Chiral cyclopentadienyl ligands as stereocontrolling element in asymmetric C-H functionalization

Article abstract of DOI:10.1126/science.1226938

Metal complexes coordinated by a single cyclopentadienyl (Cp) ligand are widely used, versatile catalysts, but their application to asymmetric reactions has been hindered by the difficulty of designing Cp substituents that effectively bias the coordination sphere. Here, we report on a class of simple C₂-symmetric Cp derivatives that finely control the spatial arrangement of the transiently coordinated reactants around the central metal atom. Rhodium(III) complexes bearing these ligands proved to be highly enantioselective catalysts for directed carbon-hydrogen (C-H) bond functionalizations of hydroxamic acid derivatives.

Full text of DOI:10.1126/science.1226938

Chiral Cyclopentadienyl Ligands as Stereocontrolling Element in
Asymmetric C −H Functionalization
Baihua Ye and Nicolai Cramer
Science 338, 504 (2012);
DOI: 10.1126/science.1226938
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REPORTS
Achieving high levels of stereoselectivity for this
association is a key hurdle for successful asymmetric
catalysis. The facial selectivity of the ligand asso-
ciation must be imposed by the chiral space crafted
by an enantiopure Cp congener. We identified three
criteria to design catalysts for an efficient enantiose-
lective process: (i) use of C2-symmetric Cp deriva-
tives to avoid the complicating factor of diastereomer
formation in coordination of the metal to either lig-
and face; (ii) restriction of rotation around the Cp
moiety to lock in one of two substrate alignments,
which must be highly preferred over the other, as this
ratio reflects the maximum attainable selectivity; and
(iii) steric blocking perpendicular to the Cp plane to
induce approach of the incoming reactant RC from
just one side. Taking these constraining factors into
Chiral Cyclopentadienyl Ligands as
Stereocontrolling Element in
Asymmetric C–H Functionalization
Baihua Ye and Nicolai Cramer*
Metal complexes coordinated by a single cyclopentadienyl (Cp) ligand are widely used, versatile catalysts,
but their application to asymmetric reactions has been hindered by the difficulty of designing Cp
substituents that effectively bias the coordination sphere. Here, we report on a class of simple C2-symmetric
Cp derivatives that finely control the spatial arrangement of the transiently coordinated reactants around
the central metal atom. Rhodium(III) complexes bearing these ligands proved to be highly enantioselective
catalysts for directed carbon-hydrogen (C–H) bond functionalizations of hydroxamic acid derivatives.
ince the discovery of ferrocene 70 years ago, type [(h5-C5H5)ML1L2L3] are chiral-at-metal (24, 25), account, we hypothesized that a 1,2-disubstituted
cyclopentadienyl (Cp)–coordinated metal arising from a face-selective approach of the third Cp ligand would favor the two orientations of the
complexes contributed tremendously to the ligand L3 to the fluxional 16-electron intermediate, small and large substrate parallel to the positional
S
rise of organometallic chemistry. Countless transition- leading without a controlling element to a racemate. locks (SS and SL, structures A and B, Fig. 1). A
metal complexes have been prepared with Cp itself
or its most popular pentamethylcyclopentadienyl
analog (Cp*), and many of them are highly efficient
catalysts for a broad range of transformations (1).
Despite such favorable characteristics as stability
and robustness, Cp ligands have been largely by-
passed by other classes of ligands—such as diamines,
phosphines, and carbenes—as carriers of chiral bias
in asymmetric catalysis (2). The simple Cp or Cp*
motif appears often in mixed-ligand designs com-
prising one or more additional coordination groups
responsible for the chiral environment (3, 4). How-
ever, only a few chiral Cp derivatives with non-
coordinating substituents, and their corresponding
metal complexes, have been synthesized (5–11), and
they have rarely been applied as catalysts. With the
exception of the Co(I)-catalyzed cyclotrimerizations
reported by Heller, Hapke, and Gutnov (12–14), no
notable chiral induction has been achieved with
their respective late-transition metal complexes in
catalytic reactions.
This discrepancy might derive from inherent dif-
ficulties linked to the design and synthesis of chiral
Cp ligand derivatives. Although representing a
long-standing problem in asymmetric catalysis, it
has been systematically neglected. The striking op-
portunities inherent in addressing these shortcom-
Fig. 1. Conceptual design of the chiral Cpx* complexes.
ings become clear by just considering half-sandwich
complexes (15, 16) with a d6-electron count such as
Cp Rh(III), Ir(III), Ru(II), and Co(I), which catalyze
a range of important reactions (17–23). Often, these
reactions require that, during the catalytic cycle, all
three remaining coordination sites bind substrate(s)
and reactants, leaving Cp as the sole permanent
ligand on the metal. This characteristic makes the
development of catalytic asymmetric versions enor-
mously challenging because selectivity stems from
the arrangement of the three other ligands around
the central metal. Pseudotetrahedral complexes of the
Ecole Polytechnic Fédérale de Lausanne, School of Basic Sci-
ences, Institute of Chemical Sciences and Engineering, Labora-
tory of Asymmetric Catalysis and Synthesis, BCH 4305, CH-1015
Lausanne, Switzerland.
*To whom correspondence should be addressed. E-mail:
nicolai.cramer@epfl.ch
Fig. 2. Structure of the chiral Cpx*Rh(I) complexes 1a to 1f.
504
26 OCTOBER 2012 VOL 338 SCIENCE www.sciencemag.org

REPORTS
bulky backbone should prevent the approach of the from the corresponding C2-symmetric cyclopenta- (DBPO) delivered directly a competent catalyst,
reactant RC from the back. The C2-symmetric chi- diene precursors (27). These Rh(I) complexes are presumably Rh(III) bis-benzoate complex 5 (33).
ral space, illustrated by the upward- and downward- relatively air-stable and easy to handle. In keep- Complex 1g, bearing only remote stereochem-
oriented positional locks, should preferentially ing with our interest in C–H bond functionalization ical substitution, displayed as expected only neg-
orient the larger ligand SL away from the steric using rhodium catalysts (28, 29), we chose the ligible selectivity (table S1, entry 1). Installing steric
bulk and thus favoring conformer B. Association of Cp*Rh(III)-catalyzed C–H functionalization (30) bulk closer to the Cp ring improved the enantio-
RC would lead then to C as a single diastereomer, of hydroxamic acid derivative recently reported meric ratio (er) to 73:27 (table S1, entry 2). Unex-
competent for selective downstream reactions (26). by Fagnou (31) and Glorius (32) as an optimal re- pectedly, when the methyl group was replaced with
We prepared a range of rhodium(I) complexes action to challenge the viability of our concept. In any larger substituent—e.g., an isopropyl group—
(1a to 1g, Fig. 2) with different backside shielding situ oxidation of complex 1 with dibenzoylperoxide the enantioselectivity dropped sharply (table S1,
entry 3). We next evaluated the influence of the ri-
gidifying trans-acetal group. With the two oxygen
Table 1. Substrate scope of the enantioselective activation/addition.
atoms being in syn-relation to both methyl groups
of the cyclohexene, these are forced into the pseudo-
axial position, increasing the bulk near the metal
center and giving increased selectivity of 90:10 er
(table S1, entry 6). In addition to this conformation-
al effect, the acetal group protects the metal from
backside approach by the olefin. Different larger
groups were evaluated as well, and a benzophenone
acetal moiety (1c) proved to be optimal, provid-
ing 4aa with 92:8 er (table S1, entry 7).
We next turned our attention to the size of
the acyl substituent R of the oxygen atom of the
hydroxamate substrate, which we expected would
influence the ratio of the two specific orientations
of the cyclometalated intermediate 7. Several acyl
and carbonate derivatives were tested, and the read-
ily accessible Boc-derivative (R=OtBu) was opti-
mal, giving complex 1c 96:4 er (entry 10). The high
solubility of the starting Rh(I) complex allowed a
wide variation of solvents with conserved selectivity
(entries 12 to 15), although the yields proved high-
est in ethanol. The catalyst loading could be low-
ered to 1 mole % without diminishing the reaction
performance (entry 16). The activation proceeds
even at 0°C with a slightly increased selectivity
(entry 17).
The scope of the reaction was explored with the
optimized catalyst 1c and is outlined in Table 1. On
the olefin acceptor side, a variety of styrenes are
competent reaction partners, and the observed en-
antioselectivity is consistently excellent (Table 1, en-
tries 1 to 7). Some structurally and electronically
different terminal and cyclic olefins were tested, per-
forming reliably, albeit in some instances with slight-
ly reduced enantioselectivity (entries 8 to 13). Uniquely,
vinyl trimethyl silane gives 4aj with the opposite
regioselectivity (>10:1, entry 9). The process is also
general for the aryl hydroxamates 2a to 2h and
different electronic and steric variations have little
influence on yield and selectivity (entries 13 to 20).
The catalytic cycle of the reaction is presumably
initiated by oxidation of the Cpx*Rh(I) complex
1 by DBPO, giving 5 (fig. S4). Based on published
mechanistic studies of the racemic version of this
transformation (31, 34), ligand exchange binds sub-
strate 2a, forming 6. Cyclometalation by concerted
metalation deprotonation mechanism and loss of
benzoic acid leads to the crucial cyclometalated
16-electron species 7. In the enantioselectivity-
determining step, coordination of the olefin in a
highly diastereoselective manner leads to 18-electron
chiral-at-metal complex 8, and its incorporation
forms 10 (35). With the benzoic acid present in
Br
4ia
1 : 1.3
4ia
www.sciencemag.org SCIENCE VOL 338 26 OCTOBER 2012
505

REPORTS
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regenerates 5 and expels product 4 and t-butyl hy-
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tBuOH without changing the overall acidity of the
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to be (R)-4a (36). The underlying selectivity of the
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Acknowledgments: This work is supported by the European
Research Council (ERC) under the European Community’s
Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement 257891. We thank R. Scopelliti for x-ray
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www.sciencemag.org/cgi/content/full/338/6106/504/DC1
Materials and Methods
Figs. S1 to S3
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4 July 2012; accepted 10 September 2012
10.1126/science.1226938
In conclusion, we have described a class of chiral
Cpx* analogs with low molecular weight that de-
symmetrize a rhodium(III)-catalyzed directed C–H
bond functionalization. The reaction proceeds under
mild conditions and is high yielding and enantiose-
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506
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