Highly active chiral ruthenium catalysts for asymmetric ring-closing olefin metathesis

Article abstract of DOI:10.1021/ja055994d

The synthesis of olefin metathesis catalysts containing chiral, monodentate N-heterocyclic carbenes and their application to asymmetric ring-closing metathesis (ARCM) are reported. These catalysts retain the high levels of reactivity found in the related

Full text of DOI:10.1021/ja055994d

Published on Web 01/19/2006
Highly Active Chiral Ruthenium Catalysts for Asymmetric
Ring-Closing Olefin Metathesis
Timothy W. Funk, Jacob M. Berlin, and Robert H. Grubbs*
Contribution from the Arnold and Mabel Beckman Laboratory of Chemical Synthesis,
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
Received August 31, 2005; E-mail: rhg@caltech.edu
Abstract: The synthesis of olefin metathesis catalysts containing chiral, monodentate N-heterocyclic
carbenes and their application to asymmetric ring-closing metathesis (ARCM) are reported. These catalysts
retain the high levels of reactivity found in the related achiral variants (1a and 1b). Using the parent chiral
catalysts 2a and 2b and derivatives that contain steric bulk in the meta positions of the N-bound aryl rings
(catalysts 3-5), five- through seven-membered rings were formed in up to 92% ee. The addition of sodium
iodide to catalysts 2a-4a (to form 2b-4b in situ) caused a dramatic increase in enantioselectivity for many
substrates. Catalyst 5a, which gave high enantiomeric excesses for certain substrates without the addition
of NaI, could be used in loadings of e1 mol %. Mechanistic explanations for the large sodium iodide effect
as well as possible mechanistic pathways leading to the observed products are discussed.
Introduction
interest in ruthenium-based olefin metathesis catalysts stems
from their increased functional group tolerance compared to the
The development of well-defined catalysts has made olefin
metathesis an important, reliable, and widespread method for
constructing carbon-carbon double bonds.1 Since the initial
report of asymmetric olefin metathesis for small molecule
synthesis,2 a variety of chiral, ruthenium- and molybdenum-
based alkylidene catalysts have been developed.3,4 The molyb-
denum catalysts have been shown to give excellent enantio-
selectivities in asymmetric ring-closing metathesis (ARCM),
asymmetric ring-opening/ring-closing metathesis (ARORCM),
and asymmetric ring-opening/cross metathesis (AROCM).5,6 Our
molybdenum systems, as well as their stability to air and
moisture.6b Two classes of chiral ruthenium catalysts have been
explored (Chart 1): those containing monodentate N-hetero-
cyclic carbenes (NHCs) with chirality in the backbone of the
carbene (2a and 2b) developed in our laboratory3c and those
containing chiral, bidentate NHC/binaphthyl ligands (6a and 6b)
developed by Hoveyda et al.3a,b While catalysts of the latter
type gave good enantioselectivities and yields for AROCM
reactions,7 they exhibited reduced reactivity and selectivity
toward ARCM relative to those of the former class.
The ruthenium catalysts containing monodentate, chiral
NHCs (2a and 2b) had the same air and moisture stability of
the parent catalyst 1a, as well as a similar level of reactivity.8
Additionally, we achieved a single example of 90% ee using
2b.3c On the basis of this initial discovery, and because ARCM
remains challenging for 6a and 6b, we decided to modify 2a
and 2b to enhance enantioselectivity and expand the substrate
scope of ARCM. The synthesis of new chiral ruthenium catalysts
for asymmetric olefin metathesis, as well as their reactivity and
selectivity in expanding the scope of ARCM, is reported herein.
Catalysts containing substitution on the aryl ring para to the
o-isopropyl group (3a, 3b, 4a, and 4b) showed enantioselec-
(1) For recent reviews on olefin metathesis, see: (a) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. (b) Trnka,
T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (c) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012-3043. (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (e) Ivin, K. J. J. Mol. Catal. A.: Chem.
1998, 133, 1-16.
(2) (a) Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499-
2500. (b) Fujimura, O.; de la Mata, F. J.; Grubbs, R. H. Organometallics
1996, 15, 1865-1871.
(3) Ruthenium catalysts: (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) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 4954-4955. (c) Seiders, T. J.; Ward,
D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228.
(4) Molybdenum catalysts: (a) Totland, K. M.; Boyd, T. J.; Lavoie, G. G.;
Davis, W. M.; Schrock, R. R. Macromolecules 1996, 29, 6114-6125. (b)
Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock, R. R.
J. Am. Chem. Soc. 1998, 120, 4041-4042. (c) Zhu, S. S.; Cefalo, D. R.;
La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R.
J. Am. Chem. Soc. 1999, 121, 8251-8259. (d) Alexander, J. B.; Schrock,
R. R.; Davis, W. M.; Hultzsch, K. C.; Hoveyda, A. H.; Houser, J. H.
Organometallics 2000, 19, 3700-3715. (e) Aeilts, S. L.; Cefalo, D. R.;
Bonitatebus, P. J., Jr.; Houser, J. H.; Hoveyda, A. H.; Schrock, R. R. Angew.
Chem., Int. Ed. 2001, 40, 1452-1456. (f) Tsang, W. C. P.; Schrock, R.
R.; Hoveyda, A. H. Organometallics 2001, 20, 5658-5669. (g) Hultzsch,
K. C.; Bonitatebus, P. J.; Jernelius, J.; Schrock, R. R.; Hoveyda, A. H.
Organometallics 2001, 20, 4705-4712. (h) Schrock, R. R.; Jamieson, J.
Y.; Dolman, S. J.; Miller, S. A.; Bonitatebus, P. J.; Hoveyda, A. H.
Organometallics 2002, 21, 409-417. (i) Tsang, W. C. P.; Jernelius, J. A.;
Cortez, G. A.; Weatherhead, G. S.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 2591-2596.
(5) (a) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2005, 127, 8526-8533. (b) Jernelius, J. A.;
Schrock, R. R.; Hoveyda, A. H. Tetrahedron 2004, 60, 7345-7351.
(6) For reviews of asymmetric olefin metathesis reactions, see: (a) Hoveyda,
A. H. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vol. 2, Chapter 2.3. (b) Schrock. R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (c) Hoveyda,
A. H.; Schrock. R. R. Chem. Eur. J. 2001, 7, 945-950.
(7) (a) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 12288-12290. Also see: ref 7.
(8) Scholl, M.; Ding, S.; Less, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
9
1840
J. AM. CHEM. SOC. 2006, 128, 1840-1846
10.1021/ja055994d CCC: $33.50 © 2006 American Chemical Society

Ring-Closing Olefin Metathesis Catalysts
A R T I C L E S
Chart 1. Ruthenium Olefin Metathesis Catalysts
Table 1. Relative Reactivity and Selectivity of Asymmetric
Ruthenium Catalysts
11 to 12a
13 to 14a
catalyst
eeb (%)
convc (%)
eeb (%)
convc (%)
2a
3a
4a
5a
2b
3b
4b
5b
35
31
30
46
90
84
87
90
>98
>98
>98
>98
>98
>98
>98
>98
83
81
75
92
86
90
85
92
>98
>98
>98
>98
68
>98
>98
58
a Reactions with 2a-5a (2 mol %) run in CH2Cl2; catalysts 2b-5b
generated by stirring 2a-5a (4 mol %) in THF with 25 equiv of NaI.
b Enantiomeric excesses determined by chiral GC; see Supporting Informa-
tion for chromatograms and proof of absolute stereochemistry. c Determined
1
by H NMR spectrum of crude reaction mixture.
tivities very similar to those of the parent chiral catalysts 2a
and 2b. However, substitution on the same side of the ring as
the o-isopropyl group (5a and 5b) caused an increase in
enantioselectivity to the extent that, in a number of substrates,
the dichloride catalyst 5a could be used at very low catalyst
loadings to obtain high enantiomeric excesses and conversions.
was present as a synthetic handle and was not expected to affect
enantioselectivities due to its remote location relative to the Ru
center. The chiral diamines were reacted with triethylortho-
formate to form dihydroimidazolium BF4- salts 9a-d in good
yields over two or three steps. Ligand substitution with bis-
phosphine compound 10 gave the desired chiral ruthenium
benzylidenes as brown solids.11 All of these ruthenium com-
pounds were purified using silica gel chromatography with non-
degassed solvents, and they were stored in air without significant
decomposition over a period of at least 3 months. Conversions
for the ligand substitution step were generally 90%, but
challenging chromatographic separations gave varied isolated
yields. The analogous catalysts with two iodides bound to the
ruthenium (2b-5b) were generated in situ by dissolving the
dichloride catalyst in THF in the presence of 25 equiv of NaI.
Enantioselectivities and Reactivities of Chiral Ru Catalysts
for ARCM. In our previous study we discovered that substrate
11, derived from (2E,5E)-3,5-dimethylhepta-2,5-dien-4-ol, gave
the highest enantioselectivities and good conversions, so this
substrate and a silyl ether analogue (13) were used to examine
the reactivities and enantioselectivities of the new catalysts. The
presence of trisubstituted alkenes was critical to obtaining high
enantiomeric excess using catalyst 2b with triene 11. As can
be seen in Table 1, catalysts 2a-4a gave relatively similar
enantioselectivities and conversions for substrate 11. In all of
these cases, the diiodide catalysts (2b-4b) caused dramatic
increases in the enantioselectivity of the reaction (i.e. 35% ee
with 2a, 90% ee with 2b). There is no simple pattern for
selectivity based on the steric bulk in the meta-position for
Results and Discussion
Design and Synthesis of Chiral Ruthenium Catalysts. In
our initial study we discovered that NHCs derived from
enantioenriched 1,2-diamines could transfer the chirality of the
backbone to the ortho-substituted N-aryl rings.3c This “gearing”
effect, which results in the ortho-subtituent of the unsymmetri-
cally substituted arene rings to reside on the face opposite to
the phenyl groups on the backbone, has been shown to induce
asymmetry in the ring-closing metathesis of prochiral trienes.
Using the ring-closing metathesis of 11 to form 12 as a test
reaction, we varied the backbone of the NHC as well as the
substituent in the ortho-position of the N-aryl rings and
discovered that 2b was the most successful catalyst, forming
dihydrofuran 12 in 90% ee. On the basis of the success of
varying the ortho-substitution, we explored catalysts containing
substitution in the meta-position of the N-bound aryl rings.
The synthesis of the chiral dihydroimidazolium salts (9a-
9d) was straightforward and modular (Scheme 1). Pd2(dba)3/
BINAP was used to couple the substituted aryl bromides (7a-
d) to commercially available (1R,2R)-diphenylethylenediamine.9,10
Compound 7b was used as a mixture of aryl bromides; thus,
the diamine coupling reaction was followed by a Pd-catalyzed
reduction to yield 8b. The p-methoxy group in aryl bromide 7c
(11) Although we have been unable to obtain X-ray quality crystals of 2a-5b,
the carbene derived from chiral salt 9d has been bound to [Rh(COD)Cl]2,
and an X-ray crystal structure of this complex shows that the isopropyl
groups are oriented anti to the phenyl rings on the NHC backbone. See
Supporting Information.
(9) Wolfe, J. P.; Buchwald. S. L. J. Org. Chem. 2000, 65, 1144-1157.
(10) Both enantiomers of 1,2-diphenylethylenediamine are commercially avail-
able. See Supporting Information for the synthesis of the aryl bromides
7b-d and other experimental details.
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A R T I C L E S
Funk et al.
Scheme 1. Synthesis of Chiral Ruthenium Olefin Metathesis Catalysts
catalysts 2-4: increasing the size of the meta group from H to
tert-butyl caused a sequential decrease in the enantiomeric
excess (2a-4a); but when NaI was added (2b-4b), it decreased
for m-isopropyl but increased again when the larger tert-butyl
group was in the meta-position. The largest difference in
selectivity was seen when catalyst 5a was used. An increase of
11% ee was observed relative to 2a, and 5b gave 90% ee just
as 2b. High conversions were obtained with all of the catalysts
in 2 h at 40 °C.
of the catalyst and therefore protecting it from various bi-
molecular decomposition pathways.12
Expanded Substrate Scope for ARCM. The ability of the
chiral ruthenium catalysts 2-5 to give high conversions and
enantioselectivities for the ARCM reactions of 11 and 13
encouraged us to examine other substrates which afford five-
to eight-membered rings upon ARCM. On the basis of the
results from our initial screen, catalysts 2b and 5a were used.
Two types of prochiral trienes were explored: alkenyl ethers
and alkenyl silyl ethers (Table 2). Conversions >90 and 90%
ees were obtained when generating five- and six-membered rings
12 and 16. The isolated yields were moderately reduced due to
the volatility of the products during the purification procedure.
The synthesis of a seven-membered ring from 17 occurred in
85% ee when 2b was used. Unfortunately the formation of the
desired product was only ∼5%, with the major species being
unreacted starting material and homocoupled product. The yield
for the same reaction could be drastically increased when
catalyst 5a was used,13 and because 5a is more selective than
the other catalysts in the absence of NaI (65% ee for 18 using
2a), the desired product could be obtained in 92% yield and
76% ee. Synthesis of an eight-membered ring was more
challenging, and 2b catalyzed the ARCM reaction of 19 to 20
in 85% ee, but with only a ∼2% yield. Attempts to increase
the yield using 5a resulted in a similar yield and a reduced
enantiomeric excess. This result was not surprising, as generating
When 13 was reacted with these catalysts, higher enantio-
selectivities were obtained without the need for NaI. As with
substrate 11, selectivity decreased as steric bulk in the meta-
position increased (catalysts 2a-4a). When the diiodide catalysts
2b-4b were used, enantioselectivities increased for all of the
reactions relative to those obtained using 2a-4a. Introducing
meta-substitution adjacent to the o-isopropyl group (catalyst 5a)
resulted in a 92% ee for the ring closing of 13 without the need
for NaI. This result was the highest enantiomeric excess for
ring-closing metathesis we had observed. Moreover, since the
dichloride catalysts are generally more reactive than the cor-
responding diiodide catalysts, complete conversion could be
achieved with lower catalyst loadings of 5a! Conversions with
catalysts 2b and 5b decreased relative to the reactions with the
dichloride catalysts when substitution was on just one side of
the N-bound aryl rings. On the other hand, conversions remained
high for catalysts 3b and 4b, which possess substitution on both
sides of the aryl rings. This increase in conversion may be due
to the substituent in the meta-position increasing the steric bulk
(12) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126,
7414-7415.
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Ring-Closing Olefin Metathesis Catalysts
A R T I C L E S
Table 2. ARCM Reactions with Chiral Ruthenium Catalystsa
a Conditions for reactions with 2b: NaI (25 equiv relative to catalyst) and 2a in THF (0.055 M in triene) for 1 h at room temperature, then add triene,
and stir for 2 h at 40 °C. Conditions for reactions with 5a: triene, CH2Cl2 (0.055 M in triene), and 5a for 2 h at 40 °C. b Enantiomeric excesses determined
1
by chiral GC; see Supporting Information for chromatograms and proof of absolute stereochemistry. c Determined by H NMR spectrum of crude reaction
mixture. d See footnote 13. e Never isolated as a pure compound. f Reaction done on a 4 mmol (0.95 g) of 13 scale. nd ) not determined.
eight-membered rings via ring-closing olefin metathesis is a
challenging problem.
Table 2 provides the best results between catalysts 2b and
5a. In most reactions (ARCM of 11, 13, 15, 21, and 23), the
yields and enantioselectivities are very similar whether catalyst
2b, 5a, or 5b is used. Because both 2b and 5a promote the
ARCM of five- to seven-membered rings, there is no need for
specific catalyst/substrate matching.
Trienes other than those discussed above were also examined
in the ARCM reactions (Table 3). Substrates analogous to 13
and 23, but lacking a terminal methyl group on the olefin (25
and 27), formed cyclic products 26 and 28 in reduced enantio-
selectivities and conversions. When the diiodide catalysts were
used, conversions were <20%. The lower conversions using
25 and 27 relative to 11 and 23 may be due to the formation of
a ruthenium methylidene versus a ruthenium ethylidene, re-
spectively. Ruthenium methylidenes are known to decompose
more rapidly than other ruthenium alkylidenes, and in these
cases decomposition may have occurred more quickly than the
cross-metathesis that introduces the ring-closing substrate to the
catalyst.14
Silyl ethers proved to be excellent substrates, as both six-
and seven-membered rings (14 and 22) formed in good
conversions and 92% ee with 5a. Catalyst loadings of 1 mol %
or less could be used in these reactions. The ring-closing of 13
illustrated that the high yield and enantiomeric excess were
maintained when the reaction was scaled up to almost 1 g of
substrate. Using the analogous diiodide catalyst 5b for ARCM
of 13 and 21 resulted in six- and seven-membered rings with
the same enantiomeric excesses but lower conversions than with
the dichloride catalyst 5a. Substrate 23, which placed the
prochiral center further from the trisubstituted olefins, also
underwent ARCM to form a seven-membered ring in good
enantiomeric excess and excellent yield with a substitution
pattern different from that of 22.
(13) A 1 mol % amount of 5a is added at the beginning of the reaction, and
then another 1 mol % is added after 2 h, and the seven-membered ring 18
is isolated in 92% yield with a 76% ee. When 2 mol % catalyst 5a is used
at the beginning of the reaction, a 74% yield is obtained. Presumably all
of the starting material is homocoupled first, and then a second metathesis
reaction forms the ruthenium alkylidene that leads to product. The
A number of variables other than catalyst and substrate in
the ARCM reactions were examined. Using a variety of solvents
typical for olefin metathesis, such as CH2Cl2, tetrahydrofuran
homocoupling reaction forms
a ruthenium methylidene, which may
decompose at roughly the same rate as it performs the desired olefin
metathesis reaction. Adding fresh catalyst allows most of the remaining
unreacted starting material and homocoupled product to proceed to the
desired seven-membered ring.
(14) (a) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207. (b)
Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
6543-6554. (c) Reference 12.
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A R T I C L E S
Funk et al.
Table 3. Challenging ARCM Substrates
Figure 3. Ethenolysis of 12.
meric excesses and reduced yields. No difference in enantio-
selectivity or conversion was observed when dry NaI was used
in place of ACS-grade NaI stored on the benchtop. This fact is
a testament to the moisture stability of these ruthenium-based
catalysts.
25 to 26a
27 to 28a
catalyst
eeb (%)
convc (%)
eeb (%)
convc (%)
2a
3a
5a
2b
3b
16
45
30
nd
nd
72
92
93
<2
6
-5
-5
-8
3
>98
>98
>98
15
Mechanistic Considerations in Model Determination. To
rationally design more reactive and selective chiral ruthenium
catalysts for olefin metathesis, we must first develop a model
which explains the enantioselectivity in these reactions. If the
ARCM reaction has a degree of reversibility, a decrease in
enantiomeric excesses over time would be expected. Although
this was not observed, further experiments were performed to
support the irreversibility of this reaction. When enantioenriched
14 was exposed to achiral catalyst 1a, no erosion of the
enantiomeric excess was observed, which suggests that once
the ring is formed, it does not undergo a secondary ring-opening/
ring-closing process. The same conclusion was drawn when
enantioenriched 12 was heated under 60 psi of ethylene in the
presence of 1a (Figure 3). Under these forcing conditions, the
enantiomeric excess of unreacted 12 did not erode, and the
ethenolysis product 28 also retained the stereochemistry from
the ARCM reaction.16
15
18
a Reactions with 2a-5a (2 mol %) run in CH2Cl2; catalysts 2b and 3b
generated by stirring 2a and 3a (4 mol %) in THF with 25 equiv of NaI.
b Enantiomeric excesses determined by chiral GC; see Supporting Informa-
tion for chromatograms and proof of absolute stereochemistry. c Determined
1
by H NMR spectrum of crude reaction mixture. nd ) not determined.
Figure 1. Solvent effect on enantioselectivity of ARCM.
In the ARCM reactions of the trienes described above, most
likely a ruthenium alkylidene derived from the least-substituted
olefin initially forms. This species binds one of the diastereotopic
olefins and, through a metallacyclobutane intermediate/transition
state, forms the ring-closed product. Our initial model3c assumed
olefin coordination occurred cis to the NHC (Scheme 2, lower
pathway), on the face opposite the isopropyl group (structure
30), and that interaction determined the absolute stereochemistry
of the product. The interaction of a halide ligand with a
substituent on the ring of the cyclic intermediate was also
proposed to be an important, stereodefining interaction.17 The
actual position of the coordinating olefin relative to the NHC
is unclear; experimental evidence exists to support olefin binding
both cis and trans to the NHC (Scheme 2).18 In the most recent
report on this issue,18c Piers and co-workers provide compelling
evidence for the observation of a 14-electron ruthenacyclobutane
trans to the NHC. Computational studies support olefin binding
trans to the NHC,19 and a recent computational study of 2b
reacting with 11 calculated that the diastereotopic olefin
coordinated trans to the NHC (Scheme 2, upper pathway).19a
Figure 2. Temperature effect on enantioselectivity of ARCM.
(THF), and benzene, had very little affect on the conversions
and enantiomeric excesses (Figure 1). The slight reduction in
selectivity for ARCM reactions in benzene suggests that solvent
coordination to the catalyst is not involved as in the molybdenum
systems.15 Lowering the temperature of the reactions to 0 °C
led to a small increase (4-5%) in enantiomeric excesses when
2a and 2b were used, but catalysts 3b and 5a formed the product
with slightly reduced (2-3%) enantioselectivities (Figure 2).
In all cases, the conversions were reduced to no greater than
40% even when 5 mol % of the catalyst was used and the
reaction was allowed to proceed for 24 h. The reactions which
used I- to form the diiodide catalysts had the best enantiose-
lectivities when NaI in THF was used; NaI in CH2Cl2 and
[Bu4N]I in either THF or CH2Cl2 resulted in reduced enantio-
(16) See Supporting Information for more details.
(17) Allowing the hydrogen instead of the nonmetal bound vinyl group to interact
with the iodide also puts the vinyl group in the pseudoequatorial position
of the ring (see 30).
(18) Evidence for cis-coordination: (a) Trnka, T. M.; Day, M. W.; Grubbs, R.
H. Organometallics 2001, 20, 3845-3847. Evidence for trans-coordina-
tion: (b) Tallarico, J. A.; Bonitatebus, P. J., Jr.; Snapper, M. L. J. Am.
Chem. Soc. 1997, 119, 7157-7158. (c) Romero, P. E.; Piers, W. E. J. Am.
Chem. Soc. 2005, 127, 5032-5033.
(19) (a) Costabile, C.; Cavallo, L. J. Am. Chem. Soc. 2004, 126, 9592-9600.
(b) Adlhart, C.; Chen, P. J. Am. Chem. Soc. 2004, 126, 3496-3510. (c)
Fomine, S.; Vargas, S. M.; Tlenkopatchev, M. A. Organometallics 2003,
22, 93-99. (d) Cavallo, L. J. Am. Chem. Soc. 2002, 124, 8965-8973. (e)
Vyboishchikov, S. F.; Bu¨hl, M.; Thiel, W. Chem. Eur. J. 2002, 8, 3962-
3975.
(15) Teng, X.; Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 10779-10784.
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Ring-Closing Olefin Metathesis Catalysts
A R T I C L E S
Scheme 2. Proposed Pathways Leading to the Desired Product
Due to the tilt of the ortho-substituted N-bound aryl ring,20 the
alkylidene is positioned underneath the isopropyl group (struc-
ture 32), which was found to be the “smaller” side of the aryl
ring (Figure 4), instead of underneath the ortho C-H bond
(structure 31). In addition to the position of the alkylidene
determining the absolute stereochemistry of the product, the
cyclic intermediate formed upon olefin binding is also important.
The pendent olefin not involved in the ring-closing reaction
prefers to be in the pseudoequatorial position of the forming
ring. Although the discussion presented here focuses on a
substrate that forms a five-membered ring, substrates that form
other ring sizes presumably have an energetically favored ring
conformation once olefin binding occurs. Therefore the topics
mentioned above can be extended to other ring-closing sub-
strates. The importance of the position of the substituents on
the ring in the cyclic transition state could explain the higher
enantioselectivities observed for the substrates containing di-
methylsilyl groups: there are more non-hydrogen substituents
on the ring, and therefore the energy differences for various
ring conformations are greater than those for substrates with
only methylenes in the ring.
excess of the product increased. With recent experimental and
computational studies providing evidence for olefin binding trans
to the NHC, we sought to relate our experimental data to the
suggested trans-binding mechanism. If olefin binding occurs
trans to the NHC, exchanging the chloride ligands for iodides
should not have a major steric impact on the transition state.21
Instead, the iodide ligands may have an electronic effect. When
the chlorides in 1a were exchanged for iodides (1b), phosphine
dissociation occurred more rapidly, but the reactivity of the
active species did not increase.14b In the case of the chiral
catalysts 2b-4b, a lower reactivity could increase the enantio-
selectivity by causing the reaction to proceed through a late,
more product-like transition state.22 The added steric bulk in
5a may hamper its reactivity enough to mimic the electronic
deactivation present in the diiodide catalysts 2b-4b, resulting
in a late transition state and higher degree of stereochemical
communication between the catalyst and the substrate. Substrates
25 and 27, which have alkenes with less steric hindrance
compared to substrates 13 and 23, may form products in lower
enantiomeric excess due to a higher reactivity with the catalyst.
Although recent studies suggest olefin binding occurs trans to
the NHC, and the observed absolute stereochemistry can be
justified using a proposed model based on trans binding, the
Our initial cis-binding hypothesis was supported by the fact
that when a larger halide ligand was present, the enantiomeric
(20) The X-ray crystal structure of an analogue of 2a in ref 3c shows that the
plane of the N-bound aryl ring is not orthogonal to the plane of the NHC.
QM/MM calculations in ref 19a concluded that the N-bound aryl rings of
a substrate-bound ruthenium alkylidene also are not orthogonal to the plane
of the NHC.
(21) Computations suggest that as the halide ligand increases in size (van der
Waals radii) from Cl- to I-, the X-Ru-X bond angle also increases. A
larger bond angle positions the halides closer to the RudCHR moiety (a
smaller angle means the halides are pulled away from the alkylidene), which
puts the halides in closer proximity to the reacting olefin, creating a smaller
pocket, and therefore a more selective reaction. See ref 19a.
(22) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Gu¨ler, M. L.; Ishida, T.; Jacobsen,
E. N. J. Am. Chem. Soc. 1998, 120, 948-954.
Figure 4. Suggested alkylidene position in trans-binding transition state.
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A R T I C L E S
Funk et al.
experimental data do not provide enough support to rule out a
cis-binding mechanism.
the forming ring also plays an important role in the transition
state.
The general interest in developing ruthenium olefin metathesis
catalysts stems from their ease of handling and their different
functional group tolerance relative to that of the molybdenum
catalysts. Catalysts 2a-5b, much like the achiral analogues,
are also stable to air and moisture, making them simple to use.
The synthesis of enantioenriched five- to seven-membered rings
has been illustrated, and although further development is needed
to expand the substrate scope of ruthenium-catalyzed ARCM,
catalysts containing chiral, monodentate NHC ligands are
promising due to their high activity, low catalyst loadings, and
ease of handling.
Conclusions
We have synthesized novel asymmetric olefin metathesis
catalysts, which contain chiral, monodentate NHC ligands and
have shown their use in asymmetric ring-closing metathesis of
prochiral trienes containing trisubstituted alkenes. Adding
substitution to the position para to the o-isopropyl group of the
N-bound aryl rings (3a and 4a) of the parent compound 2a had
a relatively small effect on the enantioselectivities of the ARCM
reactions. By exchanging the chloride ligands for iodides, an
increase in enantioselectivity was observed for catalysts 2b-
4b relative to 2a-4a. In the case of catalyst 5a, substitution on
the same side of the aryl ring results in enantiomeric excesses
in up to 92% and very high conversions with low catalyst
loadings (less than 1 mol %). Two proposed models for the
formation of the observed products have been discussed: if the
incoming olefin binds cis to the NHC, the stereodefining
interaction is the face of the ruthenium to which the olefin binds;
if the incoming olefin binds trans to the NHC, the stereodefining
interaction is the position of the alkylidene under the N-bound
aryl ring. In both cases, the position of the pendent olefin in
Acknowledgment. We thank the NIH for financial support,
Dr. Steven D. Goldberg and Angela Blum for helpful discus-
sions, and Donde Anderson, Dr. Michael Day, and Larry
Henling for the crystal structure of the Rh compound.
Supporting Information Available: Experimental procedures
and spectral data for catalysts, substrates, and products (pdf).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA055994D
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1846 J. AM. CHEM. SOC. VOL. 128, NO. 6, 2006