Part I - Synthesis of the Tetracyclic Skeleton of the Lycopodium Alkaloid Lycopladine H part Ii - Synthesis of the Tetracyclic Core of the Apparicine Class of Indole Alkaloids via a Key Intermolecular Nitrosoalkene Conjugate Addition

Open Access
Author:
Chauhan, Pradeep Singh
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
February 11, 2015
Committee Members:
  • Steven M Weinreb, Dissertation Advisor
  • Scott T Phillips, Committee Member
  • Alexander Thomas Radosevich, Committee Member
  • Ming Tien, Special Member
Keywords:
  • synthesis
  • lycopodium
  • alkaloids
  • apparicine
  • nitrosoalkene
  • hydroformylation
  • indole
  • chlorooxime
  • dialdehyde
  • dialkene
Abstract:
Abstract Part I A synthesis of the tetracyclic framework 220 of the structurally unique Lycopodium alkaloid lycopladine H (21) has been achieved in 19 steps from phenol 60. A key step involved a novel double alkene hydroformylation/intramolecular reductive amination of 217 to form the azocane and spiropiperidine moieties of the natural product in the form of advanced tetracyclic intermediate 220 via intermediate dialdehyde 218. Disappointingly, we have been unable to convert this compound into the natural product. Part II A convergent and concise synthetic route to the tetracyclic core 61 of the apparicine-type alkaloids has been achieved in only four steps in 80% overall yield from the known 3-formylindole ester 113 and 3-piperidone-derived α-chloroketoxime 80. Key transformations involve use of an intermolecular ester enolate/nitrosoalkene conjugate addition to form the C-15/16 bond of 117, followed by a reductive cyclization to form the C-ring of the tetracycle core 61, which has appropriate handles in place at C-16 and C-20, to easily access a number of the members of the apparicine class of indole alkaloids.