Silica-immobilized chiral dirhodium(II) catalyst for enantioselective carbenoid reactions

Article abstract of DOI:10.1021/ol403006r

A silica-supported dirhodium(II) tetraprolinate catalyst was synthesized in four steps from l-proline and used in a range of enantioselective transformations of donor/acceptor carbenoids. These include cyclopropenation, cyclopropanation, tandem ylide form

Full text of DOI:10.1021/ol403006r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Silica-Immobilized Chiral Dirhodium(II)
Catalyst for Enantioselective
Carbenoid Reactions
Kathryn M. Chepiga,† Yan Feng,‡ Nicholas A. Brunelli,‡ Christopher W. Jones,*,‡ and
Huw M. L. Davies*,†
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia
30322, United States, and School of Chemical & Biomolecular Engineering, Georgia
Institute of Technology, 311 Ferst Drive, Atlanta, Georgia 30322, United States
hmdavie@emory.edu; cjones@chbe.gatech.edu
Received October 20, 2013
ABSTRACT
A silica-supported dirhodium(II) tetraprolinate catalyst was synthesized in four steps from L-proline and used in a range of enantioselective transformations
of donor/acceptor carbenoids. These include cyclopropenation, cyclopropanation, tandem ylide formation/[2,3] sigmatropic rearrangement, and a variety
of combined CꢀH functionalization/Cope rearrangement reactions. The products of these transformations were obtained in yields and levels
of enantioselectivity comparable to those obtained with its homogeneous counterpart, Rh2(S-DOSP)4. The silica-supported Rh2(S-DOSP)4
derivative was successfully recycled over five reactions.
Dirhodium(II) complexes are versatile and powerful
catalysts for reactions of diazo compounds, catalyzing
a wide array of challenging synthetic transformations
such as cyclopropanations, dipolar cycloadditions, ylide
formations, and CꢀH, NꢀH, OꢀH, and SiꢀH insertion
reactions.1 Rh2(S-DOSP)4 is the most generally effective
chiral dirhodium(II) catalyst for highly enantioselective
transformations involving donor/acceptor carbenoid inter-
mediates. These transformations include cyclopropanation,2
cyclopropenation,3 [3 þ 4] and [3 þ 2] cycloadditions,4
tandem carbonyl ylide formationꢀ1,3-dipolar cycloaddi-
tions,5 tandem ylide formation/[2,3] sigmatropic re-
arrangements,6 CꢀH insertions,4 SiꢀH insertions,7 com-
bined CꢀH functionalization/Cope rearrangements
(CHCR),8a CHCR followed by retro-Cope rearrange-
ments,8b and CHCRꢀelimination reactions.9 Several of
† Emory University.
‡ Georgia Institute of Technology.
(3) Briones, J. F.; Hansen, J.; Hardcastle, K. I.; Autschbach, J.;
Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 17211–17215.
(4) Davies, H. M. L. Elec. Enc. Reag. Org. Synth.; John Wiley & Sons:
2002; Vol. 303, p 640.
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Exposito, C. M. A. J. Org. Chem. 2003, 68, 6153–6159. (b) Hodgson,
D. M.; Labande, A. H.; Pierard, F. Y. T. M. Synlett 2003, 59–62.
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(b) Li, Z.; Boyarskikh, V.; Hansen, J. H.; Autschbach, J.; Musaev, D. G.;
Davies, H. M. L. J. Am. Chem. Soc. 2012, 134, 15497–15504. (c) Zhang,
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Davies, H. M. L.; Walji, A. M. In Rhodium(II)-Stabilized Carbenoids
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H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (h) Padwa, A.
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r
10.1021/ol403006r
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these Rh2(S-DOSP)4-catalyzed transformations have been
used as key steps in the syntheses of natural products.4
Despite its versatility, an effective strategy for recovery
of Rh2(S-DOSP)4 is still lacking. Although considerable
advances have been made in the immobilization of
various dirhodium(II) catalysts,10 efforts to alleviate the
cost associated with Rh2(S-DOSP)4 by synthesis of reusa-
ble heterogeneous derivatives10n have been met with lim-
ited success.10i,k,l,11 Immobilization of Rh2(S-DOSP)4 has
been achieved by using a highly cross-linked polystyrene
resin modified with pyridine linkers.11 This polymer was
effective for immobilizing a wide range of dirhodium
catalysts by the cooperative effect of microencapsulation
and coordination of the pyridyl nitrogen to one of the axial
binding sites of dirhodium, leaving the remaining axial
site uncoordinated and available for catalysis.10k A draw-
back to this immobilization strategy was the high level
of rhodium leaching observed on recycling after the first
reaction. We envisioned overcoming this complication
by covalent attachment of a carboxylate ligand to a solid
support in order to develop a broadly applicable and highly
enantioselective immobilized variant of Rh2(S-DOSP)4
(Figure 1). Herein we present the successful immobiliza-
tion, recycling, and application of covalently immobilized
Rh2(S-DOSP)4 in a broad range of enantioselective
transformations.
that is characteristic of these complexes, the attachment
needed to be designed carefully to limit negative influence
on the enantioselectivity of the resulting catalyst.1a Re-
cently, Hashimoto reported immobilization of another
dirhodium catalyst, Rh2(S-PTTL)4, containing a modi-
fied ligand, which was effective in intramolecular CꢀH
insertion.12 Inspired by these results, immobilization of
Rh2(S-DOSP)4 was achieved by sulfonylation of L-proline
with4-bromobenzenesulfonylchloride toprovide3 in81%
yield followed by Suzuki coupling of 3 with 4-vinylphe-
nylboronic acid (4) to provide N-(arylsulfonyl)prolinate 5
in 96% yield which was subjected to single ligand exchange
with Rh2(S-DOSP)4 (1) to provide 6 in 34% yield along
with a 43% recovery of Rh2(S-DOSP)4 (Scheme 1).
Scheme 1. Synthesis of Rh2(S-DOSP)4 Derivative for
Immobilization
While either polymer or silica supports could be used for
immobilizing this ligand, a silica support was selected as
these systems are typically recoverable in high yield post-
reaction, do not require extensive washing, and often play
a complementary role to polymer-supported catalysts.13
Silica-supported catalysts can allow for faster reaction
rates than conventional polymer resin-bound reagents,
where the reaction is often slowed by the rate of diffusion
through the polymer.14 Also, silica neither swells nor
shrinks in solvents, whereas, polymer-supported catalysts
have the ability to swell, which can dramatically narrow
the scope of solvents that can be used for a reaction.15
Commercial silica (7) was functionalized with styrylethyl-
trimethoxysilane (8) to give 9 followed by capping the
free hydroxyl groups with hexamethyldisilazane (HMDS)
to provide 10. Dirhodium complex 6 was then grafted to
the functionalized silica (10) by AIBN-initiated radical
coupling to provide Rh2(S-DOSP)3(S-silicaSP) (2), a Rh2-
(S-DOSP)4 derivative with three S-DOSP ligands and
one silica-supported sulfonyl prolinate ligand (S-silicaSP)
Figure 1. Chiral dirhodium(II) catalysts used in this study.
We sought to exchange a single ligand of Rh2(S-DOSP)4
with a ligand that could undergo a grafting reaction to a
solid support. As immobilization by covalent attachment
of a resin to a single ligand could break the high symmetry
(10) (a) Bergbreiter, D. E.; Morvant, M.; Chen, B. Tetrahedron Lett.
1991, 32, 2731–2734. (b) Doyle, M. P.; Eismont, M. Y.; Bergbreiter,
D. E.; Gray, H. N. J. Org. Chem. 1992, 57, 6103–6105. (c) Cotton, F. A.
W., R. A., Multiple Bonds Between Metal Atoms, 2nd ed.; Oxford
University Press: Oxford, 1993. (d) Nagayama, S.; Endo, M.; Kobayashi,
S. J. Org. Chem. 1998, 63, 6094–6095. (e) Kobayashi, S.; Nagayama, S.
J. Am. Chem. Soc. 1998, 120, 2985–2986. (f) Kobayashi, S.; Endo, M.;
Nagayama, S. J. Am. Chem. Soc. 1999, 121, 11229–11230. (g) Kobayashi,
S.; Ishida, T.; Akiyama, R. Org. Lett. 2001, 3, 2649–2652. (h) Doyle,
M. P.; Timmons, D. J.; Tumonis, J. S.; Gau, H. M.; Blossey, E. C.
Organometallics 2002, 21, 1747–1749. (i) Nagashima, T.; Davies, H. M. L.
Org. Lett. 2002, 4, 1989–1992. (j) Doyle, M. P.; Yan, M.; Gau, H. M.;
Blossey, E. C. Org. Lett. 2003, 5, 561–563. (k) Davies, H. M. L.; Walji,
A. M.; Nagashima, T. J. Am. Chem. Soc. 2004, 126, 4271–4280. (l) Davies,
H. M. L.; Walji, A. M. Org. Lett. 2005, 7, 2941–2944. (m) Candeias, N. R.;
Afonso, C. A.; Gois, P. M. Org. Biomol. Chem. 2012, 10, 3357–3378. (n)
Heitbaum, M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006, 45,
4732–4762.
(12) (a) Takeda, K.; Oohara, T.; Anada, M.; Nambu, H.; Hashimoto,
S. Angew. Chem., Int. Ed. 2010, 49, 6979–6983. (b) Takeda, K.; Oohara,
T.; Shimada, N.; Nambu, H.; Hashimoto, S. Chem.;Eur. J. 2011, 17,
13992–13998. (c) Oohara, T.; Nambu, H.; Anada, M.; Takeda, K.;
Hashimoto, S. Adv. Synth. Catal. 2012, 354, 2331–2338.
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(15) Haag, R.; Roller, S. Top. Curr. Chem. 2004, 242, 1–42.
B
Org. Lett., Vol. XX, No. XX, XXXX

anchored to the silica surface through an organic
linker (Scheme 2). The loading of 2 was determined to be
0.06 mmol/g by elemental analysis.
Scheme 3. Cyclopropenation and Cyclopropanation
Scheme 2. Immobilization Strategy
Initial comparison studies between Rh2(S-DOSP)3-
(S-silicaSP) (2) and Rh2(S-DOSP)4 were conducted with
standard cyclopropenation and cyclopropanation reactions
of donor/acceptor carbenoids. These studies were con-
ducted with the most widely used donor/acceptor carbenoid
precursors, styryl diazoacetate (12) and phenyl diazoacetate
(16). The reactions were conducted using the optimal
conditions developed previously for Rh2(S-DOSP)4-cata-
lyzed reactions. Rh2(S-DOSP)3(S-silicaSP) (2)-catalyzed
cyclopropenation of 1-pentyne (11) and cyclopropanation
of styrene (14) with styryl diazoacetate 12 provided the
corresponding cyclopropene 13 and cyclopropane 15 in
g95% ee, comparable to the results obtained under Rh2-
(S-DOSP)4-catalyzed conditions (Scheme 3). Similarly,
2-catalyzed cyclopropanation of styrene (14) or 1,1-dipheny-
lethylene (18) with phenyl diazoacetate 16 gave comparable
results to the Rh2(S-DOSP)4-catalyzed reactions. Cyclopro-
pane 17 was formed in 80% ee with Rh2(S-DOSP)3-
(S-silicaSP) (2) vs 88% ee with Rh2(S-DOSP)4,2c whereas
cyclopropane 19 was formed in 97% ee using either the
immobilized or the homogeneous catalyst.2a
We then sought to determine the capability of Rh2-
(S-DOSP)3(S-silicaSP) (2) in more exotic reactions of donor/
acceptor carbenoids. A new transformation for these inter-
mediates is the tandem ylide formation/[2,3] sigmatropic
rearrangements with allylic and propargylic alcohols.6 Rh2-
(S-DOSP)3(S-silicaSP)-catalyzed reaction of allylic alcohol
20 with styryl diazoacetate 12 provided the corresponding
rearrangement product 21 with a high level of asymmetric
induction (96% ee), comparable to the results with Rh2-
(S-DOSP)4 (Scheme 4, 98% ee).6a Similarly, Rh2(S-DOSP)3-
(S-silicaSP)-catalyzed ylide formation/[2,3] sigmatropic
rearrangement of propargylic alcohol 22 with 12 provided
23 with a high level of enantiocontrol.6b
Scheme 4. Ylide Formation/[2,3] Sigmatropic Rearrangement
The Rh2(S-DOSP)3(S-silicaSP)-catalyzed reaction was ap-
pliedtoarangeofCHCRreactions as illustrated in Scheme 5.
The 2-catalyzed CHCR reaction of (methoxymethylene)-
cyclohexane (24) with 12 provided 25 in 79% yield and
94% ee.5,8a The tandem CHCR/retro-Cope rearrange-
ment of 1-methyl-3,4-dihydronaphthalene (26) with 12
provided 28 in 90% yield and 96% ee. The 1,2-dihydro-
naphthalene 27 performed similarly in the 2-catalyzed
CHCR/retro-Cope rearrangement cascade providing
29 in 75% yield and 90% ee.8b Finally, the CHCR
reactionꢀelimination cascade of 4-acetoxy-6,7-dihy-
droindole (30) with 12 provided the indole 31 in 59%
yield and 96% ee.9 All of these reactions proceeded with
levels of enantioinduction close to those obtained with
Rh2(S-DOSP)4.
The promising activity and enantioselectivity of the im-
mobilized complex led us to evaluate the robustness of the
immobilization process via a filtration test to assess catalyst
heterogeneity and stability. Conversion of substrate was
monitored as a function of time, removing the solid catalyst
by filtration while allowing the solid-free solution to con-
tinue to react.16 Phenyl diazoacetate (16) was added to a
Donor/acceptor carbenoids have been shown to be
versatile reactants for stereoselective CꢀH functionaliza-
tion. A particularly robust transformation is the combined
CꢀH functionalization/Cope rearrangement (CHCR).
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 1. Catalyst 2 Recycling Study
Scheme 5. CꢀH Functionalization
cycle
yield (%)
ee (%)
1
72
78
75
76
78
88
80
81
79
77
79
88
2
3
4
5
Rh2(S-DOSP)4
second half of the solution of 16. The amount of product in
the filtrate remained constant after the filtration despite the
additional phenyl diazoacetate addition, indicating robust
immobilization of 2 on the silica surface (Figure 2).
The ultimate advantage of heterogeneous catalysts is their
potential to be recycled over several consecutive reactions.
We therefore sought to determine the recyclability of 2.
Thus, 2-catalyzed cyclopropanation was repeated over five
consecutive reactions using the same batch of catalyst and
proved to provide a similar level of both yield and enan-
tioinduction in each consecutive reaction (Table 1).
This study describes an effective method for covalent
immobilization of a highly versatile and robust17 dirho-
dium catalyst onto a silica support. Also, this represents
the first successful immobilization, recycling, and applica-
tion of animmobilizedRh2(S-DOSP)4 analogue in a broad
range of enantioselective transformations with compar-
able enantioinduction to its homogeneous counterpart. It
is anticipated that this catalyst may prove useful in flow
reactors, which will be the subject of future investigation.
Acknowledgment. ThisworkwassupportedbytheNSF
under the CCI Center for Selective CꢀH Functionalization,
No. CHE-1205646.
Figure 2. Filtration test demonstrating lack of activity in absence
of solid catalyst.
Supporting Information Available. General experimen-
tal procedures, characterization of new compounds, and
spectral data.This material is available free of charge via
the Internet at http://pubs.acs.org.
mixture of 14, catalyst 2, and mesitylene in hexanes by
syringe pump, stopping at 7.5 min. After filtering 2, the
filtrate was transferred to a new flask before addition of the
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254–257.
(16) Hamlin, J. E.; Hirai, K.; Millan, A.; Maitlis, P. M. J. Mol. Catal.
1980, 7, 543–544.
The authors declare no competing financial interest.
D
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