trans-directing ability of amide groups in cyclopropanation: Application to the asymmetric cyclopropanation of alkenes with diazo reagents bearing two carboxy groups

Article abstract of DOI:10.1002/anie.200804586

(Chemical Equation Presented) Highly stereoselective: A highly enantioselective (up to 97 % ee) and diastereoselective (>30:1 d.r.) Rh ^II-catalyzed cyclopropanation of alkenes using a diazo reagent bearing two carboxy groups is described. This new methodology exploits the powerful trans-directing ability of amides to improve enantiocontrol. Mono- and disubstituted olefins are cyclopropanated in good yields. nttl=N-1,8-naphthoyl- tert-leucine.

Full text of DOI:10.1002/anie.200804586

Angewandte
Chemie
DOI: 10.1002/anie.200804586
Asymmetric Synthesis
trans-Directing Ability of Amide Groups in Cyclopropanation:
Application to the Asymmetric Cyclopropanation of Alkenes with
Diazo Reagents Bearing Two Carboxy Groups**
David Marcoux and Andrꢀ B. Charette*
The cyclopropane unit is an integral component of many
natural products and synthetic drugs.[1] In addition, cyclo-
propanes bearing two geminal electron-withdrawing groups
(for example, 1–3, Scheme 1) are suitable precursors of
R = Me) and [Rh2{4-Br(S-nttl)}4].[12] Currently, the most
efficient and reliable means to generate enantioenriched
cyclopropane 1,1-diesters requires several steps using the
Sharpless dihydroxylation,[13] a Davies cyclopropanation[14] or
a kinetic resolution of the racemate.[7a] Herein, we report a
novel stereoselective synthesis of cyclopropane bearing
geminal dicarboxy groups with excellent enantio- and diaste-
reocontrol utilizing the unprecedented trans-directing ability
of an amide [Eq. (1)].
Scheme 1. Synthesis of cyclopropane derivatives bearing two electron-
withdrawing groups (EWG). RL and RS are large and small R groups,
respectively.
biologically important cyclopropyl a- and b-amino acids.[2,3]
This important class of cyclopropane derivatives is also
known for its unique electrophilicity.[4] For example, cyclo-
propane 1,1-diesters, such as 1, have been shown to undergo
cycloaddition reactions or react with nucleophiles with
complete preservation of the stereochemical information.[5–9]
Among the methods to generate cyclopropane gem-diesters,
transition metal-catalyzed intermolecular cyclopropanation
of readily available alkenes with the corresponding diazo
reagent is an efficient and straightforward strategy
(Scheme 1).
The asymmetric cyclopropanation of electron-rich
alkenes using unsubstituted a-diazoesters in the presence of
Cu, Rh, and Ru complexes bearing chiral ligands involves the
two competing transition state structures A and B (Figure 1).
Many Cu- and Ru-based catalysts are very effective at
blocking one of the two prostereogenic faces (a) of the
metal carbene thus leading to formation of the trans isomer in
high enantiomeric excess. The level of diastereoselectivity
However, to achieve this transformation asymmetrically
remains
a formidable challenge, especially with diazo
reagents bearing two geminal carboxy groups.[10] For example,
direct access to 1 (R = Me) using diazo reagent 5a (R = Me)
gave low enantiocontrol in the cyclopropanation of styrene
(44% ee) using [Rh2(4S-meaz)4].[11] To date, the highest
enantioselectivity for the cyclopropanation of styrene is
82% ee which was obtained using precursor 5b (Scheme 1,
[*] D. Marcoux, Prof. A. B. Charette
Department of Chemistry, Universitꢀ de Montrꢀal
P.O. Box 6128, Station Downtown, Montreal, QC H3C 3J7 (Canada)
Fax: (+1)514-343-5900
E-mail: andre.charette@umontreal.ca
[**] This work was supported by NSERC (Canada), the Canada Research
Chair Program, the Canadian Foundation for Innovation, and the
Universitꢀ de Montrꢀal. D.M. is grateful to NSERC (ES D), Manuvie
Financial and the Universitꢀ de Montrꢀal for postgraduate fellow-
ships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804586.
Figure 1. Transition-state structures for Cu- and Rh-catalyzed cyclo-
propanation.
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usually depends on the bulkiness of the ester group. It has
a-diazoacetate compounds were screened (Table 1,
Figure 2).[18]
[Rh2(S-nttl)4] was the most promising catalyst, giving
75% ee and > 30:1 d.r. when using diazo reagent 6a. The
been postulated that the ester prefers to adopt an out-of-
plane conformation that leads to a stabilization of the
developing partial positive charge on the b carbon of the
alkene, and thus acting as a trans-directing group.[15] The
asymmetric cyclopropanation of a metal carbene derived
from a-diazomalonate is slightly more complex, since the
metal carbene can exist in three different conformations. X-
ray crystal structures of Ru carbenes derived from malo-
nates[16] are consistent with the postulate that the most stable
conformation is that in which both ester groups are out-of-
plane (out–out) relative to the carbene.[17]
Table 1: Optimization of the asymmetric cyclopropanation using a-
amido diazoacetates.
For steric reasons, it is believed that out–out is not the
reactive conformation in the cyclopropanation reaction. It
can also be assumed that the reaction does not proceed
through the in–in conformer (both ester groups in the plane of
the metal carbene), since it should be significantly higher in
energy owing to the conjugation of two electron-withdrawing
substituents, and its resultant inability to stabilize the devel-
oping positive charge.[15]
Entry
Diazo
Reagent
[Rh2(L*)4]
Yield
[%][a]
d.r.[b] cis/
trans
ee [%]
cis[c]
1
6a
6a
6a
6a
6b
6c
6d
6b
6b
[Rh2(S-
ntv)4]
[Rh2(S-
nttl)4]
[Rh2(S-
ptv)4]
[Rh2(S-
pttl)4]
[Rh2(S-
nttl)4]
[Rh2(S-
nttl)4]
[Rh2(S-
nttl)4]
[Rh2(S-
nttl)4]
83
71
69
76
71
35
48
75
79
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
54
75
30
70
95
85
54
96
96
We postulate that in–out will be the preferred conforma-
tion in the transition state, as it provides increased electro-
philicity of the metal carbene, owing to conjugation of the
electron-withdrawing group, and allows stabilization of the
partial positive charge on the alkene. The alkene will attack
the electrophilic carbene by orienting its largest substituent
on the side of the in-plane ester group. However in the case of
a symmetric malonate derivative, the metal carbene a carbon
is not prostereogenic. The design of chiral ligands that will
discriminate between the two transition state structures C and
D is quite challenging even if the catalyst is very effective at
blocking one face of the metal carbene, and it probably
explains why low enantioselectivities have been reported thus
far in cyclopropanations using a-diazomalonates. Our pro-
posed solution for the cyclopropanation of a-diazomalonate
derivatives was to use an a-diazodicarboxy derivative pos-
sessing two carboxy groups with different trans-directing
abilities, to discriminate between C and D, and a chiral
catalyst effective at blocking one prostereogenic face of the
metal carbene. In this context, our initial work aiming to
establish a relative scale of the “trans-directing ability” of
various carboxy derivatives led to the use of a-amido-a-
diazoacetate derivatives. Indeed this class of compounds led
to very high diastereoselectivities when various a-diazo-1,3-
dicarboxy derivatives were treated with rhodium(II) octa-
noate (Scheme 2) with a general trend of trans-directing
ability in cyclopropanation being amide > ketone > ester.
Encouraged by the result obtained using the amide, chiral
rhodium complexes and various structurally related a-amido-
2
3
4
5
6
7
8[d]
9[e]
[Rh2(S-
nttl)4]
1
[a] Yield of isolated product. [b] Determined by H NMR analysis of the
crude mixture. [c] Determined by super fluid chromatography (SFC) on
chiral stationary phase. [d] Reaction carried out in dichloroethane (DCE).
[e] Using diazo compound (3 equiv) and styrene (1 equiv) in DCE.
Figure 2. Ligands (L*H) for [Rh2(L*)4]-catalyzed cyclopropanation.
nttl=N-1,8-naphthoyl-tert-leucine; pttl=N-phthaloyl-tert-leucine;
ntv=N-1,8-naphthoylvaline; ptv=N-phthaloylvaline.
methyl ester of the diazo 6a offered a better enantioselectiv-
ity than that for the ethyl ester 6d (Table 1, entries 2 and 7).
Exchanging the N,N-dimethyl amide for the N-ethyl-N-
methyl amide 6c increased the enantioselectivity to 85% ee
but lowered the yield to 35% (Table 1, entry 6). The use of
pyrrolidine amide 6b led to outstanding enantio- and
diasteroselectivities (95% ee, > 30:1 d.r.) (Table 1, entry 5).
Slightly higher enantioselectivities were obtained if the
Scheme 2. Diastereoselective cyclopropanation of various a-diazo-1,3-
dicarboxy derivatives.
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reaction was run in 1,2-dichloroethane (DCE, Table 1,
entry 8). Similar levels of enantioselectivity and efficiency
were detected if the alkene was used as the limiting reagent
(Table 1, entry 9).
Employing the optimal conditions (6b (three equiva-
lents), [Rh2(S-nttl)4] (1 mol%), alkene (one equivalent, 0.1m
solution in DCE) at room temperature), the scope of the
cyclopropanation was investigated (Table 2). Excellent yields
vinylpyrrole (Table 2, entry 14) also reacted under these
conditions to afford the corresponding cyclopropanes with
high enantiocontrol and good to excellent diastereocontrol. It
should be emphasized that diazo reagents 6a–d are stable for
prolonged periods (> 5 months) at 08C and can be readily
used without additional purification with no adverse effect on
yields or enantioselectivities.
To demonstrate the versatility of these novel cyclopro-
panes, 8b was transformed into the corresponding diester 9
with preservation of the enantiomeric purity of the starting
material (Scheme 3). Furthermore, 8b is sufficiently electro-
philic to give the corresponding linear chain 10 upon reaction
with BuCuLiCN. Alternatively, treatment of 8b with LiAlH4
afforded the corresponding amino alcohol 11. These com-
pounds have been shown to be selective serotonin reuptake
inhibitors.[20]
Table 2: Scope of the Cyclopropanation.
Entry Alkene
Yield [%][a] d.r.[b] cis/
ee [%]
trans
cis[c]
=
1
2
3
4
5
6
7
PhCH CH2 (7a)
79
89
77
81
92
82
51
63
63
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
96
96
97
96
93
96
84
89
95
95
94
=
=
=
4-tBuPhCH CH2 (7e)
4-FPhCH CH2 (7 f)
4-ClPhCH CH2 (7g)
4-MeOPhCH CH2 (7h)
=
=
4-MePhCH CH2 (7i)
indene (7j)
8[d]
9
=
Ph(Me)C CH2(7k)
1-napthylCH CH2 (7 l)
=
10
86
11[e]
24
=
2-BrPhCH CH2 (7m)
[85][f]
78
Scheme 3. Derivatization of cyclopropane 8b.
=
=
12
(E)-PhCH CHCH CH2
(7n)
9:1
87
=
13
14
BuOCH CH2 (7o)
70
9:1
>30:1
89
90
=
Chemoselective reduction of the amide in the presence of
the ester[21] could be carried out using borane–THF com-
plexes, giving the b-aminocarboxy ester 12 containing a
cyclopropane ring.[2b]
In summary, a highly enantio- and diastereoselective
synthesis of cyclopropane 1,1-dicarboxylic derivatives has
been developed. The diazo reagent 6b reacts with a variety of
mono- and disubstituted alkenes in good to excellent yields.
The resulting cyclopropanes are useful scaffolds for further
synthetic transformations. Other applications of this trans-
directing ability of amides in cyclopropanation will be
reported in due course.
N-Me-2-(CH CH2)-pyrrole 31
(7p)
[a] Yield of the isolated cis isomer. [b] Determined by 1H NMR spectros-
copy of the crude mixture. [c] Determined by SFC on chiral stationary
phase. [d] 2 mol% of catalyst was used. [e] Reaction carried out at 508C.
[f] Yield based on recovered starting material.
(92%) and enantioselectivities (93% ee) were observed with
styrene derivatives substituted with electron-donating groups
(Table 2, entry 5). 1,2-Disubstituted Z-alkenes such as indene
7j (Table 2, entry 7) gave slightly lower enantioselectivity. 1,1-
Disubstituted a-methylstyrene 7k gave an excellent 95% ee
(Table 2, entry 9). Sterically hindered 1-naphthyl 7l afforded
the cyclopropane in good yield (86%, Table 2, entry 10)).
Using 2-bromostyrene (7m) dramatically diminished the
yield of isolated product, but a high level of enantiocontrol
was still achieved (24% yield, 94% ee, Table 2, entry 11). The
same substrate was reported to give low enantiocontrol as a
result of the proximity to the double bond of the basic ortho
Br.[19] Aliphatic olefins gave only trace amounts of the
corresponding cyclopropane under these conditions. This
problem could be overcome by the selective cyclopropanation
of the less-hindered double bond of diene 7n followed by
hydrogenation (H2, Pd(OH)2/C, EtOAc, 20 min, 94%) to
afford alkylsubstituted cyclopropane in good yield and
enantiomeric excess (Table 2, entry 12). Enol ether 7o
(Table 2, entry 13) and heteroaromatic olefin N-methyl-2-
Experimental Section
General procedure for the synthesis of enantioenriched cyclopro-
panes (Table 2): DCE (1 mL) and the corresponding alkene
(0.20 mmol, 1.00 equiv) were added to [Rh2(S-nttl)4] (2.9 mg,
0.002 mmol, 1 mol%) in a sealed, argon-purged 10 mL microwave
tube. The diazo compound (0.60 mmol, 3.00 equiv) dissolved in DCE
(1 mL) was added to the reaction mixture over a period of 2 h using a
syringe pump (Chemyx Fusion 200) at room temperature. Following
complete addition, the resulting mixture was stirred for an additional
14 h at room temperature. After complete consumption of the diazo
reagent, the reaction mixture was purified by column chromatog-
raphy on silica gel (gradient elution, 100% hexane to 100% Et2O). In
cases where the rhodium dimer is complexed to the product, the green
mixture was dissolved in DCM and poly(4-vinylpyridine) (50 mg) was
added. The color changed from green to red, and the mixture was then
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filtered through Celite to afford a rhodium-free product after
concentration under reduced pressure.
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Published online: November 26, 2008
Keywords: amino acids · cyclopropanes · directing groups ·
.
homogeneous catalysis · rhodium
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