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.
A ring‐size‐selective macrolactonization and the early introduction of the saccharide portions are the main features of a total synthesis of the 20‐membered macrolide apoptolidin (see formula), which induces apoptosis in rat glia cells transformed with oncogenes.
The intramolecular glycosylation of thiomannoside donors linked through C6¢ by a phthaloyl group to C3 of a diol mannoside acceptor is described. The unexpected results led us to undertake a systematic analysis of the factors affecting the regioselectivity of the intermolecular process. The substituents on the diol mannoside acceptor have been found to play an important role.The interest in carbohydrate derivatives is increasing because of their function in many biological processes. 3 The preparation of complex oligosaccharides still requires enormous effort by synthetic organic chemists, and strategies that avoid protecting group manipulations through regioselective processes would be a tremendous advance. 3c As a part of our program directed at developing regio-and stereoselective glycosylation methods based on intramolecular glycosylation 4 we applied this approach to the synthesis of a trimannan branched at C3 and C6, through a combined intramolecular-intermolecular onepot glycosylation with minimal hydroxyl group protection. 4d On the other hand, recent work by Fraser-Reid and coworkers 5b,6 has shown that the, normally overlooked, substituent at O-2 plays an important role in determining the regioselectivity on the glycosylation of diols. In this work we have drawn the attention to the, normally unnoticed, substituents at O-6 and O-3 in a mannoside-2,4-diol. Furthermore, we have compared intramolecular with intermolecular glycosylation processes.The synthesis of mannosides branched at the C2 and C4 positions has been less studied than that of the 6,3-and 6,2-substituted oligomannosaccharides; however, some interesting results regarding regioselectivity have been published. 5 For example, position 4 of acceptors 4a and 4b is glycosylated in a regioselective manner, respectively, by donors 1 and 3, which have participating groups at C2 (Figure 1). 5a In contrast, when donor 2 with a non-participating group is used, the C2 hydroxyl group of the mannose acceptor 4a undergoes complete regioselective glycosylation. 5b It has also been shown that glucosamine donors with phthalimide as the participating protecting group at C2 also react regioselectively with the C4 hydroxyl group of the acceptor. 7The results of our investigations into the regioselectivity of the equivalent reaction in the context of intramolecular glycosylation appeared to complement to those described previously for intermolecular processes and led us to undertake a thorough examination of the factors involved.
Figure 1 Regioselective glycosylations of mannoside acceptors 4 and donors with participating (1 and 3) and non-participating (2) groupsWe first investigated the regioselectivity of glycoside donors in reactions with mannose diol acceptors analogous to 4 in an intramolecular glycosylation of diols 5 (Figure 2). The effects of both participating and nonparticipating groups at position C2 of the donors were analyzed. The C6¢ and C3 positions were chosen as the anchoring sites for the donor and acceptor, respectively. In order to analyze th...
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