Highly Z-selective and enantioselective ring-opening/cross-metathesis catalyzed by a resolved stereogenic-at-Ru complex

Article abstract of DOI:10.1021/ja4046422

The synthesis of a ruthenium complex that catalyzes Z-selective (up to 98% Z) asymmetric ring-opening/cross-metathesis with high enantioselectivity (up to 95% ee) is reported. The synthesis of the catalyst features the resolution of a chelating N-heterocyclic carbene complex by ligand substitution with a chiral carboxylate.

Full text of DOI:10.1021/ja4046422

Communication
pubs.acs.org/JACS
Highly Z‑Selective and Enantioselective Ring-Opening/Cross-
Metathesis Catalyzed by a Resolved Stereogenic-at-Ru Complex
John Hartung and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
a
Scheme 1. Synthesis of Homochiral Complex 4
ABSTRACT: The synthesis of a ruthenium complex that
catalyzes Z-selective (up to 98% Z) asymmetric ring-
opening/cross-metathesis with high enantioselectivity (up
to 95% ee) is reported. The synthesis of the catalyst
features the resolution of a chelating N-heterocyclic
carbene complex by ligand substitution with a chiral
carboxylate.
a
(a) (1) (S)-AgO2CCH(Ph)(OMe) (2) (2 equiv), THF, 23 °C, 1.5 h,
97%; (2) chromatographic separation, 45%. (b) (1) pTsOH·H2O,
THF, 5 min; (2) NaNO3, THF/MeOH, 15 min, 43%.
lefin metathesis is a powerful carbon−carbon bond-
1
Oforming reaction that is widely used in organic synthesis,
carboxylate 3 with p-toluenesulfonic acid and sodium nitrate
produced the enantioenriched nitrate complex 4 in 43% yield.
polymer chemistry,2 materials science,3 and biochemistry.4
Asymmetric olefin metathesis methodologies have proven
useful for the synthesis of enantiopure natural products and
other biologically relevant compounds.5 Consequently, the
development of chiral catalysts for methods such as asymmetric
ring-opening/cross-metathesis (AROCM) is a field of ongoing
interest.6
The earliest catalysts, which contained molybdenum, were
capable of generating AROCM products in high ee (80−99%)
but suffered from limited substrate scope and functional group
compatibility.7 Ruthenium-based catalysts wherein the chirality
is built into the N-heterocyclic carbene (NHC) ligand have
been developed.8 Most of these molybdenum and ruthenium
catalysts are capable of performing AROCM with high levels of
E selectivity (up to >98% E).9
Recently, Z-selective AROCM of oxabicycles has been
achieved with molybdenum catalysts.10 While Z-selective
AROCM has been accomplished with ruthenium catalysts, to
date it has been limited to reactions involving heteroatom-
substituted terminal olefin cross-partners.11 Recent advances
have produced ruthenium catalysts with chelating NHC ligands
possessing exquisite Z selectivity in cross-metathesis.12 We
anticipated that enantiopure versions of the newly developed
catalysts would exhibit high Z selectivity and enantioselectivity
in AROCM because of the rigidity imparted by the Ru−C
chelate. Herein we report a new homochiral stereogenic-at-
ruthenium complex that exhibits high enantioselectivity in the
AROCM of norbornene derivatives.
Figure 1. ORTEP drawing of 3.
While complex 3 exhibited low enantioselectivity in
AROCM, a 1 mol % loading of complex 4 catalyzed the
reaction of norbornene derivative 5 with excess allyl acetate (6)
to produce a 64% yield of the diene (1S,2R,3S,4R)-7 with 95%
Z selectivity and 93% ee (eq 1).13 The highly selective reaction
Enantioenriched 4 was synthesized by resolution as shown in
Scheme 1. Treatment of racemic iodide 112c with silver
carboxylate 2 cleanly formed a 1:1 mixture of diastereomers in
97% yield. Chromatographic separation of the mixture afforded
a 45% yield of 3 (90% of the theoretical maximum) with >95:5
dr. The absolute stereochemistry of complex 3 was confirmed
by X-ray crystallography (Figure 1). Sequential treatment of
produces four contiguous stereocenters in a tetrasubstituted
cyclopentane ring. Optimization of the process revealed that 7
Received: May 8, 2013
Published: July 3, 2013
© 2013 American Chemical Society
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Communication
a
equiv of terminal olefin, a catalyst loading of 1 mol % at 23 °C
and a concentration of 0.5 M in tetrahydrofuran (THF)
afforded the highest yield and selectivity. Ethereal solvents were
optimal, with the catalyst solubility improved in THF over
diethyl ether.
Table 2. Influence of the Norbornene Reactant
To demonstrate the scope of Z-selective catalyst 4, a variety
of terminal olefins bearing diverse functionality were employed
in order to determine their effect on the efficiency and
enantioselectivity of the reaction. As illustrated in Table 1,
a
Table 1. AROCM with Different Terminal Olefin Partners
a
Yields correspond to isolated products; Z/E ratios were determined
by GC; the ee’s of the pure products were measured with chiral SFC.
b
Conducted at a catalyst loading of 3 mol % for 5 h.
offers indirect evidence of the active catalytic species. The result
suggests that the enantiodetermining step most likely precedes
the olefin-geometry-determining step.15 This conclusion
requires the initial enantiodetermining ring-opening event to
occur with a ruthenium methylidene (Scheme 2). Subsequent
cross-metathesis of the ring-opened product bearing a
ruthenium alkylidene with 1 equiv of terminal olefin would
then afford the observed product.
a
Yields correspond to isolated products; Z/E ratios were determined
by 500 MHz 1H NMR analysis of the crude reaction mixtures; the ee’s
of the pure products were measured with chiral supercritical fluid
chromatography (SFC).
Scheme 2. Proposed Model of Enantioselectivity
replacing allyl acetate with N-Boc-allylamine provided amine-
containing product 8a with equally high enantioselectivity (94%
ee). Utilizing an olefin bearing a remote ester did not impact
the Z selectivity and afforded 8b with 91% ee.
Bulkier allylic substituents such as p-methoxyphenyl and
pinacol boronic ester gave products 8c and 8d with moderate
enantioselectivity (81 and 75% ee, respectively). A simple α-
olefin such as 1-hexene also gave good yield, Z selectivity, and
enantioselectivity (8e, 89% ee), demonstrating that allylic
functionality is not required to confer a selective reaction. The
examples in Table 1 suggest that catalyst 4 is capable of
producing a range of AROCM products.14
The norbornene component was then altered to investigate
its impact on the Z selectivity and enantioselectivity. As a basis
for comparison, the substrates were treated with 7 equiv of allyl
acetate under the optimized catalytic conditions. Norbornenes
bearing coordinating functionality such as acetate (to form 9a)
and N-phenylsuccinimide (to form 9b) resulted in reduced
yield and slower reaction, respectively. The dimethyl-
substituted anhydride afforded a 65% yield of 9d, which
contains two vicinal all-carbon quaternary stereocenters,
demonstrating the power of AROCM to afford otherwise
synthetically challenging products with high ee (95%). Aryl
ether 9e was produced with 95% ee, although interestingly as a
7:3 Z/E mixture. The results in Table 2 support the observation
that substrates bearing 2,3-endo substitution react with high Z
selectivity, while substrates lacking this substitution pattern
show reduced diastereoselectivity.
On the basis of this indirect mechanistic evidence and the
absolute configuration of the isolated product, we propose that
the methylidene shown in Scheme 2 initially reacts with the
norbornene component in an enantioselective ring-opening
event. It is hypothesized that the enantioselectivity is governed
by the approach of the methylidene to the less-hindered exo
face, while the mesityl “cap” forces the bulk of the norbornene
component to be oriented away from the NHC ligand.16 The
proposed methylidene is most likely produced by initial cross-
metathesis of 4 with a molecule of terminal olefin, resulting in
epimerization at the ruthenium center. Studies to provide a
better understanding of the mechanism and origin of the
enantioselectivity in the AROCM catalyzed by complex 4 are
currently underway.
In summary, we have developed an enantioenriched
ruthenium metathesis catalyst capable of highly Z-selective
and enantioselective ROCM. An NHC ligand that chelates
through a Ru−C bond is key to the design of the catalyst, which
features a stereogenic Ru atom. The reaction is amenable to
modification of both the terminal olefin and norbornene
components, which significantly broadens the scope of this
methodology.
The fact that (Z)-9e and (E)-9e were formed with identical
enantioenrichment has important mechanistic implications and
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(10) (a) Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 3844−3845. (b) Yu, M.; Ibrahem, I.; Hasegawa,
M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134,
2788−2799.
(11) (a) Khan, R. K. M.; O’Brien, R. V.; Torker, S.; Li, B.; Hoveyda,
A. H. J. Am. Chem. Soc. 2012, 134, 12774−12779. (b) Khan, R. K. M.;
Zhugralin, A. R.; Torker, S.; O’Brien, R. V.; Lombardi, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 2012, 134, 12438−12441.
(12) (a) Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 8525−
8527. (b) Keitz, B. K.; Endo, K.; Herbert, M. B.; Grubbs, R. H. J. Am.
Chem. Soc. 2011, 133, 9686−9688. (c) Keitz, B. K.; Endo, K.; Patel, P.
R.; Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc. 2012, 134, 693−
699. (d) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.;
Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276−1279.
(13) Absolute configurations were assigned by analogy to that of 9c,
which was determined by X-ray crystallography (see the Supporting
Information for details).
(14) Attempts to employ a heteroatom-substituted olefin (butyl vinyl
ether) resulted in no ROCM product, presumably because of catalyst
deactivation.
(15) This assumes that secondary metathesis processes proceed at a
negligible rate relative to the productive (ROCM) reaction. Measure-
ments of the formation of 9e (see the Supporting Information)
showed that the Z/E ratio was constant during the course of the
reaction and for several hours after complete conversion.
(16) Liu, P.; Xu, X.; Dong, X.; Keitz, B. K.; Herbert, M. B.; Grubbs,
R. H.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 1464−1467.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral data for the products, and
crystallographic information files. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
rhg@caltech.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NIH
(5R01GM031332-27 to R.H.G.). The authors thank Mr. L.
M. Henling for X-ray crystallography. The Bruker KAPPA
APEXII X-ray diffractometer was purchased via an NSF
CRIF:MU Award to the California Institute of Technology
(CHE-0639094). The authors also thank Materia, Inc. for its
donation of metathesis catalysts and Drs. Daryl Allen (Materia,
Inc.) and Scott Virgil (Caltech Center for Catalysis and
Chemical Synthesis) for helpful advice.
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