Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis.
The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.
Evans
David A
DA
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. evans@chemistry.harvard.edu
Kvaernø
Lisbet
L
Dunn
Travis B
TB
Beauchemin
André
A
Raymer
Brian
B
Mulder
Jason A
JA
Olhava
Edward J
EJ
Juhl
Martin
M
Kagechika
Katsuji
K
Favor
David A
DA
D000447:Aldehydes / Q000737:chemistry; D000838:Anions / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D002614:Chelating Agents / Q000737:chemistry; D017613:Iodine Compounds / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008387:Marine Toxins / Q000138:chemical synthesis* / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013450:Sulfones / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry; D000095702:Polyether Toxins
D000447:Aldehydes; D000838:Anions; D002244:Carbon; D002614:Chelating Agents; D017613:Iodine Compounds; D008387:Marine Toxins; D013141:Spiro Compounds; D013450:Sulfones; D014753:Vinyl Compounds; C406592:azaspiracid; D000095702:Polyether Toxins