Organic Chemistry

Several α,β,α- or α,γ,α-tripeptides, consisting of a central cyclobutane β- or γ-amino acid being flanked by two d- or l-proline residues, have been synthesized and tested as organocatalysts in asymmetric aldol additions. High yields and enantioselectivities have been achieved with α,γ,α-tripeptides, being superior to peptides containing a cyclobutane β-amino acid residue. This is probably due to their high rigidity, which hinders some of the peptide catalysts to adopt the proper active conformation. This reasoning correlates with the major conformation of the peptides in the ground state, as suggested by ¹H NMR and computational calculations. The configuration of the aldol products is controlled by the proline chirality, and consequently, the R/S configuration of aldol products can be tuned by the use of either commercially available d- or l-proline. The enantioselectivity in the aldol reactions is reversed if the reactions are carried out in the presence of water or other protic solvents such as methanol. Spectroscopic and theoretical investigations revealed that this effect is not the consequence of conformational changes in the catalyst but rather caused by the participation of a water molecule in the rate determining transition state, in such a way that the preferential nucleophilic attack is oriented to the opposite enantiotopic aldehyde face.

A novel approach for the fast and efficient structural discrimination of molecules containing multiple stereochemical centers is described. A robust J-resolved HSQC experiment affording highly resolved ¹J_CH/¹T_CH splittings along the indirect dimension and homodecoupled ¹H signals in the detected dimension is proposed. The experiment enables in situ distinction of both isotropic and anisotropic components of molecules dissolved in compressed PMMA gels, allowing a rapid and direct one-shot determination of accurate residual dipolar coupling constants from a single NMR spectrum.

Three series of new γ‐peptides have been synthesized by starting from conveniently protected cis‐3‐amino‐2,2‐dimethylcyclobutane‐1‐carboxylic acid derivatives. The first series is constructed with only one enantiomer of this γ‐amino acid, whereas in the second one both enantiomeric cyclobutane residues are joined in alternating fashion. The high degrees of rigidity in these γ‐peptides induce the adoption of extended but sterically constrained conformations in both cases. The third series is the product of alternation of a cyclobutane residue with linear γ‐aminobutyric acid (GABA). Conformational bias in these three systems accounts for the cyclobutane being a major disrupting factor to the formation of strong intramolecular hydrogen bonds, leading to extended conformations. In contrast, investigation of cyclobutane/GABA hybrid γ‐peptides of a fourth series, in which the carbocyclic moiety is not a part of the polyamide skeleton but acts as a chiral polyfunctional platform, reveals that these peptides are able to produce intramolecular hydrogen bonds leading to well defined folded conformations.

Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The cis-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the transform manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane beta-peptides is based on QM calculations. Predictions are corroborated by high resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers.

Several oligomers constructed with (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, beta-alanine, and gamma-amino butyric acid (GABA), respectively, joined in alternation have been synthesized and studied by means of NMR and CD experiments as well as with computational calculations. Results account for the spacer length effect on folding and show that conformational preference for these hybrid peptides can be tuned from beta-sheet-like folding for those containing a C-2 or C-4 linear segment to a helical folding for those with a C-3 spacer between cyclobutane residues. The introduction of cyclic spacers between these residues does not modify the extended ribbon-type structure previously manifested in poly(cis-cyclobutane) beta-oligomers.

Three new bis(cyclobutane) -dipeptides have been synthesized from appropriate derivatives ofcis- andtrans-2-aminocyclobutane-1-carboxylicacid, respectively. The predominance of eight-membered hydrogen-bonded rings has been manifested for (trans,trans)- and (trans,cis)- B-dipeptides while the formation of six-membered rings is preferred for the (cis,trans)-B-dipeptide similarly to the previously described(cis,cis)-diastereomer.

The synthesis and structural study of the fumarate of (S,S)-α,α‘-bis(trifluoromethyl)-1,8-anthracenedimethanol by NMR spectroscopy are reported. The conformational study of the 13-membered macrocycle is presented. The cited alcohol is assayed as a chiral auxiliary in a Diels−Alder reaction with cyclopentadiene, and after methanolysis, provides the norbornene derivative with high enantioselectivity.