Multicomponent catalytic asymmetric aziridination of aldehydes

Article abstract of DOI:10.1021/ol202472z

The first multicomponent catalytic asymmetric aziridination reaction is developed to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity from aromatic and aliphatic aldehydes. This new method pushes the boundary of the aziridination reaction to substrates that failed with preformed imines.

Full text of DOI:10.1021/ol202472z

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5866–5869
Multicomponent Catalytic Asymmetric
Aziridination of Aldehydes
Anil K. Gupta, Munmun Mukherjee, and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824,
United States
wulff@chemistry.msu.edu
Received September 14, 2011
ABSTRACT
The first multicomponent catalytic asymmetric aziridination reaction is developed to give aziridine-2-carboxylic esters with very high diastereo-
and enantioselectivity from aromatic and aliphatic aldehydes. This new method pushes the boundary of the aziridination reaction to substrates
that failed with preformed imines.
In recent times, multicomponent reactions have been
quite extensively studied and applied in the field of asym-
metric catalysis.1 Over the past few years, considerable ad-
vances have been made in the field of catalytic asymmetric
aziridination.2 However, to the best of our knowlegde, no
example of a multicomponent catalytic asymmetric aziridi-
nation has been reported.1,3À5 A true multicomponent reac-
tion involves the reaction of three or more reagents added
simultaneously.1 Multicomponent reactions that involve re-
action between two reagents and then interception of the
resulting intermediate by the addition of a third reagent are
sequential component reactions.1,4 Herein, we report the first
multicomponent catalytic asymmetric aziridination (MCAZ)
which incorporates the most simplified protocol yet developed
for our catalytic asymmetric aziridination reaction (Figure 1).
We have previously developed chiral catalysts for the
asymmetric synthesis of aziridines from the reaction of
diazo compounds and imines (AZ reaction) (Figure 1A).6
(1) (a) Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry
2007, 18, 693–700. (b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2005, 44, 1602–1634. (c) Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: 2005.
Figure 1. (A) Catalytic asymmetric aziridination of imines.
(B) Three-component catalytic asymmetric aziridination.
(2) Pellissier, H. Tetrahedron 2010, 66, 1509.
(3) For multicomponent aziridinations with nonchiral catalysts, see:
(a) Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685–686. (b) Kubo,
T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 625–626. (c) Yadav,
J. S.; Reddy, B. V. S.; Rao, M. S.; Reddy, P. N. Tetrahedron Lett. 2003,
44, 5275–5278. (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. N.; Rao,
M. S. Synthesis 2003, 1387–1390. (e) Ishii, Y.; Sakaguchi, S. Bull. Chem.
Soc. Jpn. 2004, 77, 909–920.
(4) For a sequential component aziridination with a chiral catalyst,
see: Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445–2447.
(5) For a stoichiometric asymmetric multicomponent aziridination,
see: (a) Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.; Komatsu, M.
Angew. Chem., Int. Ed. 1998, 37, 3392–3394. (b) Nishimura, M.;
Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M. J. Org.
Chem. 2002, 67, 2101–2110.
(6) (a) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff, W. D.
Chem.;Eur. J. 2008, 14, 3785–3803. (b) Zhang, Y.; Lu, Z.; Desai, A.;
Wulff, W. D. Org. Lett. 2008, 8, 5429–5432. (c) Zhang, Y.; Lu, Z.; Wulff,
W. D. Synlett 2009, 2715–2739. (d) Hu, G.; Huang, L.; Huang, R. H.;
Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615–15617. (e) Mukherjee,
M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010,
75, 5643–5660. (f) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010,
132, 13100–13103. (g) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am.
Chem. Soc. 2010, 132, 13104–13107. (h) Ren, H.; Wulff, W. D. Org. Lett.
2010, 12, 4908–4911. (i) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee,
M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675.
r
10.1021/ol202472z
Published on Web 10/11/2011
2011 American Chemical Society

Scheme 1. Methods for Catalyst Formation
Scheme 2. Self-Condensation of Imine 13g
(Scheme 2).8 This mixture of species appears to kill the
catalyst, and this may very well be due to the amine 12
which is released in the formation of 14g. This imposes a
serious limitation on the implementation of the AZ reac-
tion, and the molecules in Figure 2 are illustrative of the
point.9
Given the greater basicity of an amine versus an imine, it
was anticipated that the MEDAM amine 12 could also
generate the boroxinate catalyst from VAPOL and B(OPh)3
in much the same way as does imine 13a (Scheme 1), and
indeed this was confirmed by NMR analysis (see Support-
ing Information). What was not clear was whether the
amine would be subsequently converted completely to the
imine such that the more basic amine will not tie up the
catalytst and stop the reaction.
With chiral Brønsted acid catalysts generated from the
VANOL and VAPOL ligands (Scheme 1), it is possible to
obtain aziridine-2-carboxylates of the type 3 with very high
enantio- and diastereoselectivities. The highest stereoselec-
tivities are typically delivered by imines derived from the
amine 12 which bears a bis(dimethylanisyl)methyl group
(MEDAM).6e The catalyst for the AZ reaction has been
identified as the novel boroxinate species 11 which is an ion
pair consisting of a boroxinate anion and a protonated
iminium.6d,g,i The boroxinate catalyst is typically generated
with either of two methods (Scheme 1). Heating VANOL or
VAPOL with B(OPh)3 and then removing volatiles under
vacuum with heating generates a mixture of 9 and 10 as a
precatalyst, both of which are converted to the boroxinate
upon treatment with the imine at ambient temperature
(Method B). Although B(OPh)3 and VAPOL are inert to
each other at room temperature, the boroxinate is formed
immediately upon addition of imine (Method A).6i
Up to this point, all of the aziridination reactions we have
published have involved preformed imines. A drawback to
the use of imines of course is the requirement of an additional
step. The difficulty in the purification of imines can vary from
drawback to limitation. The method of choice for purifica-
tion is crystallization since most imines tend to decompose on
silica gel or upon distillation. For noncrystalline imines this
usually necessitates the use of nonpurified imines. This can be
a serious problem, especially for unbranched aliphatic alde-
hydes where in many cases no aziridine product is observed at
all.7 We found, in these cases, the imine cannot be generated
in a clean fashion. For example, when aldehyde 4g is treated
with amine 12, long before complete formation of the
imine 13g can be realized, self-condensation of the imine
beginstooccur whichgives risetothe conjugated imine14g
Figure 2. Biologically important alkyl aziridines. 15: antimicro-
bial activity against Gram-positive bacteria.9b 16 and 17: cyto-
toxic and antimicrobial activity.9c 18: inhibitor of arachidonate
epoxygenase.9d
Given the problems with aliphatic aldehydes described
above, the multicomponent aziridination was first exam-
ined with benzaldehyde (Scheme 3). The VAPOL ligand
was mixed with 3 equiv of B(OPh)3 and 20 equiv of amine
12 and stirred in toluene at 80 °C for 0.5 h to ensure
complete formation of the boroxinate catalyst. This was
(8) For a related self-condensation of a DAM imine, see ref 6e.
(9) (a) Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M. Eur. J.
Med. Chem. 2009, 44, 3373 and references therein. (b) Kabara, J. J.;
Vrable, R.; Lie Ken Jie, M. S. F. Lipids 1977, 12, 753–759. (c) Metzger,
€
J. O.; Furmeier, S. Eur. J. Org. Chem. 1999, 661–664. (d) Falck, J. R.;
(7) Wulff, W. D.; Antilla, J. A.; Pulgam, V. R.; Zhang, Y.; Gilson-
Osminksi, W. Unpublished results.
Manna, S.; Viala, J.; Siddhanta, A. K.; Moustakis, C. A.; Capdevila, J.
Tetrahedron Lett. 1985, 26, 2287–2290.
Org. Lett., Vol. 13, No. 21, 2011
5867

Table 1. Optimization of the Multicomponent AZ Reaction for
n-Butanal 4ba
Scheme 3. Multicomponent AZ Reaction of Benzaldehyde 4a
˚
followed by the addition of 4 A MS and benzaldehyde.
After subsequent addition of EDA 2, the resulting mixture
was stirred at 25 °C for 24 h to give the aziridine 19a in 97%
yield and 98% ee (Procedure B, Scheme 3). It was also found
that generating the catalyst at 25 °C for 1 h gave the same
results (Procedure A, Scheme 3). Very similar results were
obtained if the diazo compound 2 was added before the
aldehyde 4a, and this reveals that this is a true multicompo-
nent reaction since imine formation can occur in the presence
of all other components.10 Interestingly, the reaction stops if
0.6 equiv of 4a is added (Scheme 3) which suggests that the
amine can kill the catalyst which is consistent with the failure
of preformed imine 13g to give any aziridine (Scheme 2).
The problem of imine self-condensation was encountered
in the multicomponent aziridination (MCAZ) of n-butanal
4b (Table 1). The three-component aziridination of n-
butanal with MEDAM amine 12 at room temperature with
5 mol % VANOL catalyst gave only a 25% yield of aziridine
19b along with a 20% yield of the condensation product 14b.
However, the formation of the side-product 14b was found
to be disfavored at lower temperatures (entry 2). The yield
was increased to 74% at 0 °C with 10 mol % catalyst (entry 4).
With 5 mol % catalyst, increased yields up to 94% were ob-
served with increased amounts of ethyl diazoacetate 2 (entries
8 and 9).11 Finally, it was found that reaction with 3 mol %
catalyst and 2 equiv of EDA provides 2.4 g (5.5 mmol) of
aziridine 19b in 92% yield and 96% ee (entry 12).
A series of eight additional aliphatic aldehydes were
screened in the multicomponent aziridination reaction
(Table 2). Excellent asymmetric inductions were observed
for the aziridination of a number of functionalized
unbranched, R-branched, and R,R-branched aliphatic alde-
hydes. These include a number of “problem” aldehydes that
have failed to give aziridines via in situ generated imines such
as dihydrocinnamyl aldehyde 4g, phenyl acetaldehyde 4h, and
ethyl-5-oxopentanoate 4e due to the problem pertaining to the
condensation product (Scheme 2).7,8 Even with the three-
component protocol, the aziridination of the “problem”
aldehyde 4g proceeds to give only a 24% yield of the aziridine
19g (entry 8). The yield can be increased to 96% if an excess
a Unless otherwise specified, all reactions were performed with 0.5 mmol
of amine 12 (0.5 M) and 1.05 equiv of n-butanal 4b and 1.2 equiv EDA 2with
Procedure A or B (see Scheme 3) and went to 100% completion. nd = not
determined. b Isolated yield. c Determined by chiral HPLC. d Yield deter-
1
mined by H NMR with Ph3CH as internal standard. e Reaction went to
61% completion. f Reaction on 2.5 mmol scale. g Reaction on 6 mmol scale.
(8 equiv) of EDA is used, and this is interpreted to mean that
the imine undergoes aziridination before it can self-condense
(entry 9).11 The MCAZ is also readily scalable as aziridine 19c
can be obtained with essentially the same induction and in
slightly higher yield when the scale is increased 10-fold
(Table 2, entries 1 and 2). It was observed that excellent results
could be obtained for 2° and 3° aliphatic aldehydes at room
temperature (Table 2, entries 14À17).
A survey of the scope of the multicomponent protocol for
aromatic aldehydes is given in Scheme 4. Excellent yields and
asymmetric inductions were observed for a number of sub-
stituted benzaldehydes including those with both electron-
withdrawing and -donating groups. The reaction with ben-
zaldehyde 4a was complete in 1 h with 5 mol % catalyst by 1H
NMR.12 Excellent inductions could also be obtained with
heteroaryl aldehydes giving aziridines 19pÀ19s in 90À97%
ee.11,13
The synthetic utility of MCAZ reaction is illustrated by
the direct transformation of aldehyde 4a to R-amino esters
21 and 22 in a one-pot fashion (Scheme 5). The crude
aziridine 19a obtained from MCAZreactionissubjectedto
deprotection followed by water assisted ring opening and
boc protection of free amine in 20 to afford β-hydroxy-R-
amino ester 21 in very high optical purity in 60% overall
yield from amine 12. Alternatively, the crude aziridine 19a
(12) Minimum reaction times were not determined for all substrates.
(13) (a) We have compared the preparation of aziridine 19r by the
MCAZ method described here with that of a two-step method involving
the isolation of the imine from aldehyde 4r and amine 12. Substantial
material loss is encountered in the two-step method as a result of
purification of the imine (see Supporting Information). (b) Pyridine-3-
carboxaldehyde gave no aziridine (not shown).
(10) In this experiement, EDA 2 was added with the VAPOL, B-
(OPh)3, and amine 12.
(11) No attempt was made to optimize the amount of EDA.
5868
Org. Lett., Vol. 13, No. 21, 2011

Table 2. Multicomponent AZ Reaction of Alkyl Aldehydesa
Scheme 4. Multicomponent AZ Reaction of Aryl Aldehydesa
a Unless otherwise specified, all reactions were performed as described
in Table 2 with 1.2 equiv of 2 with Procedure A and went to 100%
completion and gave aziridine 19 with a cis/trans ratio of >50:1. Data in
parentheses are with 8 equiv EDA 2. bIsolated yield. cDetermined by
chiral HPLC. dCis/trans = 20:1. eCis/trans = 25:1 with 8 equiv of EDA.
fCis/trans= 8.3:1 with 8 equiv of EDA. gReaction with 2 equiv of EDA 2.
Scheme 5. One-Pot Synthesis of Amino Esters 21 and 22
a Unless otherwise specified, all reactions were performed with
0.5 mmol of amine 12 (0.5 M) with 1.05 equiv aldehyde 4 and 1.2 equiv
EDA 2with Procedure A or B (see Scheme 3) and went to 100% completion
with a cis/trans ratio of >50:1. b Isolated yield. c Determined by chiral
HPLC. d Reaction on 5.0 mmol scale. e Yield determined by 1H NMR with
Ph3CH as standard; nd = not determined. f Reaction at 25 °C.
with imines from unbranched aliphatic aldehydes in two-
component methods. The fact that the imines are gener-
ated in situ permits introduction of functionality in the
aziridine not possible with two-step methods.
can be treated under reductive deprotection and ring-
opening conditions to afford R-amino ester 22 in high
optical purity and in 70% overall yield from amine 12.
In summary, a highly robust multicomponent catalytic
asymmetric aziridination reaction has been realized.14 This
method incorporates a very simplified protocol, and it
provides aneffective solution tothe long-standing problem
Acknowledgment. This work was supported by NSF
Grant CHE-0750319 and the National Institute of General
Medical Sciences (GM094478).
Supporting Information Available. Synthetic proce-
dures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Part of this work was presented at the 240th American Chemical
Society National Meeting, Boston (2010), ORGN 636.
Org. Lett., Vol. 13, No. 21, 2011
5869