Olivomycin

The A-B disaccharide moiety 247 was constructed by the glycosidation of the glycosyl acetate 244, which was prepared from the glycal 242 and the glycal 245 using I (iym-colhdine)2C104 as 

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Cblorotriruethylsilane-accelerated divinylcuprate addibon to enal 61, followed by a Wibig oleflnation, provided enoate 62 as a single stereoisomer in excellent yield (Sdieme 6.10) [23]. Hie enoate 62 cnUld be transformed in ftillher steps into olivin i63), die aglygon of olivomycin. 

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

Hydrolysis reactions are illustrated by the deacylation of colchicine (10) (amide hydrolysis), olivomycin A (29), Rifamycin B (46) or thymoxamine (52) (ester hydrolysis). The reduction of pentoxyfylline (32), zearalenone (56) or warfarin (65) are examples of the common reduction of keto groups, generally affording, with a high stereospecificity, one of the alcohol stereoisomers. 

Finally, the 4 -benzoate function was also saponified. The unblocked 3, 4 -diol component did indeed undergo a smooth NIS glycosylation with tfie L-olivomycal This occured regiospecifically in overall 64% yield with formation of only the interglycosidic (l"->3 )-linkage and also proceeded stereospecifically towards the a-glycoside with respect to the terminal saccharide. The E-D-C derivative was further hydrogenated to the trisaccharide unit 39 of chromomycin As (22) and olivomycin A ). ""... 

Syntheses of each of the sugar residues in olivomycin A from commercially available carbohydrate precursors were known at the time our studies were initiated.30.3 We elected not to synthesize these compounds via literature procedures, however, since we felt that totally synthetic methods might provide a more convenient and general solution,... 

Our development of the tartrate ester modified allylboronates c.h suggested to us that many of these problems could be avoided by using the reaction of a chiral aldehyde and a chiral allylboronate as a means of establishing the stereochemistry of the sugar backbone. This strategy has been used in our synthesis of the AB disaccharide unit of olivomycin A (Figures 16, 17).3 ... 

The synthesis of disaccharide 61 is reasonably efficient (10 steps from 53,17% overall yield) and is readily amenable to scale up. Nevertheless, in contemplating extensions of this chemistry to the synthesis of differentially protected derivatives of D-olivose (e.g., 63, Figure 18) needed for construction of the olivomycin CDE trisaccharide, it became apparent that this approach is unattractive because the required starting... 

Figure 15. Reactions of epoxyalcohol intermediates in synthesis of olivomycin monosaccharides.

We began these studies with the intention of applying this tandem asymmetric epoxidation/asymmetric allylboration sequence towards the synthesis of D-olivose derivative 63 (refer to Figure 18). As the foregoing discussion indicates, our research has moved somewhat away from this goal and we have not yet had the opportunity to undertake this synthesis. This, as well as the synthesis of the olivomycin CDE trisaccharide, remain as problems for future exploration. Because it is the enantioselectivity of the tartrate ester allylboronates that has limited the success of the mismatched double asymmetric reactions discussed here, as well as in several other cases published from our laboratorythe focus of our work on chiral allyiboronate chemistry has shifted away from synthetic applications and towards the development of a more highly enantioselective chiral auxiliary. One such auxiliary has been developed, as described below. 

The method was used for oxidation of an unsaturated nitrile (1) to an aromatic acyloin (2) in a projected synthesis of a model for olivin (4), an aglycone of olivomycin antibiotics.2... 

For the synthesis of Olivomycin A. the Roush group used a crotyl ether to protect a phenolic hydroxyl group,42 In the final lap of the synthesis, deprotection of the phenolic crotyl ether in 226.1 was achieved with Pd(0) and tributylstan-nane [Scheme 4.226]. No harm befell the sensitive cyclopentylidene acetal and chloroacetate groups. 

Raney nickel is occasionally used as a catalyst for the cleavage of BOM ethers and it will remove a BOM ether without detriment to a / -methoxybenzyl ether, Roush and co-workers used Raney nickel in its traditional role as a desuifurisa-tion agent and as a hydrogenation catalyst in order to remove two phenylthio ethers, one phenylseleno ether and a BOM group in the penultimate step of a synthesis of Olivomycin A [Scheme 4.276].428... 

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