Photomediated ring contraction of saturated heterocycles

Abstract

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.

Fig. 1.. Approaches to piperidine diversification.

(A) Peripheral functionalization and skeletal remodeling. (B) Selected examples of ring contractions on piperidine frameworks. (C) Seminal report of Seebach and co-workers’ unusual THIQ ring contraction (20). (D) Contraction of carbohydrates reported by Suárez and co-workers (21). (E) Norrish type II approach to piperidine skeletal framework modification (this work).

Fig. 2.. Reaction development.

(A) Proposed mechanism for piperidine ring contraction. (B) Potential undesired side reactivity through Norrish type I and Norrish–Yang cyclization processes. (C) Reaction optimization for light-mediated ring contraction. Reactions were performed on a 0.05 mmol scale. Relative stereochemistry is depicted. *Yields were determined by ¹H NMR integration using Ph₃CH as an internal standard. †Diastereomeric ratio (d.r.) was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude mixture. ‡Reaction was performed on a 1-g scale in flow, with an isolated yield of major diastereomer reported. §High throughput experimentation (HTE) conducted to identify 3-cyanoumbelliferone. Conversion was determined by liquid chromatography–mass spectrometry analysis.

Fig. 3.. Scope of substrates in piperidine ring contraction.

Reaction conditions: Starting material (0.2 mmol), benzene (0.05 M), 400 nm LED, 18 to 24 hours. Isolated yields reported and relative stereochemistry are shown. Diastereomeric ratio was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. (A) Scope of protecting groups in ring contraction. *Additive IX (30 mol%) was added to the reaction mixture. †0.2 mmol scale trials conducted in the absence of additive IX. (B) Scope of aryl ketone in ring contraction. ‡Ring-opened product after a subsequent Norrish type II process is also observed. §(With N-Ts) Norrish–Yang azetidinol product observed in 12% (19% brsm). ¶(With N-Ts) Reaction irradiated with a medium-pressure mercury lamp for 24 hours. (C) Scope of heterocyclic core in ring contraction. #Reaction conducted on a 0.14 mmol scale. **Reaction conducted on a 0.11 mmol scale. ††Selected examples conducted on a 0.05 mmol scale using p-xylene (0.05 M) as a solvent. Yield was determined by ¹H NMR integration using Ph₃CH as an internal standard (see the supplementary materials for more details).

Fig. 4.. Applications toward biologically relevant compounds.

(A) Selected examples of bioactive drug molecule contraction. (B) Ring contraction–mediated peptide editing (see the supplementary materials for more details). (C) Sugar editing enabled by targeted “digestion.” Reaction conditions: Starting material (0.2 mmol), benzene (0.05 M), 400 nm LED, 24 hours. Isolated yields reported and relative stereochemistry are shown. Diastereomeric ratio was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. *Reaction conducted on a 0.1 mmol scale, where yield was determined by ¹H NMR integration using Ph₃CH as an internal standard and d.r. was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. †Ring-opened product also observed in 4.5% yield (see the supplementary materials for more details).

Fig. 5.. Computational studies on ring contraction mechanism.

(A) Reaction profile for the piperidine ring contraction. (B) Experimentally and computationally (normalized) determined absorption profiles for the starting material (3b) and product (4b). (C) Imine-enol geometries and transition states calculated for the diastereoselective ring closure.

Fig. 6.. Development of an asymmetric ring contraction variant.

*Reaction conducted on a 0.05 mmol scale in which yields were determined by ¹H NMR integration using Ph₃CH as an internal standard and d.r. was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. For the major diastereomer, e.r. was determined by SFC analysis. †10 mol% (R)-TRIP (CPA1) used as chiral phosphoric acid. ‡10 mol% (R)-XYL-SPA (CPA2) used as chiral phosphoric acid.