β-Peptides:  From Structure to Function

Cheng, Richard P.; Gellman, Samuel H.; DeGrado, William F.

doi:10.1021/cr000045i

Cited by 1,798 publications

(1,264 citation statements)

References 193 publications

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“…2 Our attention was drawn to formaldehydederived substrates, because β-amino aldehydes from such substrates can be used to generate β 2 -amino acids, which are valuable building blocks for β-peptide foldamers and other targets. 3 Many routes to enantio-enriched β 2 -amino acids have been described; most involve chiral auxiliaries, and few are amenable to large-scale synthesis. 4 Here we report an enantioselective organocatalytic method for aminomethylation of aldehydes, which leads to a new and efficient synthesis of β 2 -amino acids (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids

2006

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Organocatalytic Mannich addition of aldehydes to a formaldehyde-derived iminium species catalyzed by proline-derived chiral pyrrolidines provides β-amino aldehydes with ≥ 90% ee. Mechanistic analysis of the proline-catalyzed reactions suggests that non-hydrogen-bonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome. The β-amino aldehydes from our process bear a substituent adjacent to the carbonyl and can be efficiently converted to protected β 2 -amino acids, which are important building blocks for β-peptide foldamers that display useful biological activities.The Mannich reaction, 1 in which an enol or enolate attacks an imine or an iminium ion, is a powerful tool for introducing aminoalkyl fragments into organic molecules. Imines derived from aryl aldehydes have been common substrates in recent efforts to develop asymmetric organocatalytic versions of this reaction; these substrates necessarily provide Mannich adducts containing aryl substituents adjacent to nitrogen. 2 Our attention was drawn to formaldehydederived substrates, because β-amino aldehydes from such substrates can be used to generate β 2 -amino acids, which are valuable building blocks for β-peptide foldamers and other targets. 3 Many routes to enantio-enriched β 2 -amino acids have been described; most involve chiral auxiliaries, and few are amenable to large-scale synthesis. 4 Here we report an enantioselective organocatalytic method for aminomethylation of aldehydes, which leads to a new and efficient synthesis of β 2 -amino acids (Scheme 1). Our observations provide evidence that non-Hbonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome.Formaldehyde does not form stable imines, 5 so we examined formaldehyde derivatives such as A that can generate a methylene iminium species in situ. 6 We examined L-proline and chiral pyrrolidines as catalysts for nucleophilic activation of aldehyde reactants. The Mannich reaction products, α-substituted β-amino aldehydes, were immediately reduced to the corresponding β-substituted γ-amino alcohols to avoid epimerization. Initial studies involving pentanal revealed modest enantioselectivity when the reaction was carried out with 20 mol % catalyst in DMF at -25 °C for 24 hr. The enantiomeric preference observed with L-proline was opposite that observed with 2-alkyl-pyrrolidines derived from L-proline, such as B or C 7 (used with equimolar acetic acid). A comparable switch in product configuration for organocatalytic Mannich reactions involving aryl imines and for α-amination of aldehydes has been observed by Barbas, Jørgensen, List, Córdova and others. 2, 11c The commonly accepted rationale for this stereochemical preference switch involves hydrogen bonding: 8 the carboxylic acid group of the L-proline-derived enamine is thought to H-bond to the electrophile at the transition state, while the substituent of a 2-alkyl-pyrrolidine sterically repels the electrophile, forcing it to approach the enamine from ...

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Section: Introductionmentioning

confidence: 99%

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids

2006

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“…Particularly fascinating is the design of new foldamers because, as we have seen in many examples, conformational control constitutes a tremendous challenge rewarded by improved efficiency. Although the ability to predict conformation using α-amino acids in very short sequences has improved considerably as the result of the seminal work done by Toniolo and his group, scientists are introducing new building blocks (β-and γ-amino acids for instance) [136] thus expanding the repertoire of accessible foldamers. These molecules, in contrast with standard peptides, might not be cleaved by proteins and, hence, are excellent candidates for new drugs.…”

Section: Discussionmentioning

confidence: 99%

Artificial (Pseudo)peptides for Molecular Recognition and Catalysis

Prins

Scrimin

2005

Functional Synthetic Receptors

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“…Oligomers of b-amino acids (''b-peptides'') can have greater secondary structural stability, on a per-residue basis, than do conventional peptides and are resistant to degradation by proteases. [1][2][3][4] These attributes encourage the exploration of proteins containing b-peptide modules. A key question endures: Which b-peptide modules are truly useful?…”

Section: Introductionmentioning

confidence: 99%

Protein prosthesis: β‐peptides as reverse‐turn surrogates

et al. 2013

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The introduction of non-natural modules could provide unprecedented control over folding/unfolding behavior, conformational stability, and biological function of proteins. Success requires the interrogation of candidate modules in natural contexts. Here, expressed protein ligation is used to replace a reverse turn in bovine pancreatic ribonuclease (RNase A) with a synthetic b-dipeptide: b 2 -homoalanine-b 3 -homoalanine. This segment is known to adopt an unnatural reverse-turn conformation that contains a 10-membered ring hydrogen bond, but one with a donor-acceptor pattern opposite to that in the 10-membered rings of natural reverse turns. The RNase A variant has intact enzymatic activity, but unfolds more quickly and has diminished conformational stability relative to native RNase A. These data indicate that hydrogen-bonding pattern merits careful consideration in the selection of beneficial reverse-turn surrogates.

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β-Peptides: From Structure to Function

Cited by 1,798 publications

References 193 publications

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids

Artificial (Pseudo)peptides for Molecular Recognition and Catalysis

Protein prosthesis: β‐peptides as reverse‐turn surrogates

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β-Peptides: From Structure to Function

Cited by 1,798 publications

References 193 publications

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β2-Amino Acids

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β2-Amino Acids

Artificial (Pseudo)peptides for Molecular Recognition and Catalysis

Protein prosthesis: β‐peptides as reverse‐turn surrogates

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Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β²-Amino Acids