An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

Abstract

An efficient and highly stereoselective synthesis of cytotoxic 8-epipuupehedione (1b) was achieved starting from natural (-)-drimenol (6). The key step to obtain stereoselectivity was the simultaneous demethylation and oxidation of the dihydrobenzopyran methoxy derivatives 10a and 10b.Marine sponges are recognized as a rich source of structurally unique and biologically active terpenoids. 1 Puupehedione (1a) was isolated from a sponge of the order Verongida and was characterized as a metabolite featuring a sesquiterpene unit joined to a shikimate-derived moiety. 2 The cytotoxic activity of 1a and its synthetic, non-natural, 8-epimer 1b was assayed against the cell lines P-338, A-549, 3 and the most active compound was found to be 8-epipuupehedione (1b).The syntheses previously reported for 1a and 1b 3,4 were based on electrophilic cyclization of suitable intermediates to the respective dihydrobenzopyrans as methylenedioxy derivatives (2a and 2b), followed by oxidative cleavage of the methylenedioxy moiety. As we have previously established, 3 the oxidative process involves ring opening and subsequent cyclization to obtain 1a and 1b in the same 1:4 relative proportion, independent of the C-8 epimeric ratio for the starting methylenedioxy derivatives.Our strategy here involves nucleophilic addition of the organolithium derived from 5 to drim-7-en-11-al (7), 5 easily available from natural (-)-drimenol (6) 6,7 (Figure 1). The aromatic synthon 5 was prepared in high yield from 3,4-dimethoxybenzaldehyde (Figure 2). Addition of aldehyde 7 to the aryllithium derived from 5, and subsequent deprotection of the silyl ether, afforded 8/9 in a ratio of 3:1 ( 1 H and 13 C NMR). Acid-mediated cyclization of the mixture gave 10a and 10b in a ratio of 1:3. Simultaneous demethylation and oxidation of the epimeric dihydrobenzopyrans 10a(C 8 -Me R ) and 10b(C 8 -Me ) with AgO-HNO 3 8 led to o-quinones 1a and 1b (1:3). A further straightforward route was studied. Direct treatment of the condensation product with acid, without previous deprotection of the tert-butyldimethylsilyl ether, afforded 10a and 10b in a ratio 1:8.Simultaneous demethylation-oxidation of the mixture gave the epimeric 1a and 1b (1:8). The relative proportion was the same as that obtained for the dihydrobenzopyran methoxy derivatives, since the well-known reaction with AgO in acid medium 8 avoids ring opening, due to very fast oxidation. These results suggest that, under acidic conditions, the main product arises from attack on the less hindered R side, and the epimeric ratio seems to depend on the effective free nucleophilic group.The present work represents the shortest and most efficient synthesis for the highly bioactive 8-epipuupehedione (1b).

Synthesis and Cytotoxic Activity of Geranylmethoxyhydroquinone Derivatives

“…Our first objective was the preparation of compound (9) from commercially available asaronaldehyde (7). The first step involves a Baeyer Villiger oxidation reaction and subsequent saponification of formate 8 24 , according to the synthetic route shown in scheme 1. The formation of compounds 1 and 2 was not possible to explain it by the EAS strategy, probably the coupling reaction ocurred from a different pathway, competing with the EAS.…”

Pleiotropic Role of Puupehenones in Biomedical Research

“…Concerning the synthesis of 8-epipuupehedione, different approaches have also been described. After the report of Álvarez-Manzaneda et al [ 18 ], the same group described the synthesis of this molecule using natural drimenol as the initial molecule [ 20 ]. Moreover, 8-epipuupehedione and puupehedione syntheses were previously described through concomitant O -allyl deprotection and electrocyclization of an intermediate dione molecule derived from (−)-carvone [ 21 ].…”

Synthesis of Fluorinated Aromatic Compounds by One-Pot Benzyne Generation and Nucleophilic Fluorination

“…Rf: 0.2 (hexane/EtOAc = 5:1). 1 Table 2, entry 1): An oven dried recovery flask (100 mL) was charged with tbutyldimethylsilyl 2-bromo-4,5-dimethoxyphenyl ether [5] (3.6 g, 10 mmol) and capped with an inlet adapter with a 3-way stopcock and then evacuated and back-filled with argon. Anhydrous THF (35 mL, 0.30 M) was added via syringes and cooled down to -78 ºC.…”