D. Huw Davies

Structures of the aminoglycoside antibiotics 66–40B and 66–40D produced by Micromonospora inyoensis

The novel amino-glycoside antibiotics 66–40B and 66–40D produced as minor components by fermentation of Micromonospora inyoensis have been shown to be O-2,6-diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-3-methylamino-α-D-xylopyranosyl-(1→6)]-2-deoxy-D-streptamine and O-2,6-diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-3-methylamino-β-L-arabinopyranosyl-(1→6)]-2-deoxy-D-streptamine, respectively. The novel 3-deoxy-3-methylamino-β-L-arabinopyranosyl sugar unit of 66–40D has not previously been found in any amino-glycoside antibiotic. Both 66–40B and D exhibit broad spectrum antibacterial activity.

Synthesis of γ-lactones from intermediate 2-(γ-hydroxyacyl)-imidazoles by N-methylation and base-catalyzed C C bond cleavage. Application to the synthesis of (±)- cavernosine

Abstract Reaction of the allyl anions of O -trialkylsilyl- N -alkyl-2-(1′-hydroxyprop-2′-enyl)imidazoles with aldehydes and ketones gives products of α- and γ-attack. Greater steric hindrance in the anion (triisopropylsilyl vs t-butyldimethylsilyl) and in the aldehyde or ketone favours the γ-products. Sequential desilylation, N -methylation and treatment with base resulted in cleavage of these products to γ-lactones. The method was applied to the synthesis of (±)-cavernosine.

Non-oxidative conversion of ketone carbonyls into carboxy carbonyls. Comparison of 2-acylthiazoles and 2-acylimidazoles in the aldol condensation and the stereospecific cleavage of an example of the latter to a β-hydroxy ester via the azolium salt

The synthesis of some 2-acyl-thiazoles and -imidazoles is described. In the subsequent aldol condensation of these ketones, the imidazole congeners were much better behaved. N-Methylation of the imidazole aldols was only partially successful and suffered from competing O-methylation of the hydroxy group. A diastereoisomeric imidazolium salt from one of the aldols did not close to a β-lactone on treatment with base but did undergo clean de-acylation in the presence of methanol and base to give the corresponding β-hydroxy ester stereospecifically.

C-C bond cleavage of 2-acylimidazolium salts in a sequence involving a new ester homoenolate equivalent. A synthesis of γ-lactones

Reaction of the anion of 2-(1-tri-isopropylsiloxyallyl)-N-methoxymethylimidazole with ketones and aldehydes proceeds regioselectivity to give the enol silyl ethers of 2-acylimidazoles which suffer cleavage to γ-lactones after desilylation, N-methylation, and base treatment.

Stereocontrolled ring-opening of some enantiomerically enriched epoxy ketones and epoxy alcohols using trimethylaluminium: synthesis of (S)-2-arylpropanoic acids

Poly-(D)-leucine-catalysed epoxidation of chalcone furnished epoxide (+)-6; treatment of this epoxide with trimethylaluminium followed by zinc borohydride reduction and oxidative cleavage furnished (S)-2-phenylpropanoic acid 11. In a complementary sequence epoxy ketones (−)-6 and 25 were converted into (S)-2-phenylpropanoic acid and (S)-fenoprofen 5 respectively by reduction with zinc borohydride, reaction with trimethylaluminium and oxidative cleavage. Similarly epoxy ketones (−)-6, 21 and 28 were treated with methylmagnesium iodide, trimethylaluminium and the resultant alcohols subjected to oxidative cleavage to afford (S)-2-phenylpropanoic acid (from the first two substrates) and (S)-naproxen 1.

Semisynthetic aminoglycoside antibacterials. Part 9. Synthesis of novel 1- and 3-substituted and 1- and 3-epi-substituted derivatives of sisomicin and gentamicin from the 1- and 3-oxo-derivatives

The conversion of selectively protected gentamicin and sisomicin derivatives into the 1- and 3-oxo-compounds by reaction with 3,5-di-t-butyl-1,2-benzoquinone is described. By application of suitable reductive techniques these oxo-aminoglycosides have been converted into novel 1- and 3-epi-, 1- and 3-deamino-1- and -3-hydroxy-, 1- and 3-deamino-1- and -3-epi-hydroxy-, and 1-deamino-derivatives. A study of the 13C n.m.r. parameters of the 1-epi- and 1-deamino-derivatives has led to the assignment of novel solution conformations for these new aminoglycosides.

Structure of aminoglycoside 66-40 C, a novel unsaturated imine produced by Micromonospora inyoensis

The aminoglycoside 66-40 C, produced as a minor component in the fermentation of Micromonospora inyoensis, has been shown by spectroscopic and chemical degradative studies to have the novel dimeric structure (5), containing αβ-unsaturated imine groups not previously encountered in any aminoglycoside antibiotic.

Synthesis of methyl gentosaminide, methyl 3-deoxy-3-methylaminoarabinopyranoside, and related amino-sugars

The synthesis of both α- and β-anomers of methyl gentosaminide (methyl 3-deoxy-3-methylamino-D-xylopyranoside), a component of the amino-glycoside antibiotics gentamicin A and 66-40B, is described. A number of novel 3-alkylamino-analogues of gentosamine have been prepared and the synthesis of the L-enantiomer is also discussed. The preparation of methyl 3-deoxy-3-methylamino-α-D-arabinopyranoside and of the L-enantiomer, involving use of novel epoxy-ketone intermediates, is described. The L-enantiomer has recently been demonstrated to be a component of the amino-glycoside antibiotics 66-40D and gentamicins A1, A3, and B2.