Mark A. Lipton

Synthesis and analysis of the sterically constrained l-glutamine analogues (3S,4R)-3,4-dimethyl-l-glutamine and (3S,4R)-3,4-dimethyl-l-pyroglutamic acid

Abstract The nonproteinogenic amino acids (3 S ,4 R )-3,4-dimethyl- l -pyroglutamic acid and (3 S ,4 R )-3,4-dimethyl- l -glutamine—found in the cyclic depsipeptides callipeltin B, callipeltin A, and papuamide A—were synthesized from a common intermediate derived from l -pyroglutamic acid. The diastereoselective introduction of the methyl groups was accomplished by cuprate addition and enolate alkylation, followed by a kinetic epimerization of the C-4 methyl substituent. (3 S ,4 R )-3,4-Dimethyl- l -glutamine shows a conformational restriction of its side chain which may be related to its biological function in the natural products where it is found.

A new reagent for solid and solution phase synthesis of protected guanidines from amines

A new reagent -- 4-nitro-1-H-pyrazole-1-[N, N′-bis(tert-butoxycarbonyl)]car☐amidine -- has been developed to effect the rapid and efficient synthesis of bis(carbamate)-protected guanidines from primary and secondary amines. The reagent is a more electrophilic, and consequently more reactive, derivative of the literature reagent 1-H-pyrazole-1-[N, N′-bis(tert-butoxycarbonyl)]car☐amidine. The increased reactivity of the new reagent affords it increased yields in solution and the need for fewer equivalents when guanylating resin-bound amines.

Solid phase synthesis of a diketopiperazine catalyst containing the unnatural amino acid (S)-norarginine

Abstract A cyclic dipeptide containing the unnatural amino acid ( S )-norarginine, recently shown to display useful catalytic activity, has been synthesized in good yield and high chemical purity using a solid phase protocol. All reactions in the sequence, including a Hofmann rearrangement and cyclization to diketopiperazine, were performed on the Merrifield polystyrene resin and proceed in high yield. In addition to its improved yield, this new synthesis offers easy access to derivatives and a potential to employ combinatorial strategies to the search for novel catalytic cyclic dipeptides.

Entropy-driven population distributions in a prototypical molecule with two flexible side chains: O-(2-acetamidoethyl)-N-acetyltyramine

Resonant two-photon ionization (R2PI), resonant ion-dip infrared (RIDIR), and UV-UV hole-burning spectroscopies have been employed to obtain conformation-specific infrared and ultraviolet spectra under supersonic expansion conditions for O-(2-acetamidoethyl)-N-acetyltyramine (OANAT), a doubly substituted aromatic in which amide-containing alkyl and alkoxy side chains are located in para positions on a phenyl ring. For comparison, three single-chain analogs were also studied: (i) N-phenethyl-acetamide (NPEA), (ii) N-(p-methoxyphenethyl-acetamide) (NMPEA), and (iii) N-(2-phenoxyethyl)-acetamide (NPOEA). Six conformations of OANAT have been resolved, with S(0)-S(1) origins ranging from 34,536 to 35,711 cm(-1), denoted A-F, respectively. RIDIR spectra show that conformers A-C each possess an intense, broadened amide NH stretch fundamental shifted below 3400 cm(-1), indicative of the presence of an interchain H bond, while conformers D-F have both amide NH stretch fundamentals in the 3480-3495 cm(-1) region, consistent with independent-chain structures with two free NH groups. NPEA has a single conformer with S(0)-S(1) origin at 37,618 cm(-1). NMPEA has three conformers, two that dominate the R2P1 spectrum, with origin transitions between 35,580 and 35,632 cm(-1). Four conformations, one dominate and three minor, of NPOEA have been resolved with origins between 35,654 and 36,423 cm(-1). To aid the making of conformational assignments, the geometries of low-lying structures of all four molecules have been optimized and the associated harmonic vibrational frequencies calculated using density functional theory (DFT) and RIMP2 methods. The S(0)-S(1) adiabatic excitation energies have been calculated using the RICC2 method and vertical excitation energies using single-point time-dependent DFT. The sensitivity of the S(0)-S(1) energy separation in OANAT and NPOEA primarily arises from different orientations of the chain attached to the phenoxy group. Using the results of the single-chain analogs, tentative assignments have been made for the observed conformers of OANAT. The RIMP2 calculations predict that interchain H-bonded conformers of OANAT are 25-30 kJ/mol more stable than the extended-chain structures. However, the free energies of the interchain H-bonded and extended structures calculated at the preexpansion temperature (450 K) differ by less than 10 kJ/mol, and the number of extended structures far outweighs the number of H-bonded conformers. This entropy-driven effect explains the presence of the independent-chain conformers in the expansion, and cautions future studies that rely solely on relative energies of conformers in considering possible assignments.

Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide.

SummaryA novel cyclic dipeptide —cyclo[(S)-His-(S)-NorArg] — has been prepared which catalyzes an enantioselective version of the Strecker amino acid synthesis. The catalyst, when present in 2 mol % quantity in methanol solution, catalyzes the addition of hydrogen cyanide toN-alkylimines to affordα-amino nitriles in high yield and high enantiomeric excess. Furthermore, acid hydrolysis ofN-benzhydryl-α-amino nitriles afforded the correspondingα-amino acids directly. This methodology affords a variety of arylglycines in exceptionally high enantiomeric excess, but aliphatic amino acids were obtained with low enantioselectivity. Current efforts are underway to expand the scope of this reaction, as well as to elucidate the mechanism of catalysis and the roles played by substrate and catalyst in determining the stereochemical outcome of the reaction.

Diastereoselective recognition of β anomers of phenyl glucosides by a cyclobis(paraquat-p-phenylene) receptor: A computational study

The preference of a cyclobis(paraquat-p-phenylene) receptor for binding phenyl β-glucopyranoside over the α- anomer was investigated by constant temperature molecular dynamics simulations conducted using the AMBER∗ force field and the GB/SA continuum solvation model. The energy difference between the complexes of the β- and α- anomers in water was found to be 0.3 ± 0.1 kcal·mol−1 using a stochastic dynamics algorithm and 0.1 ± 0.1 kcal·mol−1 for a mixed mode Monte Carlo/stochastic dynamics method. This same trend was found in gas phase simulations, in which the complex with the β anomer was more stable by 0.4±0.1 kcal·mol−1. In all cases the complex of the β anomer was shown to be more stable, indicating a possible steric origin for the diastereoselectivity of binding.

The stereoselective synthesis of (E)-alkene dipeptide isosteres

Abstract A diastereo- and enantio-selective synthesis of the ( E )-alkene dipeptide isostere of l -Ala- l -Ala from l -alanine has been developed which proceeds via stereocontrolled addition of a ( Z )-vinyllithium reagent followed by a [2,3]-Wittig rearrangement. The synthesis proceeds in seven steps overall from l -alanine methyl ester. It is believed that this approach will provide a fairly general and convenient route to isosteres of a number of different dipeptides.

Small Molecule Inhibitors of Anthrax Toxin–induced Cytotoxicity Targeted Against Protective Antigen

Two molecular scaffolds were designed using the CAVEAT molecular design package to inhibit the oligomerization of protective antigen (PA63), a key protein component of anthrax toxin. The inhibitors were designed to prevent heptamerization of PA63 by mimicking key residues of PA63 needed for the intermolecular interactions that stabilize the heptamer. Using the scaffolds identified by CAVEAT, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxin–induced cytotoxicity, with three of the agents demonstrating modest inhibition in murine J774A.1 macrophage cells.

Stereodivergence in an intramolecular Horner-Emmons macrocyclization. Effect of reaction conditions on product distribution

In a macrocyclization by intramolecular Horner-Emmons reaction, it has been shown that employment of K2CO3/18-crown-6 leads to formation of an E-disubstituted olefin as the major isomer whereas the use of LiCl/DBN affords the Z-isomer as the major product. Changes were made to the base, solvent and reaction temperature in an attempt to identify the factors which influence the stereochemical outcome of the cyclization. The results of this study suggest that the stereodivergence arises from a change in the rate-determining step of the reaction, possibly attributable to the strength of the base employed. Such an effect has been previously invoked in the intermolecular Horner-Emmons reaction to account for Z-selective conditions.

Differential self assembly of amphiphilic helical peptides

SummaryA series of amphiphilic, helical peptides was designed and synthesized to investigate the components necessary for formation of helical bundles with differing aggregation states. Minimalistic sequences were employed for the peptides which contained either four (Leu4), six (Leu6) or eight (Leu8) leucine residues within a sixteen amino acid sequence. All peptides were highly helical as evaluated by circular dichroism, and the helical content of each peptide exhibited a concentration dependence. Size exclusion chromatography confirmed aggregation states of dimer/trimer forLeu4, tetramer forLeu6, and hexamer octamer forLeu8. Disulfide crosslinking studies also confirmed that the dimer ofLeu4 favored a parallel orientation with respect to the helical dipole. This systematic study clearly defines the role of hydrophobicity in the self assembly of helical peptides; peptides with a small hydrophobic face favor small bundle sizes, whereas peptides containing larger hydrophobic faces form correspondingly larger helical bundles.