Chiral Ru-based complexes for asymmetric olefin metathesis: Enhancement of catalyst activity through steric and electronic modifications

Article abstract of DOI:10.1021/ja0302228

Design, synthesis, characterization, and catalytic activity of six enantiomerically pure Ru-based metathesis catalysts are disclosed (3a-3f). The new chiral catalysts were prepared through steric and electronic alterations of the parent catalyst system (3

Full text of DOI:10.1021/ja0302228

Published on Web 09/18/2003
Chiral Ru-Based Complexes for Asymmetric Olefin
Metathesis: Enhancement of Catalyst Activity through Steric
and Electronic Modifications
Joshua J. Van Veldhuizen, Dennis G. Gillingham, Steven B. Garber,
Osamu Kataoka, and Amir H. Hoveyda*
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received April 11, 2003; E-mail: amir.hoveyda@bc.edu
Abstract: Design, synthesis, characterization, and catalytic activity of six enantiomerically pure Ru-based
metathesis catalysts are disclosed (3a-3f). The new chiral catalysts were prepared through steric and
electronic alterations of the parent catalyst system (3). The present studies indicate that the effect of structural
modifications of chiral complex 3 does not always correspond to those of the related achiral complexes.
The present findings illustrate that modified Ru complexes (3e and 3f) deliver reactivity levels that are
more than 2 orders of magnitude higher than 3. Reactivity and physical data are provided that shed light
on the origin of activity differences. Some members of the new generation of chiral Ru catalysts promote
asymmetric ring-opening (AROM) and ring-closing (ARCM) metatheses that cannot be effected by the first
generation chiral catalyst (3).
Chart 1
Introduction
Since isolation of 1a in these laboratories in 1996 (Chart 1),1
we have been involved in the development of a variety of
practical Ru-based metathesis catalysts2 that bear a bidentate
styrene ether ligand. Notably, these efforts have led to the
synthesis and characterization of recyclable Ru complexes 1b3
and 2.4 It has also been demonstrated that 2 exhibits reactivity
profiles that are unavailable through the related phosphine-
containing Ru catalysts.5 The unique stability and mechanism
of action5k of 1 and 2 has subsequently resulted in disclosures
regarding syntheses of supported variants.6 While the present
studies were in progress, electronically and sterically modified
benzylidene ether derivatives 2a7 and 2b8 were shown to exhibit
higher activity than 2; however, no data were provided regarding
the recyclability of these modified catalysts.
In connection to an initiative related to the development of
chiral variants of Ru catalysts represented by 2, we recently
reported the stereoselective synthesis and activity of optically
pure styrenyl ether carbene 3 as a complex that promotes
asymmetric olefin metathesis (AOM).9,10 We demonstrated that
asymmetric ring-opening metathesis/cross-metathesis (AROM/
(1) (a) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am.
Chem. Soc. 1997, 119, 1488-1489. (b) Harrity, J. P. A.; La, D. S.; Cefalo,
D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343-
2351.
(2) For reviews on catalytic olefin metathesis, see: (a) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. (b) Schmalz, H.-G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1833-1836. (c) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (d) Ivin,
K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization;
Academic Press: San Diego, 1997. (e) Furstner, A. Top. Catal. 1997, 4,
285-299. (f) Alkene Metathesis in Organic Synthesis; Furstner, A., Ed.;
Springer: Berlin 1998. (g) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 371-388. (h) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413-4450. (i) Randall, M. L.; Snapper, M. L. Strem Chemiker 1998, 17,
1-9. (j) Phillips, A. J.; Abell, A. D. Aldrichchim. Acta 1999, 32, 75-89.
(k) Wright, D. L. Curr. Org. Chem. 1999, 3, 211-240. (l) Furstner, A.
Angew. Chem., Int. Ed. Engl. 2000, 39, 3012-3043. (m) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(5) (a) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001,
624, 327-332. (b) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451-
1454. (c) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001,
430-432. (d) Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun. 2001,
1796-1797. (e) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001,
1692-1693. (f) Cossy, J.; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta,
V. Synlett 2002, 1595-1606. (g) Lazarova, T.; Chen, J. S.; Hamann, B.;
Kang, J. M.; Homuth-Trombino, D.; Han, F.; Hoffmann, E.; McClure, C.;
Eckstein, J.; Or, Y. S. J. Med. Chem. 2003, 46, 674-676. (h) Hale, K. J.;
Domostoj, M. M.; Tocher, D. A.; Irving, E.; Scheinmann, F. Org. Lett.
2003, 5, 2927-2930. (i) Nosse, B.; Chhor, R. B.; Jeong, W. B.; Bohm, C.;
Reiser, O. Org. Lett. 2003, 5, 941-944. (j) Demel, S.; Riegler, S.; Wewerka,
K.; Schoefberger, W.; Slugovc, C.; Selzer, F. Inorg. Chim. Acta 2003, 345,
363-366. For a study shedding light on the mechanistic principles that
govern the reactivity of nonphosphine Ru catalysts, see: (k) Love, J. A.;
Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl.
2002, 41, 4035-4037.
(3) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J.
Am. Chem. Soc. 1999, 121, 791-799.
(4) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179.
9
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J. AM. CHEM. SOC. 2003, 125, 12502-12508
10.1021/ja0302228 CCC: $25.00 © 2003 American Chemical Society

Efficient Chiral Ru-Based Complexes
A R T I C L E S
Chart 2. Second Generation Chiral Ru-Based Metathesis Catalysts Bearing Styrene Ether Ligands
Scheme 1
a 1. ClCF2CO2Me, CuI, KF, DMF, 120 °C, 16 h; 78%. 2. NBS, MeCN, 3 h; 82%. b Mg, THF, then 6, C6H6, 60 °C, 48 h; 95:5 diastereoselectivity; 84%.
c 1. KOH, EtOH, 80 °C, 18 h. 2. EtCO2Cl, Et3N; NaN3, -15 °C, C6H6, 80 °C; KOH; 84% overall. 3. BBr3, CH2Cl2; 90%. d 1. MesN(Boc)CH2CHO,
Na(OAc)3BH, 22 °C, 2 h. 2. HCl, MeOH, -78 °C, 5 min. 3. HC(OEt)3, 120 °C, 4 h; 81% overall. e PPh3 (vs PCy3) derivative of 1b, Ag2CO3, THF, C6H6,
75 °C, 30 min; 48%. Mes ) 2,4,6-trimethylphenyl.
CM) can be promoted with high enantioselectivity (up to 96%
ee) by 3 in cases where such processes are not feasible with
chiral Mo-based systems (competitive oligomerization).11 Fur-
thermore, we showed that reactions may be carried out in air
and with commercial grade undistilled solvents. As with
complexes 1 and 2, catalyst 3 can be recovered and reused.
Nonetheless, 3 proved to be less reactive than its achiral
analogue (2) probably as a result of various steric (large chiral
ligand) and electronic factors (replacement of a Cl with an
aryloxide). To access more active catalysts, we set out to prepare
new optically pure Ru carbenes through modifications of the
benzylidene and chiral ligands in 3. Synthesis and metathesis
activity of six new enantiomerically pure Ru carbenes are
described herein. The present findings illustrate that 3d and 3f
(Chart 2) deliver reactivity levels that are more than 2 orders
of magnitude higher than 3, and readily promote AOM reactions
that cannot be effected by the first generation chiral catalyst.
These studies indicate that the effect of structural modifications
in chiral complex 3 do not always correspond to those of the
achiral complexes, and that stereochemical attributes of a
substrate may exert a significant effect on the outcome of a
catalytic metathesis process.
(6) (a) Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto,
M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem., Int.
Ed. Engl. 2001, 40, 4251-4255. See also: (b) Grela, K.; Trynowski, M.;
Bieniek, M. Tetrahedron Lett. 2002, 43, 9055-9059. (c) Connon, S. J.;
Dunne, A. M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2002, 41, 3835-
3838. (d) Dowden, J.; Savovic, J. Chem. Commun. 2001, 37-38. (e) Yao,
Q. Angew. Chem., Int. Ed. Engl. 2000, 39, 3896-3898.
(7) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed.
Engl. 2002, 41, 4038-4040. For a related more recent disclosure, see: (b)
Grela, K.; Kim, M. Eur. J. Org. Chem. 2003, 963-966.
Results and Discussion
(8) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2002, 41, 2403-
2405.
Initial Mechanistic Considerations and Selection of Modi-
fied Chiral Ru Catalysts. For a variety of reasons we decided
to prepare the modified chiral catalysts that are shown in Chart
2. We surmised that the electron-withdrawing NO2 (para to the
ligating Oi-Pr) in 3a would weaken i-PrOfRu chelation and
facilitate initiation of the catalytic cycle. A similar influence
might also be expected from the electron-releasing OMe (para
to the RudC bond) in 3c where increased electron donation
(9) VanVeldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J.
Am. Chem. Soc. 2002, 124, 4954-4955.
(10) For an alternative class of chiral Ru catalysts for olefin metathesis, see:
Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-
3228.
(11) As an example, the reaction shown in Tables 1-2 affords only polymer-
ization products in the presence of chiral Mo-based complexes. For an
overview of Mo-catalyzed enantioselective olefin metathesis, see: (a)
Hoveyda, A. H.; Schrock, R. R. Chem., A Eur. J. 2001, 7, 945-950. (b)
Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 2003, 42, in
press
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A R T I C L E S
Van Veldhuizen et al.
Table 1. Relative Efficiency of Chiral Ru Catalysts
rel. ratea
rel. ratea
catalyst
R ) Ph
R ) n-C H
6
13
3
1
3
2
1
130
3
1
3
2
1
110
3
3a
3b
3c
3d
3e
3f
160
140
a See the Supporting Information for details on measurement of relative
rates.
Figure 1. Relative rates of AROM/CM reactions (to afford 11a) catalyzed
by various chiral Ru catalysts (22 °C). (Reactions with catalysts 3 and 3c
require 4000 min to proceed to >98% conv).
into the metal center would reduce its Lewis acidity. The above
hypotheses find support in reports regarding the catalytic activity
of achiral 2a (Chart 1);7a in addition, the validity of such
proposals in relation to chiral Ru complexes would be further
substantiated if 3b proved to be significantly less active than 3.
Complex 3d would establish whether a recent observation
regarding higher activity of its corresponding achiral analogue
(cf. 2 in Chart 1) pertains to this class of chiral Ru catalysts.8
Enantiomerically pure carbenes 3e and 3f allow us to determine
the significance of reduced electron donation to the Ru center
by the aryloxide oxygen.12
Table 2. Comparison of the Activity of Selected Chiral Ru
Catalystsa
entry
R
catalyst
time; conv (%)b
yield (%)c
1
2
3
4
5
6
Ph
Ph
Ph
n-C6H13
n-C6H13
n-C6H13
3
66 h; >98
22 h; >98
25 min; >98
46 h; >98
14 h; >98
20 min; >98
35
55
85
nd
74
54
3e
3f
3
3e
3f
a Enantioselectivities (75-82%) were determined by analysis of the (R)-
MTPA esters derived from the reduced diols (chiral HPLC; chiralpak AD
column). b Determined by 400 MHz 1H NMR analysis. c Isolated yields after
silica gel chromatography. nd ) not determined.
Synthesis of New Enantiomerically Pure Chiral Ligands
and Ru Catalysts. Ru carbenes 3a-3f were prepared in the
optically active form by reaction of the requisite chiral imida-
zolinium salt and an appropriate achiral Ru carbene (e.g., 1b,
Chart 1).9,13 The more electron deficient chiral ligand 9, needed
for access to complexes 3e and 3f, was obtained with excellent
diastereoselectivity (>98%) by the route depicted in Scheme
1. All the Ru complexes in Chart 2 are isolated as brownish
green solids, and can be purified by silica gel chromatography
in air with reagent grade solvents (hexanes and CH2Cl2). Chiral
Ru carbenes shown in Chart 2 are stable idefinitely under an
atmosphere of N2. Complexes 3b-3d and 3e are air stable; 3a
and 3f undergo ∼5% decomposition after one week and 48 h,
which promotes the AROM/CM of 10 (with styrene or 1-octene)
more than 100 times faster than 3 (see Table 1).Consistent with
extant mechanistic paradigms regarding the significance of the
relative Lewis acidity of the Ru center and the facility of the
coordination of the olefin substrate to the catalyst,12 the
electronically modified 3e is three times more potent than 3 in
promoting AROM/CM of 10. As can be seen from the data
shown in Figure 1 and Table 1, the positive effects detected
for 3d and 3e are additive: the doubly modified chiral complex
3f possesses the highest level of potency among those studied
(relative rate ) 140-160). It should be noted that all transfor-
mations shown in Table 1 proceed with approximately the same
levels of enantioselectivity as observed with 3 (75-82% ee).14
Moreover, product enantiopurities remain unchanged after
extended reaction times, indicating that observed selectivities
do not arise from kinetic resolution.
1
respectively (as judged by 400 MHz H NMR analysis).
Relative Reactivity of Various Chiral Ru Catalysts. To
examine the relative efficiency of the new chiral Ru catalysts,
their activity in promoting the AROM/CM reactions of 10 with
styrene and 1-octene was explored. The results of these studies
are illustrated in Table 1 and Figure 1 (for reaction of 10 with
styrene to afford 11a). As the data in Table 1 indicate, although
the presence of a NO2 group leads to a chiral catalyst (3a) that
is three times more active than 3, enhancement of reactivity is
significantly lower than that observed for 2a (vs 2).7 Further-
more, the presence of an electron-donating OMe group in 3b
results in a catalyst that is still twice as active as its parent
complex. Our studies indicate that electron donation to the Rud
C in 3c does not affect its catalytic activity. In contrast to the
above-mentioned electronic modifications, the steric alteration
that resulted in the highly active achiral catalyst 2b8 also seems
to enhance significantly the efficiency of chiral complex 3d,
The enhanced reactivity of the new generation of chiral
catalysts is especially evident by the representative data depicted
in Table 2. Reactions with 3e (entries 2 and 5, Table 2) proceed
significantly more efficiently than those promoted by 3 (entries
1 and 4), and the same transformations proceed to completion
(13) See the Supporting Information for experimental details. It should be noted
that the electron deficient styrene ether complex related to 3c (CF3 instead
of OMe) could not be prepared due to susceptibility of the requisite styrene
to undergo rapid polymerization.
(14) These are the same enantioselectivities observed with parent complex 3.
In our previous report (ref 9), enantioselectivity values for non-UV-active
products from reactions of 10 with 1-heptene and vinylcyclohexane were
measured by HPLC/ELSD methods to be >98% ee. Subsequent investiga-
tions indicated that ELSD methods are unreliable in measuring ee values
(of at least this class of compounds). Alternative approaches led us to
determine subsequently that the above reactions proceed in 80-82% ee.
The remaining enantioselectiVities in ref 9 are correct as initially reported.
(12) Sanford, M. S.; Henling, L. M.; Day, M. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 3451-3453.
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Efficient Chiral Ru-Based Complexes
A R T I C L E S
Table 3. Comparison of the Activity of Chiral Ru Catalysts 3 and 3da
a Conditions: 5 mol % catalyst, 2 equiv terminal olefin, 22 °C, THF, under N2 atm. b Determined by analysis of 400 MHz 1H NMR of the upurified
1
mixture. c Isolated yields after silica gel chromatography. d Determined by chiral HPLC and 400 MHz H NMR analysis of the derived (R)-MTPA esters.
nd ) not determined.
within minutes in the presence of chiral catalyst 3f (entries 3
and 6).
(2) Relative stereochemistry within a disubstituted olefin
substrate can exert a profound influence on enantioselectivity
of the Ru-catalyzed AROM/CM. For example, as depicted in
Table 3, although reactions of exo-anhydride 12 are only slightly
less selective than those with endo-anhydride 10, reactions of
endo 14 (85-88% ee; entries 7-8 of Table 3) are significantly
more enantioselective than similar transformations carried out
with exo substrate 20 (10% ee; entries 17-18 of Table 3).
(3) The stereochemical identity of the more substituted
AROM/CM substrate can significantly alter the efficiency of
the metathesis process. As shown in entries 15-16 and 19-20
of Table 3, whereas endo diol 18 is recovered unreacted even
Additional cases of Ru-catalyzed AROM/CM are shown in
Table 3. In all instances, reactions with chiral complex 3d are
notably more facile than those promoted in the presence of Ru
catalyst 3. As the data in entries 3-6 and 9-12 of Table 3
illustrate, such rate differences are more pronounced when
aliphatic olefin partners are involved. Several other issues
regarding the data presented in Table 3 merit mention:
(1) In all cases, the less reactive chiral catalyst 3 is recovered
more efficiently than complex 3d (see below for a more detailed
discussion on catalyst recovery).
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A R T I C L E S
Van Veldhuizen et al.
after 24 h, the derived exo substrate 22 readily undergoes
reaction (>98% conv in 0.25 to 1 h) albeit with minimal
enantioselectivity. The high reactivity of 22, and the fact that
reaction of 10 with styrene proceeds in the presence of one equiv
of n-octanol with identical efficiency and selectivity (with 5
mol % 3 or 3d), indicate that the positioning of the Lewis basic
sites relative to Ru carbene (formed through reaction of the
catalyst with the strained olefin) determines whether a neighbor-
ing alcohol function inhibits the AROM/CM.
catalysts (3d and 3f) are recovered less efficiently. Therefore,
it may be argued that factors which influence the release of the
active Ru catalyst may also reduce the facility with which the
styrene ether reassociates with the active Ru system (e.g., Ru-
methylidene) to regenerate the original chiral complex. It could
be suggested that, due to increased steric bulk of the chiral
ligand, and in contrast to complex 2, there is minimal regenera-
tion of the styrene ether Ru complex. That is, higher catalyst
activity resulting from more facile release of styrene ether could
lead to lower yield of chiral catalyst recovery.17
(4) Ru-catalyzed AROM/CM can be effected in air (vs under
an N2 atm) to afford the desired products in similar yields and
selectivities, but with lower yield of recovered catalyst. As an
example, the reaction shown in entry 7 (5 mol % 3) of Table 3
delivers 15a in 74% yield and 85% ee along with recovered 3
in 52% isolated yield (>98% conv in 2 h at 22 °C). When Ru
complex 3d (10 mol %)15 is used in air (cf. entry 8), reaction
proceeds to >98% conv in 30 min and the desired product (15a)
is isolated in 60% yield and 77% ee (<10% recovered 3d).
Possible Origins of Higher Catalytic Activity. In connection
to studies regarding electronically modified achiral catalyst 2a
(see Chart 1), it has been suggested7a that the higher activity of
3d and 3f may be the result of faster initiation of the catalytic
cycle due to a more facile release1 of the sterically demanding
phenyl-substituted benzylidene. This proposal finds credence
in the X-ray structure of 3d, illustrated in Figure 2. The presence
of the benzylidene’s phenyl group appears to restrict the space
available to the adjacent Oi-Pr, causing an increase in the C37-
C38-O-C39 dihedral angle and Ru-O bond length in 3d (vs
3).16 The congested steric environment of the phenyl-substituted
benzylidene in 3d is further manifested in the upfield shift of
its Oi-Pr methine proton (C39-H in Figure 2: δ 4.77 in 3 vs
δ 4.10 in 3d). This likely arises from restricted conformational
mobility of Oi-Pr and phenyl groups in 3d, situating the
methine C-H over the face of the adjacent aromatic ring.
To address the above questions, a crossover experiment
involving deuterium-labeled chiral Ru catalyst d6-3 was carried
out. We established that, as illustrated in eq 1, when catalytic
AROM/CM of 10 leading to 11 is affected in the presence of
an equivalent amount of nondeuterated styrene ether 24, 95%
of the recovered catalyst remains deuterated (as judged by 400
MHz 1H NMR analysis; >98% conversion after 4 h at 50 °C).
This finding suggests that, in the case of chiral Ru complexes
such as 3, the catalyst recovered at the end of a metathesis
reaction for the most part represents the unreleased chiral Ru
complex (11a obtained in ∼80% ee), and that return of the
styrene ether ligand is inefficient (otherwise, the presence of
24 would result in recovery of some amount of 3).18 Several
related points should be mentioned: (1) Treatment of d6-3 with
1 equiv of 24 in the absence of substrate (0.01 M solution in
THF; 4 h, 50 °C) leads to recovery of the deuterated catalyst in
90% yield without any detectable amount of 3 (<2% by 400
1
MHz H NMR). (2) Subjection of the more active 3d to one
equivalent of 24 in the absence of substrate (0.01 M) results in
a relatively more facile rate of exchange to afford 3 (∼10%
after 6 h at 22 °C). (3) Similar studies regarding achiral carbene
2 clearly indicate that, in contrast to the more sterically hindered
chiral catalysts, efficient return of the released ligand does
occur.4
Utility of the New Chiral Ru Catalysts in Efficient AOM.
1. Ru-Catalyzed AROM/CM. The enhanced activity of
aforementioned chiral catalysts allow for Ru-catalyzed AROM/
CM reactions to proceed with significantly lower catalyst
loadings. For example, formation of 11a is complete within 2
h in the presence of only 0.5 mol % 3f at 22 °C (65% isolated
yield), whereas with 5 mol % 3 reaction is complete (>98%
conv) after 66 h.
(15) Reaction in air with 5 mol % 3d proceeded to 50% conv after one h,
presumably due to instability of the more reactive and sensitive catalyst.
(16) Consistent with the above hypotheses, X-ray crystal structures of 3 and 3d
indicate that the Ru-O1 bond length is slightly longer in 3d than in 3.
Thus, Ru-O1 bond length is 2.252 Å in 3 and for 3d the two molecules in
the unit cell show bond lengths of 2.267 and 2.294 Å, respectively.
(17) The low recovery yield for 3a might be the result of less favorable
reassociation of the less Lewis basic p-NO2 styrene ether.
(18) Accordingly, the significantly lower yield of recovery of 3f (cf. data in
Table 3) is likely due to a combination of inefficient styrene ether return
and lower stability of the CF3-bearing Ru carbene. Moreover, recovery of
the fluorinated Ru catalysts, including 3e, is more cumbersome than the
derived nonfluorinated analogues.
Figure 2. X-ray crystal structure of chiral Ru complex 3 and 3d.
Efficiency of Catalyst Recovery and Its Mechanistic
Implications. As illustrated in Table 4, the two most active
9
12506 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Efficient Chiral Ru-Based Complexes
A R T I C L E S
Scheme 2
Scheme 3. Ru-Catalyzed ARCM Reactions
Table 4. Relative Efficiency of Chiral Catalyst Recovery from
Synthesis of 11Aa
partner; use of vinylcyclohexane leads to the formation of 26b
in 87% ee but with 1-octene 26c is obtained in 68% ee. The
enantiomerically enriched N-containing products can be func-
tionalized in a variety of manners, as exemplified by the
stereoselective formation of 27.
rec. cat.
yield (%)c
entry
catalyst
time (h)b
yield (%)c
1
2
3
4
5
6
7
3
3a
3b
3c
3d
3e
3f
66
21
29
58
0.5
22
0.4
35
74
83
94
82
55
85
90
65
92
92
65
88
<20
2. Ru-Catalyzed ARCM. Another important class of AOM
reactions examined are asymmetric ring-closing metathesis
(ARCM) processes.21 Several examples from our initial studies
(20) For representative reports on Mo-catalyzed AROM/CM, see: (a) Weath-
erhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 1828-1829. (b) La, D. S.; Sattely, E. S.;
Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,
7767-7778. (c) 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.
(21) For representative reports on Mo-catalyzed ARCM, see: (a) Alexander, J.
B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem.
Soc. 1998, 120, 4041-4042. (b) La, D. S.; Alexander, J. B.; Cefalo, D. R.;
Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120,
9720-9721. (c) Zhu, 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) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson,
J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553-
9559. (e) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.; Jamieson, J. Y.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139-3140. (f) Kiely,
A. F.; Jernelius, J.; A.; Schrock, R.; R.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 2868-2869. (g) Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.;
Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997.
a Conditions: 5 mol % catalyst, THF, 22 °C. b Time required for >98%
conv. c Isolated yield after silica gel chromatography.
The availability of highly effective chiral complexes gives
rise to new possibilities in catalytic AOM. The examples shown
in Scheme 2 are illustrative. Whereas Ru-catalyzed AROM/
CM of 2519 leads to <10% conversion with 3 (and likely result
in rapid polymerization with chiral Mo catalysts),20 in the
presence of 10 mol % 3d, diamide 26a is generated in 92% ee
and 65% isolated yield. As illustrated in Scheme 2, with this
class of heterocyclic olefin substrates enantioselectivity varies
depending on the steric requirements of the terminal alkene
(19) Ellis, J. M.; King, S. B. Tetrahedron Lett. 2002, 43, 5833-5835.
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A R T I C L E S
Van Veldhuizen et al.
in this area are outlined in Scheme 3. Noteworthy points
regarding the Ru-catalyzed ARCM transformations are:
the binding cavity of the chiral Ru complex; further mechanistic
details must await the outcome of additional studies.
(1) In all cases shown, in the presence of chiral catalyst 3,
<5% conversion to the desired product is observed.
Conclusions
(2) The present class of chiral Ru catalysts are more efficient
in effecting RCM of 1,6-dienes (to dihydrofurans) than 1,7-
dienes (to unsaturated pyrans); reactions of 1,7-dienes require
10 mol % catalyst loading to proceed to completion (45-50%
conv under identical conditions with 5 mol % 3d). It should be
noted that similar catalyst dependency has been observed in
Mo-catalyzed ARCM reactions20a,c and likely points to signifi-
cantly different structural requirements for the binding pockets
of chiral catalysts that effect five- vs six-membered ring
closures.22
We have prepared and examined the catalytic activity of
several sterically and electronically modified chiral Ru-based
catalysts for AOM. The chemistry of Ru carbenes 3a-3f and
the available crystallographic data shed light on various
mechanistic aspects of this class of nonphosphine Ru carbenes.
Furthermore, enhanced catalytic activities give rise to signifi-
cantly more efficient asymmetric processes (lower catalyst
loadings) and offer new possibilities for the development of
practical and synthetic protocols that cannot be promoted by
the alternative chiral metathesis catalysts.
(3) In reactions of 1,6-dienes (28, 31, and 34 in Scheme 3)
leading to five-membered ring products significant amounts of
homodimeric products (30 and 33) are formed when reactions
are carried out in THF. In contrast, reactions of 1,7-dienes (35,
37,23 and 39 in Scheme 3), although less efficient, do not
generate any homodimers in THF (<2% as judged by analysis
Given the stability of Ru carbenes (reactions can often be
carried out in air and with undistilled solvents) and their
functional group stability (complementary to Mo-based cata-
lysts),11 asymmetric Ru-catalyzed olefin metathesis promises
to make available practical protocols for useful methods in
enantioselective synthesis. Toward this end, as the present
studies indicate, additional classes of chiral Ru-based metathesis
catalysts must be designed and developed. Processes that
promote the formation of a wide range of cyclic structures
through efficient Ru-catalyzed ARCM likely receives priority.
This will probably be feasible only if an array of chiral
catalysts21 are made available that can be selected for particular
applications.
1
of 400 MHz H NMR).
(4) As illustrated in Scheme 3 (left column), ARCM of 1,6-
dienes in THF lead to the formation of significant amounts of
homodimeric compounds. When reactions are carried out in
toluene, <2% of these byproducts are formed with small or no
reduction in enantioselectivity.
(5) In contrast to triene 31 which bears cis olefins, attempted
ARCM of 34 in the presence of 5 mol % 3d leads to complete
recovery of the starting material (22 to 60 °C after 24 h in THF
or toluene). The remarkable difference in reactivity between
trienes 31 and 34, which incidentally does not exist in the case
of trienes 37 and 39, suggests strict geometrical constraints in
Acknowledgment. Financial support was provided by the
NSF (CHE-0213009). We thank Jason S. Kingsbury and
Elizabeth S. Sattely for helpful discussions.
Supporting Information Available: Additional experimental
procedures and crystallographic data (53 pages, print/PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) For a discussion of the concept of “catalyst generality”, see: Hoveyda, A.
H. In Handbook of Combinatorial Chemistry Nicolaou, K. C.; Hanko, R.;
Hartwig, W., Eds.; Wiley-VCH: Weinheim; 2002; pp 991-1016.
(23) The reaction of triene 37 in THF affords 38 in 65% ee; subsequent brief
solvent screening proved dichloroethane to be a superior medium.
JA0302228
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