In this review, applications of the amide reductive functionalization methodology for the synthesis and modification of bioactive compounds are covered. A brief summary of the different protocols is presented in the introduction, followed by the synthetic application of these in late-stage functionalization, leading to known pharmaceuticals or to their derivatives, including bioisosteres, with potential higher activity as the main axis of the article. The synthetic approach to natural products based on amide reduction is also discussed; however, this is given in a condensed form focusing on recent or as yet unexplored applications due to a number of recently published excellent reviews covering this topic. The aim of this review is to illustrate the potential of reductive functionalization of amides as an elegant and useful tool in the synthesis of bioactive compounds and inspire further work in this field.

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The Dja Faunal Reserve located in southeastern Cameroon represents the largest and best protected rainforest patch in Cameroon. Here we make available a dataset on the inventory of tree species collected across the Dja. For this study nine 5 km long and 5 m wide transects were installed. All species with a diameter at breast height greater than 10 cm were recorded, identified and measured. A total of 11546 individuals were recorded, corresponding to a total of 312 species identified with 60 genera containing unidentified taxa. Of the 54 identified families Fabaceae, Rubiaceae and Malvaceae were the most species rich, whereas Fabaceae, Phyllantaceae and Olacaceae were the most abundant. Finally, Tabernaemontanacrassa was the most abundant species across the Reserve. This dataset provides a unique insight into the tree diversity of the Dja Faunal Reserve and is now publically available and usable.

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Chromatographic separation of the pod extract of Angylocalyx pynaertii resulted in the isolation of 13 sugar-mimic alkaloids (1-13). The structures of the new alkaloids were elucidated by spectroscopic methods as the 6-O-beta-D-glucoside (10) and N-hydroxyethyl derivative (11) of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) (1), 1,6-dideoxynojirimycin (12), and 1,3,4-trideoxynojirimycin (13). 2,5-Imino-1,2,5-trideoxy-L-glucitol (7), 2,5-dideoxy-2,5-imino-D-fucitol (8), and beta-homofuconojirimycin (9), isolated from the pods as well as the bark, were very specific inhibitors of alpha-L-fucosidase with no significant inhibitory activity toward other glycosidases. In this work, 1,4-dideoxy-1,4-imino-D-ribitol (6) was found to be a better inhibitor of lysosomal beta-mannosidase than 2,5-imino-1,2,5-trideoxy-D-mannitol (2). N-Hydroxyethyl-1-deoxynojirimycin (miglitol), which is commercially available for the treatment of diabetes, retained its inhibitory potential toward rat intestinal maltase and sucrase, whereas 11 and the synthetic N-hydroxyethyl derivative of 2,5-dideoxy-2,5-imino-D-mannitol markedly lowered or abolished their inhibition toward all enzymes tested.

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The extract of bark of Angylocalyx pynaertii (Leguminosae) was found to potently inhibit mammalian alpha-L-fucosidases. A thorough examination of the extract resulted in the discovery of 15 polyhydroxylated alkaloids, including the known alkaloids from seeds of this plant, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), 1-deoxymannojirimycin (DMJ) and 2,5-imino-1,2,5-trideoxy-D-mannitol (6-deoxy-DMDP). Among them, eight sugar-mimic alkaloids showed the potent inhibitory activity towards bovine epididymis alpha-L-fucosidase and their Ki values are as follows: 6-deoxy-DMDP (83 microM), 2,5-imino-1,2,5-trideoxy-L-glucitol (0.49 microM), 2,5-dideoxy-2,5-imino-D-fucitol (17 microM), 2,5-imino-1,2,5-trideoxy-D-altritol (3.7 microM), DMJ (4.7 microM), N-methyl-DMJ (30 microM), 6-O-alpha-L-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 microM), and beta-L-homofuconojirimycin (beta-HFJ, 0.0053 microM). We definitively deduced the structural requirements of inhibitors of alpha-L-fucosidase for the piperidine alkaloids (DMJ derivatives). The minimum structural feature of alpha-L-fucosidase inhibitors is the correct configuration of the three hydroxyl groups on the piperidine ring corresponding to C2, C3 and C4 of L-fucose. Furthermore, the addition of a methyl group in the correct configuration to the ring carbon atom corresponding to C5 of L-fucose generates extremely powerful inhibition of alpha-L-fucosidase. The replacement of the methyl group of beta-HFJ by a hydroxymethyl group reduced its inhibitory potential about 80-fold. This suggests that there may be a hydrophobic region in or around the active site. The existence or configuration of a substituent group on the ring carbon atom corresponding to the anomeric position of L-fucose does not appear to be important for the inhibition. Interestingly, Rha-DMJ was a 70-fold more potent inhibitor of alpha-L-fucosidase than DMJ. This implies that the lysosomal alpha-L-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.

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A polyhydroxy alkaloid has been isolated from the seeds of the African legume Angylocalyx pynaertii and identified as a 2-hydroxymethyl-3,4-dihydroxy-5-methylpyrrolidine by ms and 1H- and 13C-nmr spectroscopy. The absolute stereochemistry was established, by a stereochemically unambiguous synthesis from diacetone glucose, as 2,5-imino-1,2,5-trideoxy-D-mannitol, which may also be regarded as 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) [2] in which a hydroxymethyl group is deoxygenated, i.e., 6-deoxy-DMDP [1]. Whereas the structurally related polyhydroxypyrrolidine alkaloids which have previously been discovered are inhibitors of alpha- and beta-glucosidase, 6-deoxy-DMDP is unique in inhibiting beta-mannosidase. In addition to this novel alkaloid and 2-hydroxymethyl-3,4-dihydroxypyrrolidine [3], previously shown to be present in several Angylocalyx species, the known piperidine alkaloids deoxymannojirimycin [4] and fagomine [5] were identified for the first time as constituents of An. pynaertii seeds.

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