A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d-glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l-phenylalanine and l-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Microbial hydroxylation of o-bromophenylacetic acid provided 2-bromo-5-hydroxyphenylacetic acid. This enabled a route to the key intermediate 4-bromo-2,3-dihydrobenzofuran for synthesizing a melatonin receptor agonist and sodium hydrogen exchange compounds. Pd-mediated coupling reactions of 4-bromo-2,3-dihydrobenzofuran provided easy access to the 4-substituted-2,3-dihydrobenzofurans.

An efficient and practical process to generate beta-C-arylglucoside derivatives was achieved. The process described involves Lewis acid mediated ionic reduction of a peracetylated 1-C-aryl methyl glucoside derived from the addition of an aryl-Li to selectively protected delta-D-gluconolactone. The reduction of the 2-acetoxy-1-C-oxacarbenium ion intermediates proceeds with a high degree of selectivity to give beta-C-arylglucosides without 2-acetoxy group participation. Furthermore, during the reduction process we also identified an unprecedented critical role of water. By changing from the usual benzyl ether protecting groups because of cost and chemical compatibility concerns, the new process is made additionally efficient and highly selective.

The 2-nitramino functionality in 2-nitramino-4-picoline was successfully exploited not only as a protecting group but also as a directional handle to afford an efficient, atom-economic, and regioselective synthesis of 2-amino-5-bromo-3-nitro-4-picoline (4), a precursor for a drug candidate in development.

Transformation of 4,7-dimethoxy-6-azaindole into 4-hydroxy-7-methoxy-6-azaindole or 7-hydroxy-4-methoxy-6-azaindole can be readily controlled by careful selection of a reagent. Treatment with concentrated HCl results in hydrolysis at the 4-position exclusively, while TMS-I provides demethylation at the 7-position only. Products were unambiguously identified by single crystal X-ray crystallography.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Reduction of tetra-O-benzyl-protected 1C-phenylglucoside using triethylsilane and BF3·OEt2 has been reported (Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610–612) to give exclusively 2,3,4,6-tetra-O-benzyl-β-1C-phenyl-1-deoxyglucoside. We have determined that this reduction actually gives a 4:1 mixture of anomers (β:α). We observed that the selectivity of the reduction is influenced by the steric bulk of the silane. The use of triisopropylsilane as a reducing agent gives >35:1 ratio (β:α) of 2,3,4,6-tetra-O-benzyl-β-1C-phenyl-1-deoxyglucoside.

Cephalosporin derivatives containing a unique combination of lipophilic C-7 sidechains and polar C-3 thiopyridinium groups were synthesized and found to exhibit potent anti-MRSA activity in vitro and in vivo. The optimum C-7 sidechains utilized were 2,5-dichlorophenylthioacetamido and 2,6-dichloropyrid-4-ylthioacetamido. The C-3 thiopyridinium rings were substituted at nitrogen with amino acid and pyruvic acid groups that were designed to confer aqueous solubility as required for IV formulation. This paper describes the characteristics of these novel cephalosporins and highlights synthetic methods developed to allow their practical, large-scale syntheses.