Complete Relative Stereochemistry of Maitotoxin

Abstract

By addressing the relative stereochemistry of the four acyclic portions via organic synthesis, the complete relative stereochemistry of maitotoxin (MTX) has been established as 1B. The relative stereochemistry of the C.1−C.15 portion was elucidated via a two-phase approach: (1) the synthesis of the eight diastereomers possible for model C, representing the C.1−C.11 portion, and the eight diastereomers possible for model D, representing the C.11−C.15 portion, and the comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 9 and 35 represent the relative stereochemistry of the corresponding portions of MTX; (2) the synthesis of the two remote diastereomers 51 and 52, and comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 51 represents the relative stereochemistry of the C.1−C.15 portion of MTX. The relative stereochemistry of the C.35−C.39, C.63−C.68, and C.134−C.142 acyclic portions was established via (1) the synthesis of the 8, 8, and 16 diastereomers possible for models E, F, and G, respectively, and (2) the comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 81, 117, and 187, respectively, represent the relative stereochemistry of the corresponding portions of MTX. Some biogenetic considerations have been given to speculate on the absolute configuration of MTX. The vicinal proton coupling constants observed for models 51, 81, 117, and 187 were used to elucidate their preferred solution conformation. Assembling the preferred solution conformations found for the four acyclic portions allows one to suggest that the approximate global conformation of MTX is represented by the shape of a hook, with the C.35−C.39 portion being its curvature. MTX appears to be conformationally relatively rigid, except for conformational flexibility around the C.7−C.9 and C.12−C.14 portions. On the basis of the experimental results gained in the current work, coupled with those in the AAL-toxin/fumonisin area, it has been pointed out that the structural properties of 51, 81, 117, 187 and their diastereomers are inherent to the specific stereochemical arrangement of the small substituents on the carbon backbone and are independent from the rest of the molecule. Thus, it has been suggested that each of these diastereomers has the capacity to install a unique structural characteristic through a specific stereochemical arrangement of substituents on the carbon backbone, and that fatty acids and related classes of compounds may be able to carry specific information and serve as functional materials in addition to structural materials.

Zur Struktur des Maitotoxins

“…[1][2][3][4] Hierbei erwies sich das Maitotoxin (1, Abbildung 1) nicht nur als hoch wirksame Substanz, sondern auch als das größte Naturstoffmolekül außerhalb der Proteinfamilie. Die Maitotoxinstruktur umfasst 32 Ringe und 99 stereochemische Elemente (98 Stereozentren und eine dreifach substituierte Doppelbindung).…”

“…Die Maitotoxinstruktur umfasst 32 Ringe und 99 stereochemische Elemente (98 Stereozentren und eine dreifach substituierte Doppelbindung). Eine Absolutkonfiguration wurde in mehreren zwischen 1992 und 1996 publizierten Arbeiten der Gruppen um Yasumoto, [2] Tachibana [3] und Kishi [4] vorgeschlagen. Im Jahr 2006 äußerten Gallimore und Spencer [5] Zweifel bezüglich der Konfiguration an der Verknüpfungs-stelle der J-und K-Ringe (C51/C52), die ursprünglich entgegen der aus biosynthetischen Überlegungen zu erwartetenden Konfiguration zugewiesen worden war.…”

“…In diesem Essay diskutieren wir einige alternative Strukturen des Maitotoxins und werden zu dem Schluss kommen, dass der ursprüngliche Strukturvorschlag höchstwahrscheinlich richtig ist. [2][3][4] . Essays beobachteten NOEs jedoch schwerlich erklären lassen.…”

“…Zu bemerken ist aber, dass auch die Struktur 3 p nicht in Einklang mit allen für diesen Molekülteil ermittelten NMR-Daten ist. Wie wir weiter unten ausführen werden, haben letztlich beide ¾nderungen am ursprünglichen Strukturvorschlag [2][3][4] zur Folge, dass weitere Revisionen am Molekülrückgrat vorzunehmen sind.…”

The Art and Science of Organic and Natural Products Synthesis

“…Structures of unprecedented molecular architecture, complexity, and size such as vancomycin (116), CP-263,114 (117), antibiotic 13,384-1 (118), and maitotoxin (119) (Fig. 50) still stand tall, challenging and daring the synthetic chemist, while myriad others remain to be discovered.…”