Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide

Abstract

Organocatalytic access to a cis-Cyclopentyl-gamma-amino acid: an intriguing model of selectivity and formation of a stable 10/12-helix from the corresponding gamma/alphapeptide.

First Crystal Structures of alpha,delta-Peptidic Foldamers and Solution State NMR Show an Unusual 13/11 Helix: Rational Design and Application as a Minimalist Aldolase Mimic

“…Unsurprisingly, the (e,e) was observed as the major state of 2 in solution, confirmed by a large 3 JHH-coupling (10.3 Hz) of the vicinal protons on the substituted cyclohexyl ring at the terminus. 20 Then, using unrestrained Monte-Carlo Multiple minimization (MCMM), followed by clustering and abundant DFT energy minimizations (ωB97M-D3BJ/def2-TZVP// ωB97XD/6-31G*) on hundreds of distinct conformations including both helical and non-helical scaffolds, 15,21 13 geometries were afforded as low energy conformers of 2 under solution states (15 kJ/mol threshold, Figure 4A and SI). The computational ensembles of these 13 low-energy geometries in solution also suggested the (e,e)-helix are predominant whereas the (a,a)-helix were calculated to be less stable according to DFT energies (> 30 kJ/mol).…”

“…-for example by the groups of Gellman, 10, 11 Sharma, 8c,8h,12 Gopi, 8a,8b,13 Tomasini, 14 and recently our own, where we described a highly stable 10/12-helix made from a cis-cyclopentyl-g-amino acid. 15 d-Amino acid heteromers on the other hand, also proposed by Hofmann and co-workers, 9 have received far less attention despite their broad predicted range of helices, with the only examples coming from the same report, and from Gervay-Hague and co-workers. 16 These hybrid systems are of particular interest, because an a,d-dipeptide corresponds to an a-amino acid trimer unit and has the potential to replace this in peptides and proteins.…”

Crystal Structure and NMR of an α,δ‐Peptide Foldamer Helix Shows Side‐Chains are Well Placed for Bifunctional Catalysis: Application as a Minimalist Aldolase Mimic**

“…Such helices are described as being “mixed”—and have the potential for hydrogen bonds to alternately point into forward and backward directions along the sequence, in contrast to helices with unidirectional hydrogen bonds. Among the various possible 1 : 1 heteromers of α‐amino acids with higher homologated amino acids, α,β‐ and α,γ‐hybrid peptides predominate the literature [11] —for example by the groups of Gellman, [12, 13] Sharma, [9c,h, 14] Gopi, [9a,b, 15] Tomasini, [16] and recently our own where we described a highly stable 10/12‐helix made from a cis ‐cyclopentyl‐γ‐amino acid [17] . However, despite their broad predicted range of helices, the corresponding δ‐hybrid systems proposed by Hofmann and co‐workers, [10] have recieved far less attention—with the only examples coming from the same report, and from Gervay‐Hague and co‐workers [18] .…”

The influence of backbone fluorination on the helicity of α/γ-hybrid peptides

“…38,39 Alternatively, mechanical constraints in the form of CvC double bonds or appended ring structures have also been exploited for a similar purpose. 14,27,29,[40][41][42][43] A less-explored strategy for controlling peptide shape is to exploit electronic effects. 44,45 In compounds that contain a F-C-C-X motif (i.e.…”