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Aromatic electron-deficient heterocycles, such as pyridines, are found in many biologically relevant structures, including those with medicinal applications. Methods for their substitution can streamline the synthesis of valuable molecules and allow access to unexplored chemical space. However, enantioselective methods for these derivatizations remain lacking, especially at remote stereocenters. Here, we present a photoenzymatic reaction for the reductive coupling of electron-deficient heterocycles with alkenes using flavin-dependent “ene”-reductases. This transformation results in the generation of a γ-stereocenter with high enantioselectivity. We propose that this light-driven transformation proceeds via excitation of a transient enzyme–substrate complex, enabling the enzyme to access the reductive potential needed for radical initiation when the substrates are bound in the active site. This work represents a stereoselective method for synthesizing derivatives of pyridine and similar heterocycles and an expansion of the substrate capabilities of “ene”-reductases in chemical synthesis.
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Photomediated ring contraction of saturated heterocycles
Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light–mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.
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- Award ID(s):
- 1700982
- PAR ID:
- 10346090
- Date Published:
- Journal Name:
- Science
- Volume:
- 373
- Issue:
- 6558
- ISSN:
- 0036-8075
- Page Range / eLocation ID:
- 1004 to 1012
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1126/science.abi7183
