The development of an expedient method for the synthesis of a diverse series of cyclopropane alpha-amino acids.

摘要

This thesis presents a collection of developments made in the field of diazo chemistry involving the cyclopropanation of olefins. The main goal of this research was to develop a new and efficient synthetic methodology for the synthesis of cyclopropane alpha-amino acids. This class of amino acids appears in natural and synthetic products and has been shown to have very interesting biological properties. An expedient and efficient method was developed for the preparation of alpha-nitro-alpha-diazocarbonyls. These diazo compounds undergo efficient cyclopropanation reactions with olefins catalyzed by Rh(II) and Cu(I) complexes. Accordingly, the presence of chiral ligands on these metal complexes allow for the catalytic asymmetric preparation of 1-nitro cyclopropanecarboxylates in modest enantioselectivities.; The cyclopropanation reaction was also found to proceed in aqueous media, an interesting observation due to the synthetic efficiency of O-H insertion reactions with diazo compounds. This led to the development of an in situ method for generation of ethyl diazoacetate. This methodology permits the controlled formation of ethyl diazoacetate in the reaction mixture; representing a safe alternative for diazo-mediated cyclopropanations on a large scale.; A method involving the in situ generation of phenyliodonium ylides derived from alpha-nitrocarbonyls, which represent synthetic equivalents of diazos, was also developed to eliminate potential explosion hazards associated with the use of alpha-nitro-alpha-diazocarbonyls. These ylides undergo Rh(II)-catalyzed cyclopropanation reactions in a very similar manner to those observed with the corresponding diazo compounds.; The sensitive nature of 1-nitro cyclopropanecarboxylates made their reduction very challenging. Pd-based hydrogenation catalysts, which are often used to reduce nitro groups, led only to the destruction of the cyclopropane moiety. However, zinc dust in 2-propanol enabled an efficient reduction of these cyclopropanes to the desired cyclopropane amino esters in excellent yields. These compounds can then be easily transformed into the desired cyclopropane alpha-amino acids upon saponification of the ester.; The nitro cyclopropanecarbonyl moiety can also serve as a useful synthon in organic synthesis. Dihydropyrroles could be prepared upon treatment of 1-nitro-1-ketocyclopropanes with a variety of primary amines. Oxidation of these dihydropyrroles then allows rapid access to densely functionalized pyrroles. 1-Nitro cyclopropane carboxylates can also participate in cascade reactions. A cascade reaction involving an intramolecular rearrangement to an isoxazoline N-oxide followed by a 1,3-dipolar cycloaddition reaction with an olefin was developed. A strategy was envisioned using this approach for the synthesis of densely functionalized beta-lactams.