Toward the total synthesis of maoecrystal V: an intramolecular Diels–Alder route to the maoecrystal V pentacyclic core with the appropriate relative stereochemistry

Abstract

A diastereoselective route to the maoecrystal V core compound (6) has been achieved. Key transformations include an intramolecular Diels-Alder cyclization and an exo-glycal epoxide rearrangement sequence.The unique and complex structure of maoecrystal V (1, Fig. 1), first isolated by Sun and coworkers in 2004, serves to render it a challenging target for total synthesis. Adding to the level of interest in maoecrystal, is its potent in vitro activity against HeLa cells (IC 50 = 20 ng/ml).1 Particularly noteworthy in this regard is the apparent specificity of its cytotoxicity against gynecological cells.Among the defenses which maoecrystal V mounts against those who would undertake its total synthesis, are two contiguous quaternary carbon stereocenters and a tertiary alcohol, embedded within a rigid pentacyclic scaffold. Not withstanding the complexity of the problem, a number of groups, including our own,2c have initiated investigations directed toward the total synthesis of maoecrystal V.2In designing our program, we envisioned recourse to an intramolecular Diels-Alder (IMDA) cyclization, hoping thereby to gain access to the bicyclo [2.2.2]-octane core substructure of maoecrystal. In preliminary investigations, the highly functionalized precursor, 2, was indeed found to undergo IMDA cyclization, albeit with the undesired sense of facial selectivity (Fig. 1).2c We sought to circumvent this setback through the design of a modified sequence, featuring IMDA of a less densely functionalized and symmetrical precursor (cf. 4→5). In devising this new route, we were not insensitive to the potential difficulties inherent in fashioning the requisite trans-fused furanoid ring junction3 (6, see ring B and its junction to ring A). Fortunately, these challenges have now been met, and a concise synthesis of the maoecrystal V core compound (6) in the required stereochemical sense has now been accomplished for the first time. The manner in which we reached this important milestone may well have broader implications in the design of total syntheses. © 2010 Elsevier Ltd. All rights reserved. Our route to the IMDA precursor 4 commenced with a Birch-type vinylogous acylation between substrates 7 and 8, thus providing intermediate 9, possessing one of the requisite quaternary carbon centers (Scheme 1). The latter was subjected to global DIBAL-H reduction, followed by selective MnO 2 -mediated reoxidation of the resulting allylic alcohol, to afford 10. A two-step sequence, involving esterification with acyl chloride 11,4 followed by formation of the TBS enol ether, provided the target IMDA substrate, 4. In the event, compound 4 readily underwent thermally-induced IMDA cyclization in reasonable yield to generate the desired cycloadduct. Upon exposure to TBAF, the TBS group was hydrolyzed and the phenyl sulfone moiety suffered spontaneous elimination to afford key intermediate 5 in 62% isolated yield.We next turned to the stereoselective emplacement of the requisite C 10 tertiary alcohol. Initial attempts to accomplish direct ins...

Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins

“…Peng and Danishefsky reported their approach toward maoecrystal V ( 66 ) in 2011 (Figure ). As part of their route, they made use of a Mukaiyama/Magnus enone α-hydroxylation reaction to install the alcohol of 65 from enelactone 64 , and this was effected in 80% yield with 1.5:1 diastereoselectivity for the desired epimer at 2 mol % catalyst loading.…”

The Total Synthesis of Isodon Diterpenes

“…In 2012, Danishefsky and Peng at Columbia University and the Sloan‐Kettering Institute for Cancer Research reported the second total synthesis20 of maoecrystal V by leveraging the information gathered in their previous studies 12c,i. Their successful synthesis (Scheme ) commenced with the union of ester 34 with 3‐chlorocyclohexenone ( 35 ), followed by the adjustment of oxidation states to afford alcohol 36 .…”

Die Totalsynthese von Isodon‐Diterpenen

“…2012 beschrieben Danishefsky und Peng von der Columbia University und dem Sloan‐Kettering Institute for Cancer Research die zweite Totalsynthese20 von Maoecrystal V, für die sie Informationen aus vorherigen Untersuchungen nutzten 12c,i. Ihre erfolgreiche Synthese (Schema ) begann mit der Verknüpfung des Esters 34 mit 3‐Chlorcyclohexenon ( 35 ), der die Anpassung der Oxidationszustände unter Bildung des Alkohols 36 folgte.…”