The enediyne natural products are potent antitumor antibiotics. According to the presence of a bicyclo[7.3.0]-dodecadienediyne or a bicyclo[7.3.1]tridecadiynene unit, they are further divided into nine-membered or ten-membered sumfamilies. Enediynes are capable of causing single or double DNA strand lesion due to their propensity to undergo cycloaromatization reactions to generate 1,4-benzenoid diradical species under biological conditions. We envision that the establishment of the enediyne skeleton of uncialamycin, a ten-membered enediyne, is biosynthetically derived from a linear precursor via an heterointramolecular Diels–Alder reaction without enzymatic catalysis. Hence, we aim to synthesize a key intermediate in order to examine this proposal. Meanwhile, a related study on the generic biosynthesis of the nine-membered enediynes had resulted in the serendipitous discovery of the underutilized hexadehydro-Diels–Alder (HDDA) reaction. During such an event, a 1,3-diyne moiety engages an intramolecularly placed alkyne moiety in a formal [4+2]-cycloaddition reaction to produce a fused bicyclic benzyne intermediate, which is subsequently trapped in situ to yield highly substituted benzenoid products. We are dedicated to the investigation of mode of reactivity between the HDDA-generated benzynes and sulfur-based nucleophiles. Thus, consistent with the prior reports, sulfides react with benzyne to form the S-arylsulfonium ylides, which we further utilize in the development of a highly versatile three-component process. We describe the first examples of the reactions between aromatic thioamides and the HDDA-generated benzynes to form dihydrobenzothiazines through an unusual thiolate-relayed 1,3-proton migration of the pivotal ortho-mercaptoaryliminium betaine intermediate. The trapping reaction manifold with thioamide is found to be altered by tuning the electronic property to give rise to 2,2-disubstituted benzothiazoline derivatives. On the other hand, vinyl sulfoxides are shown to participate a tandem three-component reaction the produce ortho-sulfanylaryl ethers and benzooxathiine derivatives. These new trapping reactions are not only rich in mechanistic content, but also show potential in drug discovery industry.
University of Minnesota Ph.D. dissertation. August 2016. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); xii, 295 pages.
Enediyne to Polyyne: Spontaneity in the Biosynthesis of Uncialamycin and Intermolecular Trapping of Benzynes Generated from the Hexadehydro-Diels–Alder Reaction.
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