Syntheses of Novel Anthracyclines with Chiral Dioxanes

Abstract

Lewis acids promoted cyclisations of the chiral ortho allyl C-2 and C-1 anthraquinonyl dioxanes has been investigated. Titanium tetrachloride mediated cyclisation on chiral ortho allyl C-2 dioxanes 156 and 206 produce diastereomerically pure anthracyclines [157 (7R,9R) (64%) and 158 (7R,9S)(6%)] and [294 (7s,9s) (8%), 295 (7s,9R) (17%),296(7R,9R) (12%) and 297(7R,9S) (28%)] respectively, with retention of the acetal side chains in the products. These anthracyclines were converted into their respective tetracyclic C7-alcohols (313 and 315) and (302,303,304 and 305) by applying a two step oxidative-elimination procedure and the absolute stereochemistries were assigned to these products using a combination of X ray, ID and 2D NMR. Titanium tetrachloride mediated cyclisation of the chiral ortho allyl C-1 dioxane 210 gave a pair of tetracyclic cis disubstituted (313+314) (39%) (+0.091°) and trans disubstituted (315+316) (23%) (-18.8°) C7-alcohols. A similar reaction with its monomethoxy analogue 211 yielded a pair of tetracyclic cis disubstituted (302+304) (25%), trans disubstituted (303+305) (65%) (+3.78°) C7 tetracyclic alcohols and a product with the appended side chain (308 or its diastereomer 309) (l0%). A small diastereoselectivity observed in generating chirality at the C7 centres of all these tetracyclic C7-alcohols suggest that the C-1 symmetrical dioxanes are poorer chiral templates than its analogous C-2 equivalent. An alternative route to prepare the precursor for the synthesis of 156 and 210 has been investigated. Aldehyde 332 was prepared from quinizarin 26 in an 8 step pathway which involved a selective cis dihydroxylations a key step. This route allowed the possibility of attaching the expensive chiral diols 107 and 108 to the aldehyde 332 in the last step of the synthesis prior to intramolecular cyclisation with titanium tetrachloride. Attempts to synthesize 385-388, the potential precursors for the synthesis of 4- demethoxyfeudomycinone 382 were unsuccessful. The ester acetals 383 and 384 were unreactive towards the titanium tetrachloride promoted attack of the silyl enol ether 389. Similarly attempt to react silyl enol ether with the ester acetal 398 was unsuccessful. An attempt was made to determine if the factors contributing to this failure of the C. 1(398) or the C-2(383 and 384) ester-dioxanes to reach with the silyl enol ether in the presence of titanium tetrachloride were sterically related. The dimethoxy acetal without the bulkier ester ortho substituent 399 was synthesized and subjected to the same reaction conditions and its reactivity was found to be centered at the quinone carbons.