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Total Synthesis of (−)‐Salicylihalamide
Author(s) -
Fürstner Alois,
Dierkes Thorsten,
Thiel Oliver R.,
Blanda Gaetano
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20011217)7:24<5286::aid-chem5286>3.0.co;2-g
Subject(s) - chemistry , moiety , negishi coupling , enyne , total synthesis , metathesis , stereochemistry , ruthenium , sonogashira coupling , catalysis , medicinal chemistry , carbene , ligand (biochemistry) , combinatorial chemistry , palladium , organic chemistry , biochemistry , polymer , receptor , polymerization
Abstract A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B ( 1 a , b ) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of β ‐keto esters 18 and 32 catalyzed by [(( S )‐BINAP)RuCl 2 ] 2 ⋅ NEt 3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the “second‐generation” ruthenium carbene complex 24 as the catalyst which bears an imidazol‐2‐ylidene ligand. The E / Z ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl 2 ‐mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper‐catalyzed cross‐coupling process with the ( Z , Z )‐configurated carboxamide 42 to form the labile enamide moiety of 1 . Compound 42 was derived from a palladium‐catalyzed Negishi coupling between butynylzinc chloride and 3‐iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.