The first part of this dissertation (Chapter 2) describes the development of a novel class of doubly activated dienes – oxazolidinebutadienes – for the Diels-Alder reactions. In this dissertation, we focused our research efforts on two different classes of pericyclic reactions, the Diels-Alder reaction and Claisen rearrangement, and their application towards the total synthesis of the natural products Hinckdentine and Melonine. Despite the significant interest from the synthetic community, multiple aspects of pericyclic reactions still remain unexplored. Their ability to provide access to complex and sterically hindered structures in a regio- and stereo-controlled manner in a highly atom economical fashion has played a crucial role in the total synthesis of innumerable complex natural products over the past several decades. Cyclopropene 38 reaction product was confirmed previously, cyclopropene 37 reactant and the reaction product are confirmed in Figure S2 in the Supporting Information.Pericyclic reactions are, arguably, one of the most important classes of reactions in organic synthesis. Stars correspond with measured fluorescence scan colors (cyclopropene 37 reactions in green, 38 in blue). Inset: the reactions upon completion, visualized under a long range UV lamp. Final reacted fluorescein emission traces using the cyclopropene probes after freeze-thaw cycles are shown in green and blue, respectively. Reaction progress was measured by the unquenching of fluorescein emission that is initially quenched by the unreacted tetrazine (trace in black). e) Cyclopropene–DNA probes ( 37 in green trace, 38 in blue) were treated with the neighboring tetrazine probes along a DNA template. d) Similarly, after five freeze-thaw cycles, 13 nucleotide 3′ cyclopropene carbamate probe 38 shows 95 % degradation, estimated from the HPLC trace peak areas. Initial and final HPLC traces are shown overlaid. c) After five freeze-thaw cycles, 13 nucleotide 3′ cyclopropene amide probe 37 shows lower than 1 % degradation, based on a gradient HPLC trace of 260 nm absorbance peak containing expected probe product mass peaks. Illustration depicts the placement of fluorescein (star) and tetrazine quencher that results in fluorescence turn-on (green star) after reaction with the cyclopropene probe. b) Modified DNA probe reaction upon hybridization to a fully complimentary DNA template.
a) Synthesis scheme of the modified DNA cyclopropene probes. Stability of cyclopropene–DNA oligonucleotide probes. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.īioconjugation bioorthogonal cycloaddition cyclopropene density functional calculations tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. Surprisingly, 3-amidomethyl substituted methylcyclopropene reacts faster than trans-cyclooctenol with a sterically hindered and extremely stable tert-butyl substituted tetrazine. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. An outcome of these studies is the discovery of a novel 3-amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1-methyl-3-substituted cyclopropene while retaining excellent aqueous stability. The substituents also have a dramatic effect on aqueous stability. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The rates at which the various substituted cyclopropenes undergo Diels-Alder cycloadditions with 1,2,4,5-tetrazines were measured.
#REACTIVITY OF DIENOPHILES SERIES#
Here, the synthesis and comparison of the reactivity of a series of 1-methyl-3-substituted cyclopropenes with different functional handles is described. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Substituted cyclopropenes have recently attracted attention as stable "mini-tags" that are highly reactive dienophiles with the bioorthogonal tetrazine functional group.
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