Control of olefin geometry in macrocyclic ring-closing metathesis using a removable silyl group

Article abstract of DOI:10.1021/ja202012s

Introducing a silyl group at one of the internal olefin positions in diolefinic substrates results in E-selective olefin formation in macrocyclic ring-forming metathesis. The application of this method to a range of macrocyclic (E)-alkenylsiloxanes is described. Protodesilylation of alkenylsiloxane products yields novel Z-configured macrocycles.

Full text of DOI:10.1021/ja202012s

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pubs.acs.org/JACS
Control of Olefin Geometry in Macrocyclic Ring-Closing Metathesis
Using a Removable Silyl Group
Yikai Wang,† Miguel Jimenez,† Anders S. Hansen,† Eun-Ang Raiber,‡ Stuart L. Schreiber,†,‡ and
Damian W. Young*,‡
†Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
‡Chemical Biology Program, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States
S Supporting Information
b
Scheme 1. RCM with Silyl Group Incorporation
ABSTRACT: Introducing a silyl group at one of the
internal olefin positions in diolefinic substrates results in
E-selective olefin formation in macrocyclic ring-forming
metathesis. The application of this method to a range of
macrocyclic (E)-alkenylsiloxanes is described. Protodesily-
lation of alkenylsiloxane products yields novel Z-configured
macrocycles.
ing-closing metathesis (RCM) reactions1 have enabled ad-
R
vances in materials science,2 chemical biology,3 and natural
product,4 medicinal,5 and diversity-oriented synthetic chemistry.6
However, in efforts to synthesize macrocyclic compounds via
RCM reactions, control of the stereochemistry of the resulting
olefin is often problematic (Scheme 1A). Since a variety of factors
can determine the stereochemical outcome,1d,7 general strategies
that give rise to either Z- or E-configured products remain a
significant challenge. Additionally, in the absence of a strong steric
or electronic bias, the 1,2-disubstituted olefin in RCM products is
difficult to modify regiospecifically, limiting the potential of further
functionalization and diversification (Scheme 1A). Postmetathesis
functionalization has in general been limited to “symmetrical”
transformations such as hydrogenation, dihydroxylation,6d,8
epoxidation,8b,9 and aziridination.10
Although the influence of various silyl groups on RCMs has
not been studied extensively, there are many examples of
their use in cross-metathesis (CM) reactions. Pietraszuk et al.15
demonstrated that the influence of the silyl groups on the yield of
CM reactions is associated with electronic effects of the substit-
uents on silicon. Silyl groups with electron-withdrawing substit-
uents such as EtO, AcO, and Cl gave better yields than those with
Me and/or Ph groups. Accordingly, although vinyltrialkylsilanes
yielded a variety of five- and six-membered rings, they failed to
produce medium- and large-sized rings.16 These observations are
consistent with the few examples of RCM reactions leading to
exocyclic vinylsilanes and vinylsiloxanes that have been reported
in the literature.17 With this knowledge, we next focused on
vinylsiloxanes. We prepared several salicylate-derived substrates
with one of the olefins bearing a triethoxysilyl group at the
internal position. The vinylsiloxane substrates were obtained in
excellent yields from the corresponding alkyne precursors
through hydrosilylation.17a,c Using the second-generation Grubbs
catalyst afforded a 14-membered salicylate macrocycle (2a),
albeit in low yield (Scheme 2). When the same conditions were
applied to substrate 3a, the yield of the 15-membered ring 4a
dropped to 3% (Scheme 2). We used this demanding substrate to
optimize the reaction conditions.
Two major advances that address the stereoselectivity of RCM
reactions have been achieved. One approach involves ring-
closing alkyne metathesis and selective reduction of the alkyne
intermediate to yield Z or E olefins,11 but it has been applied only
to ring sizes of 12 and larger.12 The other approach, which is
based on the development of Z-selective catalysts,13 has not yet
been reported for macrocyclic RCM reactions. Both strategies
generate 1,2-disubstituted olefins, which are primarily limited to
symmetrical postmetathesis transformations. To address these
limitations, we investigated the use of vinylsiloxanes as substrates
to access trisubstituted macrocyclic silylalkenes.
We imagined that a silyl group at an internal position of one of
the olefins could serve two purposes (Scheme 1B). First, the sterics
of the silyl group would be expected to favor formation of the (E)-
silylalkene product. The Z-disubstituted olefin would then be
obtained following protodesilylation. Second, the exocyclic silyl
substituent would be expected to enable functionalization of the
RCM product, thus yielding specific trisubstituted olefins.14 In this
report, we explore the ability of vinylsiloxanes to undergo productive
RCM reactions, their influence on the stereochemistry of the
resulting products, and their protodesilylation following ring closure.
Received: March 14, 2011
Published: May 11, 2011
r
2011 American Chemical Society
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Scheme 2. Initial Successful Vinylsiloxane RCM and the
Model Substrate Used for Reaction Optimization
Scheme 3. Yields for (a) RCMs and (b) Protodesilylation of
Alkenylsiloxanes
Table 1. Influence of the Silyl Group on the RCM Yield
a Isolated % yield, unless otherwise indicated. b Yield determined by 1H
NMR analysis of the reaction mixture.
Among commercially available Ru-based metathesis catalysts,
catalyst A was best able to increase the yield under the original
reaction conditions [see the Supporting Information (SI) for
details]. In contrast to the second-generation Grubbs catalyst, A
bears one methyl group at the ortho position of each phenyl ring,
making it less sterically hindered and more reactive.18 After
varying the solvent, temperature, and concentration, we found
that optimal results (4a, 63%) were obtained using benzene or
toluene as the solvent, a temperature of 35 °C, and a catalyst
loading of 20 mol % (Scheme 2).
substituents to a methyl group (3a vs 3b) improved the yield,
while the change to a phenyl group (3b vs 3d) halved the yield.
Our results indicate that the diethoxymethylsilyl group delivers
the best reaction outcomes by maintaining a balance between the
steric and electronic effects.
Using the diethoxymethylsilyl group, we synthesized macro-
cyclic alkenylsiloxane compounds with a range of ring sizes in
moderate to excellent yields (Scheme 3). Diastereomers gave
differing yields of purified products. For some substrates, a silyl
group was incorporated at one or the other alkene terminus of
the diene. The trans-cyclohexanediols with silyl groups at differ-
ent termini behaved similarly (12 and 14), while the silyl
regioisomers of cis-cyclohexanediols behaved differently (13
and 15). To test the generality of this method, two more complex
substrates inspired by previous work22 were prepared with
vinylsiloxanes on different alkene termini. The 16-membered rings
were both formed in moderate yields (18 and 21).
As envisaged, the trisubstituted olefins in the macrocyclic
products had the E configuration (except for 17 and 21, which
were mixtures of both stereoisomers with high E selectivity). This
suggests that one of the two productive metallocyclobutane inter-
mediates is preferably formed, leading to the (E)-silylalkene; how-
ever, further mechanistic studies are required. All of the correspond-
ing Z-disubstituted olefins were obtained by protodesilylation in good
to excellent yields while maintaining the geometry of the olefins.
We next sought to understand the role of the silyl group in
controlling the stereochemical outcome of the reaction. For
comparison, all of the corresponding simple (non-silyl-contain-
ing) RCM precursors were synthesized in order to determine the
intrinsic stereoselectivities of the substrates (Table 2). Upon
treatment with the optimized reaction conditions as well as
Under the optimal reaction conditions, unreacted starting
material was still observed, indicating that the catalyst was
deactivated before the reaction reached completion. To explore
this observation further, catalyst stability studies were performed.
It was determined that catalyst A decomposed at a similar rate
upon treatment of any olefin substrate, with or without the silyl
group (see the SI for details). In addition to the commonly
observed decomposition pathways,19 C(sp2)ÀH bond insertion
in the N-aryl ring of the NHC ligand can also lead to fast
deactivation of catalyst A.20 Our results suggest that vinylsiloxane
substrates do not intrinsically cause catalyst deterioration.
We next examined the influence of different silyl groups on the
yield of the RCM reaction (Table 1). The results are in alignment
with those for CM reactions. Generally, ethoxy substituents
promote the formation of product and lead to higher yields in
comparison with alkyl and/or aryl substituents (compare aÀd
with e and f). More ethoxy substituents are preferred over fewer
(compare b with c). Pietraszuk and Fischer21 noted that electron-
withdrawing substituents shut down an undesired pathway that
leads to catalyst deactivation. We suggest that these unproductive
processes are operative in macrocyclization reactions as well and
require the appropriate siloxane group to suppress them. In
contrast to the CM precedents, the sterics of the silyl group also
influenced the reaction yield. This effect was seen with the more
demanding substrates 3aÀf, while substrates 1aÀf showed the
same trend but to a lesser degree. Changing one of the ethoxy
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Table 2. Influence of a Silyl Group on the Stereoselectivity of RCMs
Conditions I: cat. A (20 mol %), toluene, 35 °C. Conditions II: Grubbs II (10 mol %), 1,4-benzoquinone (20 mol %), toluene, 35 °C. a For silylated
substrates, the Z:E assignment is based on the protodesilylated products. b A single stereoisomer is reported for Z:E ratios >98:2. Otherwise the Z:E ratio
determined by 1H NMR analysis of the crude reaction mixture is given. c c. mix. = complex mixture of products (cyclized and uncyclized oligomers).
d The stereochemistry of the cyclized monomer is reported in parentheses for all cases in which the proportion of that monomer within the complex
mixture was sufficient for determination. e Reaction was performed at room temperature. f Reaction was performed in refluxing DCM.
typical RCM conditions using the second-generation Grubbs
catalyst, Z-selective (entries 1, 2, 6, 7, 9, 10, and 11), E-selective
(entries 4, 5, 8, 12, and 14), and nonselective (entry 13)
outcomes were observed. The introduction of the silyl group
was found to reinforce the intrinsic stereoselectivity and, more
dramatically, to override it completely for some substrates. This
confirmed our initial hypothesis that a silyl group serves as an
effective controlling group in macrocyclic RCM reactions.
It is also noteworthy that several of the simple substrates gave
rise to complex mixtures of products (Table 2, entries 2, 4, and
6À10), sometimes without detectable levels of cyclized monomer
(entry 3). LCÀMS analysis of the crude reaction mixture indicated
the formation of cyclized dimers and other polymeric byproducts.
This is a general problem for macrocyclic RCM reactions of simple
olefins.23 While the reaction conditions for the simple substrates
were not optimized, these results point to the ability of the silyl
group to suppress the formation of undesired products.
On the basis of our data, we propose the model for the reaction
pathways depicted in Scheme 4. Several unproductive pathways
are involved in RCM reactions of simple olefins, including
reopening of the monocyclized product (AÀ), CM to generate
an acyclic dimer or oligomer (B or C), and possible cyclization at
either of these stages (C or D). In contrast, when the silyl group is
incorporated into one of the olefins, pathway A leading to the
desired product is no longer reversible. When we resubjected the
purified trisubstituted silylalkene product to the reaction condi-
tions, no reactivity was observed. Pathway B to generate the
acyclic dimers exists, but only through CM between the
simple olefins—the 2-silylalkene remains a spectator to CM
under our reaction conditions.24 However, when resubjected
to the reaction conditions, the purified acyclic cross-dimers of
Scheme 4. Reaction Pathways for Macrocyclic RCMs with
and without a 2-Silyl Group
the silylated substrates yielded macrocyclic products with
conversion comparable to that starting from monomer.25
Additionally, since the 2-silylalkene remains a spectator to
CM, pathway C is shut down. Pathway D is also blocked
because the formation of a tetrasubstituted alkene with two silyl
groups is highly disfavored.
Overall, the silyl group is able to lower the reactivity of the
attached olefin, thereby suppressing nonproductive pathways
while yielding the desired product. In accord with this analysis,
for the substrates that gave low yields, only unreacted starting
material, the acyclic cross-dimers, and a styrene derivative were
observed along with the product. To explore the “trapping” role
of the silyl group, the monocyclized (Z)-alkene compound 7b
(not observed in the RCM of the simple diene; Table 2, entry 3)
obtained from protodesilylation of compound 7 was subjected to
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reaction conditions II. Not surprisingly, it was almost completely
consumed to generate dimers and oligomers (see the SI).
Because the silyl group can be removed, this method offers a
means of cyclizing recalcitrant substrates using RCM.
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In summary, 8- to 16-membered macrocyclic rings containing
E-trisubstituted silyl olefins and the corresponding Z-disubsti-
tuted olefins can be accessed using RCM of vinylsiloxane
substrates. This study illustrates the use of a silyl group in
controlling the stereoselectivity of RCM reactions in macrocyclic
systems. Additionally, productive RCMs of vinylsiloxanes allow
access to challenging simple olefin products that may be other-
wise disfavored in comparison with acyclic or cyclic dimers
and oligomers. Studies exploring the use of alkenylsiloxanes as
chemical handles for further functionalization and diversification
of the RCM products are underway.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete refs 14b and 22,
b
experimental procedures, and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
dyoung@broadinstitute.org
’ ACKNOWLEDGMENT
We gratefully acknowledge Drs. Tuoping Luo, Drew Adams,
Mingji Dai, Sivaraman Dandapani, Giovanni Muncipinto, Bhaumik
Pandya, Eamon Comer, and Qiu Wang for helpful discussions and
Christopher Johnson and Joachim Azzi for their assistance with
SFCÀMS analyses. This work was funded by the NIGMS-
sponsored Center of Excellence in Chemical Methodology and
Library Development (Broad Institute CMLD; P50 GM069721).
S.L.S. is an Investigator with the Howard Hughes Medical Institute.
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