Synthesis of Biologically Active Nonnatural Palmarumycin Derivatives

Abstract

Diels–Alder reaction of benzoquinone monoacetal 1 with 1‐methoxy‐1,3‐butadiene (4) and dimethyl(1‐methyl‐3‐vinylcyclohex‐3‐enyl)(phenyl)silane (5) gave the expected adducts 2 and 3, whereas with siloxy‐dienes such as 3‐methyl‐1‐(trimethylsiloxy)‐1,3‐butadiene (6) a 1,2‐aldol‐type adduct 9 was isolated. The Diels–Alder adduct 2 was isomerized under mild basic conditions to the olefin 10 and eliminated to the diene 11 under mild acidic or thermal conditions. The olefins 2, 10 and 11 were subjected to epoxidation with m‐chloroperbenzoic acid and tert‐butyl hydroperoxide under mild basic conditions to afford the epoxides 12, 15, and 18 under the former conditions and 13, 14, 16, 17, 19, and 20 under the latter conditions. The olefins 1, 2, 10, 11, and 20 were also transformed into the respective cis‐diols 21a and 23a–26a. From theses diols the corresponding diacetates (b) andacetonides (c) were prepared. The compounds were tested against the Gram‐negative bacterium Escherichia coli, the Gram‐positive bacterium Bacillus megaterium, and the fungus Microbotryum violaceum. Whereas compound 25b was the most active of the diacetates and the epoxide 18 the most active of all substances, all of the compounds were biologically active against the three test organisms, equalling and surpassing those of the natural palmarumycins.

Total Synthesis and Antifungal Activity of Palmarumycin CP17 and Its Methoxy Analogues

“…This was followed by a reported catalytic asymmetric approach to construct the tertiary naphthoquinol stereogenic center present in the spiroxin framework [25]. Since the first synthesis of racemic spiroxin C and several preussomerin analogues, there have been no new syntheses of Type B and C spirobisnaphthalenes since 2004, due to their synthetic complexity [19,20,24], so attention remained focused on elaborations of the type A class and their bioactivity evaluation [16][17][18].…”

“…Although the total syntheses of a range of similar palmarumycins, including CP 1 , CP 2 and CJ-12371, was accomplished by direct acetalization as the key step [31][32][33][34][35], the existence of the sensitive 8-hydroxyl or 8-chlorine substituents found in type A spirobisnaphthalenes such as CJ 12372, ascochytain, palmarumycin B 6 , CP 17 , and CP 18 offer a new challenge. In order to gain insights into the structure-activity relationships of both natural and non-natural spirobisnaphthalenes, we have used the direct acetalization approach, following the synthetic protocol of preussomerin G and I [31,32,36], to complete the total synthesis of palmarumycin CP 17 (6a), its 8-methoxy analogue (6b), and 5,8-dimethoxy CJ 12372 (8) as well as the other 6-methoxy,7-methoxy and 6,7-dimethoxy spirobisnaphthalene derivatives (18)(19)(20) (Schemes 2-4). These compounds were then evaluated for their antifungal activities.…”

“…Since then, several new spirobisnaphthalene natural products have been isolated and the total syntheses of some of these have been accomplished by different research groups. In addition, many non-natural derivatives have been prepared by synthesis and evaluated for their biological activities [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The spirobisnaphthalenes isolated from fungi along with their biological activities were further reviewed in 2010 [19,20].…”

Spirobisnaphthalenes effectively inhibit carbonic anhydrase

“…The spirobisnaphthalenes are a growing group of fungal secondary metabolites, which contain two 1,8-dihydroxynaphthalenederived units bridged through a spiroketal linkage. This group could be mainly classified as spairoxin, preussomerin, palmarumycin and urnucratin-type spirobisnaphthalenes, according to their structural features 51,80 . The chemical formula of spirobisnaphthalenes, which are used in this study, are given in Figure 1.…”

“…At present, strong CAIs have been discovered using modified moieties such as sulfonamide or sulfamate among others 50 . The synthesis of spirobisnaphthalenes derivatives (1-16) was performed as described previously 51 . In this study, we have examined the inhibition effects of spirobisnaphthalenes derivatives (1-16) against the both human cytosolic CA isoforms (hCA I and II).…”