Novel anthracyclines from anthraquinone cyclisations

Abstract

Lewis acid mediated cyclisations of ortho-allylated anthraquinonyl l,3-dioxanes and l,3-dioxolanes have provided new mechanistic insights into substitution reactions at C2 as well as asymmetric syntheses of a variety of novel anthracyclines. Anthraquinones envisaged as containing a putative enediyne moiety have been synthesised, and their antibacterial properties tested. Titanium(IV) chloride mediated cyclisation of the ortho-methoxylated l,3-dioxane (31) gave a high yield of the 7R-chlorotetracycles (101) and (102)(10:1) which are epimeric at C9. The exclusive formation of the 7R stereochemistry has been explained as resulting from SN2-like attack of the olefin on a chelate involving the ortho-methoxy group and the dioxane ring. Ion pairing also plays a major role in determining the C9 stereochemistry, with internal delivery of a chloride giving the major product (101). The presence of a hydroxy group meta to the l,3-dioxane as n (27) did not affect the C7 stereoselectivity but gave a C10 substituted product (86), as well as the C9 chlorotetracycles (89) and (90), indicating that carbocation rearrangements are involved in some cases. The use of a methylpropenyl side chain has a profound effect on the C7 stereoselection, indicating that the increased steric requirement of this side chain inhibits the chelation controlled pathway. It is proposed that whereas the tin(IV) chloride mediated reaction of the l,3-dioxane (32) proceeds via an ion pair in which the tin is monodentately coordinated, reaction using titanium(IV) chloride with this substrate occurs via an oxocarbenium ion. Novel fluorine containing anthracyclines resulted when boron trifluoride etherate was used, but trimethylsilyl triflate proved unsatisfactory. 2,3-Alkynyl anthraquinones which can be envisaged as containing an enediyne moiety were synthesised, and their behaviour under Bergmann type cyclisation conditions studied. Also cyclisation reactions of 2,3-bis(propenyl)anthraquinones were investigated and yielded a number of products. Mechanisms for the formation of most of these products have been proposed. Other 2,3-bisallylated anthraquinones were synthesised by reductive Claisen rearrangements of the mixed allyl ethers, (292) and (313). Novel ethoxyiodomethyldihydro- and iodomethyl- furans like (350) and (356) were produced from reactions of chloroallyl substituted anthraquinones with iodine.