ALKYNYLIODONIUM SALTS IN ORGANIC SYNTHESIS. APPLICATION TOWARDS THE SYNTHESIS OF THE CORE OF (±)-HALICHLORINE. AND ATTEMPTS TOWARDS THE SYNTHESIS OF KINAMYCIN F.

Open Access
Author:
Perkins, Angela L
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
May 25, 2005
Committee Members:
  • Ken S Feldman, Committee Chair
  • Blake R Peterson, Committee Member
  • RAYMOND LEE FUNK, Committee Member
  • Squire J Booker, Committee Member
Keywords:
  • halichlorine
  • alkynyliodonium salts
  • alkylidenecarbene
  • kinamycin
  • nazarov cyclization
Abstract:
Alkynyliodonium salts are synthetically useful intermediates that serve as electrophilic acetylene equivalents due to the electron withdrawing nature of the hypervalent iodine. In one example, reaction of an alkynyliodonium salt with soft nucleophiles via conjugate addition, followed by loss of iodobenzene, generates alkylidenecarbenes. Alkylidenecarbenes are divalent, short lived intermediates capable of participating in a various bond-forming processes depending upon the functionality present within the molecule. Due to the wide variety of possible reactions, alkylidenecarbenes are useful reactive intermediates in natural product synthesis. The application of alkynyliodonium salts to generate alkylidenecarbenes is described in the first part of this thesis. Chapter 1 discusses the formation of alkynyliodonium salts and their application towards the generation of alkylidenecarbenes. The total synthesis of radermachol, a natural product target, was examined utilizing an alkylidenecarbene addition to a double bond as a key step. However, preliminary results shifted the focus away from this synthesis. Instead, aryl C-H insertion was examined by the reaction of phenoxide anions of naphthol derivatives with an alkynyliodonium salt. A variety of naphthol derivatives were used to study the preference for C-H insertion in these aromatic systems. Halichlorine is a natural product target to which alkynyliodonium chemistry was applied in chapter 2. Halichlorine is a structurally unique marine alkaloid, which has interesting biological activity, in that it is a selective inhibitor of VCAM-1. The focus of the synthesis of halichlorine centers on the formation of a key quaternary center of the spirocyclic ring system. This bond can be formed using an alkynyliodonium salt to generate an alkylidenecarbene, which can undergo a 1,5-C-H insertion to generate the quaternary center with retention of stereochemistry. This synthesis highlights the use of alkynyliodonium salt chemistry for increasing molecular complexity in a single operation. The final project discussed in this thesis is the progress made towards the total synthesis of kinamycin F. Kinamycin F is a compound in a class of potent antibiotics, whose members have also exhibited interesting cytotoxicity to a variety of tumor cell lines via cleavage of double stranded DNA. The proposed mechanism of action of these kinamycin compounds is thought to be through a bio-reductive process, generating a radical species which interacts with DNA leading to strand scission. Completion of the total synthesis of kinamycin F will permit a more thorough evaluation of the hypothesized biological mechanism of action.