Total synthesis of the aspercyclides.
Two different approaches to the eleven-membered biaryl ether lactones of the aspercyclide family are disclosed. The core regions of these highly strained targets, which are able to interfere with the binding of immunoglobulin E to its high affinity receptor, can either be forged by ring-closing olefin metathesis (RCM) or by a highly diastereoselective chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction. Whereas the RCM approach turned out to be responsive to minor changes in the substitution pattern of the substrate, the NHK route is more generally applicable. The preparation of the required cyclization precursor 43 hinged on a palladium-catalyzed ortho-iodination reaction of 2-methylbenzoic acid, an efficient copper-catalyzed Ullmann coupling, and a Takai-Utimoto olefination as the key steps. Moreover, the esterification of the 2,6-disubstituted benzoic acid 34 with the sterically hindered secondary alcohol 37 was far from trivial. However, this and related transformations were accomplished by recourse to the corresponding acid fluorides, which provided excellent yields in cases in which the more commonly used acid chlorides or mixed anhydrides failed to afford any of the desired products.
Pospísil
Jirí
J
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
Müller
Christoph
C
Fürstner
Alois
A
D001688:Biological Products / Q000737:chemistry; D002857:Chromium / Q000737:chemistry*; D003500:Cyclization; D004987:Ethers / Q000737:chemistry; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D015394:Molecular Structure
D001688:Biological Products; D004987:Ethers; D007783:Lactones; D047028:Macrocyclic Compounds; C542833:aspercyclide A; C542834:aspercyclide B; C519042:aspercyclide C; D002857:Chromium