Tetracyclic anthracyclinone

A novel route to anthracyclinones is based on the chemistry of quinone-isobenzofuran adducts (77TL3537). The 3-methoxybenzyne-furan adduct (1) was reacted with a-pyrone to give a mixture of lactones (2). Thermolysis of this intermediate in the presence of quinone (3) gave in 93% yield the tetracyclic adduct (4) as a stereoisomeric mixture. Aromatization with sodium acetate in acetic acid gave quinone (5) which was subjected to reduction, C-ring oxidation and mild acid hydrolysis to afford a mixture of ( )-7-deoxydaunomycinone (6) and its 1-methoxy regioisomer (Scheme 1). 

Intramolecular Marschalk reactionAn intramolecular Marschalk reaction (9, 376) can be used to effect a synthesis of anthracyclinones from anthraquinones. Thus the a-hydroxy aldehyde 2, formed on saponification of the a-hydroxydichloride 1, on reduction of the quinone group cyclizes in the alkaline medium to the tetracyclic trans- and cw-diols (3 and 4) in about equal amounts. Cyclization under phase-transfer conditions results in improved yields and, more importantly, can alter the stereoselectivity. Triton B is the most effective catalyst for stereoselective cyclization to the desired natural trans-diol. 

Hauser has used repetitive annelations of this type tor synthesis of linear aromatic systems. This methodology provides a simple regiospecific route to the tetracyclic system of the antibiotic anthracyclinones. For this purpose 5-ethoxy-2(5Ff)-furanone (2) is used as the Michael acceptor in the first annelation of the anion of 1. After methylation, 3 is obtained in 65% yield. It is then converted into 4, for a second annelation with cyclohexenone or a derivative (5). The reaction results in a tetracyclic hydronaphthacene 6. 

Enantioselective dihydroxylations [59] and epoxidations [60] of various other tetracyclic systems related to anthracyclinones have also been studied. 

Enantioselective syntheses of anthracyclinone tetracyclic intermediates or AB building blocks have also been carried out by Diels-Alder reactions uti-... 

Chiral precursors have been also used for the preparation of enantiopiu-e dienes utilized in the construction of an AB segment [175] and a tetracyclic moiety [176] of the anthracyclinones. 

There has been further activity in the use of sugars as precursors for the A ring of anthracyclinones. The aldehyde (3), previously reported (Vol. 18, p, 248), has been prepared by an improved procedure and converted into (4), a suitable intermediate for an AB + CD approach to the tetracycle. Similar routes to those described earlier (Vol. 18, p. 248) have been used in the synthesis of (5), containing the key tertiary carbinol function, from diiso-propylidene glucose via a Marschalk reaction, and earlier work has... 

On treatment with dilithio phenolate 455, attack mainly took place at the more hindered carbonyl group of the anhydride and led to diester 456 in a 95 5 ratio [156]. Hydrogenation followed by Fries rearrangement converted 456 into the tetracyclic ring system of the anthracyclinones (see 457). 

---