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Title page for ETD etd-06272011-200439


Type of Document Dissertation
Author Fadeyi, Olugbeminiyi
Author's Email Address fadni@yahoo.co.uk
URN etd-06272011-200439
Title Application of organocatalysis to the synthesis of pharmacological relevant scaffolds: chiral β-fluoroamines and aziridines. Total synthesis of carpanone, polemannone b & c and brevisamide, and a general approach for the construction of azabicyclic ring-containing alkaloids
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Lindsley Committee Chair
Gary sulikowski Committee Member
Jens Meiler Committee Member
Lawrence Marnett Committee Member
Keywords
  • benzoxanthanone
  • alkaloids
  • polyether
  • aziridine
  • brevisamide
  • fluoroamines
  • Fluorination
  • grandisine A
  • grandisine D
  • stemaphylline
  • azepine
  • stemona
  • indolizidine
  • homocoupling
  • polemannone
  • carpanone
  • oxidative phenolic coupling
Date of Defense 2011-06-10
Availability unrestricted
Abstract
In the field of organocatalysis, the use of small organic molecules has had a significant impact on chemical synthesis, providing a mild and practical alternative to the more conventional metal based catalyst. The selective introduction of fluorine in organic molecules has been shown to enhance binding interactions, improve metabolic stability, increase CNS penetrability and eliminate ancillary ion channel activity by attenuating amine basicity (pKa). On this basis, we have developed a rapid, general route to enantiopure β-fluoroamines (65-82% yield, 94-98% ee) and β,β-difluoroamines (64-78% yield) employing organocatalysis in both a two and one-pot procedure as relevant therapeutic scaffolds. Based on the extension of enantioselective α- fluorination of aldehydes to enantiopure β-fluoroamines, a simple, direct, one-pot organocatalytic approach to the formation of optically active non-activated aziridines will be presented. The approach is based on enantioselective α-chlorination of aldehydes, followed by reductive amination with readily available amines and subsequent base induced cyclization to afford chiral aziridines.

A catalytic CuCl2/(-)-sparteine oxidative β,β-phenolic coupling/tandem inverse-electron demand Diels-Alder reaction cascade of styrenyl phenols to give highly oxygenated benzoxanthanone natural product polemannones B & C, carpanone, and related unnatural congeners was achieved. The total synthesis of brevisamide, a marine cyclic ether alkaloid from Karenia brevis, was completed. This streamlined synthesis proceeds in 21 steps, in 5.2% overall yield and features a key SmI2 reductive cyclization step to access the tetrasubstituted pyran core.

The azabicyclic ring skeleton is an important structural subunit present in numerous biologically active alkaloid natural products and pharmaceutically significant compounds. Notable examples are pyrrolidine, quinolizidine, indolizidine, azocine and azepine (such as stemona alkaloids) alkaloids. A novel approach for the construction of highly diastereoselective azabicyclic compounds has been developed. The methodology is been applied towards the total synthesis of indolizidine and azepine alkaloids (stemaphylline and grandisine A & D).

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