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.
The Ugi reaction is applied for the preparation of (R)-lacosamide, an important drug for the treatment of epilepsy. To this end, key issues associated with the Ugi reaction, such as a practical preparation of the foul-smelling isocyanide as well as the efficient introduction of chirality via a cheap and easily removable chiral directing group were solved. Enantiomerically pure (>99.9% ee) drug substance meeting all required purity specifications is prepared in operationally simple four steps in 40% overall yield from the commodity chemical benzylamine.
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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