Scope of the Chirality Transfer Allyl Cyanamide [3,3]-Sigmatropic Rearrangement to Afford Enantioenriched Carbodiimides that are Trapped by Amines as an Entry Into Enantioenriched Guanidines.
Makinde, Kehinde
Makinde, Kehinde
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Abstract
The guanidine functionality is widely distributed across natural products and biological systems. Given the prevalence of guanidine natural products and their structural complexity, there is a continuing need for efficient synthetic strategies that can access guanidines while introducing the complexity typically associated with natural products. This project focuses on exploring the scope, optimizing the conditions, and expanding the utility of the [3,3]-sigmatropic rearrangement of enantioenriched allyl cyanamides for the synthesis of structurally diverse, enantioenriched guanidine scaffolds. In the first component of this work, a systematic synthetic methodology was developed for the [3,3]-sigmatropic rearrangement of enantioenriched allyl cyanamides, with an emphasis on understanding the effects of protecting groups, substitution patterns, ring elongation, and ?-bond conjugation on rearrangement efficiency, stereocontrol, and functional group tolerance. Tert-butyldimethylsilyl (TBS) protection emerged as the reliable benchmark, affording high yields and excellent chirality transfer. Additionally, tert-butyloxycarbonyl (Boc) protection provided comparable reactivity and prevented undesired neighboring group participation. Unfortunately, the synthesis of the para-methoxybenzyl (PMB) substrate derivative yielded a complex mixture after several attempts; however, we plan to revisit this approach. Substrate scope investigations revealed that the rearrangement proceeded most easily with enantioenriched tri-substituted allyl cyanamides, followed by disubstituted (methyl, benzyl, and isopropyl) analogs, delivering excellent yields, high fidelity of chirality transfer, and reduced reaction times, which was consistent with our computational findings. The methodology also displayed broad functional group tolerance and resilience to both steric and electronic effects, as demonstrated during nucleophilic base trapping, ultimately granting access to seven novel enantioenriched allyl cyanamide derivatives and more than seventy enantioenriched guanidine derivatives, as well as an enantioenriched guanidine scaffold with a pseudo-quaternary center found in complex natural products.
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Date
1/1/2026
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Graduate Student
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Oral Presentation
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Chemistry
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College of Arts and Sciences
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Physical Science