Enantioselective Total Synthesis of the Potent Antitumor Agent (−)-Mucocin Using a Temporary Silicon-Tethered Ring-Closing Metathesis Cross-Coupling Reaction

Abstract

The potent antitumor agent mucocin (1) was isolated from the leaves of Rollinia mucosa (jacq.) Baill. (Annonaceae) by McLaughlin and co-workers in 1995. 1-3 This agent has exquisite selectivity for the inhibition of A-549 (lung cancer) and PACA-2 (pancreatic cancer) solid tumor cell lines with potency 10,000 times that of adriamycin (doxorubicin). Annonaceous acetogenins selectively inhibit cancerous cells through the blockage of the mitochondrial complex I (NADH-ubiquinone oxidoreductase), and the inhibition of the plasma membrane NADH oxidase, which depletes ATP and induces apoptosis (programmed cell death) in malignant cells. 4In a program directed toward the construction of nonadjacent tetrahydrofuran containing acetogenins, we have developed a new approach to the construction of C 2 -symmetrical 1,4-diols, using a temporary silicon-tethered (TST) ring-closing metathesis (RCM) homo-coupling reaction. 5 Herein, we now describe a novel and expeditious synthesis of mucocin (1), which utilizes the TST-RCM cross-coupling reaction (Scheme 1). 6,7 This approach capitalizes on the localized C 2 -symmetry and thereby permits the construction of 2 and 3 from a common synthetic intermediate, the known homoallylic epoxide 5. 8 We further envisioned that the C4-C5 bond could be formed by enantioselective addition of the alkyne 3 to the aldehyde 4, thereby providing a new strategic disconnection for this class of biologically important molecules. 9 The key feature of this approach is the utilization of a triply convergent strategy, that can be adapted to facilitate the synthesis of related annonaceous acetogenins, resulting in one of the most expeditious syntheses of a complex acetogenin developed to date.The synthesis of the 3-hydroxy-2,6-disubstituted tetrahydropyran 2 was accomplished using the novel six-step strategy outlined in Scheme 2. Mitsunobu inversion of the allylic alcohol 5 using p-methoxyphenol afforded the requisite aryl ether. 10 Regiospecific ring opening of the epoxide with the homoenolate equivalent 11 derived from tert-butyldimethylsilyl protected divinyl carbinol, followed by an in situ protection of the resultant secondary alcohol, afforded the differentially protected triene 7 in 96% overall yield. Chemoselective Sharpless asymmetric dihydroxylation of the triene 7 using AD-mix-β furnished the hydroxy ketone 8 in 70% yield (ds ≥99:1 by HPLC), after recycling the recovered triene 7 (2×). 12 The alkyl side chain was then introduced via the conjugate addition of the cuprate derived from octylmagnesium bromide and copper cyanide to furnish the ketone 9 and thereby set the stage for the reductive etherification. Treatment of 9 with bismuth tribromide and tert-butyldimethylsilane in acetonitrile, followed by in situ protection of the secondary alcohol, furnished the tertbutyldimethylsilyl ether 10 in 93% yield (ds ≥19:1 by NMR). 13 Finally, the p-methoxyphenyl Note Added after ASAP. In the version posted 11/5/O3, in Scheme 2 the absolute configuration for the secondary tert-butyldimethylsilyl ether in 7,...

Anticancer Agents from the Australian Tropical Rainforest: Spiroacetals EBC‐23, 24, 25, 72, 73, 75 and 76

“…Unfortunately, however, the Mitsunobu reaction proceeded with slight A C H T U N G T R E N N U N G (%10 %) epimerization [30] as determined from the (S)-ibuprofen derivative 48 (Scheme 7). This stereochemical issue could be avoided by substituting p-nitrobenzoic acid with pmethoxyphenol in the Mitsunobu reaction, but it was discovered that the change from a silyl protecting group (i.e., 44) to an aromatic ether (i.e., 49 [31] ) completely prevented the linchpin coupling shown in Scheme 8.…”

Stereodivergent Construction of Cyclic Ethers by a Regioselective and Enantiospecific Rhodium‐Catalyzed Allylic Etherification: Total Synthesis of Gaur Acid

“…Regioselective ring-opening of the known epoxide 8 with the cuprate derived from nheptyllithium and copper(i) cyanide at À78 8C, gave the desired alcohol 9 in 71 % yield. [13,14] Benzyl protection of the secondary alcohol 9, followed by oxidative cleavage of the pmethoxyphenyl group, furnished the allylic alcohol 10 in 76 % yield (two steps). [15] The enantiomerically enriched allylic carbonate 12 was prepared by an initial Sharpless kinetic resolution of the allylic alcohol rac-11, followed by acylation of the product (R)-11 (!…”

Metathesereaktionen in der Totalsynthese

“…[53] Eine interessante Entwicklung auf dem Gebiet der Alken-Metathese ist die von der Gruppe um Evans eingeführte Verwendung temporärer Siliciumbrücken in Ringschlussmetathesen, deren Nutzen am Beispiel der Totalsynthese des Tumortherapeutikums (À)-Mucocin (21, Schema 6) deutlich wird. [54] Die Ringschlussmetathese scheint sich zum Aufbau aller drei Ringe der Zielverbindung 21 geradezu anzubieten, es wurde jedoch nur die Kohlenstoff-KohlenstoffBindung zwischen C17 und C18 mit dieser Methode geknüpft. Obgleich es durchaus denkbar wäre, diese Bindung durch eine selektive Kreuzmetathese (siehe unten) zwischen den Vorstufen 17 und 18 herzustellen, ist auf den ersten Blick nicht ersichtlich, dass sie mit einer Ringschlussmetathese geknüpft werden kann.…”