Convergent Total Synthesis of Principinol D, a Rearranged Kaurane Diterpenoid

Abstract

The total synthesis of principinol D, a rearranged kaurane diterpenoid, is reported. This grayanane natural product is constructed via a convergent fragment coupling approach, wherein the central seven-membered ring is synthesized at a late stage. The bicyclo[3.2.1]octane fragment is accessed by a Ni-catalyzed α-vinylation reaction. Strategic reductions include a diastereoselective SmI 2mediated ketone reduction with PhSH and a new protocol for selective ester reduction in the presence of ketones. The convergent strategy reported herein may be an entry point to the larger class of kaurane diterpenoids.The grayanane diterpenoids-well-known as the active components in "mad honey" due to inhibition of voltage-gated sodium ion channels 1 -have recently been identified as structurally novel allosteric inhibitors of carbonic anhydrases 2 and phosphatases. 3 Due to the ubiquity of various subtypes of these molecular targets, potential therapeutic development could span numerous different disease areas from neurological dysfunction to cancer. 4,5 Grayananes are among a broader class of rearranged kauranes that also includes gibberellanes and 6,7-seco-kauranes (Figure 1A). The tetracyclic diterpenoid grayananes are formed by rearrangement of the kaurane 6,6-A/B ring system to a 5,7-ring system. 6 The kauranes are derived from rearrangement and cyclization of pimaranes via the beyeranes. 7,8 The first total synthesis of (±)-kaurene was completed in 1962 by Ireland and co-workers, 9 and in recent years several groups have completed elegant syntheses of members of this broader class employing a diverse array of synthetic strategies. 10 Nevertheless, much of the >1000 kaurane diterpenoids that have been isolated remain inaccessible by previously reported synthetic approaches. Synthetic efforts toward the grayananes have been especially limited 11 despite their compelling biological activities.

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

“…[12] While the kaurane diterpenes have been extensively studied, [13] fewer syntheses of grayanane natural products have been reported. [14] In 2019, Newhouse and coworkers [15] described ac onvergent route to the grayanane diterpene (+ +)-principinol D( 25), [16] as outlined below.…”

Samarium(ii) iodide-mediated reactions applied to natural product total synthesis

“…In 2019, Newhouse and colleagues 102 reported the first asymmetric total synthesis of principinol D 233 in 19-steps. The key steps contain a SmI 2 -mediated reductive cyclization to construct the central seven-membered ring of the grayanane skeleton, a convergent fragment coupling protocol through a 1,2-addition reaction between a bicyclo[3.2.1]octane fragment 229 and a cyclopentyl fragment 230, and Ni-catalyzed α-vinylation reaction to establish the bicyclo[3.2.1]octane.…”

Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale

“…Die Kauran‐Diterpene wurden eingehend untersucht, [13] dagegen sind für Grayanan‐Naturstoffe weniger Synthesen bekannt [14] . Newhouse et al [15] . beschrieben 2019 eine konvergente Synthese des Grayanan‐Diterpens (+)‐Principinol D ( 25 ) [16] …”

“…[12] Die Kauran-Diterpene wurden eingehend untersucht, [13] dagegen sind fürG rayanan-Naturstoffe weniger Synthesen bekannt. [14] Newhouse et al [15] beschrieben 2019 eine konvergente Synthese des Grayanan-Diterpens (+ +)-Principinol D( 25). [16] Die Retrosynthese des Naturstoffs 25 ergab unter Zerlegung des Siebenrings den Aldehyd 26 und das Iodid 27 (Schema 4).…”