Selective alkylidene carbene insertion reactions - studies towards the synthesis of ingenol

Munro, Kevin Ross (2013). Selective alkylidene carbene insertion reactions - studies towards the synthesis of ingenol. University of Birmingham. Ph.D.

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Alkylidene carbenes are reactive intermediates in organic chemistry. Intramolecular 1,5 C-H insertion reactions lead to cyclopentenes with retention of configuration. Insertions into O-Si or O-H bonds form dihydrofurans. Chapter 1 reviews of the chemistry of alkylidene carbenes, focusing on their reactivity and the techniques that can be employed for their in situ generation. Factors governing the selectivity of these reactive intermediates are discussed. Previous investigations in the Grainger group on the use of alkylidene carbenes in model studies towards the synthesis of the cyclopentene A-ring of ingenol, a biologically active diterpene, are described.
Chapter 2 describes an investigation into hydroxycyclopentene annulation using the 1,5 C-H insertion reaction of α-hydroxyalkylidene carbenes on a 2,4-dimethyl-substituted 8-oxabicyclic ring system. Syntheses of α,β-epoxy-N-aziridinylimines, known precursors to α-hydroxyalkylidene carbenes, are achieved in 5-6 steps through initial stereoselective addition of a vinyl lithium species to 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one. The diastereoselectivity (diastereotopic group selectivity) of the alkylidene carbene insertion reaction is reversed upon protection of a tertiary alcohol at C-3 of the oxabicylic ring system as a trimethylsilyl ether.
Application of the hydroxycyclopentene annulation on an 8-oxabicyclic ring system bearing a benzyloxy substituent on the 2-position is described in chapter 3. Selective insertion adjacent to the benzyloxy group is observed irrespective of the tertiary alcohol substituent at C-3. Competing O-H and O-Si insertion, fragmentation and 1,2-rerrangement occur to a much greater extent than for the 2,4-dimethyl system.
Chapter 4 compares the selectivity of alkylidene carbenes generated in the dimethyl and benzyloxy-substituted oxabicyclic ring systems. Alkylidene carbenes lacking the α-hydroxy group, generated via either the deprotonation of vinyl chlorides, or the reaction of ketones with lithio(trimethylsilyl)diazomethane, show similar reactivity differences in the 3-trimethylsilyloxyoxabicyclic systems as those bearing the α-hydroxyl group. The ratio of C-H insertion to O-Si insertion depends on the method of generation employed.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Engineering & Physical Sciences
School or Department: School of Chemistry
Funders: None/not applicable
Subjects: Q Science > QD Chemistry


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