Microcolin B, a potent new immunosuppressant isolated from
blue-green alga Lyngbya majuscula
off the Venezuelan coast, has been made using a methyl-directed
asymmetric hydrogenation reaction
with rhodium on alumina catalyst on lactone 4 for the
synthesis of the key (R,R)-2,4-dimethyloctanoic acid fragment 1. A new, direct mixed imide
formation reaction was also developed for the
production of the unusual prolylpyrrolen-2-one 2 portion of
microcolin. The pentafluorophenyl ester
of CBZ-proline 5 was reacted with the lithium imidate of
lactam 6, providing the mixed imide in
80% yield. Coupling of acid 1 with the N-terminus of
the tripeptide, followed by coupling with
pyrrolylproline 2, gave microcolin B. The new
mixed-imide forming reaction was also applied to a
formal total synthesis of microcolin A. The pentafluorophenyl
ester of TBS-protected cis-hydroxyproline was coupled with lactam 6, and the resultant
imide was converted to the key
pyrrolylproline made previously for microcolin A.
Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A
convergent strategy required methodologies for preparation of
an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and
a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner.
A [3+2] cycloaddition of an enantiopure azomethine ylide
followed by a diastereoselective crystallization was employed
to prepare the benzopyranopyrrolidine in high diastereomeric
and enantiomeric purity. Conditions for reduction of an O-aryl
lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished
in high yield. The thienopyrazine was prepared by condensation
of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen
substitutive deamination to prepare regiospecific trisubstituted
pyrazines will be described.
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
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