Die Entdeckung und Synthese von marinen Polyethern

Abstract

Die beispiellose Struktur des marinen Naturstoffs Brevetoxin B wurde 1981 von den Arbeitsgruppen um Nakanishi und Clardy aufgeklärt. Das leiterförmige Molekülgerüst dieses kondensierten Polyethers, die starke Toxizität und der faszinierende Wirkmechanismus durch Angriff am spannungsgesteuerten Natriumkanal sorgten für Aufmerksamkeit. Syntheseversuche führten zur Entwicklung zahlreicher neuer Methoden und Strategien zum Aufbau von Etherringen und wurden schließlich durch die Totalsynthesen von Brevetoxin B und einigen verwandten, ähnlich anspruchsvollen Zielverbindungen gekrönt. Unter den marinen Polyethern nimmt Maitotoxin als kompliziertester und giftigster Vertreter eine Sonderstellung ein; die Verbindung ist der größte bekannte nichtpolymere Naturstoff überhaupt. Dieser Aufsatz beginnt mit einer kurzen Geschichte zur Isolierung der Biotoxine und beleuchtet ihre biologischen Eigenschaften und Wirkmechanismen. Dann werden Syntheseversuche beschrieben, wobei besonders neue Methoden berücksichtigt werden, die im Laufe dieser Studien entwickelt wurden. Den Abschluss bilden eine Diskussion der noch nicht abgeschlossenen Totalsynthese von Maitotoxin sowie ein Ausblick auf die weitere Entwicklung des Forschungsgebiets.

A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

“…These products continue to garner much interest due to their innate structural complexity, their potential as anti-cancer and anti-bacterial agents (Figure 1), 1 as well as their undesirable environmental and economic consequences, such as harmful algal blooms. 2 It has been proposed by Nakanishi, 2b,3 Shimizu, 4 and Nicolaou 5 that Nature may construct these elaborate structures via a ring-opening/ring-closing sequence of a polyepoxide precursor. Laboratory emulation of these proposed cascades has been hindered by the fact that the 5- exo product (tetrahydrofuran, THF) is generally favored over the desired 6- endo product (tetrahydropyran, THP), as demonstrated by Coxon in the 1970s (Scheme 1 A ).…”

The Effect of Sulfoxides on the Stereoselective Construction of Tetrahydrofurans: Total Synthesis of (+)‐Goniothalesdiol

“…The use of PhMgBr as nucleophile gave rise, in 80 % conversion, to a mixture of hydroxy phenyl ketone (2S,3R,4R,SR)-26, and cyclic hemiketal (3S,4S,5R,SR)-27, as a mixture of epimers at C-2. The addition of Lewis acids such as ZnBr 2 3 SiH and TMSOTf acting as a Lewis acid. The cis relative configuration of the 2,5-substituents of 28 was established from an NOE spectroscopy experiment, which demonstrated the close spatial arrangement of the two hydrogen atoms H2 and H5 situated on the carbon atoms adjacent to the heterocyclic oxygen atom.…”

“…However, the known fragility of the C-arylglycoside bond under hydrogenolytic conditions (H 2 , Pd/C, MeOH) [43] prompted us to try a stepwise hydrogenation and deprotection. We first hydrogenated the double bonds of the mixture of 31 and 32 (and the C-5 epimers) by using the Wilkinson catalyst [RhClA C H T U N G T R E N N U N G (Ph 3 P) 3 ] [44] in THF/tBuOH under H 2 to give hydrogenated derivatives 33 in 92 % yield (Scheme 9). We then attempted to selectively cleave the benzylic ethers of 33 with BBr 3 in CH 2 Cl 2 .…”

“…[3c, 6] One of them, the Et 3 SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed synthesis of ethers by reductive condensation of carbonyl compounds and alkoxysilanes [7] or alcohols [8] has been applied by us to the asymmetric synthesis of a number of different sized cyclic ethers. The Et 3 SiH/TMSOTf-promoted reductive cyclization of enantiopure b-hydroxy sulfinyl ketones, in turn accessible through the well-established diastereoselective reduction of an adequately functionalized enantiopure b-ketosulfoxide, [9] facilitated the synthesis of 5-, [10] 6-, [10,11] 7-, [12] and 8-membered [13] cyclic ethers with 2,w-cis disubstitution in a highly diastereoselective manner. We have tested the validity of our asymmetric approach by completing the total enantioselective synthesis of structurally simple natural products such as (À)-centrolobine, [10,11] (+)-cis-6-(methyltetrahydropyran-2-yl)acetic acid, [10] and (+)-isolaurepan.…”

“…Stereoselective approaches to substituted tetrahydrofuran and -pyran derivatives continue to attract considerable attention due to the widespread appearance of these structural motifs in a number of natural products that exhibit important biological properties, such as C-glycosides or nucleosides, [1] potent antitumor agents, annonaceous acetogenins, [2] the polyether antibiotics, [3] some macrolide antibiotics, [4] and the brevetoxins. [5] The various strategies currently available for the stereoselective syntheses of these heterocyclic systems have been recently reviewed.…”