Investigation Of The Reactivity Ofα-diazophosphonates Derivatived From Natural Amino Acids

The demand for efficient ways to construct complex chemical structures from simple, readily available precursors is always the research hot spot of chemists. Among most of the methods, a very attractive way to meet this demand would be through selective functionalization of carbon-hydrogen (C-H) bonds. Moreover diazo compounds are the most commonly used carbene precursors, they can be dediazonized to highly reactive free carbene intermediates or metal cabenoid under thermolytic, photolytic or transition metal catalysts. Then varieties of chemical transformations can be proceeded, such as X-H (X=C, N, O, S, Si etc) insertions, cyclopropanations, ylide formations and1,2-hydrogen migration reactions. Varieties of chemical compounds could be synthesized through these methods. Therefore, it provides efficient strategy for the synthesis of pharmaceuticals, natural products and other bioactive moleculars.In contrast to the extensive and fruitful studies of a-diazo carboxylates, the research of a-diazo phosphonates remains scarce. It is known that organic phosphorous chemistry occupies an important position in life scientific research. Phosphorus also plays an important role in the origin of life and life activities. Because of organic phosphorous compounds exhibit extensive bioactivity and pharmaceutic activity, they have attracted lots of attentions of scientists. Among varieties of organic phosphorous compounds, β-amino phosphoric acids as the analogous of β-amino acids play an important role in organic phosphorus chemistry. Because they exhibits antibiotics, antivirius, weeding control, plant growth regulators and enzyme inhibit activities properties, the synthesis of β-amino phosphoric acids has become the research hot spot of chemists.In order to develop new method for the synthesis of β-amino phosphoric acids and synthesize some β-amino phosphoric acids with novel structures, we synthesized a series of novel a-diazo phosphonates derivatived from natural amino acid and hopes to utilize the reactive properties of theses a-diazo phosphonates to realize the above purpose. The author’s subject mainly involes the following specific contents: Firstly, through the research of the reaction of these a-diazo phosphonates with alcohols, the author discovered that they exhibited unique reactive properties. When they were decomposed under Cu(MeCN)4PF6to form carbenoid and underwent the O-H bond insertion reaction, the insertion site is not the diazo carbon, but the ortho position of the diazo carbon. Commonly the insertion site of carbene should be the diazo carbon. The net reaction process is a combined C-H functionalization/O-H insertion reaction, and the reaction produced (3-amino-β-alkoxyl substituted phosphonates, followed by the (Z)-β-enaminophosphonates formed as the1,2-hydrogen migration product. The total yield of the reaction was between32%and89%. The author investigated the reaction mechanism through the deuterium labeling experiments. It was found that the reaction initiated with the1,2-hydrogen migration after the decomposed of the a-diazo phosphonates under the catalysis of Cu(MeCN)4PF6. The carbocation would occur at the β-carbon of the phosphonates. It was then captured by the alcohols and the desired product was formed after1,3-hydrogen migration.Secondly, during the investigation of the reaction of these a-diazo phosphonates catalyzed by Cu(MeCN)4PF6and iodine, the author discovered an unexpected β,γ-dihydrogen shift reaction. The hydrogen on the β and y carbon of these a-diazo phosphonates would migrate to the diazo carbon to produce β-alkenyl substituted β-amino phosphonates. The plausible mechanism was considered to be that the y hydrogen was absorbed to the carbene center after the copper carbenoid was formed. Then1,2-hydrogen migration occurred to give the desired dihydrogen shift products β-alkenyl substituted β-amino phosphonates.Thirdly, the author utilized the1,2-hydrogen migration reaction of these a-diazo phosphonates to prepare different β-enaminophosphonates. After the optimized condition screening, it was found that these a-diazo phosphonates would decomposed to (Z)-enaminophosphonates with good Z/E selectivity (Z/E mole ratio was between72:28and100:0) and good yield (the yield was between63%and94%) under the catalysis of AgOTf. The excellent stereoselectivity was attributed to the steric hindrance of these a-diazo phosphonates during the reaction.Fourthly, the author discovered that these a-diazo phosphonates would undergo combined C-H functionalization/S-H insertion reactions with mercaptans or thiophenols under the catalysis of boron trifluoride to give the β-amino-β-sulfur substituted phosphonates. An N,S-acetal contained quaternary carbon was constructed in the product. The yields of the reaction were good and the substrate scopes were widely. The reaction mechanism was similar to the combined C-H functionalization/O-H insertion reaction.Fifthly, the author also investigated the reaction between these a-diazo phosphonates and indoles or pyrroles. It was found that a combined C-H functionalization/C-H insertion reaction would occur under the catalysis of boron trifluoride to give an aze-quaternary carbon center contained products. The yields of this reaction were moderate and the substrate scopes were wide. It was worthly mentioned that the amino group of the indoles or pyrroles did not need protection during the reaction. The plausible reaction mechanism was considered to be that the boron trifluoride coordinated with indoles or pyrroles first, then the complex decomposed the a-diazo phosphonates, the nitrogen then released followed by the1,2-hydrogen migration. The carbocation occurred at the β-position of the phosphonates was then captured by indoles or pyrroles. After the1,3-hydrogen migration, the desired products were obtained.The above research results indicate that these a-diazo phosphonates derivatived from natural amino acids exhibited novel reactivites as a kind of useful synthon. They exhibited good reactivites in O-H, S-H, C-H bond insertion and hydrogen shift reactions. They could be used for the synthesis of novle β-amino phosphoric acids and the research of the asymmetric synthesis of these compounds is under way in our laboratory at present.