Catalytic asymmetric aziridination with a chiral VAPOL-boron Lewis acid

Full text of DOI:10.1021/ja9905187

J. Am. Chem. Soc. 1999, 121, 5099-5100
5099
Scheme 1
Catalytic Asymmetric Aziridination with a Chiral
VAPOL-Boron Lewis Acid
Jon C. Antilla and William D. Wulff*
Department of Chemistry, Searle Chemistry Laboratory
The UniVersity of Chicago, Chicago, Illinois 60637
ReceiVed February 18, 1999
Aziridines are versatile intermediates that have great value in
organic synthesis.1 A recent review on the asymmetric synthesis
of aziridines reveals that nearly all nonracemic aziridines are made
from other chiral materials.2 Therefore, there is a need for the
development of new methods for the asymmetric catalytic
synthesis of aziridines. Previous reports have focused on three
different strategies to this problem as outlined in Scheme 1. Most
past effort has involved the transfer of a nitrene from [N-(p-
toluenesulfonyl)imino]phenyl iodinane to an alkene mediated by
a chiral metal catalyst which can result in the production of N-tosyl
aziridines in good asymmetric inductions with certain alkene
substrates.3 An alternate method involves the transfer of a carbene
to an imine which has been reported with a chiral copper catalyst4a
and more successfully with a rhodium catalyst that was mediated
by a chiral sulfur ylide.4b A third strategy arises from the recent
observation that simple Lewis acids can catalyze the formation
of aziridines from ethyl diazoacetate and imines.5,6 However, a
screen of this reaction with a variety of chiral Lewis acids failed
to produce aziridines with significant asymmetric induction.5c
Previously we reported that chiral Lewis acid catalysts derived
from the vaulted biphenanthrol 13 (VAPOL) proved effective in
providing excellent asymmetric inductions in Diels-Alder reac-
tions with both ester and aldehyde dienophiles.7 We now report
that a catalyst prepared from VAPOL and borane-tetrahydrofuran
complex can give very high asymmetric inductions in the
formation of aziridines from the reaction of benzhydryl imines
with ethyl diazoacetate. This catalyst was prepared by treating
Scheme 2
S-VAPOL with 3 equiv of borane-THF complex, heating at 55
°C for 1 h, removing the volatiles, and then heating the residue
at 55 °C for 30 min under a high vacuum8 (Scheme 2). Entry 4
in Table 1 shows that this catalyst produces a 74% yield of the
aziridine 10a in 98% ee and only small amounts of the acyclic
products 11a and 12a were observed. The cis-aziridine is produced
with a diastereoselectivity of greater than 50:1 with the catalyst
generated from S-VAPOL but this falls to 8:1 with the catalyst
prepared from R-BINOL (entry 1). In addition the enantiomeric
excess with the R-BINOL catalyst falls to 17% ee. Entries 2 and
3 in Table 1 reveal that the catalysts that were most effective for
Diels-Alder reactions7 were not optimal for the present aziridi-
nation reaction.
The asymmetric induction observed for 10a is not a function
of the substrate-to-catalyst ratio and remains constant as the
catalyst loading is reduced from 10 to 1 mol % (entries 5-9).
The rate of the reaction significantly drops when the amount of
catalyst is reduced from 10 to 2.5 mol %, but interestingly, the
rate of the reaction is greatly accelerated if the imine is added by
slow addition. Entries 7 and 8 reveal that the order of addition of
reagents does not affect the rate. However, the data in entries 7
and 9 reveal that the reaction time can be reduced from 20 to 2
h for reactions with 2.5 mol % catalyst if the imine is added over
a period of 1 h.
(1) (a) Tanner, D., Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b) Pearson,
W. H.; Lian, B. W.; Bergmeier, S. C. In ComprehensiVe Heterocyclic
Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol 1A, pp
1-60. (c) Rai, K. M. L.; Hassner, A. In ComprehensiVe Heterocyclic Chemistry
II; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol 1A, pp 61-96.
(2) Sweeney, J.; Osborn, H. M. I. Tetrahedron Asymetry 1997, 8, 1693.
(3) (a) Evans, D. A.; Woerpel, Hinman, M. M.; Faul, M. M. J. Am. Chem.
Soc. 1991, 113, 726. (b) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett.
1991, 32, 7373. (c) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc.
1993, 115, 5326. (d) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson,
B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328. (e) Noda, K.; Hosoya,
N.; Irie, R.; Ito, Y.; Katsuki, T., Synlett 1993, 469. (f) Evans, D. A.; Faul, M.
M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742. (g) Tanner, D.;
Andersson, P. G.; Harden, A.; Somfai, P. Tetrahedron Lett. 1994, 35, 4631.
(h) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889.
(i) Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37, 9245. (j) Harm, A.
M.; Knight, J. G.; Stemp, Synlett 1996, 677. (k) Muller, P.; Baud, C.; Jacquier,
Y.; Moran, M.; Nageri, I. J. Phys. Org. Chem. 1996, 9, 341. (l) Lai, T.-S.;
Kwong, H.-L.; Che, C.-M.; Peng, S.-M. Chem. Commun. 1997, 2373. (m)
Sodergren, M. J.; Alonso, D. A.; Andersson, P. G. Tetrahedron: Asymmetry
1997, 8, 3563.
(4) (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 676. (b) Rasmussen, K. G.; Jorgensen, K. A. J. Chem.
Soc., Chem. Commun. 1995, 1401. (c) Aggarwal, V. K.; Thompson, A.; Jones,
R. V. H.; Standen, M. C. H. J. Org. Chem. 1996, 61, 8368.
(5) (a) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J.
Org. Chem. 1996, 61, 8358. (b) Ha, H.-J.; Kang, K.-H.; Suh, J.-M.; Ahn,
Y.-G. Tetrahedron Lett. 1996, 37, 7069. (c) Rasmussen, K. G.; Jorgensen, K.
A. J. Chem. Soc. Perkin Trans. 1, 1997, 1287. (d) Nagayama, S.; Kobayashi,
S. Chem. Lett. 1998, 685.
The rate of the reaction can be affected by the purity of the
imines. The reactions in Tables 1 and 2 were performed with
imines that were crystallized from ethanol.9 Imine 8a contained
(6) For other approaches, see: (a) Aires-de-Sousa, J.; Lobo, A. M.;
Probhakar, S. Tetrahedron Lett. 1996, 37, 3183. (b) Verstappen, M. M. H.;
Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491.
(7) (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993,
115, 3814. (b) Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 3321. (c)
Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.;
Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am.
Chem. Soc. 1996, 118, 3392. (d) Heller, D. P.; Goldberg, D. R.; Wulff, W.
D. J. Am. Chem. Soc. 1997, 119, 10551.
(8) The same selectivity is observed with a catalyst prepared with 1.0 equiv
of borane-THF complex, but catalyst formation requires longer periods of
time.
(9) The imines 8a-i were prepared13 by reaction of benzhydrylamine with
1.0 equiv of aldehyde in methylene chloride at rt in the presence of anhydrous
magnesium sulfate. After filtration, the solvent is removed and the imine
purifed by crystallization from ethanol with the exception of 8h which is an
oil and was used without purification.
10.1021/ja9905187 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/14/1999

5100 J. Am. Chem. Soc., Vol. 121, No. 21, 1999
Communications to the Editor
Table 1. Asymmetric Aziridination of Imine 8a (R3 ) Ph) with (S)-VAPOL-Boron Catalyst 14a
entry
catalyst (mol %)
time, h
yield cis-10b
% ee cis-10c
cis-10/trans-10d
yield 11e
yield 12e
1
2
3
4
5
6
7
8
9
10
10
10
10
10
5
2.5
2.5k
2.5l
1l
20
20
18
0.5
0.5
3
42f
53g
41h
74
17
66
5
98
97
97.5
97
97
98
99
8:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
42:1
8
13
17
10
6
14
2
2
78i,j
74
2.5
1.7
1-1.5
1.6
e1
3.7
2.1
0.7
1-1.5
1.0
e1
2.5
20
17
2
73
74
79
72
10
16m
a Unless otherwise specified, all reactions were run in methylene chloride with 0.1 mmol of (S)-VAPOL at 22 °C with 1.1 equiv of ethyl
diazoacetate with respect to imine 8. 9 was added all at once to a mixture of imine and catalyst. Imine 8 was crystallized from ethanol and 9 was
used as supplied by Aldrich. Imine concentration is 0.5 M for entries 1-6, and 2.0 M for entries 7-10. b Isolated after purification by silica gel
1
1
chromatography. c Determined by HPLC on a Chiralcel OD column. d Determined by H NMR of crude reaction mixture. e Determined by H
NMR of crude reaction mixture by integration relative to cis-10. f Catalyst prepared from (R)-BINOL and BH3-THF which gave the enantiomer
of 10a. g Catalyst prepared from (S)-VAPOL and BH2Br-Me2S. h Catalyst prepared from (S)-VAPOL and Et2AlCl. i Reaction with (R)-VAPOL
which gave the enantiomer of 10a. j 80% recovery of VAPOL. k Imine added all at once to a mixture of catalyst and 9. l Imine aded over 3 h by
syringe pump to a mixture of the catalyst and 9. m Imine crystallized from CH2Cl2/hexane.
Table 2. Asymmetric Aziridination of Imine 8 with (S)-VAPOL-Boron Catalyst 14a
entry
imine
R3
time
yield cis-10b
% ee cis-10c
cis-10/trans-10d
yield 11e
yield 12e
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
Ph
5
4
24
16
24
4
8
7
3
77
97
97
91
96
98
97
94.5
91
96
>50:1
16:1
11:1
40:1
3:1
30:1
16:1
>50:1
35:1
e1
3.9
e1
3.6
8.1
1.5
e1
9.6
e1
e1
2.0
<1
3.0
6.5
1.4
e1
6.4
e1
p-BrC6H4
p-NO2C6H4
p-OAcC6H4
o-MeC6H4
2-Naphthyl
2-furyl
64
68f
67
51i
70g,h,i,j
55
n-Propyl
c-C6H11
54f
72
a Same as footnote a in Table 1 except solvent is toluene, 10 mol % catalyst is used, and imine is added by syringe pump over 3 h. Imine
concentration varies from 0.20-0.50 M. b -eSee Table 1. f Reaction started at 0 °C and warmed to rt after 4-5 h. g CH2Cl2 as solvent and 5 mol
% catalyst. h 0.05 mole of VAPOL. i 5 mol % catalyst used. j Substrate 9 added all at once to a mixture of catalyst and imine.
traces of ethanol as revealed by 1H NMR, but this was only found
to be detrimental to the rate with very low catalyst loadings. More
reasonable reaction times were observed with 1 mol % catalyst
when the imine was purified by crystallization from pentane/CH2-
Cl2. The effect of ethanol was confirmed when the reaction in
entry 10 of Table 1 was repeated in the presence of 10 mol %
ethanol and found to proceed only to the extent of 18% conversion
in 17 h.
Scheme 3
This asymmetric aziridination reaction was found to be slightly
faster in methylene chloride than in toluene although the latter
solvent in some cases gave higher inductions for the cis-aziridine
and less of the acyclic products 11 and 12. For this reason, the
scope of the reaction was explored in toluene for the substrates
listed in Table 2. As can be seen, high enantioselectivities were
observed over a range of imine substrates derived from both
electron-rich and electron-poor aryl aldehydes and with branched
and unbranched aliphatic aldehydes.10 The reaction times shown
in Table 2 are not reflective of rate differences in the imine
substrates since the concentrations varied due to solubility and
since minimum reaction times were not determined. It was
observed that the p-bromo and p-nitro substituted imines 8b and
8c are more reactive than the phenyl imine 8a under the same
conditions. The imine prepared from p-methoxy benzaldehyde
was slower than imine 8a and did go to completion in methylene
chloride in 24 h, but the aziridine was not stable to purification
on silica gel.
of this material was found to be [R]D ) -23.0 (c ) 3.2, EtOH)
which is to be compared with the value of [R]D ) +23.8 (c )
3.2, EtOH) reported for L-phenyl alanine ethyl ester11 and which
is consistent with the fact that the aziridine 10a used for this
reaction was determined to be 99.2% ee by HPLC with a Chiralcel
OD column.12
The present method allows for the first generally applicable
method for the catalytic asymmetric aziridination reaction. Further
studies on the scope, mechanism and applications of this process
are in progress.
Acknowledgment. This work was supported by the National Institutes
of Health. We would like to thank Professor Milton R. Smith, III for
helpful discussions and suggestions.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
The absolute configuration of aziridine 10a was confirmed by
reductive ring-opening to phenyl alanine ethyl ester. Transfer
hydrogenation with formic acid lead to selective reduction of the
nitrogen-benzyl carbon bond of the aziridine and also to the
cleavage of the benzhydryl-protecting group on the nitrogen to
give the ethyl ester of phenyl alanine (Scheme 3). The rotation
JA9905187
(11) O’Connor, M. J.; Ernst, R. E.; Schoenberrn, J. E.; Holm, R. H. J. Am.
Chem. Soc. 1968, 1744.
(12) The enantiomeric excess of the aziridine 10a can be improved from
97.0 to 99.2% with one crystallization from methylene chloride and pentane.
(13) Armesto, D.; Ortiz, M. J.; Perez-Ossoria, R., J. Chem. Soc., Perkin
Trans. I 1986, 2021.
(10) Imines derived from pivaldehyde and 1-naphthylaldehyde would not
undergo reaction under the conditions in Table 2.