Total Synthesis of Norzoanthamine

Abstract

Norzoanthamine, an alkaloid isolated from Zoanthus sp., can suppress the loss of bone weight and strength in ovariectomized mice. Norzoanthamine derivatives can also strongly inhibit the growth of P-388 murine leukemia cell lines and human platelet aggregation. However, norzoanthamine's densely functionalized complex stereostructure and scarce availability from natural sources have proved a synthetic challenge. We report the stereoselective total synthesis of norzoanthamine in 41 steps, with an overall yield of 3.5% (an average of 92% yield each step).

Totalsynthese des tetracyclischen Sesquiterpens (±)‐Punctaporonin C

“…Der Ringschluss gelang nach Oxidation [13] des freien Alkohols zum Aldehyd 9 durch eine Aldoladdition. Nach Eliminierung [14] und chemoselektiver Hydrierung [15] der Doppelbindung wurde das gewünschte Keton 10 erhalten. Die Grignard-Addition des sehr leicht herstellbaren MeMgI ergab überraschenderweise bei tiefen Temperaturen (À10 8C) das falsche Diastereomer (Diastereomerenverhältnis d.r.…”

Oxidation of Alcohols, Carbohydrates and Diols

“…[170]; the vinca alkaloid (+)-catharanthine [171]; 2-epibotcinolide (primary alcohol to aldehyde TPAP oxidation also involved) [89]; the spirobicyclic sesquiterpene (±)-erythrodiene (nitro to ketone oxidation also involved; cf. 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].…”

“…The reagent TPAP/NMO/PMS/CH 2 Cl 2 was also used in a step in the synthesis of the colony-stimulating factor leustroducsin B (TPAP) [96]; for the antiparasitic spiroketal macrolide (+)-milbemycin a 1 [97]; the antiparasitic insecticide (+)-milbemycin-b 1 (secondary alcohol to a ketone step also) [98]; the sesquiterpenes nortrilobolide, thapsivillosin F and trilobolide (a second step involving the reagent was a lactol-to-lactone transformation) [64]; the marine alkaloid norzoanthamine (secondary alcohol to ketone step also) [99]; the eunicellin ophirin B [84]; the biologically active diterpene phomactin A [100]; the macrolide prelactone B (primary alcohol to lactone) [101]; the spiroketal ionophore antibiotic routiennocin [102,103]; the macrolides salicylihalamides A and B [104]; the anti-tumour microtubulin stablising agents sarcodictyins A and B [105]; the polypropionate siphonarienolone [106]; the antibiotic (+)-tetronomycin [107], and the aglycon of the antitumour antibiotic tetronolide [108]. During synthesis of the protein phosphatase inhibitor okadaic acid three oxidations with TPAP/NMO/PMS/CH 2 Cl 2 were used, two of a primary alcohol to aldehydes and one of a diol to a lactone [109]; the reagent was used in the synthesis of a fragment of the antibiotic sorangicin A [110].…”

Intramolecular cyclization strategies toward the synthesis of zoanthamine alkaloids

“…The combination of challenging chemical structure and unexplored biology invited the development of chemical strategies toward the synthesis of these metabolites, culminating in the synthesis of norzoanthamine by the Miyashita 9 and the Kobayashi groups. 10 More recently, Miyashita and co-workers also reported the total synthesis of zoanthenol via oxidation of norzoanthamine hydrochloride.…”