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Towards the synthesis of cytochalasin B

University of British Columbia

Chapter I of this thesis deals with the syntheses of the key fragments for use in a proposed synthesis of cytochalasins A, B and F. The chiral precursor 86 of the macrocyclic fragment of the target molecules was prepared in good overall yield from (+)-citronellol using a new reagent which was developed for this purpose. Dienes 87, 88 and 89 were prepared from (E)-2-methyl-2-butenal following literature procedures. The chiral dienophile 124 which was required for an intermolecular Diels-Alder reaction was prepared in good overall yield from L-phenylalanine. A model Diels-Alder reaction between (E,E)-2,4-hexadiene and 124 provided a quantitative yield of the Diels-Alder adduct 126. However, Diels-Alder reactions between 87-89 and 124 were unsuccessful. Substrates 39-41 required for a proposed intramolecular Diels-Alder reaction were prepared. Attempted intramolecular reactions of 39-41 were unsuccessful. [Figure 1] The development and synthetic applications of two ethanedial (glyoxal)-based reagents are discussed in Chapter II. Chapter II-A deals with the preparation and alkylation studies of enamines of 2,2-bis(ethylthio)ethanal (162). This compound was prepared in good yield from ethanedial. Alkylation of the potassium salts of various enamines of 162 followed by in situ hydrolysis provided high yields of the alkylation products. This new reagent was used in the synthesis of compound 86, mentioned above, as well as the physiologically active diolides pyrenophorin and norpyrenophorin. Chapter II-B deals with the preparation and alkylation of 2,2-bis(ethyl-thio)acetonitrile (211). This compound was prepared in high yield from 162. Alkylation of the potassium salt of 211 with various electrophiles and conjugate addition with cyclic a,6-unsaturated ketones provided high yields of the alkylation products. The potential 1- and 2- carbon chain extension capability of this reagent has been demonstrated. [Figure 2] In Chapter III of this thesis a mechanistic investigation of a thermal [l,3]-alkyl shift in compounds 174 and 246-252 is described. An intermolecular, free-radical pathway for the migration was proposed on the [Figure 3] basis of the results of a crossover experiment, a significant positive entropy of activation combined with the lack of a solvent effect. An electron spin resonance signal observed during the rearrangement of 174 was consistent with the proposed radical pathway.

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2010-05-02

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http://hdl.handle.net/2429/24345

Chemistry

University of British Columbia

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