Improved solid-phase synthesis and study of arylopeptoids with conformation-directing side chains

Hjelmgaard, Thomas; Faure, Sophie; Santis, Emiliana De; Stærk, Dan; Alexander, Bruce D.; Edwards, Alison A.; Taillefumier, Claude; Nielsen, John

doi:10.1016/j.tet.2011.12.049

Cited by 19 publications

(40 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using these methods as a starting point, we then investigated the solid‐phase synthesis of a selection of model ortho ‐arylopeptoid hexamers 6a – h with free acids at the C ‐terminus (Scheme and Table 3). We have previously used the highly acid labile 2‐chlorotrityl chloride polystyrene resin (cleavage in HFIP/CH 2 Cl 2 , 1:4) for solid‐phase synthesis of the analogous meta ‐ and para ‐arylopeptoids 12a,12b. However, we found that the rapid conversion of 2‐(chloromethyl)benzoic acid into the derived phthalide under basic conditions excluded the use of the 2‐chlorotrityl chloride linker.…”

Section: Resultsmentioning

confidence: 97%

“…Furthermore, the extended reaction time caused the formation of minor amounts of unidentified impurities. Using our most recently developed conditions,12a we then found that monomer 2b could be converted cleanly into intermediate 5 in less than 2 min by reaction with 2‐(chloromethyl)benzoyl chloride (3.0 equiv.) as a 0.5 M solution in CH 2 Cl 2 in the presence of DIPEA (Table 2, entry 6).…”

Section: Resultsmentioning

confidence: 99%

“…The promising results obtained in the above model study thus indicated that we could adapt our previously developed methods for solid‐phase synthesis of meta ‐ and para ‐arylopeptoids based on the use of chloromethylbenzoyl chlorides in the coupling steps directly to the synthesis of ortho ‐arylopeptoids. These methods are derived from the optimal conditions found in the model studies, albeit with extended reaction times in both the acylation steps (20 min) and the substitution steps (1 h at 50 °C) because this proved advantageous 12a,12b. Using these methods as a starting point, we then investigated the solid‐phase synthesis of a selection of model ortho ‐arylopeptoid hexamers 6a – h with free acids at the C ‐terminus (Scheme and Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…For comparison, aminolysis of arylopeptoids from the more bulky 2‐chlorotrityl chloride linker only appeared to be a problem when using extended reaction times (3 h) or DMSO/water mixtures in the substitution steps 12a,12b. Isoindolinone formation after the first substitution step could represent an additional or alternative explanation.…”

Section: Resultsmentioning

confidence: 99%

“…Since then, we have begun to unveil the potential of this promising class of aromatic oligoamides by developing greatly improved synthetic methods and undertaking the first conformational studies. Thus, we have recently developed the first convenient solution‐phase synthesis of meta ‐ and para ‐arylopeptoids using bromomethyl benzoyl bromides in the coupling steps,12c and two solid‐phase methodologies based on the use of either COMU‐activated chloromethylbenzoic acids12b or chloromethylbenzoyl chlorides12a in the coupling steps. These methods all rely on “submonomer” approaches wherein the arylopeptoid residues are created in an iterative manner directly on the growing oligoamide chains using a unique acylation‐substitution cycle.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

Hjelmgaard

Nielsen

2013

Eur J Org Chem

Self Cite

View full text Add to dashboard Cite

Even though aromatic oligoamides composed of aromatic amino acids in a “one‐way sequence” attract ever increasing research interest, backbones connected through ortho‐linked aromatics remain rare. Herein, we present the first synthesis and study of N‐alkylated ortho‐aminomethyl‐benzamides termed “ortho‐arylopeptoids”. The ortho‐arylopeptoids may, with a few exceptions, be synthesized either in solution or on solid‐phase using unique and highly efficient submonomer methods with similar levels of high generality and efficiency to those previously demonstrated for meta‐ and para‐arylopeptoids. NMR studies indicated a more restricted rotation about the amide bonds in ortho‐arylopeptoids, presumably due to a more congested backbone structure resulting from the ortho‐connectivity pattern. Intriguingly, tert‐butyl and phenyl side chains offer complete control over the amide conformations; whereas arylopeptoid residues with tert‐butyl side chains adopt a 100 % cis amide conformation, the opposite 100 % trans amide conformation was observed in arylopeptoids with phenyl side chains. The tert‐butyl moiety can furthermore serve as a protecting group during synthesis, which can later be removed to allow the amide to adopt a 100 % trans conformation instead.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

Hjelmgaard

Nielsen

2013

Eur J Org Chem

Self Cite

View full text Add to dashboard Cite

show abstract

N‐Alkylated Aromatic Poly‐ and Oligoamides

et al. 2021

Self Cite

View full text Add to dashboard Cite

N-alkylated aromatic poly-and oligoamides are a particular class of abiotic foldamers that is deprived of the capability of forming intramolecular hydrogen-bonding networks to stabilize their tri-dimensional structure. The alkylation of the backbone amide nitrogen atoms greatly increases the chemical diversity accessible for aromatic poly-and oligoamides. However, the nature and the conformational preferences of the N,N-disubstituted amides profoundly modify the folding properties of these aromatic poly-and oligoamides. In this Review, representative members of this class of aromatic poly-and oligoamides will be highlighted, among them N-alkylated phenylene terephthalamides, benzanilides, pyridylamides, and aminomethyl benzamide oligomers. The principal synthetic pathways to the main classes of N-alkylated aromatic polyamides with narrow to broad molecular-weight distribution, or oligoamides with specific sequences, will be detailed and their foldameric properties will be discussed. The Review will end by describing the few applications reported to date and future prospects for the field.

show abstract

Advances towards Aromatic Oligoamide Foldamers: Synthesis and X‐ray Structures of Dimeric Arylopeptoids with Conformation‐Directing Side Chains

et al. 2014

Self Cite

View full text Add to dashboard Cite

We have efficiently synthesized 36 arylopeptoid dimers with ortho‐, meta‐, and para‐substituted aromatic backbones and tert‐butyl or phenyl side chains. The dimers were synthesized by using a “submonomer method” on solid phase, by applying a simplified common set of reaction conditions. X‐ray crystallographic analysis of two of these dimers disclosed that the tert‐butyl side chain invokes a cis amide conformation with a comparatively more closely packed structure of the surrounding aromatic backbone while the phenyl side chain results in a trans amide conformation with a more open, extended structure of the surrounding aromatic backbone.

show abstract

Improved solid-phase synthesis and study of arylopeptoids with conformation-directing side chains

Cited by 19 publications

References 38 publications

Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

N‐Alkylated Aromatic Poly‐ and Oligoamides

Advances towards Aromatic Oligoamide Foldamers: Synthesis and X‐ray Structures of Dimeric Arylopeptoids with Conformation‐Directing Side Chains

Contact Info

Product

Resources

About