Total synthesis of the spirocyclic imine marine toxin (-)-gymnodimine and an unnatural C4-epimer.
The first total synthesis of the marine toxin (-)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels-Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki-Hiyama-Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (-)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, USA.
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D000818:Animals; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D003300:Copper / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D006844:Hydrocarbons, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry; D008387:Marine Toxins / Q000138:chemical synthesis* / Q000737:chemistry; D010125:Ostreidae / Q000737:chemistry; D010080:Oxazoles / Q000737:chemistry; D013237:Stereoisomerism
D006575:Heterocyclic Compounds, 3-Ring; D006844:Hydrocarbons, Cyclic; D007097:Imines; D008387:Marine Toxins; D010080:Oxazoles; D003300:Copper; C407350:gymnodimine