The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-D-arabinitol] from Lerythronolactone and of 4-C-Me-LAB [from D-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pK a of the salt around 8.4] is discussed and illustrates the need for care in analysis of both coupling constants and chemical shift. 4-C-Me-DAB (for rat intestinal sucrase K i 0.89 μM, IC 50 0.41 μM) is a competitive -whereas 4-C-Me-LAB (for rat intestinal sucrase K i 0.95 μM, IC 50 0.66 μM) is a noncompetitive -specific and potent α-glucosidase inhibitor. A rationale for the α-glucosidase inhibition by DAB, LAB, 4-C-Me-DAB, 4-C-Me-LAB, and isoDAB -but not isoLAB -is provided. Both are inhibitors of endoplasmic reticulum (ER) resident α-glucosidase I and II. This paper describes the synthesis of the enantiomers 4-C-Me-DAB 1D [1,4-dideoxy-1,4-imino-4-C-methyl-D-arabinitol] and 4-C-Me-LAB 1L with only a single acetonide needed as a protecting group, both of which are micromolar inhibitors of some α-glucosidases; in accord with Asano's hypothesis, i the D-iminosugar 1D is a competitive inhibitor, whereas the enantiomer 1L is a non-competitive inhibitor. Synthetic enantiomers of natural iminosugars Correspondence to: George W. J. Fleet, george.fleet@chem.ox.ac.uk. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. are frequently powerful glycosidase inhibitors. ii Natural and synthetic iminosugars comprise a major family of glycosidase inhibitors. iii The introduction of an alkyl substituent into a sugar mimic usually removes any significant glycosidase inhibition, iv however, introduction of a C6 methyl branch into the piperidine ring of L-swainsonine increases the inhibition of naringinase by an order of magnitude v in comparison to the parent indolizidine, Lswainsonine. vi The natural product DAB 3D is a good -but the enantiomer LAB 3L is a more potent and more specific -inhibitor of α-glucosidases. vii The isomer isoDAB 2D is also a very good inhibitor of α-glucosidases but the enantiomer 2L shows no inhibition of any glycosidase. This paper provides a rationale for isoLAB 2L being the only one of the six simple pyrrolidines 1, 2, and 3 which does not inhibit α-glucosidases; isoLAB 2L is the only one of the sugar mimics which partially rescues the defective F508del-CFTR function in cystic fibrosis. viii N-Alkylation of monocyclic iminosugars can enhance glycosidase inhibition by several orders of magnitude; ix such modification of the alkyl-branched parent structures may access a series of new bioactive compounds. NIH Public...
Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ.
Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. Azido-γ-lactones are very useful intermediates in the synthesis of iminosugars and polyhydroxylated amino acids. In this study two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination. A side-by-side glycosidase inhibition profile of 11 of the possible 16 HNJ stereoisomers derived from d-glucose and d-mannose is presented.
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