Pyrroles lamellarins

Didemnum Phenylethylamlne derivatives pyridoacridines alkaloids of pyrrole (lamellarins), Indole (eudistomins), carbazole and guanidine aromatic and heteroaromatic S/N derivatives (thiazole-rich cyclic peptides) halogenated nucleosides... 

The pyrrole ring in numerous natural products has been constructed using a PK synthesis. Examples include lamellarin L, funebrine, magnolamide, and... 

Following the communcation in 2004, a full report appeared that described type Ilac cyclocondensation reactions between dihydroisoquinolines and a-nitrocinnamates leading to complex fused pyrroles <06JOC9440>. The latter were converted into the lamellarin alkaloids and related analogues. 

Type Ilbd pyrrole syntheses fall into three general categories (1) Hinsberg-type (2) azomethine ylide cycloadditions and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594,06TL3755>. 

Banwell s group has provided an alternative strategy [32] for obtaining the lamellarin framework and it is presented in Scheme 10. The methodology involves the formation of a 2,4-disubstituted pyrrole (53) containing an acid... 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Boger has reported efficient total syntheses of the marine alkaloids ningalin A, lamellarin O, lukianol A, and stomiamide A each of which possess a common 3,4-diaryl-substituted pyrrole nucleus bearing 2- or 2,5-carboxylates <99JA54>. A key step in each of these syntheses utilized a zinc mediated reductive ring contraction of 1,2-diazines such as 29 to pyrrole 30, a precursor in... 

Banwell has developed a new approach to the core associated with several members of the lamellarin class of marine natural products. This approach utilized some interesting pyrrole arylation reactions including a Negishi. cross coupling of the iodopyrrole 46 followed by a double-barrelled Heck cyclization of the resultant arylpyrrole 47 yielding the core structure 48... 

Treatment of the dihydroisoquinolinium salt 699 with Hiinig s base (/-PrzNEt) produces the corresponding azomethine ylide, which can undergo intramolecular cycloaddition with the tethered alkyne to afford the chro-meno[3,4- ]pyrrol-4(3//)-one 700 in high yield. Subsequent deprotection of the isopropyl protecting groups affords the marine natural product lamellarin K (Scheme 173) <1997CC2259>. 

A route involving annulation of ketene-AiA-acetals has been developed, as illustrated by the transformation of the substrate 143 into the tetrasubstituted pyrrole 144 (Equation 41). This methodology was used for the synthesis of some key pyrrole intermediates toward the alkaloids lukianol A and lamellarin Q <2005TL475>. 

Heating of the dihydroisoquinoline 285 with the nitrostyrene 286 allowed practical preparation of the system 287 en route to the natural product lamellarin K <2004AGE866>. Reactions between nitroalkenes and enaminones have also been employed as the key step in a solid-phase approach to pyrrole-3-carboxamide derivatives (Equation 88) <1998TL8263>. 

While for the pyrrole derived lamellarins and related compounds no activity has been described, several pentacyclic lamellarins show important cytotoxic activities. Lamellarin D at a concentration of 19 pg/ml caused a 78% inhibition of cell division in the fertilized sea urchin egg assay while lamellarin C caused 15% inhibition but lamellarins A and B were inactive <85JA5492>. Lamellarins I, K and L present significant cytotoxicity against P338 and A549 cultured cell lines and lamellarins K and L also exhibit immunomodulatory activity <93AJC489>. 

From a synthetic point of view, lamellarins are rather complex molecules. In the literature, there are described several approaches, which fall into two main synthetic categories (i) by pyrrole formation as the key step of the synthesis and (ii) by transformation of a pre-existent pyrrole derivative through cross-coupling reactions. Although and due to the structural... 

Furstner et al. synthesized lamellarin O dimethyl ether following their previous research on carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling reactions <94JOC5215, 95JA4468>. A new titanium-mediated approach to pyrrole synthesis, based on the cyclization of a 3-acylamino-enone, was reported <95JOC6637>. 

A similar approach was described by Kim et al. <01MI1403> to build the Furstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed Intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Furstner approach <95JOC6637>. 

The Michael addition /ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCOs to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respeetively. 

A cross-coupling methodology was also used by Banwell et al. to build the lamellarin framework around the pyrrole core 122 using Negishi and double-barrelled Heck-type reactions to establish key carbon-carbon bonds from 121 <99AJC755>. 

Using another approach, starting from the pyrrole core <04TL0000> syntheses of lamellarins Q and O were also achieved. In this work, the methyl A -(triisopropylsilyl)-3,4-dibromopyrrole-2-carboxylate 102 was used as the initial scaffold. Banwell et al. <97CC207> used the dibromopyrrole 102 in an elegant convergent synthesis of several compounds from this family of marine alkaloids (shown above). 

The pentacyclic pyrrole-containing systems lamellarins U 40 and L 41 have been synthesized on solid phase, involving a [3 + 2] cycloaddition of a 3,4-dihydroisoquinolinium salt with an alkyne as the pyrrole ring-forming key step <03OL2959>. In another application... 

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