Daunomycinone derivs

Daunomycinone derivatives Demethylation Corresponding demethylated Carminomycinone derivatives Sepedonlum chrysospermum Beauveria sulfurescens... 

As illustrated, glycosylation of the daunomycinone derivative 152 with the L-daunosamine p-nitrobenzoate 151 afforded the glycoside 153 as only the a-isomer in a 99% yield. This was deprotected giving 4-demethoxydaunorubicin 154. 

This alkylation methodology has been employed in the synthesis of enantiomerically pure daunomycinone derivatives (Scheme 28). The AB building block 215 is constructed by alkylation of 170 with 2,5-dimethoxybenzyl iodide (208) to give 209 followed by cyclization of 210 to the tetralone 211 [75]. Selective reduction of the ketone with zinc borohydride gives a mixture of alcohols, 45% of the a-OH (212) and 36% of the corresponding j5-OH. 

Oxidation of 215 with CAN produces naphthoquinone 216 which, in a single cycloaddition step with bisketenes generated photochemically from 1,2- benzocyclobutanediones 217, gives daunomycinone derivatives 218 [76]. 

Synthetic approaches to anthracycline antibiotics have been reviewed. Several papers report syntheses of daunorubicin analogues by the glycosidation of daunomycinone derivatives with amino-sugars glycosides of daunomycinone have been prepared from 3-epf-L-daunosamine, D-acosamine, D-daunosamine, D-ristosamine, and 3-ep(-D-daunosamine, and 4-demethoxy-9-deoxy-9-methyl... 

New anthracycline antibiotics rubomycins F and H, isolated from S. coeruleorubidus along with other daunomycinone derivatives, have been shown to be A -acylated derivatives of daunorubicin. Rubomycin M and N are disaccharide derivatives of daunomycinone, having a daunosamine unit glycosylated at C-4 with either of two 2,6-dideoxy-L-hexopyranoses. 

Similar results are obtained with the /htetralone derivatives 12, which are useful building blocks in the synthesis of anthracycline antibiotics. Furthermore, the usefulness of the diastereoselec-tive addition to ot-oxo acetals was impressively demonstrated in the synthesis of (-)-7-deoxy-daunomycinone, which uses the completely stereoselective addition of (trimethylsi-lylethynyl)magnesium chloride to the /i-tetraione acetal 12 (R =OMOM R2 = Br) as the key reaction31. 

This is also the reason for the many attempts to introduce one or more additional carbohydrate moieties. Reaction of daunomycinone with diols providing its 7-0-hydroxyalkyl derivatives enabled attachment of the sugars in a different manner leading to derivatives with lower toxicity [48]. 

A 5-deoxy derivative of the above compound has been synthesised in 84% yield as an intermediate towards daunomycinone from the cyclopropane depicted by treatment at ambient temperature in acetic acid with a catalytic quantity of boron trifluoride etherate (ref 189). 

Furanoside analogues of daunorubicin or adriamycin have been prepared, derived from D-ribofuranose and daunosamine the latter sugar coupled to daunomycinone gave compounds which were less active than the pyranosyl analogue, but were much. less toxic and... 

The 7-0-j3-D-glucosamine derivative of daunomycinone was the first compound prepared in which the daunosamine residue is replaced [70]. The compound is however inactive in vivo [223] due to its inability to bind to DNA [213]. Esterification of the 7-OH group of daunomycin has also been attempted, for example compounds (89-93) show some activity in vivo [86,224]. It is interesting to compare the related compounds (94) and (95). The latter appears to have the greater degree of cellular penetration since it is about three times more active as an inhibitor of cellular nucleic acid synthesis, yet it shows no in vivo activity whereas compound (94) shows low activity [72]. The simpler analogue (95) therefore has an unfavourable distribution or is more rapidly hydrolysed. 

Other antibiotics of the an-thracyclinone group are derived from aglycones of the daunomycinone type by glycoside formation with various sugars [(5]. The available evidence for their absolute configurations has been summarized [d]. 

A review of the synthesis of anthracyclinones by elaboration of anthraquinones includes a section on the use of sugars as chiral templates. Glycosylations of the daunomycinones (46)-(48) led to the corresponding daunomycin derivatives (49)-(51). The L-fyxo-, L-arabino- and L-nfeo-isomers of the isorhodomycin compounds (52) have been made and tested for cytotoxicity. Several analogues of the anthracycline antibiotics, eg. (53), having a 1,2,3-triazolyl moiety in the sugar, have been described. ... 

The 2-fluoro-daunosamine derivative (7) has been coupled to daunomycinone to give, after deprotection,... 

Deoxy-2-0-methyl-of-L-talopyranosyl derivatives of daunomycinone and adriamycinone, made by standard procedures from a fucose precursor, show improved antitumour activity compared with daunorubicin... 

D-Quinic acid has been converted into the cyclitol derivative (71) a precursor in a synthesis of daunomycinone. ... 

Daunomycinone has been prepared by asymmetric synthesis using a benznaphthaquinone derivative in Diels-Alder reaction with a... 

Epoxide (25), derived from L-fucose, was opened with KHF2 in ethylene glycol to give the 2-fluoro sugar (26) which was converted to the talo-isomer (27) and coupled with daunomycinone to give an... 

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