Synthesis of a Non-Symmetrical Disorazole C1-Analogue and Its Biological Activity.

The synthesis of a novel disorazole C1 analogue is described, and its biological activity as a cytotoxic compound is reported. Based on our convergent and flexible route to the disorazole core, we wish to report a robust strategy to synthesize a non-symmetrical disorazole in which we couple one half of the molecule containing the naturally occurring oxazole heterocycle and the second half of the disorazole macrocycle containing a thiazole heterocycle. This resulted in a very unusual non-symmetrical disorazole C1 analogue containing two different heterocycles, and its biological activity was studied. This provided exciting information about SAR (structure-activity-relationship) for this highly potent class of antitumor compounds.

Extending the Structure-Activity Relationship of Disorazole C1 : Exchanging the Oxazole Ring by Thiazole and Influence of Chiral Centers within the Disorazole Core on Cytotoxicity.

The synthesis of novel disorazole C1 analogues is described and their biological activity as cytotoxic compounds is reported. Based on our convergent entry to the disorazole core we present a flexible and robust strategy to construct a variety of interesting new analogues. In particular, two regions of the molecules were examined for structural modification: 1. Replacement of the heterocyclic moiety by an exchange of the oxazole ring by a thiazole; and 2. Evaluation of the influence of the absolute configuration of the chiral centers of the molecule. Predicated on our flexible strategy we were able to construct all analogues in an efficient way and could perform an exciting SAR (structure-activity-relationship) study to obtain insight in the cytotoxic activity influenced by the chiral centers of the disorazole core.

Synthesis of desfluorinated nebivolol isomers.

The syntheses of all possible stereoisomers of desfluorinated side products of the potent antihypertensive ß-blocker nebivolol are reported. A straightforward approach using a common racemic precursor was employed to obtain the desired optically active building blocks. For one series of compounds, a Sharpless asymmetric epoxidation (SAE) route yielded in a direct fashion the required compounds whereas a Mitsunobu reaction was selected to obtain the other series of compounds. This offers a flexible approach to all desfluoronebivolol side-products in order to fully characterize them.

Total Synthesis of (-)-Disorazole C1.

Disorazoles represent a powerful class of highly potent antitubulin natural products isolated from myxobacteria. Herein, we describe a scalable and robust synthesis of (-)-disorazole C1 with high stereoselectivity, featuring quite simple reaction conditions that can be used to produce large quantities of this remarkable biologically active compound.

(3R*,5'S*)-6,7-Dimeth-oxy-3-(4'-meth-oxy-6'-methyl-5',6',7',8'-tetra-hydro-1,3-dioxolo[4,5-g]isoquinolin-5'-yl)isobenzofuran-1(3H)-one (racemic α-noscapine).

In the racemic title compound, C(22)H(23)NO(7), the dihedral angle between the fused ring systems is 51.87 (6)°. Two of the meth-oxy groups are disordered over two orientations in 0.688 (5):0.312 (5) and 0.672 (15):0.328 (15) ratios. In the crystal, weak C-H⋯O inter-actions link the mol-ecules.

Synthesis of furano-epothilone D.

The total synthesis of furano-epothilone D by a convergent route is reported. The key fragments are available on a large scale to provide sufficient material for biological evaluation. The approach involves a palladium-catalyzed coupling that generates a highly functionalized aldehyde which is connected in a stereoselective aldol reaction to yield the framework of furano-epothilone D. Finally, a macrolactonization provides furano-epothilone D.