Total Synthesis of (−)‐Spiroleucettadine

Abstract

One of a number of intriguing new alkaloids isolated from the Leucetta sp. sponge in 2004, spiroleucettadine displayed unique structural features on a restricted scaffold: a trans-fused 5,5-bicyclic ring system together with an amino hemiketal moiety. Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity, and structure revision ensued in 2008; no successful synthetic approach has been reported to date. Herein, we describe the enantiospecific total synthesis of (-)-spiroleucettadine by a highly efficient biomimetic approach starting from l-tyrosine. One of two key hypervalent-iodine-mediated oxidation reactions forged the spirocyclic center, and the other enabled the installation of the methylamine side chain in the penultimate step. Our approach provides synthetic access to a new class of spiroannulated natural products and will enable future studies of the structure-biological-activity relationships of these antibacterial compounds.

Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

“…Recently, Hawkings and co-workers 97 reported the first stereoselective synthesis of (−)-spiroleucettadine (223), corroborating the revised structure proposed by Crews and co-workers 96 (Scheme 32). In their synthetic proposal, commercially available N-Boc tyrosine methyl ester (224) was converted to bis-aryl ketone 225, which was transformed into trifluoroacetate 226 after removal of the protecting groups.…”

Marine natural products

“…492 The peptides ciliatamides A and D (revised to 1212 and 1213 respectively), 493 euryjanicin E, 494 reniochalistatin E, 495 and theonellapeptolide Id 496 and the diaryl ether tedarene A have all been synthesised. 497 The absolute congurations of purpuroine A 1214 and nakirodin A 1215 have been revised following their synthesis, 498 while spiroleucettadine 499 and both madangamines C and E 500 have been made. Similarly, the signs of the specic rotation for natural hyrtioreticulins C and D have been reversed following their synthesis, 501 while the structure of topsentin C has also been revised to 1216 some 37 years aer its initial report.…”

Total Synthesis of (−)‐Spiroleucettadine

“…Indeed, the treatment of compounds 10 and 20 with PIDAin 2,2,2-trifluoroethanol at 0 8 8C( Scheme 3) yielded one major product, [16] as indicated by TLC analysis and inspection of the 1 HNMR spectrum of the crude residue.F ollowing purification, analysis of the 1 HNMR spectrum indicated the presence of the cyclohexadienone with the appearance of characteristic resonances at 6.84, 6.35, 6.12, and 6.07 ppm. [17] Fori ncorporation of the methylamine side chain, we decided to employ the hypervalent-iodine-mediated oxidation of secondary amides to imides developed by Nicolaou and Mathison to oxidize the C5 carbon atom. [17] Fori ncorporation of the methylamine side chain, we decided to employ the hypervalent-iodine-mediated oxidation of secondary amides to imides developed by Nicolaou and Mathison to oxidize the C5 carbon atom.…”