The significance of degenerate processes to enantioselective olefin metathesis reactions promoted by stereogenic-at-Mo complexes

Article abstract of DOI:10.1021/ja907805f

(Chemical Equation Presented) The present study provides spectroscopic and experimental evidence demonstrating that degenerate metathesis is critical to the effectiveness of this emerging class of chiral catalysts. Isolation and X-ray characterization of

Full text of DOI:10.1021/ja907805f

Published on Web 10/20/2009
The Significance of Degenerate Processes to Enantioselective Olefin
Metathesis Reactions Promoted by Stereogenic-at-Mo Complexes
Simon J. Meek,† Steven J. Malcolmson,† Bo Li,† Richard R. Schrock,‡ and Amir H. Hoveyda*,†
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, and
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received September 14, 2009; E-mail: amir.hoveyda@bc.edu
Scheme 1. Isolation and X-ray Crystal Structure of R-1
We recently disclosed a class of chiral Mo-based complexes
(e.g., S-1 and S-2, Figure 1) that are prepared diastereoselectively
(7.0:1 and 2.2:1, respectively) and used in situ to promote olefin
metathesis1,2 with high reactivity and enantioselectivity.3
A
notable feature of the new catalysts is the presence of a donor
(pyrrolide) and an acceptor (aryloxide or alkoxide) ligand (vs
two acceptor ligands as utilized previously),2a which, on the basis
of initial theoretical studies,4 is likely critical to achieving high
efficiency. The fluxional pyrrolide-aryloxides bear only mono-
dentate ligands and a stereogenic metal center, which undergoes
inversion with every sequence that involves formation of a
metallacyclobutane (MoRdC + substrate olefin f metalla-
cyclobutane f CdMoS + product olefin).5 In the simplest
analysis, each olefin metathesis catalytic cycle includes two
inversion processes: cross-metathesis leading to a substrate-
derived alkylidene and a subsequent ring-closing, ring-opening,
or cross-metathesis. Under such a regime, a stereogenic-at-metal
complex emerges from a reaction as the same stereoisomer that
begins the process (net retention). Inversion at the metal,
however, might occur beyond the boundaries of a productive
catalytic cycle as a result of degenerate metathesis; such
isomerizations can have significant consequences on reaction
efficiency as well as enantioselectivity. Herein, we provide
evidence demonstrating that degenerate metathesis, which is
prevalent in transformations catalyzed by stereogenic-at-metal
complexes, is critical to the effectiveness of enantioselective ring-
closing metathesis (RCM) processes.
Table 1. Time Dependence of Conversion and Selectivity in
Catalytic RCM with Pure R-1 (Minor Diastereomer)a
a See the Supporting Information for all experimental details,
including spectroscopic data for R-1. b Based on 400 MHz 1H NMR
analysis of unpurified mixtures. c Based on HPLC analysis (see the
Supporting Information for details).
Figure 1. Stereogenic-at-Mo complexes (major diastereomers).
points to a rationale for such reactivity differences. Approach
of an alkene to S-1 trans to the pyrrolide7 is hindered by a Br,
which can be moved out of the way by a slight rotation about
the Mo-O bond. In R-1, however, olefin coordination is blocked
by the larger (vs Br) tetrahydronaphthyl ring of the aryloxide.
Furthermore, a bromide substituent of the aryloxide ligand
resides within 3.04 Å of the Mo in R-1, suggesting a Mo-Br
interaction.8 Such association discourages rotation around the
Mo-O bond, which is required if the metal center is to be
accessible to a substrate molecule.
We began with the determination of the structure of R-1,
generated as the minor diastereomer (7:1 S/R). In spite of being
the less predominant component, R-1 was isolated in sufficient
quantities to allow us to secure its X-ray structure (Scheme 1;
the X-ray structure of S-13a is also shown).6 Earlier studies had
indicated that g95% of R-1 remains intact in an RCM reaction
(Table 1) that proceeds to completion in 30 min with a 7:1 S-1/
R-1 mixture.3a A comparison of the structures of S-1 and R-1
With a pure sample of R-1 available, we examined the ability
of this diastereomer to promote enantioselective RCM. As the
† Boston College.
‡ Massachusetts Institute of Technology.
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J. AM. CHEM. SOC. 2009, 131, 16407–16409 16407

C O M M U N I C A T I O N S
Table 2. Time Dependence of Conversion and Selectivity in
Catalytic RCM with Pure S-1 (Major Diastereomer)a
Scheme 2. Initial Mechanism without Mo-Center Isomerization
Outside the Main Catalytic Cycle
a-c See Table 1, footnotes a-c.
data summarized in Table 1 indicate, R-1 does promote RCM
of triene 5, but at a lower rate than when S-1 is used (180 vs 20
min for >98% conv; Tables 1 and 2). Surprisingly, however,
the RCM with R-1 delivers the same major product enantiomer
(S-6) as obtained when S-1 is employed, with nearly the same
enantioselectivity (96:4 vs 96.5:3.5 er; see Tables 1 and 2).
The observations in eq 1 regarding RCM of 7, a key
intermediate in the recent enantioselective total synthesis of
quebrachamine,3a,b offer an additional example: triene 7 reacts
with R-1 significantly more slowly (12 h vs 1 h with S-1), but
as with S-1, R-8 is generated with precisely the same level of
enantioselectivity (98:2 er) and sense of absolute stereochemistry
(R-8 major).9 The above data imply that the stereochemical
identity of the stereogenic-at-metal complex is significant vis-
a`-vis the rate of initiation of the initial neophylidene but has no
bearing on the eventual stereochemical outcome. Isomerization
of the two diastereomers of the chiral complex is therefore likely
to be more facile than ring closure; that is, Curtin-Hammett
conditions10 apply for a significant duration of the catalytic cycle.
Another set of mechanistically critical observations, depicted
in Tables 1 and 2, shows that irrespective of whether pure R-1
or S-1 is used, the initial enantioselectivity is lower than that of
the final product (see entries 1). A rationale for such findings
will be provided below.
symmetrically substituted metallacyclobutane 13; such a process might
furnish S-9, an alkylidene that can deliver the observed major
enantiomer S-6 via metallacyclobutane 14. However, an experiment
involving the reaction of a 1:1 mixture of allylamines 15 and d3-15 in
the presence of pure S-1 (eq 3), which did not lead to any detectable
amounts of deuterium scrambling, serves as evidence against inversion
at Mo through a substrate-induced degenerate process.
Scheme 3. Mo Isomerization by Substrate-Induced Degenerate
Metathesis
The observations described above undermine the validity of the
simplest form of the catalytic cycle involving two inversions at the
metal center. Two other issues detract from the pathway in Scheme
2: (1) The lower activity of alkylidenes bearing an R Mo center should
apply to R-9 as well; S-9 is expected to be more reactive. (2) RCM
through R-9 would likely afford R-6, the minor enantiomer observed
in the reactions shown in Tables 1 and 2.
The results of RCM of tetraene 12 performed with pure S-1 (eq
2), which affords S-6 as the predominant enantiomer (90:10 er),
further substantiate that additional inversions at the metal center,
outside the confines of a catalytic cycle that involves only a double
inversion, play a crucial role. The simplest catalytic cycle for
conversion of 12 to 6 would include three olefin metathesis reactions
(vs two for 5 or 7). In the absence of any additional isomerizations
at Mo, the catalyst would have undergone net inversion after
formation of every molecule of 6 (from 12), leading to generation
of 6 in low enantiomeric purity.
Ethylene, although not present at the earliest stages of the RCM
process, can promote degenerate olefin metathesis as well. As shown
in Scheme 2, through the first RCM, S-1 sheds the neophylidene unit
of the initial complex, leading to methylidene S-11,11 which may
proceed through cross-metathesis with substrate 5 to produce ethylene
Inversion at the Mo center can also occur through degenerate olefin
metathesis. Thus, as illustrated in Scheme 3, reaction of alkylidene
R-9 (Scheme 2) with another molecule of 5 might afford the
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C O M M U N I C A T I O N S
Scheme 4. Mo Isomerization by Ethylene-Induced Degenerate
Metathesis
Scheme 5. Equilibria Promoted by Ethylene Critical to Efficiency
and Enantioselectivity
reaction is thus independent of the identity of the initiating
alkylidene S-1 or R-1 (Curtin-Hammett kinetics).10
An important feature of metal-catalyzed olefin metathesis
promoted by stereogenic-at-metal complexes is that with each
reaction the metal center is inverted. We have demonstrated that
at steady state, such inversions are faster than product formation.
The absence of multidentate ligands, which can raise the barrier to
inversion at the metal and reduce catalyst activity, is therefore a
significant attribute of the present class of catalysts. Our study
highlights the principle that diastereomeric—not enantiomeric—chiral
catalysts might be preferable to those that contain a C2-symmetric
bidentate ligand2a (and thus a nonstereogenic metal center). In
diastereomeric complexes that undergo rapid interconversion of
metal center configuration by degenerate metathesis, stereomutation
at the metal becomes inconsequential and, as a result, stereoselective
synthesis of a chiral catalyst candidate is not required.
(and regenerate R-9). Degenerate metathesis and inversion at the Mo
center can thus occur by rapid interconversion of S-11 and R-11 via
unsubstituted metallacyclobutane 16 (Scheme 4).3e Cross-metathesis
of R-11 with 5 would give S-9, which would readily undergo RCM to
afford S-6.
Three additional findings support the proposal that ethylene
initiates degenerate metathesis and promotes high enantioselectivity:
(1) Treatment of d3-5 with 2 mol % pure S-1 leads to deuterium
scrambling within 7 min (eq 4).
Acknowledgment. Financial support was provided by the NIH
(GM-59426) and AstraZeneca (graduate fellowship to S.J.M.). We
thank Professor K. Tan and A. Zhugralin for helpful discussions and
Dr. B. Bailey and K. Wampler for the X-ray structure of S-1.
Supporting Information Available: Experimental procedures,
spectral and analytical data for all reaction products, and crystallographic
data for R-1 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(2) As shown in eq 5, when RCM of 5 is performed with 100 mol
% diallyl ether (to generate ethylene and promote rapid methylidene
generation), high enantioselectivity is observed early in the reaction
(95:5 er vs entries 1, Tables 1 and 2). The more rapid initiation (vs
Table 2) points to a more facile formation of 11.
References
(1) For recent reviews of catalytic olefin metathesis, see: (a) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003.
(b) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
(2) For reviews of high-oxidation-state complexes used in catalytic olefin metathesis,
see: (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592. (b) Schrock, R. R. Chem. ReV. 2009, 109, 3211.
(3) RCM of tetraene 12 with 5 mol % pure S-1 delivers 6 in
only 60.5:39.5 S/R after ∼2% conversion (eq 6; compare to eq 2).
Thus, without sufficient ethylene, the catalytic cycle in its simplest
form is largely operative (triple inversion at Mo).
(3) (a) Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H.
Nature 2008, 456, 933. (b) Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943. (c) Ibrahem, I.; Yu,
M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844. (d)
Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 10652.
(e) Marinescu, S. C.; Schrock, R. R.; Mu¨ller, P.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 10840.
(4) (a) Solans-Monfort, X.; Clot, E.; Cope´ret, C.; Eisenstein, O. J. Am. Chem. Soc.
2005, 127, 14015. (b) Poater, A.; Solans-Monfort, X.; Clot, E.; Cope´ret, C.;
Eisenstein, O. J. Am. Chem. Soc. 2007, 129, 8207.
(5) For applications of stereogenic-at-Ru complexes to enantio- or product-selective
olefin metathesis reactions, see: (a) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber,
S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502. (b)
Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 12288. (c) Bornand, M.; Chen, P. Angew. Chem., Int. Ed.
2005, 44, 7909.
(6) See the Supporting Information for details of the crystal structure of R-1.
(7) For crystallographic evidence that a Lewis basic PMe3 associates trans to the
pyrrolide, see: Marinescu, S. C.; Schrock, R. R.; Li, B.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 58.
(8) The observed Mo-Br distance (3.04 Å) is significantly less than the sum of the
van der Waals radii for Mo and Br (1.85 and 2.00 Å, respectively).
(9) For additional examples, see the Supporting Information.
(10) For selected instances where Curtin-Hammett conditions have been illustrated
for metal-catalyzed enantioselective reactions, see: (a) Halpern, J. Science 1982,
217, 401. (b) Hughes, D. L.; Lloyd-Jones, G. C.; Krska, S. W.; Gouriou, L.;
Bonnet, V. D.; Jack, K.; Sun, Y.; Mathre, D. J.; Reamer, R. A. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5379. For additional cases, see the Supporting
Information.
The proposed mechanism, summarized in Scheme 5, offers a
rationale for low enantioselectivity at the nascent stages of RCM
with S-1 or R-1 (Tables 1 and 2). In reactions that commence with
S-1, little or no ethylene is initially present; thus, RCM likely
proceeds via R-9 to afford a significant amount of R-6 (minor
product enantiomer). When the catalytic cycle is initiated by R-1,
the faster-reacting S-9 is formed, and the major product isomer S-6
can be generated. If ethylene is available only at low concentration,
however, maximum enantioselectivity (∼96:4 er) cannot be achieved,
since ethylene can convert R-1 to S-11, which reacts with 5 to form
R-9, leading to the minor product enantiomer (R-6). Only when
sufficient ethylene is present, allowing inversion at Mo to occur at
an appropriately high rate, can S-9 become easily accessible, leading
to high enantioselectivity. The stereochemical outcome of the RCM
(11) For an X-ray structure of a monoaryloxide-monopyrrolide W-based methylidene
complex, see: Jiang, A. J.; Simpson, J. H.; Mu¨ller, P.; Schrock, R. R. J. Am. Chem.
Soc. 2009, 131, 7770.
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