trans selectivity probably via an intermediate enolate.
On the basis of these results we have reported a new few
steps synthesis11 of trans chiral aziridines, starting from
chiral 3-benzyloxyamino imides 2 and 3, easily prepared
in turn by the 1,4-addition of O-benzylhydroxylamine to
1 promoted by a Lewis acid15 (Scheme 1).
(7) (a) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem.
Soc. J pn. 1978, 51, 1577. (b) Kuyl-Yeheskiely, E.; Lodder, M.; Van der
Marel, G. A.; Van Boom, J . H. Tetrahedron Lett. 1992, 33, 3013.
(8) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D. Tetrahedron Lett. 1989, 30, 5709.
(9) (a) Garner, P.; Dogan, O.; Pillai, S. Tetrahedron Lett. 1994, 35,
1653. (b) Cardillo, G.; Gentilucci, L.; Tomasini, C.; Visa Castejon-
Bordas, M. P. Tetrahedron: Asymmetry 1996, 7, 755.
(10) (a) Legters, J .; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 16. (b) Legters, J .; Willems, J . G. H.; Thijs, L.;
Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111, 59. (c) Dauban,
P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd, R. H. J . Org. Chem. 1995,
60, 2035 and references therein.
(11) Cardillo, G.; Casolari, S.; Gentilucci, L.; Tomasini, C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1848.
(12) Baldwin, J . E.; Farthing, C. N.; Russell, A. T.; Schofield, C. J .;
Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761.
(13) Ha, H. J .; Kang, K. H.; Suh, J . M.; Ahn, Y. G. Tetrahedron Lett.
1996, 37, 7069.
(14) (a) Blatt, A. H. J . Am. Chem. Soc. 1939, 61, 3494. (b) Cromwell,
N. H.; Barker, N. G.; Wanker, N. A.; Vanderhorst, P. J .; Olson, F. W.;
Anglin, J . H. ibid 1951, 73, 1044. (c) Nagel, L. D.; Woller, P. B.;
Cromwell, N. H. J . Org. Chem. 1971, 36, 3911.
(15) Amoroso, R.; Cardillo, G.; Sabatino, P.; Tomasini, C.; Trere`, A.
J . Org. Chem. 1993, 58, 5615.
S0022-3263(97)01254-1 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Enantiomerically Pure Aziridine-2-imides
J . Org. Chem., Vol. 62, No. 26, 1997 9149
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. 1,4-Ad d ition of O-Ben zylh yd r oxyla m in e to 6
Lewis
acid
time
(h)
temp
(°C)
7a
(%)
8a
(%)
entry
solvent
1
2
3
4
5
TiCl4
AlMe2Cl
-
-
-
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.2
0.2
72
72
24
0
0
∆
∆
∆
75
51
30
25
18
15
49
45
45
68
PhMe
a
Calculated after purification by flash cromatography on the
basis of recovered 6.
The interest of this addition reaction rests in the fact
that a predominant (S) or (R) configuration of the newly
introduced stereogenic center depends on the Lewis acid
selected, thus a unique substrate 1 makes it possible to
obtain the desired diasteroisomer in an enriched form.
At first we unsuccessfully tried to perform the cycliza-
tion of these compounds using sodium methoxide. Sub-
sequently, considering the high tolerance of our sub-
strates to Lewis acids, we thought enolates could be
prepared under the conditions reported by Evans.16
Addition of the complex formed by 2 or 3 with 1 equiv of
TiCl4 to a solution of triethylamine in CH2Cl2 under
nitrogen at room temperature turned the reaction mix-
ture red, thus showing the formation of an intermediate
enolate.16 After 30 min pure aziridines 4 and 5 were
obtained by flash chromatography in high yield and
complete trans diastereoselectivity (Scheme 2). No trace
of the cis isomer was observed in the crude reaction
mixture. The yield of this procedure was strongly sensi-
tive to the reaction conditions. In particular it was
observed that the presence of quite small moisture traces
caused a fast enolate quench, giving poor yields of
cyclization products. The possibility of utilizing boron
enolates as useful intermediates to aziridines was also
exploited. Nevertheless, any attempt to obtain boron
enolates by means of the commercially available Bu2-
BOTf17 has at the moment failed.
and mild reaction took place, and aziridine-2-carboxylates
were obtained again in high yield in complete trans
diastereoselectivity without any reproducibility problem.
To our knowledge, only a few examples of optically active
aluminum enolates prepared under these conditions are
reported.18
The cyclization to 3′-alkylaziridines easily occurs from
the enantiomerically pure reagents 2 and 3, while 3′-
benzyloxyamino-3′-aryl derivatives are not accessible
throughtout the 1,4-addition of O-benzylhydroxylamine
to cinnamoyl derivatives promoted by Lewis acids.
The preparation of 3′-unsubstituted aziridines required
as a first approach the preparation of acryloylimidazo-
lidin-2-one 6, which was carried out under the conditions
reported above.15 The magnesium salt of (4R,5S)-1,5-
dimethyl-4-phenylimidazolidin-2-one19 was treated with
acryloyl chloride in dry THF to give 6 in 80% yield.
Better yields were obtained in the preparation of 6 when
diisopropyl ethylamine was used as base in the presence
of catalytic amounts of CuCl, which avoids the polymer-
ization of acryloyl chloride.20 The direct addition of
O-benzyl hydroxylamine to 6 was troublesome. Indeed,
in the presence of AlMe2Cl, the addition took place
smootly. Unfortunately, however, the reaction afforded
almost completely an undesired product, 7, which was
isolated and identified as the result of a further 1,4-
addition of the desired 3′-(benzyloxyamino)propanoyl
derivative 8 to the reagent 6. To obtain high conversion
of the starting material to 8, the addition of O-benzyl-
hydroxylamine was performed under a variety of condi-
tions (Scheme 3, path A).
In contrast, when 1.1 equiv of AlMe2Cl was used as a
Lewis acid under the same conditions as above, a clean
(16) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J . S.; Bilodeau, M.
T. J . Am. Chem. Soc. 1990, 112, 8215.
(17) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127.
(18) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Tetrahe-
dron 1995, 32, 8941.
(19) (a) Close, W. J . J . Org. Chem. 1950, 15, 1131. (b) Roder, H.;
Helmchen, G.; Peters, E. M.; Peters, K.; von Shering, H. G. Angew.
Chem., Int. Ed. Engl. 1984, 23, 898.
(20) (a) Seki, M.; Yamanaka, T.; Miyake, T.; Ohmizu, H. Tetrahedron
Lett. 1996, 37, 5565. (b) For a more recent procedure for the synthesis
of 6 see also: Kriel, K. N.; Emslie, N. D. Tetrahedron Lett. 1997, 38,
109.
An improvement was observed simply reversing the
order of reagent addition by transferring the complex
Lewis acid-6 to a solution of O-benzyhydroxylamine
(Table 1, entries 1 and 2). Better results were obtained
in different solvents at reflux in the absence of Lewis
acids and in the presence of 1 equiv of triethylamine
(entries 3-5). Carrying out the reaction in toluene at
reflux the amount of 7 was reduced and 8 was obtained
in a 68% yield (entry 5).

9150 J . Org. Chem., Vol. 62, No. 26, 1997
Bongini et al.
Sch em e 4
F igu r e 1.
Sch em e 5
F igu r e 2.
Since the direct addition of O-benzylhydroxylamine to
6 did not yield adequate amounts of product 8, a two-
step procedure was finally followed which allowed us to
obtain 8 in an almost quantitative yield (Scheme 3, path
B). O-Benzylhydroxylamine was first transformed into
the N-BOC derivative 9 by means of di-tert-butyl dicar-
bonate. Treatment of a mixture of 6 and 9 with 0.3 equiv
of NaH in DMF15a and subsequent acid deprotection of
the resulting 1021 afforded the desired 3′-benzyloxyamino
imide 8.
The cyclization of 8 to aziridine was attempted in the
same conditions described above. The titanium tetra-
chloride complex of 8 was treated with an excess of
triethylamine in CH2Cl2 at room temperature, and in 30
min a mixture of two isomeric aziridines, 11 and 12, was
obtained in a 86/14 diastereomeric ratio, respectively, and
95% overall yield (Scheme 4). Using 1.1 equiv of AlMe2-
Cl instead of TiCl4, the reaction was inefficient, with a
cyclization yield of 8 to 11 and 12 less of 10%.
To determine the absolute stereochemistry of the two
diastereoisomers the major product was isolated and
treated with lithium benzyloxide,9b,22 in THF at -10 °C
(Scheme 5). Under these conditions, 11 was converted
into the corresponding benzyl aziridine-2-carboxylate 13
in excellent yield. At the same time the chiral auxiliary
(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one was re-
moved without racemization and quantitatively recovered
after flash chromatography.
The aziridine-2-ester 13 was subsequently derivatized
with trityl chloride in the presence of triethylamine, and
the absolute stereochemistry of the resulting N-trityl
benzyl aziridine-2-carboxylate 14 proved to be (2R) by
F igu r e 3.
affect the geometry of the nearby centers toward a
preferential semi-W transition state that induces a trans
relationship between the substituents in the final aziri-
dines23 (Figure 1).
To obtain additional information about the preferential
structure of the transition state, we carried out some
semiempirical AM1 calculations24 on the Z enolate an-
ion25 of the (4S)-4-(methoxyamino)pentan-2-one. This
species was able to reproduce the reliable model of the
reactant in Blatt’s reaction, which occurred when sodium
methoxide was used. After minimization of several
conformations affording by cyclization cis or trans aziri-
dines, the more stable ones resulted to be 15a and 15b,
respectively (Figure 2).
Conformation 15b, having H4 almost eclipsed to the
enolate oxygen, resulted to be the more stable one. The
HOMO coefficient is very high in C3 of the enolate and
presents a proper geometry and phase with respect to
the LUMO that is located on the nitrogen carrying the
leaving group (Figure 3). This structure shows a C3-N
distance of 2.49 Å, an N-OMe distance of 1.33 Å, and a
C3-C4-N angle of 113.49°. On the contrary, the con-
formation 15a is so high in energy that it corresponds to
less than 1% of the population.
To simulate a qualitative reaction pathway for the ring
closure of enolate 15b through a model transition state,
different kinds of distance variations were examined. The
C3-N distance was shortened to 1.83 Å, and the N-O
bond was slightly broken by imposition of a N-OMe
distance of 1.81 Å (Figure 4). Minimization by AM1 of
this structure 15c caused it to collapse to a 15d structure
that presents a C3-N distance of 1.43 Å, N-OMe
distance of 4.5 Å, and C3-C4-N, C4-N-C3, and N-C3-
C4 angles close to 60°. At the same time C3 looses its
evaluation of its specific rotation power (for 14: [R]D
)
+90 (c 0.7, THF); lit.7a (2S) isomer: [R]D ) -95.5 (c 1.0,
THF)).
Discu ssion
In the formation of trans 3-keto aziridine reported by
Blatt and elucidated by Nagel,14 it is reasonable to
assume that an intermediate enolate will form and
develop into ring closure. Delocalization of electrons can
(23) Nikon, A.; Werstiuk, N. H. J . Am. Chem. Soc. 1967, 89, 3914.
(24) Design and distributed by Hypercube Inc., 419 Phillip Street,
Waterloo, Ont., N2L 3X2, Canada.
(25) E enolates have been also considered and calculated but always
resulted in much less stability.
(21) Stahl, G. L.; Walter, R.; Smith, C. W. J . Org. Chem. 1978, 43,
2285.
(22) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737.

Synthesis of Enantiomerically Pure Aziridine-2-imides
J . Org. Chem., Vol. 62, No. 26, 1997 9151
F igu r e 6.
F igu r e 4.
F igu r e 5.
F igu r e 7.
sp2 character and acquires an (R) configuration, while
the carbonyl function is restored. This structure 15d is
substantially coincident with the probable structure of
the trans 3-keto aziridine experimentally obtained in the
cyclization of 4-(methoxyamino)pentan-2-one.
On the contrary, when C3-N and N-OMe distances
are imposed at 2.02 and 1.71 Å, respectively, the struc-
ture obtained, 15e, collapses after AM1 minimization to
the reagent structure 15b. This leads us to suppose that
the transition state structure must be an average struc-
ture somewhere between 15c and 15e.
F igu r e 8.
This procedure was repeated for the less stable enolate
conformation 15a . AM1 minimization of a slightly
distorted 15f structure by imposition of the same dis-
tances of 1.83 Å for C3-N and of 1.81 Å for N-O afforded
a 15g structure corresponding to the cis 3-keto aziridine,
but the energy of the modelistic 15f transition structure
results considerably higher (Figure 5) than 15c.
On the basis of these considerations it is possible to
suggest that the high diastereoselectivity experimentally
observed14 is due not only to the lower energy of the
reagent in anti conformation, but presumably also to the
lower energy of the transition state that leads to the
formation of trans aziridines.
To evaluate the effect of the presence of a chelating
cation on the cyclization stereoselectivity, we introduced,
in the 4-(methoxyamino)pentan-2-one enolate, a lithium
cation complexed with two molecules of water. The
energy of a number of cyclic and acyclic enolate structures
were calculated by AM1, and the more stable one resulted
to be the conformation 15h . In this structure the HOMO
and LUMO are properly disposed to yield trans 3-keto
aziridine by way of cyclization (Figure 6).
The high trans selectivity observed in the ring closure
of 3-benzyloxyamino imides 2 and 3 performed with
AlMe2Cl or TiCl4 can be justified by the formation of a
cyclic titanium or aluminum complex that may be
converted into the corresponding enolate by addition of
a base. The enolate obtained from 2 can in principle
assume two possible kinds of conformations, A and B
(Figure 7). A shows R and the leaving group trans to
each other, while B shows R and the leaving group cis.
B seems disfavored because of the substituents interac-
tion. The favored conformation, A, leads, by cyclization,
to the experimentally observed trans aziridine, obtained
as the sole isomer.
Encouraged by these coherent results, we calculated
the preferential conformation of the aluminum enolate,26
the likely intermediate in the synthesis of trans alkyl
aziridine 4a , obtained by treatment of 2a with triethyl-
amine in the presence of AlMe2Cl. After minimization
by means of AM1 calculations of several conformations
that could afford cis or trans aziridines by cyclization,
structure 16 (Figure 8) was found to be the most stable
one.27 Moreover, because of the proper reciprocal position
and phase displayed by HOMO and LUMO, 16 seems to
be the most likely arrangement for the anti nucleophilic
substitution that is to afford the trans aziridine 4a .
The proposed qualitative model just proposed provides
a rationalization of the observation that only the trans
configuration is obtained in the cyclization of 2 and 3 to
aziridines 4 and 5, respectively, as a consequence of the
cyclic enolate formation.
(27) An alternative conformation collection, showing aluminum
chelating both the enolate oxigen and the heterocyclic carbonyl oxygen,
was also considered, but the energy was always higher than in the
case of 16.
(26) Minimization of the corresponding titanium enolate was also
attempted by means of ZINDO Hamiltonian in HYPERCHEM package,
but the results were unsatisfactory.

9152 J . Org. Chem., Vol. 62, No. 26, 1997
Bongini et al.
(2′S,3′R)-5b: IR (Nujol) ν 3260, 1720, 1650 cm-1; 1H NMR
(CDCl3) δ 0.81 (d, 3H, J ) 6.6 Hz), 1.02 (t, 3H, J ) 7.4 Hz),
1.45-1.62 (m, 2H), 1.87 (br.s, 1H), 1.94 (dt, 1H, J ) 2.5 Hz,
5.9 Hz), 2.86 (s, 3H), 3.76 (d, 1H, J ) 2.5 Hz), 3.98 (dq, 1H, J
) 6.6 Hz, 8.4 Hz), 5.25 (d, 1H, J ) 8.4 Hz), 7.09-7.41 (m, 5H);
13C NMR (CDCl3) δ 10.9, 14.7, 25.8, 27.9, 35.8, 42.0, 54.2, 59.6,
126.5, 128.1, 128.5, 136.1, 155.5, 171.1; MS m/z 287 (M+, 25),
272 (15), 258 (3), 231 (16), 217 (4), 191 (100), 175 (18), 132
(30); [R]D ) -75 (c 1.2, CHCl3); mp ) 140-145 °C. Anal.
Calcd for C16H21N3O2: C, 66.9; H, 7.4; N, 14.6. Found: C, 66.8;
H, 7.4; N. 14.5.
In conclusion, chiral 3′-benzyloxyamino imides are
suitable precursors of 3′-alkylaziridine-2-carboxylates,
which are obtained via chiral titanium or aluminum
enolates. A mechanicistic study by AM1 calculations
suggests that the complete trans diastereoselectivity can
be attributed to the preferred conformation displayed by
the intermediate cyclic enolate, which shows the alkyl
group and the leaving group trans to each other. In the
synthesis of 3′-unsubstituted aziridines, diastereoselec-
tivity is lower, probably owing to the absence of the
substituent in position 3′.
(2′S,3′R)-5c: IR (Nujol) ν 3270, 1720, 1660 cm-1; H NMR
1
(CDCl3) δ 0.83 (d, 3H, J ) 6.6 Hz), 0.95 (t, 3H, J ) 7.3 Hz),
1.46-1.56 (m, 4H), 1.72 (br.s, 1H), 2.00 (m, 1H), 2.89 (s, 3H),
3.80 (d, 1H, J ) 2.7 Hz), 4.00 (dq, 1H, J ) 6.6 Hz, 8.3 Hz),
5.26 (d, 1H, J ) 8.3 Hz), 7.10-7.41 (m, 5H); 13C NMR (CDCl3)
δ 13.7, 14.8, 20.2, 28.0, 34.8, 35.8, 40.6, 54.2, 59.7, 126.5, 127.1,
128.4, 128.5, 136.2, 155.5, 171.1; MS m/z 301 (M+, 10), 286
(6), 258 (3), 231 (15), 217 (6), 191 (100), 175 (10), 132 (24), 113
(26), 84 (27), 77 (13); [R]D ) -54 (c 1.4, CHCl3); mp ) 112-
116 °C. Anal. Calcd for C17H23N3O2: C, 67.8; H, 7.7; N, 13.9.
Found: C, 67.9; H, 7.7; N. 14.0.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, and chemical shifts were
reported in ppm relative to the solvent peak of CHCl3. IR
spectra were recorded using a FT-IR spectrometer. Melting
points are uncorrected and are determined in open capillaries.
Flash chromatography was performed using Merck silica gel
60 (230-400 mesh). Solvents for flash chromatograpy were
simply distilled. THF was distilled from sodium benzophenone
ketyl. CH2Cl2 was distilled from P2O5. DMF was distilled
from activated molecular sieves. O-Benzylhydroxylamine was
used as a 0.5 M solution in CH2Cl2. This solution was obtained
by treatment of O-benzylhydroxylamine hydrochloride (2.0 g,
12.5 mmol) with NaOH (0.75 g, 18.8 mmol) in water (5 mL)
followed by extraction with CH2Cl2 (4 × 10 mL). The organic
layers were dried over Na2SO4 and partially evaporated at
reduced pressure. Finally the solution volume was adjusted
to 25 mL with dry CH2Cl2. AlMe2Cl was used as a 1 M solution
in cyclohexane.
Molecular mechanics MM+ and semiempirical AM1 calcula-
tions were achieved on the HYPERCHEM calculation pack-
age.24 MM+ was set on a dipole-dipole electrostatic force field.
Geometry optimizations were performed using a Polak-Ribiere
conjugate gradient algorithm until a gradient of 0.01 kcal/mol
was reached. The Monte Carlo method is available on the
CHEMPLUS24 package. The preferential geometry of chelate
and nonchelate Z enolate for (4S)-4-(methoxyamino)pentan-
2-one was fully optimized with semiempirical AM1 calcula-
tions. The AM1 optimization was performed over a collection
of stable conformations obtained with the Monte Carlo method
and minimized with MM+. The Monte Carlo method provided
100 random conformations by varying C3-C4, C4-N, and
N-O torsion angles. The result of HYPERCHEM/AM1 full
optimization was confirmed by MOPAC 6.028 AM1 calculations.
The preferential conformation of the aluminum complex 16
was fully optimized by means of AM1 calculations performed
on stable conformations obtained with a Monte Carlo method
and minimized with MM+. 300 Random conformations were
considered varying O-Ti, C4-Ph, N3-C1′, C1′-C2′, C2′-C3′,
C3′-N′, N′-O′, O′-CH2Ph, and CH2-Ph torsion angles.
(4R,5S)-1,5-Dim eth yl-3-a cr yloyl-4-p h en ylim id a zolid in -
2-on e (6). To a stirred solution of (4R,5S)-1,5-dimethyl-4-
phenylimidazolidin-2-one (0.7 g, 3.7 mmol) in anhydrous
CH2Cl2 (3 mL), were added diisopropylethylamine (0.95 mL,
5.5 mmol), acryloyl chloride (0.45 mL, 5.5 mmol) and catalytic
CuCl under an inert athmosphere at rt. The reaction was
refluxed for 2 h and then was quenched with 1 M NH4OH and
extracted with CH2Cl2 (3 × 25 mL). The organic layers were
dried over Na2SO4, and the solvent was evaporated at reduced
pressure. The residue was purified by crystallization from
EtOAc/cyclohexane affording 6 (0.87 g, 97%) as a solid. IR
(Nujol) 1710, 1670, 1620 cm-1; 1H NMR (CDCl3) δ 0.83 (d, 3H,
J ) 6.6 Hz), 2.86 (s, 3H), 3.94 (dq, 1H, J ) 6.6 Hz, 8.5 Hz),
5.37 (d, 1H, J ) 8.5 Hz), 5.77 (dd, 1H, J ) 10.4 Hz, 2.0 Hz),
6.40 (dd, 1H, J ) 17.0 Hz, 2.0 Hz), 7.40-7.15 (m, 5H), 7.72
(dd, 1H, J ) 10.4 Hz, 17.0 Hz); 13C NMR (CDCl3) δ 14.8, 28.1,
53.8, 59.3, 126.8, 127.9, 128.4, 128.6, 128.7, 128.8, 129.7, 136.3,
155.5, 164.4; MS m/z 244 (M+, 24), 229 (3), 189 (44), 175 (13),
143 (5), 132 (100), 105 (10), 91 (8), 77 (27), 58 (13), 55 (30);
[R]D ) -100.6° (c 1.0, CHCl3); mp 135-140 °C. Anal. Calcd
for C14H16N2O2: C, 68.8; H, 6.6; N, 11.5. Found: C, 69.0; H,
6.6; N. 11.5.
N-(ter t-Bu toxyca r bon yl)-O-ben zylh yd r oxyla m in e (9).
To a mechanically stirred solution of O-benzylhydroxylamine
hydrochloride (0.15 g, 0.94 mmol) in water (2 mL) and CH2-
Cl2 (2 mL) was added NaHCO3 (0.174 g, 2 mmol) in small
portions at 0 °C. When foaming ceased, di-tert-butyl dicar-
bonate (0.25 g, 1.1 mmol) was added at 0 °C and strirring was
continued for 3 h. The reaction was stopped by addition of 3
mL of a saturated solution of NaHCO3 and extracted three
times with CH2Cl2. The organic layers were dried over Na2-
SO4. After evaporation of the solvent at reduced pressure, 9
(0.21 g, 99%) was obtained without further purification. 1H
NMR (CDCl3) δ 1.48 (s, 9H), 4.86 (s, 2H), 7.11-7.48 (m, 6H).
(4R,5S)-1,5-Dim eth yl-3-[(3′-alkyl-2′-azir idin yl)car bon yl]-
4-p h en ylim id a zolid in -2-on e (4, 5). To a stirred solution of
2 or 3 (1 mmol) in dry CH2Cl2 (5 mL) under an inert
atmosphere either AlMe2Cl (1 M in cyclohexane, 1.1 mL, 1.1
mmol) or TiCl4 (0.12 mL, 1.1 mmol) was added at rt. After 15
min, the solution was transferred dropwise over 1 min at rt
and under an inert atmosphere by means of a Teflon cannula
to a solution of triethylamine (0.28 mL, 2 mmol) in CH2Cl2 (5
mL). The reaction was quenched with water after 30 min (5
mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
layers were dried over Na2SO4, and the solvent was evaporated
at reduced pressure. The residue was purified by flash
chromatography on silica gel (for 4 cyclohexane/ethyl acetate
1/1, for 5 cyclohexane/EtOAc 1/2) yielding 4 or 5 as a solid
(70-97%).
(4R,5S)-1,5-Dim eth yl-3-[3′-[(ter t-bu toxyca r bon yl)(ben -
zyloxy)am in o]pr opan oyl]-4-ph en ylim idazolidin -2-on e (10).
To a suspension of NaH (0.002 g, 0.08 mmol) in dry DMF (1.5
m) was added 9 (0.055 g, 0.25 mmol) under an inert athmo-
sphere at rt. After 15 min, 6 (0.050 g, 0.2 mmol) was added,
and stirring was continued for 3 h. The reaction was diluted
with 30 mL of CH2Cl2 and washed four times with small
portions of water. The organic solvent was dried over Na2-
SO4 and evaporated at reduced pressure. The residue was
purified by flash chromatography on silica gel with cyclohex-
ane/EtOAc 70/30 affording 10 (0.090 g, 96%) as an oil. IR
1
(Nujol) 1730, 1680 cm-1; H NMR (CDCl3) δ 0.76 (d, 3H, J )
6.6 Hz), 1.49 (s, 9H), 2.80 (s, 3H), 3.23 (dt, 1H, J ) 7.1 Hz,
16.9 Hz), 3.43 (dt, 1H, J ) 6.9 Hz, 16.9 Hz), 3.70-3.87 (m,
3H), 4.80 (s, 2H), 5.18 (d, 1H, J ) 8.5 Hz), 7.09-7.44 (m, 10H);
13C NMR (CDCl3) δ 14.8, 28.2, 33.5, 45.2, 53.8, 59.2, 81.2, 126.8,
127.9, 128.2, 128.3, 129.3, 135.5, 136.5, 155.6, 156.3, 170.5;
MS m/z 244 (19), 189 (34), 175 (13), 149 (9), 132 (100), 117 (6),
References 9b and 11 include characterization data for
(2′R,3′S)-4, and (2′S,3′R)-5a , respectively.
(28) Stewart, J . J . P. QCPE455 Indiana University, Bloomington,
IN.

Synthesis of Enantiomerically Pure Aziridine-2-imides
J . Org. Chem., Vol. 62, No. 26, 1997 9153
105 (7); [R]D ) -32° (c 1.5, CHCl3). Anal. Calcd for
C26H33N3O5: C, 66.8; H, 7.1; N, 9.0. Found: C, 66.6; H, 7.1;
N. 9.1.
1H, J ) 2.9 Hz, 5.7 Hz), 5.33 (d, 1H, J ) 8.8 Hz), 7.15-7.40
(m, 5H); 13C NMR (CDCl3) δ 15.1, 28.3, 28.7, 29.7, 54.2, 59.5,
127.0, 127.8, 128.7, 136.0, 155.6, 171.8; MS m/z 259 (M+, 40),
243 (15), 231 (9), 217 (5), 203 (3), 189 (100), 175 (28), 148 (11),
133 (16), 132 (75), 117 (45), 91 (36); [R]D ) -68° (c 0.9, CHCl3).
Anal. Calcd for C14H17N3O2: C, 64.9; H, 6.6; N, 16.2. Found:
C, 65.0; H, 6.6; N, 16.0.
(2′S)-12: IR (Nujol) 1710, 1660, 1450 cm-1; 1H NMR (CDCl3)
δ 0.83 (d, 3H, J ) 6.6 Hz), 1.77 (s, 1H), 1.85-1.98 (m, 2H),
2.88 (s, 3H), 3.90-4.11 (m, 2H), 5.27 (d, 1H, J ) 8.6 Hz), 7.10-
7.40 (m, 5H); 13C NMR (CDCl3) δ 14.8, 28.0, 28.4, 29.5, 54.3,
59.8, 126.7, 128.4, 128.5, 128.6, 136.1, 155.6, 171.6; MS m/z
259 (M+, 15), 244 (18), 191 (29), 189 (83), 175 (28), 132 (100),
117 (25), 91 (26); [R]D ) -140.7° (c 0.2, CHCl3). Anal. Calcd
for C14H17N3O2: C, 64.9; H, 6.6; N, 16.2. Found: C, 64.8; H,
6.7; N, 16.2.
(4R,5S)-1,5-Dim eth yl-3-[3′-(ben zyloxyam in o)pr opan oyl]-
4-p h en ylim id a zolid in -2-on e (8). P a th w a y A. To a stirred
solution of 6 (3.66 g, 15 mmol) in dry toluene (30 mL) were
added triethylamine (1.04 mL, 7.5 mmol) and O-benzylhy-
droxylamine (54 mL, 0.5 M in CH2Cl2, 27 mmol) at rt under a
nitrogen atmosphere. The solution was warmed at 50 °C, CH2-
Cl2 was completely removed under a nitrogen current, and
then the solution was refluxed for 20 h. After cooling at rt,
the reaction was quenched with water and extracted with
EtOAc (3 × 30 mL). The organic layers were dried over Na2-
SO4, and the solvent was evaporated at reduced pressure. The
residue was purified by flash chromatography on silica gel with
cyclohexane/EtOAc 70/30 affording 8 (3.74 g, 68%) as a waxy
solid and 7 (0.82 g, 18%) as a major byproduct.
Ben zyl (2R)-Azir id in e-2-ca r boxyla te (13). To a stirred
solution of BnOH (6 mmol, 0.65 g) in dry THF (10 mL) under
an inert atmosphere, was added n-BuLi (4.5 mmol, 1.6 M in
hexane, 2.8 mL) was added dropwise at -10 °C. After 20 min,
this solution was added dropwise at -10 °C to a solution of
11 (3 mmol, 0.78 g) in anhyd THF (10 mL). The reaction was
quenched after 30 min with 1 M NH4Cl, THF was removed at
reduced pressure, and the residue was extracted three times
with Et2O. The organic layers were dried over Na2SO4, and
solvent was evaporated at reduced pressure, affording directly
13 (0.48 g, 90%) as an oil, not further purified. 1H NMR
(CDCl3) δ 1.82-1.96 (m, 1H), 2.00-2.10 (m, 1H) 2.59 (dd, 1H,
J ) 2.8 Hz, 5.0 Hz), 5.18 (d, 1H, J ) 12.2 Hz), 5.23 (d, 1H, J
) 12.2 Hz), 7.10-7.40 (m, 5H); MS m/z 177 (M+, 5), 162 (7),
132 (9), 91 (100), 65 (33).
Ben zyl (2R)-1-Tr ityla zir id in e-2-ca r boxyla te (14). To a
stirred solution of 16 (2 mmol, 0.35 g) in dry CH2Cl2 (10 mL)
under an inert atmosphere were added triethylamine (4 mmol,
0.55 mL) and TrCl (2 mmol, 0.56 g) at 0 °C. The reaction was
quenched after 20 h with water and extracted three times with
CH2Cl2. The organic layers were dried over Na2SO4, and
solvent was evaporated at reduced pressure. The residue was
purified by flash chromatography over silica gel with cyclo-
hexane/EtOAc 90/10 affording 14 (0.80 g, 95%) as a solid. 1H
NMR (CDCl3) δ 1.43 (dd, 1H, J ) 1.6 Hz, 6.1 Hz), 1.95 (dd,
1H, J ) 2.8 Hz, 6.1 Hz), 2.30 (dd, 1H, J ) 1.6 Hz, 2.8 Hz),
5.21 (d, 1H, J ) 12.2 Hz), 5.27 (d, 1H, J ) 12.2 Hz), 7.10-
7.40 (m, 20H); MS m/z 341 (5), 281 (5), 260 (22), 183 (74), 154
(30), 105 (100), 77 (66), 51 (13); [R]D ) +90° (c 0.7, THF).7a
Anal. Calcd for C29H25NO2: C, 83.0; H, 6.0; N, 3.3. Found C,
83.2; H, 6.0; N, 3.3.
7: IR (Nujol) ν 1730, 1670 cm-1; 1H NMR (CDCl3) δ 0.83 (d,
6H, J ) 6.6 Hz), 2.79 (s, 6H), 3.00-3.50 (m, 8H), 3.86 (dq, 2H,
J ) 6.6 Hz, 8.5 Hz), 4.71 (s, 2H), 5.22 (d, 2H, J ) 8.5 Hz),
7.10-7.40 (m, 15H); 13C NMR (CDCl3) δ 14.6, 27.8, 33.1, 53.3,
53.5, 58.9, 74.8, 126.6, 127.2, 127.5, 127.6, 127.8, 127.9, 128.1,
128.8, 136.5, 137.1, 155.5, 170.8; MS m/z 367 (6), 244 (46), 189
(50), 175 (41), 132 (100), 91 (80), 77 (26), 58 (75).
P a th w a y B. To a stirred solution of 10 (0.09 g, 0.19 mmol)
in EtOAc (3 mL) was added 3 M HCl (2 mL) at rt. After 30
min, water (3 mL) and solid NaHCO3 were added until basicity
was reached. The mixture was extracted with EtOAc (3 × 15
mL), and the organic layers were dried over Na2SO4. The
solvent was evaporated at reduced pressure, and the residue
was purified by flash cromatography on silica gel with cyclo-
hexane/EtOAc 70/30 affording 8 (0.068 g, 97%) as a waxy solid.
1
8: IR (Nujol) 1730, 1670 cm-1; H NMR (CDCl3) δ 0.79 (d,
3H, J ) 6.6 Hz), 2.83 (s, 3H), 3.18-3.40 (m, 4H), 3.86 (dq, 1H,
J ) 6.6 Hz, 8.5 Hz), 4.66 (s, 2H), 5.25 (d, 1H, J ) 8.5 Hz),
7.05-7.50 (m, 10H); 13C NMR (CDCl3) δ 14.9, 28.1, 33.5, 47.1,
54.0, 59.3, 75.8, 126.9, 127.6, 128.3, 128.5, 136.5, 138.0, 171.6,
180.6; MS m/z 244 (19), 189 (34), 175 (13), 149 (9), 132 (100),
117 (6), 105 (7); [R]D ) -77 (c 0.9, CHCl3). Anal. Calcd for
C21H25N3O3: C, 68.6; H, 6.9; N, 11.4. Found: C, 68.5; H, 7.0;
N, 11.4.
(4R ,5S )-1,5-D im e t h y l-3-(2′-a zir id in y lc a r b o n y l)-4-
p h en ylim id a zolid in -2-on e (11, 12). A solution of 8 (5 mmol,
1.84 g) and TiCl4 (5.5 mmol, 0.6 mL) in CH2Cl2 (15 mL) was
added dropwise at rt and under an inert atmosphere by means
of a Teflon cannula to a solution of triethylamine (1.4 mL, 10
mmol) in CH2Cl2 (15 mL). After 30 min, the reaction was
quenched with water and extracted three times with CH2Cl2.
The organic layers were dried over Na2SO4, and the solvent
was removed at reduced pressure. The residue was purified
by flash chromatography on silica gel with cyclohexane/EtOAc
50/50, and 11 (1.05 g, 81%) and 12 (0.18 g, 14%) were obtained
as waxy solids.
Ack n ow led gm en t. This work was supported in part
by H.U.R.S.T (40%), by C.N.R., by University of Bologna
(funds for Selected Research Topics), and by a NATO
collaborative Research Grant with Pr. Konopelsky of
University of Santa Cruz (CGR 950049).
(2′R)-11: IR (Nujol) 1710, 1660, 1450 cm-1 1H NMR
;
(CDCl3) δ 0.84 (d, 3H, J ) 6.6 Hz), 1.75 (s, 1H), 1.82-1.98 (m,
2H), 2.88 (s, 3H), 3.96 (dq, 1H, J ) 6.6 Hz, 8.8 Hz), 4.07 (dd,
J O971254E