Title

Rhodium-catalyzed addition of terminal alkynes to vinyl ketones and studies toward the synthesis of peyssonenynes A and B

Date of Award

2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Keywords

Rhodium-catalyzed, Synthesis, 1, 4-addition, Enynes, Dimerization, DNMT-1, Peyssonenynes

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

The 1,4-addition of terminal alkynes to conjugated ketones is a problematic reaction because typical copper-mediated additions perform poorly. To address this limitation, a rhodium catalyzed reaction was developed. After some optimization, the best reaction conditions involved the use of catalytic Rh(acac)(CO) 2 and catalytic P-( o -C 6 H 4 OCH 3 ) 3 in refluxing benzene.

Formation of γ,δ-alkynyl ketones is a synthetically useful reaction, as they can be transformed into other key structures and are present in many natural products. In contrast to other methods, the rhodium catalyzed 1,4-addition of alkynes to enones does not require anhydrous conditions, strong Lewis acids and/or a stoichiometric amount of activating agent. The reaction is also compatible with a variety of functional groups including unprotected alcohols, halides and esters.

These studies also resulted in the discovery of a rhodium-catalyzed three component coupling reaction leading to a conjugated enyne 1,4-addition adduct under similar conditions. By altering the phosphine ligand to P-( o -C 6 H 5 CH 3 ) 3 , we can dramatically increase the yield of this dimer-addition product while suppressing the 1,4- addition reaction manifold. Using 2D-NMR studies we established the connectivity and the geometry of the enyne 1,4-addition product. Other studies included optimization of this reaction and determination of the scope with respect to alkyne and enone.

Additionally, studies toward the total synthesis of peyssonenynes A & B were performed. Harvested and extracted in minute quantities from a red marine alga, Peyssonnelia caulifera , these natural products strongly inhibit the activity of DNA methyltransferases. Due to the minute quantities isolated and facile decomposition of these natural products, their structural assignment remains incomplete. An efficient synthesis of peyssonenynes A & B will provide material for biological testing and complete structural assignment.

Several approaches toward the synthesis of peyssonenynes A & B are discussed. The four pathways differ by featuring different key reactions such as: (1) a rhodium-catalyzed 1,4 addition of a terminal enediyne to acrolein, (2) the Sonogashira reaction, (3) a linear Cadiot-Chodkiewicz approach and (4) a convergent Cadiot-Chodkiewicz approach.

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