Here, we report the first asymmetric
total synthesis of (+)-talassimidine
and (+)-talassamine, two hetidine-type C20-diterpenoid
alkaloids. A highly regio- and diastereoselective 1,3-dipolar cycloaddition
of an azomethine ylide yielded a chiral tetracyclic intermediate in
high enantiopurity, thus providing the structural basis for asymmetric
assembly of the hexacyclic hetidine skeleton. In this key step, the
introduction of a single chiral center induces four new continuous
chiral centers. Another key transformation is the dearomative cyclopropanation
of the benzene ring and subsequent SN2-like ring opening
of the resultant cyclopropane ring with water as a nucleophile, which
not only establishes the B ring but also precisely installs the difficult-to-achieve
equatorial C7–OH group.
A Fe(NO 3 ) 3 -mediated ring-opening arylation of cyclopropanol with the electron-rich pyrrole has been developed, which might proceed through oxidative radical ring opening of cyclopropanol followed by cyclization to the pyrrole motif and then aromatization. This method enables direct arylation of cyclopropanol without prefunctionalization and thus allows rapid access to a diverse array of chiral 5,6,7,8-tetrahydroindolizines from easily available chiral amino acid esters. The synthetic utility has been demonstrated by the asymmetric synthesis of alklaoids (−)-indolizidine 167B, (+)-indolizidine 209D, (+)-monomorine I, and a natural product analogue.
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