Mapping the active site in a chemzyme: Diversity in the N-substituent in the catalytic asymmetric aziridination of imines

Article abstract of DOI:10.1021/ol802431v

(Chemical Equation Presented) The active site of the aziridination catalyst derived from either the VANOL or VAPOL ligand and B(OPh)₃ is larger than expected and can accommodate not only significant substitution on the diarylmethyl unit of the imine but also that alkyl (but not perfluorylalkyl) substituents on the aryl groups lead to enhanced rates and enantioselection. The screen of diarylmethyl N-substituents on the imine revealed that the 3,5-di-tert-butyldianisylmethyl group (BUDAM) gave exceptionally high asymmetric inductions for imines of aryl aldehydes.

Full text of DOI:10.1021/ol802431v

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5429-5432
Mapping the Active Site in a Chemzyme:
Diversity in the N-Substituent in the
Catalytic Asymmetric Aziridination of
Imines
Yu Zhang, Zhenjie Lu, Aman Desai, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@chemistry.msu.edu
Received October 21, 2008
ABSTRACT
The active site of the aziridination catalyst derived from either the VANOL or VAPOL ligand and B(OPh)3 is larger than expected and can
accommodate not only significant substitution on the diarylmethyl unit of the imine but also that alkyl (but not perfluorylalkyl) substituents
on the aryl groups lead to enhanced rates and enantioselection. The screen of diarylmethyl N-substituents on the imine revealed that the
3,5-di-tert-butyldianisylmethyl group (BUDAM) gave exceptionally high asymmetric inductions for imines of aryl aldehydes.
One of the truly remarkable observations that was made
during the development of the catalytic asymmetric aziridi-
nation (AZ reaction) of imines with ethyl diazoacetate was
that nearly identical asymmetric inductions were observed
for catalysts derived from triphenylborate and either the
VANOL or VAPOL ligands.1,2 This was not true for other
reactions involving the VANOL and VAPOL ligands in
aluminum- and zirconium-derived catalysts,3 as their cyclic
phosphoric acid catalysts,4 or as stand alone catalysts,5 where
either VAPOL or VANOL was demonstrated to be superior.
Recent studies have revealed that the reaction of either
VANOL or VAPOL with triphenylborate produces a mixture
of the mesoborate 6 and the pyroborate 7 (Scheme 1) in favor
of the latter, which gives a higher asymmetric induction than
the former in the AZ reaction.1g Since 7 has two Lewis acidic
centers, the question of how imine 1 interacts with the
catalyst is suddenly rendered doubly complicated. It is known
that the N-benzhydryl group in imine 1e (R ) CHPh2) was
optimal among the readily available electron-neutral N-
protecting groups examined in the original screen of the
(1) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099–
5100. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518–4521. (c) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675–3678.
(d) Patwardan, A.; Pulgam, V. R.; Zhang, Y.; Wulff, W. D. Angew. Chem.,
Int. Ed. 2005, 44, 6169–6172. (e) Deng, Y.; Lee, Y. R.; Newman, C. A.;
Wulff, W. D. Eur. J. Org. Chem. 2007, 2068–2071. (f) Lu, Z.; Zhang, Y.;
Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185–7194. (g) Zhang, Y.;
Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff, W. D. Chem.sEur. J. 2008,
(3) (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993,
115, 3814–3815. (b) Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995, 36,
3321–3324. (c) Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem.
Soc. 1997, 119, 10551–10552. (d) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D.
Angew. Chem., Int. Ed. 2001, 40, 2271–2774. (e) Bolm, C.; Frison, J.-C.;
Zhang, Y.; Wulff, W. D. Synlett 2004, 1619–1621. (f) Heller, D. P.;
Goldberg, D. R.; Wu, H.; Wulff, W. D. Can. J. Chem. 2006, 84, 1487–
1503.
14, 3785–3803
.
(4) (a) Rowland, E. B.; Roland, G. B.; Rivera-Otero, E.; Antilla, J. C.
J. Am. Chem. Soc. 2007, 129, 12084–12085. (b) Li, G.; Liang, Y.; Antilla,
J. C. J. Am. Chem. Soc. 2007, 129, 5830–5831.
(2) The VANOL and VAPOL ligands are now commercially available
from Sigma-Aldrich and Strem Chemicals, Inc.
10.1021/ol802431v CCC: $40.75
Published on Web 11/07/2008
2008 American Chemical Society

reaction. Thus, in considering how the N-benzhydrylimine
1e will interact with the catalyst, one must include not only
Lewis base/Lewis acid interactions but also any potential
CH-π interactions6 and π-π stacking interactions7 of the
phenyl rings of the benzhydryl group with the arene rings
of the ligands. In addition, these interactions should be
consistent with the fact that there is little difference between
the VANOL- and VAPOL-derived catalysts. In an effort to
begin to address these questions, we have undertaken an
investigation designed to extensively probe the effects of
changes in the conformation, electronics, and sterics of the
two phenyl groups in the N-benzhydryl substituent. The
results of these studies have not only provided a clearer
picture of the types of interactions that are important between
the catalyst and the imine substrate but also have identified
an N-substituent that provides exceedingly clean and high-
yielding reactions with near-perfect asymmetric inductions
for aryl imines in the AZ reaction.
conditions shown in Scheme 1 (CH2Cl2 at room temperature
in 24 h). Under the same conditions the benzhydryl imine
1e gives 83% yield and 89% ee for aziridine 3e. As controls,
the 5-nonylimine 1c and the dicyclohexylmethyl imine 1b
gave reduced asymmetric inductions compared to benzhydryl
imine 1e and even more noticeably reduced rates (4- and
25-fold, respectively).8 The reactions with the imines 1d,
1f, and 1g reveal that the orientation of the two phenyl groups
is important. Imines 1f and 1g both afford higher inductions
than the benzhydryl imine 1e, whereas the fluorenyl imine
1d gives a lower induction. This suggests that the lower
induction for 1d is not due to the twist angle between the
phenyl groups but rather to the degree to which the two
phenyl groups are thrust forward toward the ligand when
the imine is bound to the catalyst.
Scheme 1. AZ Reaction
Figure 1. Diarylmethyl N-substituents are optimal.
Favorable non-covalent contacts between arenes include
π-π stacking and CH-π interactions, and both types of
contacts are known to be subject to the electronic nature of
the substituents on the arene rings.6,7,9 Thus, in an effort to
probe the importance of these effects, a series of electron-
rich and electron-poor benzhydryl imines were prepared and
evaluated in the AZ reaction (Figure 2). In addition, the size
of the binding site of the catalyst is not known, and this was
the impetus for the inclusion of a number of 3,5-disubstituted
benzhydryl derivatives in the screen. The 10 imines shown
in Figure 2 were evaluated in the AZ reaction with both the
VANOL- and VAPOL-derived catalysts according to the
conditions outlined in Scheme 1, and the isolated yields and
asymmetric inductions for the aziridine 3 are indicated in
Figure 2. In addition, relative rates were determined for each
of the imines. This was done in a pairwise manner in
competition experiments in which 1.0 equiv of imine 1e and
1.0 equiv of a competitor imine (1h-p) were reacted with
The first set of experiments was designed to probe whether
the relative orientation of the two phenyl groups in the
N-substituent of the imine was important for the binding of
the substrate to the active site of the VAPOL catalyst, and
the results are summarized in Figure 1. That two phenyl
groups are required in the N-substituent of the imine is
demonstrated by the fact that the AZ reaction of N-benzyl
imine 1a gives aziridine 3a in 51% yield and in only 43%
ee with 10 mol % of the (S)-VAPOL catalyst under the
(5) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923.
(6) For a review, see: Nishio, M. Tetrahedron 2005, 61, 6923–6950.
(7) For recent reviews, see: (a) Janiak, C. J. Chem. Soc., Dalton Trans.
2000, 3885–3896. (b) Roesky, H. W.; Andruh, M. Coord. Chem. ReV. 2003,
236, 91–119. (c) Bhosale, S.; Sisson, A.; Sakai, N.; Matile, S. Org. Biomol.
Chem. 2006, 4, 3031–3039.
(8) The relative rates were determined as described in Figure 2.
(9) For leading references, see: Bhayana, B.; Wilcox, C. W. Angew.
Chem., Int. Ed. 2007, 46, 6833–6836
.
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Org. Lett., Vol. 10, No. 23, 2008

Figure 2. Relative rates, yields, and asymmetric inductions for the aziridinations of N-diarylmethylimines. Aziridination reactions were
carried out as indicated in Scheme 1 at 0.5 M in imine. Relative rates studies were carried out in pairwise competitions in CCl4 with 1 equiv
of 1e, 1 equiv of a competitor imine (1h-1p), 0.2 equiv of 2, and 5 mol % of the catalyst at 25 °C for 24 h.
a deficiency of ethyl diazoacetate 2 (0.2 equiv) in the
presence of 5 mol % of catalyst in CCl4 at 25 °C for 24 h.
The data reveals that there is a very good correlation between
the relative rates and the asymmetric inductions. A general
trend was found where more electron-rich phenyl groups
gave higher rates and asymmetric inductions than the
benzhydryl imine 1e, and the reverse was observed with
electron-withdrawing groups where decreased rates and
inductions were observed.
The near-perfect performance of the imine 1p prompted
a more thorough study of this family of imines with the tetra-
tert-butyldianisylmethyl (BUDAM) substituent. The requisite
amine from which these imines are prepared is available in
four steps and 70% overall yield from 2,6-di-tert-butylphenol,
which is commercially available at $29/kg (see the Support-
ing Information). The results of the aziridination reactions
of N-BUDAM imines prepared from 11 different aldehydes
are presented in Table 1. Extremely high asymmetric
inductions are observed for all eight of the imines derived
from aromatic aldehydes. Although most of the reactions
shown in Table 1 are complete in much less time, in an effort
to accommodate the range of rates for all the substrates, all
reactions were run for 24 h. No effort was made to minimize
the reaction time. The reaction of the N-BUDAM imine of
benzaldehyde 1p is complete within 20 min with 2 mol %
of catalyst in toluene. The reactions of imines with electron-
withdrawing groups are complete in less time, while those
with electron-donating groups take longer. The reaction of
the p-methoxyphenyl-substituted N-BUDAM imine 10p is
complete within 24 h with 2 mol % of the VAPOL catalyst;
however, under the same conditions the corresponding
benzhydryl imine 10e only goes to 73% completion in 24 h
It is quite remarkable that both the VANOL and VAPOL
ligands give essentially the same profile in asymmetric
induction with the various imines examined in Figure 2. With
the exception of the 3,5-bis(trifluoromethyl)-substituted imine
1h, the difference in asymmetric inductions for the VANOL
and VAPOL catalysts is no more than 3% ee across the range
of imines. The presence of an o-methyl group (imine 1i)
slows the reaction by a factor of 20 (for VAPOL), and the
asymmetric induction drops slightly. This is likely due to a
steric effect since a methyl group in the para position (imine
1l) increases the rate by a factor of 2.3 and also increases
the asymmetric induction. Interestingly, two methyl groups
in the 3- and 5-positions (imine 1n) increase the rate by a
factor of 10 and also increase the asymmetric induction. This
is in stark contrast to the 3,5-bis(trifluoromethyl) analogue
1h which is 500 times slower than imine 1n and gives the
aziridine 3h in only 37% ee (for VAPOL). This is most
consistent with an electronic effect that is presumably due
to electrostatic repulsions rather than a steric effect since a
CF3 group is smaller than a tert-butyl group and yet the 3,5-
di-tert-butyl-substituted imine 1p is in fact the most reactive
and selective imine in the screen. The reaction of imine 1p
is 16.3 times faster than the benzhydryl imine 1e (with
VAPOL) and gives the aziridine 3p in 99% ee and 96-97%
yield with both the VANOL and VAPOL ligands.10
with 5 mol % of VAPOL catalyst.1g The H NMR spectra
1
of the crude mixtures from the reactions of the N-BUDAM
imines are also extremely clean compared to those from the
corresponding benzhydryl imines. The AZ reactions of
benzhydryl imines are generally highly cis selective but in
some cases significant amounts of the trans aziridine are
formed. For example, the reaction of the o-bromophenyl
benzhydryl imine 11e gives a 2:1 mixture of cis- and trans-
aziridines,1g but in contrast, the N-BUDAM imine analogue
11p gives only the cis-aziridine as a single diastereomer with
no detectable amount (e1:50) of the trans-aziridine. This is
true for all of the imines shown in Table 1. This is also true
for the non-cyclized enamine side product which can be
formed in the AZ reaction of benzhydryl imines with yields
(10) A catalyst (10 mol %) prepared from (S)-BINOL according to the
protocol in Scheme 1 will catalyze the AZ reaction of imine 1p to give
aziridine 3p in 71% yield and 67% ee under the conditions shown in
Scheme 1.
Org. Lett., Vol. 10, No. 23, 2008
5431

aldehydes are not as high as those derived from aromatic
aldehydes (entries 17-22). The same has been found to be
true for the benzhydryl imines1g and also for imines derived
from the N-dianisylmethyl (DAM) protecting group (series
m).1f Given the greater surface area of the arene rings in
VAPOL compared to VANOL, it is quite astonishing that
both ligands give nearly the same asymmetric inductions for
each of the imines in Table 1. The average difference in the
asymmetric inductions from these two ligands over the 11
substrates is 1.5% ee. The BINOL ligand is not effective
for this reaction.10 Finally, the BUDAM substituent can be
removed without causing ring opening to give the N-H
aziridine in excellent yield employing conditions developed
for the N-dianisylmethyl (DAM) protecting group (Scheme
2).1f
Table 1. Scope of the BUDAM Imines in the AZ Reactiona
yieldb eec
(%)
entry imine
R1
C6H5
ligand
aziridine
(%)
1
2
1pd
1p
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
3p
3p
98
97
97
96
95
98
87
90
84
83
99
99
92
91
93
96
62
57
89
87
60i
76j
99
98
99
96
99
98
98
98
96
90
99
98
96
97
99
98
93
87
89
84
78
80
C6H5
3
8p
2-MeC6H4
2-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4 (S)-VAPOL
4-MeOC6H4 (S)-VANOL
18p
18p
19p
19p
20p
20p
21p
21p
22p
22p
23p
23p
24p
24p
25p
25p
26p
26p
27p
27p
4
8p
5
9p
6
9p
7
8
10p
10p
9
11pe 2-BrC6H4
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
10
11
12
13
14
15
16
17
18
19
20
21
22
11pe 2-BrC6H4
Scheme 2. Deprotection of the BUDAM Group
12p
12p
13pf
13pf
14p
14p
15p
15p
4-BrC6H4
4-BrC6H4
4-NO2C6H4 (S)-VAPOL
4-NO2C6H4 (S)-VANOL
1-naphthyl (S)-VAPOL
1-naphthyl (S)-VANOL
C2H5
C2H5
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
16pg c-C6H11
16pg c-C6H11
17ph t-butyl
17ph t-butyl
The data from the screening of the imines 1a-p has
provided considerable information on the size and electronic
requirements for the N-substituent of the imine in the AZ
reaction with VANOL and VAPOL catalysts. This study lead
to the identification of the tetra-tert-butyldianisylmethyl
substituent (BUDAM) as clearly superior giving extremely
clean and fast reactions with yields and enantioselectivities
that make it the most effective catalytic asymmetric aziri-
dination known. Further work will be needed to more
precisely determine the nature of the interactions between
the imine and catalyst.
a Unless otherwise specified, all reactions were run at 0.25 M in imine
in toluene with 2.0 mmol of imine and 1.1 equiv of ethyl diazoacetate and
went to completion with 2 mol % of catalyst at 25 °C for 24 h. Reaction
times were not minimized. All imines were purified by crystallization. Cis/
trans selectivity was >50:1 in each case as determined by 1H NMR on the
crude reaction mixture. b Isolated yield after chromatography on silica gel.
c Determined by HPLC on a Pirkle covalent (R,R)-Whelk-O 1 column. d
A
97% yield and 99% ee was obtained with reaction time of 20 min (98%
conversion observed after 5 min). e <2% of enamine product also observed.
f Imine was 0.22 M in a 5:1 mixture of toluene/CH2Cl2. g 4 mol % of catalyst.
h 10 mol % of catalyst. i 75% completion. j 95% completion.
Acknowledgment. This work was supported by a grant
from the NIH (GM 63019). We also thank H. Gru¨tzmacher
and T. Zweifel (ETH Zurich) for providing procedures for
the preparation of some amines.
in the range of <1 to 24%.1g The only imine in Table 1 that
gave any detectable amount of the enamine side product was
the o-bromophenyl imine 11p (<2%). The AZ reactions of
all other BUDAM imines shown in Table 1 do not give any
detectable amounts of the enamine side product, and in all
Supporting Information Available: Experimental pro-
tocols, characterization procedures, and spectral data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
cases, the H NMR spectra of each crude reaction mixture
after workup reveals a clean mixture of only the aziridine
and the VANOL or VAPOL ligand. The asymmetric induc-
tions for the N-BUDAM imines derived from aliphatic
OL802431V
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Org. Lett., Vol. 10, No. 23, 2008