Synthesis of Siloxy-α-Lapachone Derivatives by Chemo- and Regioselective Diels-Alder Reactions of 3-Methylene-1,2,4-naphthotriones with Silyl Enol Ethers

Abstract

o-Quinone methides, generated in situ from the Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with aliphatic and aromatic aldehydes, take part in chemoselective hetero-Diels-Alder reactions with silyl enol ethers to give a series of siloxy-containing naphtho[2,3-b]pyran-5,10-dione (a-lapachone) derivatives in moderate to high yield. These reactions regioselectively gave a-lapachone derivatives with an acetal structure. This regioselectivity can be rationalized by considering the frontier molecular orbital interactions of the o-quinone methide with the silyl enol ether, and by taking into account the energetically more favorable pathway leading to a zwitterion-like transition state of lower energy in a Michael addition between the two reactants.Naturally occurring naphthoquinones comprise an important class of natural products with a wide range of biological activity 1,2 arising from their ability to cause DNA modification via redox cycling of the quinone moiety and the generation of reactive oxygen species. 2c,3 In the structurally diverse naphthoquinone natural products, dihydropyranonaphthoquinones (a-and b-lapachones) have attracted special attention because of their promising antitumor ability, 4 among various other bioactivities. Heterocyclic naphthoquinones of the lapachone family are found as minor components in the stem bark of many trees of the Tabebuia genus in Central and South America. 5 a-Lapachones have a wider distribution than b-lapachones, and are additionally found in Ekmanianthe longiflora in America 6 and in Capalta ovata trees in many east Asian countries. 7 Of these pyranonaphthoquinones, b-lapachone derivatives have so far received the most extensive investigations, mainly owing to their stronger antitumor activity. 8 However, more recent investigations have shown that a-lapachone is an effective DNA topoisomerase II inhibitor and is a potential lead compound for the development of drugs for the treatment of multidrug resistant cell lines with low expressions of topoisomerase II. 9 In addition, alapachone derivatives possess their own special biological activities ranging across antibacterial, 10 antipsoriatic, 11 antifungal 12 and trypanosidal 13 activity. Furthermore, in the recently rapidly developing research area of cancer chemoprevention as a promising tool in cancer control, 14 quinone compounds have proven to be one of the most important classes of potential cancer chemopreventing agents (antitumor promoters). 15 Extensive studies of a large variety of quinone compounds points to the 1,4-and 1,2-naphthoquinones, including a-and b-lapachones, as privileged structures, 16 with the 1,4-naphthoquinones having great cancer-preventing potential. 17 Structureactivity relationship studies in lapachones have shown that structural modification to the redox center (the quinone functionality) 13a and the C-ring, 13a,16b leads to significant changes in bioactivities and are important in the search for possible lead compounds with more potent pharmaceutical activity and less toxicity. L...