Enantioselective olefin metathesis with cyclometalated ruthenium complexes

Article abstract of DOI:10.1021/ja506611k

The success of enantioselective olefin metathesis relies on the design of enantioenriched alkylidene complexes capable of transferring stereochemical information from the catalyst structure to the reactants. Cyclometalation of the NHC ligand has proven to be a successful strategy to incorporate stereogenic atoms into the catalyst structure. Enantioenriched complexes incorporating this design element catalyze highly Z-And enantioselective asymmetric ring opening/cross metathesis (AROCM) of norbornenes and cyclobutenes, and the difference in ring strain between these two substrates leads to different propagating species in the catalytic cycle. Asymmetric ring closing metathesis (ARCM) of a challenging class of prochiral trienes has also been achieved. The extent of reversibility and effect of reaction setup was also explored. Finally, promising levels of enantioselectivity in an unprecedented Z-selective asymmetric cross metathesis (ACM) of a prochiral 1,4-diene was demonstrated.

Full text of DOI:10.1021/ja506611k

Article
pubs.acs.org/JACS
Open Access on 08/19/2015
Enantioselective Olefin Metathesis with Cyclometalated Ruthenium
Complexes
John Hartung,† Peter K. Dornan,† and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: The success of enantioselective olefin meta-
thesis relies on the design of enantioenriched alkylidene
complexes capable of transferring stereochemical information
from the catalyst structure to the reactants. Cyclometalation of
the NHC ligand has proven to be a successful strategy to
incorporate stereogenic atoms into the catalyst structure.
Enantioenriched complexes incorporating this design element
catalyze highly Z- and enantioselective asymmetric ring
opening/cross metathesis (AROCM) of norbornenes and
cyclobutenes, and the difference in ring strain between these
two substrates leads to different propagating species in the
catalytic cycle. Asymmetric ring closing metathesis (ARCM) of
a challenging class of prochiral trienes has also been achieved. The extent of reversibility and effect of reaction setup was also
explored. Finally, promising levels of enantioselectivity in an unprecedented Z-selective asymmetric cross metathesis (ACM) of a
prochiral 1,4-diene was demonstrated.
catalyst design, however, significant challenges remain.
Controlling olefin geometry in AROCM and ACM while
maintaining high enantioselectivity is difficult. Furthermore,
ARCM of unhindered trienes has so far been unsuccessful,
resulting in extremely low enantioselectivities.
INTRODUCTION
■
Olefin metathesis is a powerful method for the construction of
CC bonds in a large number of synthetic contexts, including
target oriented synthesis,1 polymer chemistry,2 and renewable
feedstock derivatization.3 Extensive efforts have been made to
design tailored catalysts for each application.4 The development
of asymmetric olefin metathesis catalysts has enabled the
synthesis of enantioenriched compounds containing olefin
functional groups, which are useful functional handles for
further transformations. Generations of Mo- and Ru-based
catalysts have been developed for asymmetric ring opening
cross metathesis (AROCM), asymmetric ring closing meta-
thesis (ARCM), asymmetric ring rearrangements (ARR) and
asymmetric cross metathesis (ACM) (Figure 1). These
methods have been applied in the synthesis of useful synthetic
building blocks and natural products.5 Despite progress in
The first chiral Ru-based catalyst (1, Figure 2)6 possessed a
C2-symmetric NHC ligand with chiral centers on the backbone
of the NHC and unsymmetrical N-aryl substituents. This chiral
information was relayed to the metal center through a gearing
effect.7 Complex 1 catalyzed desymmetrizing ARCM to afford
dihydropyrans in high ee. It was found that substitution of
chloride for iodide ligands resulted in higher ee but lower yield.
The highest levels of enantioinduction were obtained on
substrates with E-trisubstituted enantiotopic olefins; Z-trisub-
stituted or 1,1-disubstituted enantiotopic olefins reacted with
much lower selectivity. Subsequent modifications of the N-aryl
substituents resulted in a more selective catalyst (2)8 for ARCM
and AROCM, although the latter transformation took place with
poor E/Z selectivity.9 C1-symmetric NHC ligands employing a
geared arene substituent have also been developed by Collins10
and Blechert.11 For example, C1-symmetric catalyst 3 was
capable of performing ARCM to generate tetrasubstituted olefins
with good enantioselectivity.10e
Hoveyda has developed stereogenic-at-Ru complexes bearing
a binaphthyl aryloxide NHC substituent.12 These complexes,
which can be isolated as a single diastereomer, were used in
Figure 1. Representative examples of the four manifolds of asymmetric
olefin metathesis.
Received: July 1, 2014
Published: August 19, 2014
© 2014 American Chemical Society
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a
Scheme 1. Resolution of (rac)-5
a
(a) NaI, THF, 75% yield; (b) (S)-AgO2CCH(Ph)(OMe) (8)
(2 equiv), THF, 23 °C, 1.5 h, 97%; (c) (1) 6a, pTsOH·H2O, THF,
5 min; (2) NaNO3, THF/MeOH, 15 min, 43%.
facilitated a second exchange with enantiopure silver carbox-
ylate 8 (Scheme 1). Attempted exchange with several other
carboxylates was unsuccessful, for example, reaction with
the silver salts of α-methoxy-α-(trifluoromethyl)phenyl acetic
acid, N-acetyl tert-leucine, or N-acetyl phenylglycine resulted in
rapid decomposition. The mandelate-derived diastereomers 6a
and 6b were chromatographically separable (under N2
atmosphere), to afford a 45% yield (90% of theoretical) of
diastereomer 6a (>95:5 dr).18 A more rapid, but lower yielding,
route was discovered wherein trituration of the mixture of 6a
and 6b with 1:1 Et2O/pentane resulted in the isolation of pure
6a (77% of theoretical) due to the large difference in solubility
between the diastereomers. The latter procedure is a marked
improvement in the speed at which synthetically useful quantities of
enantioenriched 5 can be produced. Waste is avoided by the easy
recyclability of the washes containing the partially enriched
diastereomeric mixture. Pure carboxylate 6a was then converted
to the nitrate 5 by treatment with p-TsOH followed by NaNO3.20
Asymmetric Ring Opening Cross Metathesis
(AROCM). AROCM of strained olefins is a powerful method
for the construction of enantioenriched cyclic and acyclic
dienes containing up to 5 stereocenters. The products contain
two differentially substituted alkenes, which are poised for
subsequent chemoselective transformations.9,11−15,18,19,21
We proposed that the cyclometalated NHC complexes 5 and
6, which contain stereogenic carbon and Ru atoms, would
control the approach of the strained olefin reactant to the
reactive metal center leading to a highly stereoselective
AROCM reaction. The bulky adamantyl group limits approach
of the reactant olefin solely toward the opposite face of the
alkylidene. Strong preference for side-bound metallacyclic
intermediates would result in higher fidelity communication
of the stereochemical information stored in the NHC ligand.
Finally, the pocket capped by the N-aryl substituent of the
NHC is well suited for the Z-selective ring opening as it favors
the formation of all-cis metallacyclobutanes, which had been
previously observed in the context of ring opening metathesis
polymerization (ROMP).22
Figure 2. Selected enantioenriched Ru-based olefin metathesis
catalysts.
E-selective AROCM and ARCM of trienes containing
disubstituted enantiotopic olefins. Later, a modified complex
4 containing NHC backbone chirality and a biphenyl aryloxide
substituent was reported to have improved activity in E-selective
AROCM of terminal olefins,13 and to catalyze Z-selective
AROCM with vinyl ethers and vinyl sulfides.14 Subsequent
studies demonstrated that a higher energy diastereomer (differing
in configuration at Ru) is accessible. These diastereomers can
interconvert either through olefin metathesis, or a nonmetathesis
based polytopal rearrangement (thermal or Brønsted acid
catalyzed).15
Substantial progress has been made in the development of
cyclometalated Ru complexes such as (rac)-5, which catalyze
the Z-selective cross metathesis of terminal olefins.16 We
anticipated that these complexes could also be highly
enantioselective catalysts in asymmetric metathesis. A mechanistic
proposal has been developed based on the preference of these
complexes to react through side-bound metallacyclobutanes (syn
to the NHC). This orientation forces all substituents in the
forming metallacyclobutane to point away from the NHC N-aryl
group, thus favoring the formation of the Z-olefin product.17
Recently, it has been shown that (rac)-5 can be resolved to
generate enantioenriched 5. Complex 5 performs enantio- and
Z-selective AROCM of norbornenes18 and cyclobutenes.19
Herein, we disclose a full account of our synthetic and
mechanistic studies involving cyclometalated Ru-complexes 5
and 6 in Z-selective AROCM. Furthermore, these complexes
are shown to provide promising levels of enantioinduction in
two previously challenging transformations: ARCM of trienes
composed of terminal olefins and ACM of prochiral 1,4-dienes.
The impact of X-type ligand substitution on reactivity and
selectivity is also analyzed leading to identification of nitrate 5
as the optimal catalyst for desymmetrizing transformations.
In accord with this proposal, enantioenriched cyclometalated
complex 5 catalyzed the AROCM of norbornenes18 and
cyclobutenes,19 resulting in the first ruthenium-catalyzed
Z-selective and enantioselective ring opening of these strained
rings with simple terminal olefins (Table 1). 2,3-Di-endo-
substituted norbornenes afforded products in high Z-selectivity,
RESULTS AND DISCUSSION
Catalyst Synthesis. Resolution of (rac)-5 was accom-
plished by ligand exchange of nitrate for iodide, which
■
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Table 1. Selected Examples of Z-Selective AROCM Catalyzed by 5
a
b
c
d
Determined by chiral SFC on chromatographically purified products. From ref 18. Determined by 1H NMR spectroscopy. Determined by GC.
e
From ref 19.
and 2,3-dibenzyloxy substitution resulted in high enantiose-
lectivity (93%, Table 1, entry 1). Substrates bearing 7-anti and
7-syn substitution (9c and 9d) were well tolerated, affording
products in high ee (entries 3 and 4). However, the lack of 2,3
disubstitution appeared to have a strong influence on the
diastereoselectivity of the reaction. The strongest effect arose
from 7-syn substitution, which resulted in a preference for the E
product.23 Benzonorbornadiene 9e, possessing sp2 carbons at
the 2 and 3 positions, also resulted in reduced Z-selectivity,
although the products were formed in excellent enantiomeric
excess. Regardless of the E/Z selectivity, it was observed that in
cases where both geometrical isomers could be isolated, the E
and Z isomers were formed with identical enantioenrichment
(entries 3−5).
tolerated commonly used oxygen protecting groups as well as
free alcohols on both the cyclobutene (9f) and terminal olefin
(10c) reactants. Notably, in stark contrast to the outcome for
the norbornene AROCM, the ee’s of the Z and E products
differed considerably. This difference was observed in all 7 cases
where both isomers could be analyzed. The ee’s of Z and E
products ranged from 91 and 67% ee, to 93 and 86% ee (for
example, Table 1, entries 6−9).
To determine the stereochemical relationship between the
double bond isomers, E-9e and Z-9e were hydrogenated to
afford 12. Both reactions afforded the same major enantiomer
of 12 as determined by chiral SFC (Scheme 2), demonstrating
that the absolute configurations at the stereogenic carbons of E-
9e and Z-9e were identical. The equal magnitude and sense of
enantioenrichment suggests a common intermediate in the
AROCM of norbornenes from which the E and Z products are
ultimately generated.
In contrast to the reactions employing norbornenes, the
AROCM of cyclobutenes occurred with higher yield and
comparable levels of Z-selectivity.19 AROCM of cyclobutenes
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configuration of the AROCM products requires that the
methylidene intermediate of the cyclobutene AROCM possess
the opposite configuration at ruthenium compared to the
alkylidene in the norbornene AROCM. Nonproductive meta-
thesis events could potentially be responsible for epimerization
of the ruthenium center, providing access to the necessary
active species.
Scheme 2. Determination of Relative Stereoinduction in E
and Z Products
The effect of terminal olefin equivalents and concentration
on stereoselectivity has previously been studied for certain
catalysts.9,21a,f In an attempt to better understand the impact of
concentration and stoichiometry on the AROCM of
norbornenes and cyclobutenes, the reactions of 9b and 9c
with allyl acetate were studied in further detail. In the case of
2,3-di-endo substituted norbornene 9b, the Z/E ratio remained
constant and ee was only slightly affected by concentration and
equivalents of olefin (Table 2). A similar independence of
A possible explanation for the identical enantioenrichment of
the Z- and E-isomers is that a secondary metathesis process
isomerizes some of the Z product to the more thermodynami-
cally favored E product. However, this was ruled out by the
observation that the E/Z ratio of AROCM products was
constant throughout the course of the reaction and for several
hours after complete conversion. Likewise in the cyclobutene
AROCM, resubmission of product Z-11f to the reaction
conditions in the presence of enantiopure catalyst 5 resulted in
recovery of the pure Z product in identical enantioenrichment
and Z/E ratio. These experiments strongly suggest that
secondary metathesis proceeds at a negligible rate as compared
to the productive AROCM reaction.
Table 2. Effect of Concentration and Equivalents of
Terminal Olefin on the AROCM of Norbornene 9b
Our observations regarding AROCM of norbornenes and
cyclobutenes suggest that the structure and strain energy of the
cyclic olefin reactant dramatically alter the catalytic pathway
responsible for the mono-cross products (Scheme 3). The
identical enantioenrichment of the E and Z products formed in
the AROCM of norbornenes suggests that a methylidene
intermediate is involved in the enantiodetermining ring-
opening step. The resultant alkylidene then reacts with an
equivalent of terminal olefin to afford the monocross products.
Since the enantiodetermining step precedes the olefin geometry
determining step, the E and Z products must necessarily have
identical enantioenrichment.
In contrast, the E and Z AROCM products derived from
cyclobutenes are formed with different ee’s, suggesting that the
initial ring-opening step occurs through the alkylidene derived
from the terminal olefin. In the proposed pathway for the
AROCM of cyclobutenes with 5, the initial ring opening of the
strained olefin with an alkylidene derived from the terminal
olefin is diastereo- and enantiodetermining, resulting in the
difference in enantioenrichment for the E and Z products.24
The increased strain and lower steric demand of the
cyclobutenes result in propagation through a Ru-alkylidene
species, while the bulkier and less strained norbornenes result
in propagation through a Ru-methylidene. The absolute
a
b
c
concentration (M) equiv 10a conversion (%)
Z/E ratio
Z ee (%)
d
0.05
0.1
7
7
7
3
>95
>95
>95
40
97:3
97:3
98:2
97:3
75
74
75
72
e
0.5
0.5
a
b
Determined by 500 MHz 1H NMR. Determined by GC.
c
Determined by chiral SFC on chromatographically purified products.
Full conversion achieved after 16 h. Full conversion achieved after 4 h.
d
e
diastereoselectivity and ee were observed in the AROCM of
cyclobutenes.19
While the ee of Z-11c produced by the AROCM of 9c with
allyl acetate was unaffected by concentration and equivalents of
terminal olefin, the Z/E ratio was dependent on both variables
with higher concentration and more terminal olefin favoring
Z-11c (Table 3). Thus, in the absence of chelating substituents
on the strained olefin component, the diastereodetermining
cross metathesis with the terminal olefin is dependent on the
concentration of the terminal olefin. A similar dependence of
olefin geometry on concentration is observed in ROMP
catalyzed by homogeneous alkylidene initiators.25 In ROMP,
Scheme 3. Proposed Change in Mechanism for AROCM of Norbornenes and Cyclobutenes
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initial alkylidene formation occurs on one of the two
enantiotopic olefins, followed by cyclization with the unique
olefin. If initial alkylidene formation is irreversible, then this
step is enantiodiscriminating. In pathway B, initial alkylidene
formation occurs with the unique olefin, and this alkylidene
subsequently cyclizes with one of the two enantiotopic olefins
in the enantiodiscriminating step. To a first approximation, an
enantiodiscriminating cyclization step is more likely to be
highly enantioselective than alkylidene formation, because of
the ordered nature of a cyclic transition state. Furthermore, in order
to achieve high enantioselectivity, it is desirable to ensure that only
one pathway is operating. Competing pathways will lead to
decreased enantioselectivity unless they are both highly enantiose-
lective for the same product enantiomer (an unlikely scenario).
The substitution pattern of the enantiotopic olefins can also
impact the relative energy of diastereomeric transition states.
Cavallo has performed computational studies on the origin of
stereoselectivity with geared NHC Ru complexes.7 It was found
that the nonreacting olefin is oriented in pseudo-equatorial and
pseudo-axial positions in the respective diastereomeric cyclization
transition states. Higher selectivities are therefore expected when
this substituent is large, leading to a large energy difference
between pseudo-equatorial and pseudo-axial configurations.
We felt that the necessity of employing highly substituted
enantiotopic olefins has limited the potential utility of ARCM
products. We have previously observed that chelated complexes
such as (rac)-5 are sensitive to steric bulk at the allylic
position.16e We hypothesized that resolved complex 5 would be
an ideal candidate for ARCM of trienes such as 13, since this
catalyst would likely disfavor initial alkylidene formation with
the enantiotopic olefins and favor initial reaction with the allyl
fragment. This preference would bias the system to undergo
enantiodetermining ring closing metathesis, a pathway that is
likely to lead to higher enantioinduction. Success of this
strategy would improve the scope of the ARCM reaction by
allowing the generation of cyclic products lacking the
cumbersome substitution on the resultant product alkenes.
Furthermore, we wondered whether the addition of further
steric bulk, through modification of the X-type ligand, could
positively impact enantioselectivities. Complexes 6b−6i
(Scheme 5) were prepared by ligand exchange from enantio-
enriched iodide ent-7.29 This reaction proceeded to full
conversion based on 1H NMR and afforded products of
sufficient purity after concentration, redissolution in benzene,
and filtration through a short plug of Celite.
Table 3. Effect of Concentration and Equivalents of
Terminal Olefin on the AROCM of Norbornene 9c
a
b
c
concentration (M) equiv 10a conversion (%)
Z/E ratio
Z ee (%)
0.1
0.5
0.5
7
7
3
>95
>95
>95
44:56
70:30
59:41
96
95
96
a
b
Determined by 500 MHz 1H NMR. Determined by GC.
c
Determined by chiral SFC on chromatographically purified products
it has been proposed that the concentration dependence arises
from a rate competition between first order rotation of the
alkylidene and second order [2 + 2] cycloaddition with the
incoming monomer. Higher concentrations have a greater
influence on the second order process. In the current
AROCMs, we propose that a similar effect is occurring with
the dependence on concentration and the incoming reactant.
This dependence suggests that cross metathesis to release the
mono-cross product competes with rotation of the alkylidene.
Asymmetric Ring Closing Metathesis (ARCM). A
considerable amount of work has been performed on catalyst
development and applications for ARCM.6,8,10,11a,12b,26 The
products of desymmetrizing ARCM are potentially useful in
target-oriented synthesis since two differentiated olefins are
present in the final enantioenriched product. These olefins
provide an ideal platform for further functionalization. ARCM
has been used as the key step in a number of natural product
total syntheses.5b,26n,p,27 Despite much progress, ARCM
substrates have largely been limited to cases where the unique
olefin is considerably less bulky than the enantiotopic olefins.
Only isolated examples of all-terminal trienes lacking allylic
quaternary substitution have proven successful.26h,n,28 Further-
more, it has been noted in several reports that attempted ARCM
of various all-terminal trienes have been unsuccessful, due either
to low ee26f,g,o,s or formation of oligomers.26i The ARCM of
unhindered trienes is particularly challenging due to the difficulty
in controlling the cyclization pathway, and the need to
differentiate between relatively small enantiotopic groups.
The RCM of prochiral trienes can, in principle, proceed
through two distinct pathways (Scheme 4). In pathway A, the
Complexes containing achiral carboxylate ligands (6c−6e)
and enantiopure carboxylates (6b, 6f−6i) were obtained. While
the cyclometalated iodide complex ent-7 was inactive in RCM,
all of the carboxylate complexes were found to be competent
catalysts with varying levels of enantioselectivity (Table 4).
Thus, while κ2 ligands are more active than monodentate
ligands, the electronics and sterics of the carboxylate ligand also
impact the ARCM reaction.
Scheme 4. Possible Pathways to ARCM Products
More substituted aliphatic carboxylates, such as the pivalate
6e and N-acetyl amino carboxylates 6g−6i, were more
competent catalysts than acetate 6c, forming the product in
essentially full conversion (entries 5, 7−9). While the steric
bulk of the amino acid side chain had little bearing on the
enantioselectivity (no difference was observed between alanine
and valine), the presence of an electron-withdrawing heteroatom
in the α position of the carboxylate afforded a more
enantioselective catalyst. For example, the 2-phenylbutyric acid-
derived catalyst 6f generated the product in only 18% ee, while
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a
Scheme 5. Synthesis of Carboxylate Complexes
Table 5. Scope of ARCM Reaction with 5
Table 4. Efficiency and Enantioselectivity of 1, 5, 6b−6i, and
ent-7 in ARCM of 13
a
b
entry
catalyst
conversion (%)
ee (%)
1
ent-7
6b
6c
6d
6e
6f
<2
>98
35
ND
42
36
53
46
18
42
43
40
54
0
2
3
4
35
5
76
6
>98
>98
48
7
6g
6h
6i
8
9
72
10
11
5
>98
a
Reaction conditions: triene (0.5 M), 5 (5 mol %), THF, 23 °C, 24 h.
Determined by H NMR using mesitylene as an internal standard.
1
20
b
1
a
b
1
Determined by H NMR spectroscopy; Determined by chiral SFC
c
Using 10 mol % catalyst.
analysis
the relatively isosteric O-methyl mandelate 6b provided 13 in
42% ee (entries 6 and 2).30 The stereochemistry of the
carboxylate has little influence on the stereochemical outcome
of the ARCM as complexes 6g and 6h, containing either D- or
L-alanine carboxylates, gave identical ee (entries 7 and 8). We
concluded that the nitrate catalyst 5 (98% conversion, 54% ee,
entry 10) was a significant improvement to the previous
generation geared catalyst 1 (20% conversion, 0% ee, entry 11)
and sought to study the reaction scope enabled by this advance.
We next probed the influence of substitution in the allylic
position, nature of the heteroatom, and ring size on the
efficiency and enantioselectivity of ARCM. Prochiral trienes
composed of monosubstituted olefins were cyclized cleanly,
resulting in generally high yields (Table 5). Moving from a
dimethyl siloxy to the bulkier diphenyl siloxy tether resulted in
a slower cyclization and required an increase in catalyst loading
to achieve good conversion (entries 1 and 2). Triene 19, which
contains trisubstituted enantiotopic olefins, did not undergo
ring closure (entry 3). Saturated nitrogen-containing hetero-
cycles were formed in high yield and moderate enantioselec-
tivity, (entries 4 and 5).
A particularly challenging substrate 23, bearing a fully
substituted carbon in the allylic position of the 1,4-diene
moiety, completely shut down the reaction (entry 6). On the
other hand, the presence of a fully substituted carbon in the
homoallylic position, as in 25, restored reactivity (entry 7).
These results suggest that reducing the steric bulk of the
catalyst, perhaps through the use of alternative cyclometalated
NHC ligands, may expand the scope of the reaction to form
synthetically challenging tertiary ether products.
Triene 27, containing a homoallyl diphenyl silyl group, was
synthesized in order to test the efficiency of forming seven
membered rings (Figure 4a). In contrast to triene 17, 27
underwent ring closure under the standard conditions in good
yield, indicating that the additional methylene unit was
sufficient to relieve the steric bulk of the diphenylsilyl unit.
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Surprisingly, the product was racemic. To probe whether
enantioselectivity is lost due to reversibility, the reaction was
1
performed in a sealed NMR tube and monitored by H NMR
(Figure 3). After 4 h, 71% conversion had been achieved.
Figure 5. ORTEP drawing of 14.
The absolute configuration of diene 14 (Figure 5) produced
by ARCM of 13 with 5 was determined by X-ray crystallo-
graphic analysis to be (2S). On the basis of the absolute
configuration of 14, we propose that enantioinduction arises
from the favorable conformational effect of placing the
unreacted vinyl group of the 1,4-diene fragment in a pseudo-
equatorial, as opposed to pseudo-axial, orientation (Figure 6).
Figure 3. Time course for the ARCM of 27 (closed NMR tube).
However, the reaction eventually stalled at 78% conversion.
Upon purging ethylene from the NMR tube, the reaction
resumed and eventually reached 92% conversion. This result
suggests that in a closed vessel, the RCM of 27 is reversible,
and equilibrium can be reached prior to full conversion. The
reversibility of the reaction erodes any enantioenrichment that
is initially achieved. Therefore, efficient removal of ethylene is
required to obtain enantioenrichment.
To remove ethylene during the course of the ARCM
reaction, the reaction was performed in an open vial in a
nitrogen filled glovebox (Figure 4). After 24 h, full conversion
Figure 6. Tentative transition state model for the formation of (2S)-14.
Asymmetric Cross Metathesis (ACM). Cross metathesis
of prochiral 1,4, 1,5, or 1,6 dienes to afford desymmetrized
metathesis products has remained an elusive method for the
construction of allylic and homoallylic stereocenters. The lack
of success is likely due to three factors: (1) difficulty in
controlling the nature of the propagating species; (2) limiting
secondary metathesis events resulting in symmetrical products;
and (3) designing a chiral environment capable of high levels of
enantioinduction. However, a previous example of ACM
suggested that enantiopure Ru-based metathesis catalysts are
capable of desymmetrizing cross metathesis, although in
modest yields (17−54%) and ee’s (4−52%).9
After optimization of reaction conditions, we have observed
that cyclometalated complex 5 catalyzes the ACM of 1,4 diene
29 with cis-1,4-diacetoxy-2-butene in 35% yield and with a
promising ee of 50% (eq 1). In contrast to the previous report
Figure 4. (a) Effect of open vial on enantioselectivity in ARCM of triene
27; (b) Effect of open vial on enantioselectivity in ARCM of triene 13.
of starting material was achieved, and the 7-membered product
was generated in 37% ee. This result demonstrates the
importance of assessing reversibility in ARCM reactions and
suggests that removal of ethylene limits reversibility. Triene 13
was also subjected to open vial conditions (Figure 3b). Although
reactivity was slightly diminished relative to closed vial conditions,
the product was generated in an almost identical 58% ee,
(compared to 54% ee for closed vial).31 Therefore, reversibility is
not significant with triene 13. The reversible nature of the ARCM of
27, but not 13, is most likely due to the increased ring strain of 28.
of E-selective ACM with C2-symmetric catalysts, this method
provides the Z-isomer. While these results are preliminary,
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they suggest that further optimization of the ligand set and
choice of the proper substitution on the pro-stereogenic carbon
atom of the diene reactant may result in highly enantioenriched
1,4-diene products, which will be useful chiral building blocks in
complex molecule synthesis.
REFERENCES
■
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CONCLUSION
■
Cyclometalated ruthenium complexes, which are resolved by
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diversified by ligand exchange, have demonstrated high levels
of enantioinduction in the reaction manifolds comprising
enantioselective olefin metathesis. AROCM of cyclobutenes
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
rhg@caltech.edu
■
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8527. (b) Keitz, B. K.; Endo, K.; Herbert, M. B.; Grubbs, R. H. J. Am.
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10185.
Author Contributions
†J.H. and P.K.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NIH (5R01GM031332-
27 to R.H.G.) and the NSF (CHE-1212767 to R.H.G.). Thanks to
Mr. L. M. Henling for X-ray crystallography. The Bruker KAPPA
APEXII X-ray diffractometer was purchased via an NSF CRIF:MU
award to the California Institute of Technology (CHE-0639094).
NMR spectra were obtained by instruments supported by the NIH
(RR027690). Materia, Inc. is thanked for its donation of metathesis
catalysts. Dr. Daryl Allen of Materia, Inc., Dr. Jeffrey Cannon,
Zachary Wickens and Dr. Scott Virgil of the Caltech Center for
Catalysis and Chemical Synthesis are thanked for helpful advice.
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(20) The configurational stability of the adamantyl stereocenter
throughout these X-ligand modifications was confirmed: Conversion
of the enantioenriched nitrate complex 5 to the corresponding iodide
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determinants of the sense of enantioinduction.
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reaction medium may explain the small increase in ee (from 54 to 58)
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