title: A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: investigation of the unusual kinetically controlled RCM stereochemistry.
abstract: Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.
authors.affiliation: Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I. Università degli Studi di Milano, Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR, Via G. Venezian, 21, 20133 Milano, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Castoldi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Caggiano
authors.forename: Laura
authors.initials: L
authors.lastname: Panigada
authors.forename: Ofer
authors.initials: O
authors.lastname: Sharon
authors.forename: Anna M
authors.initials: AM
authors.lastname: Costa
authors.forename: Cesare
authors.initials: C
authors.lastname: Gennari
mesh_terms: D002384:Catalysis; D003500:Cyclization; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D004224:Diterpenes; D050257:Tubulin Modulators; C109551:eleutherobin