Directed catalytic asymmetric olefin metathesis. Selectivity control by enoate and ynoate groups in Ru-catalyzed asymmetric ring-opening/cross- metathesis

Article abstract of DOI:10.1021/ja070187v

A new concept in catalytic asymmetric olefin metathesis is introduced: a nonreacting enoate or ynoate group can be used to alter and significantly enhance the enantioselectivity. Catalytic asymmetric ring-opening/cross-metathesis (AROM/CM) processes proce

Full text of DOI:10.1021/ja070187v

Published on Web 03/08/2007
Directed Catalytic Asymmetric Olefin Metathesis. Selectivity Control by
Enoate and Ynoate Groups in Ru-Catalyzed Asymmetric Ring-Opening/
Cross-Metathesis
Russell E. Giudici and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received January 10, 2007; E-mail: amir.hoveyda@bc.edu
Table 2. Ru-Catalyzed AROM/CM Reactions of Cyclopropene 1a
Catalytic asymmetric olefin metathesis offers unique and efficient
pathways for the synthesis of enantiomerically enriched molecules.1
High enantioselectivity has been achieved through steric and/or
electronic tuning of catalysts,1,2 as well as by manipulation of the
structure of olefins.3 Herein, we demonstrate that R,â-unsaturated
carbonyls within a cross partner can significantly alter and enhance
enantioselectivity in asymmetric ring-opening/cross-metathesis
(AROM/CM) reaction.
The present study arose as part of a program directed toward
development of processes that deliver products of asymmetric cross-
metathesis,4 particularly those with an all-carbon quaternary ste-
reogenic center.3,5 We have probed the ability of chiral Ru
complexes, developed in these laboratories, to promote AROM/
CM2a,6 of cyclopropenes, a diverse and readily available class of
substrates.7 Because of the near exclusive use of styrenes in previous
investigations,4,6,8 our focus is on transformations that involve non-
styrenyl alkenes as cross partners.
Key initial findings are summarized in Table 1. In the presence
of 5 mol % chiral Ru complex 6,6 reaction of cyclopropene 1 with
styrene (2) delivers R-7 in 93% ee and 90% yield (entry 1); with
the less hindered 1-octene (3, entry 2), R-8 is obtained in only 17%
ee. Catalytic AROM/CM with iso-butyrate 4 (entry 3) is noteworthy
because, although it is not highly selective (30% ee), it furnishes
Supporting Information); assignment refers to major enantiomer.
the S isomer predominantly. More noteworthy is that when enoate
a Conditions: see Table 1. b Isolated yields of E and Z mixtures; all
conversions >98%. c 1H NMR analysis. d Chiral HPLC analysis (see the
5 is used, S-10 is generated in 85% ee and 77% isolated yield.
Thus, an ester (4) or, more efficiently, an enoate (5) can significantly
influence (enhance and reverse) the sense of asymmetric induction
in an olefin metathesis process.
7-8). (3) As indicated by the formation of 17 (86% ee, entry 7),
an alkyne can influence a catalytic AROM/CM. (4) In addition to
allowing access to products of high enantiomeric purity, coordinat-
ing groups can be used for further functionalization (e.g., conjugate
additions, catalytic cross-metathesis or 15-16 in catalytic cross
coupling). (5) In all instances, <2% of cyclic lactones from RCM
Table 1. Initial Observations
1
of the diene cross partners is detected (400 MHz H NMR). (6)
Reactions are only slightly less selective at 22 °C (e.g., 13 is
obtained in 83% ee, 3:1 E/Z, 71% yield). (7) Products shown in
Table 1 can, in principle, be obtained by catalytic asymmetric cross-
metathesis4 of 1,4-pentadienes bearing an all-carbon quaternary
stereogenic center at the allylic C3 position. Such processes,
however, would likely be inefficient, since the allylic all-carbon
quaternary center renders the requisite acyclic substrates unreactives
a complication resolved by the strain of cyclopropenes.
Other cyclopropenes can be used (eqs 1 and 2); 18 and 21
undergo reaction to afford 20 and 22 in 90% and 86% ee,
respectively. Three of the substituents of the stereogenic center in
22 are amenable to further functionalization. Products are hydro-
a Determined by chiral HPLC analysis; selectivity of E olefin products.
b Isolated yields of E/Z mixtures.
As illustrated in Table 2, substrates bearing a range of unsaturated
carbonyl groups undergo catalytic AROM/CM, providing E alkene
products in up to 98% ee. Several additional points are notewor-
thy: (1) Terminal (entry 1), trisubstituted (entries 2-4), and cyclic
(entries 2, 3) olefins have a significant positive effect on enanti-
oselectivity. (2) Minor Z olefin isomers are generated in lower ee
(entries 2-4 and 6), with the R isomer predominating (same as
9
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J. AM. CHEM. SOC. 2007, 129, 3824-3825
10.1021/ja070187v CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Probing the Origins of the Directing Effecta
Ia.13 Because of the bidentate NHC, formation of Ia (and 29)14 or
Ib via a metallacyclobutane15 proceeds with inversion at the Ru
center.16 Reaction of Ib with a diene cross partner (e.g., 28) gives
II (Ru inversion). Enoate coordination17 affords a Z carbene, causing
the approach of cyclopropene proximal to the biphenylate ligand
(alternative mode blocked by the chelated olefin), with the smaller
Me pointing syn to the complex.18 Reaction of 1 with II results in
another Ru inversion and initiates a fresh catalytic cycle. Ben-
zylidene III (Ia + styrene) reacts via an E carbene, causing 1 to
approach from the less hindered direction, leading to the opposite
sense of enantioselectivity (e.g., R-7). The minor E alkene enan-
tiomers, Z olefins, and aliphatic 8 likely arise through non-
coordinated variants of II and III (i.e., via E and Z carbenes, as
the barrier to carbene rotation is low).17
Chelation with Ru may involve a η2 or η4 complexation; the lat-
ter mode could entail Ru-I dissociation (IV f S-11) to allow for
substrate coordination. Cationic Ru complexes have been shown to
serve as olefin metathesis catalysts.19 The lability of Ru-halogen
bonds finds support in facile conversion of Ru chlorides to
iodides,2,6 and a recent study20 illustrates that with the achiral Ru
complexes bearing a bidentate carbene,21 halogen ligands readily
exchange at 22 °C.
a Same conditions as shown for Tables 1 and 2.
lyzed (aq LiOH, THF; 85-98% yield) to afford the corresponding
alcohols; E and Z allylic alcohols are separated by chromatography
to afford pure E olefins.
A rationale regarding the above findings relates to the affinity
of NHC-coordinated Ru for enoates and ynoates.9 This scenario is
supported by the observation that in the presence of 10 mol % PPh3,
AROM/CM of 1 and 5 (>98% conversion 48 h) leads to S-10 in
40% ee (vs 85% ee). The phosphine can compete for Ru binding
(reversible) with the resident enoate; alternatively, PPh3 may
conjugatively add (also reversible) to the enoate, thus diminishing
Ru complexation.10 Such a model (II and IV, Scheme 2) suggests
that chelation of a more distal enoate would be entropically less
favored. Homologous triene 23a is thus formed in 59% ee, and
23b, which benefits from the organizing effects of a gem-dimethyl,
is obtained in 79% ee. Also consistent is that the increase in the
size of ynoate substituents leads to lower ee: in contrast to alkyne
17 (entry 7, Table 2; 86% ee), Me- and Si-substituted 24a and 24b
are formed in 71% and 37% ee, respectively.
Acknowledgment. We are grateful to the NSF (Grant CHE-
0213009) for support. R.E.G. is a LaMattina Graduate Fellow.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
The involvement of Ru‚enoate chelation suggests that ligand-
to-metal donation as well as Ru f enoate back-bonding11 is critical.
Significant reduction of π Lewis basicity thus discourages enoate-
Ru chelation and lowers ee: γ-ketoester S-25 is formed in 66% ee
(vs 12 in 90% ee). Similarly, when the distal alkene is the less
Lewis basic (η2) phenyl group, (S)-26 is generated in 40% ee. Strong
diminution of π Lewis acidity can also be detrimental to selectivity:
diallyl ether S-27 (Scheme 1) is obtained in 27% ee (vs 85% ee for
S-10). The exceptionally high ee observed for vinylbromides (entries
5, 6, Table 2), particularly 15 (98% ee), may be partly due to the
halogen serving as a σ-donor (i.e., Br f Ru chelation). Halogen-
metal chelation is particularly favorable with d6 octahedral com-
plexes (e.g., II in Scheme 2).12 Studies to clarify this possibility
are in progress.
(1) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-
4633.
(2) (a) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502-12508. (b) Funk,
T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840-
1846.
(3) Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A.
H. J. Am. Chem. Soc. 2006, 128, 5153-5157 and references cited therein.
(4) Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed.
2006, 45, 7591-7595.
(5) Quaternary Stereocenters: Challenges and Solutions for Organic Syn-
thesis; Christophers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2006.
(6) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J.
Am. Chem. Soc. 2005, 127, 6877-6882.
(7) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis 2006, 1221-1245.
(8) La, D. S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J.
Am. Chem. Soc. 2001, 123, 7767-7778.
(9) Jia, G.; Meek, D. W.; Galluci, J. Organometallics 1990, 9, 2549-2555.
(10) This suggests that phosphine-bearing Ru carbenes would likely not be
effective in implementing this strategy (cf. ref 2b).
(11) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543-6554. (b) Sanderson, M. D.; Kamplain, J. W.; Bielawski, C.
W. J. Am. Chem. Soc. 2006, 128, 16514-16515.
Preliminary mechanistic models are presented in Scheme 2. The
catalytic cycle is initiated by the reaction of 6 with 1, affording
Scheme 2. Preliminary Mechanistic Models
(12) Kulawiec, R. J.; Crabtree, R. H. Coord. Chem. ReV. 1990, 99, 89-115.
(13) NMR experiments indicate the rapid formation (>98% conversion) of a
new carbene upon treatment of 1 with 6. When complex 6 is treated with
styrene, significant amounts of unreacted carbene remain after 24 h.
(14) Chiral styrenes represented by 29 can be detected by 1H NMR. Isolation
and determination of the corresponding E/Z and % ee, data that may shed
light on the mechanism of catalyst initiation, are in progress.
(15) Aldhart, C.; Chen, P. J. Am. Chem. Soc. 2004, 126, 3496-3510.
(16) Bornand, M.; Chen, P. Angew. Chem., Int. Ed. 2005, 44, 7909-7911.
(17) The proposed mode of chelation is supported by recent theoretical
studies: (a) Straub, B. F. Angew. Chem., Int. Ed. 2005, 44, 5974-5978.
(b) Correa, A.; Cavallo, L. J. Am. Chem. Soc. 2006, 128, 13352-13353.
(18) Preliminary studies indicate that cyclopropene substituents must be
significantly different in size for high enantioselectivity to be achieved.
(19) For examples of cationic Ru-based olefin metathesis catalysts, see:
Fu¨rstner, A.; Liebl, M.; Lehmann, C. W.; Picquet, M.; Kunz, R.; Bruneau,
C.; Touchard, D.; Dixneuf, P. H. Chem.sEur. J. 2000, 6, 1847-1857.
(20) Tanaka, K.; Bohm, V. P. W.; Chadwick, D.; Roeper, M.; Braddock, D.
C. Organometallics 2006, 25, 5696-5698.
(21) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179.
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