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.

A concise high yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is avoided, and only a single aqueous workup is performed. The novelty of the synthesis lies in the intermediacy of an enaminone for the construction of the central pyrrole ring. The overall yield of the product is among the highest reported to date.

A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.

Modular syntheses of naturally occurring lamellarin ε (5) and the synthetic analogue dehydrolamellarin J (6), both of them promising lead candidates for anticancer activity, were accomplished in high overall yields. Key steps in these routes are a late‐stage installation of the central pyrrole core by [4 + 1] cyclocondensation between ethyl bromoacetate and an enaminone possessing the remaining components of the lamellarin skeleton; and our recently revealed demethylative lactonization for building the chromenone components. Additionally, a mild and nearly quantitative new method for cleaving isopropyl‐protected phenols at room temperature with the comparatively green reagent methanesulfonic acid has been developed. The feasibility of exploiting the simplicity and efficiency of the new reactions on a multi‐gram scale was demonstrated by preparing over 25 g of dehydrolamellarin J, one of the most cytotoxic anticancer agents in the lamellarin family, without the need for chromatographic purification of intermediates.

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