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.
Eleutherobin and dictyostatin are antimitotic compounds which exert their cytotoxic activity by a taxol-like mode of action, i.e., hypernucleating tubulin assembly and interfering with the dynamic instability of the cytoskeleton during mitosis. A formal total synthesis of eleutherobin was accomplished by accessing a key intermediate reported by Danishefsky and coworkers in their 1998 synthesis of the natural product. The key step of our strategy, used for obtaining the [8.4.0] fused bicyclic ring system, is a ring-closing metathesis (RCM) reaction of a densely functionalized diene under forcing conditions, using Grubbs' second-generation catalyst. Synthetic approaches to dictyostatin are also described, and in particular the preparation of the C15-C23 fragment of the macrolide, containing 5 of its 11 stereocenters.
Der Schlüsselschritt in einer formalen Totalsynthese von Eleutherobin war die bisher unbekannte kinetisch kontrollierte RCM‐Reaktion des hochfunktionalisierten Diens 1 mit zwei PMP‐geschützten Allylalkoholeinheiten in Gegenwart eines Grubbs‐Katalysators der zweiten Generation. Isomerisierung des 10‐gliedrigen E‐Endions 2 zum stabileren Z‐Isomer und Abspaltung der Alkoholschutzgruppe führte zur bekannten Vorstufe 3. PMP=p‐Methoxyphenyl.
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