Stereoselective synthesis of trisubstituted aziridines with N -α-diazoacyl camphorsultam

Article abstract of DOI:10.1021/ol100104v

A Bronsted acid-catalyzed reaction of α-substituted α-diazocarbonyl compounds bearing camphorsultam as a chiral auxiliary and N-alkoxycarbonyl imines was implemented as an unprecedented means to provide trisubstituted aziridines in a highly stereodefined manner.

Full text of DOI:10.1021/ol100104v

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1668-1671
Stereoselective Synthesis of
Trisubstituted Aziridines with
N-r-Diazoacyl Camphorsultam
Takuya Hashimoto, Hiroki Nakatsu, Shogo Watanabe, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received January 15, 2010
ABSTRACT
A Brønsted acid-catalyzed reaction of r-substituted r-diazocarbonyl compounds bearing camphorsultam as a chiral auxiliary and
N-alkoxycarbonyl imines was implemented as an unprecedented means to provide trisubstituted aziridines in a highly stereodefined manner.
As enantiomerically pure aziridines can serve as chiral
building blocks in the preparation of nitrogen-containing
complex molecules,1,2 considerable efforts have been devoted
to the development of reliable methods to access chiral
aziridines stereoselectively.1,3
Originating from Brookhart and Templeton’s discovery,4
acid-catalyzed reaction of imines and R-unsubstituted R-dia-
zocarbonyl compounds (Figure 1, R1 ) H) has increasingly
been studied as a unique and promising tool for the
stereoselective synthesis of aziridines and has already
culminated in the establishment of catalytic asymmetric
methods affording either cis or trans 2,3-disubstituted aziri-
dines with high enantioselectivities, using chiral Lewis acids
or Brønsted acids.5-9 However, when it comes to the
Figure 1. Acid-catalyzed aziridination of R-diazocarbonyl com-
pounds and imines.
stereoselective synthesis of trisubstituted aziridines, neither
this method nor most of the other existing aziridinations
provide a general solution. To the best of our knowledge,
the only successful method reported to date is the aza-
Darzens reaction with chiral N-sulfinyl imines and R-halo
enolates by Davis and co-workers.10
(1) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006
(2) (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347. (b) Hu, X. E.
Tetrahedron 2006, 60, 2701
.
.
(3) (a) Jacobsen, E. N. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany,
1999; Vol. 2, p 607. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(c) Sweeney, J. Eur. J. Org. Chem. 2009, 4911
.
(6) For other chiral Lewis acid-catalyzed reactions, see: (a) Juhl, K.;
Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 2293.
(b) Redlich, M.; Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987. (c) Wipf,
P.; Lyon, M. A. ARKIVOC 2007, xii, 91.
(4) Casarrubios, L.; Pe´rez, J. A.; Brookhart, M.; Templeton, J. L. J.
Org. Chem. 1996, 61, 8358. See also the references included in ref 6.
(5) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
For a recent review, see: (b) Zhang, Y.; Lu, Z.; Wulff, W. D. Synlett 2009,
2715.
(7) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008,
130, 14380.
10.1021/ol100104v  2010 American Chemical Society
Published on Web 03/16/2010

In this context, we communicate herein the modification
of Brookhart and Templeton’s aziridination to include the
asymmetric synthesis of trisubstituted aziridines. This goal
was accomplished by use of N-Boc imines and R-alkyl-R-
diazocarbonyl compounds which bear a camphorsultam as
a key combination of substrates.11 Furthermore, by taking
advantage of thus-obtained N-Boc protected aziridines, a ring
rearrangement was conducted to provide stereodefined R,R-
disubstituted ꢀ-hydroxy-R-amino acid derivatives.
strated the difficulty to simply extend the Brookhart and
Templeton method to the synthesis of trisubstituted aziri-
dines. Namely, attempts to use N-phenyl or N-benzyl imines
with ethyl R-methyl-R-diazoacetate 1a, which only differ
from their original procedure in that the methyl group is
attached at the R-position of the diazoacetate (see Figure
1), gave no or a trace amount of aziridines, respectively
(entries 1 and 2). We then turned our attention to screen
other imines having tert-butoxycarbonyl, diphenylphospho-
nyl, or N-tosyl moieties, respectively. Although the imines
with the two latter N-substituents remained intact (entries 4
and 5), use of the N-Boc imine at low temperature afforded
the desired aziridine, albeit in low yield (entry 3).
We commenced our study by systematically investigating
the influence of the N-substituent of imines derived from
benzaldehyde and the substituent attached to the carbonyl
As the use of other strong Lewis and Brønsted acids aimed
at increasing the efficiency was found to be unfruitful (entries
6 and 7),12 we set out to examine the effect of the template
attached to the carbonyl carbon of the diazo compounds in
view of its drastic influence on the reaction pathway observed
in our related studies.7,11d Accordingly, two sets of R-dia-
zocarbonyl compounds 1b and 1c having oxazolidin-2-one
and 1,3-propanesultam substituents were examined in com-
bination with benzaldehyde N-Boc imine under the influence
of a catalytic amount of BF3·Et2O (entries 8 and 9).
Gratifyingly, the outcome of the reaction was dramatically
varied in both cases, giving the aziridines as a major product.
Irrespective of the substituents attached to the carbonyl
carbon, the trans-aziridine was solely obtained, probably
circumventing the steric repulsion between the hindered
carbonyl moiety and the aryl group in the course of the
aziridine ring-closure step.
Table 1. Preliminary Exploration of Aziridinations with Various
R-Methyl-R-diazocarbonyl Compounds and Benzaldehyde-Derived
Iminesa b
,
At this stage, the focus was set on the development of an
asymmetric variant of this unprecedented trisubstituted
aziridine synthesis. Since the high stereochemical fidelity of
the camphorsultam as a chiral auxiliary of R-diazocarbonyl
compounds in acid catalysis has been recently established
in our laboratory,11d,13 asymmetric aziridination was then
implemented with use of N-R-diazoacyl (-)-camphorsultam
a Reactions were performed with 2 (0.10 mmol) and imine (0.15 mmol)
in the presence of 20 mol % of catalyst in CH2Cl2 for 5-20 min. b Trans/cis
ratio was determined by H NMR of the crude material. c Isolated yield.
1
(12) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612.
(13) Ma, M.; Peng, L.; Li, C.; Zhang, X.; Wang, J. J. Am. Chem. Soc.
carbon of the diazo compound, using BF3·Et2O as a common
Lewis acid catalyst (Table 1). This study clearly demon-
2005, 127, 15016
.
(14) The reaction was quenched after the complete consumption of the
diazo compound. Several unidentified materials were observed by 1H NMR
of the crude material in small quantities which could be easily removed by
column chromatography on silica gel.
(8) (a) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445. (b)
Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036.
(c) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc.
2009, 131, 15615.
(15) A catalytic amount of camphorsulfonic acid indeed facilitated the
reaction of 1b and N-Boc imine smoothly, although the aziridine was
obtained in a racemic form. In our preliminary experiments, neither chiral
phosphoric acid nor dicarboxylic acid (see refs 6 and 7) promoted the
reaction even at room temperature.
(9) For asymmetric aziridination with diazoalkanes and imines mediated
by chiral sulfur ylides, see: (a) Aggarwal, V. K.; Thompson, A.; Jones,
R. V. H.; Standen, M. C. H. J. Org. Chem. 1996, 61, 8368. (b) Aggarwal,
V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem., Int. Ed. 2001, 40, 1433.
(16) For reviews on Brønsted acid catalysis, see: (a) Akiyama, T. Chem.
ReV. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008, 4097.
(17) Hasegawa, T.; Yamamoto, H. Synlett 1998, 882.
(10) (a) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996,
37, 5473. (b) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J. Org. Chem. 1999, 64, 7559. (c) Davis, F. A.; Deng, J.; Zhang, Y.;
Haltiwanger, R. C. Tetrahedron 2002, 58, 7135. (d) Davis, F. A.; Deng, J.
Org. Lett. 2007, 9, 1707.
(18) The reaction provided a mixture of the corresponding aziridine,
oxazolidin-2-one, and 2-benzyloxyoxazoline.
(19) (a) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153. (b) Lu,
Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185, and
references cited therein.
(11) For the use of R-substituted R-diazocarbonyl compounds in acid-
catalyzed stereoselective synthesis, see: (a) Hashimoto, T.; Naganawa, Y.;
Kano, T.; Maruoka, K. Chem. Commun. 2007, 5143. (b) Hashimoto, T.;
Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008, 131, 2434. (c)
Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 130,
6614. (d) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K. J. Am.
Chem. Soc. 2009, 131, 11280.
(20) For recent reviews on asymmetric synthesis of R,R-disubstituted
R-amino acids, see: (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005,
5127. (b) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007, 5, 406. (c) Cativiela,
C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569. (d)
Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry 2008, 19,
2755.
Org. Lett., Vol. 12, No. 8, 2010
1669

2a (Scheme 1). As anticipated, the desired trans-aziridine
3a could be obtained as a single stereoisomer in 43% yield
Table 2. Brønsted Acid-Catalyzed Asymmetric Aziridinationa b
,
Scheme 1
.
Asymmetric Aziridination with N-R-Diazoacyl
(-)-Camphorsultam
entry
R1
R2
R3
yieldc (%) drd (trans)
1
2
Me (2a) Boc Ph
74 (3a)
60 (3b)
63 (3c)
59 (3d)
54 (3e)
62 (3f)
56 (3g)
62 (3h)
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
2-tolyl
3
3-tolyl
4-tolyl
2-Np
4-ClC6H4
4-PivOC6H4
3-MeOC6H4
Cy
4e
5
6
7
8
9
10
11f
12f
13f
14
15f
Et (2b)
Me (2a) Cbz Ph
2-tolyl
Ph
50 (3i)
61 (3j)
64 (3k)
66 (3l)
55 (3m)
56 (3n)
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
by use of BF3·Et2O.21 Further investigation revealed the high
efficiency of a strong Brønsted acid, triflic acid, with which
the reaction led to completion within 10 min giving the
aziridine in 74% yield.14 It is also worth mentioning that
the use of a weaker acid, methanesulfonic acid, with longer
reaction times was equally effective.15,16
The chiral auxiliary of the so-obtained aziridine could
easily be removed by treatment with tetrabutylammonium
hydroxide and hydrogen peroxide as shown in Scheme 2.17
3-tolyl
4-BrC6H4
3-MeOC6H4
a Reactions were performed with 2 (0.10 mmol) and imine (0.15 mmol)
in the presence of 20 mol % of catalyst in CH2Cl2 for 5-20 min. b Trans/cis
ratio was determined by H NMR of the crude material. c Isolated yield.
1
d Determined by 1H NMR of the crude material. e Performed with 3 equiv
of imine. f Performed with 20 mol % of CH3SO3H for 1-4 h under otherwise
identical conditions.
acyloxy group as the 4-substituent of the imine was proven
to be intolerant, use of 4-pivaloyloxybenzaldehyde N-Boc
imine as their surrogate provided the aziridine in reasonable
yield (entry 7). At present, this method is not applicable to
the reaction of N-Boc imines derived from aliphatic alde-
hydes (entry 9). R-Ethyl-substituted diazo compound 2b
could be utilized as well, giving the corresponding aziridine
in 50% yield with equally high stereoselectivity (entry 10).
Considering the practicality of the benzyloxycarbonyl
(Cbz) group as a protective group of amines, this newly
developed aziridination was then applied to the reactions with
N-Cbz imines (entries 11-15). As it became obvious that
triflic acid was too strong as catalyst to stop the reaction at
the stage of the aziridine,18 we opted for the use of
methanesulfonic acid as a milder acid in anticipation of the
attenuation of undesired overreactions. Consequently, N-Cbz
aziridines could be obtained in yields ranging from 56% to
66% with uniformly high diastereoselectivities. The only
exception was the aziridination with 4-bromobenzaldehyde
N-Cbz imine, wherein the reaction was very sluggish
probably due to the lower affinity of this imine for the acid
catalyst. This issue could be solved by returning to the
catalytic use of triflic acid, giving the aziridine in 55% yield
(entry 14).
Scheme 2. Removal of the Chiral Auxiliary
Esterification of the crude acid 4 with TMSCHN2 furnished
the aziridine carboxylate 5 in 83% yield. The enantiomeric
purity of this material was determined to be 98% ee by chiral
HPLC analysis.
With these fundamental results in hand, the scope of this
asymmetric trisubstituted aziridine synthesis was investigated
in detail (Table 2). Irrespective of the substituent pattern and
electronic property of the aromatic ring of N-Boc imines,
the reactions generally proceeded uneventfully, furnishing
the corresponding trans-aziridines with high stereoselectivity
(entries 2-8). Although the incorporation of methoxy or
With the enantioenriched N-Boc protected aziridines in
hand, we became interested in the acid-catalyzed rearrange-
ment of N-Boc aziridines to the corresponding oxazolidin-
2-ones19 as a means of generating R,R-disubstituted ꢀ-hydroxy-
R-amino acid derivatives (Scheme 3).20 Accordingly, the
aziridine 3a was subjected to an acidic condition that was
(21) CCDC 710136 (3a) and CCDC 750124 (6) contain the supple-
mentary crystallographic data for this paper. The crystallographic
coordinates have been deposited with the Cambridge Crystallographic
Data Centre; deposition nos. 710136 and 750124. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.
ac.uk/conts/retrieving.html.
1670
Org. Lett., Vol. 12, No. 8, 2010

In conclusion, we developed herein an unprecedented
protocol for the stereoselective synthesis of trisubstituted
aziridines, building on the judicious combination of imines
and R-substituted R-diazocarbonyl compounds bearing
camphorsultam as a chiral auxiliary. Research is currently
underway to develop a catalytic enantioselective version
of this aziridination with use of chiral Lewis acid or
Brønsted acid, and will be reported in due course.
Scheme 3
.
Acid-Catalyzed Ring Rearrangement of Aziridine to
Oxazolidin-2-one
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the MEXT,
Japan. T.H. thanks a Grant-in-Aid for Young Scientists (B).
Mr. Yuki Naganawa and Mr. Hisashi Miyamoto (Kyoto
University) are thanked for initial experiments.
only slightly different from the above aziridination condition
in that a higher reaction temperature was employed. As
anticipated, triflic acid facilitated the reaction to give the
corresponding oxazolidin-2-one 6a in 69% yield. This
rearrangement proceeded with the retention of the configu-
ration at the ꢀ-carbon, and gave the trisubstituted trans-
oxazolidin-2-one as an essentially single isomer.21
Supporting Information Available: Experimental details,
characterization data for new compounds, and crystal data
for compounds 3a and 6a. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100104V
Org. Lett., Vol. 12, No. 8, 2010
1671