Solvent enhancement of reaction selectivity: A unique property of cationic chiral dirhodium carboxamidates

Article abstract of DOI:10.1021/ja202676a

1,3-Dipolar cycloaddition reactions of nitrones with α,β- unsaturated aldehydes catalyzed by a cationic chiral dirhodium(II,III) carboxamidate with (R)-menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands in toluene increase reaction rates, give optimum regioselectivities, and enhance stereoselectivities compared to the same reactions performed in traditionally used halocarbon solvents. Rate and enantioselectivity enhancements were also obtained in hetero-Diels-Alder and carbonyl-ene reactions performed in toluene over those obtained in dichloromethane using the diastereomeric chiral cationic dirhodium(II,III) carboxamidate with (S)-menthyl (S)-2-oxopyrrolidine-5- carboxylate ligands. These enhancements are attributed to diminished or absent association of toluene with the catalyst which lessens the relative importance of the uncatalyzed background reaction, and they may also be a consequence of different coordination angles for aldehyde association with rhodium in the different solvent environments. Overall, the enhancement of reaction rates and selectivities with cationic chiral dirhodium(II,III) carboxamidates in toluene suggests broad applications for them in Lewis acid catalyzed reactions.

Full text of DOI:10.1021/ja202676a

ARTICLE
pubs.acs.org/JACS
Solvent Enhancement of Reaction Selectivity: A Unique Property of
Cationic Chiral Dirhodium Carboxamidates
Xiaochen Wang, Carolin Weigl, and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S Supporting Information
b
ABSTRACT: 1,3-Dipolar cycloaddition reactions of nitrones
with R,β-unsaturated aldehydes catalyzed by a cationic chiral
dirhodium(II,III) carboxamidate with (R)-menthyl (S)-2-oxo-
pyrrolidine-5-carboxylate ligands in toluene increase reaction
rates, give optimum regioselectivities, and enhance stereoselec-
tivities compared to the same reactions performed in traditionally
used halocarbon solvents. Rate and enantioselectivity enhance-
ments were also obtained in hetero-DielsꢀAlder and carbonyl-
ene reactions performed in toluene over those obtained
in dichloromethane using the diastereomeric chiral cationic
dirhodium(II,III) carboxamidate with (S)-menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands. These enhancements are attributed
to diminished or absent association of toluene with the catalyst which lessens the relative importance of the uncatalyzed background
reaction, and they may also be a consequence of different coordination angles for aldehyde association with rhodium in the different
solvent environments. Overall, the enhancement of reaction rates and selectivities with cationic chiral dirhodium(II,III)
carboxamidates in toluene suggests broad applications for them in Lewis acid catalyzed reactions.
’ INTRODUCTION
examples of highly selective nitrone 1,3-dipolar cycloaddition
with R,β-unsaturated aldehydes that are monodentate dipolar-
ophiles (2),9 and only those using methacrolein have shown
consistently high selectivities.
Chiral dirhodium(II) carboxamidates are powerful catalysts
for highly enantioselective metal-carbene transformations of
diazoacetates.1ꢀ3 When applied as Lewis acids, high enantiocon-
trol with high turnover numbers have been achieved with chiral
dirhodium(II) carboxamidates in hetero-DielsꢀAlder reac-
tions.4 However, dirhodium(II) carboxamidates are weak Lewis
acids, and attempts to effectively catalyze other Lewis acid
catalyzed transformations have not been successful. Subsequent
research has shown that cationic dirhodium(II,III) compounds,
conveniently prepared by oxidation of dirhodium(II) carboxa-
midates with nitrosonium salts, possess enhanced Lewis acidity
and improve catalyst selectivities for both hetero-DielsꢀAlder
and nitrone dipolar cycloaddition reactions to methacrolein.5
Still, regioselectivities in nitrone dipolar cycloaddition reactions
with these catalysts have limited their broader applications.
The regio- and stereoselective synthesis of isoxazolines by 1,3-
dipolar cycloaddition of nitrones with electron-deficient alkenes
has been a challenge for asymmetric catalysis.6 Their selective
formation by cycloaddition is particularly attractive because
isoxazolines are conveniently converted to β-amino acids and
β-lactams, and they are precursors to γ-amino alcohols.7 En-
antioselective approaches involving transition metal catalysts
have been successful with bidentate dipolarophiles (1) such as
those derived from oxazolidinones that provide two-point bind-
ing to the chiral Lewis acid (Scheme 1),6,8 but the structural
requirements for bidentate dipolarophiles are limiting; and their
applications are synthetically inefficient. Although, use of un-
saturated aldehydes would be ideal, there have been few
Dirhodium(II) carboxamidates are ineffective promoters of
dipolar addition reactions of nitrones. They exhibit weak co-
ordination with reacting carbonyl substrates,4e and catalytic
reaction rates do not compete with the background reaction.
However, we have recently discovered that the chiral dirhodium-
(II,III) carboxamidate catalyst [Rh2(5S,R-MenPy)4]SbF6 (3),
which exhibits preferential binding to the aldehyde rather than
nitrones, provides high enantioselectivities and modest regio-
control in reactions with methacrolein.5 Yet application of this
same catalyst to acrolein in nitrone cycloaddition reactions
exhibited limitations in both reaction rate and selectivity.10 We
now report that the low enantioselectivity that we initially
observed in reactions with acrolein can be overcome and
regioselectivity can be substantially improved by performing
the cycloaddition reaction in toluene rather than in chlorocarbon
solvents and that the resulting high regioselectivity and stereo-
control is broadly applicable to cycloaddition reactions between
nitrones and R,β-unsaturated aldehydes but is unique to the
chiral dirhodium carboxamidate catalysts. Furthermore, solvent
enhanced reactivity and selectivity of [Rh2(5S,R-MenPy)4]SbF6
(3) and its diastereomeric form [Rh2(5S,S-MenPy)4]SbF6 (4)
makes possible effective applications to other Lewis acid
Received: March 24, 2011
Published: May 18, 2011
r
2011 American Chemical Society
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Scheme 1
catalyzed carbonꢀcarbon bond forming reactions also with
For comparison, published results from four catalytic systems
(8,9g 9,9d 10a,9b and 10b9b) that have been effectively employed
for the same transformation are also reported in Table 1. The
Kanemasa catalyst 8 provides good enantiocontrol, but cycload-
dition occurs with poor regioselectivity.9g Maruoka has reported
reactions of N-benzyl-R-phenylnitrone instead of N,R-diphenyl-
nitrone for catalytic reactions with his μ-oxo bis-Ti(IV) oxide
catalyst 9, but yield, stereocontrol, and regioselectivity are high
with the benzyl-substituted nitrone.9d Extensive studies by
Carmona and co-workers with cationic Cp*Rh(III)L* (10a)
and Cp*Ir(III)L* (10b) catalysts that possess a chiral bis-
phosphine ligand (L*) also show high regioselectivity in this
dipolar cycloaddition reaction, but enantiocontrol is metal ion
dependent with the Ir(III) catalyst exhibiting higher enantiocon-
trol than that with Rh(III).9b,e,f The reported reactions catalyzed
by 8ꢀ10 were performed in dichloromethane at various reaction
temperatures, and solvent effects with these systems were not
available for comparison with results from the use of 3 or 4.
Reported cycloaddition reactions catalyzed by 8-10 were
performed at temperatures ranging from ꢀ10 to ꢀ40 °C, and
we presume that they were optimized at the reported tempera-
tures. However, with [Rh2(5S,R-MenPy)4]SbF6 (3) the influ-
ence of temperature on selectivity is negligible, although the rate
of reaction is lower at ꢀ20 °C than at 0 °C. One can conclude
from these comparative data that catalysis of nitrone cycloaddi-
tion to acrolein by 3 in toluene provides selectivities that are at
least as good as the best of the alternatives and that reactions
catalyzed by 3 occur at a faster rate under milder conditions.
To better understand the effect of solvent in catalytic reactions
of N,R-diphenylnitrone with acrolein catalyzed by 3, we followed
percent conversion of nitrone as a function of time. The rates of
reaction in the various solvents decrease from toluene to
iodobenzene (Figure 1), and they are significantly less in
dichloromethane. Even two equivalents of iodobenzene, based
on acrolein, in toluene produce a 1ꢀ2% decrease in regioselectivity
enhanced selectivities.
’ RESULTS AND DISCUSSION
Nitrone cycloaddition reactions were performed by first
preparing the [Rh2(5S,R-MenPy)4]SbF6 (3) catalyst from its
dirhodium(II,II) precursor, Rh2(5S,R-MenPy)4, by treatment
with nitrosonium hexafluoroantimonate in the presence of 2,6-
di-tert-butylpyridine and 4 Å molecular sieves in the reaction
solvent and then sequentially adding the R,β-unsaturated alde-
hyde and nitrone. With 5 mol % of 3 in dichloromethane at 0 °C
the cycloadducts of acrolein and N,R-diphenylnitrone were
obtained after 5 h that, following borohydride reduction, were
analyzed as a 70:30 ratio of 3,4-(6a):3,5-(7a) regioisomers in
73% isolated yield (eq 1). The diastereomeric ratio of 3,4-endo
(6a-endo) to 3,4-exo product was 92:8, and 6a-endo was obtained
with 78% enantiomeric excess (ee). In an effort to improve
selectivity by variation of the solvent, we discovered an excep-
tionally large influence of reaction solvent on reactivity and
selectivity (Table 1). Changing the reaction solvent from di-
chloromethane to chloroform resulted in a slight increase in
regio- and enantiocontrol, but percent conversion over the same
reaction time decreased dramatically. Percent conversion in-
creased in cyclohexane, and there was also a substantial increase
in regio- and enantiocontrol. Suggestive of heteroatom influence
on reactivity and selectivity, reactions performed in monohalo-
benzene solvents also exhibited enhanced percent conversion
and regioselectivity in fluorobenzene compared to iodobenzene,
with chlorobenzene in between. However, reactivity and selec-
tivities were optimal in toluene. Similar rate and selectivity
enhancements in toluene occurred with the diastereomeric
[Rh2(5S,S-MenPy)4]SbF6 (4), although enantioselectivity and
regiocontrol for the production of 6a were somewhat lower than
those with [Rh2(5S,R-MenPy)4]SbF6 (3).
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Table 1. Influence of Solvent on Regioselectivity and Stereocontrol in Chiral Dirhodium(II,III) Carboxamidate Catalyzed
Reactions of N,R-Diphenylnitronewith Acrolein and Comparison of Selectivities withReported Results Using Alternative Catalysts
catalyst/mol %
solvent
T (°C)
t (h)
yield (%)a
6a:7ab
dr of 6ab
ee of 6a-endo (%)c
3/5
CH2Cl2
CHCl3
c-C6H12
PhI
0
0
5
5
73
40
70:30
75:25
88:12
83:17
83:17
91:9
92:8
91:9
78
83
91
90
90
92
94
93
71
90
27
76
91
93
78
90
3/5
3/5
0
2
93
93:7
3/5
0
2
73
94:6
3/5
PhCl
0
2
91
93:7
3/5
PhF
0
2
92
94:6
3/5
PhMe
0
1
94
96:4
94:6
3/5
PhMe
ꢀ20
0
4
93
96:4
94:6
4/5
CH2Cl2
PhMe
5
55
74:26
94:6
91:9
4/5
0
1
94
94:6
5/5
CH2Cl2
PhMe
0
5
67
67:33
88:12
26:74
>99:1
>99:1h
>99:1h
92:8
5/5
0
2
92
93:7
8d/10
9e/10
10af/5
10bf/5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ10
ꢀ40
ꢀ25
ꢀ25
72
24
16
16
75
95:5
94
>97:3
>99:1h
>99:1h
(100)g
(100)g
a Isolated product yield following chromatography. b Determined by 1H NMR spectroscopy. c Determined by HPLC analysis (OD-H column).
d Reference 9g. e Reference 9d, N-benzyl-R-phenylnitrone was used instead of N,R-diphenylnitrone in this case. f Reference 9b, a 7-fold molar excess of
acroleinwas used. g Percent conversion based on1H NMR analysis;isolatedproduct yield not given. h Onlythe6a-endo cycloadditionproduct was reported.
Solvent influences on reaction rates and selectivities in 1,3-
dipolar cycloaddition reactions have been reviewed,12 and in at
least one case solvents of low polarity have been predicted to
enhance regioselectivity based on computational analyses of
activation energies.13 However, solvent effects in catalytic reac-
tions with transition metal compounds have been attributed to
many causes, including solvent coordination to transition
metals14 and stabilization or destabilization of transition state
by solvent medium.15 The evidence presented in Figure 1
strongly suggests that the rate inhibition that is found in this
dipolar addition reaction catalyzed by 3 is due to competitive
association of the halocarbon solvent with the dirhodium(II,III)
catalyst at an axial coordinating site thereby inhibiting association
with acrolein.
There is no difference in the rates of the background reactions
of N,R-diphenylnitrone with acrolein in dichloromethane and
toluene. After 24 h of reaction at room temperature, the back-
Figure 1. Plot of conversion (%) as a function of time for the standard
reaction of N,R-diphenylnitrone with acrolein catalyzed by [Rh2(5S,R-
MenPy)4]SbF6 in PhMe, PhCl, PhI, and CH2Cl2 at 0 °C.
ground reaction in both solvents resulted in 78% conversions to
cycloaddition products with a 16:84 ratio of regioisomers 6a:7a
and a diastereomeric ratio of 3,4-endo:3,4-exo of 74:26, showing
no dependence on solvent selection. Since the solvent does not
influence either rate or selectivity in the background reaction, the
and enantioselectivity. Use of acetonitrile as the solvent com-
pletely terminates the catalytic cycloaddition reaction, presum-
ably because of strong axial coordination on 3 by acetonitrile.11
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Scheme 2
Table 2. Effect of Nitrone Substituents on Regioselectivity
and Enantiocontrol in Cycloaddition Reactions with Acrolein
Catalyzed by [Rh2(5S,R-MenPy)4]SbF6 (3)
ee of
yield
t (h) (%)a
6-endo
(%)c
entry
R
Ar
6:7b
dr of 6b
1
2
3
4
5
6
7
8
Ph Ph
1
1
1
3
3
4
2
3
94
92
94
86
90
89
90
91
96:4
>99:1
99:1
94:6
95:5
94:6
92:8
94
Ph 4-MeOC6H4
Ph 4-MeC6H4
Ph 4-ClC6H4
Ph 4-CF3C6H4
Ph 2-furyl
98
96
96
96
95:5
87:13 94:6
>99:1
99:1
88:12 90
Ph 2-naphthyl
Bn Ph
94:6
98:2
97
95 (S,S)d
>99:1
a Isolated product yield. b Determined by 1H NMR spectroscopy.
c Determined by HPLC analysis (OD-H column). d The absolute
configuration was determined by comparison with literature.9d
þ
Figure 2. Energy minimized geometries of acrolein-Rh2(5S-IPPy)4
complex in dichloromethane (A) and toluene (B) obtained from DFT
calculation (B3LYP). Hydrogens are omitted for clarity.
of one side of acrolein in toluene suggests greater facial differ-
entiation of acrolein. Regiocontrol for 6a in this 1,3-dipolar
cycloaddition reaction is dependent on the extent of the un-
catalyzed reaction (Scheme 2), on the Lewis acidity of the
catalyst,9a,g,16 and, potentially, on stereoelectronic factors ema-
nating from the catalyst ligands (note the conformational
differences in ligands in A and B of Figure 2).
The generality of the high selectivity observed for nitrone
cycloaddition to acrolein catalyzed by 3 is suggested by the data
in Table 2 for reactions with various substituted nitrones. High
yields, excellent regiocontrol, and enantioselectivities equal to or
greater than 90% characterize the cycloaddition reactions cata-
lyzed by [Rh2(5S,R-MenPy)4]SbF6 (3). As was previously
established by us with methacrolein,5 and confirmed by K€undig,9a
electron withdrawing groups in Ar decrease regioselectivity
without changing stereoselectivity; but for reactions performed
in toluene, even nitrones having electron-withdrawing groups in
Ar such as trifluoromethyl (entry 5) provide high regiocontrol for
the 3,4-cycloaddition product (6). And in comparing results
from the use of the N-benzyl nitrone in Table 2 (entry 8) at 0 °C
with the previously reported outcome of this same reaction with
Maruoka’s μ-oxo bis-Ti(IV) oxide catalyst at ꢀ40 °C (9 in
Table 1),9d the efficiency and effectiveness of [Rh2(5S,R-Men-
Py)4]SbF6 as the catalyst is pronounced.
The comparative advantages of the use of 3 for dipolar
cycloadditions to methacrolein (11a) and trans-crotonaldehyde
(11b) are reported in Table 3. Solvent enhancement of regio-
selectivity is evident in these results. With N-phenyl-R-anisylni-
trone, for example, regioselectivity for 12:13 increases from a
modest 70:30 to 97:3 upon changing the solvent from dichloro-
methane to toluene. In addition, enantioselectivities for 12 that
were already high from reactions catalyzed by 3 performed in
dichloromethane are further enhanced with reactions performed
in toluene. Enantiocontrol in catalytic formation of the 3,4-endo
cycloadduct obtained from these substrates using 3 is at
the highest level reported compared to the previously reported
solvent effect in the Rh(II)/Rh(III) catalyzed reaction must
come from the association between R,β-unsaturated aldehyde
and the Rh(II)/Rh(III) catalyst. The influence on reaction rate
arises from solvent association at the axial positions of the
dirhodium catalyst (Scheme 2). Competition between solvent
and acrolein for the catalytically active site inhibits the rate of
catalytic conversion of acrolein to its dipolar cycloaddition
products and increases the importance of the uncatalyzed path-
way to these same products. Since the uncatalyzed reaction
produces racemic 6a and favors regioisomer 7a over 6a, the
influence of solvent on selectivity can also be appreciated from
the competition depicted in Scheme 2.
Although Scheme 2 explains reactivity and selectivity qualita-
tively and may be responsible for most of the selectivity
enhancement, the effects of solvent on reactivity, regioselectivity,
and enantioselectivity are variable (for example, the use of
chloroform produces a significant decrease in reactivity, but a
slight increase in selectivity, compared to dichloromethane). In a
search for other contributing factors to selectivity in this dipolar
cycloaddition reaction, DFT calculations were performed on the
complex of acrolein with the isopropyl analog of 3 and 4, Rh2(5S-
IPPy)4þ(5) whose solvent-dependent selectivities are recorded
in Table 1. The B3LYP functional with the LANL2DZ basis set
and the CPCM solvation model was applied in this calculation. In
the energy minimized geometries, which were calculated in the
solvent environment of dichloromethane and toluene separately,
acrolein coordination to Rh adopted different dihedral angles
relative to catalyst ligands. In dichloromethane (A in Figure 2),
the dihedral angle involving the atoms O—Rh(catalyst)—
OdC(acrolein) was 32.7°, whereas in toluene (B in Figure 2)
the same angle decreased to 6.6°. Considering that enantiocon-
trol occurs by selective shielding of the top and bottom sides of
acrolein by two esters of the chiral pyrrolidinone ligands on each
rhodium face (represented as E in Figure 2), the greater shielding
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examples.9 The advantages of the cationic catalyst [Rh2(5S,R-
MenPy)4]SbF6 (3) are evident.
mol % [Rh2(5S,R-MenPy)4]SbF6 (3), reactions of p-nitroben-
zaldehyde with 17 in both solvents at room temperature are
relatively slow, they do not exhibit rate enhancement by changing
the solvent from dichloromethane to toluene, but enhancement
in enantioselectivity is evident. However, the diastereomeric
[Rh2(5S,S-MenPy)4]SbF6 (4) noticeably improved reaction
rates and exhibited substantial rate enhancement by changing
the reaction solvent to toluene. In this latter case there was not a
significant solvent-induced change in enantioselectivity.
As noted earlier, results from the use of catalysts 8ꢀ10 have
been reported in dichloromethane but not toluene. Is the solvent
enhancement observed with 3 general for other Lewis acids used
for nitrone cycloaddition reactions or is it confined to this chiral
dirhodium(II,III) carboxamidate? To answer this question we
have investigated the effect of solvent with Maruoka’s μ-oxo bis-
Ti(IV) oxide (9). Reactions in dichloromethane and toluene
result in a similar degree of selectivity, and no rate enhancement
was observed (Table 4). In his earlier communication, Maruoka
investigated the reactions of N-benzyl-R-phenylnitrones, but not
N,R-diphenylnitrones, and he reported formation of only the 3,4-
endo isomer in high yield and enantioselectivity.9d However,
enantioselectivity and diastereoselectivity in reactions with acro-
lein are lower with N-phenyl substituted nitrones, and with
methacrolein regioselectivity is very low. Maruoka also pointed
out that a sterically encumbered N-substituent on the nitrone was
essential for high stereocontrol with his μ-oxo bis-Ti(IV) oxide
catalyst, and N-diphenylmethyl-substituted nitrones were used in
place of the N-benzyl analogues when these cycloaddition
reactions were carried out with methacrolein.9c Interestingly, in
reactions with methacrolein catalyzed by Maruoka’s μ-oxo bis-
Ti(IV) oxide catalyst a higher % ee was obtained for the 3,5-endo
product than for its 3,4-endo regioisomer, which is the reverse of
what is observed with [Rh2(5S,R-MenPy)4]SbF6 (3). However,
no similar solvent effect was observed.
Table 4. μ-Oxo-bis-Ti(IV) Oxide (9) Catalyzed 1,3-dipolar
Cycloaddition reactionsa
yield
ee%
enal
Ar
solvent t (h) (%)b 15:16c drc (15-endo/16-endo)d
14a Ph
14a Ph
14b Ph
14b Ph
CH2Cl2
PhMe
1
1
2
2
2
3
95 99:1
95 99:1
86:14
86:14
87/-
82/-
CH2Cl2
PhMe
88 56:44 >99:1
89 52:48 >99:1
70 82:18 >99:1
92 40:60 >99:1
81/98
80/98
77/95
67/95
14b 4-MeOPh CH2Cl2
14b 4-CF3Ph CH2Cl2
Solvent enhancement of reaction selectivities was further
investigated in two other Lewis acid catalyzed reactions: the
hetero-DielsꢀAlder reaction17 and the carbonyl-ene reaction.18
Hetero-DielsꢀAlder reactions between trans-1-methoxy-3-
(trimethylsilyloxy)-1,3-butadiene (the Danishefsky diene, 17)
and aldehydes have been successfully carried out with Rh(II)Rh-
(III) catalysts.4a,5 p-Nitrobenzaldehyde is chosen as the substrate
for the investigation of the solvent influence (Table 5). With 5
a The reactions were carried out with 0.5 mmol nitrone, 0.8 mmol enal,
and 0.05 mmol μ-oxo bis-Ti(IV) oxide; reactions with 14a were carried
out at ꢀ20 °C; reactions with 14b were carried out at 0 °C.
b Isolated yield. c Determined by 1H NMR spectroscopy; complete
diastereoselectivity for endo product was observed for cycloadditions
with 14b. d Determined by 1H NMR after formation of diastereomeric
imines with (R)-(þ)-R-methylbenzylamine or by HPLC (OD-H
column) after borohydride reduction.
Table 3. [Rh2(5S,R-MenPy)4]SbF6 (3)-Catalyzed Asymmetric Nitrone Cycloaddition Reactions with Methacrolein (11a) and
trans-Crotonaldehyde (11b)
entry
enal
Ar
solvent
time (h)
yielda (%)
12:13b
ee% (12-endo/13-endo)c
1
2
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
4-MeOPh
4-MeOPh
Ph
CH2Cl2
PhMe
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
5
5
40
91
42
95
96
82
96
91
96
78d
70:30
97:3
96/63
99/ꢀ
94/66
98/56
97/60
99/72
96/62
98/54
95/52
95e/ꢀ
3
5
34:66
79:21
89:11
53:47
30:70
79:21
70:30
>99:1
4
Ph
5
5
4-MePh
4-ClPh
4-CF3Ph
2-furyl
4
6
20
20
20
20
24
7
8
9
2-naphthyl
10
Ph
1
a Isolated yield. b Determined by H NMR spectroscopy; complete diastereoselectivities for endo products were observed for these cycloaddition
reactions. c Determined by 1H NMR after formation of diastereomeric imines with (R)-(þ)-R-methylbenzylamine. d Borohydride reduction was carried
e
out in this case; Isolated yield of the product after reduction. Determined by high-performance liquid chromatography (HPLC) analysis (OD-H
column).
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Table 5. Solvent Influence on the Asymmetric Hetero-DielsꢀAlder Reaction of p-Nitrobenzaldehyde with the Danishefsky Diene
Catalyzed by Rh(II)Rh(III) Catalystsa
catalyst
solvent
t (h)
yield (%)b
ee%c
[Rh2(5S,R-MenPy)4]SbF6 (3)
[Rh2(5S,R-MenPy)4]SbF6 (3)
[Rh2(5S,S-MenPy)4]SbF6 (4)
[Rh2(5S,S-MenPy)4]SbF6 (4)
CH2Cl2
PhMe
24
24
24
2
68
52
86
97
83
91
91
94
CH2Cl2
PhMe
a The reactions were performed with 0.5 mmol p-nitrobenzaldehyde, 0.6 mmol Danishefsky diene, 0.025 mmol catalyst, 0.1 mmol 2,6-di-t-BuPyr, and
300 mg of 4 Å MS in 1.5 mL solvent at room temperature. b Isolated yield. c Determined by HPLC (OD-H column); The absolute configuration of the
product was determined to be S by comparison with literature.4d,f
Table 6. Solvent Influence on the Asymmetric Carbonyl-ene
Reaction of Ethyl Glyoxylate with r-Methylstyrene Catalyzed
by Rh(II)Rh(III) Catalystsa
for reactions that take place at the more remote R,β-carbons of
unsaturated aldehydes.
’ CONCLUSIONS
We have discovered solvent-dependent rate and selectivity
enhancements with chiral cationic dirhodium(II,III) carboxami-
dates in nitrone dipolar cycloaddition reactions, hetero-DielsꢀAlder
reactions, and carbonyl-ene reactions. With 1,3-dipolar
cycloaddition reactions of nitrones with R,β-unsaturated alde-
hydes use of Rh2(5S,R-MenPy)4SbF6 (3) in toluene provided
rate enhancements as well as significant improvements in regios-
electivities and enantioselectivities over those obtained in di-
chloromethane. Rate and enantioselectivity enhancements were
obtained with [Rh2(5S,S-MenPy)4]SbF6 (4) in hetero-Dielsꢀ
Alder and carbonyl-ene reactions over those obtained in dichlor-
omethane. These enhancements are attributed to diminished or
absent association of toluene with the catalyst which lessens the
relative importance of the uncatalyzed background reaction.
Different coordination angles for aldehyde association with
rhodium in the different solvent environments may also con-
tribute to enhanced enantiocontrol in toluene. Further research
is underway to uncover the generality of these rate and selectivity
improvements.
catalyst
solvent
yield (%)b
ee%c
[Rh2(5S,R-MenPy)4]SbF6 (3)
[Rh2(5S,R-MenPy)4]SbF6 (3)
[Rh2(5S,S-MenPy)4]SbF6 (4)
[Rh2(5S,S-MenPy)4]SbF6 (4)
a The reactions were performed with 2.5 mmol R-methylstyrene,
0.5 mmol ethyl glyoxylate, 0.025 mmol catalyst, 0.1 mmol 2,6-di-t-BuPyr,
and 300 mg of 4 Å MS in 1.0 mL solvent at 0 °C. b Isolated yield.
c Determined by HPLC (AD-H column). The absolute configuration of
the product was determined to be S by comparison with literature.19d
CH2Cl2
PhMe
60
37
52
90
38
70
63
94
CH2Cl2
PhMe
The carbonyl-ene reaction is one of the most convenient
methods for carbonꢀcarbon bond formations, and the resulting
homoallylic alcohols can be further transformed into more
functionalized products by taking advantage of the car-
bonꢀcarbon double bond.18 Substantial effort has been directed
toward developing catalytic enantioselective variants with Lewis
acid catalysis.18,19 In our survey of Lewis acid catalyzed reactions
with Rh(II)/Rh(III) carboxamidates the carbonyl-ene reaction
of ethyl glyoxylate with R-methylstyrene using 5 mol % [Rh2(5S,
R-MenPy)4]SbF6 (3) in dichloromethane at 0 °C was found to
produce the homoallylic alcohol 18 in 60% yield and with 38% ee
(Table 6). Similar to the results from the hetero-DielsꢀAlder
reactions (Table 5), changing the solvent to toluene resulted into
a lower yield but higher ee. However, with [Rh2(5S,S-Men-
Py)4]SbF6 (4) under the same conditions, the reaction in
dichloromethane produced 18 in 52% yield and 63% ee, and
using toluene as the reaction solvent improved the yield to 90%
and the enantiomeric excess to 94%. From this limited study,
[Rh2(5S,S-MenPy)4]SbF6 (4) exhibits higher rates and selectiv-
ities for reactions occurring directly with a carbonyl group,
whereas [Rh2(5S,R-MenPy)4]SbF6 (3) gives higher selectivities
’ EXPERIMENTAL SECTION
Materials. Rh2(5S,R-MenPy)4,5 Rh2(5S-IPPy)4,20 trans-1-methoxy-
3-(trimethylsilyloxy)-1,3-butadiene,21 and nitrones22 were prepared
according to the literature procedures. Acrolein, trans-crotonaldehyde,
methacrolein, ethyl glyoxylate, and R-methylstyrene were obtained from
commercial sources and freshly distilled before use. Solvents were used
after distillation. All the other chemicals were obtained from commercial
sources and used without further purification.
Synthesis of (S)-[(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl]
2-Oxopyrrolidine-5-carboxylate. A flask was charged with L-pyr-
oglutamic acid (1.29 g, 10 mmol), (þ)-menthol (1.56 g, 10 mmol), and
4-dimethylaminopyridine (0.24 g, 2 mmol) and purged with nitrogen.
Dry CH2Cl2 (20 mL) was added, and the mixture was cooled to 0 °C. A
solution of N,N0-dicyclohexylcarbodiimide (2.27 g, 11 mmol) in CH2Cl2
(20 mL) was added to the reaction mixture over a period of 30 min, and
then the reaction mixture was stirred at room temperature for 20 h. The
white solid was removed by filtration. The solution was evaporated to
dryness under reduced pressure, and the residue was dissolved in ethyl
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Journal of the American Chemical Society
ARTICLE
acetate (100 mL) and washed with 1 M HCl (20 mL), 5% NaHCO3
(20 mL), and brine (20 mL). The organic layer was dried over
anhydrous MgSO4, and the solvent was removed under reduced
pressure. The resulting solid was purified by column chromatography
(ethyl acetate:hexane = 5:2) to yield a white solid product (2.30 g, 86%
yield). 1H NMR (CDCl3, 500 MHz): δ 6.44 (s, 1H, NH), 4.74 (dt, 1H,
J = 4.4, 10.9 Hz), 4.23 (dd, 1H, J = 5.4, 8.6 Hz), 2.55ꢀ2.45 (m, 1H),
2.40ꢀ2.32 (comp, 2H), 2.22ꢀ2.16 (m, 1H), 2.02ꢀ1.96 (m, 1H),
1.85ꢀ1.80 (m, 1H), 1.72ꢀ1.66 (comp, 2H), 1.55ꢀ1.39 (comp, 2H),
1.10ꢀ0.85 (comp, 9H), 0.76 (d, 3H, J = 7.0 Hz). 13C NMR (CDCl3, 125
MHz): δ 177.68, 171.47, 75.73, 55.61, 46.87, 40.66, 34.05, 31.33, 29.28,
mixture was then dissolved in THF (5.0 mL) and treated with NaBH4
(56.7 mg, 1.50 mmol) at room temperature for 30 min. The mixture was
then poured into a saturated solution of NH4Cl (aq) (20 mL) and
extracted with ethyl acetate (3 ꢁ 15 mL). The combined organic layer
was dried with anhydrous Na2SO4 and concentrated. The resulting oil
was purified by flash chromatography (hexane:ethyl acetate = 2:1) to
obtain the final product that was then analyzed for enantiomeric excess
by HPLC analysis.
General Procedure for the Asymmetric 1,3-Dipolar Cy-
cloaddition Reactions of Nitrones with r,β-Unsaturated
Aldehydes Catalyzed by the μ-Oxo Bis-Ti(IV) Oxide
Catalyst.9c,d To a stirred mixture of Ag2O (12 mg, 0.05 mmol) in
CH2Cl2 (0.5 mL) was added 1.0 M hexane solution of ClTi(Oi-Pr)3
(100 μL, 0.10 mmol) at room temperature. After stirring for 5 h at room
temperature, a solution of (S)-BINOL (28.6 mg, 0.10 mmol) in CH2Cl2
(0.7 mL) was added to the mixture, which was then stirred for 2 h at
room temperature to afford the dark orange solution of chiral μ-oxo bis-
Ti(IV) oxide. The solution was cooled to ꢀ20 °C (or to 0 °C
for methacrolein). To the catalyst solution was added acrolein (54 μL,
0.80 mmol) and was followed by the nitrone in CH2Cl2 (1.3 mL). The
resulting mixture was stirred at ꢀ20 °C until the completion of the
reaction. The workup was identical to the procedure described for
[Rh2(5S,R-MenPy)4]SbF6.
26.26, 24.97, 23.21, 21.89, 20.71, 16.08. [R]20 = þ59.3 (c 0.96,
D
CH2Cl2). HRMS (ESI) calculated for C15H26NO3, m/z 268.1907
([M þ H]þ); found, m/z 268.1912.
Synthesis of Dirhodium(II) Tetrakis{(S)-[(1S,2R,5S)-2-isopro-
pyl-5-methyl-cyclohexyl] 2-Oxopyrrolidine-5-carboxylate},
Rh2(5S,S-MenPy)4. The previously reported standard procedure
was followed.20 Dirhodium(II) acetate (330 mg, 0.747 mmol), (S)-
[(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl] 2-oxopyrrolidine-5-car-
boxylate (2.1 g, 7.85 mmol) and chlorobenzene (20 mL) were mixed
in a flask fitted with Soxhlet extraction apparatus into which was placed a
cellulose thimble containing 2:1 Na2CO3/sand. The resulting mixture
was heated at vigorous reflux for 20 h, at which time HPLC analysis
(Microsorb-MV 100ꢀ5 CN column, 2% MeCN in MeOH, flow
1.0 mL/min) showed the reaction to be complete. After cooling to
room temperature, the solvent was removed under reduced pressure,
and the resulting blue oil was chromatographed on BAKERBOND-CN
silica (40 μm Prep LC packing) eluting with MeOH. The first brown
band was the excess ligand, and then using 1% MeCN in MeOH to wash
off the desired catalyst band which had a red color. The solvent of the
collected catalyst band was removed under reduced pressure and the
resulting blue solid material was heated at 120 °C under high vacuum for
2 h. The catalyst was finally obtained as a green powder (696 mg, 73%
yield). 1H NMR (CDCl3, 500 MHz): δ 4.67ꢀ4.59 (comp, 4H),
4.28ꢀ4.24 (comp, 2H), 3.94ꢀ3.89 (comp, 2H), 2.85ꢀ0.71 (comp,
88H). 13C NMR (CDCl3, 125 MHz): δ 188.58, 187.44, 174.40, 173.89,
74.44, 74.13, 66.41, 47.29, 47.24, 41.56, 40.88, 34.55, 34.26, 31.49, 31.39,
31.32, 26.68, 26.60, 26.22, 23.54, 23.36, 22.18, 20.77, 20.72, 16.29. 16.13
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, characterization of all new compounds, and computational
details. This material is free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mdoyle3@umd.edu
’ ACKNOWLEDGMENT
(missing 4 carbons due to overlapping signals). [R]20 = ꢀ113.85 (c
D
Financial support from the National Institutes of Health (GM
46503) is gratefully acknowledged. We thank Prof. Herman O.
Sintim, as well as Maxim Ratnikov for assistance with DFT
calculations.
0.130, i-PrOH). HRMS (ESI) calculated for C60H97N4O12Rh2, m/z
1271.5208 ([M þ H]þ); found, m/z 1271.5207.
General Procedure for the Asymmetric 1,3-Dipolar Cy-
cloaddition Reactions of Nitrones with r,β-Unsaturated
Aldehydes Catalyzed by [Rh2(5S,R-MenPy)4]SbF6. A 10-mL
Schlenk flask charged with a magnetic stir bar and 4-Å Molecular Sieves
(300 mg) was placed under high vacuum and heated by Bunsen burner
to dryness. After cooling to room temperature, Rh2(5S,R-MenPy)4
(33.8 mg, 0.026 mmol), 2,6-di-tert-butylpyridine (22 μL, 0.10 mmol),
and toluene (1.0 mL) were added under the flow of N2. The resulting
green solution was stirred for 10 min before NOSbF6 (6.6 mg, 0.025
mmol) was added. The solution was allowed to stir for additional 30 min,
during which time the color gradually turned from green to deep red.
Freshly distilled acrolein (54 μL, 0.80 mmol) was added via a micro-
syringe to the flask that was then placed in an ice bath, and the mixture
was stirred for 10 min. The nitrone (0.50 mmol) in toluene (1.5 mL) was
added dropwise (gentle heating aids dissolution of nitrones in toluene;
N-phenyl-R-(4-chlorophenyl)nitrone and N-phenyl-R-(4-trifluoro-
methylphenyl)nitrone were added as solids because of their relatively
poor solubility, followed by the addition of 1.5 mL toluene). The
solution was stirred at 0 °C until the completion of the reaction. The
entire reaction mixture was then loaded on a short silica column and
eluted with CH2Cl2 to remove the catalyst and 4-Å molecular sieves. The
collected solution was concentrated, and regioselectivity and diastereo-
selectivity were determined by 1H NMR analyses. The aldehyde product
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