Catalytic Asymmetric Epoxidation of Aldehydes with Two VANOL-Derived Chiral Borate Catalysts

Article abstract of DOI:10.1002/anie.201809511

A highly diastereo- and enantioselective method for the epoxidation of aldehydes with α-diazoacetamides has been developed with two different borate ester catalysts of VANOL. Both catalytic systems are general for aromatic, aliphatic, and acetylenic aldehydes, giving high yields and inductions for nearly all cases. One borate ester catalyst has two molecules of VANOL and the other only one VANOL. Catalysts generated from BINOL and VAPOL are ineffective catalysts. An application is shown for access to the side-chain of taxol.

Full text of DOI:10.1002/anie.201809511

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Catalytic Asymmetric Epoxidation of Aldehydes with Two
Different Borate Catalysts of VANOL
Authors: Anil K. Gupta, Xiaopeng Yin, Munmun Mukherjee, Aman A.
Desai, Aliakbar Mohammadlou, Kelsee Jurewicz, and William
Dean Wulff
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809511
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10.1002/anie.201809511
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric
Catalysis
Catalytic Asymmetric Epoxidation of Aldehydes with Two Different
Borate Catalysts of VANOL
Anil K. Gupta, Xiaopeng Yin, Munmun Mukherjee, Aman A. Desai, Aliakbar Mohammadlou, Kelsee
Jurewicz and William D. Wulff*
Scheme 1. Epoxides from Ketones and Aldehydes
Abstract.
A highly diastereoselective and enantioselective
method for the epoxidation of aldehydes with α-diazoacetamides
has been developed with two different borate ester catalysts of
VANOL. Both catalytic systems are general for aromatic,
aliphatic and acetylenic aldehydes giving high yields and
inductions for nearly all cases. One borate ester catalyst has two
molecules of VANOL and the other only one VANOL.
Catalysts generated from BINOL and VAPOL are ineffective
catalysts. An application is made to the side-chain of taxol.
O
O
R5
S
O
R3
R1
R1
X
EWG
R2
R2
R2
R5
R3
R4 = EWG
R4
R3
base
R4
O
R1
R3
EWG
R4 = EWG
Zr, Ti catalyst
The tactical repertoire for the conversion of an aldehyde or
ketone to an epoxide largely consists of two transformations
indicated in Scheme 1: i) the Darzens condensation of an α-halo
stabilized carbanion with the a carbonyl compound,1,2 ii) the
Corey-Chaykovsky reaction which involves a sulfur ylide as a
carbene surrogate in the synthesis of epoxides.3-7 A third method
involving the formation of epoxides from the reactions of diazo
compounds are not that common and have not been particularly
useful.8,9,10 However, efficient catalytic asymmetric versions
have been more recently reported by Gong and coworkers for the
reactions of aldehydes with secondary α-diazoacetamides.11a,b
These reactions gave high asymmetric inductions with chiral
complexes of titanium or zirconium with BINOL and BINOL
derivatives. Two additional titanium complexes have also been
reported.11c,d We report here the first non-transition metal
catalyzed asymmetric epoxidation of aldehydes with diazo
compounds. We also report the discovery of two different chiral
borate catalysts that are nearly equally effective for this reaction.
Prior to this work, chiral borate esters have not been engaged in
aldehyde activation other than for a Diels-Alder reactions.12,13
We have previously reported asymmetric methods for the
synthesis of both cis- and trans-substituted aziridines by the
addition of diazo compounds to imines with a BOROX catalyst
derived from either VANOL or VAPOL. The diazo ester 4
reacts to give cis-aziridines,14 whereas, the diazo acetamide 2
reacts with the same imine and with the exact same catalyst
N2
O
R1
EWG = electron withdrawing group
R2
(either VANOL or VAPOL) to give trans- aziridines.15,16 The
structure of the BOROX catalyst 8/9 for the aziridination
reactions was determined to have a boroxine ring by NMR, X-
ray analysis, and KIE and computational studies.15b,17a,c The
BOROX catalyst can be assembled in-situ by the imine substrate
from the ligand by a number of methods but the most common is
either with B(OPh)3 or BH3•SMe2 and phenol.14e,17,18 Most
amines and imines are basic enough to cause assembly of the
BOROX catalyst.
Scheme 2. Cis and Trans Aziridines from Imines
O
O
Ar
Ar
Ar
Ar
R
NHR'
OEt
4
Ar
N2
N2
2
N
N
R
N
Ar
BOROX
catalyst
BOROX
catalyst
CO2Et
CONHR'
R
3
1
3
5
B(OPh)3
H2O
base
OPh
2
1
O B
–
OR
O
4
Ph
Ph
[H-base]+
Ph
Ph
OH
OH
B
O
O
BH3•SMe2
HOPh
H2O
O B
OPh
base
[∗]
Mr. A. K. Gupta, Mr. X. Yin, Ms. M. Mukherjee, Mr. A, A.
Desai, Mr. A. Mohamadlou, Ms. K. Jurewwicz and Prof. W.
D. Wulff
VANOL / VAPOL BOROX catalyst
VANOL / VAPOL
6 / 7
8 / 9
Attempts to utilize the BOROX catalyst for the generation of
epoxides from aldehydes and ethyl diazoacetate have been
unsuccessful and this is undoubtedly due to the fact that neither
substrate is capable of generating the BOROX catalyst.14e First
an aldehyde is not a strong enough base to assemble a BOROX
catalyst. Second, ethyl diazoacetate reacts with VAPOL and
B(OPh)3 to only give the alkylated VAPOL derivative 14a in
80% yield which prevents the formation of the BOROX catalyst
(Scheme 3). The actual reaction of ethyl diazoacetate with
benzaldehyde in the presence of VAPOL and B(OPh)3 has been
previously carried out for a different purpose and the epoxide 12
(R=Ph) was only produced, inter alia, in 3% yield.14e
Department of Chemistry
Michigan State University
East Lansing, MI 48824
Fax: 517-3353-1793
E-mail: wulff@chemistry.msu.edu
Homepage:
http://www2.chemistry.msu.edu/faculty/wulff/myweb26/inde
x.htm
[∗∗] (This work was supported by a grant from the National
Institute of General Medical Sciences (GM094478).
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.201809511
Angewandte Chemie International Edition
Scheme 3. Epoxides from Aldehydes with a BOROX catalyst?
heating 3 equiv BH3•SMe2, 2 equiv phenol, 1 equiv VANOL and
3 equiv H2O in toluene at 100 °C followed by exposure to high
vacuum to remove volatiles and then to add 1 equiv of DMSO at
25 °C for an hour. With 10 mol% of this catalyst, the
epoxidation of benzaldehyde with diazoacetamide 2a is achieved
in 88% yield and 99% ee with >100:1 selectivity for the cis-
diastereomer (entry 1). The formation of the cis-epoxide was
unexpected since the same diazo compound gives trans-
aziridines with imines (Scheme 2). The origins of this
stereochemical outcome is not understood at the present time.
Excellent asymmetric inductions were observed for the
epoxidation of a number of aldehydes including electron rich
and electron poor aryl aldehydes. Slightly lower inductions were
observed for o-substituted aryl aldehydes (entries 6 and 14) and
for aliphatic aldehydes (entry 17 and 18).
There is the question of the nature of the catalyst for the
reaction in Table 1. Is it a BOROX catalyst of the type 8/9 that
is effective in the aziridination reaction (Scheme 2)? To probe
whether a BOROX type catalyst is involved, the catalyst was
prepared by leaving out the water and the phenol with the result
that the reaction in entry 1 was unaffected (92% yield and 99%
ee, see supporting information). This certainly means that the
BOROX species 8 can’t be the catalyst. After extensive
additional optimization studies which are given in the supporting
information, it was found that the epoxidation reaction can be
optimized to give a catalyst prepared from two molecules of the
VANOL ligand and only one molecule of BH3•SMe2. A survey
of aldehydes with catalyst B is given in Table 2.
CO2Et
CONHR'
O
2
4
N2
N2
O
O
R
H
B(OPh)3
VAPOL
B(OPh)3
VAPOL
10
CO2Et
R
CONHR'
R
?
11
12
OH
+
COXR
O
COXR
+
B(OPh)3
*
*
N2
CDCl3
25 °C, 10 min
13
4
OH
OH
3 equiv
2 equiv
14a XR = OEt 80%
14b XR = NHPh
(S)-VAPOL 7
The question remains whether the epoxidation of an
aldehyde with a diazo acetamide can be effected with a BOROX
catalyst. VAPOL and B(OPh)3 do not react by themselves, but
in the presence of diazoacetamide 2a, a reaction occurs but,
unlike ethyl diazoacetate, the O-H insertion product 14b was not
observed. A small amount of a boron species that could be
assigned as a BOROX complex was observed but other three
coordinate boron species were evident. At this point it was
thought that it might be possible to add a non-reacting basic
species that could cause the assembly of the BOROX catalyst
but not interfere with the reaction itself. A number of bases
were screened and many were found to be efficacious in the
reaction of benzaldehyde 15 and diazoacetamide 2a including
aniline and DMSO (dimethyl sulfoxide) with VANOL the
optimal ligand (see supporting information).
1) 30 mol% BH3•SMe2
20 mol% PhOH
30 mol% H2O
A
wide range of electron-poor and electron-rich aryl
3) 10 mol% DMSO
toluene, 25 °C, 1 h
10 mol%
VANOL
VANOL
catalyst A
aldehydes could be epoxidized with excellent asymmetric
inductions. The reaction of para-methoxybenzaldehyde is far too
slow to be useful, however, its surrogate para-
acetoxybenzaldehyde gives the epoxide 49a in 92% yield and
toluene, 100 °C, 1 h
2) 0.5 mm Hg, 100 °C, 0.5 h
(S)-VANOL
catalyst A
(10 mol%)
O
O
O
O
O
+
+
NH-n-Bu
R
H
R
NH-n-Bu
epoxide
R
NH-n-Bu
ketoamide
99% ee (entries 12 vs 13).
With aliphatic aldehydes, it was
toluene
–60 °C, 24 h
N2
O
2a
found that asymmetric inductions of >99% ee could be realized
with unbranched, α-branched and α,α-bis-branched aliphatic
aldehydes (entries, 27, 31, 33, 35). The reaction could also be
extended to acetylenic aldehydes with excellent inductions but
not to alkenyl aldehydes (entries 36-39). The absolute
configuration of 41b, 60b and 62b are known10 and that of 41a
was determined by conversion to the taxol side chain 72
(Scheme 4) and the rest were assumed to be homo-chiral. The
reaction of diazoacetamide 2a with benzaldehyde could be
scaled up ten-fold to 6.0 mmol and in 20 min gives a 95% yield
of 41a (1.25 g) with >99% ee. The reaction of benzaldehyde is
slightly slower (~5X) with catalyst A than it is with catalyst B
(Table 1, entry 3 vs Table 2, entry 1). The reactions without
DMSO tend to be a little slower with the inductions dropping
slightly with diazo acetamides 2a and 2b, however, for the diazo
acetamide 2c there a small or no difference between reactions
run with or without DMSO (Table 2, entries 3, 18, 31, 33, 39).
The approach to epoxides involving the formal addition of a
carbene to a carbonyl exemplified by the present work is
complimentary to that which involves a formal addition of an
oxygen to an α,β-unsaturated carbonyl compound (Scheme 4).
A significant body of literature exists on the asymmetric
epoxidation of electron-deficient alkenes.19 However, most all
methods involve the epoxidation of trans-alkenes of the type 67.
There are several asymmetric catalysts that have been reported
for the asymmetric epoxidation of electron-deficient cis-alkenes
of the type 70 but most led to mixtures of cis- and trans-isomers
and/or low asymmetric induction.20 Two catalysts give both high
diastereo- and enantioselection.21 Cis-epoxides of the type 69
are desirable intermediates for access to the syn-diastereomer of
products resulting from nucleophilic ring-opening of the
Table 1. Asymmetric Epoxidation of Aldehydes of VANOL Catalyst A. a
% yield
cis/transd
% yield % ee
epoxide b epoxidec
ketoamidee
entry
R
aldehyde
epoxide
1
2 f
C6H5
C6H5
15
15
15
15
15
16
17
18
19
21
23
25
26
< 1 (5)
5
41a
41a
41a
41a
41a
42a
43a
44a
45a
47a
49a
51a
52a
55a
57a
58a
60a
61a
88 (79)
90 (76)
38
99 (90)
98 (72)
90
>100:1
>50 : 1
3 g C6H5
4 h C6H5
5 i
51
52
<1
<1
<1
<1
6
21
20 e
54
C6H5
37
6
2-MeC6H4
4-MeC6H4
1-naphthyl
2-naphthyl
60
80
>100:1
>100:1
35:1
7
80
98
8
97
92
9
92
98
>100:1
31:1
10 3-MeOC6H4
11 4-AcOC6H4
80
90
4
82
97
>100:1
>100:1
>100:1
39:1
12 3-BrC6H4
13 4-BrC6H4
4
88
96
<1
9
88
99
14 2-F-4-BrC6H3 29
70
80
15 4-CNC6H4
16 4-NO2C6H4
17 n-propyl
18 n-octyl
31
32
34
35
<1
8
84
96
>100:1
13:1
70
92
9
65
78
nd
6
84
90
nd
a Unless otherwise specified, all reactions were run with 10 mol% (S)-VANOL-BOROX
catalyst with 0.2 mmol of 2a as a 0.05 M solution in toluene with 1.1 equiv of aldehyde
at –60 °C for 24 h and went to 100% completion. The pre-catalyst was prepared by
heating (S)-VANOL (10 mol%), (30 mol%), BH3•SMe2 (30 mol%) and PhOH (20 mol%) in
toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg)
for 0.5 h at 100 °C. The pre-catalyst was treated with 1 equiv DMSO (10 mol%) in toluene
for 1 h at 25 °C and then cooled to –60 °C and 2a was added as a solution in toluene prior
to the addition of the aldehyde. b Isolated yield; Data in parentheses are reactions run
without DMSO c Determined by HPLC, Data in parentheses are reactions run without
DMSO d The cis:trans ratio was determined by integration of the methine protons of the
cis- and trans-epoxides in the 1H NMR spectrum of the crude reaction mixture. e Deter-
mined from the 1H NMR spectrum of the crude reaction mixture with the aid of Ph3CH as
internal standard. f Reaction at –40 °C for 1 h. g Reaction at –40 °C for 10 min with 5 mol%
catalyst. h Catalyst prepared from (S)-BINOL. i Catalyst prepared from (S)-VAPOL.
A suitable protocol for the epoxidation of aldehydes was
found which is given in Table 1. The catalyst was prepared by
2
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10.1002/anie.201809511
Angewandte Chemie International Edition
epoxide; much like the case of cis-aziridines.14f A case in point
is the taxol side-chain 72.22 Conversion of the epoxy amide 41a
to the ester 71 and then ring-opening with trimethylsilyl azide
gives a syn-azido-alcohol which is benzoylated on oxygen and
were added to the catalyst preparation protocol. From the
optimized stoichiometry, catalyst B appears to consist of two
molecules of VANOL and one boron atom suggesting the
Scheme 4
1) 5 mol% BH3•SMe2
3) 10 mol% DMSO
chiral
catalyst
chiral
catalyst
EWG
EWG
10 mol%
VANOL
VANOL
catalyst B
R
R
toluene, 100 °C, 0.5 h
toluene, 25 °C
*
*
O
*
EWG
EWG
70
2) 0.5 mm Hg, 100 °C, 0.5 h
R
*
O
[O]
[O]
R
67
68
69
(R)-VANOL
catalyst B
(5 mol%)
O
O
O
O
R
O
O
1) TMSN3
ZnCl2
1) n-BuLi,
Boc2O
NHR1
+
n-Bu
NH
Ph
NH
O
NHR1
H
R
N2
toluene
OEt
O
1 = n-Bu
1 = Ph
1 = Bn
2) NaOEt
2) BzCl
3) CuCl
OEt
–40 °C, time
2a
2b
2c
R
R
R
O
O
OH
epoxide
71 72%
(NH4)2S
(2R,3S)-72 86%
99% ee
taxol side-chain
(2R,3R)-41a
>99% ee
Table 2. Asymmetric Epoxidation of Aldehydes with the VANOL catalyst B. a
borate species 73 with
a trigonal boron (Scheme 5).
% yield
% ee
time
(h) b
epoxide
aldehyde
entry
R
epoxide b,c epoxide b,d
Alternatively, this species could exist as 74 which has a
tetrahedral boron that is bound to all four oxygens. We
investigated the nature of 73/74 via computation at the level of
B3LYP/6-31(d) and found that this compound prefers the
structure 73 containing a trigonal planar boron incorporating
three of the phenol functions and the fourth was H-bonded to an
oxygen of the opposing VANOL ligand (O-H, 2.07 Å) (see
supporting information). The B-O distance to the fourth phenol
unit is too long for any significant interaction (3.47 Å vs. 1.36-
1.38 Å for the other three B-O bonds). The structure 74 is
higher in energy and is not a local minimum. VANOL borate 73
1
C6H5
0.17 (2)
12
15
15
15
15
15
16
17
18
19
20
21
22
23
24
24
25
26
26
27
28
30
31
32
41a
41b
41c
41a
41a
42a
43a
44a
45a
46a
47a
48a
49a
50a
50c
51a
52a
52c
53a
54a
56a
57a
58a
59a
60a
60b
60c
61b
61b
61b
61c
62b
62c
63b
63c
64a
65a
66a
66c
99 (86)
93
>99 (93)
98
2
C6H5
3
C6H5
1 (3)
24
93 (98)
3
>99 (97)
—
4 e
5 f
6
C6H5
C6H5
24
13
—
2-MeC6H4
4-MeC6H4
1-naphthyl
2-naphthyl
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-AcOC6H4
2-BrC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-BrC6H4
3-ClC6H4
3,4-Cl2C6H4
2-F-5-BrC6H3
4-CNC6H4
4-NO2C6H4
2
89
97
7
0.17
1
94
99
8
88
97
9
0.25
0.17
0.17
24
91
>99
94
10
11
12g
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29 h
30 i
31
32
33
34
35 k
36
37 j
38
39
92
92
97
19
—
presumably acts as a Brønsted acid assisted Lewis acid catalyst,
Scheme 5. Possible Structures of Catalyst B
0.25
0.5
92
>99
90
94
(1)
(96)
96
(97)
98
H
BH3•SMe2
0.5 equiv
0.17
0.17 (2)
3 (3)
0.17
0.25
24
O
O
Ph
Ph
O
O
Ph
Ph
Ph
Ph
OH
OH
B
99 (72)
98 (91)
93
>99 (90)
99 (97)
98
toluene,
100 °C, 0.5 h
96
99
O
82
63
(S)-VANOL 6
(S,S)-VANOL borate 73
R
H
0.25
3
98
96
87
94
3-NO2-4-ClC6H3
n-propyl
R
H
1
33
34
34
34
35
35
35
35
36
36
37
37
38
39
40
40
98
89
H
0.25
12
87
96
O
H
O
O
O
O
n-propyl
94
90
Ph
Ph
Ph
Ph
O
O
O
B
Ph
Ph
Ph
Ph
B
n-propyl
12
96
>99
89
O
n-octyl
12
88
n-octyl
24
72
63
n-octyl
24
92
83
(S,S)-75
n-octyl
12 (12)
12
93 (82)
99
>99 (99)
98
(S,S)-VANOL borate 74
cyclohexyl
cyclohexyl
t-butyl
2 (1)
36
99 (93)
70
>99 (>99)
92
Scheme 6
Catalyst formation at 100 °C
t-butyl
24
47
>99
1) 5 mol% B(OPh)3
3) 10 mol% DMSO
toluene, rt
10 mol%
VANOL
VANOL
catalyst C
trans-PhCH=CH
PhC=C
24
< 5
53
toluene, 100 °C, 0.5 h
2) 0.5 mm Hg, 100 °C, 0.5 h
4
93
CH3(CH2)12C=C
CH3(CH2)12C=C
24
63
91
(R)-VANOL
catalyst C
(5 mol%)
O
O
24 (1)
64 (75)
>99 (93)
O
+
N
H
Ph
NH
a Unless otherwise specified, all reactions were run with 5 mol% (R)-VANOL catalyst B
with 0.5 mmol of 2 as a 0.1 M solution in toluene with 1.2 equiv of aldehyde
at –40 °C and went to 100% completion. No trans-epoxides could be detected in
the 1H NMR spectrum of the crude reaction mixture and the amount of ketoamide
side-product was ≤5% in all reactions. The pre-catalyst was prepared by heating
(S)-VANOL (10 mol%) and BH3•SMe2 (5 mol%) in toluene at 100 °C for 0.5 h,
followed by removing all volatiles under high vacuum (0.5 mm Hg) for 0.5 h at 100 °C.
The pre-catalyst was mixed with DMSO (10 mol%) at rt in toluene and immediately cooled
to –40 °C and then added to a mixture of the aldehyde and 2 and in toluene that had
been pre-cooled to –40 °C. b Data in parentheses are for reactions runs without DMSO.
c Isolated yield. d Determined by HPLC on purified cis-epoxide. e Catalyst prepared from
(R)-BINOL and gave 47% conversion. f Catalyst prepared from (R)-VAPOL and gave
73% conversion. g 65% conversion. h 20 mol % phenol added with DMSO. i A solution of
25 mol% BH3•SMe2, 20 mol% PhOH and 30 mol% H2O was heated in toluene at 100°C
for 0.5 h and then all volatiles were removed at 100 °C at 0.5 mm Hg for 0.5 h. This mixture
was added to the pre-catalyst with the DMSO as described in footnote a. j 89% conversion
of 2a. k 10 mol% catalyst, 78% conversion.
Ph
H
toluene
–40 °C, 10 min
N2
O
(2R,3R)-41a
76% yield, >99% ee
2a
Catalyst formation at 25 °C
2) 10 mol% DMSO
toluene, rt
1) 5 mol% B(OPh)3
toluene, rt, 0.5 h
VANOL
catalyst C
10 mol%
VANOL
(R)-VANOL
catalyst C
(5 mol%)
O
O
O
NHR1
+
NHR1
Ph
Ph
H
toluene
–40 °C, time
N2
O
R1 = n-Bu
R1 = Bn
2a
2c
(2R,3R)-41a
(2R,3R)-41c
(2R,3R)-41c
10 min
3 h
12 h
75% yield, >99% ee
92% yield, 99% ee
89% yield, 95% ee (w/o DMSO)
upon azide reduction23 suffers benzoyl migration giving 72.
It is clear that catalyst B for the reactions in Table 2 is not a
BOROX catalyst of the type 8 since neither phenol or water
or BLA catalyst (i.e. 75), as pioneered by Yamamoto with
BINOL and BINOL derivatives.12 BLA catalysts have not been
previously reported for VANOL (or VAPOL). It should be noted
3
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10.1002/anie.201809511
Angewandte Chemie International Edition
that neither catalysts A or B prepared from either BINOL or
VAPOL are effective in this reaction (Table 1, entries 4 & 5,
Table 2, entries 4 & 5).
the enantiomeric purity of the VANOL ligand and the
enantiomeric purity of the epoxide product. We were quite
surprised to find that there was a large difference between the
two catalysts (Figure 1, Supporting Information). Catalyst A
displayed a linear relationship (squares) which would be
consistent with the BOROX catalyst 8 containing one molecule
of VANOL. Catalyst B had a strong nonlinear relationship
(circles) which would be consistent with the VANOL borate 73
which contains two molecules of VANOL. The nonlinear study
clearly shows that the two catalysts are not the same. VANOL
borate 73 may activate the aldehyde by coordination to the boron
as in structure 75. For catalyst A two possibilities for aldehyde
activation are: 1) the boroxinate anion sequesters the two
substrates via H-bonding to give a species of the type 76a, or 2)
the boroxinate core is protonated giving a neutral pyro-borate
which activates the aldehyde by coordination to a Lewis-acidic
boron as in structure 76b. The structure 76a is proposed based
on similar H-bonding interactions observed in KIE and
computational studies on BOROX catalyzed aziridinations.15b,17c
The structure 76b is proposed by on an similar structure reported
for a BINOL borate species.12a Experiments will be pursued that
can differentiate between these two possibilities.
Triphenylborate is an alternative to BH3•SMe2 as a boron
source for catalyst formation and, although not always pure from
commercial suppliers, it is more convenient to use. As outlined
in Scheme 6, commercial B(OPh)3 was used to generated a
catalyst with a 2 : 1 ratio of VANOL to boron (Catalyst C). In
addition, two different protocols were investigated for catalyst
formation, heating VANOL and B(OPh)3 in toluene at 100 °C
and then removal of volatiles, and a much simpler protocol
involving stirring in toluene at room temperature without
removing volatiles. These different protocols for catalyst
formation were evaluated for the epoxidation of benzaldehyde
with diazo acetamide 2a. The protocol with catalyst formation
at 100 °C gives the epoxide 41a in >99% ee but with lower
isolated yield that the catalyst generated from BH3•SMe2 (76%
vs 99%, Table 2, entry 1). The much simpler protocol for
catalyst formation at 25 °C gives the exact same outcome as that
at 100 °C. The yield can be improved from 75% to 92% by
employing the N-benzyl diazo acetamide 2c instead of 2a while
maintaining the same asymmetric induction (99% ee). Finally, it
is to be noted that by employing an even simplier procedure that
involving catalyst formation at 25 °C and eliminating the
addition of DMSO, the epoxide 41c can be obtained in the 89%
yield with only a drop in induction from 99% to 95% ee.
Scheme 7 Possible Structures for Catalyst A
3
OR3
H
3
OR3
1
O
B
B
2
1
*
O
O
B
4
O
Catalysts B and C are thought to be the same since they both
involve a 2:1 ratio of VANOL to boron. In contrast, catalysts A
and B are formed from different stoichiometries of VANOL and
boron and thus would be expected to be different. Catalyst A
involves a 1:3 ratio of VANOL to boron and Catalyst B a 2:1
ratio. In addition catalyst A involves the addition of phenol and
water. However, just because all of these ingredients were
added certainly does not mean that all were incorporated into the
catalyst. In fact our thought was that catalysts A and B are the
same since the asymmetric inductions for each aldehyde are
similar with each catalyst. To probe this issue, nonlinear
studies24 were performed to determine the relationship between
B
*
O
4
O
B
O
OR3
O
O
H-base+
O
B
OR3
H
H
H
H
N
O
N
O
N2
R
H
R1
N2
R
R1
H
O
O
76a
Brønsted acid Species
76b
Lewis acid Species
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: asymmetric catalysis · aldehydes · VANOL · borate
esters · epoxides
‡ These authors contributed equally to this work.
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5
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6
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Entry for the Table of Contents (Please choose one layout)
Asymmetric Catalysis
O
O
R2
N
H
+
R1
H
Anil, K. Gupta, Xiaopeng Yin, Munmun
Mukherjee, Aman A. Desai, Aliakbar
Mohammadlou, Kelsee Jurewicz and
William D. Wulff*__________ Page –
Page
N2
Catalyst A or B
O
H
N
R2
R1
Catalytic Asymmetric Epoxidation of
Aldehyde with Two Different Borate
Catalysts of VANOL
O
A
B
Boron/VANOL 3:1
Boron/VANOL 1:2
A Tale of Two Catalysts Two different and effective borate catalysts for the
epoxidation of aldehydes with diazoacetamides can be generated with either a 3:1
or 1:2 ratio of boron to VANOL. That these catalysts are different is demonstrated
by a non-linear study (see graph) on the relationship of the enantiopurity of the
product epoxide versus that of the VANOL ligand. Yet despite their structural
differences, both catalysts display a strikingly similar substrate scope profile with
excellent asymmetric inductions over a series various aryl and aliphatic aldehydes.
7
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