172695-25-9

In the field of chiral Br?nsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Br?nsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich-type reaction of α-phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Br?nsted base catalysts and significantly broaden the utility of Br?nsted base catalysis in asymmetric organic synthesis.

Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters

A promising strategy for mediating protein-protein interactions is the use of non-peptidic mimics of secondary structural protein elements, such as the α-helix. Recent work has expanded the scope of this approach by providing proof-of-principle scaffolds that are conformationally biased to mimic the projection of side-chains from one face of another common secondary structural element - the β-strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side-chain were pre-formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six-membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a β-strand, demonstrated herein by mimicry of the i, i+2, i+4 and i+6 residues.

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.

The invention relates to compound of the formula (I): in which the substituents are as defined in the specification; in free form or in salt form; to its preparation, to its use as medicament and to medicaments comprising it.

A novel approach to the synthesis of Boc-core, a key starting material for ritonavir and lopinavir involving an unprecedented diastereoselective nitroaldol reaction on β-amino aldehyde is disclosed.

The invention relates to compound of the formula (1) in which the substituents are as defined in the specification; m free form or in salt form; to its preparation, to its use as medicament and to medicaments comprising it.

Soft and weak cooperation: Conformationally flexible organic compounds were found to promote the title transformation. These "soft" organocatalysts, which are able to control processes through the differential activation entropies (ΔΔS*S-R) of

Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of disea

Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters

N-Substituted tetralactams (cyclo-β-tetrapeptides) have been identified as potential molecular scaffolds by computer-aided design; compound 2, arising from L-β-homophenylalanine, has been prepared as a model system and its structure elucidated by single c

We describe a new chemoenzymatic synthesis of enantiopure 4-amino-2-hydroxy acids using two biotransformations in a single-pot process in aqueous medium. These compounds are valuable as γ-turn mimics for investigations into the secondary structure of peptides. The enzyme substrates are a series of carbobenzyloxy (CBZ)-protected 4-amino-2-keto esters, prepared efficiently from the L-amino acids, alanine, leucine, phenylalanine, and valine. First, the α-amino acids were converted to the corresponding β-amino acids in a simple five-step procedure. A further one-carbon homologation via ozonolysis of the corresponding β-keto cyanophosphoranes gave the required α-keto esters in good yield. The enzyme catalyzed hydrolyses of all the α-keto esters to the corresponding α-keto acids proceeded smoothly with the lipase from Candida rugosa. Using the same reaction pot, it was found that wild-type lactate dehydrogenases from either Bacillus stearothermophilus CBS-LDH) or Staphylococcus epidermidis (SE-LDH) could be used to specifically reduce the ketone of the alanine-derived α-keto acid 2, giving the (S)- and CR)-2-hydroxy acids, respectively, in good yields. However, the more bulky α-keto acids 3, 4, and 5 (derived from valine, leucine, and phenylalanine) were not substrates for these enzymes. In contrast, the genetically engineered H205Q mutant of D-hydroxyisocaproate dehydrogenase proved to be an ideal catalyst for the reduction of all the α-keto acids 2-5, giving excellent yields of the CBZ-protected (2R,4S)-4-amino2-hydroxy acids as single diastereomers. This genetically engineered oxidoreductase has great potential value in synthesis due to its broad substrate specificity and high catalytic activity. For example, reduction of 1 mmol of N-protected (S)-4-amino-2-oxopentanoic acid 2 took just 4 h with the H205Q mutant giving, after esterification, the CR)-2-alcohol 25 in 85% yield, whereas with SE-LDH the reaction required 4 days to give a 67% yield of 25.

Enantiopure N-Boc-β-aminoaldehydes are efficiently prepared in good yields from N-Boc-β-aminonitriles by reduction of the nitrile function with diisobutylaluminium hydride (DIBAL-H) - Keywords: β-aminoaldehyde; β-aminonitrile; α-aminoacid; homochiral; enantiomeric excess; reduction; DIBAL-H

Enantiopure N-and/or C-protected homo-β-amino acids are prepared readily and in good yields from N-protected α-amino acids with the same side chain, via reduction of the carboxyl function and conversion of the resulting N-protected β-amino alcohol into the corresponding β-amino iodide and then β-amino cyanide. The key step of this strategy is represented by the synthesis of the enantiopure N-protected β-amino iodides 2 and 3 that are smoothly obtained from the parent amino alcohols 1 by polymer bound triarylphosphine-I2 complex in anhydrous dichloromethane.

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