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Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine
Author(s) -
Yoshimura Fumihiko,
Sasaki Minoru,
Hattori Izumi,
Komatsu Kei,
Sakai Mio,
Tanino Keiji,
Miyashita Masaaki
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200900310
Subject(s) - total synthesis , intramolecular force , chemical synthesis , stereochemistry , chemistry , yield (engineering) , alkaloid , stereoselectivity , biological activity , combinatorial chemistry , in vitro , organic chemistry , biochemistry , materials science , metallurgy , catalysis
Highly effective : We report herein the first and highly efficient total syntheses of norzoanthamine and zoanthamine in full detail, which involves stereoselective synthesis of the requisite triene for an intramolecular Diels–Alder reaction via three‐component coupling reactions, the intramolecular Diels–Alder reaction, and subsequent crucial bis‐aminoacetalization as the key steps.The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthu s sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely, norzoanthamine ( 1 ) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic drug, while zoanthamine ( 2 ) has exhibited potent inhibitory activity toward phorbol myristate‐induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P‐388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. Their distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of norzoanthamine ( 1 ) and zoanthamine ( 2 ) in full detail, which involve stereoselective synthesis of the requisite triene ( 18 ) for an intramolecular Diels–Alder reaction via the sequential three‐component coupling reactions, the key intramolecular Diels–Alder reaction, and subsequent crucial bis‐aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of norzoanthamine ( 1 ) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of zoanthamine ( 2 ) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from ( R )‐5‐methylcyclohexenone ( 3 ), respectively.