Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins

Abstract

Modular gram-scale syntheses of the trimethyl ethers of lamellarins G (6) and D (7) were achieved from readily accessible precursors in the highest overall yields reported to date (6, six steps, 82%; 7, seven steps, 86%). A novel demethylative lactonization between an aryl methyl ether and a neighboring carboxylic acid was developed for creating the chromenone unit of the targets to avoid the need for additional protection and deprotection steps. The central pyrrole core was constructed in a late-stage [4 + 1] condensation between ethyl bromoacetate and an enaminone possessing the remaining components of the lamellarin skeleton. Exhaustive demethylation of both permethyl ethers 6 and 7 gave the polyphenolic natural lamellarins A4 (3) and H (5), respectively.

Formation of 3,4‐Diarylpyrrole‐ and Pyrrolocoumarin Core of Natural Marine Products via Barton–Zard Reaction and Selective O‐Demethylation

“…Obviously, this is a rare and interesting example of a selective O‐demethylation induced by a substituent remote from the reacting methoxy group – in this case by COOEt fragment in the pyrrole ring (to the best of our knowledge, no such examples were reported for aryl‐substituted pyrrole carboxylates) , . Moreover, such an approach allows one to avoid a separate step of introducing O‐protective groups, as discussed above (cf.…”

Cyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions

“…The strategy we planned for preparing the key enaminones 4 is shown in disconnection form in Scheme 1. Eschenmoser sulfide contraction, 4,5 a method we have used with much success in our routes to alkaloids and related nitrogen heterocycles, [6][7][8][9][10] was envisaged between pyrrolidine-2-thiones 7 and appropriately substituted phenacyl halides 8. Intermediates 7 would themselves be made by thionation of the corresponding lactams 9, which would in turn be prepared by N-alkylation of pyrrolidin-2-one (10) with phenacyl halides 8'.…”

“…A final set of investigations was prompted by our continuing interest 7,25 in the synthesis of lamellarins, an important group of marine alkaloids possessing an impressive range of biological activities. 26 Typical alkaloids such as lamellarin D (31) contain a fully substituted pyrrole core.…”

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

“…Due to its biological activity, many groups have devoted their time to develop methods for its synthesis [107][108][109][110] as well as the synthesis of other members of the family [111][112][113][114]. More recently, Michael and coworkers have published the synthesis of lamellarin D trimethyl ether 162 by using enaminones as intermediates to alkaloids and other nitrogen heterocycles [117]. Eschenmoser sulfide contraction between bromoketone 164 and thiolactam 163, in the presence of triphenylphosphine and trimethylamine, afforded the desired heptamethoxylated enaminone 165 in high yields (96-100%).…”

“…Eschenmoser sulfide contraction between bromoketone 164 and thiolactam 163, in the presence of triphenylphosphine and trimethylamine, afforded the desired heptamethoxylated enaminone 165 in high yields (96-100%). Conventional heating More recently, Michael and coworkers have published the synthesis of lamellarin D trimethyl ether 162 by using enaminones as intermediates to alkaloids and other nitrogen heterocycles [117]. Eschenmoser sulfide contraction between bromoketone 164 and thiolactam 163, in the presence of triphenylphosphine and trimethylamine, afforded the desired heptamethoxylated enaminone 165 in high yields (96-100%).…”