Redox reaction of the Pd0 complex bearing the Trost ligand with meso-cycloalkene-1,4-biscarbonates leading to a diamidato Pd(II) complex and 1,3-cycloalkadienes: enantioselective desymmetrization versus catalyst deactivation.

The Pd(0) complex 1 that bears the Trost ligand 2 undergoes a facile redox reaction with 1,4-biscarbonates 5b-d and rac-22 under formation of the diamidato-Pd(II) complex 7 and the corresponding 1,3-cycloalkadienes 8b-d. The redox deactivation of complex 1 was the dominating pathway in the reaction of 5b-d with HCO(3)(-) at room temperature. However, at 0 degrees C the six-membered biscarbonate 5b, catalytic amounts of complex 1, and HCO(3)(-) mainly reacted in an allylic alkylation, which led to a highly selective desymmetrization of the substrate and gave alcohol 6b with > or = 99% ee in 66% yield. An increase of the catalyst loading in the reaction of 5b with 1 and HCO(3)(-) afforded the bicyclic carbonate 12b (96% ee, 92%). Formation of carbonate 12b involves two consecutive inter- and intramolecular substitution reactions of the pi-allyl-Pd(II) complexes 16b and 18b, respectively, with O-nucleophiles and presumably proceeds through the hydrogen carbonate 17b as key intermediate. The intermediate formation of 17b is also indicated by the conversion of alcohol rac-6b to carbonate 12b upon treatment with HCO(3)(-) and 1. The Pd(0)-catalyzed desymmetrization of 5b with formation of 12b and its hydrolysis allow an efficient enantioselective synthesis of diol 13b. The reaction of the seven-membered biscarbonate 5c with ent-1 and HCO(3)(-) afforded carbonate ent-12c (99% ee, 39%). The Pd(0) complex 1 is stable in solution and suffers no intramolecular redox reaction with formation of complex 7 and dihydrogen as recently claimed for the similar Pd(0) complex 9. Instead, complex 1 is rapidly oxidized by dioxygen to give the stable Pd(II) complex 7. Thus, formation of the Pd(II) complex 10 from 9 was most likely due to an oxidation by dioxygen. Oxidative workup (air) of the reaction mixture stemming from the desymmetrization of 5c catalyzed by 1 gave the Pd(II) complex 7 in high yield besides carbonate 12c.

Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost.

We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.