No abstract

A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer-Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

A series of seven bis(2,5-diphenylphospholane) ligands has been evaluated for utility in rhodiumcatalyzed asymmetric hydroformylation. The ligands differ in the nature of the moiety that bridges the two phospholane rings. Hydroformylation of styrene, vinyl acetate, and allyl cyanide was performed in tandem using parallel pressure vessels. Significant differences in rate, regioselectivity, and enantioselectivity were observed between catalysts. Ligands with two-carbon bridges exhibited selectivities comparable to the ethylene-bridged (S,S)-Ph-BPE. Electron-deficient heterocyclic bridges (pyrazine and quinoxaline) gave increased rates over (S,S)-Ph-BPE. Bis(2,5-diphenylphospholane) ligands with -CH 2 -, -CH 2 CH 2 CH 2 -, and 1,1′-ferrocenyl bridges led to significantly lower selectivities and rates than (S,S)-Ph-BPE. X-ray crystal structures of [(S,S)-Ph-Quinoxaline]Rh(acac), [(R,R)-Ph-BPM]Rh(acac), and [(S,S)-Ph-5-Fc]Rh(acac) are reported. The P-Rh-P bite angles in these complexes are 87.46(3)°, 74.10(5)°, and 99.06(3)°, respectively. As with asymmetric olefin hydrogenation using bis-phospholane ligands, the maximum enantioselectivity in asymmetric hydroformylation was found with bis-phospholanes that adopt P-Rh-P bite angles near 85°.

Bis-sulfamyl imines are shown to be potentially ideal substrates for rhodium-catalysed asymmetric additions of arylboron nucleophiles as they show: (i) near perfect enantioselectivities (11 examples, 98-99 + % ee), (ii) good to excellent diastereoselectivities (10-32:1 rac:meso), and (iii) high functional group tolerance in removal of the low molecular weight protecting group via mild heating in aqueous pyridine.

Four chiral diphosphine ligands consisting of bis(2,5-diphenylphospholan-1-yl) groups connected by the sp(2) carbon linkers 2,3-quinoxaline ((S,S)-Ph-Quinox), 2,3-pyrazine ((S,S)-Ph-Pyrazine), maleic anhydride ((S,S)-Ph-MalPhos), and 1,1'-ferrocene ((S,S)-Ph-5-Fc) were synthesized, and their cationic [rhodium(I)(COD)] complexes were prepared. These complexes were tested in asymmetric hydrogenation of functionalized olefins. [((S,S)-Ph-Quinox)Rh(COD)]BF4 showed high activity and selectivity against itaconate and dehydroamino acid substrates. The corresponding (S,S)-Ph-Pyrazine and (S,S)-Ph-MalPhos complexes exhibited lower activities and selectivities. [((S,S)-Ph-5-Fc)Rh(COD)]BF4 showed high activity with low selectivity for these substrates, but high activity and selectivity against 2-C-substituted cinnamate salts, whereas rhodium complexes of (S,S)-Ph-Quinox and (R,R)-Ph-BPE showed low activity and selectivity against 2-C-substituted cinnamate salts.