Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates

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Science  12 Oct 2018:
Vol. 362, Issue 6411, pp. 216-219
DOI: 10.1126/science.aau0817

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An acid inaccessible to aldol products

The aldol reaction is a venerable and widely applicable method for making carbon-carbon bonds. Ironically, it is most challenged by the simplest substrates. The trouble is that the product looks a lot like one of the reactants, and so it can latch onto the coupling partner instead. Schreyer et al. report that a bulky phosphorus-based acid catalyst alleviates this problem. The acidic site is buried in a pocket that is too small to activate the product for further reaction. The chiral geometry of the catalyst also induces high enantioselectivity.

Science, this issue p. 216


Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.

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