Martin Woods

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.

Dispiroketals in synthesis (part 2): A new group for the selective protection of diequatorial vicinal diols in carbohydrates.

Dispiroketal formation as a new method for the selective protection of trans diequatorial vicinal diols in carbohydrate systems is reported.

Stereospecific synthesis of the anaesthetic levobupivacaine

Abstract Enantiomerically pure (S)-Bupivacaine is synthesised from the chiral pool using cheap and readily available (S)-lysine. The key steps in this efficient synthesis include an oxidative de-amination and stereospecific ring closure to form the pipecolamide core structure.

Dispiroketals in synthesis (part 10): Further reactions of dispoke protected lactate and glycolate enolates

Abstract α-Hydroxy acids have been reacted with bis-dihydropyrans to give dispiroketal adducts (1,8,13,16-tetraoxadispiro[5.0.5.4]-hexadecan-14-ones). The enolates derived from these compounds undergo reaction with electrophiles with generally high levels of diastereoselectivity. Subsequent deprotection of these compounds gives α-hydroxy esters of high enantiomeric excess.

Dispiroketals in synthesis (part 6): Highly stereoselective alkylation of dispiroketal protected lactate and glycolate enolates☆

Abstract Protected lactic acid enolates have been alkylated with a range of electrophiles to give the substituted adducts with moderate to excellent stereoselectivity. A chiral protected glycolic acid adduct has also been doubly alkylated with high stereoselectivity.

Dispiroketals in synthesis (part 4): Enantioselective desymmetrization of glycerol using a c2-symmetric disubstituted bis-dihydropyran.

Abstract Glycerol may be simultaneously protected and enantioselectively desymmetrised by dispiroketal formation with (S,S)-2,2′-dimethyl-3,3′,4,4′-tetrahydro- 6,6′-bi-2H-pyran 1.

Dispiroketals in synthesis (part 7): Protection of D-glucopyranose substrates

Abstract The formation of 1,8,13,16-tetraoxadispiro[5.0.5.4]hexadecanes (dispiroketals) of various D-glucopyranosyl substrates is described.

The Use of PeptiCLEC-TR in the Preparation of Dipeptides

Dipeptides are important intermediates in many pharmaceutical products. To support a research programme on matrix metalloproteinases (MMP) we needed to prepare the dipeptide, Leu-Phe-NHMe (3). Chemical methods provided the material but not to the quality required, and thus an alternative preparation was sought. The use of enzymes in chemical synthesis was a tool that we had used before but not in the preparation of dipeptides. This contribution will show the utility of PeptiCLEC-TR in the preparation of dipeptide (3) and its application to other dipeptides. It will highlight the amenability of PeptiCLEC-TR to scale-up and demonstrate the recycling of this enzyme, which will make this a cost-effective route.

A short, scaleable synthesis of both enantiomers of 2-benzoylsulfanyl-5-phthalimidopentanoic acid from ornithine

Abstract An efficient “one-pot” synthesis of (R)- and (S)-2-bromo-5-phthalimidopentanoic acid from ornithine is described. Subsequent reaction with potassium thiobenzoate affords a concise, scaleable route to (R)- and (S)-enantiomers of 2-benzoylsulfanyl-5-phthalimidopentanoic acid, an intermediate in the synthesis of MMP inhibitors.