Our research group is focused on the development of synthetic methodologies that allow for the synthesis of enantiomerically enriched materials. The primary reaction that we have investigated is the asymmetric aldol addition reaction. We developed a chiral template for this reaction from enantiomerically pure materials such as the Ephedra alkaloids and alpha-amino acids. Once prepared, these compounds are known as oxadiazinones and they can serve as templates for the aldol reaction. The success of the asymmetric induction in the oxadiazinone mediated aldol reaction is believed to be due to the stereogenic N4-nitrogen. This is based on the observed diastereoselectivities for the asymmetric aldol reaction which ranges from 3:1 to 99:1 when the N4-substituent is a sterically undemanding methyl group, and ranges from 10:1 to 99:1 when the N4-substituent is a more sterically demanding isopropyl group. The conformation and, consequently, the configuration of the N4-nitrogen is a result of chiral relay where stereochemical information is relayed from the C5 and C6 positions of the oxadiazinone ring system. The diastereoselectivity of the asymmetric aldol increases as the steric demand of the N4-position increases. However, the ease of the cleavage of the newly formed asymmetric aldol chain becomes compromised. We determined that it would be of more value to have a stereodirecting N4-group that could be removed under oxidative conditions so as to facilitate the cleavage of the side-chain. We were able to prove this proposed ideal with an oxidatively sensitive p-methoxyphenyl group. However, this group is not sterically demanding. To further pursue this chemistry, we have engaged in the synthesis of an N4-2-naphthylmethyloxadiazinone. This group is more sterically demanding and is expected to enhance the diastereoselectivity of the overall asymmetric process. Beyond this, there is also a plan to synthesis the even more sterically demanding N4-diphenylmethyl system via the use of benzophenone imine. This poster presents the work that has been achieved thus far in the development of a new class of oxadiazenones and their ultimate usage in the synthesis of gamma-amino acid lyrica.

Developing a chiral auxiliary platform for the asymmetric synthesis of gamma-amino acids lyrica, baclofen, and rolipram: Synthesis and asymmetric aldol reactions with an oxidatively cleavable N4-2-naphthylmethyloxadiazinone

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.