3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors.

A chemo- and regioselective cross-coupling reaction of the functionalized aryl triflate 5 with octylmagnesium bromide catalyzed by cheap, nontoxic, and environmentally benign Fe(acac)(3) sets the basis for a practical and scaleable synthesis of the octylbenzene derivative 6, which serves as a key building block for the preparation of FTY720 (1). This 2-amino-1,3-propanediol derivative shows highly promising immunosuppressive properties and is currently in human clinical phase III trials.

General. NMR spectra were recorded with a Bruker DPX 300, AV 400, or DMX 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ C = 77.0 ppm; residual CHCl 3 in CDCl 3 : δ H = 7.24 ppm; CD 2 Cl 2 : δ C = 53.8 ppm; residual CH 2 Cl 2 in CD 2 Cl 2 : δ H = 5.32 ppm). Where indicated, the signal assignments are unambiguous; the numbering scheme is arbitrary and is shown in the inserts. The assignments are based upon 1D and 2D spectra recorded using the following pulse sequences from the Bruker standard pulse program library: DEPT; COSY (cosygs and Negishi carboalumination: Preparation of vinyl iodide 25.A solution of AlMe 3 (2.0 M in heptane, 21.2 mL, 42.4 mmol) was added to a suspension of Cp 2 ZrCl 2 (4.64 g, 15.9 mmol) in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of alkyne 24 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added dropwise. The resulting yellow solution was stirred for 24 h at ambient temperature before the mixture was cooled to −20°C and a solution of iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly added. After stirring for 20 min at −20°C and 30 min at 0°C, the reaction was carefully quenched with water (10 mL). A sat. aq. Na 2 SO 3 solution was then added and the layers were separated. The aqueous phase was extracted twice with CH 2 Cl 2 (40 mL each), the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. .7, 135.7, 134.0, 129.7, 127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 was added dropwise to a solution of epoxide 7 (7.6 g, 30.84 mmol) in toluene (25 mL) at −78°C over the course of 1 h. The temperature was then raised to −40°C and stirring continued for 4 h before the reaction was carefully quenched at −60°C with a solution of tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an icecold solution of Rochelle's salt (85g in 250 mL water) and vigorously stirred for 2 h until a clear separation of the phases was reached. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (hexanes:EtOAc, 1:1) to give product 8 as a

General. NMR spectra were recorded with a Bruker DPX 300, AV 400, or DMX 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ C = 77.0 ppm; residual CHCl 3 in CDCl 3 : δ H = 7.24 ppm; CD 2 Cl 2 : δ C = 53.8 ppm; residual CH 2 Cl 2 in CD 2 Cl 2 : δ H = 5.32 ppm). Where indicated, the signal assignments are unambiguous; the numbering scheme is arbitrary and is shown in the inserts. The assignments are based upon 1D and 2D spectra recorded using the following pulse sequences from the Bruker standard pulse program library: DEPT; COSY (cosygs and Negishi carboalumination: Preparation of vinyl iodide 25.A solution of AlMe 3 (2.0 M in heptane, 21.2 mL, 42.4 mmol) was added to a suspension of Cp 2 ZrCl 2 (4.64 g, 15.9 mmol) in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of alkyne 24 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added dropwise. The resulting yellow solution was stirred for 24 h at ambient temperature before the mixture was cooled to −20°C and a solution of iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly added. After stirring for 20 min at −20°C and 30 min at 0°C, the reaction was carefully quenched with water (10 mL). A sat. aq. Na 2 SO 3 solution was then added and the layers were separated. The aqueous phase was extracted twice with CH 2 Cl 2 (40 mL each), the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. .7, 135.7, 134.0, 129.7, 127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 was added dropwise to a solution of epoxide 7 (7.6 g, 30.84 mmol) in toluene (25 mL) at −78°C over the course of 1 h. The temperature was then raised to −40°C and stirring continued for 4 h before the reaction was carefully quenched at −60°C with a solution of tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an icecold solution of Rochelle's salt (85g in 250 mL water) and vigorously stirred for 2 h until a clear separation of the phases was reached. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (hexanes:EtOAc, 1:1) to give product 8 as a

Nature is a pretty unselective "chemist" when it comes to making the highly cytotoxic amphidinolide macrolides of the B/G/H series. To date, 16 different such compounds have been isolated, all of which could now be approached by a highly convergent and largely catalysis-based route (see figure). This notion is exemplified by the total synthesis of five prototype members of this family.Dinoflagellates of the genus Amphidinium produce a "library" of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making "non-natural" analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille-Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides.