Unified Total Synthesis of (−)‐Enigmazole A and (−)‐15‐O‐Methylenigmazole A

Abstract

The total synthesis of cytotoxic marine phosphomacrolides, (À)-enigmazole A and (À)-15-O-methylenigmazole A, is described in detail. The 2,6-cis-substituted tetrahydropyran ring was efficiently elaborated by using a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction. The 18-membered macrolactone skeleton was forged via a Au-catalyzed propargylic benzoate rearrangement/ macrocyclic ring-closing metathesis sequence. Late-stage diversification of a common intermediate enabled unified total synthesis of (À)-enigmazole A and (À)-15-O-methylenigmazole A.

Marine natural products

“…483 The rst total synthesis of the structure reported for halisphingosine A has called into question the congurational assignment of the NP. 484 Other rst total syntheses include that of an acetylene, 485 two peptides, 486,487 and two macrolides, 488,489 the latter describing the construction of the highly complex halistatins 1 and 2. The synthesis of the proposed structure of poly-cationic alkaloid protoaculeine B has been achieved, although the spectroscopic data of the natural and synthetic material differ, suggesting revision is necessary.…”

The phosphate ester group in secondary metabolites

“…81 Subsequent treatment with K 2 CO 3 in MeOH/H 2 O cleaved the C15 acetate and both 9-fluorenylmethyl groups at the phosphate ester to provide 46 as its potassium salt, which was converted to the sodium salt after HPLC purification. The groups of Smith III, 257 Fürstner, 258 and Fuwa 259 a described a similar strategy for the preparation of 181 (R = PMB, TBDPS, Ac) to obtain synthetic 46 . Fuwa and collaborators have recently extended this procedure in their synthesis of 15- O -methylenimazole A ( 47 ).…”

An Overview of Bioactive 1,3-Oxazole-Containing Alkaloids from Marine Organisms

“…However, their actual cellular targets are still unknown [124]. The first chemical synthesis of 195 and 196 required a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction [125].…”