A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All the hydroxy groups in the scaffold were stereoselectively introduced, and a modified reducing reagent, Me 4 NBH(O 2 C i Pr) 3 , has been developed. The sugar moiety fragment was prepared via three consecutive carbon−oxygen bond-forming reactions, and the glycosylation was accomplished using Wan's protocol.C otylenin A (Figure 1) was initially isolated as a plant growth regulator; 1 however, biological studies later revealed that it induces the differentiation of murine and human myeloid leukemia cells and the apoptosis of a wide range of human cancer cell lines by combined treatment with interferon-α. 2 The crystal structure of cotylenin A in a complex with 14-3-3 protein and a phosphopeptide of H + -ATPase (QSYpTV-COOH) has been reported 3 to confirm that cotylenin A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259 but not the activating interaction site, pSer621. Moreover, the combined treatment of cotylenin A with an anti-epidermal growth factor receptor antibody is reported to synergistically suppress tumor growth in vitro and in vivo, which provides a novel pharmacologic strategy for treatment of RAS mutant cancers. 4

The asymmetric Mukaiyama-Michael reaction of cyclic α-alkylidene β-oxo phosphates and phosphine oxides that proceeds in a highly enantioselective manner is described. It is possible to carry out these reactions using a catalytic amount of a bisoxazoline-Cu(II) complex without decreasing the enantioselectivity, and one of the products has been successfully used for the first enantioselective synthesis of (R)-homosarkomycin.

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General Information. 1 H and 13 C NMR spectra were recorded on a JEOL AL-400 spectrometer or a JEOL ECZ500R spectrometer. Chemical shifts are reported in ppm with the residual solvent resonance as internal standard (CDCl 3 1 H, δ = 7.26 ppm, 13 C, δ = 77.16 ppm). The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sep, septet; br, broad. IR spectra were recorded on a JASCO FT/IR-8300. Optical rotations were measured using a 2 ml cell with a 1 dm path length on a JASCO DIP-1000. Mass spectra and elemental analyses were provided at the Materials Characterization Central Laboratory, Waseda University. All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions, unless otherwise noted. Melting point (mp) is uncorrected, recorded on a Yamato capillary melting point apparatus. Chiral HPLC analysis was performed on a JASCO PU-980 and UV-970 detector. Chiral gas chromatography analysis was performed on capillary column RT-γ-DEXsm, SUPELCO, 30 m×0.25 mm×0.25 μm at 150 °C constant, pressure: 138 kPa, column flow amount: 2.50 ml/min, line speed: 53.9 m/s, ratio of sprit: 40.0, total flow amount: 106 ml/min, SPRIT, and career gas was He. All reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and phosphomolybdic acid and heat as developing agents. E. Kanto Chemical Silica Gel 60N (spherical, neutral, 63-210 μm or 40-50 μm partial size) was used for flash chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on self-made 0.3 mm E. Merck silica gel plates (60F-254). TLC Rfs of purified compounds were included. Materials. THF and Et 2 O were distilled from sodium/benzophenone ketyl, and CH 2 Cl 2 , benzene, and hexane from calcium hydride. DMF and DMSO were distilled from calcium hydride under reduced pressure. Toluene and EtOH were distilled from sodium. MeOH was distilled from magnesium and I 2. All reagents were purchased from Aldrich, TCI, Merck, or Kanto Chemical Co. Ltd.