Unified Route to the Palmarumycin and Preussomerin Natural Products. Enantioselective Synthesis of (−)-Preussomerin G

Abstract

The total syntheses of eight members of the palmarumycin family have been achieved, with identification of the absolute stereochemistry for three of these natural products. In addition, the ras-farnesyl transferase inhibitor (-)-preussomerin G has been synthesized, achieving the first enantioselective route for accessing this family of natural products. Highlights of the synthetic work include an asymmetric epoxidation of a cyclic enone in excellent yield and enantiomeric excess and a potentially biomimetic oxidative spirocyclization for the introduction of the bis-spiroketal array unique to the preussomerin natural products.

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

“…These include a biomimetic synthesis by oxidative cyclization to the binaphthyl ether [29,30], direct acetalization [31,32], a silver-mediated cationic cyclization following Suzuki-Miyamura cross-coupling [33], and a Diels-Alder approach in combination with the biomimetic oxidative cyclization of naphthyl phenyl ether [16]. 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).…”

Cleavage of Phosphodiesters and of DNA by a Bis(guanidinium)naphthol Acting as a Metal‐Free Anion Receptor

“…Starting from dibromotoluidine 13, [13] the cyano and iodo substituents of intermediate 14 were introduced in a Rosenmundvon-Braun reaction, [14] followed by Sandmeyer replacement. Oxidation and esterification then led to 15, a compound activated for nucleophilic displacement of iodide by the naphthol [15] moiety. Boc-protected diamine 17 was obtained by catalytic hydrogenation of the nitriles.…”

“…A solution of 1,8-dihydroxynaphthalene (1 g, 6.2 mmol) in dry DMF (8 mL) was added slowly, and the resulting mixture was stirred for an additional 30 min. A solution of 19 [15] (1.6 g, 6.2 mmol) in dry DMF (8 mL) was added dropwise, and the mixture was heated (90 8C, 6 h). The solution was cooled to room temperature and quenched by pouring into ice-cooled aqueous HCl (30 mL, 1 m).…”

Flexible Route to Palmarumycin CP1 and CP2 and CJ‐12.371 Methyl Ether

“…The data of the synthetic product were identical to those of the natural product. [11,31] CJ-12.371 Methyl Ether (17): A solution of 16 (102 mg, 0.31 mmol) in ethyl acetate (7.0 mL) was treated with Pd/C (10 %, 30 mg), and the suspension was stirred under hydrogen (atmospheric pressure) for 12 h. The catalyst was filtered off, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography over silica gel (3.0 g) to afford 17 [8] Palmarumycin CP 2 (5): To a solution of 18 (25 mg, 0.074 mmol) in dry dichloromethane (2.0 mL) was added dropwise at -78°C a solution of BBr 3 (1.0  in DCM, 0.15 mL). The initially pale yellow solution turned red as the addition proceeded.…”

“…The data of the synthetic material were identical to those of the natural product. [11,31] Crystal Structure solved by direct methods, [43] full-matrix least-squares refinement [43] with 4031 independent reflections based on F 2 and 227 parameters, all but H atoms refined anisotropically, H atoms from difference Fourier maps refined with riding model on idealized positions with U = 1.5 U iso (methyl-C) or 1.2 U iso (C). Compound 15 crystallizes in the noncentrosymmetric space group Pna2 1 ; however, in the absence of significant anomalous scattering effects, the Flack [44] parameter is essentially meaningless.…”