Of lamellarins

In 1997, Steglich reported (Scheme 7) the synthesis [29] of lamellarin G trimethyl ether (36) based on the biosynthetic proposal that such compounds arise from 3,4-dihydroxyphenylalanine (DOPA) secondary metabolites. 

Ishibashi and coworkers [26] have reported a very efficient method for synthesizing a variety of lamellarin alkaloids and the preparation of lamellarin D and H are presented in Scheme 8. 

Scheme 7 Steglich Group Synthesis of Lamellarin Natural Products...

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. 

Lamellarin T-V and Y sulfates (67-70) were isolated from an unidentified ascidian from the Arabian Sea coast of India [97]. Four additional lamellarin sulfates, the 20-sulfates of lamellarins B, C and L and lamellarin G 8-sulfate (71-74) were isolated from Didemnum chartaceum from the Great Barrier Reef [98]. Unusually long relaxation times were observed for certain signals in the H NMR spectra of these compounds. Lamellarin a 20-sulfate (75) was isolated from an unidentified ascidian from India and was an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase [99]. 

Another interesting investigation of the use of microwave irradiation for the synthesis of alkaloids was recently reported by M. Alvarez et al., where the authors investigated a modular total synthesis of Lamellarin D [93]. After 20 years of the first isolation of this compound from the marine prosobranch mollusk Lamellaria sp, this family currently comprises more than 30 members, isolated from various natural sources. With its recent identification as... 

Lamellarins were originally extracted from a marine prosobranch mollusk Lamdlaria sp. and subsequently from primitive chordate ascidians (tunicates) [23]. These ascidian species, knovm to produce many bioactive metabolites, likely represent the original producer of lamellarins because these organisms are presumed to be the dietary source of the Lamdlaria mollusks. Lamellarins have been isolated from different tunicates, including recently from the Indian ascidian Didemnum obscurum... 

Fig. 7.2 Schematic illustration of the targets and mode of action of lamellarins.

The lamellarins constitute an important group of natural products isolated from marine invertebrates such as sponges, molluscs and tunicates with structures without precedents in natural or synthetic compounds. They are characterized for possessing important biological activities. The aim of this review is to provide an overview of the work published since the isolation of the first group of lamellarins <85JA5492> from the marine prosobranch mollusc Lamellaria sp, imtil the beginning of 2004. 

Lamellarin a 20-sulfate inhibits integrase terminal cleavage activity with an IC50 of 16 pM and strand transfer activity with an IC50 of 16 pM and possesses a low toxicity with an LD50 of 274 pM whereas other sulfated lamellarins (lamellarin U 20-sulfate and lamellarin V 20-sulfate) were toxic in the 100 pM range and lamellarins T and N without the sulfate ester were more toxic. The site of action of lamellarin a 20-sulfate was mapped and it was postulated that it binds to a site composed of multiple integrase domains. 

In order to adapt this strategy to the synthesis of lamellarin O dimethyl ether, a 3-unsubstituted keto-enamine 4 was prepared by hydrogenolysis of precursor isoxazole 3. 

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>. 

Following on from their previous work on the biomimetic synthesis of marine natural products, Steglich et al. proposed a biomimetic lamellarin synthesis in which an oxidative dimerization of an arylpyruvic acid and condensation of the resulting 1,4-dicarbonyl compound with a suitable 2-arylethylamine would be the key steps of the synthesis. Thus, the synthesis of lamellarin G trimethyl ether was achieved by coupling two molecules of 3-(3,4-dimethoxyphenyl)pyruvic acid and the appropriate 2-phenylethylamine <9579941, 97AG(E)155>. The use of a mixture of two different arylpyruvic acids afforded the unsymmetrical lamellarin L <00MI1147>. 

The same approach was applied again to the synthesis of lamellarin G trimethyl ether as shown in series b. The first three steps proceeded as expected, however the oxidation of compound 47b with manganese dioxide gave lamellarin G trimethyl ether in a disappointing yield (20%). The by-product was found to be the quinone derivative 50 formed by the preferred oxidation of the electron-rich phenolic ring. For this reason the oxidation was carried out with bromobenzene, palladium acetate and triphenylphosphine using DMF as the solvent and potassium carbonate as the base. Lamellarin G trimethyl ether was formed in 80% yield. 

Using a similar strategic procedure Faulkner et al. <02BMC3285> synthesized and evaluated 20-sulfate analogues of lamellarin a. 

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