Biomimetic Organocatalytic C–C-Bond Formations
97
After γ-alkylation of 116 with methyl bromoacetate and subsequent
condensation with (R)-phenethylamine, the resulting imine 117 was diastereoselectively hydrogenated, cyclized, and deprotected to give lactam 118. The cis-tricyclic triazolium salt 119 was then obtained as a solid
in 24% yield by a modified three-step procedure reported by Knight
and Leeper (1998).
Two different concepts were chosen to increase the steric demand of
the carbene catalysts and thus increase the asymmetric induction. A triazolium salt synthesis starting from l-pyroglutamic acid (120), which
is among the cheapest chiral sources available, might generate an extremely flexible catalyst system. The tert-butyldimethylsilyl (TBS) and
triisopropylsilyl (TIPS) protected lactams 122 could be synthesized in
almost quantitative yields from l-pyroglutamic acid (120) by reduction
to the hydroxymethyl-substituted lactam 121 and subsequent reaction
with the silyl chlorides (Acevedo et al. 2001). The bulkiness at the stereogenic centre might be modified by a simple exchange of the protecting
group. Conversion into the triazolium salts could be achieved by following an optimized one-pot procedure recently reported by Rovis and
co-workers (Kerr et al. 2005). The lactams 122 were methylated with
Meerwein’s reagent to form the corresponding amidates. These were
treated in situ with phenylhydrazine to yield the hydrazonium salts,
which were directly cyclized with trimethyl orthoformate in methanol
to give the triazolium salts 123 in moderate yields as crystalline solids
(Scheme 31).
For the structural optimization of the tricyclic triazolium salt 119 the
cis-tricyclic lactam 126 was chosen as the precursor for the synthesis
of the tetracyclic triazolium salt 127. The diastereo- and enantiopure
γ-lactam 126 was synthesized following a procedure reported by Ennis et al. (Scheme 32) (Ennis et al. 1996; Nieman and Ennis 2000).
α-Tetralone (124) was α-alkylated with ethyl bromoacetate and subsequently hydrolyzed to the corresponding carboxylic acid. Condensation
with (R)-phenylglycinol yielded the lactam 125 as a single stereoisomer. Stereoselective reduction, dehydration of the alcohol, and acidcatalyzed enamine hydrolysis provided the cis-tricyclic lactam 126. The
one-pot procedure that had previously been successful in the synthe-
97
After γ-alkylation of 116 with methyl bromoacetate and subsequent
condensation with (R)-phenethylamine, the resulting imine 117 was diastereoselectively hydrogenated, cyclized, and deprotected to give lactam 118. The cis-tricyclic triazolium salt 119 was then obtained as a solid
in 24% yield by a modified three-step procedure reported by Knight
and Leeper (1998).
Two different concepts were chosen to increase the steric demand of
the carbene catalysts and thus increase the asymmetric induction. A triazolium salt synthesis starting from l-pyroglutamic acid (120), which
is among the cheapest chiral sources available, might generate an extremely flexible catalyst system. The tert-butyldimethylsilyl (TBS) and
triisopropylsilyl (TIPS) protected lactams 122 could be synthesized in
almost quantitative yields from l-pyroglutamic acid (120) by reduction
to the hydroxymethyl-substituted lactam 121 and subsequent reaction
with the silyl chlorides (Acevedo et al. 2001). The bulkiness at the stereogenic centre might be modified by a simple exchange of the protecting
group. Conversion into the triazolium salts could be achieved by following an optimized one-pot procedure recently reported by Rovis and
co-workers (Kerr et al. 2005). The lactams 122 were methylated with
Meerwein’s reagent to form the corresponding amidates. These were
treated in situ with phenylhydrazine to yield the hydrazonium salts,
which were directly cyclized with trimethyl orthoformate in methanol
to give the triazolium salts 123 in moderate yields as crystalline solids
(Scheme 31).
For the structural optimization of the tricyclic triazolium salt 119 the
cis-tricyclic lactam 126 was chosen as the precursor for the synthesis
of the tetracyclic triazolium salt 127. The diastereo- and enantiopure
γ-lactam 126 was synthesized following a procedure reported by Ennis et al. (Scheme 32) (Ennis et al. 1996; Nieman and Ennis 2000).
α-Tetralone (124) was α-alkylated with ethyl bromoacetate and subsequently hydrolyzed to the corresponding carboxylic acid. Condensation
with (R)-phenylglycinol yielded the lactam 125 as a single stereoisomer. Stereoselective reduction, dehydration of the alcohol, and acidcatalyzed enamine hydrolysis provided the cis-tricyclic lactam 126. The
one-pot procedure that had previously been successful in the synthe-