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All biological systems are composed of molecules of a single chirality. Although many different scenarios can lead to chiral symmetry breaking, the transmission of the absolute configuration of one compound to another one remains challenging. We here demonstrate that during crystallization-induced chiral symmetry breaking by Viedma ripening, a cascade of different and counteracting processes can occur: solid-solution formation and dissolution inhibition favor symmetry breaking towards the same absolute configuration, while enantioselective growth inhibition favors symmetry breaking towards the opposite absolute configuration. These insights offer a new playground for controlling symmetry breaking processes that are of fundamental and practical importance.

Change of heart: A solution-phase enantiomeric excess that has the handedness of the minor population of the solid phase is observed during grinding of a slurry of racemic conglomerate crystals. This excess is the driving force for a net flux of molecules from crystals of the minor handedness to crystals of the major handedness, thus explaining the complete deracemization of the solid phase.

Going forward in reverse: The configuration of the product of grinding-induced symmetry breaking can be controlled simply by the order in which the different reaction-mixture components are combined. The underlying mechanism is based on a subtle balance between enantioselective crystal growth and dissolution.

The total resolution of five structurally similar racemizable amino acid derivatives, three of which have racemic crystal structures, was performed simultaneously. By enantioselective incorporation in an amino acid derivative that forms a conglomerate the other four were deracemized on attrition-induced grinding. The outcome of the resolution was random (R) or (S), but all compounds had the same absolute configuration and high enantiomeric purities.

Integramide A is a 16-amino acid peptide inhibitor of the enzyme HIV-1 integrase. We have recently reported that the absolute stereochemistries of the dipeptide sequence near the C terminus are L-Iva(14)-D-Iva(15). Herein, we describe the syntheses of the natural compound and its D-Iva(14)-L-Iva(15) diastereomer, and the results of their chromatographic/mass spectrometric analyses. We present the conformational analysis of the two compounds and some of their synthetic intermediates of different main-chain length in the crystal state (by X-ray diffraction) and in solvents of different polarities (using circular dichroism, FTIR absorption, and 2D NMR techniques). These data shed light on the mechanism of inhibition of HIV-1 integrase, which is an important target for anti-HIV therapy.

An inexpensive, reliable resolution method for the resolving agent, 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinan 2-oxide (phencyphos) was required. Anhydrous phencyphos is a racemic compound, but the hydrate is known to be a conglomerate. After examination of various solvent mixtures a preferential crystallization process in methanol/water solvent mixtures was chosen to deliver the pure enantiomers in good yields. The preferential crystallization process can be repeated up to 50 times without significant loss of efficiency.

The recently discovered technique of deracemization by means of attrition-induced grinding of a solid conglomerate in contact with a solution wherein racemization occurs has been used with a derivative of 2-chlorophenyl glycine, the key chiral component in the synthesis of Clopidogrel (Plavix). Deracemization of the racemate proceeds to a single enantiomer and in essentially absolute enantiomeric excess. Further conversion of enantiomerically pure material to Clopidogrel was achieved in 88% yield.

C-alpha-Methyl-L-proline, or L-(alpha Me)Pro, is probably the most conformationally constrained alpha-amino acid. In particular, its omega and phi torsion angles are restricted to about 180 and -60 degrees, respectively, and only three ranges of values arc theoretically available for psi in mono- or longer peptides, namely, about -30 degrees (cis', 3(10)/alpha-helical structure), 60 degrees (inverse gamma turn), or 140 degrees (trans', poly(L-Pro)(n) II structure). In this work, we examined the tendency of a number of N-alpha-acyl dipeptide N'-alkylamides of the type RCO-(alpha Me)Pro-Xxx-NHR' or RCO-Xxx-(alpha Me)Pro-NHR', in which Xxx is L (or D)-Ala, Aib (alpha-aminoisoburyric acid), or L (or D)-(alpha Me)Pro, long enough to fold into intramolecularly hydrogen-bonded gamma or beta turns. The results are compared with those obtained for the corresponding dipeptides based on Pro, a well-known turn-forming residue. For the crystal-state 3D-structural analysis we used X-ray diffraction, whereas our solution conformational analysis was heavily based on the FTIR absorption and H-1 and C-13 NMR spectroscopy techniques. We conclude that (alpha Me)Pro is able to explore both trans' and cis' psi areas of the conformational space, but in (alpha Me)Pro the latter is overwhelmingly more populated, in marked contrast to the Pro preference. This finding is a clear indication that in (alpha Me)Pro the major 3D-structural determinant is the C-alpha-methyl group. The circular dichroism (CD) signature of a peptide type III' beta-turn conformation is also proposed.

Peptide foldamers based on alpha,alpha-disubstituted glycyl residues were synthesized and chemically characterized to investigate the effects of the electric field generated by a 3(10)-helix on the rate of intramolecular photoinduced electron-transfer reactions. To this end, two new octapeptides having identical sequences were suitably side-chain functionalized with the same electron-transfer donor-acceptor pair, but inverting the position of the pair along the main chain. The electron-transfer rate constants, measured by time-resolved spectroscopy techniques (nanosecond transient absorption and time-resolved fluorescence), indicated that, in the case of the 3(10)-helix, the electrostatic effect is significant, but smaller than that obtained for alpha-helical peptides. This finding can be likely ascribed to the distortion of the H-bond network with respect to the helical axis taking place in the former secondary structure. Overall, these results could have implications on electron-transfer phenomena in model and biomembranes facilitated by peptaibiotics.

The highly selective cross‐aldol addition of hydroxyacetone (HA) to p‐nitro and m‐nitrobenzaldehyde is reported; the reaction is catalyzed by three different di‐ or tripeptides all containing D‐Pro in the N‐terminal position and one or two residues of β3‐homophenylglycine (β3‐hPhg): H‐D‐Pro‐(R)‐β3‐hPhg‐OBn, H‐D‐Pro‐(R)‐β3‐hPhg‐(S)‐β3‐hPhg‐OBn and H‐D‐Pro‐[(S)‐β3‐hPhg]2‐OBn. Several reaction conditions have been tested, always in the absence of a protecting group on the HA hydroxyl. This reaction affords the desired compounds with complete regioselectivities being the other regioisomer completely avoided. Furthermore high enantioselectivities and satisfactory diastereoselectivities, always favouring the syn diastereoisomers, were obtained. The stereochemistry of the diols was further confirmed by the analysis of the 1H NMR spectrum of the corresponding carbonates, obtained by reaction of the syn/anti mixtures with triphosgene in presence of dimethylamino‐pyridine (DMAP).

The evolution of a single chiral solid state is reported for an amino acid derivative starting from a nearly racemic mixture of solid left- and right-handed crystals. Attrition-enhanced dissolution and recrystallization processes based on solubility considerations of the Gibbs−Thomson rule, coupled with solution-phase racemization, drive this near-equilibrium system inexorably to single chirality in the solid phase.

Methylation at the C(alpha)-position of a Pro residue was expected to lock the preceding tertiary amide (omega) torsion angle of the resulting (alphaMe)Pro to the trans disposition and to restrict the phi,psi surface to the single region where the 3(10)/alpha-helices are found (in this five-membered ring residue phi is severely constrained to about +/-65 degrees by its cyclic nature). The results of the present X-ray diffraction work on a selected set of four N(alpha)-blocked, (alphaMe)Pro-containing, dipeptide N'-alkylamides clearly show that, although the region of the conformational map largely preferred by (alphaMe)Pro would indeed be that typical of 3(10)/alpha-helices, the semi-extended [type-II poly(Pro)(n) helix] region can also be explored by this extremely sterically demanding C(alpha)-tetrasubstituted alpha-amino acid. In addition, the known high propensity for beta-turn formation of the Pro residue is further enhanced in peptides based on its C(alpha)-methylated derivative.

An efficient procedure for highly chemo- and stereoselective cyclization of (S)-allylalanine derivatives is reported (diastereomeric ratios up to 96:4) where the reaction course can be completely controlled by switching from gamma-lactones to cyclic carbamates simply with the proper choice of the amino acid protecting groups. Both processes are stereoconvergent and afford the (S,S)-products in high yields, short reaction times, and mild reaction conditions.

The synthesis and conformational analysis of a novel class of foldamers containing (S)-β3-homophenylglycine [(S)-β3-hPhg] and D-4-carboxy-oxazolidin-2-one (D-Oxd) residues in alternate order is reported. The experimental conformational analysis performed in solution by IR, 1H NMR, and CD spectroscopy unambiguously proved that these oligomers fold into ordered structures with increasing sequence length. Theoretical calculations employing ab initio MO theory suggest a helix with 11-membered hydrogen-bonded rings as the preferred secondary structure type. The few formal helix alternatives can be excluded in particular by steric effects of the oxazolidin-2-one rings. The novel structures enrich the field of peptidic foldamers and might be useful in the mimicry of native peptides. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Cα-tetrasubstituted α-amino acids constitute a powerful tool for controlling the conformation of short peptide sequences. Chiral peptides may be used in stereoselective reactions both for asymmetric induction and in kinetic resolution. By reviewing recent data from our own laboratories and by presenting new results on the stereoselective oxidation of chalcone to the corresponding oxide, this contribution shows that the control of peptide conformation is a critical issue in order to achieve successful stereoselective catalysis. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 84: 97–104, 2006 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Peptides characterized by single or multiple N-methylated, C(alpha)-trisubstituted (e.g., protein) amino acids are of great interest in medicinal chemistry. Several naturally occurring peptides, remarkably stable to enzymatic attacks, are based on N-methylated residues. The classical conditions (CH(3)I/Ag(2)O in DMF, 24 h, room temperature) for N-methylation of the peptide function are useful tools for distinguishing solvent exposed from intramolecularly H-bonded -CO-NH- groups in peptides. In this work we have extended this reaction to N(alpha)-acylated, linear peptides based exclusively on helicogenic C(alpha)-tetrasubstituted alpha-amino acids, e.g., Aib (alpha-aminoisobutyric acid) or (alphaMe)Nva (C(alpha)-methyl norvaline) residues. Under the experimental conditions used, only amide monomethylation (on the N-terminal, acylated, residue) takes place. Methylation of internal peptide groups linking two C(alpha)-tetrasubstituted residues was not observed. Our FT-IR absorption, NMR, and X-ray diffraction investigations support the view that the beta-turn and 3(10)-helical conformations preferred by the original peptides are not dramatically perturbed in the derivatives monomethylated at position 1. In particular, the tertiary amide bonds are trans. Conversely, the packing modes in the crystals are strongly influenced by the reduction of the number of H-bonding donors. The MeXxx-Xxx peptide bond is readily disrupted under mild acidic conditions.

In a previous study we examined by the exciton-coupled circular dichroic method the distance effect generated by three-rigid-turn and helical-peptide spacers. In this connection porphyrins were confirmed to be excellent reporter chromophores. In the present investigation we have completed this research by expanding the original analysis to the assessment of the combined role of the chromophore distance and orientation with use of the same porphyrin derivatives and additional four analogous spacers of different main-chain lengths. We find that not only the intramolecular separation of the chromophores, but the angular dependence between the directions of their effective transition moments as well, are responsible for the onset and modulation of the intensity of the exciton-coupling phenomenon of the porphyrin Soret band.

The 3(10)-helix is a relatively common secondary structure motif in peptides and proteins. Its building block is one of various types of beta-bend conformation which comprises an N(alpha)-acylated dipeptide alkylamide system. A complete 3D-structural characterization of this ternary helix has been achieved, thus allowing its unambiguous discrimination from the closely related a-helix. Recent applications of rigidified peptide beta-bends and 3(10)-helices as templates for investigations in synthetic organic chemistry (macrocyclization, catalysis), host-guest chemistry (molecular recognition), and physical chemistry (donor-acceptor interaction) will be discussed.

With the aim of designing a new calcium receptor, the synthesis and the conformational analysis of a small library of dipeptides having the general formula Ac–Oxx–L-Xaa–OBn [Oxx = L-Oxd, (4S,5R)-4-methyl-5-carboxyoxazolidin-2-one; D-Oxd, (4R,5S)-4-methyl-5-carboxyoxazolidin-2-one; or D-Oxac (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid] is reported. Ac–L-Oxd–L-Ala–OBn was identified as the most promising compound by MS–ESI analysis and this outcome was confirmed by photoluminescence spectroscopy.

Recent applications in our laboratories of electronic circular dichroism to the study of peptide secondary structures and their changes under external stimuli are briefly reviewed. More specifically, this article deals with: 1). characterization of a novel peptide conformation; 2). origin of amino acid homo-chirality on Earth; 3). bend and helical peptides as spacers; and 4). transfer and propagation of chirality in peptides.

A growing evidence has recently been accumulated on the presence of chiral, Cα- tetrasubstituted α-amino acids with a significant L (S) enantiomeric excess (up to 15%) in carbonaceous chondritic meteorites. The amino acids analysed to date, extracted from several samples of the Murchison and Murray meteorites, include isovaline (Iva), Cα-methyl norvaline [(αMe)Nva], Cα-methyl valine [(αMe)Val], Cα-methyl isoleucine [(αMe)Ile], and Cα-methyl allo isoleucine [(αMe)aIle] (Cronin and Pizzarello, 1997; Pizzarello and Cronin, 2000; Pizzarello et al., 2003).

The crystal-state conformations of two octapeptides, pBrBz-(D-Iva)8-OtBu (8I) and Ac-[L-(αMe)Val]8-OH (8II), the heptapeptide Z-[L-(αMe)Val]7-OH (7), the hexapeptide Z-[L-(αMe)Leu]6-OtBu (6) and the tetrapeptide alkylamide Z-(Aib)2-L-Glu(OMe)-L-Ala-L-Lol (5) were assessed by x-ray diffraction analyses. Two independent molecules are observed in the asymmetric unit of each L-(αMe)Val homo-peptide. All four homo-peptides are folded in a regular 310-helical structure (only the C-terminal H-bonded conformation of the D-Iva octapeptide is distorted to a type-I β-turn). The hydroxyl groups of the C-terminal carboxyl moieties of the two L-(αMe)Val homo-peptides participate in an oxy-analogue of the type-III β-turn conformation. While the two L-(αMe)Val 310-helices are right-handed, the D-Iva and L-(αMe)Leu helices are left-handed. The tetrapeptide alkylamide is 310-helical at the N-terminus, but it is mixed 310/α-helical at the C-terminus. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.

A practical asymmetric synthesis of nearly enantiomerically pure (S)-1-aminoindane has been developed. The key step involves the diastereoselective heterogeneous metal-catalyzed reduction of the ketimine of 1-indanone with the chiral auxiliary (R)-phenylglycine amide. The selectivity of the asymmetric hydrogenation step was optimized with regard to metal catalyst, solvent and catalyst loading. The chiral auxiliary was removed by means of a novel non-reductive procedure. Thus, (S)-1-aminoindane with an ee of 96% was prepared in 58% overall yield from (R)-phenylglycine amide in an effective three-step procedure.

A N-(8-mercaptooctanoyl)heptapeptide, comprising six CĄ-tetrasubstituted amino acids and a C-terminal histidine residue, has been synthesized by solution methods. The preferred conformation of this peptide and its hexapeptide precursor is that of a 310-helix. Gold nanoparticles have been functionalized with the peptide-thiol by place exchange reaction and the spectroscopic data indicate that the helical conformation of the peptide is maintained in the aggregate. The material obtained may constitute a synthetic model of a globular protein.

A series of [L-(alphaMe)Leu]n (n = 1-5) homo-peptides have been covalently linked to Tentagel and POEPOP resins and submitted to a conformational study using HRMAS NMR spectroscopy. Whereas the mono- and dipeptide are mainly fully-extended, stable 3(10)-helical structures are formed beginning from the trimer.

The heptapeptide H-Iva-Api-Iva-ATANP-Iva-Api-Iva-NHCH 3 (P1a), where Iva is (S)-isovaline, Api is 4-amino-4-carboxypiperidine, and ATANP is (S)-2-amino-3-[1-(1,4,7-triazacyclononane)]propanoic acid, has been synthesized. Its conformation in aqueous solution is essentially that of a 3 10 -helix. By connecting three copies of P1a to a functionalized Tris(2-aminoethyl)amine (Tren) platform a new peptide template, [T(P1) 3 ], was obtained. This molecule is able to bind up to four metal ions (Cu II or Zn II ): one in the Tren subsite and three in the azacyclononane subunits. The binding of the metals to the Tren platform induces a change from an open to a closed conformation in which the three short, helical peptides are aligned in a parallel manner with the azacyclonane units pointing inward within the pseudocavity they define. T(P1) 3 shows a peculiar behavior in the transphosphorylation of phosphate esters; the tetrazinc complex is a catalyst of the cleavage of 2-hydroxypropyl- p -nitrophenyl phosphate (HPNP), whereas the free ligand is a catalyst of the cleavage of an oligomeric RNA sequence with selectivity for pyrimidine bases. In the case of HPNP, Zn II acts as a positive allosteric effector by enhancing the catalytic efficiency of the system. In the case of the polyanionic RNA substrate, Zn II switches off the activity, thus behaving as a negative allosteric regulator. It is suggested that the opposite behavior of the catalyst induced by Zn II is associated with the change of conformation of the Tren platform, and consequently of the relative spatial disposition of the three linked peptides, that occurs after binding of the metal ion.

[reaction: see text]. Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in 76-93% yield and dr > 99/1. The diastereomerically pure alpha-amino nitrile obtained from pivaldehyde (R1 = t-Bu, R2 = H) was converted in three steps to (S)-tert-leucine in 73% yield and >98% ee.

By a chemo-enzymatic approach we carried out a large-scale synthesis of four enantiopure, sterically constrained, C α -tetrasubstituted α-amino acids, all characterized by a sidechain C γ C δ double bond. By using one of them ( l -Mag), we prepared an N α -protected tetrapeptide benzylamide which was shown to adopt a β-turn conformation and to efficiently undergo ring-closing olefin metathesis.

By a chemo-enzymatic approach we synthesized the chiral, Cα-methylated α-amino acid Mag, characterized by a side-chain CγCδ bond. We also prepared a series of model peptides containing Mag in combination with Aib and Ala. All of the peptides were fully characterized and their conformational preference was determined in solution by FT-IR absorption and 1H NMR investigations. X-Ray diffraction analyses of l -Mag, a derivative and three peptides are also presented. We find that this Cα-methylated α-amino acid is an excellent β-turn and 310-helix former. A peptide with two Mag residues one on top of the other after one complete turn of the 310-helix has been synthesized and characterized.

Two water-soluble 310-helical peptides are synthesized and fully characterized for the first time. The sequence of these terminally blocked heptamers comprises two residues of the Cα-trisubstituted α-amino acid 2-amino-3-[1-(1,4,7-triazacyclononyl)]propanoic acid and five residues of a Cα-tetrasubstituted α-amino acid (either α-aminoisobutyric acid or isovaline). Using CD and NMR techniques we were able to show that both heptapeptides are well structured in water, and that the type of conformation adopted is indeed the ternary 310-helix.