Halocyclizations and cycloisomerizations of 1,6-diynes, and sequence-defined, self-replicating polymers
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The exploration of chemical space in search of molecules that perturb or mimic biological systems is essential to understanding human biology. The first part of this dissertation (Chapters 1-4) describes efforts to aid in the exploration of biologically relevant space through the invention of new π-cyclization methodologies. This strategy can be viewed as part of a “top-down” approach to investigating biology: the construction of small molecule drugs or probes which modify the behavior of the existing system. The second part of this dissertation (Chapter 5) describes preliminary efforts to expand life-like chemical space beyond the nucleic acids of DNA and RNA. This can be viewed as a “bottom-up” approach to biology: the construction of systems which mimic the features of biochemical processes. In part one, cyclizations of nitrogen tethered 1,6-diynes were developed as a means to new heterocyclic scaffolds. A GaX3 promoted halocyclization transformed the acyclic diynes into tetrahydropyridine rings with exocyclic vinyl halides. In the presence of strong acid, the tetrahydropyridine products were further cyclized to tetrahydroindenopyridine scaffolds. These scaffolds were then diversified through Pd(0)-catalyzed cross-coupling reactions of the vinyl halide, and modifications to the tethering amino nitrogen. Subsequently, a Brønsted acid-catalyzed cyclization was developed, transforming N-sufonyl tethered bis-aryl 1,6-diynes to dihydroindenopyridines. Using unsymmetric bis-aryl diynes, the regio- and chemoselectivity of this Brønsted acid-catalyzed cyclization was investigated, and compared to the GaX3 Lewis acid promoted cyclization developed previously. The regiochemical preference of the initial cyclization step was found to be reversed under the two different conditions. In part two, a means to sequence-defined synthetic polymers which emulate the information storage and self-replication abilities of nucleic acid-based biopolymers was designed. Information was encoded in two dimers as a specific sequence of aniline and benzaldehyde subunits, which were linked together by a diethynyl benzene backbone. These dimers functioned as a template for the synthesis of new dimers with a complementary sequence. Unpolymerized ethynylaniline and ethynylbenzaldehyde monomers, associated to a polymer template by reversible imine bonds, were polymerized via Sonogashira cross coupling with diiodobenzene. Under the same set of conditions, the sequence of two parent dimers was transferred to the daughters.