Enediyne to Polyyne: Spontaneity in the Biosynthesis of Uncialamycin and Intermolecular Trapping of Benzynes Generated from the Hexadehydro-Diels–Alder Reaction

University of Minnesota Ph.D. dissertation. August 2016. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); xii, 295 pages.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