Efficient Route to Canagliflozin via Anhydroketopyranose.

The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.

Benzimidazoles from Aryl Alkyl Ketones and 2-Amino Anilines by an Iodine Catalyzed Oxidative C(CO)-C(alkyl) Bond Cleavage.

Novel molecular iodine catalyzed cyclization reactions of 2-amino anilines with aryl alkyl ketones under oxidant and metal-free conditions are described. The reaction likely involves sequential C-N bond formation followed by C(CO)-C(alkyl) bond cleavage. Various 2-substituted benzimidazoles are obtained in moderate to good yields in a single step from readily available acetophenones, propiophenones, and phenylacetophenones.

Substitution dependent stereoselective construction of bicyclic lactones and its application to the total synthesis of pyranopyran, tetraketide and polyrhacitide A.

A novel bicyclization strategy has been developed for the stereoselective synthesis of bicyclic lactones, i.e. 7-aryl or alkyl-2,6-dioxabicyclo[3.

Solution Nuclear Magnetic Resonance Studies of Sterol Carrier Protein 2 Like 2 (SCP2L2) Reveal the Insecticide Specific Structural Characteristics of SCP2 Proteins in Aedes aegypti Mosquitoes.

Sterol carrier protein 2 like 2 from Aedes aegypti (AeSCP2L2) plays an important role in lipid transport in mosquitoes for its routine metabolic processes. Repeated unsuccessful attempts to crystallize ligand free SCP2L2 prompted us to undertake nuclear magnetic resonance (NMR) spectroscopy to determine its three-dimensional structure. We report here the three-dimensional structures and dynamics of apo-AeSCP2L2 and its complex with palmitate.

The unique functional role of the C-HS hydrogen bond in the substrate specificity and enzyme catalysis of type 1 methionine aminopeptidase.

It is intriguing how nature attains recognition specificity between molecular interfaces where there is no apparent scope for classical hydrogen bonding or polar interactions. Methionine aminopeptidase (MetAP) is one such enzyme where this fascinating conundrum is at play. In this study, we demonstrate that a unique C-HS hydrogen bond exists between the enzyme methionine aminopeptidase (MetAP) and its N-terminal-methionine polypeptide substrate, which allows specific interaction between apparent apolar interfaces, imposing a strict substrate recognition specificity and efficient catalysis, a feature replicated in Type I MetAPs across all kingdoms of life.

The facile synthesis of 1-benzoazepine derivatives via gold-catalyzed regioselective cycloisomerization reactions of N-(o-alkynylaryl)-N-vinyl sulfonamides.

Gold-catalyzed, regioselective cycloisomerization of N-(o-alkynylaryl)-N-vinyl sulfonamides afforded high yields of 2-sulfonylmethyl-1-benzoazepine derivatives. This 7-endo-dig selective cyclization proceeds via the incorporation of an exocyclic double bond by a labile 1-benzoazepine intermediate. The cyclization substrates were assembled in two steps from readily available materials using Sonogashira coupling and a Cs2CO3-mediated formal vinylic substitution.

Nazarov cyclization of divinyl ketones bearing an ester group at the β-position: a remarkable effect of α-substitution and alkene geometry on regioselectivity.

The Nazarov cyclization of divinyl ketones with an ester at the β-position was examined with particular reference to where the cyclic double bond forms. We observed unprecedented regioselectivity, dictated by the subtle substitution patterns at the α-position and alkene geometry of α,β and mostly, this selectivity is regardless of substitutions at α'- and β'-positions. The major implications of these observations are an aromatic group at the α-position with E-olefin geometry provides a cyclopentenone in which the double bond is not in conjugation with an ester, whereas Z-olefin provides a cyclopentenone in which the double bond is in conjugation with an ester; and divinyl ketones bearing an ester group at the β-position and an alkyl group at the α-position with E-olefin geometry provide a cyclopentenone in which the double bond is in conjugation with the ester.

Sequential aza-Piancatelli rearrangement/Friedel-Crafts alkylation for the synthesis of pyrrolo[1,2-d]benzodiazepine derivatives.

2-Furylcarbinols undergo a smooth aza-Piancatelli rearrangement followed by Friedel-Crafts alkylation with a bifunctional substrate, (1H-pyrrol-1-yl)aniline, in the presence of 10 mol% In(OTf)3 in acetonitrile at room temperature to afford the corresponding hexahydrobenzo[b]cyclopenta[f]pyrrolo[1,2-d][1,4]diazepin-11(4aH)-one scaffolds in good yields. This method offers significant advantages such as high conversions, mild reaction conditions, short reaction times, and high selectivity. The relative stereochemistry of the product was established by nOe studies.

Total synthesis of a piperidine alkaloid, microcosamine A.

The first asymmetric total synthesis of a new natural piperidine alkaloid, microcosamine A, has been accomplished from d-serine and d-methyl lactate as chiral pool starting materials. Key features of the strategy include the utility of Horner-Wadsworth-Emmons reaction, Luche reduction, intramolecular carbamate N-alkylation to form the piperidine framework and Julia-Kocienski olefination to install the triene side-chain.

Domino Strategy for the Stereoselective Construction of Angularly Fused Tricyclic Ethers.

A stereoselective synthesis of decahydrofuro[3,2-d]isochromene derivatives has been achieved by the condensation of 2-cyclohexenylbutane-1,4-diol with aldehydes in the presence of a stochiometric amount of BF3·OEt2 in dichloromethane at -78 °C. Similarly, the condensation of 2-cyclopentenylbutan-1,4-diol with aldehydes provides the corresponding octahydro-2H-cyclopenta[c]furo[2,3-d]pyran derivatives in good yields with high diastereoselectivity. It is an elegant strategy for the quick construction of tricyclic architectures with four contiguous stereogenic centers in a single step.

Catalyst-controlled divergence in cycloisomerisation reactions of N-propargyl-N-vinyl sulfonamides: gold-catalysed synthesis of 2-sulfonylmethyl pyrroles and dihydropyridines.

Gold-catalysed, divergent synthesis of 2-sulfonylmethyl pyrroles and dihydropyridines from N-propargyl-N-vinyl sulfonamides has been achieved. Echavarren's gold(I) catalyst promoted the formation of pyrrole derivatives whereas the combination of PPh3AuCl and AgSbF6 afforded dihydropyridines. The aza-enyne precursors for the cycloisomerisation reaction were prepared by a base-mediated formal vinylic substitution reaction of 2-bromoallyl sulfones.

Cu(OAc)2-Et3N mediated oxidative coupling of α-azido ketones with pyridinium ylides: utilizing in situ generated imines for regioselective synthesis of imidazo[1,2-a]pyridines.

Phenacyl azides were reacted with pyridinium ylides in the presence of Cu(OAc)2 (2 mol%) and Et3N utilizing molecular oxygen as a green oxidant to yield imidazo[1,2-a]pyridines in exclusive regioselectivity. Following the optimized protocol, 28 different fused heterocycles were synthesized in high yields (71-92%). In order to get mechanistic insight into the reaction, a few control experiments were carried out and the role of the copper salt was discussed.

Chemical shift assignments of zinc finger domain of methionine aminopeptidase 1 (MetAP1) from Homo sapiens.

Methionine aminopeptidase Type I (MetAP1) cleaves the initiator methionine from about 70 % of all newly synthesized proteins in almost every living cell. Human MetAP1 is a two domain protein with a zinc finger on the N-terminus and a catalytic domain on the C-terminus. Here, we report the chemical shift assignments of the amino terminal zinc binding domain (ZBD) (1-83 residues) of the human MetAP1 derived by using advanced NMR spectroscopic methods.

One-pot, three-component approach to the synthesis of 3,4,5-trisubstituted pyrazoles.

An operationally simple and high yielding protocol for the synthesis of polyfunctional pyrazoles has been developed through one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo compounds as well as tosyl hydrazones. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3-dicarbonyl, and diazo component individually.

Regioselective synthesis of substituted arenes via aerobic oxidative [3 + 3] benzannulation reactions of α,β-unsaturated aldehydes and ketones.

Facile conversion of α,β-unsaturated aldehydes and ketones into highly substituted arenes via a base-mediated, completely regioselective, air-oxidative [3 + 3] benzannulation reaction with readily available 4-sulfonylcrotonates or 1,3-bisphenylsulfonylpropene is reported. The reaction can also be carried out as a one-pot, three-component operation using 4-bromocrotonates, aryl sulfinates, and cinnamaldehyde. This open-flask, metal-free reaction does not require anhydrous solvents, proceeds under mild conditions, and uses atmospheric oxygen as the oxidant to afford high yields of the 3-(arylsulfonyl)benzoic acid esters.

Acetal-initiated Prins bicyclization for the synthesis of hexahydrofuro-[3,4-c]furan lignans and octahydropyrano[3,4-c]pyran derivatives.

An acetal-initiated Prins bicyclization approach has been developed for the stereoselective synthesis of hexahydrofuro[3,4-c]furan lignans. This also provides a direct way to generate a new series of octahydropyrano[3,4-c]pyran derivatives in a single-step process.

Prins cascade cyclization for the synthesis of 1,9-dioxa-4-azaspiro[5.5]undecane derivatives.

A novel Prins cascade process for the synthesis of 1,9-dioxa-4- azaspiro[5.5]undecane derivatives by the coupling of aldehydes with N-(4-hydroxy-2-methylenebutyl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide has been developed. This is the first report of the synthesis of spiromorpholinotetrahydropyran derivatives through a Prins bicyclization.

Stereoselective synthesis of hexahydro-1H-pyrano- and thiopyrano[3,4-c]quinoline derivatives through a Prins cascade cyclization.

A cascade reaction of (E)-5-(arylamino)pent-3-en-1-ols and thiols with various aldehydes in the presence of 30 mol % BF3·OEt2 in 1,2-dichloroethane at 80 °C affords a novel class of trans-fused hexahydro-1H-pyrano[3,4-c]quinolines and hexahydro-1H-thiopyrano[3,4-c]quinolines in good to excellent yields with high selectivity. The condensation of (Z)-5-(arylamino)pent-3-en-1-ol with aldehydes provides the corresponding cis-fused products under similar conditions.

Protein chaperones Q8ZP25_SALTY from Salmonella typhimurium and HYAE_ECOLI from Escherichia coli exhibit thioredoxin-like structures despite lack of canonical thioredoxin active site sequence motif.

The structure of the 142-residue protein Q8ZP25_SALTY encoded in the genome of Salmonella typhimurium LT2 was determined independently by NMR and X-ray crystallography, and the structure of the 140-residue protein HYAE_ECOLI encoded in the genome of Escherichia coli was determined by NMR. The two proteins belong to Pfam (Finn et al. 34:D247-D251, 2006) PF07449, which currently comprises 50 members, and belongs itself to the 'thioredoxin-like clan'.

NMR structure of the peptidyl-tRNA hydrolase domain from Pseudomonas syringae expands the structural coverage of the hydrolysis domains of class 1 peptide chain release factors.

The NMR structure of the peptidyl-tRNA hydrolase (PTH) domain from ( PTH domain) was solved by using recently devised protocol for high throughput protein structure determination. The PTH domain belongs to a large Pfam family PF00472, which consists of at least 1549 proteins annotated as ‘hydrolysis domains of peptidyl-tRNA’. The structure of PTH domain expands the ‘structural coverage’ of the PFam family.

Sequence-specific, dynamic covalent crosslinking in aqueous media.

This article describes an associating system that integrates the specificity of multiple hydrogen bonding and the strength of dynamic covalent interactions. Linear oligoamides that sequence-specifically pair into H-bonded duplexes in nonpolar solvents were modified with S-trityl groups, allowing the reversible formation of disulfide bonds. The disulfide-crosslinking reactions of oligoamides capable of pairing via two, four, and six intermolecular H-bonds, along with several control strands, were examined using ESI, MALDI-TOF, reverse phase HPLC, and two-dimensional NMR.