Mark J. Ford

Total synthesis of the anthelmintic macrolide avermectin B1a

A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a 1 is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide 4 followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran 3 to afford the ‘northern’ C(11)–C(25) fragment 39. Coupling of the derived C(11)–C(25) aldehyde unit 42 with a C(1)–C(10)‘southern’ fragment 2 was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion 51. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone 70 and the thiocarbonylimidazolide 69. Final deacetylation was accomplished using Super-Hydride to give the natural product 1.

Synthesis of potent inhibitors of histidinol dehydrogenase

Abstract Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 ( F i ∗ = 4.4 nM) and 19 ( K i ∗ = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC 50 ∼20μM).

Synthesis of the C12–C26 fragment of the acyltetronic acid lonophore antibiotic tetronasin (ici 139603)

Abstract Preparation of a central tetrahydropyran portion (2) of the antibiotic tetronasin (1) was achieved using an all-in-one epoxidation / cyclization modification of the Sharpless reaction. Further manipulation and coupling reactions afforded the C12–C26 fragment of tetronasin which was identical to that obtained by natural product degradation studies.

Synthesis of (±)-2′,3′-didehydro-2′,3′-dideoxy nucleosides via a modified Prins reaction and palladium(0) catalysed coupling

Cyclopentenyl allylic acetates have been prepared in diastereoisomerically enriched form by modification of the Prins reaction. Palladium(0) catalysed coupling between these allylic acetates and a heteroaromatic base provides a highly convergent and direct route for synthesising carbocyclic 2′,3′-didehydro-2′,3′-dideoxy nucleosides. The method is exemplified by the coupling reaction with adenine which yields (±)-2′,3′-didehydro-2′,3′-dideoxyaristeromycin 5′-O-acetate 22 in 50% yield. This has been converted in two steps into (±)-aristeromycin triacetate 5.

Preparation of β-ketomacrolactones and β-ketodiolides using S-t-butyl 3-oxobutanethioate and S-t-butyl 4-diethylphosphono-3-oxobutanethioate

Using S-t-butyl-3-oxobutanethioate (1) and S-t-butyl 4-diethylphosphono-3-oxobutanethioate (2) various homologation reactions with t-butyldimethylsilyl protected hydroxy-iodides and aldehydes are reported. The products of these reactions after deprotection may be treated with copper(I) trifluoroacetate to afford β-ketomacrolide or β-ketomacrodiolides ranging in ring size from 13 to 32 depending upon the linking carbon atom chains and the reaction conditions. Several of the macrocyclic structures have been studied by X-ray crystallographic methods to determine their solid state conformations

Asymmetric total synthesis of alkaloids and seco-iridoids

Abstract A chiral cyclopentenolone from Michael addition of an oxazepine derived from ephedrine to a cyclopentene-1,2-dione has been converted into pure enantiomers of established synthetic precursors to alkaloids and seco-iridoids via a novel exchange which recovers the chiral auxiliary.

Asymmetric total synthesis from cyclopentene-1,2-diones : characterisation of a diastereomerically pure michael adduct

Abstract A key cyclopentenolone intermediate in the asymmetric synthesis of alkaloids and seco-iridoids has been prepared from reaction of a chiral 5, 7-dioxoperhydro-1,4-oxazepine with a cyclopentene-1,2-dione dimer; the absolute configuration at the induced chiral centres has been assigned from n.O.e. experiments.

Formation of medium-ring diolides via intramolecular Diels-Alder reactions of dicarboxylic ester-tethered trienes

Abstract The synthesis and IMDA reactions of diester-tethered trienes 1 , 2 and 3 are described.

INTRAMOLECULAR DIELS-ALDER REACTIONS OF DIESTER-TETHERED TRIENES. SYNTHESIS OF MEDIUM RING-CONTAINING CARBOCYCLES AND HETEROCYCLES

Abstract Intramolecular Diels-Alder reactions of cyclohexane-1,2-dicarboxylic anhydride-derived diester-tethered trienes are described. The stereoselectivities of most of the cycloaddition processes studied may be rationalised in terms of an preferred ‘inside’-oriented diene giving rise to an endo-transition state.