Divergent synthesis of new α-glucosidase inhibitors obtained through a vinyl Grignard-mediated carbocyclisation.

Four new α-glucosidase inhibitors have been synthesised through 5-8 synthetic steps from a common synthetic intermediate obtained through a recently developed carbocyclisation. The compounds were designed as hybrids of the known glucosidase inhibitors valienamine, voglibose and miglitol. All four compounds showed activity against rat intestinal sucrase with the most potent inhibitor acting at low micromolar concentration. The newly synthesised compounds were not as potent as miglitol against sucrase but showed greater selectivity towards the tested glycosidases. The most potent inhibitors were docked into a homology model built for this study of rat intestinal sucrase explaining the difference in potency between two diastereoisomers with varying orientation of a secondary amine.

Vinyl Grignard-Mediated Stereoselective Carbocyclization of Lactone Acetals.

A novel Ferrier-type carbocyclization is reported. It involves a carbohydrate-derived lactone acetal synthesized from methyl α-d-glucopyranoside, which upon treatment with excess vinylmagnesium bromide provides a highly substituted carbocyclic product as a single stereoisomer. The yield is greatly increased when N,N,N',N'-tetramethylethylenediamine is added to the reaction mixture. Optimized reaction conditions have been applied to lactone acetals derived from other carbohydrates. Based on the obtained results, a possible reaction mechanism has been proposed. Furthermore, scalability of the reaction up to 15 g scale and derivatization of the carbocyclic product has been demonstrated, including the formation of a rare trans-bicyclo[4.3.0]nonene scaffold via a ring-closing metathesis. The structure of this and all carbocyclic products were confirmed by X-ray crystallographic analysis.

Efficient Water Reduction with sp3 -sp3 Diboron(4) Compounds: Application to Hydrogenations, H-D Exchange Reactions, and Carbonyl Reductions.

A series of crystalline sp3 -sp3 diboron(4) compounds were synthesized and shown to promote the facile reduction of water with dihydrogen formation. The application of these diborons as simple and effective dihydrogen and dideuterium sources was demonstrated by conducting a series of selective reductions of alkynes and alkenes, and hydrogen-deuterium exchange reactions using two-chamber reactors. Finally, as the water reduction reaction generates an intermediate borohydride species, a range of aldehydes and ketones were reduced by using water as the hydride source.

Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: evidence for a transmetallation step between two oxidative addition Pd-complexes.

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of L n Pd(0) into HCN and an aryl bromide followed by a transmetallation step to L n Pd(Ar)(CN) and L n Pd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and L n Pd(0).