Browsing by Subject "Mannich"

The direct addition of enolizable aldehydes and sulfonyl imines to α-halo thioesters to produce β-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic α-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic α-hydroxy aldehyde derivative is used. Using MgI₂ and Ph₃P, this method gives a wide range of aldol and Mannich products in good yields with high syn-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and β-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.

Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral α-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.

This dissertation deals with the development of asymmetric carbon-carbon and carbon-heteroatom bond-forming reactions and the synthesis of Lagunamide A. Asymmetric C-C and C-X bond formations are critical transformations in synthetic chemistry. While a variety of approaches are available to effect such reactions, organocatalytic methods have attracted considerable recent attention. Common themes have emerged from these studies with regard to both the mode of asymmetric catalysis and the nature of the substrates they are applied to. We have been investigating alternatives to these themes for both carbon-carbon and carbon-heteroatom bond formation. We will describe some of our efforts to expand the parameters of asymmetric organocatalysis, which include the development a novel biomimetic proximity-assisted soft enolization approach to the asymmetric Mannich reaction, as well as the use of nitrosoalkenes for the asymmetric a-sulfenylation of ketones and aldehydes. Lagunamide A was recently isolated from Palau Hantu Besar, Singapore and has shown strong antimalarial activity and cytotoxicity against leukemia. The work presented describes the progress towards the first asymmetric total synthesis of this natural product.