Asymmetric Rh(II)-catalyzed cyclopropanation of alkenes with diacceptor diazo compounds: P -methoxyphenyl ketone as a general stereoselectivity controlling group

Article abstract of DOI:10.1021/ja201237j

Different diacceptor diazo compounds bearing an α-PMP-ketone group were found to be effective carbene precursors for the highly stereoselective Rh₂(S-TCPTTL)₄-catalyzed cyclopropanation of alkenes (EWG = NO₂, CN, CO₂Me). The resulting products were readily transformed into a variety of biologically relevant enantiopure molecules, such as cyclopropane α- and β-amino acid derivatives. Different mechanistic studies carried out led to a rationale for the high diastereo- and enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally, the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented.

Full text of DOI:10.1021/ja201237j

ARTICLE
pubs.acs.org/JACS
Asymmetric Rh(II)-Catalyzed Cyclopropanation of Alkenes with
Diacceptor Diazo Compounds: p-Methoxyphenyl Ketone as a General
Stereoselectivity Controlling Group
Vincent N. G. Lindsay, Cyril Nicolas, and Andrꢀe B. Charette*
Department of Chemistry, Universitꢀe de Montrꢀeal, P.O. Box 6128, Station Downtown, Montrꢀeal, Quꢀebec, Canada H3C 3J7
S Supporting Information
b
ABSTRACT: Different diacceptor diazo compounds bearing
an R-PMP-ketone group were found to be effective carbene
precursors for the highly stereoselective Rh2(S-TCPTTL)4-
catalyzed cyclopropanation of alkenes (EWG = NO2, CN,
CO2Me). The resulting products were readily transformed into
a variety of biologically relevant enantiopure molecules, such as
cyclopropane R- and β-amino acid derivatives. Different mechan-
istic studies carried out led to a rationale for the highdiastereo- and
enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally,
the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented.
’ INTRODUCTION
Cyclopropanes are important subunits commonly found in
natural or synthetic products of pharmaceutical interest.1 In
particular, cyclopropanes bearing geminal electron-withdrawing
groups are unique synthetic intermediates due in part to their
inherent electrophilicity.2 Numerous reports have been devoted
to their use in asymmetric synthesis, mainly involving nucleo-
philic substitution reactions,3 formal cycloadditions,4 or various
functional group manipulations with complete preservation of
the stereochemical information when enantioenriched cyclopro-
panes are used. In this regard, the direct enantioselective forma-
tion of such motifs using a chiral metal-carbene intermediate
bearing two electron-withdrawing groups would, thus, be highly
desirable due to its retrosynthetic efficiency. However, success in
this field of research has been very limited.5,6 In the past few
years, Zhang et al. have demonstrated that chiral Co(II)-por-
phyrins complexes are efficient catalysts for such transformation
through “carbene radical” intermediates, and their efficiency with
acceptorꢀacceptor carbene equivalents has been recognized.6d,e
Recently, we have reported a highly enantioselective cyclopro-
panation of alkenes using R-nitro diazoacetophenones and
Hashimoto’s complex Rh2(S-TCPTTL)4 (eq 1).5a These studies
suggest that the p-methoxyphenyl ketone (PMP-ketone) moiety
of the substrate is playing a dual role, affording good diaster-
eocontrol through a stereoelectronic effect in the transition state,
and good enantiocontrol through π-stacking interactions with
the catalyst’s tetrachlorophthaloyl groups.
on the catalytic asymmetric cyclopropanation of alkenes with
R-EWG-diazoacetophenones, where EWG = NO2, CN, CO2Me,
giving access to a wide variety of highly enantioenriched cyclo-
propane derivatives. In this work, we demonstrate the unique
role of the PMP-ketone moiety acting as a highly effective
enantio- and diastereoselectivity-control group. The ketone can
be transformed into a more versatile PMP-ester following the
asymmetric cyclopropanation, permitting further functionaliza-
tion of these building blocks. The resulting cyclopropanes could
readily be obtained in enantiopure form via recrystallization and
used as substrates in diverse transformations, providing access to
valuable chiral synthons such as cyclopropane R- and β-amino
acid derivatives, tetrahydrofurans or R-chiral amines. Consider-
ing the efficiency of Rh2(S-TCPTTL)4 in many catalytic asymmetric
Considering this model, which suggests that the nitro group is
not crucial in the stereocontrol of the reaction, we were intrigued
to verify our hypothesis by replacing it with other electron-
withdrawing groups and evaluate the reactivity of these newly
designed carbene precursors. Herein we report our recent results
Received: February 16, 2011
Published: May 06, 2011
r
2011 American Chemical Society
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Journal of the American Chemical Society
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transformations, such as CꢀH amination reactions,7 1,3-dipo-
lar cycloadditions,8 and aziridinations using metal-nitrene
intermediates,9 the understanding of its stereoinduction me-
chanism in our system is of broad applicability in future catalyst
design.10
Table 1. Influence of the Carbonyl’s Nature on the Diaster-
eoselectivity of the Rh2(OAc)4-Catalyzed Cyclopropanation
of r-Carbonyl Nitrodiazomethanes with Styrene11d,12e
’ RESULTS AND DISCUSSION
Stereocontrol in Rh(II)-Catalyzed Cyclopropanation Reac-
tions. Over the past few years, our group has studied the
reactivity of a variety of metal-carbene precursors bearing two
electron-withdrawing substituents in stereoselective cyclopropa-
nation reactions.5,11 In the Rh(II)-catalyzed reaction between
terminal alkenes and gem-dicarbonyl diazo compounds, empiri-
cal evidence suggests that the diastereoselectivity level of the
cyclopropanation not only is a function of the steric properties of
the two carbonyl groups but also is highly influenced by their
relative Lewis basicity.5b This has been attributed to a stereo-
electronic effect in the transition state, first proposed by Doyle
et al., where the carbonyl’s lone pair donates electron density to
the LUMO of the approaching alkene, stabilizing the transition
state and directing the alkene’s substituent position in the final
product.12 The most basic and/or sterically hindered of the two
carbonyl functions is, therefore, denoted the trans-directing
group. For example, the cyclopropanation of alkenes with
R-amido diazoacetates or with R-cyano diazoacetamides leads
to the cyclopropane derivative where the amide is located trans to
the alkene’s substituent, due to the increased basicity/steric
demand of the amide group relative to an ester or a nitrile
functionality.5b,c Nitrocarbene equivalents bearing an R-carbonyl
group are known to somewhat behave in an analogous manner.
Indeed, the nature of the carbonyl in those compounds is found
to have a profound influence on the diastereoselectivity outcome
of the reaction (Table 1).11d,12e
entry
R1
yield (%)a
dr (cis:trans)b
1
2
3
4
5
6
OEt
Oi-Pr
Me
80
78
77
55
74
71
12:88
25:75
22:78
80:20
84:16
88:12
t-Bu
Ph
PMPc
a Isolated yield of combined diastereomers. b Determined by 1H NMR
analysis of the crude mixture. c PMP = p-MeO-C6H4.
In the case of an R-nitroester or of unhindered R-nitroketones,
the major product of the Rh2(OAc)4-catalyzed cyclopropanation
with styrene is the trans diastereomer, the more basic nitro
moiety acting here as the trans-directing group (entries 1ꢀ3). As
the steric demand and/or the basicity of the carbonyl group
becomes more important, as is the case with a t-Bu-ketone or an
acetophenone derivative, the cis:trans ratio is increased and the
cis-cyclopropane becomes the major diastereomer (entries 4ꢀ6).
This is a clear demonstration of the competition between the two
proximal electron-withdrawing groups (nitro and carbonyl) for
their trans-directing ability (Figure 1).
The red dotted lines in the transition states of Figure 1
illustrate the stereoelectronic effect discussed earlier, where
electron density is transferred from the trans-directing group’s
lone pair to the alkene’s developing positive charge. To maximize
this stabilizing interaction and reduce the distance between the
alkene LUMO and the basic oxygen, the alkene’s substituent
(here, Ph) will be oriented trans to this basic group in order to
minimize unfavorable steric constraints (between Ph and the
basic group’s oxygen).12b This proposed electronic effect is
consistent with the tendency observed in Table 1, but one must
expect the steric nature of R1 to also impact on the cis:trans ratio.
In order to ultimately prove the presence of this effect, one
must be able to dissociate the steric and electronic factors of
the transition state. To do so, we envisioned that R-nitro
diazoacetophenone derivatives could meet this requirement
(Table 2). Indeed, modifying the X or Y group on the arylketone
moiety should greatly impact on the carbonyl’s oxygen basicity
Figure 1. Competitive [2 þ 1] cycloaddition transition states showing
Doyle’s stereoelectronic effect in the cyclopropanation with R-carbonyl
nitrodiazomethanes.
without affecting the steric hindrance at the reaction center. As
depicted in Table 2 and Figure 2, the electronic nature of the
arylketone has an important effect on the diastereoselectivity
level of the reaction, either in the racemic or enantioselective
version of the reaction (conditions A or B).
The general tendency observed in diastereomeric ratios is as
expected from Doyle’s stereoelectronic model. Electron-with-
drawing substituents such as NO2 or CF3 at the para-position
afford lower ratios due to a weaker basicity of the carbonyl
group, whereas electron-rich substituents such as OMe or
NMe2 furnish improved diastereocontrol, with the steric hin-
drance around the reaction center being similar in each case.
Note that the trend in Lewis basicities is shown in Table 2 and
Figure 2a as the carbonyl’s IR wavenumber of the correspond-
ing acetophenone, data furnishing unambiguous insight onto
the polarization of the CdO bond. A Hammett correla-
tion between the diastereoselectivity and the substituents
constants also demonstrates the influence of the electronic
nature of the aromatic ring (Figure 2b). Furthermore, as noted
in our previous work for the Rh2(S-TCPTTL)4-catalyzed
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Table 2. Effect of the Arylketone’s Electronics on the
Stereoselectivity with r-Nitro Diazoacetophenones
Figure 2. (a) Relationship between the carbonyl’s basicity and the
diastereoselectivity obtained. (b) Hammett correlation between the
diastereoselectivity and the substituents constants.
νCO
(cmꢀ1
)
dr
ee
a
entry diazo
X
Y
conditions (cis:trans)b (cis, %)c
1
2
3
4
5
6
7
1a CF3
1b NO2
1c Cl
H
H
H
H
1695
1693
1685
1684
1676
1674
1657
A
B
A
B
A
B
A
B
A
B
A
B
Ad
B
4.0:1
2.3:1
4.0:1
12:1
4.7:1
24:1
4.9:1
24:1
5.7:1
49:1
7.0:1
49:1
71
91
92
94
96
93
96
1d
1e
1f
H
H
OMe
H
OMe
Figure 3. Possible conformations of metal-carbenes derived from
R-diazocarbonyl compounds.
1g NMe2
H
83:1
conformation very similar to the case of Figure 3b.13a,d This
carbene thus receives only little electronic influence of the
substituents on the aromatic ring (inductive effects only), and
the global impact on the carbene’s electrophilicity is expected to
be negligible. Moreover, in entry 5, where the meta-substituent
effect of diazo 1e should be minimal on the carbene but
significant in increasing the aromatic ring’s HOMO, we observe
an increase in enantioselectivity, in accordance with our catalyst-
substrate π-stacking hypothesis.
Stereoselective Rh2(S-TCPTTL)4-Catalyzed Cyclopropana-
tions. Since the aromatic ketone controls the diastereoselectivity
and the enantioselectivity in our model, we wished to explore the
reactivity of different R-EWG-diazoacetophenones in asymmetric
cyclopropanation. The results displayed in Table 3 show that
substituting the nitro group with a nitrile or a methyl ester also
leads to high stereocontrol, under very similar conditions. In fact,
complete reoptimization of the solvent and catalyst’s structure
provided Rh2(S-TCPTTL)4 as catalyst in Et2O as the optimal
conditions for the three transformations. In the case of substrate
1f or 1h, the diazo compound could be added in one portion in
the solid state under air, without the requirement of syringe-
pump techniques, while a slow addition was performed (over
15 min) in the case of diazo 1i. The optimal temperature had to
a νCO of the corresponding acetophenone. b Determined by H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase. d No desired product was observed under these conditions.
1
transformation, the enantioselectivity also increases with the
electron-donating character of the substituents. It is note-
worthy that this latter observation is proposed to be attributed
to a different effect dependent on the catalyst structure, i.e., the
improved favorable catalystꢀsubstrate π-stacking interactions
for electron-rich arylketones.5a
For both effects, one could argue that the increased stereo-
control can be due to a lower electrophilicity of the carbene,
leading to a later transition state. DFT calculations and X-ray
structures of metal-carbenes bearing at least one carbonyl group
fail to support this hypothesis.13 Indeed, the carbonyl group in
these systems is believed to be out of the plane of the metal-carbene
in the transition state, offering minimal orbital overlap between
the RhdC and the CdO bonds (Figure 3b).
The two situations illustrated in Figure 3 represent extreme
cases, where the in-plane conformations (j = 0° or 180°) are
uphill, while the out-of-plane conformations (j = 90° or ꢀ90°)
represent the ground state of the metal-carbene species. It is
believed, through DFT calculations, that the carbene reacts in a
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Table 3. Influence of the Nature of the Electron-Withdrawing Group (EWG) in the Rh2(S-TCPTTL)4-Catalyzed Cyclopropa-
nation of R-EWG-Diazoacetophenones with Styrene
entry
substrate
EWG
temp (° C)
yield (%)a
dr (A:B)b
ee (%)c
1
2
3
4
1f
1h
1i
1j
NO2
CN
ꢀ50
ꢀ35
ꢀ40
ꢀ50
81
98
60
9
98:2
95:5
93
84
88
98
CO2Me
99:1
Ph
>95:5
a Isolated yield of combined diastereomers. b Determined by 1H NMR analysis of the crude mixture. c ee of major diastereomer determined by SFC on
chiral stationary phase.
Figure 5. Representation of the all-up reactive conformation of Rh2(S-
TCPTTL)4.5a
of the catalyst’s structure, we have reasoned that in our system,
the carbene-formation step of the reaction with 1f is occurring on
the more accessible top face, i.e., on the side of the tetrachlor-
ophthaloyl groups.5a
Figure 4. X-ray structures of cyclopropanation products from the
reaction of styrenes with R-EWG-diazoacetophenones (EWG = NO2
(left), CN (middle), CO2Me (right)).
We sought to further explore the potential of such structural
asymmetry by studying the effect of achiral Lewis basic additives.
Indeed, assuming that this symmetry is kept in solution, such
additives could selectively block one side of the rhodium dimer
and/or impact on its electronical properties, ultimately affecting
the global stereoinduction of the reaction. Whereas weaker Lewis
bases such as sulfides, phosphonamides, or ureas had no sig-
nificant effect on the reaction’s outcome in the case of R-nitro
diazoacetophenones (Table 4, entries 3ꢀ5), pyridine derivatives
and, more precisely, DMAP had a beneficial impact on the
enantioselectivity level obtained (entry 1 vs 10).14a It should
be noted that this effect was not observed at higher temperatures
(i.e., 0 °C), indicating the reversible nature of such axial com-
plexation on the rhodium dimer.14b The pink complex immedi-
ately formed by addition of 1 mol % DMAP (1 equiv relative to
the catalyst), a more electron-rich catalyst, proved to be consider-
ably less active than Rh2(S-TCPTTL)4. Indeed, the reaction was
significantly slower, and lowering the catalyst loading to less than
1 mol % furnished only partial conversions. Using larger amounts
of DMAP led to a decreasedyield, with similar enantiomeric excess
(95% ee). This observed effect on enantioselectivity might be due
to a selective complexation of DMAP on the less enantiodiscri-
minative side of the rhodium dimer. Since we have already
concluded that the carbene formation occurs exclusively on the
top face, a second rationalization for the increment of enantioin-
duction should be taken into account (Figure 6).
be slightly increased for substrates 1h and 1i to ꢀ35 and ꢀ40 °C,
respectively, due to their lower reactivity. As expected, X-ray
analysis of the resulting cyclopropanic derivatives shows that the
PMP-ketone is trans to the alkene’s substituent in all cases in the
major product (Figure 4), and the absolute configuration of the
major enantiomer was found to be the same for the three classes
of cyclopropanic derivatives. It is noteworthy that the introduc-
tion of other EWGs at the R position of the substrate, such as
sulfones, phosphonates or ketones, led only to minimal amounts
of the desired product in the Rh2(S-TCPTTL)4-catalyzed pro-
cess. Also, replacing the EWG with a hydrogen atom afforded
good yields of the product but only poor stereocontrol (75%
yield, 60:40 dr, 45% ee), whereas the use of a R-alkyl-diazoketone
analog (EWG = Bu) led only to undesired β-hydride elimination.
Interestingly, donorꢀacceptor diazo 1j (EWG = Ph) afforded
the cyclopropane in poor yield but in outstanding stereocontrol,
confirming the importance of the PMP-ketone as the stereo-
selectivity controlling group (entry 4).
In previous work, we have provided significant evidence that
Rh2(S-TCPTTL)4, the optimal catalyst for these transforma-
tions, is reacting through an “all-up” conformation (also desig-
nated “chiral crown”).5a In such a system, the two axial sites
where the metal carbene can be formed (top face or bottom face)
are considerably different in space, leading to distinct enantioin-
duction mechanisms (Figure 5). Through experimental studies
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Table 4. Influence of Achiral Additives in the Rh2(S-TCPTTL)4-Catalyzed Cyclopropanation of R-EWG-Diazoacetophenones
with Styrene
entry
substrate
EWG
additive
dr (A:B)a
ee (%)b
1
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1h
1h
1i
1i
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
none
98:2
98:2
98:2
98:2
98:2
ND
93
93
93
93
93
78
94
94
94
95
84
72
88
79
2
DMSO
HMPA
DMPU
PhSMe
pyrazine
PBu3
3
4
5
6
7
98:2
97:3
97:3
97:3
95:5
95:5
99:1
99:1
8
NMI
9
pyridine
DMAP
none
10
11c
12c
13d
14d
CN
DMAP
none
CO2Me
CO2Me
DMAP
a Determined by 1H NMR analysis of the crude mixture. b ee of major diastereomer determined by SFC on chiral stationary phase. c Reaction perfomed
at ꢀ35 °C. d Reaction perfomed at ꢀ40 °C.
Figure 6. Rationalization for the increment of enantioselectivity with DMAP as catalytic additive.
As the carbene formation does not occur on the bottom face,
complexes such as B or C are considered to be unreactive in this
system. The DMAP-catalyst complex D can be formed either
directly from A or through the intermediacy of B and C. This
reactive complex may give rise to a later transition-state for the
asynchronous 2 þ 1 cycloaddition step of the mechanism as
compared to the native catalyst A, due to a lower electrophilicity
of the resulting carbene, globally leading to an improved
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Table 5. Scope of Alkenes with r-Nitro Diazoacetophe-
nones: Effect of DMAP as Catalytic Additive
Table 6. Scope of Alkenes with r-Cyano
Diazoacetophenones
entry
R1
R2 product yield (%)a dr (trans:cis)b ee (trans, %)c
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
Me
H
3a
3b
3c
3d
3e
3f
92
94
90
92
88
99
75
97
82
95:5
97:3
99:1
95:5
98:2
96:4
81:19
84:16
97:3
84
88
91
79
81
73
73
75
94
yield
dr (cis:
trans)b
ee
(cis, %)c
4-Cl-C6H4
4-O2N-C6H4
3-MeO-C6H4
2-Cl-C6H4
1-naphthyl
n-Bu
entry
1
R1
R2 product method (%)a
Ph
H
2f
Ad
Ae
Af
Bf
Af
Bf
Af
Bf
Af
Bf
A
81
80
80
78
76
81
65
70
91
84
88
85
74
87
75
75
85
61
54
68
60
68
53
54
36
81
78
88
5
98:2
98:2
98:2
97:3
98:2
97:3
95:5
91:9
98:2
97:3
98:2
96:4
99:1
99:1
98:2
96:4
97:3
94:6
95:5
96:4
95:5
96:4
96:4
97:3
98:2
98:2
96:4
99:1
54:46
93
93
92.9 ( 0.1
3g
3h
3i
95.0 ( 0.2
Ph
2
3
4
5
6
7
8
9
4-Me-C6H4
4-t-Bu-C6H4
4-Cl-C6H4
H
H
H
H
H
H
H
2h
2i
92.4 ( 0.5
9d OBz
94.2 ( 0.2
a Isolated yield of combined diastereomers. b Determined by 1H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase (ee of major diastereoisomer). d 10 equiv alkene was used.
87.8 ( 0.5
89.1 ( 0.2
2j
93.2 ( 0.1
95.0 ( 0.5
92
These results convinced us to undertake a two-method scope
of alkenes with R-nitro diazoacetophenones (Table 5). Method
A furnishes the product with decreased enantioselectivity but
uses 10 times less catalyst than method B, which in turn provides
better enantiomeric excesses. The results summarized in Table 5
demonstrate that both methods gave rise to similar trends in term
of enantioselectivity obtained, although method B generally
furnished a 2ꢀ3% ee increase, showing that this DMAP effect
is not dependent on the structure of the alkene. This selectivity
increment roughly represents a non-negligible 0.15ꢀ0.22 kcal/
mol increase in energy difference between the competing dia-
stereomeric transition states in play. The yield and diastereos-
electivity observed generally remain similar for both methods.
Styrene derivatives bearing substituents at the ortho, meta, or
para position are all tolerated under the reaction conditions. It is
noteworthy that styrenes bearing electron-donating groups (e.g.,
OMe) at the para position only gave rise to ring-opened or
unidentified products, due to the strong electrophilic nature of
such cyclopropane bearing two electron-withdrawing groups.
Importantly, R-methylstyrene reacted smoothly under our con-
ditions with excellent stereoselectivity, giving access to the
corresponding highly strained cis-cyclopropane R-amino acid
derivative (entry 14). Unfortunately, alkyl-substituted alkenes
did not provide the corresponding cyclopropane in useful yields
(entry 15), and dienes afforded only Cope-rearranged achiral
products.
4-F-C6H4
2k
2l
B
95
4-O2N-C6H4
4-F3C-C6H4
3-MeO-C6H4
3-O2N-C6H4
A
95
B
97
2m
2n
A
91
B
Ad
95
92
B
94
H
H
2o
2p
Ad
A
91
10 3-F3C-C6H4
11 2-Cl-C6H4
12 2-F-C6H4
13 1-naphthyl
94
B
Ag
96
H
H
H
2q
2r
2s
92
B
94
A
93
B
Ad
94
95
B
94
14 Ph
Me 2t
2u
Ah
A
98
15 n-Bu
H
42
a Isolated yield of combined diastereomers. b Determined by 1H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase (ee of major diastereoisomer). d 1 mol % of catalyst was used. e 0.5
mol % of catalyst was used. f Reaction was performed three times
and results are reported as the mean values, with standard deviation
for the ee. g Reaction perfomed at ꢀ40 °C. h Results shown are after
recrystallization.
R-Cyano diazoacetophenone 1h is also a good substrate for
the asymmetric cyclopropanation with a wide variety of olefins
(Table 6). This method usually provides very high yields of the
corresponding cyclopropanes in excellent diastereoselectivity
and good enantioselectivity, using only 2 equiv of the alkene.
Various styrene derivatives, aliphatic alkenes, and enol esters are
tolerated as substrates, with a considerable degree of variability with
respect to the electronic natureof the double bond. Itis noteworthy
that dienes and electron-rich styrene derivatives were also reactive
in this process but afforded only poor stereocontrol.
enantioinduction.14a It is interesting that using DMAP as additive
with our two analogous substrates 1h and 1i had an opposite
effect, leading to a drastic decrease in enantioselectivity
(entries 11ꢀ14). These results illustrate the complexity of
this system, and the fact that other factors, such as structural
and/or conformational changes of the catalyst, might also be
involved in this DMAP effect.
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The β-keto R-diazoester analogue 1i furnishes the corre-
sponding gem-dicarbonyl cyclopropanes in excellent stereoselec-
tivity, although generally with lower yields (Table 7). The
reaction offers optimal stereoselectivity at ꢀ40 °C with the
use of 1 mol % of Rh2(S-TCPTTL)4 as catalyst, affording
the highest selectivities with electron-poor styrene derivatives
(entries 2ꢀ4).
Applications of the Enantioenriched Cyclopropanes. With
these methods in hand, a wide variety of cyclopropane derivatives
bearing an R-PMP ketone group can be efficiently synthesized in
high stereoselectivity. Much to our delight, this ketone moiety was
found to control not only the selectivity but also the crystallinity of
the final product. Indeed, in almost all cases, the major diastereoi-
somer was a white crystalline solid, while the minor isomer was a
colorless oil. As shown in Table 8, the three methods could be
applied on a 2ꢀ3 g scale (10ꢀ14 mmol) with comparable results
of yield, dr and ee, and the products’ crystallinity permitted access
to enantiopure material when desired, in good overall yields.
The PMP group on the ketone directs the regioselectivity of a
subsequent BaeyerꢀVilliger oxidation to form activated esters
(Table 9). The optimized procedure proceeded smoothly in the
case of R-nitro acetophenone 2f5a and R-cyano acetophenone
3a, affording high yields of the corresponding esters, with total
retention of the stereochemical information. The β-ketoester 4a
proved to be significantly less reactive, and only 18% of the
corresponding gem-diester could be obtained in these conditions,
while the use of stronger peroxidation agents provoked decom-
position of the acid-sensitive starting material. This observation is
presumably due to the increased steric demand and decreased
electron-withdrawing character of the methyl ester as compared
with a nitro group or a nitrile. The regioselectivity of the transforma-
tion was found to be complete in all three cases.
Table 7. Scope of Alkenes with β-Keto r-Diazoester
entry
R
product yield (%)a dr (cis:trans)b ee (cis, %)c
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
60
31
60
10
70
54
33
52
99:1
99:1
99:1
99:1
99:1
99:1
>97:3
99:1
88
94
93
94
84
86
90
85
4-Cl-C6H4
4-F3C-C6H4
4-O2N-C6H4
4-Me-C6H4
3-Me-C6H4
2-Cl-C6H4
1-naphthyl
4g
4h
Schemes 1ꢀ3 furnish a global picture of the array of transfor-
mations that can be applied to the three types of cyclopropane
derivatives possessing geminal electron-withdrawing groups ob-
tained from our method. In the case of the R-nitro and R-cyano
a Isolated yield of combined diastereomers. b Determined by 1H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase.
Table 8. Cyclopropanation on Larger Scale to Access Enantiopure Material
entry
substrate
EWG
yield (%)a,b
dr (A:B)a,c
ee (%)a,d
1
1f
1h
1i
NO2
82 (72)
93 (66)
57 (41)
98:2 (>99:1)
95:5 (>99:1)
99:1 (>99:1)
93 (>99)
83 (98)
2e
3f
CN
CO2Me
87 (>99)
a Results in parentheses are after recrystallization. b Isolated yield of combined diastereomers. c Determined by 1H NMR analysis of the crude mixture.
d ee of major diastereomer determined by SFC on chiral stationary phase. e Reaction perfomed at ꢀ35 °C. f Reaction perfomed at ꢀ40 °C.
Table 9. BaeyerꢀVilliger Oxidation of the Resulting r-EWG Acetophenones
entry
EWG
substrate
product
yield (%)a
dr (A:B)b,c
ee (%)d,e
15a
2
NO2
2f
5a
5b
5c
82
89
18
>99:1 (>99:1)
>99:1 (>99:1)
>99:1 (>99:1)
>99 (>99)
98 (98)
CN
3a
4a
3
CO2Me
>99 (>99)
a Isolated yield of combined diastereomers. b Determined by 1H NMR analysis of the crude mixture. c dr of starting material in parentheses. d ee of major
diastereomer determined by SFC on chiral stationary phase. e ee of starting material in parentheses.
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Scheme 1. Applications of r-Nitro PMP-Ester 5a
Scheme 2. Applications of r-Cyano PMP-Ester 5b
Scheme 3. Applications of β-Ketoester 4a
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PMP-esters 5a and 5b, chemoselective reductions of either of the
geminal functionalities can be efficiently performed (Schemes 1
and 2). The PMP-ester is cleanly reduced to the primary alcohols
6 and 10 using NaBH4 at 0 °C with retention of the stereo-
chemical information. In the case of R-nitroester 5a, selective
reduction of the nitro group is achieved using In/HCl, and the
resulting R-aminoester is shown to be a suitable precursor of the
are grateful to Francine Bꢀelanger-Gariꢀepy and CYLView for
X-ray analysis.
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’ CONCLUSION
In summary, on the basis of our experimental evidence concern-
ing the stereoinduction mechanism in Rh2(S-TCPTTL)4-catalyzed
cyclopropanations, we have designed and developed a highly
stereoselective cyclopropanation of alkenes with R-EWG-diazoa-
cetophenones, where EWG = NO2, CN, or CO2Me. The methods
feature the use of a PMP-ketone as diastereo- and enantioselectivity
control group, which can be transformed to activated esters
following the cyclopropanation for further functionalization. The
efficient access to enantiopure material is demonstrated, along with
a myriad of transformations for which these cyclopropanes are
useful substrates. For instance, the synthesis of highly enantioen-
riched cyclopropane R- and β-amino acid derivatives, R-chiral
amines, and tetrahydrofurans was successfully achieved.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, com-
b
pound characterization data, and NMR spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
andre.charette@umontreal.ca
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’ ACKNOWLEDGMENT
This work was supported by the Natural Science and En-
gineering Research Council of Canada (NSERC), the Canada
Foundation for Innovation, the Canada Research Chair Program,
the Centre in Green Chemistry and Catalysis (CGCC) and the
Universitꢀe de Montrꢀeal. V.N.G.L. is grateful to NSERC (PGS D)
and the Universitꢀe de Montrꢀeal for postgraduate fellowships. We
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