Chiral methyllithiums - biodegradative studies

The chiral methyl group is the smallest chiral group in organic chemistry, which was prepared for the first time by Cornforth and Arigonis group. Its synthesis, the determination of its configuration and the numerous applications, especially in biochemistry to investigate enzyme mechanisms, made the chiral methyl group an attractive research goal. However, up to now chiral methyllithiums containing beside the hydrogen isotopes protium and deuterium, lithium (or an other metal) and a heteroatom (O, N, halogen) could not be prepared. These spezies are formally carbanions, which are configurationally unstable in the case of alkyl groups as substituents. However, the ones dealt with here should resist inversion of configuration at low temperature (at -78 C or below) because of the heteroatom present. The proposal has three focal points. a) The preparation of chiral oxygen-, nitrogen- or halogen-substituted methyllithiums from homochirally deuterated tributylstannylmethanols, whose synthesis will be improved, is described in the first part in detail. Representative examples with a variety of functional groups will be studied. Their konfigurational stability, the microscopic and macroscopic, will be evaluated as a function of temperature, solvent and ligands. Benzaldehyde will be used as standard electrophile to trap the chiral methyllithiums. The enantiomeric excess and the configuration of the methylene group in the addition product will be determined using NMR spectroscopic methods in combination with reference samples. b) In the second part, the synthesis of chirally deuterated primary alcohols, monoprotected chirally dideuterated 1,2-ethanediols and D-glucose, stereospecifically deuterated at C-6, will be described using chiral methyllithiums. c) The third part of the research proposal addresses the synthesis of the aminomethylphosphonic acid and of N- (phopshonomethyl)glycin, stereospecifically deuterated and tritiated at the PCH 2 group. The latter compound is used in large quantities as a herbicide (glyphospate, "Round Up"), which is mineralised by bacteria in part via the aminomethylphosphonic acid in the soil. The crucial step of the biodegradation of these xenobiotic phosphonates is the enzymatic cleavage of their phosphorus-carbon bond. The stereochemistry of that step will be unravelled using their stereospecifically labelled analogues.

Chiral methyllithiums consist of molecules containing a carbon atom with four different substituents, a hydrogen, a heavy hydrogen, a lithium, and a hetero-atom such as oxygen, nitrogen, sulphur, and halogen atom (fluorine, chlorine, bromine, iodine). Such compounds were prepared in two forms behaving to each other like the right and left hand at temperatures from 95 C to 0 C. In general the starting materials were tin organic compounds, in which tin with its substituents was exchanged for lithium. As the chiral methyllithiums are transformed into each other, that is enantiomerize, depending on the heteroatom and temperature, we tried to find a temperature, at which this transformation does not take place. To detect that chiral methyllithiums were reacted with benzaldehyde. The formed alcohols were derivatized to prove by spectroscopic means whether one or both spezies were detectable. It was found that enatiomerization with oxygen as heteroatom starts at temperatures above 30 C at best, with nitrogen or sulphur as heteroatoms even at 90 C. The preparation of the starting materials for the chiral halomethyllithiums was an experimental challenge. Surprisingly, all halomethylltihiums except iodomethyllithium were stable towards enatiomerization at 78 C. These results interlock nicely with quantum chemical calculations predicting that fluorine has the biggest stabilizing effect relative to all other halogens. Furthermore, the corresponding nondeuterated fluoro compound could not be prepared before. An undesired side reaction interfered with these methyllithiums, the elimination of lithium salts giving carbenes, species with one carbon atom and two substituents as reactive intermediates. We did not search for their reaction products. An oxygen-containing chiral methyllithium was rearranged to a phosphonic acid, which was used to unravel an important reaction step in the biosynthesis of the herbicide phosphinothricin used in farming with transgenic plants. This project resulted in 9 papers, two in the Journal of the American Chemical Society, the top journal in chemistry, two more are under preparation. This is my most successful project of my scientific life.