Lamellarin O dimethyl ether

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>. 

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>. 

McMurry coupling. Pyrroles and indoles are prepared from keto amides. The reaction is suitable for the synthesis of lukianol-A and lamellarin O dimethyl ether. Titanium needs to be present only in substoichiometric quantities, and trimethylsilyl chloride is a useful activator. 

Furstner, A., H. Weintritt, and A. Hupperts. 1995. A new, titanium-mediated approach to pyrroles First synthesis of Lukianol A and Lamellarin O dimethyl ether. J Org Chem 60 (20) 6637-6641. 

Furstner, A Weintritt, H and Hupperts, A. (1995) A new titanium-mediated approach to pyrroles first synthesis of hddanol A and lamellarin O dimethyl ether. /. Org. Chem., 60, 6637-6641. 

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