Total Synthesis of Cyclic Diterpene Tonantzitlolone Based on a Highly Stereoselective Substrate‐Controlled Aldol Reaction and Ring‐Closing Metathesis

Abstract

The total synthesis of the cyclic diterpene ent-tonantzitlolone (ent-1) is presented. Key steps for assembling the macrocyclic core structure of 1 are a highly selective aldol reaction and an E selective ring-closing metathesis reaction. A detailed investigation of these two steps and the final transformations towards the completion of the synthesis is disclosed.

Tonantzitlolone and other Diterpenes from Stillingia sanguinolenta

“…Therefore, the absolute configuration of 2 was assigned as depicted in Figure 1. [6,18] Figure 2. Determination of the absolute configuration of 2 after reduction of the keto group and formation of all possible Mosher esters (for details see electronic supporting information); MTPA = methoxy(trifluoromethyl)phenylacetyl.…”

“…& Arg. afforded, in addition to acetylaleuritolic acid, the diterpenes cembrene A (1), [4,5] the new flexibilanes tonantzitlolone (2) [6] and tonantzitlolone B (3), the new pimaranes 4 and 5, the kauranes 6, [7] 7, [8] 8, [9] 9, abbeokutone (10), [10,11] 11, [12,13] and 12, the atisanes 13, [14] 14, [14] and 15, [13] trachylobane 16, and the pentacyclic sanguinolane 17, with a novel skeleton. The structures of 2 and 3, each possessing a 15-membered carbocyclic flexibilane ring skeleton, were deduced from detailed evaluation of 1D and 2D NMR spectroscopic data.…”

Constituintes químicos de Sebastiania macrocarpa Muell. Arg. (Euphorbiaceae)

“…21 Do extrato hexânico do lenho da raiz foram isolados e identificados o diterpeno macrocíclico denominado tonantzitlolona (5) [22][23][24] e o triterpenóide lupeol (6). 25 O diterpeno macrocíclico (5), também, foi isolado do extrato hexânico da casca da raiz de S. macrocarpa (Figura 1).…”

“…150-151 o C, [α] D 25 +134 o (c 0,25; CHCl 3 ), que foi identificado como o diterpeno macrocíclico denominado tonantzitlolona (5). [22][23][24] O extrato hexânico do lenho da raiz (6,5 g) foi submetido à cromatografia em coluna, utilizando os eluentes hexano, clorofórmio, acetato de etila e metanol, puros ou em misturas binárias, sendo coletadas 46 frações de 25 mL. A fração 21-27 (hexano/clorofórmio 5/5) (1,6 g) foi submetida a outra coluna cromatográfica fornecendo a sub-fração 10-43 (hexano/acetato de etila 9/1) (577,5 mg), que foi purificada em coluna de gel de sílica, coletando-se frações de 7 mL, obtendo-se a fração 4-8 (hexano/clorofórmio 6/4) (26,5 mg) de um sólido branco, p.f.…”

Oxidation of Alcohols, Carbohydrates and Diols

“…5.6.4) [172]; a secondary alcohol to an enone as a step in the synthesis of the biologically active sequiterpene (−)-diversifolin [51]; the cytotoxic fasicularin [173]; the limonoid fraxinellone [174]; the plasmodial pigment fuligorubin A [160]; the antifungal gambieric acids A and C (also a primary alcohol to aldehyde step) [90]; the ether toxin gambierol (two primary alcohol to aldehyde steps) [91]; the cytotoxic gymnocin-A (also a primary to aldehyde step) [92]; the alkaloid (±)-lapidilectine B [175]; the antiparasitic and insecticide (+)-milbemycin-b 1 , (involving both oxidation of a primary alcohol group to an aldehyde and, in a later step, of a secondary alcohol to a ketone) [98]; the acetogenin muricatetrocin C [176] and the sesquiterpenes nortrilobolide, thapsivillosin F and trilobolide [64]; the glutamate receptor neodysiherbaine [177]; the marine alkaloid norzoanthamine (primary alcohol to aldehyde step also) [99]; the anticarcinogenic agent ovalicin [178]; the cytotoxic agent phorboxazole (hemi-acetal to lactone) [179]; the antibacterial agent pseudomonic acid C [180]; the antifungal agent rapamycin (cf. 1.11) [181,182]; the antigen daphane diterpene (+)-resiniferatoxin [183]; the antitumour macrolide (+)-rhizoxin D [184]; the heliobactericidal (+)-spirolaxine methyl ether [185]; the SERCA thapsigargin inhibitors [112,152,153]; the antitumour agent tonatzitlolone [186] and the therapeutic hypercholesterolemia agent zaragozic acid A [187]. For synthesis of a fragment of the protein phosphatase inhibitor calyculin A the TPAP/NMO/PMS/CH 2 Cl 2 reagent was involved [188].…”