Overcoming the Demons of Protecting Groups with Amphoteric Molecules

Abstract

Synthetic organic chemists have long depended on protecting group manipulations when faced with the challenges of chemoselectivity and functional group incompatibility. Overcoming this dependence will improve the overall efficiency of chemical synthesis. By taking advantage of orthogonally reactive functional groups, amphoteric molecules can afford access not only to more efficient and strategic syntheses but also to the development of novel chemical transformations.

Amphoteric Amino Aldehydes Enable Rapid Assembly of Unprotected Amino Alcohols

“…The resulting hemiacetal adducts are intriguing intermediates but are prone to selfcondensation above pH 5. [8] Our recent studies in the field of amphoteric molecules [9][10][11] provided an opportunity to address some of the long-standing problems associated with the rapid formation of complex nitrogen-containing molecules without protecting-group manipulations. Undesired intermolecular iminium ion formation from amphoteric aziridine aldehydes is disfavored thermodynamically owing to the increase in ring strain involved in such a process.…”

Amphoteric Amino Aldehydes Enable Rapid Assembly of Unprotected Amino Alcohols

“…Our recent studies in the field of amphoteric molecules9–11 provided an opportunity to address some of the long‐standing problems associated with the rapid formation of complex nitrogen‐containing molecules without protecting‐group manipulations. Undesired intermolecular iminium ion formation from amphoteric aziridine aldehydes is disfavored thermodynamically owing to the increase in ring strain involved in such a process.…”

The Synthesis of Macrocycles for Drug Discovery

“…However, only limited attention has been directed towards the potential of MCR for accessing the macrocyclic target class with these strategies. [291][292][293][294] In a notable exception, Yudin has described the use of amphoteric aldehydes (178) 295 in an Ugi MCR with isonitriles and linear peptides (179) to prepare a series of modified peptidomimetic macrocycles (180) with ring sizes from 9 to 18 atoms (Scheme 11.24). 296 These compounds, via nucleophilic attack on the aziridine, also can be employed as intermediates for further reactions and, hence, provide access to additional structural diversity suitable for library production.…”