Asymmetric synthesis using 4,4,6-trimethyl-1,3-dioxanes

Abstract

(2'R,6'R)-2'-Anthraquinonyl-4',4',6'-trimethyl-l',3'-dioxanes 132, 133, and 134 were synthesized from quinizarin 29 in optimized yields of 64, 56, 65, and 69%, respectively via reductive Claisen rearrangements of the appropriate allyloxy anthraquinones.A mechanism for the rearrangement has been proposed on the basis of experimental outcomes. The acceleration of the rearrangement under reductive conditions is proposed to be a consequence of internal hydrogen bonding in the activated quinone. Lewis acid mediated cyclizations of the chloroallyl dioxanes 131 and 132 were accomplished using neat titanium(IV) chloride and gave anthracyclinones 267, 268, 270, and 271 directly, but with poor selectivities. However, the dropwise addition of a solution of titanium(IV) chloride in dry dichloromethaneto 134 at -82"C generated anthracycline 282 in 67% yield. The reaction proceeded with good regio- and stereoselectivity. It was concluded that the direct synthesis of anthracyclinones in such reactions requires conditions which are incompatible with those necessary for highly selective carbon-carbon bond formation. The regio- and stereoselectivity of 282 was unambiguously determined on the basis of the 2D NMR data. The intermolecular additions of allyltrimethylsilane to 2-hexyl- and 2-phenyl-4,4,6-trimethyl-1,3-dioxanes 293 and 294 were investigated under varying reaction conditions. Homoallylic alcohols were generated directly from titanium(lV) chloride mediated allylations of 293 but the stereoselectivities of the reactions were poor. Milder Lewis acids did not efficiently promote the reaction. It was concluded that 4,4,6-trimethyl-1,3- dioxanes have little potential as chiral auxiliaries for the asymmetric synthesis of homoallylic alcohols. The interactions between dioxanes 293, 294, 313, and 314 and Lewis acids were investigated at -80, -100 and- 120"C. It was demonstrated that the trimethyl dioxanes are relatively unreactive towards Lewis acids and that the presence of an equatorial hydrogen at C2 or C4 of a dioxane ring is necessary for the selective formation of a stable 1:1 BF3-acetal complex. These results strongly suggest that Lewis acid mediated openings of trimethyl dioxanes are unlikely to proceed with high selectivity. The good selectivities observed in cyclizations of 282 were proposed to be a consequence of the overall conformation of the highly functionalized anthraquinone 134.