Regulation of orthogonal functions in a dual catalyst system. Subservient role of a nonchiral lewis acid in an asymmetric catalytic heteroatom Diels-Alder reaction

Article abstract of DOI:10.1021/ja069019d

A catalytic asymmetric heteroatom Diels-Alder reaction of unactivated imines with Danishefsky's diene is described which gives high asymmetric induction for N-benzhydryl imines derived from a variety of aldehydes. The catalyst is derived from B(OPh)₃ and the VAPOL ligand and gives good induction, but the reaction stalls and does not give high conversion (～50%). It was found that in the presence of both the chiral catalyst and excess amounts of B(OPh)₃ the reaction proceeds to completion and gives high yields of the dihydropiperidinone product. Despite the presence of large quantities of the nonchiral Lewis acid B(OPh)₃, the asymmetric induction of the product remains constant (90% ee) as the amount of B(OPh)₃ is steadily increased and does not drop off until the ratio of B(OPh)₃ to VAPOL is 100:1 (82% ee). These observations are interpreted as involving highly separated and different activities for the chiral and nonchiral Lewis acids present in the reaction. Specifically, the excess B(OPh)₃ serves to bind to the product and release the chiral catalyst to turnover more starting material. The B(OPh)₃ does not compete in turning over the starting material, and a series of binding studies reveal that this is likely due to a combination of two factors. The binding studies reveal that the chiral catalyst binds to the starting imine 7 times more strongly than does B(OPh)₃. However, in order to explain the constant asymmetric induction observed despite the addition of increasing amounts of B(OPh)₃, the rate of the reaction of the imine complexed with the chiral catalyst must be at least 10 times faster than the reaction of the imine complexed with B(OPh)₃. Finally, a catalyst generated from BINOL and B(OPh)₃ does not show this phenomenon. Copyright

Full text of DOI:10.1021/ja069019d

Published on Web 05/16/2007
Regulation of Orthogonal Functions in a Dual Catalyst System. Subservient
Role of a Nonchiral Lewis Acid in an Asymmetric Catalytic Heteroatom
Diels-Alder Reaction
Cory A. Newman,† Jon C. Antilla,†,§ Pei Chen,† Alexander V. Predeus,† Lee Fielding,‡ and
William D. Wulff*,†
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824, and Organon Laboratories
Ltd., Newhouse, Lanarkshire, Scotland ML1 5SH
Received December 16, 2006; E-mail: wulff@chemistry.msu.edu
Table 1. Heteroatom Diels-Alder Reaction with Catalyst 6a
Attempts to develop chiral catalysts for asymmetric reactions of
imines must confront the problem that the product is more basic
than the starting imine, thus leading to difficulty in turnover.1 A
scenario in which both turnover and asymmetric induction could
be realized would involve two catalysts, one chiral and one non-
chiral (eq 1). If the nonchiral catalyst was in excess, then it could
free up the chiral catalyst to turn over the reaction. Asymmetric
induction could be achieved if the chiral catalyst has a larger binding
constant than the nonchiral catalyst for imine 1 or if the chiral
catalyst promotes the reaction at a sufficiently greater rate that it
can overcome its molar disadvantage, or if both were to pertain.
We report here the discovery of such a two-catalyst system where
at least 20 turnovers can be achieved in a heteroatom Diels-Alder
reaction with no loss of induction. This type of dual-Lewis acid
catalyst system with orthogonal functions is to our knowledge
unprecedented.2,3
entry
R
(R)-BINOL
B(OPh)3
% yield 3
% ee 3
ref
1
2
3
4
5
H
H
H
100 mol % 100 mol % 68-75 77-86 4a,b, this work
10 mol %
10 mol %
100 mol %
10 mol %
41
<5
0
15-40 4b, this work
-
-
-
4b
Ph 100 mol % 100 mol %
Ph 10 mol % 100 mol %
4a, this work
this work
0
a All reactions were run at 0.03 M in 1.
Chart 1. Effect of Triphenylborate Loading with 5 mol % of
VAPOL
The first report of a heteroatom Diels-Alder reaction of an imine
catalyzed by a chiral Lewis acid involved a catalyst prepared from
(R)-BINOL and triphenylborate.4,5 With a stoichiometric amount
of catalyst 6, the reaction produces the Diels-Alder adduct 3a in
75% yield and 82% ee (Table 1, entry 1).4a However, if 10 mol %
of the catalyst is used, less than 5% yield was observed.4b
Interestingly, when 10 mol % of (R)-BINOL and 100 mol %
B(OPh)3 is used, the reaction proceeds but with a reduced
asymmetric induction as might be expected as a result of a
background reaction catalyzed by the excess B(OPh)3.
On the basis of the results from the BINOL catalyst 6 (Table 1,
entry 2), it was not unexpected to find that the same reaction with
a catalyst prepared from 10 mol % of (S)-VAPOL6 and 100 mol %
of B(OPh)3 gave a 50% yield of 3a with 36% ee (Table 2, entry
1).7 However, it was very surprising to find that the same reaction
with imine 1b (R ) Ph) gave 3b in 94% yield and 90% ee (Table
2, entry 2). It was further found that the % ee of the product does
not decrease until a 40:1 ratio of B(OPh)3 to (S)-VAPOL was used
(entry 5). The reaction of a catalyst prepared from (R)-BINOL using
the procedure for the preparation of catalyst 8 gave 3b with low
asymmetric induction and in a yield that is near that of the
background reaction (entries 7 and 9).
proved to be quite informative (Chart 1). The % ee for 3b rose to
90% with only 15 mol % of B(OPh)3 and did not drop until 500
mol % was added (82% ee). The yield of the reaction continuously
rose with each addition of more B(OPh)3 from 58% at 15 mol %
to 95% at 150 mol %. Since the % ee of 3b remained constant
over the same range, the increase in yield cannot be due to a
background reaction with B(OPh)3.
One explanation consistent with these results is that the increasing
amounts of B(OPh)3 can better compete with the chiral catalyst in
binding to the product and thus liberate the sequestered chiral Lewis
acid. The question is why does not the increasing amounts of
B(OPh)3 lead to a background reaction and loss of significant
asymmetric induction. These observations could be explained
simply by an increase in Lewis acidity that would be expected if
catalyst 8 were a cyclic borate ester.8 The question is whether the
increase in the Lewis acidity of the VAPOL-B(OPh)3 derived
catalyst 8 would be sufficient to account for the results in Chart 1.
In an attempt to answer this question, a study was undertaken to
measure the binding constants of the catalyst 8 and B(OPh)3 with
The results from a series of experiments to examine the effect
of varying amounts of excess B(OPh)3 with 5 mol % of (S)-VAPOL
† Michigan State University.
‡ Organon Laboratories, Ltd.
§ Present address: University of South Florida.
9
7216
J. AM. CHEM. SOC. 2007, 129, 7216-7217
10.1021/ja069019d CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
catalyst 8 to be 4.9 ( 0.8 M-1 with 3b and 2.1 ( 0.4 M-1 with
1b. Thus, the VAPOL catalyst 8 binds to the imine 1b 7 times
stronger than B(OPh)3, while it binds to the product 3b only about
twice as strongly. While the nature of the binding of catalyst 8 to
imine 1b is not known, these binding constants alone are not
sufficient to account for the data shown in Chart 1. Therefore, these
data must be a result of a combination of the increased binding of
the chiral catalyst and an increased rate of the reaction of imine 1b
with the chiral catalyst over that of the nonchiral catalyst. To explain
these data, the difference in rate must be at least a factor of 100.
This catalyst system was found to have utility in providing
turnover for the heteroatom Diels-Alder reaction with a variety
of other benzhydryl imines (Table 3). The reaction was fairly
general for imines prepared from aromatic aldehydes. R,â-Unsatur-
ated imines appear to need a substituent in the R-position as high
selectivity was observed for the imine of cyclohexene carboxal-
dehyde but not for cinnamyl aldehyde. Imines from unbranched
aliphatic aldehydes gave racemic product, those from R-branched
aliphatic aldehydes gave high ee, and those from R,R-disubstituted
aldehydes were unreactive.
Table 2. Diels-Alder Reaction with Catalyst 8 with Excess
a
B(OPh)3
entry
imine
(S)-VAPOL
(R)-BINOL
B(OPh)3
% yield 3 % ee 3b
1
2
3
4
5
6
7
8
9
1a R ) H 10 mol %
1b R ) Ph 10 mol %
1b R ) Ph 7.5 mol %
1b R ) Ph 5 mol %
1b R ) Ph 2.5 mol %
1b R ) Ph 1 mol %
1b R ) Ph 0 mol %
1b R ) Ph 0 mol %
-
-
-
-
-
-
-
-
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
50
94
90
85
77
66
25
46c
26
96e
97f
96
36 (S)
90 (S)
90 (S)
90 (S)
85 (S)
82 (S)
0
0
1b R ) Ph
-
10 mol %d 100 mol %
23 (R)
84 (S)
77 (S)
92 (S)
10 1b R ) Ph 5 mol %
11 1b R ) Ph 5 mol %
12 1b R ) Ph 5 mol %
-
-
-
130 mol %
130 mol %
150 mol %
While the data can be explained by the scenario outlined in eq
1, it is possible that an ionic catalyst is involved that results from
abstraction of a phenoxy group by the excess triphenylborate.9
Further studies to shed light on the workings of this catalyst system
are ongoing.
a All reactions were run at 0.2 M in 1 in a 1:1 mixture of toluene and
CH2Cl2 at -45 °C for 24 h and with slow addition of 2 equiv of 2 over 3
h by syringe pump. If 2 was added all at once, the % ee of 3 in entry 2 is
88% ee. b Configuration of 3 is given in parenthesis. c B(OPh)3 was not
heated and evacuated according to the procedure for the preparation of 8.
d Catalyst prepared with procedure used for 8 except that (R)-BINOL was
used. e Catalyst was prepared from 30 mol % of B(OPh)3, and then an
additional 100 mol % of B(OPh)3 was added with the imine. f 0.5 equiv of
phenol was added with the imine.
Acknowledgment. This work was supported by a grant from
the NIH (NIGMS 63019).
Supporting Information Available: Spectroscopic data and ex-
perimental details are included (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Table 3. Scope of Dual Catalyst Heteroatom Diels-Alder
Reactiona
References
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Chem. 2006, 10, 981-1005.
(2) Yu and co-workers have noted that B(OMe)3 will accelerate the catalytic
asymmetric allylation of aldehydes with allyl stannanes with a BINOL-
titanium complex. The mechanism of this process is not known but may
involve an alkoxide exchange between titanium and boron on the product.
Yu, C.-M.; Choi, H.-S.; Yoon, S.-K.; Jung, W.-H. Synlett 1997, 889-
890.
(3) A recent review has cited six different classes of additives and cocatalysts,
but none include the situation in eq 1 where increasing amounts of a
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Angew. Chem., Int. Ed. 1999, 38, 1571-1577.
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S.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37, 979-981. (b) Yao, S.;
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mol % of
reaction
time (h)
yieldb
(%)
eec
(%)
entry
R
(S)-VAPOL
series
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
5
5
10
5
10
10
5
5
10
5
10
10
5
24
24
24
24
24
48
50
24
46
47
24
48
24
b
c
d
e
f
g
h
i
j
k
l
m
n
85
83
78
84
69
71
84
11
45
0
90
93
90
89
73
90
89
0
93
-
93
90
0
2-MeC6H4
1-naphthyl
4-BrC6H4
4-NO2C6H4
4-MeOC6H4
4-F,2-MeC6H3
trans-â-styryl
1-cyclohexenyl
t-butyl
cyclohexyl
i-propyl
n-heptyl
90
64
41d
a All reactions were performed at 0.2 M in imine. The diene was added
over 3 h via syringe pump. Catalyst 8 was prepared from 100 mol % of
B(OPh)3 and the amount of (S)-VAPOL indicated in the table. b Isolated
yield after silica gel chromatography. c Determined by chiral HPLC analysis.
d Background reaction with 100 mol % of B(OPh)3 under the same
conditions gives a 40% yield.
both the imine 1b and product 3b. The binding constants were
determined by 1H NMR titration experiments with increasing
amounts of either catalyst 8 or B(OPh)3 added to either imine 1b
or product 3b. Monitoring the chemically induced shift of the
benzhydryl proton in 1b and the vinyl proton in 3b adjacent to the
carbonyl, the binding constant was determined for B(OPh)3 to be
2.7 ( 0.4 M-1 with 3b and 0.32 ( 0.12 M-1 with 1b and for
(8) James, T. D.; Shinkai, S. Top. Curr. Chem. 2002, 218, 159-200.
(9) We thank a reviewer for this suggestion.
JA069019D
9
J. AM. CHEM. SOC. VOL. 129, NO. 23, 2007 7217