Leslie Hough

Synthesis of 1-deoxy-6-epicastanospermine and 1-deoxy-6,8a-diepicastanospermine.

Extension of the carbon spine of 2,3;4,5-di-O-isopropylidene-beta-D-fructopyranoside by oxidation at C-1 followed by a Wittig reaction using the phosphorane Ph3P = CHCO2Et gave an oct-4-ulose derivative, which was then transformed into the key intermediate 1-azido-1,2,3-trideoxy-D-arabino-oct-4-ulose. Catalytic hydrogenolysis of this azide, followed by reductive amination between the resulting 1-amino substituent and the 4-keto-group then gave a mixture of pyrrolidines. After sulphonylation at the terminal 8-position, the pyrrolidines were then cyclised further between the nitrogen and C-8 to give 1-deoxy-6-epicastanospermine and 1-deoxy-6,8a-diepicastanospermine.

Enantiospecific synthesis of polyhydroxylated indolizidines related to castanospermine:1 1-deoxy-castanospermine.

Abstract Enantiospecific synthesis of (6S,7R,8R,8aR)-6,7,8- trihydroxyindolizidine ( 1-deoxy-castanospermine ) (3) is described from readily available D-glucose, where the key step involves oxidative bromination of a benzylidene acetal to afford 8-azido-3- o -benzoyl-5-bromo-5,6,7,8-tetradeoxy-1,2- o -isopropylidene-β-L-ido-octose (16). The synthetic indolizidine (3) was tested against a range of glycosidases.

Enantiospecific synthesis of polhydroxylated indolizidines related to castanospermine: 1 (6R,7S,8aR)-6,7-dihydroxyindolizidine and (6R,7R,8S,8aR)-6,7,8-trihydroxyindolizidine.

Abstract Enantiospecific syntheses of (6R,7S,8aR)-6,7-dihydroxy-indolizidine (3) and (6R,7R,8S,8aR)-6,7,8-trihydroxy-indolizidine (4) from methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (7) are reported. The two synthetic indolizidines (3) and (4) have been tested against a wide range of enzymes.

Enantiospecific synthesis of 1-deoxy-castanospermine, (6S,7R,8R, 8aR)-trihydroxyindolizidine, from D-glucose.

Abstract An enantiospecific synthesis of 1-deoxy-castanospermine (2) is described from D-glucose, where the key step involves oxidative bromination of a benzylidene acetal to afford 8-azido-3- O -benzoyl-5-bromo-5,6,7,8-tetradeoxy-1,2- O -isopropylidene-β-L- ido -octose (6).

Molecular mechanisms of sweet taste 3: aspartame and its non-sweet isomers

Abstract The coupling of the four diastereomers of aspartyl-phenylalanine methyl ester with the l -asparaginyl end of a helical receptor protein has been investigated by molecular modelling. The clockwise, three-point AH/B/X interaction, essential for a sweet taste, is found only in the l,l -isomer, Aspartame. None of the other isomers ( l,d -, d,l - and d,d -) could form such a three-point attachment, due to their counterclockwise glucophore, consistent with their lack of sweetness.

Bridged derivatives of sucrose: The synthesis of 6,6′-dithiosucrose, 6,6′-epidithiosucrose, and 6,6′-epithiosucrose☆

Abstract Selective iodination and bromination of sucrose at C-6 and C-6′ has been accomplished by reactions with iodine-triphenylphosphine-imidazole and carbon tetrabromide-triphenylphosphine-pyridine, respectively. Substitution of the bromo groups in 6,6′-dibromo-6,6′-dideoxysucrose hexa-acetate by CNS−, AcS−, and Me2NCS2− took place without complications, but when EtOCS2K was used, a complex reaction sequence took place leading to 6,6′-epithiosucrose hexa-acetate. Similarly, reaction of the dibromo derivative with K2CS3 afforded mainly the 6,6′-episulphide together with 6,6′-epidithiosucrose hexa-acetate, which was also formed from the dibromide by sequential treatment with thiourea and sodium metabisulphite. Oxidation of the episulphide with sodium metaperiodate afforded solely the (R)-sulphoxide, and oxidation with hydrogen peroxide afforded the sulphone. The episulphide, the episulphide S,S-dioxide, and the epidisulphide all showed conformational instability of the ring containing the sulphur atom(s), as indicated by the n.m.r. spectra, but the episulphide S-oxide did not show this behaviour.

Molecular Mechanisms of Sweet Taste. V. Sucralose and Its Derivatives

Abstract Chloro-deoxy-derivatives of sucrose, especially the intensely sweet 4, 1′,6′–trichloro-4,1′,6′-trideoxy-galacto-sucrose (Sucralose) and its derivatives, have been investigated in their peripheral interactions with a helical proteinaceous receptor model using computer graphics. In common with other high intensity sweeteners, they show multiple couplings with different side chains of the amino acid residues in the receptor protein.

Syntheses of hepta-, hexa-, and penta-pivalates of trehalose by selective pivaloylation☆

Abstract The order of esterification of the eight hydroxyl groups of trehalose with pivaloyl chloride is HO-6,6′ > HO-2,2′ > HO-3,3′ > HO-4,4′. Under the appropriate conditions of pivaloylation, heptapivalates with either HO-4 or HO-3 free, hexapivalates with either HO-4,4′ or HO-3′,4 free, and pentapivalates with HO-3′,4,4′ free were obtained. In addition, selective pivaloyation of trehalose 2,2′,3,3′-tetrapivalate afforded the 4,4′-diol and the non-symmetrical 4,4′,6′-triol. The 4-ol, the major heptapivalate, was a convenient starting material for the syntheses of 4-azido-4-deoxy- and 4-amino-4-deoxy-trehalose, together with their 4-epimers, and 4-chloro-4-deoxy-α- d -galactopyranosyl α- d -glucopyranoside. The 4,4′,6′-triol was utilised as a synthetic precursor of 4,6-dichloro-4,6-dideoxy-α- d -galactopyranosyl 4-chloro-4-deoxy-α- d -galactopyranoside and its triazido and triamino analogues.

Enantiospecific synthesis of (6R,7S,8aR)-dihydroxyindolizidine and (6R,7R,8S,8aR)-trihydroxyindolizidine from D-glucose.

Abstract Enantiospecific syntheses of (6R,7S,8aR)-dihydroxyindolizidine (1) and (6R,7R,8S,8aR)-trihydroxyindolizidine (2) from readily available methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (5) are described.

Molecular Mechanisms of Sweet Taste 1: Sweet and Non-Sweet Tasting Amino Acids

ABSTRACT A novel mechanism is proposed for the AH/B interaction of sweet molecules, such as D-α-amino acids with the L-asparagine unit at the N-terminus of a receptor protein which has a right-handed α-helical conformation. The lipophilic, dispersive bonding occurs between the side chain of the fifth amino acid residue, from the N-terminus, and either the side chain of the α-amino acid or its methine group at the carbon 2. The sequence of AH, B and X groups on the sweet amino acids occurs in a clockwise orientation, when viewed from the receptor.