One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids.

A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8) in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation, reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehydration-oxidation and reductive heteroannulation methodology is successfully utilized for the total synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).

Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

Practical, asymmetric route to sitagliptin and derivatives: development and origin of diastereoselectivity.

The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S═O, consistent with MsOH being crucial for high selectivity. The second is a novel C-H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.

New and practical method for synthesis of 1- and 1,3-substituted xanthines.

[reaction: see text] A new and practical method for the synthesis of 1- and 1,3-substituted xanthines is reported. Direct base-promoted condensation of the imidazole precursor 1 with carbamates 2 gives 1-substituted 7-PMB xanthines 7 in good yields. Alkylation of these derivatives or their potassium salts proceeds under mild conditions to give functionalized 1,3-substituted 7-PMB xanthines 9 in good to excellent yields. The obtained 7-PMB-protected derivatives can be readily deprotected to give the parent 1- and 1,3-substituted xanthines.

Aziridines and aziridinium ions in the practical synthesis of pharmaceutical intermediates--a perspective.

Recent methods for the synthesis of aziridines and aziridinium ions, the mechanisms of their nucleophilic ring-opening reactions and applications to the practical synthesis of pharmaceutical intermediates are reviewed.

Synthesis, Equilibration, and Coupling of 4-Lithio-1,3-dioxanes: Synthons for syn- and anti-1,3-Diols.

Configurationally defined alpha-alkoxylithium reagents were prepared by reductive lithiation of 4-(phenylthio)-1,3-dioxanes. A new and more general synthesis of 4-(phenylthio)-1,3-dioxanes has been developed on the basis of the reduction and in situ acetylation of 1,3-dioxan-4-ones. For each of the substitution patterns examined (23a-d), reductive lithiation gave the axial alkyllithium (24a-d) with 99:1 stereoselectivity. Equilibrations of these alkyllithium reagents were possible with unhindered substrates to give the equatorial alkyllithiums 26a and 26b with excellent stereoselectivities. The more hindered axial alkyllithium reagents (24c, 24d) did not equilibrate efficiently. The equilibrium between alkyllithium reagents 24c and 26c strongly favors the equatorial isomer 26c. The inefficient equilibration with this hindered substrate is attributed to a slow rate of equilibration rather than insufficient driving force. These alkyllithium reagents could be coupled with a variety of electrophiles with retention of configuration by direct addition, copper-mediated coupling, or transmetalation to the corresponding alkylzinc reagent followed by copper-mediated coupling.