A Novel Approach to Morita—Baylis—Hillman (MBH) Lactones via the Lewis Acid‐Promoted Couplings of α,β‐Unsaturated Lactone with Aldehydes.

Karur, Subramanian; Hardin, Justin; Headley, Allan D.; Li, Guigen

doi:10.1002/chin.200326145

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“…Testament to its catalytic power, BH32.14 can even promote enantioselective transformations of unsaturated lactones (product 5b ), which are notoriously challenging as MBH substrates. 24 , 25 BH32.14 also accepts a range of mono- and di-substituted aromatic aldehydes as substrates, although has a clear preference for para -substituted derivatives. While a modestly electron-donating p -Me substituent is well tolerated ( 5i ), introduction of a strongly donating p -OMe group leads to a significant reduction in activity ( 5j ).…”

Section: Synthetic Utility Of Engineered Mbhasesmentioning

confidence: 99%

Engineering an efficient and enantioselective enzyme for the Morita–Baylis–Hillman reaction

et al. 2021

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The combination of computational design and directed evolution could offer a general strategy to create enzymes with new functions. To date, this approach has delivered enzymes for a handful of model reactions. Here we show that new catalytic mechanisms can be engineered into proteins to accelerate more challenging chemical transformations. Evolutionary optimization of a primitive design afforded an efficient and enantioselective enzyme (BH32.14) for the Morita-Baylis-Hillman (MBH) reaction. BH32.14 is suitable for preparative scale transformations, accepts a broad range of aldehyde and enone coupling partners, and is able to promote selective mono-functionalizations of dialdehydes. Crystallographic, biochemical and computational studies reveal that BH32.14 operates via a sophisticated catalytic mechanism comprising a His23 nucleophile paired with a judiciously positioned Arg124. This catalytic arginine shuttles between conformational states to stabilize multiple oxyanion intermediates and serves as a genetically encoded surrogate of privileged bidentate hydrogen bonding catalysts (e.g. thioureas). This study demonstrates that elaborate catalytic devices can be built from scratch to promote demanding multi-step processes not observed in Nature.

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Section: Synthetic Utility Of Engineered Mbhasesmentioning

confidence: 99%