Rh2(R -TPCP)4-catalyzed enantioselective [3+2]-cycloaddition between nitrones and vinyldiazoacetates

Article abstract of DOI:10.1021/ja4069003

Rhodium-catalyzed reaction of vinyldiazoacetates with nitrones results in a formal [3+2]-cycloaddition to generate 2,5-dihydroisoxazoles with high levels of asymmetric induction. The cascade reaction begins with a vinylogous addition event, followed by an iminium addition ring-closure/hydride migration/alkene isomerization cascade. Dirhodium tetrakis(triarylcyclopropanecarboxylates) are the optimum catalysts for this process.

Full text of DOI:10.1021/ja4069003

Communication
pubs.acs.org/JACS
Rh (R‑TPCP) ‑Catalyzed Enantioselective [3+2]-Cycloaddition
2
4
between Nitrones and Vinyldiazoacetates
Changming Qin and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
*
S Supporting Information
6a−c
reactivity.
Another major breakthrough was the discovery
ABSTRACT: Rhodium-catalyzed reaction of vinyldiazoa-
cetates with nitrones results in a formal [3+2]-cyclo-
addition to generate 2,5-dihydroisoxazoles with high levels
of asymmetric induction. The cascade reaction begins with
a vinylogous addition event, followed by an iminium
addition ring-closure/hydride migration/alkene isomer-
ization cascade. Dirhodium tetrakis(triarylcyclo-
propanecarboxylates) are the optimum catalysts for this
process.
that chiral bulky dirhodium catalysts could enhance vinylogous
reactivity, especially if the trapping nucleophile is also sterically
6d
demanding.
Scheme 2 illustrates an application of a bulky dirhodium
8b
catalyst for the enantioselective functionalization of indoles.
Scheme 2. Vinylogous Reactivity of Rhodium Carbenoids
onor/acceptor-substituted rhodium carbenoids are useful
D
intermediates for a wide range of stereoselective synthetic
1
,2
methods. Among the donor/acceptor carbenoids studied,
vinylcarbenoids have emerged as particularly useful reagents. In
3
addition to the standard carbenoid reactions, the vinyl-
carbenoids can participate in a diverse array of more elaborate
4
transformations, such as the tandem cyclopropanation/Cope
4
a
rearrangement, the combined C−H functionalization/Cope
4
b
rearrangement, and the ylide formation/[2,3]-sigmatropic
rearrangement/oxy-Cope rearrangement/ene reaction cascade
sequence. Furthermore, vinylcarbenoids possess electrophilic
character at the vinylogous position, a feature recognized by us
The favored vinylogous reactivity was considered to be caused
by the carbenoid being forced by the bulky catalyst Rh (S-
4
c
2
biTISP) to react in the s-trans configuration, which blocks
2
normal carbenoid reactivity and favors vinylogous reactivity.
The cis-olefin configuration of 3 is consistent with attack
occurring on the s-trans configuration of the carbenoid followed
by protonation of the vinylrhodium with retention of
configuration.
during our early studies on donor/acceptor carbenoids
5
(Scheme 1).
Scheme 1. General Reactivity of Vinylcarbenoids
In this paper, we describe a novel [3+2]-annulation between
terminally substituted vinyldiazoacetates and nitrones (eq 1).
These studies demonstrate the important role of bulky
dirhodium catalysts and contrast with previous studies on the
reaction of vinylcarbenoids with nitrones, which resulted in
In the early studies, the vinylogous reactivity of rhodium
carbenoids was observed only when the vinylogous position of
the carbenoid is unsubstituted. Other factors found to favor
7a
5
[3+3]-cycloadditions.
At the onset of this project, we expected that a bulky catalyst
would be required to enhance the vinylogous reactivity.
Therefore, we decided to explore the effect of different
dirhodium catalysts (Figure 1) on the reaction of (E)-tert-
vinylogous reactivity were electron-deficient dirhodium cata-
lysts, polar solvents, and bulky esters on the carbenoid.
6
7
Recently, we and others have studied this unusual vinylogous
reactivity in a variety of transformations, using a combination of
experimental and theoretical studies to gain a better under-
8
standing of this chemistry. We have found that dimolybdenum,
Received: July 6, 2013
diruthenium, and especially silver catalysts enhance vinylogous
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4069003 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Table 2. Design and Synthesis of New Dirhodium Catalysts
a
entry
catalyst
Ar1
Ph
Ar2
yield (%)
1
2
Rh (R-NPCP)4
2-Nap
58
65
47
68
2
Rh (R-BPCP)4
Ph
4-PhC H -
2
6
4
b
3
Rh (S-BNPCP)4
2-Nap
Ph
4-BrC H -
6 4
2
4
Rh (R-TPCP)4
Ph
2
a
Yield refers to the isolated yield in the ligand exchange to form the
b
catalyst. Prepared using Rh (S-DOSP) as catalyst. The configuration
2
4
of Rh (S-BNPCP) is opposite to that shown.
2
4
Figure 1. Structure of chiral dirhodium catalysts.
Table 3. New Dirhodium Catalysts Evaluation
butyl 2-diazo-5-phenylpent-4-enoate 4a and nitrone 5a. When
sterically less crowded Rh (OOct) , Rh (S-DOSP) , Rh (S-
2
4
2
4
2
PTAD) , and Rh (S-PTTL) were used as catalysts, diazo
4
2
4
compound 4a was not fully decomposed, and the nitrone
starting material was recovered. In contrast, the sterically bulky
catalyst Rh (S-biTISP) afforded the formal [3+2]-cycloadduct
2
2
entry
catalyst
x
yield (%)
ee (%)
6
in 36% yield and 82% ee (Table 1, entry 5). The yield and
1
2
Rh (R-NPCP)4
1
1
1
1
2
59
58
52
67
77
94
94
94
98
98
2
Rh (R-BPCP)4
2
Table 1. Initial Optimization Results
a
3
Rh (S-BNPCP)4
2
4
Rh (R-TPCP)4
2
5
Rh (R-TPCP)4
2
a
Product stereochemistry is opposite to that shown.
the highest level of enantioselectivity (98% ee, entry 4). The
isolated yield was further improved when the catalyst loading
was 2 mol % (entry 5). These studies once again underscore
the importance of bulky dirhodium catalysts in vinylogous
reactivity of vinylcarbenoids.
Once we had developed the optimized conditions, we
examined the scope of the formal [3+2]-cycloaddition (Table
a
entry
catalyst
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Rh (S-DOSP)
pentane
pentane
pentane
pentane
pentane
pentane
DCM
<5
<5
<5
<5
36
64
61
30
2
4
Rh (S-PTAD)
2
4
Rh (S-PTTL)
2
4
Rh (OOct)
2
4
Rh (S-biTISP)
82
94
92
95
94
2
2
4
). The size of the ester group did not have a significant impact
Rh (S-BTPCP)
2
4
on the level of enantioselectivity, but the yield was highest with
the tert-butyl ester (compare ent-6 with 7a−c). Modification of
the length of a linear alkyl at the vinyl terminus of the
vinyldiazoacetate 4 had little effect on the asymmetric induction
Rh (S-BTPCP)
2
4
Rh (S-BTPCP)
acetone
hexane
2
4
Rh (S-BTPCP)
61
1
2
4
a
Isolated yield, <5% means 6 was not observed from H NMR analysis
(
7d and 7e, both 94% ee), but a branched alkyl substituent
such as an isopropyl group eroded the enantioselectivity (7f,
6% ee). The reaction can be conducted with a variety of
of the crude mixture prior to flash chromatography.
6
enantioselectivity were further improved using a more sterically
nitrones, as illustrated by the range of products 7g−o formed.
The level of asymmetric induction was high for the aryl
nitrones (85−97% ee) but much lower for the cinnamyl nitrone
(7l, 42% ee).
9
congested catalyst, Rh (S-BTPCP)4 (Table 1, entry 6).
2
Further optimization studies indicated pentane was the optimal
solvent for the reaction.
Considering the dramatic difference in outcome of the
Rh (S-BTPCP) -catalyzed reactions compared to those with
the other dirhodium catalysts, we decided to prepare and
evaluate a series of triarylcyclopropanecarboxylate catalysts
To confirm the absolute configuration of the products, ent-6
was transformed to the bicyclic product 8 in 66% yield (dr =
1.5/1, Scheme 3), which was confirmed by single-crystal X-ray
analysis (see Supporting Information). The configuration of the
other 2,5-dihydroisoxazole products is tentitively assigned by
analogy.
A catalytic cycle is proposed to rationalize the mechanism of
the formal [3+2]-cycloaddition (Scheme 4). It begins with
rhodium-catalyzed decomposition of substituted vinyldiazoace-
tate, followed by vinylogous attack on the rhodium vinyl-
carbenoid 9 to form intermediate 10. Cyclization by an
iminium addition then generates a new carbenoid 11, which
undergoes a 1,3-hydride abstraction to form the zwitterion 12
followed by a proton transfer to form 13. An alternative
2
4
(
Table 2). These catalysts were prepared in three steps in good
yields (47−68%), using a highly enantioselective cyclo-
propanation as the key step.
9a
The newly designed dirhodium carboxylate catalysts were
evaluated in the standard reaction (Table 3). All of these
catalysts provided the desired product with high levels of
enantioselectivity (94−98% ee). Increasing the size of the aryl
that has either gem- or cis-relationship to the carboxylate did not
enhance the enantioselectivity. The unsubstituted triphenylcy-
clopropanecarboxylate catalyst Rh (R-TPCP) gave ent-6 with
2
4
B
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Journal of the American Chemical Society
Communication
Table 4. Substrate Scope
Scheme 4. Proposed Catalytic Cycle
Scheme 5. [3+2]- vs [3+3]-Cycloaddition Models
Scheme 3. Derivatization via Reduction/Cyclization Process
possibility would be 1,2-hydride migration followed by alkene
isomerization. The formation of adduct 11 by a concerted
cycloaddition reaction between nitrone and s-trans-(E)-methyl
cis orientated to the iminium is formed, which has the correct
geometry to cyclize to the formal [3+3]-annulation product 17.
In our system, however, the bulky rhodium-catalyzed
decomposition of terminally substituted vinyldiazoacetates
provides a preference for further reaction to occur on the s-
trans carbenoid 9. Vinylogous attack by nitrone affords a vinyl
rhodium 10, trans orientated to the iminium, which can only
undergo the [3+2]-annulation.
In conclusion, we have demonstrated a highly asymmetric
vinylogous addition of nitrones to terminally substituted vinyl
diazoacetates for the synthesis of 2,5-dihydroisoxazole deriva-
tives. This study once again underscores the unusual reactivity
of the triarylcyclopropanecarboxylate dirhodium catalysts.
Application of the cyclopropanecarboxylate dirhodium catalysts
in new asymmetric transformations is ongoing.
10
vinylcarbenoid intermediate 9 is considered to be unlikely
because of the well-known high reactivity of rhodium carbenoid
intermediates, though such mechanisms do occur with the
11
more stable Fisher carbene complexes.
A tentative model that rationalizes the observed product
divergence from the previously reported [3+3]-annulation is
descried in Scheme 5. In the previous formal [3+3]-
cycloaddition, rhodium-catalyzed decomposition of β-silylox-
yvinyldiazoacetate 14 afforded a preferred s-cis carbenoid 15 to
minimize the steric interaction between the internal OTBS
group and the “wall” of rhodium catalyst. Upon vinylogous
attack by nitrone, a configurationally stable vinyl rhodium 16,
C
dx.doi.org/10.1021/ja4069003 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(
9) (a) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.;
ASSOCIATED CONTENT
■
Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 19198.
b) Qin, C.; Davies, H. M. L. Org. Lett. 2013, 15, 310.
*
S
Supporting Information
(
Full experimental details and X-ray crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) In a previous study on the rhodium-catalyzed reaction of methyl
7
d
2-diazo-3-butenoate with nitrones, the reaction was considered to be
initiated by a concerted or stepwise [3+2]-cycloaddition between the
nitrone and the rhodium vinylcarbene, drawn in the s-cis conformation.
It is more likely that this reaction involves vinylogous attack of the
nitrone on the s-trans conformation of the rhodium vinylcarbene,
analogous to the mechanism proposed herein.
AUTHOR INFORMATION
■
Corresponding Author
(11) Wulff, W. D.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.;
hmdavie@emory.edu
Miller, R. A.; Murray, C. K.; Yang, D. C. J. Am. Chem. Soc. 1990, 112,
Notes
3642.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based on work supported by the National
Institutes of Health (GM099142). We thank Dr. John Bacsa
and Marika Wieliczko, Emory University, for the X-ray
crystallographic structural determination.
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■
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