providing an HPLC assignment as the minor product from
CM of 7; 7A, 6A/6B, and 10A/10B were ultimately assigned
by analogy.
reactivity of 6, 7, and 10, we examined the 1H NMR
spectrum of 6 as a function of temperature.18 At low
temperature, essentially all protons appear as more than one
set of distinct resonances, suggesting the existence of multiple
conformations undergoing slow interconversion on the NMR
time scale. However, coalescence temperatures for each set
of related resonances are well below the temperature at which
the metathesis reactions are run. This indicates that confor-
mational preferences of the starting material are not a
contributing factor in determining whether the metathesis
reaction proceeds. Likewise, the rapid conformational mobil-
ity of the starting material at the reaction temperature argues
against the influence of simple aggregation, hydrophobic
collapse, or intermolecular π-π interactions,19 which one
might expect to be minimal in relatively nonpolar haloge-
nated solvent.20
Additionally, we resubjected each pure homoallylamide
tryptophan CM product (7A and 7B) separately to 10 mol
% Grubbs’ catalyst at room temperature in CH2Cl2 for 12 h.
Upon workup and concentration, we observed the same 3:1
cis:trans ratio (3.6:1 from 7A; 3.7:1 from 7B) found in the
initial cross-metathesis reaction. This verified that the
reaction is at least partially reversible and suggests that it
may be under thermodynamic control. Further experiments
will be necessary in order to test alternative possibilities.
For example, one can also envision kinetic control based on
the reactivity of an intermediate ruthenium alkylidene. While
a kinetically controlled cis selective CM employing conju-
gated enynes has recently been reported by Chang and co-
workers,15 to our knowledge this is the first report of a cis
selective CM reaction involving isolated olefins. Interest-
ingly, CM of a related series of compounds on solid phase
is trans selective.16
Given the number of bonds separating the reactive olefins
from amino acid side chain functionality, why were moderate
cis selectivity and good overall yield observed for homoallyl
amides 6, 7, and 10, but no reaction observed at all for the
other substrates? We reasoned homoallyl amides lacking
aromatic side chains might trap the catalyst in an unproduc-
tive coordination state such as that shown in Figure 1
Figure 1. Potential nonproductive chelate of ruthenium carbene.
(although several other geometries are possible). Similar
ruthenium coordination by oxygen containing functionality
has been observed by Hoveyda17 and others. Conversely, we
reasoned that homoallyl amides bearing aromatic side chains
might allow for intramolecular hydrophobic collapse, inter-
molecular π-π interactions, or a simple aggregation, thereby
interrupting destructive coordination to the catalyst. Subject-
ing a 1:1 mixture of glycine homoallylamide 5 and phenyl-
alanine homoallylamide 6 to CM conditions provided no self-
or cross-metathesis products, supporting the assertion that
simple aliphatic substrates may be able to trap the catalyst,
preventing CM.
1
Figure 2. Variable-temperature H NMR of 6.
An alternative hypothesis is that homoallylamides bearing
aromatic groups might participate in a relatively weak
π-ruthenium interaction, thereby prohibiting the relatively
strong (and destructive) carbonyl coordination and ultimately
permitting cross-metathesis. Changing the electron density
on the aromatic ring has a strong impact, as indicated by
the inability of pentafluorophenylalanine homoallylamide 11
to undergo CM. Steric effects are also important; the
histidine-derived substrate 8 is potentially prevented from
To test the hypothesis that conformational preferences or
intermolecular interactions might be responsible for the
(15) Kang, B.; Lee, J. M.; Kwak, J.; Lee, Y. S.; Chang, S. J. Org. Chem.
2004, 69, 7661.
(16) Conde-Frieboes, K.; Andersen, S.; Breinholt, J. Tetrahedron Lett.
2000, 41, 9153-9156.
(17) Harrity, J. P.; La, D. S.; Visser, A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1998, 120, 2343.
(18) NMR data were taken using a 0.1 M concentration of olefin, identical
to reaction conditions.
(19) McGaughey, G. B.; Gagne´, M.; Rappe´, A. D. J. Biol. Chem. 1998,
273, 15458.
(20) Gardner, R. R.; McKay, S. L.; Gellman, S. H. Org. Lett. 2000, 2,
2335.
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