Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and apoptolidin is one of them. The known synthetic routes to apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.

Using a combination of chiral monodentate phosphoramidite ligands in the rhodium-catalyzed conjugate addition of boronic acids to three different substrates, we have shown for the first time that the ligand combination approach is applicable for C−C bond formation. Chiral catalysts based on hetero-combinations of ligands are found to be more effective than the homo-combinations. 31 P NMR experiments show that the hetero-combinations are formed in excess over the homo-combinations.

Silylnitrilium (6) and Silyloxonium (7) ions have been synthesized by reaction of 2,3-benzo-1,4,5,6,7-pentaphenyl-7-silanorbornadiene, 4, with trityl tetrakis(pentafluorophenyl)borate in benzene in the presence of acetonitrile and diethyl ether, respectively, and have been identified by NMR spectroscopy, supported by density functional calculations of the NMR chemical shift. Solvent-free 2,3-benzo-1,4,5,6,7-pentaphenyl-7-silanorbornadien-7-ylium, 3, could not be detected under the applied conditions (room temperature, aromatic hydrocarbons or -60 °C, dichloromethane). The results of density functional calculations for the model compound 2,3-benzo-7-phenyl-7-silanorbornadien-7-ylium, 8, and isomeric C 16 H 13 Si + species suggest that 3 undergoes in hydrocarbon solution a facile exothermic rearrangement to the highly reactive π-type complex PhSi + //tetraphenylnaphthalene.

The total synthesis of apoptolidin A is described employing an early glycosylation strategy. Strategic disconnections were chosen between C11-C12 (cross-coupling) and C19O-C1 (macrocyclization). The cis-selective glycosylation at C9-OH was achieved with the new SIBA protective group at O2/O3 of the L-glucose residue. Auxiliary substitutents at the 2-position of the 2-deoxy sugars were applied to form selectively the glycosidic linkages of the C27 disaccharide. The cross-coupling of the glycosylated northern half with the glycosylated southern half was achieved with CuI-thiophene carboxylate. The macrocyclization of a trihydroxy carboxylic acid produced the 20-membered macrolide selectively. H2SiF6 was suitable for the final deprotection of the silyl ethers and the conversion of the C21 methylketal into the hemiketal. The synthetic flexibility of the approach was proven by the synthesis of some glycovariants.

Eine CuI‐vermittelte Kupplung der Nord‐ und der Südhälfte sowie eine ringgrößenselektive Makrolactonisierung sind die Schlüsselschritte der konvergenten, ersten Totalsynthese von Apoptolidinon (die Wellenlinien in der Formel geben die retrosynthetischen Schnitte an), dem Aglycon des potentiellen Tumortherapeutikums Apoptolidin.

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