Syntheses and Biological Activities of the LMNO, ent-LMNO, and NOPQR(S) Ring Systems of Maitotoxin

Abstract

Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity.

Fenton Chemistry for Achmatowicz Rearrangement

“…Achmatowicz rearrangement (AchR) is a very important reaction for the construction of six-membered heterocyclic scaffolds (dihydropyranones and dihydropyridinones), which are frequently found in bioactive molecules and natural products . The synthetic utility of AchR has been illustrated by various transformations of AchR products, including O -glycosylation, [5 + 2] cycloaddition, Kishi reduction, Ferrier allylation, ketalization, redox isomerization, and Tsuji–Trost arylation (Figure a). The importance of AchR in organic synthesis aroused great interest in developing new and more efficient oxidation protocols, which can be classified into chemical and enzymatic strategies (Figure b).…”

Regio- and Diastereoselective Synthesis of Dihydropyrans and Pyranopyrans via Oxonium–Ene Reaction of β-Allenols and Aldehydes

“…The methodology was also extended for the synthesis of pyranopyrans by using TMSOTf (Table ). It may be mentioned that a pyranopyran skeleton is found in many biologically active natural products, and they are also used as synthetic intermediates for the synthesis of polycyclic ethers such as marine toxins . The scope of the reaction with TMSOTf was studied using different substrates as shown in Table .…”

“…It may be mentioned that a pyranopyran skeleton is found in many biologically active natural products, 17 and they are also used as synthetic intermediates for the synthesis of polycyclic ethers such as marine toxins. 18 The scope of the reaction with TMSOTf was studied using different substrates as shown in Table 3. Treatment of alcohol 4a with simple phenyl, electrondonating methyl-substituted, and moderately electron-withdrawing bromo-substituted aldehydes 5a, 5l, and 5d could afford the corresponding pyranopyran products 8a, 8b, and 8c, respectively, with 40−58% yields (Table 3, entries 1−3).…”

Marine Heterocyclic Compounds That Modulate Intracellular Calcium Signals: Chemistry and Synthesis Approaches

“…After highly diastereoselective dihydroxylation and ring expansion of a six-membered to a seven-membered ring ketone, final SRQ ring 64 is obtained (Scheme 18) [51]. Similar strategies have also been applied to the synthesis of the LMNO ring system [52]. Other groups have also made great efforts in the synthesis of different parts of this amazing molecule.…”