Second generation total synthesis of (-)-Nakadomarin A
Studies toward the total synthesis of (-)-Apoptolidin A
Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2018.
Part I. The Second-Generation Total Synthesis of (-)-Nakadomarin A
The second-generation total synthesis of (-)-nakadomarin A (1) has been described.
A robust sequence toward the bicyclic lactam has been developed, allowing its production
on > 5 g scale. This has been enabled by a number of significant improvements, including
increased diastereoselectivity for the key SN2’ cyclobutane formation, a scalable cyclobutanecarboximine
formation/retro-aza-Claisen sequence, and the removal of a step from the
longest-linear sequence by use of isocyanate addition to the bicyclic lactam in lieu of a
two-step protocol. The Michael addition/spirocyclization’s catalytic potential has been investigated,
and a robust and scalable method for the synthesis of the spirocycle has been
deployed. After pentacycle formation, macrocyclization, and reduction, (-)-nakadomarin
A (1) is afforded with production of the target on over 0.5 g scale. This has resulted in a
total synthesis of 1 in 16 steps (longest linear) and 6.5% overall yield.
Part II. Studies Toward the Total Synthesis of (-)-Apoptolidin A
A route toward the potent and selective apoptosis inducer (-)-apoptolidin A has
been outlined. Production of the lactone comprising the southwestern quadrant of the natural
product on scale by a previously described route has been investigated. Small-scale
success in generating the lactone was ineffective on larger scales using the existing protocol
due to the sensitive nature of an intermediate Diels-Alder adduct. Important advancement
in material throughput was achieved by implementation of a robust two-step protocol for generating a critical intermediate alcohol on larger scales. Combined with the improvement
of a deallylation protocol, a scalable route to the lactone of the southwestern quadrant
of (-)-apoptolidin A has been established. With this, the completion of the southern hemisphere
and aglycone of (-)-apoptolidin A will be accessible.
