Total synthesis of the ristocetin aglycon.
The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.
Crowley
Brendan M
BM
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
Mori
Yoshiki
Y
McComas
Casey C
CC
Tang
Datong
D
Boger
Dale L
DL
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D012310:Ristocetin / Q000031:analogs & derivatives / Q000737:chemistry
D000900:Anti-Bacterial Agents; C488135:ristocetin aglycon; D012310:Ristocetin; D004317:Doxorubicin