Chiral titanium-alkyne complexes derived from chlorotris[( -)-menthoxyltitaniud2 PriMgCI and alkynes react with aldehydes to afford optically active allylic alcohols in up to 38% ee.Recently we have reported that the titanium(I1) compound (q2-pr~pene)Ti(OPri)~, readily generated in situ by the reaction of
An improved asymmetric synthesis
of renin inhibitor DS-8108b (1) is described. This compound
consists of three intermediates:
4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains
three stereogenic centers. Especially, the chiral lactone is a key
intermediate, and development of a scalable synthetic method was required,
considering the quality, speed, and manufacturing cost. We established
a scalable synthetic method of 1 from 4,6-O-benzylidene-d-glucose for early clinical studies. Furthermore,
a highly efficient synthetic route of the chiral lactone for manufacturing
was also successfully developed from n-butyryl chloride
via Evans stereoselective alkylation, followed by stereoselective
bromolactonization. In addition, a unique and highly efficient conversion
protocol was developed from α-bromo-N-(2-nitrobenzenesulfonyl)amide
to apparent rearranged diamine derivatives with a sequential aziridination–substitution
reaction in one-pot.
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