Photo-Flow Reaction and Enantiomer Separation as an Enabling Combination to Chiral Substituted 1,2-Cyclobutanediol

Enantiomerically pure substituted 1,2-cyclobutanediols are densely packed, small building blocks. For an internal program, we needed an efficient, reliable and scalable route to such an intermediate. Capitalizing on the vast body of knowledge addressing the synthesis of cyclobutanone derivatives via photo-chemical reaction either in batch or in flow, our own efforts presented in this article culminated in an enabling route to the desired enantiopure (1R,2R)-1-methylcyclobutane-1,2-diol, combining a Norrish–Yang photocyclization under flow conditions to produce a racemic keto-alcohol that was then diastereoselectively reduced to the desired trans 1,2-diol using NaBH(OAc)₃. The resulting racemic diol was then turned into a UV-active benzoate and the desired enantiomer separated and methanolyzed to furnish the desired enantiomerically pure product.

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