Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (−)-Xeniafaraunol A

Abstract

The first asymmetric total synthesis of the Xenia diterpenoid waixenicin A, a potent and highly selective TRPM7 inhibitor, is reported. The characteristic trans-fused oxabicyclo[7.4.0]tridecane ring system was constructed via a diastereoselective conjugate addition/trapping sequence, followed by an intramolecular alkylation to forge the 9-membered ring. While a β-keto sulfone motif enabled efficient ring-closure, the subsequent radical desulfonylation suffered from (E)/(Z)-isomerization of the C7/C8-alkene. Conducting the sequence with a trimethylsilylethyl ester allowed for a fluoride-mediated decarboxylation that proceeded without detectable isomerization. The acid-labile enol acetal of the delicate dihydropyran core was introduced at an early stage and temporarily deactivated by a triflate function. The latter was critical for the introduction of the side chain. Diverting from a common late-stage intermediate provided access to waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. A high-yielding base-mediated dihydropyran-cyclohexene rearrangement of 9-deacetoxy-14,15-deepoxyxeniculin led to xeniafaraunol A in one step.

Synthesis of Waixenicin A: Exploring Strategies for Nine‐Membered Ring Formation

“…We hypothesize that this may result from the formation of an α ‐keto radical 115 at C10, which can undergo an intramolecular 3‐ exo ‐trig cyclization onto the C7/C8 alkene yielding an intermediate cyclopropyl radical 116 . This radical would then undergo a rotation process leading to the thermodynamically more stable ( Z )‐alkene after reopening of the cyclopropane moiety [58] …”

Total Synthesis of Isoxeniolide A**

“…[32] In contrast to our experience with 7, Magauer and coworkers have recently reported the olefination of ketone 11 as part of their synthesis of waixenicin A (Figure 2C). [36,37] However, extensive screening and optimization were re- 4) [32] and C) waixenicin ( 6). [36,37] PMB = p-methoxybenzyl.…”

“…[18,19,[24][25][26][27][28] Until very recently total syntheses of xenicane-type diterpenoids had been reported only for four family members, namely antheliolide A (2; Corey, 2006), [29] coraxeniolide A (3; Leumann, 2000; [30] Corey, 2006 [31] ), blumiolide C (4; Altmann, 2008) [32] and 4-hydroxydictyolactone (5; Williams, 2009) [33] (Figure 1). [34][35] Earlier this year, this list has been extended notably by the elegant work of Magauer and co-workers on the total synthesis of waixenicin A (6; together with xeniafaraunol A), [36,37] with waixenicin A (6) being a nM inhibitor of the transient receptor membrane melastatin (TRPM) 7 channel. [38] In all cases, the major challenge was the construction of the strained nine-membered ring, which was accomplished through different approaches; for antheliolide A (2), coraxeniolide A (3), blumiolide C (4), and waixenicin (6) additional difficulties arose in conjunction with the installation of the exocyclic C11À C19 double bond (see below).…”

“…Figure 2. Installation of the C11À C19 double bond en route to A,B) blumiolide C (4)[32] and C) waixenicin (6) [36,37]. PMB = p-methoxybenzyl.…”

Die Totalsynthese von Isoxeniolid A**

“…Bis vor kurzem waren Totalsynthesen nur für 4 Vertreter der Xenican‐Familie bekannt, nämlich Antheliolid A ( 2 ) (Corey, 2006), [29] Coraxeniolid A ( 3 ) (Leumann, 2000; [30] Corey, 2006 [31] ), Blumiolid C ( 4 ) (Altmann, 2008) [32] and 4‐Hydroxydictyolacton ( 5 ) (Williams, 2009) [33] (Abbildung 1). [34][35] Zu Beginn des letzten Jahres erfuhr diese Liste dann eine markante Erweiterung, und zwar durch die eleganten Arbeiten von Magauer und Mitarbeitern zur Totalsynthese des Waixenicin A ( 6 ) und des Xeniafaraunol A [36,37] . Dabei ist anzumerken, dass es sich bei Waixenicin A ( 6 ) um einen nanomolaren Hemmstoff des transienten Rezeptorpotential‐Melastatin (TRPM) 7 Ionenkanals handelt [38] .…”