Experimental evidence for the all-up reactive conformation of chiral rhodium(II) carboxylate catalysts: Enantioselective synthesis of cis-cyclopropane α-amino acids

Article abstract of DOI:10.1021/ja9044955

(Chemical Equation Presented) Useful empirical insights onto the enantioinduction process of chiral Rh(II)-carboxylate catalysts are described in the first catalytic asymmetric cyclopropanation of alkenes with α-nitro diazoacetophenones. X-ray, solution N

Full text of DOI:10.1021/ja9044955

Published on Web 10/27/2009
Experimental Evidence for the All-Up Reactive Conformation of Chiral
Rhodium(II) Carboxylate Catalysts: Enantioselective Synthesis of
cis-Cyclopropane r-Amino Acids
Vincent N. G. Lindsay, Wei Lin, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown, Montre´al,
Que´bec, Canada H3C 3J7
Received June 3, 2009; E-mail: andre.charette@umontreal.ca
Chiral Rh(II)-carboxylate catalysts have found widespread use
in the field of metal carbene transformations, including asymmetric
cyclopropanation reactions.1 Though several enantioselective trans-
formations have been developed to date, little evidence is known
on how the chirality is projected near the reaction center by the
chiral carboxylates. Davies et al. have suggested that four main
possible symmetries have to be considered, from which only two
possess equivalent catalyst faces (Figure 1, C2 and D2).2 It has been
postulated that catalysts having two different carbene-formation sites
should not be effective in inducing enantioselectivity, since the more
kinetically active and accessible face is apparently achiral (C1 and
C4).2b
However, Fox et al. recently contradicted this concept by
reporting the highly efficient asymmetric cyclopropanation of
alkenes with R-alkyl-R-diazoesters using such a catalyst, where DFT
Figure 1. Possible symmetries adopted by rhodium(II) carboxylates.
Scheme 1. Synthesis of cis-Cyclopropane R-Amino Acids
calculations demonstrated that the all-up conformation of the
catalyst plays a prominent role in these reactions.3 Herein, we report
our concomitant work that demonstrates strong experimental
evidence in favor of the all-up symmetry as the catalyst’s reactive
conformation in an unprecedented stereoselective cyclopropanation
of alkenes with R-nitro diazoacetophenones. Moreover, the products
issued from such a process were shown to be valuable intermediates
for the expedient synthesis of optically active cis-cyclopropane
R-amino acids.
Recently, our group has been interested in the synthesis of trans-
cyclopropane R-amino acids via the enantioselective addition of
nitrocarbene equivalents to olefins,4,5 due to the high potential of
such building blocks in drug discovery.6 To obtain the correspond-
ing cis compound enantioselectively through a similar process, we
envisioned that R-nitro diazoacetophenones would be ideal candi-
dates to suit this goal (Scheme 1).7,8 Subsequent Baeyer-Villiger
oxidation, nitro reduction, and hydrolysis afford an efficient route
to optically active cis-cyclopropane R-amino acids.9
In our early investigations, we identified Hashimoto’s amino acid
derived catalysts 2a-d and 3a-e, also used in Fox’s methodology,3
as promising complexes in our system. We rapidly observed that
these two classes of catalysts had very distinct behaviors in terms
of enantioinduction, although the only apparent difference is the
replacement of aromatic hydrogen atoms by halogen atoms (Table
1).10
Apparently, these three families of catalysts possess similar
conformations in the solid state, i.e. all-up (Figure 1), a symmetry
that has long been overlooked as non-operative for enantioinduction.2
This arrangement of ligands displays two different axial sites on
the Rh dimer, suggesting a competition of two mechanisms in the
carbene formation step of the reaction and, thus possibly, different
stereoinductions in the subsequent [2+1] cycloaddition. Of the four
possible symmetries displayed in Figure 1, this is the only one where
one axial site is completely shielded from the ligand’s amino acid
side chains R, i.e. the more accessible top face. For us, the fact
that catalysts 3a-d show similar stereoselectivities regardless of
this group suggests that this is their reactive conformation, while
non-halogenated complexes 2a-d might be less rigid in solution.
As highlighted in Figure 2, 3a-e could benefit from halogen-
bonding interactions to rigidify their all-up conformation, a known
bonding event for this specific type of N-protective group.12
Additionally, VT NMR experiments made on 3d demonstrated the
rigid nature of such halogenated complexes in solution.11b
Indeed, modifying the ligand’s amino acid side chain had little
influence on the stereoselectivity for chlorinated catalysts (entries
5-8), in contrast with their N-phthaloyl analogues (entries 1-4).
We postulated these observations were due to different reactive
conformations in solution. To understand these results better, we
first resolved X-ray crystal structures of representative complexes
2c, 3c, and 3e, unraveling the puzzling symmetries of these catalysts
(Figure 2).11
1
To confirm our hypothesis, we conducted 700 MHz H-13C
heteronuclear NOESY experiments on representative catalysts 2d
and 3d, two complexes that differ only by the replacement of
hydrogens by chlorine atoms (eq 1). Indeed, if the all-up symmetry
is scrambled in solution, i.e. if at least one phthaloyl group is flipped
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J. AM. CHEM. SOC. 2009, 131, 16383–16385 16383

C O M M U N I C A T I O N S
Table 1. Influence of the Catalyst’s Structure
must recognize that the analysis of these spectroscopic results may
be complicated by the different steric and π-stacking properties of
the two complexes.
yielda
(%)
drb
(cis/trans)
eec
(%, cis)
entry
catalyst
1
2
3
4
5
6
7
8
2a
2b
2c
2d
3a
3b
3c
3d
3e
3d
3d
55
56
76
80
81
72
82
81
89
70
80
53:47
55:45
72:28
33:67
97:3
94:6
98:2
98:2
96:4
22
43
16
2
92
91
91
93
80
92
93
Table 2. Scope of the Cyclopropanation
entry
alkene
yielda
(%)
drb
(cis/trans)
eec
(%, cis)
9
10d
11e
99:1
98:2
1
2
3
4
5
6
PhCHdCH2 (4a)
80
75
65
91
88
74
75
85
68
68
54
81
88
98:2
97:3
94:6
98:2
98:2
99:1
98:2
97:3
96:4
96:4
97:3
98:2
99:1
93
92
87
93
92
95
91
92
94
92
93
95
98
4-MePhCHdCH2 (4b)
4-tBuPhCHdCH2 (4c)
4-ClPhCHdCH2 (4d)
4-FPhCHdCH2 (4e)
4-NO2PhCHdCH2 (4f)
4-CF3PhCHdCH2 (4g)
3-MeOPhCHdCH2 (4h)
3-CF3PhCHdCH2 (4i)
2-ClPhCHdCH2 (4j)
2-FPhCHdCH2 (4k)
1-naphthylCHdCH2 (4l)
PhC(Me))CH2 (4m)
a Isolated yield of combined diastereomers. Determined by H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase. d 1 equiv of 4a and 4 equiv of 1a were used. e 0.1 mol % of
catalyst was used.
b
1
7
8d
9
10e
11
12d
13f
b
a Isolated yield of combined diastereomers. Determined by H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase. d 1 mol % 3d was used. e Reaction was run at -40 °C. f Results
after recrystallization.
1
Scheme 2. Derivatization of Compound 5a
Figure 2. X-ray structure of catalysts 3c, 3e, and 2c: side view (left
column), top view and halogen-bonding distances in Å (right column); axial
solvents were omitted for clarity.
Our reaction was shown to be efficient for a wide range of styrene
derivatives, using only 0.1 mol % of catalyst 3d (Table 2). It should
be noted that diazoketones bearing an R-EWG such as 1a are
usually well-known to afford low enantioselectivities in Rh(II)-
catalyzed cyclopropanation reactions.13
Gratifyingly, the reaction could be carried out on a multigram
scale with similar efficiency, and the high crystalline nature of these
compounds permitted isolation of 5a as a single stereoisomer in
good overall yield (Scheme 2). After extensive optimization,
appropriate Baeyer-Villiger oxidation conditions provided the
corresponding cis-R-nitroester in 82% isolated yield. Furthermore,
down, one should be able to see an interaction between the side
chain’s protons and the phthaloyl’s aromatic carbons of the adjacent
ligand. In the case of chlorinated complex 3d (X ) Cl), no
interaction is observed with the N-tetrachlorophthaloyl aromatic
carbons, between either the t-Bu protons or the R-proton, suggesting
that the all-up conformation is maintained in solution. In contrast,
all aliphatic protons of complex 2d (X ) H) display a clear
interaction with four N-phthaloyl carbons, highlighting the flexible
nature of these non-halogenated catalysts in solution. However, one
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C O M M U N I C A T I O N S
Table 3. Effect of the Arylketone’s Electronics on Stereoselectivity
calculations made on non-halogenated analogues. Additional in-
sights into the mechanism of related reactions will be reported in
due course.
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada & Co., Boehringer Ingelheim
(Canada) Ltd., and the Universite´ de Montre´al. We are grateful to
F. Be´langer-Garie´py and CYLView for X-ray analysis; J. Tannous
for SFC analysis; and M. T. Phan Viet and S. Bilodeau for NMR
analysis. V.N.G.L. is grateful to NSERC (PGS D) and the Universite´
de Montre´al for postgraduate fellowships.
entry
(diazo)
yielda
(%)
drb
(cis/trans)
eec
(%, cis)
X
Y
1 (1b)
2 (1c)
3 (1a)
4 (1d)
5 (1e)
CF3
Cl
OMe
NMe2
H
H
H
H
H
80
82
81
38
72
70:30
96:4
98:2
99:1
98:2
71
92
93
96
96
OMe
Supporting Information Available: X-ray crystal structure of 3d,
experimental procedure for the preparation of compounds, and spec-
troscopic data. This material is available free of charge via the Internet
at http://pubs.acs.org.
a Isolated yield of combined diastereomers. Determined by H NMR
analysis of the crude mixture. c Determined by SFC on chiral stationary
phase.
b
1
reduction of the nitro group using In/HCl in THF furnished the
cis-R-amino ester 6, a C-protected amino acid, with a minimum
loss of stereochemical information.14 Compound 6 can then be
transformed into the known N-Boc amino acid 7 through elemental
steps.2a
References
(1) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
2003, 103, 977. (b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998. (c) Davies, H. M. L.;
Antoulinakis, E. G. Org. React. (N.Y.) 2001, 57, 1.
To gain further insight into the enantioinduction process of our
reaction, we synthesized five electronically different R-nitro diaz-
oacetophenones 1a-1e and submitted them to our reaction condi-
tions. As depicted in Table 3, electron-deficient analogue 1b
furnished decreased levels of enantioselectivity compared to our
model substrate 1a, while the more electron-rich diazo 1d afforded
superior asymmetric induction. Our working hypothesis is that the
tetrachlorophthaloyl moieties of the ellipsoidal chiral pocket induced
by the all-up symmetry of catalyst 3d (top face) could permit
π-stacking interactions with the arylketone group on the substrate,
fixing it in a conformation where one of the prochiral faces of the
carbene is blocked. With these chlorinated groups being electron-
deficient, such interactions would be more important for electron-
rich arylketones, thus providing enhanced enantioselectivity for
substrates like 1d or 1e. In addition, we noticed during our
optimization that running the reaction in aromatic solvents like
benzene led to a drastic decrease in enantioselectivity (20% ee
compared to 87% ee in Et2O), suggesting the presence of π-stacking
as a key element in the enantiodiscriminating step of the reaction.
It is noteworthy that the diastereoselectivity was also found to
be dependent on the arylketone’s electronics, confirming the
presence of Doyle’s stereoelectronic effect in our system.1b,15
Indeed, R-nitro diazoacetophenones can permit dissociation of steric
and electronic factors in the transition state, since the X group is
away from the reaction center but still strongly influences the
ketone’s oxygen basicity.
(2) (a) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J.
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(d) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313.
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nation of diazo compounds bearing two electron-withdrawing groups, see:
(a) Marcoux, D.; Charette, A. B. Angew. Chem., Int. Ed. 2008, 47, 10155.
(b) Marcoux, D.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2009, 131,
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Wurz, R.; Charette, A. B. J. Mol. Catal. A 2003, 196, 83.
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amino acids, see ref 2a and: Zhu, S.; Perman, J. A.; Zhang, X. P. Angew.
Chem., Int. Ed. 2008, 47, 8460.
(10) For examples of other types of asymmetric reactions using these catalysts,
see: (a) Anada, M.; Kitagaki, S.; Hashimoto, S. Heterocycles 2000, 52,
875. (b) Hashimoto, S.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S.
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(11) (a) The structure of 3d was also solved, and it displays a similar
conformation. (b) See Supporting Information for details.
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In summary, we report the first catalytic enantioselective
cyclopropanation of alkenes with R-nitro diazoacetophenones and
the corresponding products obtained from this reaction have been
shown to be practical precursors of optically active cis-cyclopropane
R-amino acids. All our experiments suggest that the halogenated
rhodium carboxylate catalysts used in this process react through
an all-up conformation, which is consistent with Fox’s DFT
JA9044955
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