Mechanistically inspired catalysts for enantioselective desymmetrizations by olefin metathesis

Article abstract of DOI:10.1002/chem.200800642

In asymmetric olefin metathesis reactions, the addition of halide additives is often required to augment enantioselectivities, despite the fact that the additives result in catalysts with diminished reactivities. The preparation of new chiral Ru-based catalysts was accomplished by exploiting previously reported mechanistic studies. The catalysts possess a high level of reactivity and successfully induce high levels of asymmetry in desymmetrization reactions without the use of halide additives.

Full text of DOI:10.1002/chem.200800642

DOI: 10.1002/chem.200800642
Mechanistically Inspired Catalysts for Enantioselective Desymmetrizations
by Olefin Metathesis
Pierre-AndrØ Fournier, Jolaine Savoie, Brice Stenne, Marion BØdard,
Alain Grandbois, and Shawn K. Collins*[a]
Abstract: In asymmetric olefin metathesis reactions, the addition of halide addi-
tives is often required to augment enantioselectivities, despite the fact that the ad-
ditives result in catalysts with diminished reactivities. The preparation of new
chiral Ru-based catalysts was accomplished by exploiting previously reported
mechanistic studies. The catalysts possess a high level of reactivity and successfully
induce high levels of asymmetry in desymmetrization reactions without the use of
halide additives.
Keywords: asymmetric catalysis
·
desymmetrization · N-heterocyclic
carbenes · olefin metathesis · ruthe-
nium
Introduction
Asymmetric olefin metathesis has tremendous potential as
an asymmetric technology because it has both inter- and in-
tramolecular variants, and results in the effective formation
of carbon–carbon bonds under mild and neutral condi-
tions.[1] Although the standard for asymmetric olefin meta-
thesis remains the Mo-based catalysts developed by Schrock
and Hoveyda, the development of chiral Ru-based catalysts
such as 1 and 2 (Figure 1), has continued to gain momentum
due to their bench stability and tolerance of functional
groups.[2–5] In many instances, the enantioselectivity in asym-
metric olefin metathesis reactions catalyzed by Ru-based
catalysts is improved through the addition of NaI as an addi-
tive. This results in substitution of the ClÀ ligands bound to
Ru by IÀ ligands and increases the enantioselectivity of sev-
eral different asymmetric processes. A downside to this
Figure 1. Olefin metathesis catalysts. PCy3 =tricyclohexylphosphine;
Mes=2,4,6-trimethylphenyl.
strategy is that iodide substitution can also affect the reac-
tivity of the catalyst, which is normally decreased. The lack
of sufficient reactivity in a catalyst can limit its substrate
scope. Herein we report the development of new highly re-
active catalysts for asymmetric desymmetrization reactions
that afford high enantiomeric excess (ee) values without the
use of halide additives.
[a] P.-A. Fournier, J. Savoie, B. Stenne, M. BØdard, A. Grandbois,
Dr. S. K. Collins
Department of Chemistry, UniversitØ de MontrØal
C.P. 6128 Station Downtown
Results and Discussion
MontrØal, PQ, H3C 3J7 (Canada)
Fax : (+1)514-343-7586
E-mail: shawn.collins@umontreal.ca
Recent studies into the ligand dynamics[6] of Ru-based cata-
lysts and the origin of stereoinduction in asymmetric Ru-cat-
alyzed metathesis reactions[7] have shed light onto how to
design more effective catalyst systems. Recently, our group
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800642.
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FULL PAPER
Table 1. ARCM[a] reactions with NaI and NaBr as additives.
designed the new Ru-based catalyst 4, which possesses a C1-
symmetric N-heterocyclic carbene (NHC) ligand for desym-
metrization reactions.[8] The ligand design was based upon
work by Chen and co-workers who prepared a Ru-based
olefin metathesis catalyst 3 containing a bidentate phosphine
ligand (Figure 1). During the metathesis catalytic cycle, the
two different diastereomeric carbenes possible, each exhibit
a different reactivity.[9] Moreover, stereoisomeric carbenes
have been implicated in AROM/CM (AROM=asymmetric
ring-opening metathesis, CM=cross metathesis) processes
involving catalyst 2.[10] We attempted to exploit these con-
cepts in the design of an asymmetric catalyst. Thus, the C1-
symmetric NHC ligand of catalyst 4,[11] was constructed with
an N-methyl group located syn to the carbene to afford in-
creased levels of reactivity. The enantioselectivity would be
controlled by the tBu groups of the NHC backbone, which
exert a chiral relay effect upon the adjacent N-aryl group.
Unfortunately, when catalyst 4 was used in the desymmetri-
zation of trienes, the enantioselectivity (ee) varied depend-
ing on the size of the ring formed. The triene 7 underwent
cyclization with 4 to afford the corresponding five-mem-
bered ring heterocycle in 82% ee, but the triene 8 cyclized
to the corresponding six-membered ring in only 28% ee
(Scheme 1).
Triene
n
Additive[b]
ee [%][c]
Conv [%][d]
1
none
NaBr
NaI
none
NaBr
NaI
none
NaBr
NaI
82
68
48
28
34
42
60
64
–
>98
>98
>98
>98
>98
41
2
3
>98
93
–
none
NaBr
NaI
33
35
42
>98
>98
>98
[a] ARCM=asymmetric ring-closing metathesis. [b] The solvent was
CH2Cl2 in the absence of additives and THF when additives were used.
Catalyst 4 and the additive were stirred in THF for one hour prior to the
addition of substrate. [c] Enantiomeric excesses were determined by
chiral GC: see the Supporting Information for chromatograms. [d] Deter-
1
mined by HNMR spectroscopy of the crude reaction mixture.
lization of 8 with catalyst 1a in the presence of NaI affords
excellent conversion (>98%) and ee (90%). The cyclization
of triene 9 in the presence of NaBr afforded only a slight in-
crease in ee to 64% from 60% and no conversion was ob-
served when NaI was used. Triene 10 differs from 7 in that
it lacks methyl groups on the olefins. The cyclization of 10
in the presence of additives afforded slight increases in ee.
This is in contrast to what was observed with triene 7, how-
ever the slight increase in ee for substrate 10 is similar to
what was observed by Grubbs.
The above studies demonstrate that the use of halide ad-
ditives is not certain to afford high ee values with all sub-
strates and catalysts. Given the failure of halide additives to
induce higher levels of enantiomeric excess with catalyst 4,
we were forced to envision new catalyst modifications that
could improve the enantioselection for desymmetrization of
trienes such as 8 and 9. However, any catalyst modifications
would have to conserve the high reactivity observed with 4.
On examining the mechanism for olefin metathesis, we the-
orized that a possible explanation for the lower ee values
observed with these trienes might be that NHC rotation is
possible during the catalytic cycle (Scheme 2). The oscilla-
tion of the carbene of 4 during the catalytic cycle is depicted
in Scheme 2. During the desymmetrization of trienes 7 and
8, the ring-closing step takes place at intermediate C, but
Scheme 1. Desymmetrization reactions of alkenes 7 and 8 with catalyst 4.
Due to the abundant literature precedent indicating that
iodide additives can help boost enantioselectivities in de-
symmetrization processes, we investigated the use of both
NaBr and NaI as additives in the desymmetrization of tri-
enes (Table 1). When the cyclization of triene 7 was con-
ducted in the presence of NaBr, the ee decreased to 68%
and was even lower when NaI was used (48% ee). This was
surprising as there were no previous reports of diminished ee
values when halide additives were used. In fact, Grubbs and
co-workers observed a large increase in ee (35 to 90%)
during the desymmetrization of 7, by using NaI as an addi-
tive with catalyst 1a. The conversion of triene 7 with either
1a or 4 was not affected by the halide additives. Intrigued
by these observations, we also conducted the same experi-
ments with triene 8. In the presence of NaBr or NaI addi-
tives, the ee values for the cyclization of 8 with catalyst 4
were observed to increase incrementally to 34 and 42% ee
respectively. Grubbs and co-workers have reported that cyc-
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S. K. Collins et al.
Scheme 2. Catalytic cycle for olefin metathesis, which involves carbene
rotation during a desymmetrization process.
the relative rate at which the ring-closing process occurs
should differ because cyclization of 7 produces a five-mem-
bered ring and cyclization of 8 produces a six-membered
ring. If the ring-closing reaction of 8 were to be sufficiently
slow as to permit NHC rotation at intermediate C during
the catalytic cycle, then intermediate D would be formed.
The subsequent ring closure of intermediate D would take
place in an achiral environment and erode the ee. Thus,
NHC rotation may be the cause of the low ee values ob-
tained in the desymmetrization to form six- and seven-mem-
bered rings,[8] in which the rate of ring closure may compete
with NHC rotation.
Figure 2. NOE spectroscopic analysis of catalyst 11 indicates rotation at
218C.
Table 2. ARCM reactions with chiral ruthenium catalysts 4 and 11.
NHC rotation has been observed in derivatives of catalyst
4, such as when its corresponding Hoveyda version 11 was
prepared. Interestingly, catalyst 11 was not formed as a
single rotational isomer like 4. In addition, NOE studies
confirmed that the NHC ligand of 11 was rotating at room
temperature (Figure 2).[12] If the NHC was capable of rota-
tion in the precatalyst, it was highly likely that NHC rota-
tion could occur during the catalytic cycle.
Entry
1
Triene
Catalyst
ee [%][a]
conv [%][b]
7
4
11
4
82
81
60
57
>98
>98
>98
>98
2
9
11
We were interested in seeing if NHC rotation in catalyst
11 would affect the enantioselective desymmetrizations to a
significant extent compared with catalyst 4. Interestingly,
when 11 was evaluated in two desymmetrization reactions,
the reactivity profile and enantioselectivities were similar to
those observed with 4 (Table 2). For example, the ring clo-
sure of trienes 7 and 9 with either 4 or 11 afforded ee values
within 1–3% of each other. Given the similarity of the re-
sults and that the NHC ligands of catalysts 4 and 11 are
identical, we assume that although the NHC in 11 is rotating
at room temperature, the reaction takes place in the confor-
mation in which the N-methyl group is syn to the carbene at
[a] Enantiomeric excesses determined by chiral GC: see the Supporting
Information for chromatograms. [b] Determined by HNMR spectrum of
the crude reaction mixture.
1
a much faster rate than when the N-aryl group is syn to the
carbene. This is purely an assumption, and it should be
noted that the rates of initiation of 4 and 11 are likely to be
significantly different.
Consequently, we envisioned preparing catalysts 5 and 6,
which possess additional aryl substituents (R1, see
Scheme 2). It was believed that the bulky tBu or Me groups
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Enantioselective Desymmetrizations by Olefin Metathesis
FULL PAPER
Table 3. ARCM reactions to form five- and six-membered rings.
on the N-aryl substituent would be oriented towards the car-
bene and chloride ligands and hence, might significantly
hinder rotation of the NHC ligand and thus increase the
energy barrier between intermediates C and D during the
catalytic cycle.
Triene
n
Catalyst[a] Additive ee [%][b] conv [%][c]
The NHC ligands 14 and 15 were prepared by using estab-
lished synthetic protocols[12] that were based upon those
used for the preparation of catalyst 4. The tetrafluoroborate
salts 14 or 15 were treated with (CF3)2CH3COK and Grubbs
1st generation catalyst in toluene at 608C for 6 h to afford
the catalysts 5 and 6 in 42 and 44% yield respectively
(Scheme 3). Both catalysts were isolated as a mixture of ro-
1
1b
1b
1c
1c
4
6
5
1a
4
6
–
NaI
–
NaI
–
–
–
NaI
–
30
87
46
90
82
82
81
90
28
92
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
2
–
1b
1b
1c
1c
4
–
NaI
–
NaI
–
–
75
85
92
92
6
>98
>98
>98
58
>98
>98
>98
6
5
94
75
–
1a
1a
1d
4
–
NaI
–
–
–
16
nd[d]
45
15
37
72
<2
92
>98
>98
Scheme 3. Synthesis
of
new
catalysts:
reaction
conditions:
a) (CF3)2CH3COK (1.5 equiv), PhMe then (PCy3)2Cl2Ru=CHPh
(1 equiv), 608C, 6 h. Only the major syn rotational isomer is shown
above.
6
[a] Catalyst loadings:
1
(2 mol%),
1
with NaI (4.0 mol%), 4–6
(2.5 mol%). The solvent was CH2Cl2 in the absence of additives and
THF when additives were used. Catalysts and 25 equiv of NaI were
stirred in THF for one hour prior to the addition of substrate. [b] Enan-
tiomeric excesses were determined by chiral GC (see the Supporting In-
tational isomers, in which NOE studies were used to deduce
that there was no NHC rotation in either precatalyst at
room temperature. The catalyst 5 was isolated in a 16:1 syn/
anti ratio, whereas catalyst 6 was isolated in a 3.9:1 syn/anti
ratio.[13] Neither of the two rotational isomers of either cata-
lyst could be separated by column chromatography.
1
formation for chromatograms). [c] Determined by HNMR spectroscopy
of the crude reaction mixture. For catalysts 4–6, no other products result-
ing from decomposition or from homocoupling are ever observed.
[d] nd=not determined.
Based upon the prior observations with catalyst 4, we as-
sumed that metathesis reactions involving the catalysts 5
and 6 would still show a high reactivity profile similar to
what was observed for catalyst 4. Indeed, in a series of test
reactions, catalysts 4 and 6 were allowed to react with triene
7 for five minutes and a >95% conversion was observed in
both cases.[14] A similar experiment was carried out with
triene 16. After five minutes, the catalyst 4 had achieved
37% conversion to the product while catalyst 6 had already
achieved 93% conversion. Despite the fact that catalysts 5
and 6 were obtained as a mixture of isomers, their reactivity
profiles are similar to or better than the parent catalyst 4.
We assume that all significant reactivity from catalysts 5 and
6 occurs from the major syn isomer. Hence, we would also
assume that the anti isomers of catalysts 5 and 6 would not
significantly contribute to any observed enantioselectivity
obtained during desymmetrizations.[15]
We were particularly interested in whether it was possible
to consistently attain high ee values in the absence of addi-
tives. For the ring closure of triene 7 to afford a five-mem-
bered ring, the ee values obtained with catalysts 5 and 6
were similar to those obtained with catalysts 4 and 1b when
NaI was used as an additive. Catalyst 1c can produce simi-
larly high levels of enantiomeric excess in the desymmetriza-
tion of 7 with additives, however in the absence of NaI the
ee decreases.
In the desymmetrization to form six-membered rings, cat-
alyst 6 was the optimal catalyst. In the desymmetrization of
8, the six-membered ring product was obtained in 92% ee—
a significant increase from the 28% ee that was obtained
with catalyst 4! In addition, the ee is again slightly improved
from that obtained with a mixture of 1a and NaI. Similar re-
sults were obtained for the ring-closing reaction of triene 16,
which was previously isolated in very low ee by using cata-
lyst 4. Gratifyingly, the cyclization with catalysts 5 and 6
gave the product in 75 and 94% ee respectively. Catalyst 1c
has been shown to afford similarly high levels of ee with
substrate 16, both with and without the use of NaI as an ad-
ditive, however use of NaI causes the conversion to decrease
We then tested catalysts 5 and 6 in various desymmetriza-
tion reactions and compared their results with those ob-
(Table 3).[16,17] For all entries,
tained with catalysts 4 and 1ACHTREUNG
catalysts 4, 5, and 6 are compared with catalysts containing
similar N-aryl substituents, and with the best results ob-
tained to date for that particular substrate.
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8693

S. K. Collins et al.
significantly. In addition, the ring closure of triene 17 with
catalyst 6 also afforded a higher ee than was observed with 4
(37% vs. 15%). Catalyst 1a affords the product in only
16% ee in the cyclization of 17 and lower conversion. Cata-
lyst 1d affords the highest ee for this substrate. In this case,
the use of NaI as an additive with catalyst 1a caused the re-
action to completely shutdown, demonstrating the possible
pitfalls of adding halides.
lyst 6 highlights that the rotational barrier of NHC ligands
in these catalysts may play a large role in determining their
reactivity and that it may be exploited in designing new
asymmetric catalysts. Although many studies into improving
the reactivity of Ru-based metathesis catalysts have cen-
tered on varying the structure of the benzylidene ligand,[19]
there has been renewed interest in employing modified
NHCs[20] to develop better catalysts, hence the studies de-
scribed herein should be of interest. The results with catalyst
6 also add further weight to the molecular modelling and ex-
perimental studies, which suggest that the carbene oscillates
during the catalytic cycle. The N-alkyl unit of the C1-sym-
metric NHC is of interest. The electronic and steric effects
of this unit on asymmetric olefin metathesis reactions are
currently under study. We are currently evaluating catalysts
analogous to 5 and 6, which contain different N-alkyl groups
in the hope of further clarifying the hypothesis of NHC ro-
tation. Nonetheless, the high level of reactivity and selectivi-
ty of these catalysts could open new avenues for asymmetric
olefin metathesis.
We also surveyed desymmetrizations to form seven-mem-
bered rings (Table 4). In the desymmetrization of 9 and 18,
Table 4. ARCM reactions to form seven-membered rings.
Triene
Catalyst[a]
ee [%][b]
conv [%][c]
1a
1c[d]
4
5
6
85
76
60
71
88
5
93
>98
>98
>98
Acknowledgements
1c[e]
6
92
94
65
>98
We thank the NSERC (Canada), FQRNT (QuØbec), CFI (Canada),
Boehringer Ingelheim (Canada) Ltd., Merck Frosst Centre for Therapeu-
tic Research and the UniversitØ de MontrØal for generous financial sup-
port.
[a] Catalyst loadings:
(2.5 mol%). [b] Enantiomeric excesses determined by chiral GC (see the
Supporting Information for chromatograms). [c] Determined by HNMR
spectrum of crude reaction mixture. For catalysts 4–6, no other products
resulting from decomposition or from homocoupling are ever observed.
[d] The catalyst was added in two portions. [e] Only 1 mol% of catalyst
was used.
1 (2 mol%), 1c with NaI (4.0 mol%), 4–6
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Hoveyda, in Handbook of Metathesis; R. H.Grubbs, Ed.; Wiley-
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R. R. Schrock, Chem. Eur. J. 2001, 7, 945–950. see also d) A. H.
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1
[3] a) T. W. Funk, J. M. Berlin, R. H. Grubbs, J. Am. Chem. Soc. 2006,
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catalyst 6 gave either comparable or slightly higher enantio-
selectivities than those obtained with 1c. For example, the
trienes 9 and 18 were cyclized in 88 and 94% ee respectively
with catalyst 6. Again, the advantage of these catalysts is
that halide additives, typically added with Ru-based cata-
lysts,[2,3,18] are not necessary to obtain high enantioselectivi-
ties. For example, the cyclization of 18 with catalyst 1a using
a NaI additive could afford similar ee values to catalyst 6,
but the conversion dropped to 5%. In addition, the conver-
sions of triene 18 are higher with catalyst 6 than with 1c.
[6] M. Bornand, P. Chen, Angew. Chem. 2005, 117, 8123–8125; Angew.
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[10] R. E. Giudici, A. H. Hoveyda, J. Am. Chem. Soc. 2007, 129, 3824–
3825.
[11] For other examples of olefin metathesis catalysts that contain mono-
dentate C1-symmetric NHCs see : a) K. Vehlow, S. Maechling, S.
Conclusion
The catalyst 6 was prepared by using mechanistic insight
gained from previous studies. This catalyst affords high
enantioselectivities in desymmetrization reactions without
the need for halide additives. The monodentate NHC ligand
of 6 was constructed by using a C1-symmetric design to
afford both high reactivity and high enantioselectivity. Cata-
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Enantioselective Desymmetrizations by Olefin Metathesis
FULL PAPER
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[12] See the Supporting Information for full details.
[13] Throughout this manuscript, syn refers to the case in which the N-
alkyl group of the NHC ligand is on the same side as the Ru car-
bene.
[14] Reactivity studies were performed as outlined in: T. Ritter, A. Hejl,
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[15] We have attempted to conduct variable temperature 1HNMR ex-
periments to determine the rotation barriers of the NHC ligands in
catalysts 4, 5, and 6. However, due to the instability of 5 and 6 at
higher temperatures, (catalysts 5 and 6 decompose in solution over a
period of twenty minutes making variable temperature NMR ex-
periments difficult to perform), we have not been able to collect any
meaningful data at this time.
[16] Although the high reactivity of catalyst 4 allows it to effect ring clo-
sure of five- and six-membered rings at 08C, the ee values were not
significantly improved and all desymmetrizations were performed at
reflux in CH2Cl2.
[17] The product yields from the desymmetrizations can be highly varia-
ble since many of the products are highly volatile. There is no indi-
cation that the crude reaction mixtures contain any homocoupling
or decomposition products.
[18] Halide additives have also been used with Ru-based catalysts con-
taining C1-symmetric bidentate ligands. See reference [5c].
[19] For recent efforts in improving catalyst reactivity through benzyli-
dine modification see: a) M. Bieniek, R. Bujok, M. Cabaj, N. Lugan,
G. Lavigne, D. Arlt, Grela, J. Am. Chem. Soc. 2006, 128, 13652–
13653; b) R. Bujok, M. Bieniek, M. Masnyk, A. Michrowska, A. Sar-
Received: April 3, 2008
Published online: August 7, 2008
Chem. Eur. J. 2008, 14, 8690 – 8695
ꢀ 2008 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
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