Enediyne natural products are among the most potent antitumor agents known today. Numerous synthetic methodologies for the synthesis of naturally occurring enediynes and their analogs have been developed over the last decade. Ally lit rearrangement first reported by our group is one of such methods that allow formation of the labile enediyne moiety from a stable precursor. This thesis study will emphasize on the study of allylic rearrangement of 1,2-dialkynylallyl alcohols and esters under protic or Lewis acid catalysis. A minor effort will be devoted to the study of β-hydroxyl propargylic sulfones, the well-known DNA base alkylating agents....[ Read more ]

Enediyne natural products are among the most potent antitumor agents known today. Numerous synthetic methodologies for the synthesis of naturally occurring enediynes and their analogs have been developed over the last decade. Ally lit rearrangement first reported by our group is one of such methods that allow formation of the labile enediyne moiety from a stable precursor. This thesis study will emphasize on the study of allylic rearrangement of 1,2-dialkynylallyl alcohols and esters under protic or Lewis acid catalysis. A minor effort will be devoted to the study of β-hydroxyl propargylic sulfones, the well-known DNA base alkylating agents.

An overview of the naturally occurring enediyne family including selected synthetic approaches to their model systems is outlined in Chapter 1. In Chapter 2, selected methodologies for the formation of enediynes from 1,5-diynes are reviewed followed by a background description on the allylic rearrangement strategy. A detailed account on the mechanism, regio- and diastereoselectivity of the protic acid-catalyzed rearrangement of 1,2-dialkynylallyl alcohols is then provided on the basis of new results of this thesis study. They include: (a) examination of structural requirement for facile rearrangement; (b) reactions using chiral ally1 alcohols to probe the reactive intermediates involved in the product-forming step; (c) computational calculations on the stability of substrates, products and the allylic cations for the understanding of substrate reactivity, regio- and diastereoselectivity.

Chapter 3 deals with the control of regiochemistry in the protic acid-catalyzed allylic rearrangement. C₃-aryl ally1 alcohols possessing an internal nucleophilic site (hydroxymethyl or mercarptomethyl group) are synthesized. Protic acid-catalyzed rearrangement of these substrates is shown to give the desired cis-enediynes in a complete regiocontrolled manner.

A novel Eu(fod)₃-catalyzed rearrangement of allylic esters is presented in Chapter 4. In this study, the reactivity of a number of allylic esters is examined systematically. We find that esters having an additional chelating site are capable of forming a five- or six-membered chelate with Eu(III) and migrate readily at room temperature. Among them, allylic methoxyacetates and benzyloxyacetates are the choices of esters and a number of enediynes can be prepared by this mild rearrangement.

The final chapter investigates the base-catalyzed cyclization of a series of β-hydroxyl propargylic sulfones to form (E)-exe-alkylidene tetrahydrofurans. The mechanism is established using the deuterium-trapping experiment. On the basis of these results, the diminished DNA cleaving potency of these β-hydroxyl propargylic sulfones compared to the corresponding acetates is understood and is attributed to the self-cyclization to form (E)-exe-alkylidene tetrahydrofurans.