The aim of this project is to develop agents capable of delivering halenium ions such as chloride, bromide, and iodide, in a chiral fashion, such that the products obtained are enantiomerically enriched. Historically, this goal has not been met with great success for a variety of reasons, most importantly because of the fact that halenium ions are reactive and difficult to sequester, and thus background reactions compete effectively with "coordinated" halenium delivery. Nonetheless, recent success in the principal investigator's laboratory has led to the development of a strategy for taming the halenium ion for the halolactonization chemistry that affords products in high yield and high enantiomeric excess. This early success will be extended in a hypothesis driven manner for the application of chiral halenium ions to a large number of other reactions.
With this award, the Chemical Synthesis program is supporting the research of Professor Babak Borhan of the Department of Chemistry at Michigan State University. Professor Borhan's research efforts revolve around the development of new enantio-selective methodologies that are facile, green, and economically feasible. The result of this work will expand the repertoire of enantioselective reactions to yield products of importance for the synthesis of biologically active agents and pharmaceuticals.
Discovery of new reactions is fundamental to progress in chemistry, leading to new routes for accessing molecules of interest for a variety of applications such as pharmaceuticals, manufacturing, materials, etc. Introduction of chirality into molecules is essential for many applications, yet this process greatly complicates the development of new methodologies. An example of the latter is the halogenation of double bonds to create organic halides, a reaction that is more than a 100 years old, yet has lacked a solution for asymmetric (chiral) synthesis. In 2010 we demonstrated the first example of an asymmetric chlorolactonization reaction with synthetically useful yields and enantioselectivities. The NSF grant that supported this research allowed us to expand the scope of our initial discovery to show a variety of different structural motifs can succumb to this reaction with high yields and excellent enantioselectivities. Furthermore, we were able to investigate the mechanism of this reaction, and in particular discover key factors that are responsible for enantioselectivity. This is crucial for further progress in this field, especially to alter and redesign the structure of the chiral catalyst for improvements with family of compounds that are not ideally suited for the present methodology. Figure 1 illustrates a pictoral summary of the reactions developed during the funding period. It emerged that unsaturated amides could be chlorocyclized using similar reaction conditions to give the corresponding cyclized products with exquisite enantioselectivity. 1,1-Disubstituted olefins gave chiral oxazoline products, whereas trans-disubstituted and trisubstituted olefins gave the corresponding dihydro-oxazines. Subsequent studies revealed that unsaturated carbamates could be chlorocyclized to the corresponding oxazolidinones using a slightly modified protocol. Intriguingly, this reaction exhibited a solvent dependent enantiodivergence whereby either enantiomer of the product could be accessed using the same catalyst by the judicious choice of the reaction solvent. Eyring plot analyses revealed that the origin of the observed enantiodivergence could be traced back to a solvent-selected entropy-enthalpy balance between pro-R and pro-S paths that dictates the course of the reaction. Figure 2 illustrates mechanistic investigations for our first reported reaction. Deuterium labeling studies have been illuminating in this regard. The asymmetric chlorocyclization of labeled substrates 3-D proceed with the formation of all 4 stereoisomers about the C5 and C6 carbons (Figure 2). Meticulous characterization and quantification of all four stereoisomers using preparatory chiral HPLC and NMR studies have led to surprising conclusions. Asymmetric chlorolactonization reactions proceed through a ‘syn’ addition of the chlorine atom and carboxylate nucleophile across the alkene (to give 5R,6R-4-D as the major stereoisomer) as opposed to the ‘anti’ addition resulting from the SN2 opening of a bridged chloronium ion as would have been predicted by conventional wisdom (Figure 2). These studies have made a compelling argument supporting the intermediacy of a carbocation (rather than the bridged chloronium ion) intermediate in the chlorolactonization reaction. Thus, the cyclization of the acid nucleophile on to the chloromethyl carbocation (devoid of any chirality) is templated by the catalyst; i.e. the chlorine delivery to alkene and cyclization on to the carbocation are two segregated events in the halocyclization chemistry and the enantioselectivity determining step is the cyclization event and not the alkene halogenation event (the alkene face selectivity for chlorenium capture is also determined using the same labeling study).
