The final peptide coupling brought together the ABCD tetrapeptide 43 and the acyclic tripeptide 44 and was conducted with EDCI, remarkably without detectable epimerization (Scheme 4). The final macrocyclization of the 16-membered DE ring system was accomplished with a second room temperature SNAr reaction for diaryl ether formation, using CsF (DMSO) and providing selective formation of the natural P atropisomer 45 (5:1 ratio) in high yield (95%).59,60,67 After subsequent reduction of the nitro group to the aniline, the diastereomers could be separated by column chromatography. The appropriately functionalized E ring 46 was formed through a Sandmeyer substitution reaction upon CuCl and CuCl2 treatment of the aniline-derived diazonium tetrafluoroborate salt.72?74 Next, the masked C-terminus N-methylamide was nitrosated with dinitrogen tetraoxide (N2O4) and subsequently hydrolyzed with LiOOH in 68% yield.68 Despite the potential nitrosation at other amide sites, the documented steric effects of such a competitive reaction with amides were defined,68,69 aiding in the designed and implemented selectivity first explored in the total synthesis of the orienticin aglycon.49,50 Allyl ether cleavage followed by hydrogenolysis cleavage of the benzyl ethers, using transfer hydrogenation conditions (Pd/C and 1,4-cyclohexadiene) to avoid dechlorination, afforded 49.75 The final step in the conversion to vancomycin aglycon (50) was achieved by acid-catalyzed N-terminus Boc and asparagine residue Ddm removal (83%).
The atropisomers could be separated chromatographically, which means that they are fairly stable. But note that they were separated before several final synthetic steps.
There are several routes to these ring systems described in the paper. Many of the aryl couplings are Suzuki chemistry which is very popular if I recall correctly - I don't do much organic chemistry these days; only occasionally do I find cause even to comment on it, although, truth be told, the last time I commented on organic chemistry, it happened to involve vancomycin. (I remember going to a Trost lecture many years ago, where he had "the periodic table according to Trost" which featured all of the other elements in the periodic table in the background to a giant palladium. Palladium is, indeed, a great element, for organic people and inorganic people alike.)
PM me if you'd like the full paper.
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