A Xylochemically Inspired Synthesis of Lamellarin G Trimethyl Ether via an Enaminone Intermediate

Abstract

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.

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

“…Finally, acid-induced dehydration of 22 completes the formation of the pyrrole ring, resulting in conversion into the dihydropyrrolizine 19a. This enaminone-based method for constructing a pyrrole ring is similar to that in our reported routes to lamellarin alkaloids, in which N-alkylation of (Z)-configured 3,4-dihydroisoquinoline-derived enaminones with ethyl bromoacetate under either conventional [49,50] or microwave [51] heating conditions yielded pyrrolo[2,1-a]isoquinoline products. A somewhat comparable cyclization of N-benzylenaminones has been reported under superbasic conditions [52], while base-induced pyrrole formation from N-(ethoxycarbonylmethyl)enamino esters (vinylogous urethanes) and the corresponding nitriles (vinylogous cyanamides) has also been described [53].…”

“…Finally, in view of our interest in the synthesis of natural products possessing fully substituted pyrrole rings (e.g., the lamellarin alkaloids [50][51][52]70]), we also demonstrated that dihydropyrrolizines such as 19a could easily be functionalized on the unsubstituted pyrrole position (Scheme 5). This site was readily brominated with N-bromosuccinimide in N,N-dimethylformamide [71] to afford ethyl 7-bromo-6-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate (28) in 83% yield.…”

Searching for New Biologically Active Compounds Derived from Isoquinoline Alkaloids

“…On the other hand, 3,4-dihydroisoquinolines with benzyl groups at C1, due to their instability, were obtained as iminium hydrochlorides [18]. The instability of substituted 1-benzyl-3,4dihydroisoquinoline is related to the reactivity of the benzyl position and the ease of oxidizing this position to the carbonyl group [19]. The structures and purity of imines were confirmed by NMR spectra analysis.…”

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

“…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.…”