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. 2022 Aug 3;144(30):13946-13952.
doi: 10.1021/jacs.2c05972. Epub 2022 Jul 20.

Diastereoselective Radical 1,4-Ester Migration: Radical Cyclizations of Acyclic Esters with SmI2

Charlotte Morrill  1 , Áron Péter  1 , Ilma Amalina  1 , Emma Pye  1 , Giacomo E M Crisenza  1 , Nikolas Kaltsoyannis  1 , David J Procter  1
Affiliations

Diastereoselective Radical 1,4-Ester Migration: Radical Cyclizations of Acyclic Esters with SmI2

Charlotte Morrill et al. J Am Chem Soc. .

Abstract

Reductive cyclizations of carbonyl compounds, mediated by samarium(II) diiodide (SmI2, Kagan's reagent), represent an invaluable platform to generate molecular complexity in a stereocontrolled manner. In addition to classical ketone and aldehyde substrates, recent advances in radical chemistry allow the cyclization of lactone and lactam-type substrates using SmI2. In contrast, acyclic esters are considered to be unreactive to SmI2 and their participation in reductive cyclizations is unprecedented. Here, we report a diastereoselective radical 1,4-ester migration process, mediated by SmI2, that delivers stereodefined alkene hydrocarboxylation products via radical cyclization of acyclic ester groups in α-carbomethoxy δ-lactones. Isotopic labeling experiments and computational studies have been used to probe the mechanism of the migration. We propose that a switch in conformation redirects single electron transfer from SmI2 to the acyclic ester group, rather than the "more reactive" lactone carbonyl. Our study paves the way for the use of elusive ketyl radicals, derived from acyclic esters, in SmI2-mediated reductive cyclizations.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. (A) SmI2-Mediated Radical Cyclization of Carbonyl Compounds; (B) Radical Cyclization of Acyclic Esters with SmI2 Underpins an Unusual Radical 1,4-Ester Shift (This Work)
Scheme 2
Scheme 2. Radical Cyclization of Lactones Enabled by SmI2·H2O: (A) Our Strategy: Conformational Distortion of Sm(III)-Ketyl Radical Intermediates Drives the Cyclization of Acyclic Esters; (B) Conformation Assessment of δ-Lactones 1 by X-ray Analysis; (C) Computational Studies on Ketyl Radical Anions I (ΔG Values Reported in kJ/mol)
Percentages refer to distribution of spin density.
Figure 1
Figure 1
Scope of the method. Reaction conditions: 1 (1 equiv.), SmI2 (0.1 M in THF, 2.5 equiv.), H2O (16 equiv.), HMPA (10 equiv.), in THF (0.5 mL/0.1 mmol of substrate), at −78 °C under a nitrogen atmosphere. Isolated yields. The diastereoisomeric ratio was determined by 1H NMR analysis of the crude reaction mixture. The yellow circle within general product structure 3 denotes the stereocenter at which there is a diastereoisomeric mixture.
Scheme 3
Scheme 3. Mechanistic Studies and Proposed Reaction Pathway
The diastereoisomeric ratios were determined by 1H NMR analysis of the crude reaction mixture.
See this image and copyright information in PMC

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