Chiral Phosphoric Acids (CPAs) are undoubtedly among the most used types of chiral Bronsted acid catalysis. CPAs provide mild-condition catalysis for enantioselective reactions, are easily tunable, and in general tolerate wide substrate scope and can be effectively applied to various reaction types. However, the applications of both newly developed and well-established CPAs are limited due to the high cost and low availability of these valuable catalysts (especially on the industrial scale when catalyst recycling is crucial due to its price). Current work demonstrates CPAs immobilization into the polymer matrix to create easily recovered and recyclable heterogeneous catalysts and its further application for regioselective and enantioselective synthesis. Prepared immobilized BINOL/SPINOL-based CPAs can be used back-to-back for regioselective (up to &gt; 25:1 rr) acetalization of C2 and C3 equatorial hydroxyl groups in various monosaccharides on a gram scale. Experimental results are supported by computational studies involving QM/MM DFT calculations as well as 2D NMR studies that reveal an unusual combination of two competitive mechanisms controlling reaction regioselectivity. To demonstrate a wide spectrum of immobilized CPA applications, studies of enantioselective hydrogen atom transfer (HAT) reduction of heterocycles were performed. We have discovered that valuable quinoline derivatives (2-Aryl and carboxylates) as well as 2H-benzo[b][1,4]oxazine and benzo[b][1,4]oxazine-2-ones can be effectively reduced with high yields and enantioselectivity (80-98% ee) using the polymer-immobilized CPA and Hantzsch ester in batch. Subsequently, the immobilized CPA was packed in the column to perform the synthesis in continuous flow. Impressively, we have discovered that asymmetric transfer hydrogenations could be achieved at high flow rates (2.5 ml/min) without erosion in the reaction yields and with consistent improvements in the reaction enantioselectivities. The developed protocol allows large-scale and effective transfer hydrogenation with easily recyclable catalysts that greatly reduce the price of the CPAs (and save them) usage even at the industrial scale.

Immobilized chiral phosphoric acids: Application for regioselective carbohydrate modifications and enantioselective transfer hydrogenation in-flow

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