12
B. Schmidt
tions. The catalytically active species, a metal alkylidene complex, reacts with one
of the two double-bonds to a metallacyclobutane, which undergoes a cycloreversion
with liberation of ethene. The new metal alkylidene reacts intramolecularly with the
second C=C double-bond of the starting material to a bicyclic metallacyclobutane,
which eventually undergoes a cycloreversion to regenerate the catalyst and furnish the
product. Ring-closing metathesis reactions are entropy-driven and rely on the formation of a volatile co-product, which in most cases is ethene. In principle, all steps
(and the overall reaction) are reversible, but removal of ethene shifts the equilibrium
to the formation of the product [37]. Due to their robustness, low sensitivity toward
air and moisture and high functional group tolerance in particular, the Ru-based
precatalysts introduced by Grubbs and co-workers have found many applications in
the total synthesis of natural products [38–42]. First-generation catalysts (A) are less
active (which can be an advantage in some cases, as will be discussed below) but
are cheaper and more conveniently accessible. Second-generation catalysts (B) have
one N-heterocyclic carbene (NHC) ligand. They are more active and therefore lower
catalyst loadings are required. These catalysts are also suitable for the generation
of triple- and even tetra-substituted double bonds, but they are more expensive and
their synthesis requires additional steps. The two most commonly used metathesis
catalysts are A1 [34] and B1 [35].
While the formation of five- and six-membered rings through RCM proceeds
without difficulties in most cases at substrate concentrations >0.1 M and catalyst loadings <2 mol%, medium-sized rings normally require higher dilution and increased
catalyst loadings of ca. 10 mol%. Whenever an RCM reaction is slow, as in the
case of medium-sized rings, catalyst decomposition can successfully compete with
the olefin metathesis reaction. This problem makes it necessary to use increased
amounts of catalyst from the outset or to add the catalyst in portions over a longer
period of time. In RCM reactions giving five- to nine-membered rings the configuration of the newly formed double-bond is always cis due to steric reasons. However,
for ten-membered and larger rings the RCM reactions can yield either (E)- or (Z)configured cycloalkenes, or mixtures of both diastereomers. This limitation was
observed initially in the first synthesis of a ten-membered ring via RCM ever documented in the literature. In 1997, Fürstner and Müller reported on the synthesis
of racemic jasmine ketolactone ((rac)-1, cf. Scheme 1) [43], which is obtained by
RCM of diene 36 in the presence of 10 mol% of catalyst A2 (an ancestor of the
first-generation Grubbs’ catalyst A1 with comparable activity) [44]. The (Z)- and
(E)-isomers were obtained in the ratio of 2.5:1 in toluene at 70°C. A small, but
detrimental effect on the selectivity was observed when dichloromethane at 40°C
was used as a solvent; under these conditions a similar yield was obtained, but the
(Z):(E) ratio decreased to 1.4:1 (Scheme 8).
Controlling the double-bond configuration in RCM macro-cyclization reactions
became an important issue in subsequent years. Kalesse et al. discovered in the course
of a study directed at the synthesis of epothilones [45] that diene 37 cyclizes preferably to decanolide (Z)-38, but that the minor isomer (E)-38, after chromatographic
isolation, can be converted to (Z)-38 by exposing it to the original RCM conditions.
This observation suggests that (Z)-38 is the thermodynamically preferred product,
B. Schmidt
tions. The catalytically active species, a metal alkylidene complex, reacts with one
of the two double-bonds to a metallacyclobutane, which undergoes a cycloreversion
with liberation of ethene. The new metal alkylidene reacts intramolecularly with the
second C=C double-bond of the starting material to a bicyclic metallacyclobutane,
which eventually undergoes a cycloreversion to regenerate the catalyst and furnish the
product. Ring-closing metathesis reactions are entropy-driven and rely on the formation of a volatile co-product, which in most cases is ethene. In principle, all steps
(and the overall reaction) are reversible, but removal of ethene shifts the equilibrium
to the formation of the product [37]. Due to their robustness, low sensitivity toward
air and moisture and high functional group tolerance in particular, the Ru-based
precatalysts introduced by Grubbs and co-workers have found many applications in
the total synthesis of natural products [38–42]. First-generation catalysts (A) are less
active (which can be an advantage in some cases, as will be discussed below) but
are cheaper and more conveniently accessible. Second-generation catalysts (B) have
one N-heterocyclic carbene (NHC) ligand. They are more active and therefore lower
catalyst loadings are required. These catalysts are also suitable for the generation
of triple- and even tetra-substituted double bonds, but they are more expensive and
their synthesis requires additional steps. The two most commonly used metathesis
catalysts are A1 [34] and B1 [35].
While the formation of five- and six-membered rings through RCM proceeds
without difficulties in most cases at substrate concentrations >0.1 M and catalyst loadings <2 mol%, medium-sized rings normally require higher dilution and increased
catalyst loadings of ca. 10 mol%. Whenever an RCM reaction is slow, as in the
case of medium-sized rings, catalyst decomposition can successfully compete with
the olefin metathesis reaction. This problem makes it necessary to use increased
amounts of catalyst from the outset or to add the catalyst in portions over a longer
period of time. In RCM reactions giving five- to nine-membered rings the configuration of the newly formed double-bond is always cis due to steric reasons. However,
for ten-membered and larger rings the RCM reactions can yield either (E)- or (Z)configured cycloalkenes, or mixtures of both diastereomers. This limitation was
observed initially in the first synthesis of a ten-membered ring via RCM ever documented in the literature. In 1997, Fürstner and Müller reported on the synthesis
of racemic jasmine ketolactone ((rac)-1, cf. Scheme 1) [43], which is obtained by
RCM of diene 36 in the presence of 10 mol% of catalyst A2 (an ancestor of the
first-generation Grubbs’ catalyst A1 with comparable activity) [44]. The (Z)- and
(E)-isomers were obtained in the ratio of 2.5:1 in toluene at 70°C. A small, but
detrimental effect on the selectivity was observed when dichloromethane at 40°C
was used as a solvent; under these conditions a similar yield was obtained, but the
(Z):(E) ratio decreased to 1.4:1 (Scheme 8).
Controlling the double-bond configuration in RCM macro-cyclization reactions
became an important issue in subsequent years. Kalesse et al. discovered in the course
of a study directed at the synthesis of epothilones [45] that diene 37 cyclizes preferably to decanolide (Z)-38, but that the minor isomer (E)-38, after chromatographic
isolation, can be converted to (Z)-38 by exposing it to the original RCM conditions.
This observation suggests that (Z)-38 is the thermodynamically preferred product,