An Asymmetric Formal Synthesis of Fasicularin

Abstract

An asymmetric formal synthesis of fasicularin (1) is described. This natural product, isolated from the extracts of the marine invertebrate Nephteis fasicularis, has shown modest cytotoxicity towards Vero cells. Fasicularin is among only two members of the cylindricine family of natural products, along with lepadiformine (2), to possess a trans A-B ring junction. Key steps of this approach to 1 involve a siloxy-epoxide semipinacol rearrangement of 5 to 6, a B-alkyl Suzuki-Miyaura coupling reaction by using enol trifluoromethanesulfonate 19 and a substrate-directed hydrogenation reaction of 24. This formal synthesis also highlights the difficulty in the incorporation of the thiocyanate functionality present in 1.

Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons

“…First, comparison of the first two Noyori-Ikariya reduction products to those reported in the literature confirms the stereochemistry and enantioselectivity as described herein. 23,42 Second, the stereoselective reduction of the alkynyl ketone with ( S,S )–TsDPEN ruthenium catalyst gave the correct ( S )–enantiomer and the second alkynyl ketone reduction with the same catalyst would give selectively the desired ( S,S )-intermediate 24a . This configuration was confirmed by Mosher’s ester analysis.…”

Transition metals in organic synthesis: Highlights for the year 2005

“…Asymmetric reductions of 2-amido-2-alkeneoates using rhodium as the catalyst were used in synthetic applications toward (−)-aphanorphine [953] and cribrostatin IV [428]. Asymmetric ruthenium-catalyzed Noyori-type reductions of ketones [954] were used to prepare fasicularin [955], cribrostatin IV [428], daumone [657], (−)-colchicine [745] and strongylodiols [360]. Noyori's ruthenium catalyst was used to reduce an imine in a synthesis of (+)-laudanosine and (−)-xylopine [327].…”

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].…”