Template-assisted cross olefin metathesis

Article abstract of DOI:10.1002/anie.200461777

Making ends meet: Alkene units tethered to two complementary oligoamide strands, which pair sequence-specifically into hydrogen-bonded duplexes, undergo intermolecular cross-metathesis when the two alkene moieties are in close proximity upon heating in th

Full text of DOI:10.1002/anie.200461777

Communications
Olefin Metathesis
Template-Assisted Cross Olefin Metathesis**
Xiaowu Yang and Bing Gong*
Various strategies have been developed for the control of
intermolecular association, most of which are based on the
design of molecular modules that carry linear arrays of
hydrogen-bond donors (D) and acceptors (A).[1] We recently
described information-storing hydrogen-bonded duplexes
based on linear oligoamide strands that bear arrays of
hydrogen-bond donors and acceptors.[2] The formation of
such duplexes is highly sequence-specific and involves the
pairing of a single strand with another strand of a comple-
mentary hydrogen-bonding sequence. These hydrogen-
bonded duplexes serve as specific, noncovalent templates
for the nucleation of b-sheet structures when attached to
natural oligopeptides.[3] The sequence-specificity of our
hydrogen-bonded duplexes has prompted us to explore the
possibility of directing chemical reactions by using these
molecules as templates. In recent years there has been intense
interest in the use of duplex DNA as a template for directing
chemical reactions.[4,5] Although not yet comparable to the
diverse sequence-specificity offered by duplex DNA, the
hydrogen-bonded duplexes that we have developed offer
some advantages: ready availability in large quantities, much
lower molecular weights, and compatibility with a wide
variety of organic solvents. We chose the widely utilized
olefin metathesis reaction as a demonstration of principle.
Specifically, olefin units attached to the same end of a duplex
template should be brought into close proximity upon the
formation of the hydrogen-bonded duplex in solution. Such a
supramolecular event should greatly increase the effective
molarity of the olefins that undergo the subsequent cross-
metathesis reaction and turn an otherwise intermolecular
transformation into one that is intramolecular. Here we
report the highly efficient and specific intermolecular cross-
metathesis reactions directed by a hydrogen-bonded duplex
template.
Since the development of the well-defined catalysts by
Schrock[6] and Grubbs,[7] olefin metathesis has become an
increasingly powerful tool for carbon–carbon bond formation
in organic synthesis.[8] It has been widely used in the total
synthesis of a variety of architecturally complex natural
products,[9] in polymerization,[10] and in the construction of
[*] Dr. X. Yang, Prof. B. Gong
Department of Chemistry
University at Buffalo
The State University of New York
Buffalo, New York 14260 (USA)
Fax: (+1)716-645-6963
E-mail: bgong@chem.buffalo.edu
[**] We thank the donors of the Petroleum Research Fund, administered
by the ACS, for support of this research (37200-AC4). The NIH, NSF,
and ONR are acknowledged for partial funding.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461777
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Angewandte
Chemie
peptides.[11] The metathesis reaction is routinely carried out
To test the strategy outlined above, a quadruply hydrogen-
À
for the generation of C C double bonds by using either the
bonded duplex, which consists of two different but comple-
mentary oligoamide strands that carry the unsymmetrical
hydrogen-bonding sequences ADAA and DADD, respec-
tively, was chosen as the template (Scheme 1). Alkenyl
alcohols or acids were tethered to A or B by means of DCC
(dicyclohexyl carbodiimide) coupling[15] to yield the desired
strands A1–5 and B1–5 (Scheme 2). Combination of strands
A1–5 with strands B1–5 should lead to 25 different A·B pairs.
To demonstrate the feasibility of this approach, pair A3·B2
was first examined in detail. By using commercially available
polystyrene molecular-weight standards, vapor pressure
osmometry (VPO) studies at 378C in CHCl3 over the
concentration range of 5–50 mm consistently gave an appa-
rent molecular weight of 1471 Æ 5% that corresponds to
A3·B2. The presence of the dimeric A3·B2 species in
solution was also supported by 1H NMR spectroscopic studies
in CDCl3 (5 mm) that revealed significant downfield shifts of
the signals of the aniline NH group (d = 9.97, 9.65, and
9.53 ppm) relative to that of the single strand 1c (d =
7.62 ppm).[2,3]
cross-metathesis of two acyclic alkenes or the ring-closing
metathesis (RCM) of a diene. Efforts have been made to
improve the chemical selectivity of intramolecular metathesis
(RCM) by controlling the concentrations of the reactants.[12]
Relative to olefin RCM, intermolecular cross-metathesis
reactions, particularly those which involve two different
olefins, have received less attention even though they offer
À
great potential for a range of intermolecular C C bond
constructions. The main reason for this may be a lack of
selectivity, especially because the intermolecular cross-meta-
thesis reaction often proceeds to yield three products: two
unwanted homodimeric self-metathesis products along with
the desired heterodimeric product.[13] Several methods have
recently been reported in which selective cross-metathesis
reactions can be achieved when olefins of high reactivity are
treated with bulky, electron-deficient olefins of lower reac-
tivity.[14] Except for strategies that are based on intramolec-
ular RCM,[12] highly selective cross-metathesis reactions of
olefins that exhibit similar reactivities have yet to be
developed.
A solution of A3·B2 in chloroform (2 mm) was then
treated with Grubbsꢀ catalyst[7] under heating at reflux. The
Scheme 1. Cross-metathesis of oligoamide-tethered olefins. R=n-C8H17.
Scheme 2. Preparation of strands A1–5 and B1–5. R=n-C8H17, DCC=dicyclohexyl carbodiimide, DMAP=4-dimethylaminopyridine.
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Communications
Table 1: Template-assisted olefin cross-metathesis.[a]
progress of the reaction was monitored by using ESI-MS
(Figure 1). Upon completion of the reaction (5 h), new peaks
Strands
A1
B1
B2
B3
B4
B5
with m/z values of 1536 [M+H]+ and 1557 [M+Na]+ appeared
98
(1.6:1)
97
(9:1)
99
(14:1)
87
97
(3:1)
94
(5:1)
99
(8:1)
84
91
(2:1)
93
(2:1)
97
(3:1)
83
94
(6:1)
83
36
=
(Figure 1b). The net loss of 28 (CH2 CH2) relative to the m/z
(8:1)
A2
A3
A4
A5
nr[b]
(4:1)
nr[b]
nr[b]
nr[b]
nr[b]
(20:1)
96
(7:1)
89
(4:1)
65
85
77
(11:1)
(5:1)
(4:1)
(3:1)
(7:1)
[a] All reactions were carried out at a concentration of 2 mm in CH2Cl2 in
the presence of the catalyst (10 mmol%). The yields and E/Z ratios
1
(quoted in brackets) were determined by H NMR spectroscopy. [b] No
reaction.
than for those combinations which resulted in efficient
reactions. This suggests that for the cross-metathesis reaction
to proceed, the two vinyl moieties in a duplex need to reach
each other and adopt the proper orientation, which in turn
requires spacers of sufficient length. Furthermore, the major
stereoisomers for all transformations were consistently the
thermodynamically more stable E isomers, which reflects the
reversible nature of the metathesis reactions. The highest
Figure 1. ESI mass spectra of a) the duplex A3·B2 and b) the product
=
A3 B2 after the cross-metathesis reaction.
values of the starting duplex (1563 [M+H]+ and 1585
[M+Na]+, Figure 1a) suggested that the duplex A3·B2
underwent an intermolecular cross-metathesis reaction to
=
=
afford the desired product A3 B2. Product A3 B2 was
isolated in 92% yield as a mixture of E and Z isomers (E/Z =
8:1, determined by 1H NMR spectroscopy).[16]
=
stereoselectivity was observed for the product A4 B1 with
an E/Z ratio of 20:1 and a yield of 87%.[16]
On the basis of the results obtained from the pair A3·B2,
we extended this template-directed approach to the meta-
thesis reactions of all 25 combinations (Scheme 2), the results
of which are listed in Table 1. In the presence of Grubbsꢀ
catalyst, each of the 25 pairs was heated at reflux in CH2Cl2
during 3–6 h to afford 20 of the 25 possible products. The
products formed were those expected from the cross-meta-
thesis reactions and were all obtained as inseparable mixtures
of E and Z isomers[16] with yields ranging from 36–99%.
Among the combinations, duplexes that comprised the
As a control, compound C, in which the olefin unit was
attached to the “wrong” side of the template strand, was
synthesized and then mixed with compound B1 (Scheme 3).
The formation of duplex B1·C was confirmed by both NMR
spectroscopy and VPO experiments. In duplex B1·C, the vinyl
moieties would not be able to react with each other because
they are located at the two remote ends of the duplex
template. Indeed, when a solution of duplex B1·C was
subjected to cross-metathesis in the presence of Grubbsꢀ
catalyst, the metathesis reaction did not occur. The hydrogen-
bonded duplex B1·C was the only species detected by NMR
spectroscopy or ESI-MS before and after the reaction. These
results further confirmed the template-dependence of the
above metathesis reactions, in which the reactions took place
only when the two olefin units were brought into close
proximity by the duplex template.
=
=
=
strands A1 and B1–4 gave products A1 B1, A1 B2, A1
=
B3, and A1 B4 in yields ranging from 91–98%. The
combinations of A2/A3/A4 with B1/B2/B3/B4 led to their
products in 83–99% yields. Compared with the duplexes that
contained A1, A3, and A5, those that contained A4, that is,
A4·B1, A4·B2, and A4·B3, gave slightly lower yields that
ranged from 83 to 87%. The two products from the cross-
metathesis reactions that involved B5 were obtained in lower
As shown in Scheme 1 and Scheme 2, all of the olefin units
were attached to the template through an ester linkage that
should be cleaved under basic conditions. To test if the desired
=
=
yields (A1 B5: 36%; A5 B5: 77%), whereas no other
products were obtained from the
other three combinations involv-
ing B5. Similarly, the products
=
=
A3 B4 and A4 B4 that should
have resulted from the cross-meta-
thesis of pairs A3·B4 and A4·B4
were not obtained. Examination of
the structures of those pairs which
either did not react or which gave
products in low yields revealed
that the spacers between the ter-
minal vinyl moieties and the tem-
plate strands were much shorter
Scheme 3. Attempted cross-metathesis reaction of distant olefins in B1·C. R=n-C8H17.
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Chemie
=
Scheme 4. Cleavage of product from A2 B1. R=n-C8H17.
=
2001, 5, 650; R. P. Sijbesma, E. W. Meijer, Chem. Commun.
products could be cleaved from the template, product A2 B1
was treated with an aqueous solution of NaOH. After
completion of the reaction, the insoluble residue was filtered,
and the acidified aqueous layer was extracted with CH2Cl2 to
yield the desired 8-hydroxyoct-5-enoic acid (Scheme 4).[16]
In conclusion, we have shown that a quadruply hydrogen-
bonded duplex can act as a sequence-specific template to
direct the cross-metathesis of different olefins that are
tethered to this duplex. These templated metathesis reactions
occur with extremely high selectivity, with no homodimeric
products observed. Compared to strategies that directly
tether two olefin units together, our approach has the
advantage of being combinatorial. By simply mixing the
complementary A and B strands, a large number of A·B
combinations were easily obtained. Thus, the combination
(mixing) of a group of five tethered olefins with another
group of five olefins lead to a total of 25 combinations. In
contrast, with covalently linked olefins, all 25 possibilities
have to first be synthesized before they can be tested.
Obviously, the number of combinations based on our
approach increases rapidly as the number of tethered olefins
increases. Coupled with NMR spectroscopic and mass spec-
trometric methods, our template-directing method can be
used to probe a large number of combinations that would
otherwise be difficult to examine based on previous methods.
After cleavage from the template, the desired products can be
easily obtained and the template can also be recycled. It is
envisaged that our current strategy will serve as a useful tool
to broaden the scope of cross-metathesis reactions. The
approach described here should also be generally applicable
to other types of bimolecular reactions.
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Received: August 24, 2004
Revised: October 5, 2004
Published online: January 20, 2005
À
Keywords: alkenes · C C coupling · hydrogen bonds ·
noncovalent interactions · template synthesis
.
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[15] See Supporting Information for details.
[16] The conformations of double bonds were determined from the
1
coupling constants J measured from H NMR spectra, and the
major E isomer was found to have J > 15 Hz (see Supporting
Information).
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