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40777-B1
Intramolecular Chiral Relay at Stereogenic Nitrogen: The Design, Synthesis, and Application of 3,4,5,6-Tetrahydro-2H-1,3,4-Oxadiazin-2-ones as Chiral Auxillaries
This report is an update of the research activities that my research group has been engaged in since August 2006 concerning the chemistry of compounds known as the oxadiazinones. We have prepared a variety of oxadiazinanones derived from enantiomerically enriched Ephedra alkaloids (ephedrine, norephedrine) and phenylalanine. We have applied these compounds in the asymmetric aldol reaction with a degree of success.
Our past research with these systems (2002-2005) suggested that the N4-position of the oxadiazinanone ring was responsible for the observed stereochemical outcome of the aldol addition reaction via a chiral relay tandem involving the N4-C5-C6 positions. In fact, the N4-methyl group present in the (1R,2S)-ephedrine based oxadiazinanone generated very good diastereoselectivities in the asymmetric aldol reaction. In this context, we sought to increase the diastereoselectivities beyond the capacity of N4-methyl substituent by introducing substituents that were more sterically demanding. Thus, the N4-isopropyl-oxadiazinanone gave superior diastereoselectivity results in the asymmetric aldol reaction. Unfortunately, the aldol adducts proved to be more difficult to hydrolyze than the corresponding N4-methyloxadiazinanones. The next stage of development of the oxadiazinanones involved the introduction of a bornyl group at the N4-position. The N4-bornyloxadiazinanone also gave very good asymmetric induction but the hydrolysis process proved to be more problematic than the N4-isopropyl system. This led to the conclusion that the oxadiazinanone-mediated aldol reaction was very sensitive to the steric demands of the N4-substituent.
Since 2006, we have been continually involved in the synthesis of oxadiazinone derivatives where the N4-substituent might offer an effective compromise between the issue of stereoselectivity and the issue of the hydrolysis. We have prepared a series of derivatives where the N4-group was either a neopentyl substituent, a cyclohexyl substituent, a benzyl substituent, or a phenyl substituent. In the course of work we determined that these oxadiazinanones can be used successfully in the asymmetric aldol reaction to good effect with regard to isolated yield and the diastereoselectivity of the aldol adducts obtained. However, there is an intrinsic problem associated with the hydrolysis of the aldol adducts. Simple modifications of the N4-position with either alkyl or aryl substituents are not enough to allow for both good diastereoselectivity in the aldol addition reaction and for a clean hydrolysis process. Research is underway to investigate the introduction of substituents that carry a greater possibility for influencing the final outcome of the oxadiazinanone mediated aldol reaction and the associated hydrolysis.
In terms of professional development of the undergraduate students who have worked on this research, they are pursuing a variety of career choices. Chris Kelley, an undergraduate who participated in this research program, completed his undergraduate degree and is now employed in the chemical industry in the Chicagoland area. Geoffrey Pasciak is another undergraduate student who is completing his final semester. He is currently applying for Pharmacy schools. Melissa Dean is also an undergraduate student who will be continuing in chemistry. She will be attending Illinois State University to obtain her Master's degree.
In terms of professional development of the Principal Investigator, the challenges that have emerged with oxadiazinone project have catalyzed new ideas to enhance the current project and new ideas for related projects using the oxadiazinone core.
