Synthesis of a Derivative of the Peptaibol‐Antibiotic Trichovirin I 1B by Means of the ‘Azirine/Oxazolone Method’

According to the earlier published synthesis of the C‐terminal nonapeptide of Trichovirin I 1B, Z‐Ser(^tBu)‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 5 ), the complete tetradecapeptide Z‐Aib‐Asn(Trt)‐Leu‐Aib‐Pro‐Ser(^tBu)‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 11b ), a protected Trichovirin I 1B, has now been prepared by means of the ‘azirine/oxazolone method’. With the exception of the N‐terminal Aib(1), all Aib residues were introduced by the coupling of the corresponding amino or peptide acids with 2,2‐dimethyl‐2H‐azirine‐3‐(N‐methyl‐N‐phenylamine) ( 1a ) and methyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate ( 3a ) as the Aib and Aib‐Pro synthons, respectively. Single crystals of two segments, i.e., the N‐terminal hexapeptide Z‐Aib‐Asn(Trt)‐Leu‐Aib‐Pro‐Ser(^tBu)‐OMe ( 23 ) and the C‐terminal octapeptide Z‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 17 ), were obtained and their structures have been established by X‐ray crystallography. Following the same strategy, the C‐terminal nonapeptide of Trichovirin I 4A, Z‐Ala‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 26 ), was also synthesized and characterized by X‐ray crystallography.     

Foldamers to Nanotubes: Influence of Amino Acid Side Chains in the Hierarchical Assembly of α,γ4‐Hybrid Peptide Helices

Supramolecular assembly of various artificially folded 12‐helical architectures composed of γ⁴‐Val, γ⁴‐Leu and γ⁴‐Phe residues is investigated. In contrast to the 12‐helices composed of γ⁴‐Val and γ⁴‐Leu residues, the helices with γ⁴‐Phe residues displayed unique elongated nanotubular architectures. The elongated nanotube assembly was further explored as a template for biomineralization of silver ions to silver nanowires. A comparative study using an analogous α‐peptide helix reveals the importance of the spatial arrangement of aromatic side chains along the helical cylinder in a 12‐helix. These results suggested that the proteolytically and structurally stable α,γ⁴‐hybrid peptide 12‐helices may serve as a new generation of potential templates in the design of functional biomaterials.     

Conformational structure of peptides containing dehydroalanine: Formation of β‐bend ribbon structure

α,β‐Unsaturated amino acids (dehydroamino acids) have been found in naturally occurring antibiotics of microbial origin and in some proteins. Due to the presence of the C_αC_β double bond, the dehydroamino acids influence the main‐chain and the side‐chain conformations. The lowest‐energy conformational state of the model tripeptides, Ac–X–ΔAla–NHMe, (X=Ala, Val, Leu, Abu, or Phe) corresponds to ϕ₁=−30°, ψ₁=120° and ϕ₂=ψ₂=30°. This structure is stabilized by the hydrogen bond between CO of the acetyl group and the NH of the amide group, resulting in the formation of a 10‐membered ring. In the model heptapeptide containing ΔAla at alternate position with Ala, Abu, and Leu, the lowest‐energy conformation corresponds to ϕ=−30° and ψ=120° for all the Ala, Abu, and Leu residues and ϕ=ψ=30° for all ΔAla residues. A graphical view of the molecule in this conformation reveals the formation of three hydrogen bonds involving the CO moiety of the ith residue and the NH moiety of the i+3th residue, resulting in a 10‐membered ring formation. In this structure, only alternate peptide bonds are involved in the intramolecular hydrogen‐bond formation unlike the helices and it has been named the β‐bend ribbon structure. The helical structures were predicted to be the most stable structures in the heptapeptide Ac–(Aib–ΔAla)₃–NHMe with ϕ=±30°, ψ=±60° for Aib residues and ϕ=ψ=±30° for ΔAla residues. The computational results reveal that the ΔAla residue does not induce an inverse γ‐turn in the preceding residue. It is the competitive interaction of small solvent molecules with the hydrogen‐bonding sites of the peptide which gives rise to the formation of an inverse γ‐turn (ϕ₁=−54°, ψ₁=82°; ϕ₂=44°, ψ₂=3°) in the preceding residue to ΔAla. The computational studies for the positional preference of ΔAla in the peptide containing one ΔAla and nine Ala residues reveals the formation of a 3₁₀ helical structure in all the cases with the terminal preferences for ΔAla, consistent with the position of ΔAla in the natural antibiotics. The extended structures is found to be the most stable for poly‐ΔAla. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 72: 15–23, 1999     

β‐Hairpins Generated from Hybrid Peptide Sequences Containing both α‐ and β‐Amino Acids

The incorporation of the β‐amino acid residues into specific positions in the strands and β‐turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α) C(β) bond (θ) enhances the conformational repertoire in β‐residues. The conformational analysis of three designed peptide hairpins composed of α/β‐hybrid segments is described: Boc‐Leu‐Val‐Val‐^DPro‐β Phe ‐Leu‐Val‐Val‐OMe ( 1 ), Boc‐Leu‐Val‐β Val ‐^DPro‐Gly‐β Leu ‐Val‐Val‐OMe ( 2 ), and Boc‐Leu‐Val‐β Phe ‐Val‐^DPro‐Gly‐Leu‐β Phe ‐Val‐Val‐OMe ( 3 ). 500‐MHz ¹H‐NMR Analysis supports a preponderance of β‐hairpin conformation in solution for all three peptides, with critical cross‐strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β‐hairpin conformation with two β‐residues occupying facing, non‐H‐bonded positions in antiparallel β‐strands. Notably, βVal(3) adopts a gauche conformation about the C(α) C(β) bond (θ=+65°) without disturbing cross‐strand H‐bonding. The crystal structure of 2 , together with previously published crystal structures of peptides 3 and Boc‐β Phe ‐β Phe ‐^DPro‐Gly‐β Phe ‐β Phe ‐OMe, provide an opportunity to visualize the packing of peptide sheets with local ‘polar segments' formed as a consequence of reversal peptide‐bond orientation. The available structural evidence for hairpins suggests that β‐residues can be accommodated into nucleating turn segments and into both the H‐bonding and non‐H‐bonding positions on the strands.     

Ambidextrous α,γ‐Hybrid Peptide Foldamers

Molecular chirality is ubiquitous in nature. The natural biopolymers, proteins and DNA, preferred a right‐handed helical bias due to the inherent stereochemistry of the monomer building blocks. Here, we are reporting a rare co‐existence of left‐ and right‐handed helical conformations and helix‐terminating property at the C‐terminus within a single molecule of α,γ‐hybrid peptide foldamers composed of achiral Aib (α‐aminoisobutyric acid) and 3,3‐dimethyl‐substituted γ‐amino acid (Adb; 4‐amino‐3,3‐dimethylbutanoic acid). At the molecular level, the left‐ and right‐handed helical screw sense of α,γ‐hybrid peptides are representing a macroscopic tendril perversion. The pronounced helix‐terminating behaviour of C‐terminal Adb residues was further explored to design helix–Schellman loop mimetics and to study their conformations in solution and single crystals. The stereochemical constraints of dialkyl substitutions on γ‐amino acids showed a marked impact on the folding behaviour of α,γ‐hybrid peptides.     

The Propensity of α‐Aminoisobutyric Acid (=2‐Methylalanine; Aib) to Induce Helical Secondary Structure in an α‐Heptapeptide: A Computational Study

We present a molecular‐dynamics simulation study of an α‐heptapeptide containing an α‐aminoisobutyric acid (=2‐methylalanine; Aib) residue, Val¹‐Ala²‐Leu³‐Aib⁴‐Ile⁵‐Met⁶‐Phe⁷, and a quantum‐mechanical (QM) study of simplified models to investigate the propensity of the Aib residue to induce 3₁₀/α‐helical conformation. For comparison, we have also performed simulations of three analogues of the peptide with the Aib residue being replaced by L ‐Ala, D ‐Ala, and Gly, respectively, which provide information on the subtitution effect at C(α) (two Me groups for Aib, one for L ‐Ala and D ‐Ala, and zero for Gly). Our simulations suggest that, in MeOH, the heptapeptide hardly folds into canonical helical conformations, but appears to populate multiple conformations, i.e., C₇ and 3₁₀‐helical ones, which is in agreement with results from the QM calculations and NMR experiments. The populations of these conformations depend on the polarity of the solvent. Our study confirms that a short peptide, though with the presence of an Aib residue in the middle of the chain, does not have to fold to an α‐helical secondary structure. To generate a helical conformation for a linear peptide, several Aib residues should be present in the peptide, either sequentially or alternatively, to enhance the propensity of Aib‐containing peptides towards the helical conformation. A correction of a few of the published NMR data is reported.     

Evidence that the β‐Peptide 14‐Helix is Stabilized by β3‐Residues with Side‐Chain Branching Adjacent to the β‐Carbon Atom

Oligomers of β‐substituted β‐amino acids (‘β³‐peptides') are known to adopt a helical secondary structure defined by 14‐membered ring hydrogen bonds ('14‐helix'). Here, we describe a deca‐β³‐peptide, 1 , that does not adopt the 14‐helical conformation and that may prefer an alternative secondary structure. β³‐Peptide 1 is composed exclusively of residues with side chains that are not branched adjacent to the β‐C‐atom (β³‐hLeu, β³‐hLys, and β³‐hTyr). In contrast, an analogous β‐peptide, 2 , containing β³‐hVal residues in place of the β³‐hLeu residues of 1 , adopts a 14‐helical conformation in MeOH, according to CD data. These results illustrate the importance of side‐chain branching in determining the conformational preferences of β³‐peptides.     

Synthesis,and Helix or Hairpin‐Turn Secondary Structures of ‘Mixed’ α/β‐Peptides Consisting of Residues with Proteinogenic Side Chains and of 2‐Amino‐2‐methylpropanoic Acid (Aib)

Twelve peptides, 1 – 12 , have been synthesized, which consist of alternating sequences of α‐ and β‐amino acid residues carrying either proteinogenic side chains or geminal dimethyl groups (Aib). Two peptides, 13 and 14 , containing 2‐methyl‐3‐aminobutanoic acid residues or a ‘random mix’ of α‐, β²‐, and β³‐amino acid moieties were also prepared. The new compounds were fully characterized by CD (Figs. 1 and 2), and ¹H‐ and ¹³C‐NMR spectroscopy, and high‐resolution mass spectrometry (HR‐MS). In two cases, 3 and 14 , we discovered novel types of turn structures with nine‐ and ten‐membered H‐bonded rings forming the actual turns. In two other cases, 8 and 11 , we found 14/15‐helices, which had been previously disclosed in mixed α/β‐peptides containing unusual β‐amino acids with non‐proteinogenic side chains. The helices are formed by peptides containing the amino acid moiety Aib in every other position, and their backbones are primarily not held together by H‐bonds, but by the intrinsic conformations of the containing amino acid building blocks. The structures offer new possibilities of mimicking peptide–protein and protein–protein interactions (PPI).     

Synthesis and NMR Analysis in Solution of Oligo(3‐hydroxyalkanoic acid) Derivatives with the Side Chains of Alanine,Valine, and Leucine (β‐Depsides): Coming Full Circle from PHB to β‐Peptides to PHB

Oligomers of 3‐hydroxyalkanoic acids that contain two, three, and six residues with and without O‐terminal (tBu)Ph₂Si and C‐terminal PhCH₂ protection have been synthesized in such a way that the side chains on the oligoester backbone were those of the proteinogenic amino acids Ala (Me), Val (CHMe₂), and Leu (CH₂CHMe₂). The enantiomerically pure 3‐hydroxyalkanoates were obtained by Noyori hydrogenation of the corresponding 3‐oxo‐alkanoates with [Ru((R)‐binap)Cl₂](binap=2,2′bis(diphenylphosphanyl)‐1,1′‐binaphthalene)/H₂ (Scheme 1), and the coupling was achieved under the conditions (pyridine/(COCl)₂, CH₂Cl₂, −78°) previously employed for the synthesis of various oligo(3‐hydroxybutanoic acids) (Schemes 2 and 3). The Cotton effects in the CD spectra of the new oligoesters provided no hints about chiral conformation (cf. a helix) in MeOH, MeCN, octan‐1‐ol, or CF₃CH₂OH solutions (Figs. 1 and 2). Detailed NMR investigations in CDCl₃ solution (Figs. 3–6, and Tables 1–5) of the hexa(3‐hydroxyalkanoic acid) with the side chains of Val (HC), Ala (HB), Leu (HH), Val, Ala, Leu (from O‐ to C‐terminus; 3 ) gave, on the NMR time‐scale, no evidence for the presence of any significant amount of a 2₁‐ or a 3₁‐helical conformation, comparable to those identified in stretched fibers of poly[(R)‐3‐hydroxybutanoic acid], or in lamellar crystallites and in single crystals of linear and cyclic oligo[(R)‐3‐hydroxybutanoic acids], or in the corresponding β‐peptide(s) (the oligo(3‐aminoalkanoic acid) analogs; 1 – 3 ). Thus, the extremely high flexibility (averaged or ‘random‐coil' conformation) of the polyester chain (CO−O rotational barrier ca. 13 kcal/mol; no hydrogen bonding), as compared to polyamide chains (CO−NH barrier ca. 18 kcal/mol; hydrogen bonding) has been demonstrated once again. The possible importance of this structural flexibility, which goes along with amphiphilic properties, for the role of PHB in biology, in evolution, and in prebiotic chemistry is discussed. Structural similarities of natural potassium‐channeling proteins and complexes of oligo(3‐hydroxybutanoates) with Na⁺, K⁺, or Ba²⁺ are alluded to (Figs. 7–9).     

NMR‐Solution Structures in Methanol of an α‐Heptapeptide,of a β3/β2‐Nonapeptide,and of an all‐β3‐Icosapeptide Carrying the 20 Proteinogenic Side Chains

The NMR‐solution structure of an α‐heptapeptide with a central Aib residue was investigated in order to verify that, in contrast to β‐peptides, short α‐peptides do not form a helical structures in MeOH. Although the central Aib residue was found to induce a bend in the experimentally determined structure, no secondary structure typical for longer α‐peptides or proteins was found. A β²/β³‐nonapeptide with polar, positively charged side chains was subjected to NMR analysis in MeOH and H₂O. Whereas, in MeOH, it folds into a 10/12‐helix very similar to the structure determined for a corresponding β²/β³‐nonapeptide with only aliphatic side chains, no dominant conformation could be determined in H₂O. Finally, the NMR analysis of a β³‐icosapeptide containing the side chains of all 20 proteinogenic amino acids in MeOH is described. It revealed that this 20mer folds into a 3₁₄‐helix over its whole length forming six full turns, the longest 3₁₄‐helix found so far. Together, our findings confirm that, in contrast to α‐peptides, β‐peptides not only form helices with just six residues, but also form helices that are longer than helical sections usually observed in proteins or natural peptides. The higher helix‐forming propensity of long β‐peptides is attributed to the conformation‐stabilizing effect of the staggered ethane sections in β‐peptides which outweighs the detrimental effect of the increasing macrodipole.     

N‐(tert‐Butoxycarbonyl)‐α‐aminoisobutyryl‐α‐aminoisobutyric acid methyl ester: two polymorphic forms in the space group P21/n

The title compound (systematic name: methyl 2‐{2‐[(tert‐butoxycarbonyl)amino]‐2‐methylpropanamido}‐2‐methylpropanoate), C₁₄H₂₆N₂O₅, (I), crystallizes in the monoclinic space group P2₁/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α‐aminoisobutyric acid (Aib) residues adopting ϕ and ψ values characteristic of α‐helical and mixed 3₁₀‐ and α‐helical conformations. The helical handedness of the C‐terminal residue (Aib2) is opposite to that of the N‐terminal residue (Aib1). In contrast to (I), the closely related peptide Boc‐Aib‐Aib‐OBn (Boc is tert‐butoxycarbonyl and Bn is benzyl) adopts an α_L‐P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen‐bonded parallel β‐sheet‐like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen‐bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α‐disubstituted residue.     

Conformational Study of Heteropentapeptides Containing an α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=2‐Amino‐2‐ethylhexanoic Acid) within a Sequence of Dimethylglycine (=2‐Aminoisobutyric Acid) Residues

Heteropentapeptides containing the α‐ethylated α,α‐disubstituted amino acid (S)‐butylethylglycine and four dimethylglycine residues, i.e., CF₃CO‐[(S)‐Beg]‐(Aib)₄‐OEt ( 4 ) and CF₃CO‐(Aib)₂‐[(S)‐Beg]‐(Aib)₂‐OEt ( 7 ), were synthesized by conventional solution methods. In the solid state, the preferred conformation of 4 was shown to be both a right‐handed (P) and a left‐handed (M) 3₁₀‐helical structure, and that of 7 was a right‐handed (P) 3₁₀‐helical structure. IR, CD, and ¹H‐NMR spectra revealed that the dominant conformation of both 4 and 7 in solution was the 3₁₀‐helical structure. These conformations were also supported by molecular‐mechanics calculations.     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

POSS end‐linked peptide‐functionalized poly(ɛ‐caprolactone)s and their inclusion complexes with α‐cyclodextrin

In this report, we have synthesized organic/inorganic hybrid peptide–poly(?‐caprolactone) (PCL) conjugates via ring opening polymerization (ROP) of ?‐caprolactone (CL) in the presence of two sequence defined peptide initiators, namely POSS‐Leu‐Aib‐Leu‐NH₂ (POSS: polyhedral oligomeric silsesquioxane; Leu: Leucine; Aib: α‐aminoisobutyric acid) and OMe‐Leu‐Aib‐Leu‐NH₂. Covalent attachment of peptide segments with the PCLs were examined by ¹H and ²⁹Si NMR spectroscopy, matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) and FTIR spectroscopy. Supramolecular inclusion complexations of synthesized peptide‐PCL conjugates with α‐cyclodextrin (α‐CyD) were studied to understand the effect of POSS/OMe‐peptide moieties at the PCL chain ends. Inclusion complexation of peptide‐PCL conjugates with α‐CyD produced linear polypseudorotaxane, confirmed by ¹H NMR, FTIR, powder X‐ray diffraction (PXRD), polarized optical microscopy (POM) and differential scanning calorimetry (DSC). Extent of α‐CyD threading onto the hybrid peptide‐PCL conjugated polymers is less than that of α‐CyD threaded onto the linear PCL. Thus, PCL chains were not fully covered by the host α‐CyD molecules due to the bulky POSS/OMe‐peptide moieties connected with the one edge of the PCL chains. PXRD experiment reveals channel like structures by the synthesized inclusion complexes (ICs). Spherulitic morphologies of POSS/OMe‐peptide‐PCL conjugates were fully destroyed after inclusion complexation with α‐CyD and tiny nanoobjects were produced. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3643–3651.     

Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Artificial β‐Double Helices from Achiral γ‐Peptides

Double helices are not common in polypeptides and proteins except in the peptide antibiotic gramicidin A and analogous l,d ‐peptides. In contrast to natural polypeptides, remarkable β‐double‐helical structures from achiral γ‐peptides built from α,β‐unsaturated γ‐amino acids have been observed. The crystal structures suggest that they adopted parallel β‐double helical structures and these structures are stabilized by the interstrand backbone amide H‐bonds. Furthermore, both NMR spectroscopy and fluorescence studies support the existence of double‐helical conformations in solution. Although a variety of folded architectures featuring distinct H‐bonds have been discovered from the β‐ and γ‐peptide foldamers, this is the first report to show that achiral γ‐peptides can spontaneously intertwine into β‐double helical structures.     

Benzyl tert‐but­oxy­carbonyl‐α‐amino­isobutyrate

The small synthetic peptide, benzyl 2‐(tert‐but­oxy­carbonyl‐amino)­isobutyrate, C₁₆H₂₃NO₄, has the α‐helical conformation [|?| = 55.8 (2)° and |ψ| = 37.9 (2)°] observed in peptide fragments of peptaibols containing the α‐amino­isobutyric acid (Aib) residue. The structure shows no intramolecular hydrogen bonding, which would disrupt the limited conformational freedom associated with this amino acid. Two weak intermolecular hydrogen contacts are observed.     

Towards Truly Sustainable Polymers: A Metal‐Free Recyclable Polyester from Biorenewable Non‐Strained γ‐Butyrolactone

The first effective organopolymerization of the biorenewable “non‐polymerizable” γ‐butyrolactone (γ‐BL) to a high‐molecular‐weight metal‐free recyclable polyester is reported. The superbase tert‐Bu‐P₄ is found to directly initiate this polymerization through deprotonation of γ‐BL to generate reactive enolate species. When combined with a suitable alcohol, the tert‐Bu‐P₄‐based system rapidly converts γ‐BL into polyesters with high monomer conversions (up to 90 %), high molecular weights (M_n up to 26.7 kg mol^?1), and complete recyclability (quantitative γ‐BL recovery).     

Preparation of the β2‐Homoselenocysteine Derivatives Fmoc‐(S)‐β2hSec(PMB)‐OH and Boc‐(S)‐β2hSec(PMB)‐OH for Solution and Solid‐Phase Peptide Synthesis

Fmoc‐β²hSer(^tBu)‐OH was converted to Fmoc‐β²hSec(PMB)‐OH in five steps. To avoid elimination of HSeR, the selenyl group was introduced in the second last step (Fmoc‐β²hSer(Ts)‐OAll→Fmoc‐β²hSec(PMB)‐OAll). In a similar way, the N‐Boc‐protected compound was prepared. With the β²hSe‐derivatives, 21 β²‐amino‐acid building blocks with proteinogenic side chains are now available for peptide synthesis.