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SYNTHETIC STUDIES TOWARDS THE HAMIGERANS WITH A [6–7–5] TRICYCLIC SKELETON

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SYNTHETIC STUDIES TOWARDS THE HAMIGERANS WITH A [6–7–5] TRICYCLIC SKELETON

thesis
posted on 2022-04-20, 19:06 authored by Baiyang JiangBaiyang Jiang

The hamigeran diterpenoid is a family of natural products with diverse structures and biological activities. Most of the syntheses focus on hamigerans with [6–6–5] tricyclic core, but synthetic efforts toward the more challenging [6–7–5] tricyclic hamigerans are very limited. Herein, our studies in synthesizing the [6–7–5] tricyclic hamigerans are disclosed.  Through a benzyne-β-ketoester annulative ring expansion and a Nazarov reaction, an approach toward the [6–7–5] tricyclic carbon skeleton of the hamigeran natural products was developed. A Ni-catalyzed conjugate methyl addition or a Corey–Chaykovsky reaction installed the all-carbon quaternary center, and a Suzuki cross coupling followed by reduction introduced the isopropyl group. However, the reduction of challenging tetra-substituted double bond or the regio-selective cyclopropane opening was not successful despite multiple conditions were tried. A revised synthetic strategy was proposed and resulted in a convergent total synthesis of (±)-hamigeran M, enabled by five C–H functionalization reactions and proceeding in 11 steps in 3.9% overall yield. The C–H functionalizations include a hydroxy-directed C–H borylation, one C–H metalation-1,2-addition, one C–H metalation-Negishi coupling, a late-stage oxazole-directed C–H borylation-oxidation, and one electrophilic bromination. Further elaboration of the intermediates obtained here has delivered an advanced polysubstrituted precursor towards multiple other hamigerans.

History

Degree Type

  • Doctor of Philosophy

Department

  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Mingji Dai

Additional Committee Member 2

Jianguo Mei

Additional Committee Member 3

Abram J. Axelrod

Additional Committee Member 4

Christopher Uyeda