Michael John Broadhurst

Total synthesis of some new 4-demethoxyanthracyclinones

Abstract Optically active 4-demethoxyanthracyclinoiies (39a-g) bearing a variety of substituents at the 9position have been synthesised by an analogous route to that previously employed by us for (+)-4-demethoxydaunomycinone (5). These novel anthracyclinones have been prepared in sufficient quantity for subsequent glycosidation and biological evaluation.

Anthracyclines. Part 1. The synthesis of racemic daunomycinone and some related tetrahydronaphthacenequinones

New tetrahydronaphthacenequinones, which are related in structure to the aglycones of the antitumour drugs adriamycin and daunomycin, have been synthesised. Racemic daunomycinone has been prepared by a new, mild procedure utilising a phthalide intermediate for annelation.

1H-NMR and protection studies of interactions between ligands and bovine pancreatic phospholipase A2

A number of long-chain amines and naphthylamine sulfonates have been studied for their ability to inhibit bovine pancreatic phospholipase A2 (PLA2) and to protect PLA2 against alkylation of the active site histidine by p-bromophenacyl bromide. Their areas of interaction on the enzyme were further delineated using observations of chemical shift changes of assigned aromatic signals in the 1H-NMR spectrum of PLA2, while the bound conformations of two amine inhibitors were revealed using transferred nuclear Overhauser effects. The alkyl amines bind rather non-specifically on the surface of the enzyme, over the active site cleft and the interface recognition site.

Anthracyclines. Part 2. Investigations relating to the synthesis of 4-demethoxyanthracyclinones

Three strategies for the synthesis of suitably substituted tetrahydronaphthacenequinones related to the 4-demethoxyanthracyclinone series have been investigated. The first, involving conventional Friedel–Crafts annelation required 7-substitution processes at a late stage and proved unsuitable for larger scale preparations. The second and third procedures utilised cyclisation on appropriately substituted, performed A,B-bicyclic systems; they employed a benzeneboronic acid–phthalaldehyde condensation and a Diels–Alder reaction, respectively. The latter process used trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene to give the appropriate diene in situ. A practicable synthesis of (±)-4-demethoxydaunomycinone has been achieved by this route.

Anthracyclines. Part 3. The total synthesis of 4-demethoxydaunomycin

Procedures selected from our earlier work have been applied to the synthesis of (+)-4-demethoxydaunomycinone (10) and (–)-4-demethoxy-7,9-bisepidaunomycinone. 4-Demethoxydaunomycin has been prepared from the (+)-aglycone by specific glycosidation using 1-chloro-4-O-p-nitrobenzoyl-3-N-trifluoroacetyldaunosamine and silver trifluoromethanesulphonate as catalyst. Analogous glycosidation of the (–)-algycone has given 4-demethoxy-7,9-bisepidaunomycin whose properties differ from those previously reported.

Base catalysed rearrangement of N-alkyl-O-acyl hydroxamic acids: synthesis of 2-acyloxyamides

Activated N-alkyl-O-acyl hydroxamic acid derivatives 21a–t undergo thermal and base catalysed rearrangement to give 2-acyloxyamides 22a–t in good to excellent yields (50–100%). A range of inorganic and organic bases were screened for their efficiency in mediating the rearrangement 21 to 22, however, simple organic bases such as Et3N were found to be the most efficient. Both aromatic and aliphatic derived O-acyl groups were tolerated in the reaction. The electronic nature of the O-acyl group was found to effect the rate of the rearrangement with electron withdrawing groups (21l and 21o) increasing the observed rate and electron donating groups (21m and 21n) decreasing the observed rate. Cross-over experiments with 21a and 21h indicated a mechanism involving the intermediacy of free acyloxy anions. The requirement of a readily enolisable proton adjacent to the carbonyl group of the amide was found to be neccessary for the rearrangement as 21r and 21t both failed to rearrange under the reaction conditions investigated.

Total synthesis of 4-demethoxydaunomycin

The Diels–Alder adduct prepared from the optically active, fully functionalised bicyclic precursor (8) and o-benzoquinone dimethide has been converted in good yield into (+)-4-demethoxydaunomycinone (13), glycosidation of which with the daunosamine derivative (14) gives 4-demethoxydaunomycin.

Synthesis of α-hydroxy-β,β-difluoro-γ-ketoesters via [3,3]sigmatropic rearrangements

Readily available γ,γ-difluorinated allylic alcohols obtained from trifluoroethanol were esterified efficiently. Exposure to strong base (LDA) afforded the ester enolates, in which chelation both controlled configuration and stabilised against fragmentation, which were trapped as their silyl ketene acetals. Rearrangement occurred to afford base-sensitive acid products. Esterification under mild conditions afforded the purifiable methyl esters in which the masked ketone had been released. Educts with either a benzyloxy or an allyloxy group at the α-position could be deprotected releasing the alcohols.