Abstract
A fully-telescoped, aqueous, auxiliary-mediated Diels-Alder cycloaddition in moderate selectivity is reported. The auxiliary is prepared from L-asparagine and trimethylacetaldehyde, and coupled without isolation to the acryloyl substrate. Direct addition of cyclopentadiene generates the cycloadduct, which is cleaved from the heterocycle upon mild treatment with acid and heat. A significantly reduced selectivity is observed relative to the two-pot synthesis in which the acrylamide is precipitated and washed prior to the cycloaddition. Vacuum-assisted removal of the acrylic acid contaminant prior to the cycloaddition substantially remedies the reduced selectivities achieved in the one-pot transformation relative to the two-step sequence. Four chemical transformations, not including acid/base reactions, are accomplished in this onepot synthesis.
Highlights
The auxiliary-mediated Diels-Alder reaction is a powerful technique for assembling complex organic frameworks with regio- and stereochemical control.[2]
We recently reported the development of an aqueous, asparagine-based Diels-Alder cycloaddition[6] with promising features for “greening”[7] auxiliarymediated asymmetric transformations
We report a completely telescoped variant of an aqueous, auxiliary-mediated asymmetric transformation
Summary
The auxiliary-mediated Diels-Alder reaction is a powerful technique for assembling complex organic frameworks with regio- and stereochemical control.[2] Extensive efforts have been directed at developing the conventionally applied approach, which requires multiple discrete steps for auxiliary synthesis and application, and the use of environmentally problematic solvents, reagents, and catalysts.[3] Much less work has been directed at aqueous auxiliary variants[4] or sequential, one-pot synthetic approaches (e.g. telescoping syntheses5) that would address environmental concerns. We recently reported the development of an aqueous, asparagine-based Diels-Alder cycloaddition[6] with promising features for “greening”[7] auxiliarymediated asymmetric transformations. In a second one-pot procedure the chiral dienophile was dissolved in sodium bicarbonate, reacted with cyclopentadiene, and the auxiliary was cleaved hydrolytically. Experimental yields and cycloaddition stereoselectivity in the previous work were significantly diminished and not reported. We report details of the adaptation of this system to a one-pot preparation that substantially alleviates previous deficiencies
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