The first synthesis of enantiopure α-amino ketimines and amino aziridines

Article abstract of DOI:10.1021/jo005741x

Chiral 1-aminoalkyl chloromethyl ketimines 2 are synthesized in enantiomerically pure form starting from 1-aminoalkyl chloromethyl ketones 1 and different amines. Reduction of amino ketimines 2 and subsequent spontaneus cyclization affords aminoalkyl aziridines 3 with high diastereoisomeric excess and without detectable racemization.

Full text of DOI:10.1021/jo005741x

2764
J . Org. Chem. 2001, 66, 2764-2768
Th e F ir st Syn th esis of En a n tiop u r e r-Am in o Ketim in es a n d Am in o
Azir id in es
J ose´ M. Concello´n,* Pablo L. Bernad, and Estela Riego
Departamento de Quı´mica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a 8, 33071 Oviedo, Spain
Santiago Garc´ıa-Granda and AÄ ngela Force´n-Acebal
Departamento de Quı´mica Fı´sica y Analı´tica, Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a 8, 33071 Oviedo, Spain
jmcg@sauron.quimica.uniovi.es
Received November 22, 2000
Chiral 1-aminoalkyl chloromethyl ketimines 2 are synthesized in enantiomerically pure form
starting from 1-aminoalkyl chloromethyl ketones 1 and different amines. Reduction of amino
ketimines 2 and subsequent spontaneus cyclization affords aminoalkyl aziridines 3 with high
diastereoisomeric excess and without detectable racemization.
In tr od u ction
generality,9 while aziridination of CdN suffers from
difficulty in varying the N-substituent, from the fact that
only aldimines can be used as starting materials, and
because moderate enantioselectivity is obtained.7 These
drawbacks have seriously restricted the use of the chiral
aziridine ring in organic synthesis.
In addition, although functionalized aziridines (for
example, hydroxyaziridines and aziridine-2-carboxylates)
have been reported, enantiopure amino aziridines remain
unreported10 even though their synthesis possibly could
furnish a new access to chiral 1,2-diamines.11 Thus, the
development of a simple and effective general method for
preparation of enantiopure amino aziridines would be
desirable.
While optically active R-amino aldimines have been
widely used as chiral building blocks in organic synthe-
sis,1 the synthesis of the corresponding R-amino ketimines
remains unreported.2 Another attractive starting mate-
rial for further chemical transformations, yielding prod-
ucts of predetermined stereo- and regiochemistry,3 is the
chiral aziridine ring, which has been used to obtain a
variety of biologically important molecules such as amino
acids, â-lactams, and alkaloids.4 The synthesis of the
chiral aziridine ring5 is generally achieved starting from
enantiomerically pure natural compounds (amino acids,
carbohydrates, hydroxy acids)4d,e or by direct aziridination
of CdC6 or CdN7 bonds. However, preparation from
available enantiopure natural products typically requires
a multistep transformation;8 aziridination of alkenes is
limited by its moderate enantiomeric excess and poor
Previously, we have described the synthesis of chiral
R′-amino R-chloro ketones 112 by direct reaction of easily
available R-amino esters with in situ generated chlorom-
ethyllithium. We have also described some synthetic
applications of these R-amino chloromethyl ketones: their
* To whom correspondence should be addressed. Fax: 34-98-510-
3446.
(1) For a review of the synthesis and use of R-amino aldimines, see:
(a) Reetz, M. T. Chem. Rev. 1999, 99, 1121. (b) Reetz, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531.
(7) (a) Aggarwal, V. K.; Thompson, A.; J ones, R. V. H.; Standen, M.
C. H. J . Org. Chem. 1996, 61, 8368. (b) Li, A.; Zhou, Y.; Dai, L.; Hou,
X.; Xia, L.; Lin, L. Angew. Chem., Int. Ed. Engl. 1997, 36, 1317. (c)
Zhou, Y.; Li, A.; Dai, L. Tetrahedron Lett. 1997, 38, 7225. (d) Cantrill,
A. A.; Hall, L. D.; J arvis, A. N.; Osborn, H. M. I.; Raphy, J .; Swenney,
J . B. Chem. Commun. 1996, 2631. (e) Davis, F. A.; Liu, H.; Zhou, P.;
Fang, T.; Reddy, V.; Zhang, Y. J . Org. Chem. 1999, 64, 7559.
(8) Hansen, K. B.; Finney, N. S.; J acobsen, E. N. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 676.
(2) Extensive search of the chemical literature leads us to the
conclusion that no enantiopure R-amino ketimines have been described.
(3) (a) For a general review of aziridine chemistry, see: Pearson,
W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: New York, 1996; Vol 1a. (b) Dauben, P.; Dubois, L.; Dau,
M. E. T. H.; Dodd, R. H. J . Org. Chem. 1995, 60, 2035. (c) da Zhang,
Z.; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602. (d) Bodenan, J .;
Chanet-Ray, J .; Vessiere, R. Synthesis 1992, 288. (e) Sato, K.;
Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073.
(4) (a) Muller, P. In Advances in Catalytic Process: Vol. 2 Asym-
metric Catalysis; Doyle, M. P., Ed.; J AI Press: Greenwich, CT, 1997.
(b) Kump, J . E. G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 469. (d) Tanner,
D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (e) Tanner, D. Pure
Appl. Chem. 1993, 65, 1319. (f) Hudlicky, T.; Seoane, G.; Price, J . D.;
Gadamasetti, K. G. Synlett 1990, 433.
(9) Aryl-substituted olefins (ref 7a,b) or electron-deficient alkenes
(ref 7c,d) are required as starting materials.
(10) Extensive search of the chemical literature leads us to the
conclusion that general methods for the synthesis of enantiopure amino
aziridines and their use are not known, although they are known to a
limited extent: (a) Meyer zu Reckendorf, W.; Wassiliadou-Micheli, N.
Chem. Ber. 1970, 103, 37. (b) Yoshimura, J .; Iwakawa, M.; Ogura, Y.
Bull. Chem. Soc. J pn. 1976, 49, 2506 (c) Andres, C. J .; Meyers, A. I.
Tetrahedon Lett. 1995, 36, 3491. (d) Herdeis, C.; Aschenbrenner, A.;
Kirfel, A.; Schwabenla¨nder, F. Tetrahedron: Asymmetry 1997, 8, 2421.
(e) Dollt, H.; Zabel, V. Aust. J . Chem. 1999, 52, 259.
(5) For recent review in the asymmetric synthesis of aziridines,
see: Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8,
1693.
(6) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. A. J . Am. Chem. Soc. 1993, 115, 5328. (b) Li, Z.; Conser, K.
R.; J acobsen, E. N. J . Am. Chem. Soc. 1993, 115, 5326. (c) Aires-de-
Sousa, J .; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 1996, 37, 3183.
(d) Atkinson, R. S. Tetrahedron 1999, 55, 1519.
(11) Vicinal diamines are encountered as ligands in metal-induced
stereoselective reactions, in various chemotherapeutic contexts (cis-
platin analogues and technetium-99 contrasting agents), as well in a
wide variety of natural products: Reetz, M. T.; J aeger, R.; Drewlies,
R.; Hu¨bel, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 103.
(12) (a) Barluenga, J .; Baragan˜a, B.; Alonso, A.; Concello´n, J . M. J .
Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J .; Baragan˜a,
B.; Concello´n, J . M. J . Org. Chem. 1995, 60, 6696.
10.1021/jo005741x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/20/2001

Synthesis of R-Amino Ketimines and Amino Aziridines
Sch em e 1. Syn th esis of r-Am in o Ketim in es
J . Org. Chem., Vol. 66, No. 8, 2001 2765
Sch em e 2. Syn th esis of Am in o Azir id in es
Ta ble 1. Syn th esis of r-Am in o Ketim in es 2
entry
product
R1
R2
yielda (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Me
Me
Me
i-Bu
i-Bu
Bn
allyl
Pr
C6H11
Bn
CHPh2
allyl
Bn
C6H11
p-MeOC6H4
Bn
94
90
80
73b
88
89
86
92
78
74
The obtained ketimines 2 are thermally unstable,
easily hydrolyzed by acids, and only can be stored for a
limited time (without solvents, 24 h at -10 °C). Despite
this relative instability, compounds 2 (crude products)
were characterized by NMR spectroscopy and mass
spectrometry.
Bn
Bn
10
2j
a
b
Isolated yield based on the starting ketone 1. ee >99% (see
text); HPLC (Chiralcel OD-H; UV detector; 0.8 mL/min; 215 nm;
97:3 hexane/etanol; tR ) 14.3 min).
NMR analysis (300 MHz) of the crude reactions of
R-chloroketimines 2 showed the presence of only one
diastereoisomer. The Z stereochemistry of the imino
function was determined by NOE experiments with
compound 2e. Irradiation of the hydrogen CHPh2 pro-
duced positive NOE in CH2Cl signals, while no positive
NOE was observed in the CHNBn2, indicating a trans
relative configuration between 1-aminoalkyl and R2
groups, in agreement with the previously reported ster-
eochemistry of R-amino aldimines.1
Synthesis of 2 proceeded with no detectable racemiza-
tion. Due to the decomposition of ketimines 2 under
HPLC analysis conditions, the enantiomeric purity of
R-chloroketimines 2 was determined indirectly. The
enantiomeric excess (ee) of chloromethyl ketone 1 (R1 )
Me), obtained after acid hydrolysis of the R-amino
ketimine 2d ,17 was >99%, showing that no racemization
occurred in the synthesis and in the acid hydrolysis of
ketimine 2d and, by analogy, in all the prepared
ketimines. To exclude the possibility of coelution of both
enantiomers, a racemic mixture of 1 (R1) Me) was
prepared and analyzed by HPLC.
P r ep a r a tion of En a n tiop u r e Am in o Azir id in es 3.
To prove the usefulness of enantiopure ketimines 2 in
organic synthesis, these compounds were transformed
into the corresponding amino aziridines by reduction.
Therefore, reduction of 2 gave the amide 4, which, after
spontaneous cyclization yielded aziridines 3 (Scheme 2).
Reduction of 2 was carried out using LiAlH4, NaBH4, or
NaBH3CN. Our first trials sought to determine the most
suitable reducing agent. LiAlH4 at -15 °C (Table 2)
afforded the aziridines 3 with lower yields and diastereo-
isomeric excesses (de) than NaBH3CN (see below) and
contaminated by other products.18 Reduction of 2 with
NaBH4 at -30 °C19 (Table 2) gave a mixture of the
corresponding chloro diamines 5 (obtained by hydrolysis
of 4) and amino aziridines 3.20 Treatment of this mixture
reduction gives threo-aminoalkyl epoxides;12b treatment
with organometallic compounds affords 3-azetidinols;13
their reaction with halomethyllithium leads to 2-(1-
aminoalkyl) epihalohydrines.14 We have also reported the
addition of the enolates obtained from these ketones to
aldehydes or ketones.15 The high diastereoselectivity of
these reactions and the enantiopurity of the compounds
obtained prompted us to study new synthetic applications
of chiral 1-aminoalkyl chloromethyl ketones 1 in the
synthesis of enantiomerically pure building blocks. In this
paper, we report the first preparation of enantiopure
R-amino ketimines16 2 from the corresponding 1-ami-
noalkyl chloromethyl ketones 1 and their reduction to
obtain the corresponding enantiopure amino aziridines
3.
Resu lts a n d Discu ssion
Syn th esis of En a n tiop u r e Ketim in es 2. Reaction
of 1-aminoalkyl chloromethyl ketones12 1 with different
amines in the presence of TiCl4 at room temperature gave
the corresponding 1-aminoalkyl chloromethyl ketimines
2 in high yield (Scheme 1 and Table 1). Isolation of pure
ketimines 2 only required removal of solvents (purity
1
>95%, 300 MHz H NMR spectroscopy). When amines
of high boiling point were used (benzylamine, p-meth-
oxyanisidine, or diphenylmethanamine), a mixture of
ketimine and amine was isolated, which could be used,
without further purification, to obtain the corresponding
amino aziridines (see below).
Dibenzylated ketones 1 were used as starting com-
pounds instead of other N-protected ketones due to their
stability and the high diastereoselectivity they show in
their reduction and reaction with organometallic com-
pounds.12b,13,14
(13) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem.
1997, 62, 5974.
(14) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem.
1999, 64, 2843.
(15) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem.
1999, 64, 5048.
(16) No synthesis of R-amino ketimines has been reported; however,
these compounds have been postulated in the reductive amination of
R-amino ketones: Reetz, M. T.; Schmitz, A. Tetrahedron Lett. 1999,
40, 2741-2742.
(17) The hydrolysis of amino ketimine 2d was carried out using an
aqueous solution of acetic acid at room temperature for 5 min.
(18) When reaction was performed at lower temperature, no reduc-
tion of 2 was observed.
(19) These reaction conditions were chosen taking into account the
reduction conditions of 1-aminoalkyl chloromethyl ketones using
NaBH4; see ref 12b.
(20) The ratios of compounds 3 and 5 were obtained from the crude
reaction mixtures using 1H NMR.

2766 J . Org. Chem., Vol. 66, No. 8, 2001
Concello´n et al.
Ta ble 2. Syn th esis of Am in o Azir id in es 3 Usin g Na BH4
or LiAlH4
3 was assigned by analogy. Therefore, reduction of 2 took
place under nonchelation control, based on steric con-
straints imparted by the bulky N,N-dibenzyl protecting
group. This diasterofacial preference is in agreement with
that reported previously for the reduction of 1-aminoalkyl
chloromethyl ketones12b and for the reductive amination
of R-amino ketones16 and in disagreement with the
addition of organometallic compounds to aldimines.1
In conclusion, the reported results represent the first
synthesis of enantiopure R-amino ketimines 2 with high
yield from easily available materials. Reduction of these
ketimines afforded directly the unreported chiral amino
aziridines 3 in high yield and with high diastereoisomeric
excess.
R1
R2
reaction conditions yielda (%) 3/5
deb
Me
Me
Me
Me
Me
Me
Me
i-Bu Bn
i-Bu Bn
Bn
Bn
Bn
Bn
allyl
Pr
Pr
Pr
Bn
LiAlH4, -15 °C
NaBH4, -30 °C
NaBH4, 25 °C
LiAlH4, -15 °C
NaBH4, -30 °C
NaBH4, 25 °C
NaBH4, 25 °C
NaBH4, -30 °C
NaBH4, 25 °C
NaBH4, 25 °C
NaBH4, 25 °C
NaBH4, -30 °C
NaBH4, 25 °C
36/-
43/11
95/-
62/-
15/57
47/34
80/-
35/54
87/5
63
92
91
68
94
CHPh2
C6H11
92
92
>95
>95
>95
>95
>95
>95
C6H11
p-MeOC6H4
Bn
Bn
66/6
17/23c
18/65
92/-
a
b
Isolated yield based on the starting ketone 1. Diastereoiso-
Exp er im en ta l Section
meric excess determined by 300 MHz 1H and 13C NMR analysis
of the crude products 3 and 5. c Starting ketimine 2 was recovered.
Gen er a l Meth od s. Analytical TLC was conducted in pre-
coated silica gel 60 F-254 on aluminum sheets; compounds
were visualized with UV light or iodine. 1H NMR spectra were
recorded at 300 or 200 MHz. 13C NMR spectra were recorded
at 75 or 50 MHz. Chemical shifts are reported in ppm relative
to TMS in CDCl3; coupling constants are reported in Hz. Only
the molecular ions and/or base peaks in MS are given. Optical
rotations were measured in CHCl3. The enantiomeric purity
was determined by chiral HPLC analysis using a Chiralcel
OD-H (0.46 × 25 cm, Diacel) column. Flash chromatography
was carried out on Merck Kiesegel 60 (230-400 mesh) using
mixtures of hexane and ethyl acetate as eluents.
All reagents were purchased from Aldrich, and the amines
and TiCl4 were distilled before using. Chlorinated ketones 1
were prepared according to literature procedures.12 All reac-
tions were conducted in oven-dried glassware under dry
nitrogen. All solvents were purified before using. THF and
diethyl ether were distilled from sodium in a recycling still
using benzophenone ketyl as indicator; methanol was distilled
from magnesium turnings.
Gen er a l P r oced u r e for th e Syn th esis of 1-Am in oa lk yl
Ch lor om eth yl Ketim in es 2. A solution of TiCl4 (0.06 mL,
0.55 mmol) in dry hexane (0.4 mL) was added dropwise to a
stirred solution of 1 (1 mmol) in dry diethyl ether (10 mL) at
-0 °C. The corresponding amine (4 mmol) was added to the
resulting solution with stirring. After being stirred at room
temperature for 2 h, the mixture was filtered through a pad
of Celite and the solvents were removed in vacuo, yielding the
corresponding crude ketimine 2, which was used without
purification.
Ta ble 3. Syn th esis of En a n tiop u r e Am in o Azir id in es 3
Usin g Na BH3CN
entry
3
R1
R2
yielda (%)
deb
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
Me
i-Bu
i-Bu
Bn
allyl
Pr
C6H11
Bn
CHPh2
allyl
Bn
C6H11
p-MeOC6H4
Bn
60 (55)d
72 (60)
85 (73)
66 (59)
63 (58)
74 (65)
90 (72)
91 (73)
74 (56)
78 (65)
90
93
93
95
96
>98
>98
>95c
>95c
>95c
Bn
Bn
10
3j
a
Isolated yield based on the starting ketone 1; yields after
b
column chromatography are shown in parentheses. Diastereo-
isomeric excess determined by GC/MS and 300 MHz 1H and 13C
NMR analysis of the crude products 3. c Diastereoisomeric excess
determined by 300 MHz 1H and 13C NMR analysis of the crude
d
products 3. ee >99%; HPLC (Chiralcel OD-H; UV detector; 0.4
mL/min; 215 nm; 199:1 hexane/ethanol; tr ) 10.6 min).
with methyllithium afforded the corresponding amino
aziridines 3 as the only reaction product, the de of the
reduction reaction being similar to that obtained with
NaBH3CN (see below). To obtain compounds 3 directly,
the reduction was carried out with NaBH4 at room
temperature, but, in general, compounds 3, together with
a small amount of chloro diamine 5, were isolated (Table
2).
(-)-(2S)-(Z)-N,N-Diben zyl-3-(allylim in o)-4-ch lor obu tan -
2-a m in e (2a ): Rf ) 0.32 (hexane/ethyl acetate 5/1); [R]22
)
D
-56.4 (c 0.48, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.41-
7.34 (10 H, m), 6.03 (1 H, ddt, J ) 17.2, 10.3, 5.4), 5.22 (1 H,
dq, J ) 17.2, 1.8), 5.13 (1 H, dq, J ) 10.3, 1.8), 4.19-4.14 (3
H, m), 3.96 (1 H, d, J ) 11.0), 3.67 (1 H, q, J ) 6.4), 3.66 (2 ×
2 H, AB syst, J ) 13.5), 1.32 (3 H, d, J ) 6.4); 13C NMR (CDCl3,
75 MHz) δ 167.5, 139.4, 135.4, 128.7, 128.1, 126.8, 115.1, 58.3,
When NaBH3CN was used at room temperature, the
corresponding amino aziridines were exclusively obtained
in high yield and with high diastereoselectivity. Conse-
quently, synthesis of amino aziridines was performed by
using NaBH3CN. The reaction is general, and the degree
of diastereoselectivity was only moderately affected by
the size of R1 and R2 (Table 3). The diastereoisomeric
excess of amino aziridines 3 (>95%) was determined
54.0, 53.6, 33.6, 7.6; IR (neat) 1660, 1651; MS m/z 304 (M+
-
HCl, <1), 224 (12), 91(100); HRMS calcd for C21H24N2 (M -
HCl)+ 304.1939, found 304.1944. Anal. Calcd for C21H25ClN2:
C, 73.99; H, 7.39; N, 8.22. Found: C, 73.76; H, 7.25; N, 8.20.
(-)-(2S)-(Z)-N,N-Diben zyl-4-ch lor o-3-(p r op ylim in o)bu -
1
using either 300 MHz H NMR or/and GC/MS analysis
ta n -2-a m in e (2b): Rf ) 0.39 (hexane/ethyl acetate 3/1); [R]22
D
of crude products. Yields and diastereoisomeric excesses
are summarized in Table 3.
) -118.1 (c 0.74, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 7.45-
7.30 (10 H, m), 4.13 (2 H, AB syst, J ) 10.8), 3.71 (1H, q, J )
6.5), 3.70 (2 × 2 H, AB syst, J ) 13.5), 3.62-3.47 (2 H, m),
1.82-1.70 (2 H, m), 1.35 (3 H, d, J ) 6.5), 1.03 (3 H, t, J )
7.5); 13C NMR (CDCl3, 50 MHz) δ 165.8, 139.3, 128.6, 127.9,
126.7, 57.9, 53.8, 52.8, 33.1, 23.7, 11.7, 7.5; IR (neat) 1661;
MS, m/z 306 (M+ - HCl, <1), 224 (21), 91 (100); HRMS calcd
for C21H26N2 (M - HCl)+ 306.2096, found 306.2081. Anal. Calcd
for C21H27ClN2: C, 73.56; H, 7.94; N, 8.17. Found: C, 73.68;
H, 7.82; N, 8.07.
Reduction of 2 using NaBH3CN proceeded with no
detectable racemization. The enantiomeric purity of
compound 3a was determined by chiral HPLC analysis
(Chiralcel OD-H) showing an ee >99%. To exclude the
possibility of coelution of both enantiomers, a racemic
mixture of 3a was prepared and analyzed by HPLC.
The absolute configuration of 3e and 3f, as depicted
in Scheme 2, was established by single-crystal X-ray
analysis. The configuration of the other amino aziridines
(-)-(2S)-(Z)-N,N-Diben zyl-4-ch lor o-3-(cycloh exylim in o)-
bu ta n -2-a m in e (2c): Rf ) 0.52 (hexane/ethyl acetate 5/1);

Synthesis of R-Amino Ketimines and Amino Aziridines
J . Org. Chem., Vol. 66, No. 8, 2001 2767
[R]22 ) -104.8 (c 1.05, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
(2S)-(Z)-N,N-Diben zyl-3-(ben zylim in o)-4-ch lor o-1-ph en -
ylbu ta n -2-a m in e (2j): Rf ) 0.48 (hexane/ethyl acetate 5/1);
1H NMR (CDCl3, 300 MHz) δ 7.42-7.21 (20 H, m), 4.70 (2 H,
AB syst, J ) 16.1), 4.00 (2 H, s), 3.83 (2 × 2 H, AB syst, J )
13.6), 3.82 (1 H, dd, J ) 9.8, 3.1), 3.52 (1 H, dd, J ) 13.4, 9.8),
3.09 (1 H, dd, J ) 13.4, 3.1); 13C NMR (CDCl3, 75 MHz) δ 163.4,
139.8, 139.0, 129.1, 128.4, 127.8, 127.7, 127.2, 126.5, 126.2,
126.1, 64.5, 54.4, 53.6, 34.6, 27.9; IR (neat) 1662.
Gen er a l P r oced u r e for th e Syn th esis of Am in o Azir i-
d in es 3. Meth od A. To a -15 °C stirred solution of the
corresponding ketimine 2 (1 mmol) in THF (10 mL) was added
LiAlH4 (0.3 mL of solution 1.0 M in THF, 0.3 mmol). The
resulting solution was stirred for 1 h, at the same temperature,
and added to water. The resulting solution was filtered
through a pad of Celite, and the filtrate was extracted with
diethyl ether. The combined organic layers were dried (Na2-
SO4), filtered, and concentrated in vacuo. The amino aziridines
3 were examined by 1H NMR to give the diastereomeric excess
reported in Table 2. Flash column chromatography over silica
gel (hexane/ethyl acetate ) 15:1) provided pure compounds 3.
D
7.40-7.24 (10 H, m), 4.10 (2 H, AB syst, J ) 10.9), 3.67-3.46
(2 H, m), 3.62 (2 × 2 H, AB syst, J ) 13.5), 1.85-0.93 (10 H,
m), 1.26 (3 H, d, J ) 6.5); 13C NMR (CDCl3, 75 MHz) δ 162.8,
139.2, 128.4, 127.8, 126.5, 59.1, 57.1, 53.4, 33.5, 33.1, 32.9, 25.2,
24.6, 23.8, 7.4; IR (neat) 1660; MS, m/z 346 (M+ - HCl, <1),
224 (34), 91 (100); HRMS calcd for C24H31N2 (M - HCl)+
346.2409, found 346.2413. Anal. Calcd for C24H31ClN2: C,
75.27; H, 8.16; N, 7.31. Found: C, 75.20; H, 8.28; N, 7.39.
(2S)-(Z)-N,N-Diben zyl-3-(ben zylim in o)-4-ch lor obu ta n -
2-a m in e (2d ): Rf ) 0.31 (hexane/ethyl acetate 10/1); 1H NMR
(CDCl3, 300 MHz) δ 7.61-7.47 (15 H, m), 4.88 (2 H, AB syst,
J ) 17.3), 4.30 (2 H, AB syst, J ) 10.9), 3.89 (1H, q, J ) 6.5),
3.85 (2 × 2 H, AB syst, J ) 13.5), 1.54 (3 H, d, J ) 6.5); 13C
NMR (CDCl3, 75 MHz) δ 167.1, 139.5, 139.3, 128.6, 128.0,
127.1, 126.8, 126.3, 58.4, 54.4, 54.0, 33.8, 7.6; IR (neat) 1661;
MS m/z 354 (M+ - HCl, 2), 263 (24), 91 (100); HRMS calcd for
C
25H26N2 (M - HCl)+ 354.2096, found 354.2076.
(2S)-(Z)-N,N-Diben zyl-4-ch lor o-3-(d ip h en ylm eth ylim i-
n o)bu ta n -2-a m in e (2e): Rf ) 0.44 (hexane/ethyl acetate 5/1);
1H NMR (CDCl3, 300 MHz) δ 7.46-7.21 (20 H, m), 5.96 (1 H,
s), 4.13 (2 H, AB syst, J ) 10.9), 3.69 (1 H, q, J ) 6.7), 3.64 (2
× 2 H, AB syst, J ) 13.5), 1.41 (3 H, d, J ) 6.7); 13C NMR
(CDCl3, 75 MHz) δ 165.9, 139.5, 139.3, 128.6, 128.0, 127.1,
126.8, 126.3, 67.4, 58.0, 53.9, 34.1, 7.7; IR (neat) 1660; MS,
m/z 430 (M+ - HCl, <1), 174 (57), 167 (90), 106 (91), 91 (100);
HRMS calcd for C31H30N2 (M - HCl)+ 430.2409, found 430.2403.
Meth od B. To a stirred solution of the corresponding
ketimine 2 (1 mmol) in methanol (10 mL) was added NaBH4
(0.08 g, 2.0 mmol) at room temperature. After being stirred at
the same temperature overnight, the mixture was quenched
with a saturated aqueous solution of NH4Cl (5 mL) and
extracted with diethyl ether. The combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. The amino
1
aziridines 3 were examined by H NMR to give the diastere-
(-)-(3S)-(Z)-N,N-Diben zyl-2-(allylim in o)-1-ch lor o-5-m eth-
omeric excess reported in Table 2. Flash column chromatog-
raphy over silica gel (hexane/ethyl acetate ) 15:1) provided
pure compounds 3.
ylh exa n -3-a m in e (2f): Rf ) 0.41 (hexane/ethyl acetate 10/1);
[R]22 ) -105.9 (c 1.07, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.38-7.27 (10 H, m), 6.00 (1 H, ddt, J ) 17.0, 10.5, 5.2), 5.22
(1 H, dq, J ) 17.0, 1.7), 5.10 (1 H, dq, J ) 10.5, 1.7), 4.23-
4.05 (2 H, m), 3.95 (2 H, AB syst, J ) 10.9), 3.64 (2 × 2 H, AB
syst, J ) 13.5), 3.50-3.40 (1 H, m), 2.18-2.09 (1 H, m), 1.59-
When the reaction was carried out at -30 °C, the procedure
was similar to that described above. After the mixture of
aziridine and chloro diamine was isolated, MeLi (0.45 mL of
solution 1.5 M in diethyl ether, 1 mmol) was added to a stirred
solution of this mixture in THF (5 mL) at -78 °C. The resulting
solution was stirred for 1 h at room temperature and quenched
with a saturated aqueous solution of NH4Cl (3 mL). Usual
workup provided the amino aziridines 3.
1.46 (2 H, m), 1.02 (3 H, d, J ) 6.5), 0.90 (3 H, d, J ) 6.5); 13
C
NMR (CDCl3, 75 MHz) δ 164.8, 139.7, 135.6, 128.8, 128.0,
126.8, 114.9, 60.3, 53.8, 53.2, 34.6, 30.2, 25.1, 23.8, 21.7; IR
(neat) 1662, 1650; MS m/z 346 (M+ - HCl, 1), 266 (47), 91
(100); HRMS calcd for C24H30N2 (M - HCl)+ 346.2409, found
346.2399. Anal. Calcd for C24H31ClN2: C, 75.27; H, 8.16; N,
7.31. Found: C, 75.09; H, 8.10; N, 7.28.
Meth od C. NaBH3CN (0.075 g, 1.2 mmol) was added to a
stirred solution of 2 (1 mmol) in methanol (10 mL) at room
temperature. After the solution was stirred overnight at the
same temperature, the solvents were removed in vacuo. The
resulting residue was dissolved in diethyl ether and washed
with brine (5 mL). Usual workup provided the amino aziridine
(3S)-(Z)-N,N-Diben zyl-2-(ben zylim in o)-1-ch lor o-5-m eth -
ylh exa n -3-a m in e (2g): Rf ) 0.42 (hexane/ethyl acetate 10/
1); 1H NMR (CDCl3, 300 MHz) δ 7.40-7.30 (15 H, m), 4.71 (2
H, AB syst, J ) 16.2), 4.06 (2 H, AB syst, J ) 10.8), 3.69-
3.44 (1 H, m), 3.68 (2 × 2 H, AB syst, J ) 13.7), 2.28-2.19 (1
H, m), 1.62-1.37 (2 H, m), 1.21 (3 H, d, J ) 6.4), 1.09 (3 H, d,
J ) 6.4); 13C NMR (CDCl3, 75 MHz) δ 164.5, 139.4, 128.5,
128.0, 127.8, 126.9, 126.2, 126.1, 60.3, 54.0, 53.6, 34.6, 30.1,
25.0, 23.6, 21.6; IR (neat) 1660; MS, m/z 396 (M+ - HCl, <1),
266 (68), 91 (100); HRMS calcd for C28H32N2 (M - HCl)+
396.2565, found 396.2566.
1
3, which was examined by H NMR and/or GC/MS to give the
diastereomeric excess reported in Table 3. Flash column
chromatography (silica gel, hexane:ethyl acetate ) 15:1)
provided pure compound 3.
(-)-(2S,1′S)-1-Allyl-2-[1′-(d ib en zyla m in o)et h yl]a zir i-
d in e (3a ): Rf ) 0.32 (hexane/ethyl acetate 5/1); [R]22D ) -20.2
1
(c 0.64, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.52-7.28 (10
(-)-(2S)-(Z)-N,N-Diben zyl-4-ch lor o-3-(cycloh exylim in o)-
1-p h en ylbu ta n -2-a m in e (2h ): Rf ) 0.53 (hexane/ethyl acetate
5/1); [R]22D ) -67.3 (c 1.09, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.42-7.23 (15 H, m), 3.84 (2 H, AB syst, J ) 10.7), 3.72 (2
× 2 H, AB syst, J ) 13.4), 3.60 (1 H, dd, J ) 10.0, 2.8), 3.53-
3.43 (1 H, m), 3.39 (1 H, dd, J ) 12.8, 10.0), 2.94 (1 H, dd, J
) 12.8, 2.8) 1.76-1.29 (10 H, m); 13C NMR (CDCl3, 75 MHz)
δ 159.4, 140.3, 139.6, 129.6, 128.7, 128.1, 127.6, 126.8, 125.2,
63.9, 59.5, 53.6, 34.5, 33.8, 33.2, 28.0, 25.4, 24.2, 24.1; IR (neat)
1663; MS m/z 422 (M+ - HCl, 7), 331 (26), 249 (12), 91 (100);
HRMS calcd for C30H34N2 (M - HCl)+ 422.2722, found 422.2708.
Anal. Calcd for C30H35ClN2: C, 78.49; H, 7.68; N, 6.10.
Found: C, 78.17; H, 7.70; N, 6.15.
H, m), 6.06 (1 H, ddt, J ) 17.0, 10.0, 5.7), 5.29 (1 H, dd, J )
17.0, 1.7), 5.20 (1 H, dd, J ) 10.0, 1.7), 3.83 (2 × 2 H, AB syst,
J ) 13.9), 3.02 (1 H, dd, J ) 13.9, 6.1), 2.93-2.80 (2 H, m),
1.69-1.66 (2 H, m), 1.25 (1 H, d, J ) 6.5), 1.07 (3 H, d, J )
7.0); 13C NMR (CDCl3, 75 MHz) δ 140.4, 135.5, 128.3, 127.8,
126.3, 116.1, 63.4, 54.8, 53.9, 41.5, 30.1, 11.9; IR (neat) 3027,
1656; MS m/z 306 (M+, <1), 224 (24), 215 (61), 91.0 (100);
HRMS calcd for C21H26N2 306.2096, found 306.1953. Anal.
Calcd for C21H26N2: C, 82.31; H, 8.55; N, 9.14. Found: C, 82.43;
H, 8.47; N, 9.09. Chiral HPLC analysis: ee >99% (Chiralcel
OD-H, UV detector 215 nm, 0.4 mL/min, 199/1 hexane/ethanol,
tR 10.6 min).
(-)-(2S,1′S)-2-[1′-(Diben zyla m in o)eth yl]-1-p r op yla zir i-
(2S)-(Z)-N,N-Diben zyl-4-ch lor o-3-[(p-m eth oxyp h en yl)-
im in o]-1-p h en ylbu ta n -2-a m in e (2i): Rf ) 0.51 (hexane/ethyl
d in e (3b): Rf ) 0.24 (hexane/ethyl acetate 5/1); [R]22D ) -19.0
1
(c 0.48, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.46-7.21 (10
1
acetate 5/1); H NMR (CDCl3, 300 MHz) δ 7.43-7.21 (15 H,
H, m), 3.77 (2 × 2 H, AB syst, J ) 13.4), 2.76 (1 H, dq, J )
7.0, 5.7), 2.30-2.15 (2 H, m), 1.66-1.53 (4 H, m), 1.15 (1 H, d,
J ) 7.0), 1.00 (3 H, d, J ) 7.0), 0.98 (3 H, t, J ) 7.4); 13C NMR
(CDCl3, 75 MHz) δ 140.3, 128.3, 127.8, 126.4, 63.1, 54.6, 53.9,
41.6, 30.4, 22.7, 11.7; IR (neat) 3028; MS m/z 308 (M+, <1),
224 (45), 217 (84), 91 (100); HRMS calcd for C21H28N2 308.2252,
found 308.2247.
m), 6.88-6.58 (4 H, m), 4.03 (1 H, dd, J ) 10.5, 3.5), 3.89 (2 ×
2H, AB syst, J ) 13.5), 3.88 (2 H, AB syst, J ) 10.5), 3.80 (3
H, s), 3.48 (1 H, dd, J ) 12.9, 10.5), 3.14 (1 H, dd, J ) 12.9,
3.5); 13C NMR (CDCl3, 75 MHz) δ 164.6, 156.0, 142.3, 139.6,
139.3, 129.4, 128.6, 128.2, 127.8, 126.9, 125.4, 120.0, 114.0,
61.4, 55.1, 53.9, 35.9, 28.5; IR (neat) 1657.

2768 J . Org. Chem., Vol. 66, No. 8, 2001
Concello´n et al.
(-)-(2S,1′S)-2-[1′-(Diben zyla m in o)eth yl]-1-cycloh exyl-
64.8, 57.0, 53.5, 39.4, 39.3, 31.0, 23.9, 23.5, 21.2; IR (neat) 3028;
MS m/z 398 (M+, <1), 307 (62), 266 (39), 196 (82), 91 (100);
HRMS calcd for C28H34N2 398.2722, found 398.2724. Anal.
Calcd for C28H34N2: C, 84.37; H, 8.60; N, 7.03. Found: C, 84.10;
H, 8.66; N, 6.92.
a zir id in e (3c): Rf ) 0.33 (hexane/ethyl acetate 5/1); [R]22
)
D
-31.1 (c 0.74, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.51-
7.25 (10 H, m), 3.82 (2 × 2 H, AB syst, J ) 14.1), 2.91-2.78 (1
H, m), 2.00-1.05 (14 H, m), 1.03 (3 H, d, J ) 6.9); 13C NMR
(CDCl3, 75 MHz) δ 140.4, 128.3, 127.8, 126.3, 69.3, 54.4, 53.8,
40.6, 33.0, 32.3, 28.9, 25.9, 24.7, 24.6, 11.3; IR (neat) 3027;
HRMS calcd for C24H32N2 348.2565, found 348.2576.
(-)-(2S,1′S)-1-Cycloh exyl-2-[1′-(diben zylam in o)-2′-(ph en -
yl)eth yl]a zir id in e (3h ): Rf ) 0.49 (hexane/ethyl acetate 5/1);
1
[R]22 ) -27.4 (c 0.86, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
(-)-(2S,1′S)-1-Ben zyl-2-[1′-(d iben zyla m in o)eth yl]a zir i-
7.28-7.04 (15 H, m), 3.93 (2 × 2 H, AB syst, J ) 13.9), 2.93-
2.69 (3 H, m), 2.07-1.19 (12 H, m), 1.33 (1 H, d, J ) 3.3), 1.12
(1 H, d, J ) 6.4); 13C NMR (CDCl3, 75 MHz) δ 140.1, 129.3,
128.4, 127.8, 127.7, 126.3, 125.5, 69.4, 61.4, 53.6, 38.0, 35.7,
33.6, 32.4, 29.4, 26.0, 24.8, 24.6; IR (neat) 3026; HRMS calcd
d in e (3d ): Rf ) 0.32 (hexane/ethyl acetate 5/1); [R]22D ) -13.2
1
(c 0.74, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.55-7.32 (15
H, m), 3.75 (2 × 2 H, AB syst, J ) 13.8), 3.56 (2 H, AB syst,
J ) 13.1), 2.80 (1 H, dt, J ) 6.9, 6.7), 1.85 (1 H, ddd, J ) 6.7,
6.4, 3.3), 1.72 (1 H, d, J ) 3.3), 1.42 (1 H, d, J ) 6.4), 1.14 (3
H, d, J ) 6.9); 13C NMR (CDCl3, 75 MHz) δ 140.4, 139.0, 128.3,
128.1, 127.9, 126.8, 126.3, 64.7, 54.9, 53.6, 41.4, 30.7, 12.7; IR
(neat) 3027; MS, m/z 356 (M+, <1), 265 (72), 224 (25), 91 (100);
HRMS calcd for C25H28N2 356.2252, found 356.2239. Anal.
Calcd for C25H28N2: C, 84.23; H, 7.92; N, 7.86. Found: C, 84.12;
H, 7.88; N, 7.79.
for
30H36N2: C, 84.86; H, 8.55; N, 6.60. Found: C, 84.59; H, 8.50;
N, 6.62.
C30H36N2 424.2878, found 424.2874. Anal. Calcd for
C
(-)-(2S,1′S)-2-[1′-(Diben zyla m in o)-2′-(p h en yl)eth yl]-1-
(p-m eth oxyp h en yl)a zir id in e (3i): Rf ) 0.40 (hexane/ethyl
1
acetate 5/1); [R]22 ) -75.6 (c 0.82, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.34-7.03 (19 H, m), 4.00 (2 × 2 H, AB syst, J )
13.7), 3.81 (3 H, s), 3.06-2.87 (2 H, m), 2.85-2.78 (1 H, m),
2.37 (1 H, dt, J ) 6.6, 3.4), 1.86 (1 H, d, J ) 6.6), 1.82 (1 H, d,
J ) 3.4); 13C NMR (CDCl3, 75 MHz) δ 154.7, 148.2, 139.7,
129.3, 128.4, 127.9, 126.5, 125.7, 121.3, 114.1, 61.3, 55.4, 53.8,
39.5, 35.1, 31.7; IR (neat) 3026; HRMS calcd for C31H32N2O
448.2515, found 448.2511. Anal. Calcd for C31H32N2O: C,
83.00; H, 7.19; N, 6.24. Found: C, 83.11; H, 7.10; N, 6.10.
(-)-(2S,1′S)1-Ben zyl-2-[1′-(d iben zyla m in o)-2′-(p h en yl)-
(+)-(2S,1′S)-2-[1′-(Dib en zyla m in o)et h yl]-1-(d ip h en yl-
m eth yl)a zir id in e (3e): Rf ) 0.50 (hexane/ethyl acetate 5/1);
[R]22 ) +3.3 (c 0.88, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.58-7.25 (20 H, m),3.56 (1 H, s), 3.52 (2 × 2 H, AB syst, J )
13.8), 2.78 (1 H, dq, J ) 6.9, 5.9), 1.94 (1 H, ddd, J ) 6.7, 5.9,
3.3), 1.82 (1 H, d, J ) 3.3), 1.39 (1 H, d, J ) 6.7), 1.05 (3 H, d,
J ) 6.9); 13C NMR (CDCl3, 75 MHz) δ 143.5, 143.3, 140.6,
128.4, 128.2, 128.1, 128.0, 127.7, 127.1, 126.6, 126.2, 78.9, 54.3,
53.4, 41.9, 31.3, 12.7; IR (neat) 3026; MS m/z 432 (M+, <1),
341 (M+ - 91, 10), 224 (9), 167 (51), 91 (100); HRMS calcd for
eth yl]a zir id in e (3j): Rf ) 0.40 (hexane/ethyl acetate 5/1);
1
[R]22 ) -25.3 (c 0.82, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
C
C
31H32N2 432.2565, found 432.2562. Anal. Calcd for
31H32N2: C, 86.07; H, 7.46; N, 6.48. Found: C, 86.18; H, 7.35;
N, 6.40.
7.53-7.04 (20 H, m), 3.76 (2 × 2 H, AB syst, J ) 13.9), 3.57 (2
H, s), 3.04-2.91 (1 H, m), 2.84-2.70 (2 H, m), 1.86 (1 H, dt, J
) 6.7, 3.6), 1.46 (1 H, d, J ) 3.6), 1.33 (1 H, d, J ) 6.7); 13C
NMR (CDCl3, 75 MHz) δ 140.1, 139.8, 139.0, 129.2, 128.6,
128.4, 128.2, 127.7, 127.0, 126.2, 125.5, 64.8, 61.4, 53.5, 39.2,
36.3, 31.3; IR (neat) 3026; MS, m/z 341 (M+ - 91, 36), 300 (5),
196 (15), 91 (100); HRMS calcd for C24H25N2 (M - C7H7)+
341.2018, found 341.2022.
(-)-(2S,1′S)-1-Allyl-2-[1′-(d ib en zyla m in o)-3′-(m et h yl)-
bu tyl]a zir id in e (3f): Rf ) 0.41 (hexane/ethyl acetate 10/1);
1
[R]22 ) -71.2 (c 0.80, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
7.45-7.19 (10 H, m), 6.11 (1 H, ddt, J ) 18.2, 10.3, 6.2), 5.29
(1 H, dd, J ) 18.2, 2.0), 5.23 (1 H, dd, J ) 10.3, 2.0), 3.84 (2 ×
2 H, AB syst, J ) 13.3), 3.14 (1 H, dd, J ) 13.6, 6.4), 2.87 (1
H, dd, J ) 13.6, 5.9), 2.51-2.40 (1 H, m), 1.94-1.80 (1 H, m),
1.68-1.54 (1 H, m), 1.52-1.44 (1 H, m), 1.49 (1 H, d, J ) 3.3),
1.21 (1 H, d, J ) 6.4), 1.07-0.93 (1 H, m), 0.84 (3 H, d, J )
6.7), 0.51 (3 H, d, J ) 6.7); 13C NMR (CDCl3, 75 MHz) δ 140.5,
135.8, 128.9, 127.8, 126.4, 116.3, 63.5, 56.9, 53.9, 39.4, 38.9,
30.3, 24.0, 23.5, 21.3; IR (neat) 3028, 1656; MS m/z 348 (M+,
<1), 266 (14), 257 (27), 196 (58), 91 (100); HRMS calcd for
Ack n ow led gm en t. We thank II Plan Regional de
Investigacio´n del Principado de Asturias (PB-PGI99-01)
and Ministerio de Educacio´n y Cultura (PB97-1278) for
financial support and Dra. Cecilia Go´mez (Universidad
de Alicante) for spectrometric mass determination. E.R.
thanks the Ministerio de Educacio´n y Cultura for a
predoctoral fellowship.
C
24H32N2 348.2565, found 348.2555.
(-)-(2S,1′S)-1-Ben zyl-2-[1′-(d iben zyla m in o)-3′-(m eth yl)-
bu tyl]a zir id in e (3g): Rf ) 0.42 (hexane/ethyl acetate 5/1);
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
of 3e and 3f; X-ray crystallographic data, atomic coordinates,
bond lengths and angles and torsional angles for structures
3e and 3f; and copies of the 13C NMR spectra for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
[R]22 ) -52.5 (c 0.86, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ7.60-7.30 (15 H, m), 3.70 (2 × 2 H, AB syst, J ) 13.1), 3.61
(2 H, AB syst, J ) 12.6), 2.50-2.43 (1 H, m), 2.00-1.91 (1 H,
m), 1.81 (1 H, dt, J ) 6.5, 3.5), 1.67-1.58 (1 H, m), 1.61 (1 H,
d, J ) 3.5), 1.40 (1 H, d, J ) 6.5), 1.14-1.04 (1 H, m), 0.94 (3
H, d, J ) 6.5), 0.57 (3 H, d, J ) 6.5); 13C NMR (CDCl3, 75
MHz) δ 140.5, 139.0, 128.9, 128.7, 128.2, 127.7, 127.0, 126.3,
J O005741X