Asymmetric Catalytic Meerwein-Ponndorf-Verley Reduction of Ketones with Aluminum(III)-VANOL Catalysts

Article abstract of DOI:10.1021/acscatal.0c01734

We report herein an efficient aluminum-catalyzed asymmetric MPV reduction of ketones with broad substrate scope and excellent yields and enantiomeric inductions. A variety of aromatic (both electron-poor and electron-rich) and aliphatic ketones were converted to chiral alcohols in good yields with high enantioselectivities (26 examples, 70-98percent yield and 82-99percent ee). This method operates under mild conditions (-10 °C) and low catalyst loading (1-5 mol percent). Furthermore, this process is catalyzed by the earth-abundant main-group element aluminum and employs 2-propanol as the hydride source.

Full text of DOI:10.1021/acscatal.0c01734

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Article
Asymmetric Catalytic Meerwein-Ponndorf-Verley Reduction
of Ketones¬ with Aluminum(III)-VANOL Catalysts
Li Zheng, Xiaopeng Yin, Aliakbar Mohammadlou, Ryan
Sullivan, Yong Guan, Richard J. Staples, and William D. Wulff
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01734 • Publication Date (Web): 01 Jun 2020
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ACS Catalysis
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Asymmetric Catalytic Meerwein-Ponndorf-Verley Reduction of Ke-
tones with Aluminum(III)-VANOL Catalysts
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Li Zheng, Xiaopeng Yin, Aliakbar Mohammadlou, Ryan P. Sullivan, Yong Guan, Richard Staples, and
William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, MI 48824
Email: wulff@chemistry.msu.edu
KEYWORDS asymmetric catalysis, asymmetric ketone reduction, MPV, aluminum, VANOL, 2-propanol
ABSTRACT: We report herein an efficient aluminum-catalyzed asymmetric MPV reduction of ketones with broad substrate
scope and excellent yields and enantiomeric inductions. A variety of aromatic (both electron-poor and electron-rich) and
aliphatic ketones were converted to chiral alcohols in good yields with high enantioselectivities (26 examples, 70-98% yield and
82-99% ee). This method operates under mild conditions (–10 ºC) and low catalyst loading (1–5 mol%). Furthermore, this pro-
cess is catalyzed by the earth-abundant main group element aluminum and employs 2-propanol as hydride source.
The Meerwein-Ponndorf-Verley (MPV) reduction of car-
bonyl compounds was first reported in the mid 1920s.1-3
The asymmetric MPV reduction of ketones can be
This chemoselective reaction utilizes inexpensive 2-
achieved by two strategies. One is the use of chiral alcohols
propanol as reducing agent to generate primary or se-
as sacrificial hydride source instead of 2-propanol, which
condary alcohols from aldehydes or ketones that are acti-
a) Prior Work: AlIII-BINOL complex (ref 13a, 14).
vated though coordination to a Lewis acidic aluminum
R
10 mol% (S)-catalyst 2
2-propanol (4 equiv)
O
OH
R1
center. The mechanism involves the hydride transfer from
2-propanol to carbonyl compounds via a six-membered
ring transition state.4 The classic MPV reduction of ketones
is relatively slow, so it usually requires more than stoichi-
ometric amounts of aluminum isopropoxide (Al(OiPr)3) to
achieve a satisfactory yield.4c Therefore, it was largely re-
placed by methods using boron and aluminum hydrides
after 1950.5 However, efforts to improve MPV reduction
never diminished since the use of 2-propanol as hydride
source is very attractive. To make aluminum based MPV
reductions “truly catalytic”, many methods have been es-
tablished. Rathke and co-workers6a initially discovered
rate enhancement with addition of protic acid in 1976.
Akamanchi et al. reduced the aluminum loading to 8.2
mol% in the presence of 0.32 mol% trifluoroacetic acid
(TFA) in 1995.6b Replacement of aluminum isopropoxide
with other aluminum complexes that are coordinated to
multidentate ligand can make the catalytic reduction high-
ly efficient.7 Nguyen and co-workers demonstrated that
low-aggregated Al(OiPr)3 freshly prepared from AlMe3
with 2-propanol was essential to achieve high catalytic
activity.8 Inorganic bases are also found to be effective in
aldehyde and ketone reductions.9 MPV reduction with iso-
propanol catalyzed by transition metal systems,10 such as
samarium,10a tin,10b zirconium,10c-f,i indium,7g,10g ytterbi-
um10h, ytterium10j and ruthernium10k,11 have been reported.
However, the use of aluminum, an earth-abundant main
group element, shows great advantages over those expen-
sive and hazardous transition metals.
O
O
R1
Al OiPr
toluene, rt, 16 h
1
3
R
catalyst (S)-2a
catalyst (S)-2a
catalyst (S)-2b
catalyst (S)-2c
R1 = CH3, 3a
58% yield, 28% ee
R = H, (S)-2a
R = Me, (S)-2b
R = Et, (S)-2c
R1 = CH2Br, 3g 99% yield, 83% ee
R1 = CH2Br, 3g 98% yield, 50% ee
R1 = CH2Br, 3g 97% yield, 26% ee
b) Prior Work: AlIII-Calix[4]arene complex
tBu
tBu
tBu
tBu
(ref 13b)
F
O
F
OH
Ph
10 mol% 5
O
P
O
Al
O
Ph
O
O
O
O
O
P
2-propanol,
toluene, 0 ºC
O
4
6
Ph
Ph
Ph
Ph
60% yield,
95% ee
5
c) This Work: AlIII-VANOL complex
1-5 mol % (S)-8
R7
OH
R3
O
2-propanol (80 equiv)
R2
Ph
Ph
O
O
R1
R2
Al OiPr
pentane, 4 Å MS
–10 °C, 24 h
1
3
R1 = aryl, R2 = alkyl
R
2 = aryl, R2 = alkyl
7
9
26 examples
70 to 98% yield
82 to 99% ee
R1, R2 = alkyl
R1, R2 = alkyl
R7
(S)-8
Scheme 1. AluminumIII)-catalyzed asymmetric MPV reduction of ketones.
requires far more than stoichiometric amount of enanti-
opure reagent.7b, 12-13 The other strategy employs a chiral
Lewis acid complex as catalyst and achiral 2-propanol as
reductant to achieve the prochiral ketone reduction.10a,14,15
In 2002, Nguyen and co-workers established the first cata-
ACS Paragon Plus Environment

ACS Catalysis
lytic enantioselective MPV reduction with an aluminum
Page 2 of 8
tions.17 In this work, we describe the discovery of alumi-
num-VANOL catalysts that are the first aluminum MPV
catalysts that can reduce a variety of aromatic and aliphat-
ic ketones to chiral alcohols with excellent yields and enan-
tioselectivities (Scheme 1c).
catalyst.14a The catalyst 2a is in situ generated from tri-
methylaluminum (AlMe3), BINOL and 2-propanol as shown
in Scheme 1a. Only ketones capable of 2-point binding to
aluminum, such as 2-haloacetophenones, were reduced to
alcohols with excellent yield and good enantioselectivity.
In their subsequent mechanistic studies,15 it was demon-
strated that the use of 3,3’-disubstituted BINOL derived
catalysts 2b and 2c gave poor asymmetric induction under
the same conditions. Nandi, Katz and coworkers have de-
veloped14b a calix[4]arene phosphite ligand for an alumi-
num-catalyzed MPV reaction with excellent enantioselec-
tivity (Scheme 1b). Unfortunately, the scope of this meth-
od was limited to the ketone 4 as no other ketone was
reported.
1
2
3
4
5
6
7
8
AlMe3
(S)-precatalyst
(S)-ligand
toluene, rt, 1 h
20 mol% (S)-precatalyst
2-propanol (4 equiv)
O
OH
9
Br
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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55
56
57
58
59
60
toluene, rt, 16 h
1g
3g
Table 1. Screening of ligand for the MPV reduction of 2-
bromoacetophenone 1ga
entry
ligand
(S)-L1
(S)-L2
(S)-L3
(R)-L4
(S)-L5
(S)-L6
(S)-L7
(S)-L8
(S)-L9
(S)-L10
(S)-L11
(S)-L12
(S)-L13
%yieldb
%eec
entry
16
17
18
19
20
21
22
23
24
25
26
27
28
ligand
(S)-L16
(S)-L17
(S)-L18
(R)-L19
(S)-L20
(S)-L21
(S)-L22
(S)-L22
(S)-L22
(S)-L23
(S)-L24
(S)-L25
(R)-L26
%yieldb
%eec
1
72
76
74
58
The many advantages of the aluminum mediated MPV
reduction of ketones include mild conditions, inexpensive
reagents, ease of operation and the fact that aluminum is
a) BINOL and vaulted biaryl ligands
2
24
61
83
74
3
(<1)
70
––
50
80
4
–62
56
72
–85
79
5
75
77
6
41
53
86
92
7
71
43
77
62
Ph
Ph
OH
OH
Ph
Ph
OH
OH
Ar1
Ar1
OH
OH
OH
OH
8
70
45
70
47 d
72 e
10
9
79
55
71
10
11
12
13
(<1)
(<5)
66
––
31
L2: Ar1 = Ph, VAPOL
L3: Ar1 = 4-OMe-3,5-Me2-C6H5
L5: VANOL
L1: BINOL
––
(<5)
(<1)
48
––
L4: isoVAPOL
65
—
b) VANOL derivatives
R6
R7
53
78
58
R7
14
15
(S)-L14
(S)-L15
(<3)
68
––
60
29
30
(R)-L27
(R)-L27
25
46
–43
–33
Ph
Ph
OH
OH
R3
R3
Ph
Ph
OH
OH
OH
OH
a Reactions were performed on 0.25 mmol scale at 0.1 M. b Isolated yield
are reported; yields in parentheses are determined by crude 1H NMR
using triphenylmethane as an internal standard. c Determined by chiral
d
R7
HPLC; Minus ee means that the product is the enantiomer of 3g. Reac-
R7
tion at 0.6 M. e Reaction in n-pentane.
R6
R
6 = 4-CF3-C6H5
L15:
L16:
L17:
L18:
L19:
L20:
L21:
L22:
L23:
L24:
L25:
L26:
L27:
L28:
L29:
L30:
L31:
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
7 = F
L6:
L7:
L8:
L9:
R
R
R
R
3 = 4-OMe-C6H5, R7 = H
7 = Cl
L13:
3 = 4-F-C6H5, R7 = Br
7 = Me
3 = 4-nBu-C6H5, R7 = Br
3 = 4-OMe-3,5-Me2-C6H5, R7 = Br
7 = Et
7 = nBu
At the onset of this study it was not clear whether the
vaulted biaryl ligands would be effective since introducing
alkyl groups in the 3- and 3’-positions of BINOL lead to a
drop in asymmetric induction (Scheme 1).14a,15 We selected
2-bromoacetophenone 1g as the model substrate for the
ligand screening of MPV reduction since it was the best
substrate for the BINOL catalyst (Scheme 1). As a control
we first carried out the reaction with (S)-BINOL. With 4
equivalents of 2-propanol and 20 mol% catalyst generated
L10:
R
3 = Cy, R7 = Br
7 = n-hexyl
7 = Cy
R7
7 = tBu
R8
7 = adamantyl
7 = 4-OMe-3,5-tBu2-C6H5
7 = SiPh2tBu
7 = 4-tBu-C6H5
7 = 3-thiopheneyl
7 = 2-furyl
Ph
Ph
OH
OH
Ph
OH
OH
Ar2
R8
7 = iPr
7 = isopentyl
7 = 3-phenylpropanyl
L11: Ar2 = 4-OMe-3,5-Me2-C6H5, R7 = tBu
L12: Ar2 = 4-OMe-3,5-Me2-C6H5, R7 = I
L14: R
8 = Ph
Figure 1. Ligands that were tested for MPV reaction.
from
(S)-BINOL
and
trimethylaluminum,
α-
the most common metal in the earth’s crust. Thus, it would
be highly desirable to develop a catalytic asymmetric MPV
reaction with a chiral aluminum catalyst that gave consist-
ently high yields and asymmetric inductions. We have
developed a class of vaulted biaryl ligands that include
VAPOL (L2) and VANOL (L5) for use in reactions where
the BINOL ligand L1 is not suitable (Figure 1).16 The idea
was that when VANOL and VAPOL are bound to a catalytic
center via the phenol functions, the bulk of the space that
is asymmetrically discriminated around the active site
would be greater than it would be for BINOL catalysts. The
vaulted biaryl ligands VANOL and VAPOL have been
demonstrated to be useful in a variety of asymmetric reac-
bromoacetophenone was reduced to the corresponding
alcohol (R)-3g in 72% yield and 76% ee (Table 1, entry 1).
By comparison, the VAPOL catalyst gave the alcohol 3g in
24% yield and 61% ee (entry 2) and the VANOL catalyst
gave 3g in 75% yield and 56% ee (entry 5). Both of these
vaulted biaryl ligands gave lower induction than BINOL
and this is consistent with the substituted BINOL catalysts
2b and 2c compared to BINOL. (Scheme 1). Given that the
VAPOL catalyst gives a much slower reaction than that of
VANOL, we decided to screen the large number of VANOL
ligands we have previously prepared.18 First the reaction
was screened with catalysts generated from the ligands L6
to L10 with the idea that a change in the dihedral angle
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ACS Catalysis
between the naphthalenes in these ligands might enhance
1
the inductions but to no avail (entries 6-10). The results
obtained from the C1-symmetrical ligands L11 and L12
did not lead to any significantly enhanced results (entry
11-12). The catalyst generated from the 6,6’-substituted
VANOL L13 increased the ee to 78% with good yield, indi-
cating that changes made on naphthalene rings were more
efficient than those on the backbone of the ligands (entry
13 vs entries 6-10). Low conversion was observed when
the 8,8’-diphenyl VANOL L14 was used, presumably be-
cause of the steric bulk near the active site which may have
either slowed down the reaction or hindered the formation
of catalyst (entry 14). Gratifyingly, modification of the 7,7’-
positions of VANOL gave promising results especially for
those with aliphatic substituents. It was interesting to find
that an ethyl substituent gave higher induction than a me-
thyl substituent (entries 18 vs 17) which is the opposite
trend to that observed with BINOL with substituents in the
3,3-positions (Scheme 1). Further investigation found that
a t-butyl group was too big (entry 22), an ethyl group was
too small (entry 18), but that a cyclohexyl group was just
right (entry 21). Various aryl and heteroaryl groups as well
as silyl groups were not nearly as effective.
2
3
4
5
6
7
8
9
Other reaction parameters were also screened in an ef-
fort at further optimization (see the supporting informati-
on for details). When the reduction of 1g was screened in
different solvents wih a constant amount of 2-propanol (4
equiv) it was found that strongly coordinating solvents
such a THF and ether resulted in a dramatic drop in yield
(Table S1). This is presumably due to the coordination of
solvent to the aluminum preventing the coordination of
the ketone and the formation of the proper 4 or 5 coordi-
nate aluminum transition state.15b Increasing the amount
of 2-propanol is advantageous since it helps to drive the
reaction forward and also helps by increasing the solubili-
ty of some substrates. Optimal asymmetric induction was
obtained using n-pentane as solvent (Table 1, entry 22 vs
24). Notably, lowering the concentration of the reaction
had significant impact on the enantioselectivities (15%
increase in ee from 0.6 M to 0.1 M, Table 1, entry 22 vs 23),
possibly due to the aggregation of the aluminum complex
at higher concentration. The hydride source was also eva-
luated (Table S2). The optimal conditions in Table 1 (entry
21) with primary alcohols failed to deliver the desired
product even though they have been employed in MPV
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AlMe3
(S)-precatalyst
(S)-ligand
toluene, rt, 1 h
reductions1,3
. Among the secondary alcohols that were
tested, the use of 2-propanol provided the highest enantio-
selectivity.
O
OH
(S)-precatalyst (y mol%)
2-propanol (x equiv)
pentane, temp, time
Br
Br
Further optimization was performed on the ketone 4’-
bromoacetophenone 1s with regard to temperature, the
amount of 2-propanol and catalyst loading. This substrate
gave the alcohol 3s in 70% yield with 30% ee with the
BINOL catalyst 2a in toluene under the conditions indica-
ted in Scheme 1.14a With 5 mol% catalyst prepared from
(S)-L21 (7,7’-Cy2VANOL), the corresponding alcohol 3s
was obtained in 76% yield and 85% ee at room tempera-
ture in n-pentane (Table 2, entry 1). Lowering the tempe-
rature to 0 ºC increased the induction to 92% ee but the
yield was dropped to 48% (entry 2). However, if the
amount of 2-propanol was increased from 4 equivalents to
80 equivalents, the yield was greatly improved from 48%
to 91% at the same reaction time without impacting enan-
tioselectivity (entry 2-6). Notably, the catalyst loading
could be reduced to 2 mol%, providing 3s with 81% yield
and 93% ee after 24 hours (entry 8). The best result (94%
yield and 96% ee) was obtained while running the reaction
at –10 ºC with the addition of 4 Å molecular sieves (entry
11). It was observed that reactions with VANOL and
BINOL catalysts under the optimized conditions indicated
in entry 11 of Table 2 gave less than 1-2% of the reduced
product 3s (entry 15-16).
1s
3s
Table 2. Optimization of conditions for the MPV reduction of
4’-bromoacetophenone 1s.a
y
time
(h)
temp
(ºC)
x
entry
ligand
%yieldb
%eec
equiv.
mol%
1
2
(S)-L21
(R)-L21
(R)-L21
(R)-L21
(S)-L21
(S)-L21
(S)-L21
(S)-L21
(S)-L21
(S)-L21
(R)-L21
(S)-L29
(S)-L30
(S)-L31
(S)-L5
6
6
rt
0
4
5
5
5
5
5
5
2
2
1
5
5
5
5
5
5
5
76
48
85
–92
–90
–90
94
4
3
6
0
10
20
40
80
40
80
40
80
80
80
80
80
80
80
53
4
6
0
67
5
6
0
79
6
6
0
91
94
7
6
0
67
95
8
24
12
6
0
81
93
9
0
(<5)
84
––
10
11d
12d
13d
14d
15d
16d
–10
–10
–10
–10
–10
–10
–10
96
6
94
–96
94
6
82
Under the optimal conditions established in Table 2 (en-
try 11), a variety of aromatic ketones were examined and
the results are presented in Scheme 2. Acetophenone 1a
was reduced in 88% yield and 94% ee to the alcohol 3a by
the VANOL catalyst 8 (R7 = cyclohexyl) shown in Scheme 1
whereas the same reduction with the BINOL catalyst 2a
gives 3a in 58% yield and 28% ee. Likewise, α-
bromoacetophenone 1g was reduced to the corresponding
6
89
95
6
(<5)
(<2)
(<1)
––
6
––
(S)-L1
6
––
a
Precatalyst was generated with 1.3:1 ligand/AlMe3 ratio; reactions
were performed on a mmol scale at 0.1 M. b Isolated yield are reported;
yields in parentheses are determined by crude 1H NMR using triphe-
nylmethane as an internal standard. c Determined by chiral HPLC; Mi-
nus ee means that the product is the enantiomer of 3s. d With 4 Å MS
(100mg/mmol)
ACS Paragon Plus Environment

ACS Catalysis
alcohol 3g in 87% yield and 97% ee. A number of other α-
Page 4 of 8
reduced at all. It is interesting to observe that the presence
of a bromo group alpha to the ketone can largely offset the
effect of the 4-methoxy group (1w). The absolute configu-
rations of the products in Scheme 2 were confirmed by
comparing their optical rotations with literature values,
and in addition, 3x was confirmed by its crystal structure.
The reduction of propiophenone was slow and gave the
alcohol 3y in 57% yield and 74% ee at rt in 24 h.
1
2
3
4
5
6
7
8
haloacetophenones 1d to 1g can be reduced with very high
asymmetric inductions including α-chloro, α,α-dichloro
and α,α,α-trifluoromethyl acetophenone. Also a remarka-
ble range of o-substituted acetophenones are reduced with
high enantioselectivity included those with chloro, bromo,
iodo, methyl and methoxy groups (1i to 1m). In the meta
positions, the electron withdrawing group bromine gives
high enantioselectivity (97% ee) but this drops off with the
electron releasing methoxy group (88% ee). A number of
electron-withdrawing groups in the para position do not
seem to affect the asymmetric induction (ketones 1q to
1t). Although the 4-methylacetophenone 1u can be re-
duced effectively, the 4-methoxyacetophenone 1v is not
Scheme 3. Substrate Scope for Aliphatic Ketones a
AlMe3 (5 mol%)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-precatalyst
(S)-ligand
n-pentane, rt, 1 h
6.5 mol%
5 mol% (S)-precatalyst
2-propanol (80 equiv)
O
OH
CH3
R
CH3
R
4 Å MS
n-pentane, temp, 24 h
Scheme 2. Substrate Scope for Aromatic Ketones. a
7
9
0.1 M
AlMe3 (5 mol%)
yield (%) b
alcohol 9
temp (°C) conv (%)
ee (%) c
ligand
(R)-precatalyst
(R)-L21
n-pentane, rt, 1 h
6.5 mol%
–10
–20
–10
–20
93
73
93
97
84
71
87
91
74
69
80
82
7,7’-Cy2VANOL L21
OH
7,7’-(i-Pr)2VANOL L29
7,7’(i-pentyl)VANOL L30
7,7’(i-pentyl)VANOL L30
5 mol% (R)-precatalyst
2-propanol (80 equiv)
O
OH
9a
Ar
R
Ar
R
4 Å MS
n-pentane, –10 °C, 24 h
1
3
OH
0.1 M
–10
–10
–20
71
91
75
65
81
64
70
88
85
7,7’-Cy2VANOL L21
7,7’(i-pentyl)VANOL L30
7,7’(i-pentyl)VANOL L30
OH
OH
OH
OH
CF3
9b d
OH
–10
99
84
94
7,7’(i-pentyl)VANOL L30
3a
3b b
3c
95% yield
98% ee
3d
9c d
a Unless otherwise specified, all reactions were performed on a 0.25 mmol scale with
88% yield
94% ee
78% yield
91% ee
71% yield
96% ee
5 mol% catalyst with 25 mg of activated 4 Å molecular sieves at 0.1 M in ketone at the
indicated temperature for 24 h. b Isolated yields after silica gel chromatography. c determined
by HPLC on purified product. d Yield and ee were determined after conversion to the
4-fluorobenzoate ester.
F
OH
OH
OH
OH
F
F
Cl
Br
Cl
Cl
F
F
3g c,d,e
3h b
The asymmetric reduction of simple dialkyl ketones with
a chiral aluminum catalyst has never been reported. Antic-
ipating that the degree of asymmetric induction would
correlate with the steric differential of the two alkyl groups
on the ketone, the three ketones shown in Scheme 3 were
examined. The most difficult substrate was ketone 7a
which has a methyl group and a unbranched alkyl group.
The reduction under the optimized conditions in Scheme 2
gave the alcohol 9a in 84% yield and 74% ee. Further lig-
and screening revealed that the ligand L30 with an iso-
Scheme 4. Gram-scale synthesis and explanation of chiral outcome.
3e
3f
98% yield
99% ee
94% yield
>99% ee
87% yield
97% ee
80% yield
99% ee
OH
OH
OH
OH
Cl
Br
I
3i f
3j
3k
3l b,d
96% yield
99% ee
90% yield
99% ee
96% yield
93% ee
94% yield
96% ee
OH
OH
OH
OH
OMe
1 mol% precatalyst
from (R)-L21
2-propanol
a)a
Br
OMe
3p b,c,d
3m f
3n
3o b,d
O
OH
O
K2CO3, THF
reflux, 24 h
Br
(40 equiv)
Br
93% yield
94% ee
91% yield
97% ee
82% yield
90% ee
84% yield
88% ee
pentane, 0 °C, 24 h
(S)-3g
1g
10
OH
OH
OH
OH
90% yield
97% ee
8 mmol
86% yield
1.59 gram
97% ee
b)
O2N
CF3
I
3u b,d
3q d
3r
Hindered
3t b,d
89% yield
93% ee
70% yield
92% ee
92% yield
97% ee
91% yield
97% ee
CH3
O
O
CH3
O
O
Ph
Ph
O
O
Ph
Ph
OH
OH
OH
Al
H
OH
Al
H
Br
Br
CH3
O
CH3
CH3
O
CH3
MeO
MeO
O2N
3v
<1% yield
3w b
3x b,d
3y g
11a
Favored
57% yield
74% ee
71% yield
83% ee
95% yield
98% ee
11b
Disfavored
a Reduction was performed at 0.2 M with 800 mg 4 Å MS in 16 ml pentane. Epoxidation was
performed at 0.2 M in THF with 1.5 equiv. anhydrous potassium carbonate.
a Unless otherwise specified, all reactions were performed on a 0.25 mmol scale with
5 mol% catalyst with 25 mg of activated 4 Å molecular sieves at 0.1 M in ketone at
–10 °C for 24 h. Yields and ee’s are of purified products after silica gel chromatography.
b Reaction with 10 mol% catalyst. c Reaction at 0 °C. d (S)-L21 was used. e 6 h f 16 h.
g Reaction at rt and went to 65% conversion.
pentyl group in the 7- and 7’-positions of VANOL increased
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ACS Catalysis
the selectivity to 82% ee giving 9a in 91% yield at –20 °C.
Ketone 7b with a methyl group and a cyclohexyl group on
the ketone gave the alcohol 9b in 81% yield and 88% ee.
Unsurprisingly, the ketone 7c with the bulkiest substituent
gave the highest stereochemical outcome of 94% ee in
84% yield.
tones with different electron densities and substituents are
well-tolerated and most of them can be reduced with
>90% yield and >90% ee. Notably, aliphatic ketones were
also addressed with good to excellent enantioselectivity
for the first time. The aluminum catalyst generated from
trimethylaluminum and the 7,7’-dicyclohexyl substituted
VANOL ligand L21 is very efficient giving high yields and
enantioselectivities of the reduced products under the
same conditions where the VANOL ligand without the cy-
clohexyl groups gives no product at all (<2%). It is possi-
ble that the presence of the cyclohexyl groups helps to
prevent aggregation or oligomerization of the catalyst.
1
2
3
4
5
6
7
8
9
The scalability of this MPV reduction was examined on a
32-fold
increase in scale of the reduction of α-
bromoacetopheone 1g (Scheme 4a). On an 8 mmol scale
the reduction proceeded smoothly with the catalyst load-
ing reduced to 1 mol% catalyst to give the alcohol 3g in
90% yield and 97% ee, a result which is essentially un-
changed from the 0.25 mmol scale at 5 mol% catalyst
(Scheme 2). The corresponding alcohol ((S)-3g) was then
treated with potassium carbonate to give chiral epoxide 10
with retention of enantiomeric purity (Scheme 4a).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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AUTHOR INFORMATION
Corresponding Author
The mechanism of the MPV has long been thought4 to in-
volve a four coordinate aluminum transition state with an
intramolecular transfer of hydride from an isopropoxy
substitutent on aluminum to a molecule of ketone coordi-
nated to the aluminum as indicated in Scheme 4b. In the
particular case of the BINOL aluminum catalyst 2a devel-
oped by Nguyen the mechanism of reduction was explored
by DFT analysis and this direct transfer was found to be
more energetically favorable that either a radical mecha-
nism or a hydride mechanism involving an aluminum hy-
dride.15a In the case of the substrate 1g, a transition state
for direct transfer with a five-coordinate aluminum was
proposed.15b We have performed DFT calculations at the
B3LYP 6-31G (d) level to calculate transition state energies
on the asymmetric reduction of acetophenone with (S)-
L21 (see the supporting information for details). The re-
sulting analysis suggests that the origin of the chiral out-
come is as indicated in Scheme 4b. With (S)-L21 as ligand
and acetophenone as substrate, 11b is disfavored due to
the steric interaction between the cyclohexyl group on
catalyst complex and the phenyl group on the ketone.
These calculations were performed with different solvents
(toluene, n-pentane and 2-propanol) and although the en-
ergy differences between 11a and 11b (0.38 to 0.82
kcal/mol) were not large enough to match the induction
observed (94% ee) all favored 11a leading to the correct
enantiomer produced. Given the reduced inductions ob-
served with substituted BINOL catalysts 2b and 2c com-
pared to 2a (Scheme 1a), it was a surprise to find that the
much larger VANOL ligand with substituents in the 7- and
7’-positions were so effective. While the reason for this
can’t be known for certain at this time, one interpretation
of the effect of the larger substituents is that it disfavors
aggregation of the aluminum catalyst. It has been shown
that the BINOL aluminum derivatives can aggregate.15b
* William D. Wulff – Department of Chemistry, Michigan State
University, East Lansing, MI 48824
Email: wulff@chemistry.msu.edu
Authors
Li Zheng – Department of Chemistry, Michigan State University,
East Lansing, MI 48824
Xiaopeng Yin – Department of Chemistry, Michigan State Uni-
versity, East Lansing, MI 48824
Aliakbar Mohammadlou – Department of Chemistry, Michi-
gan State University, East Lansing, MI 48824
Ryan P. Sullivan – Department of Chemistry, Michigan State
University, East Lansing, MI 48824
Yong Guan – Department of Chemistry, Michigan State Univer-
sity, East Lansing, MI 48824
Richard Staples – Department of Chemistry, Michigan State
University, East Lansing, MI 48824
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spec-
troscopic data for all new compounds. This material is availa-
ble free of charge via the internet at http://pubs.acs.org/.
ACKNOWLEDGMENT
This work was supported by the National Institute of Gen-
eral Medical Sciences (GM 094478).
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Page 6 of 8
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these were limited to glyoxolate esters.10j
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1-5 mol % (S)-catalyst
2-propanol (80 equiv)
OH
R3
1
2
3
4
O
CH3
H
R2
R1
R2
O
O
pentane, 4 Å MS
–10 °C, 24 h
O
O
Ph
Ph
R1 = aryl, R2 = alkyl
R1, R2 = alkyl
R2 = aryl, R2 = alkyl
R1, R2 = alkyl
Al
CH3
CH3
26 examples
70 to 98% yield
82 to 99% ee
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