SAMARIUM CATALYSIS

SAMARIUM CATALYSIS

Author: Dr Frédéric Beltran

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Over the last four decades, Samarium iodide (SmI₂, Kagan’s reagent) has been extensively used as a single-electron transfer (SET) reagent. “Unfortunately, SmI₂ must almost always be used in significant excess, thus raising issues of cost and waste.”¹ Of the few reports utilising catalytic SmI₂, all require the use of a super-stoichiometric amount of a metal co-reductant (magnesium, zinc amalgam, mischmetal), additives (TMSOTf, TMSCl) or electrochemistry (samarium electrodes) to achieve a turnover and regenerate Sm(II). Until recently, these systems remained state of the art.

In recent years, the Procter group has demonstrated the possibility of using solely sub-stoichiometric amounts of SmI₂ to catalyse radical cyclisation cascades to produce complex polycyclic scaffolds. The recent methods developed by the group rely on a radical-relay approach, with a careful design of the reaction mechanism, that eliminates the need for a co-reductant or additives.

The initial intramolecular SmI₂-catalysed radical cyclisation cascades reported by Procter and co-workers operated with SmI₂ loadings as low as 5 mol% and delivered complex polycyclic products containing up to four stereocentres, in high yields and typically with good diastereocontrol.^1,2

The spring-loaded nature of the cyclopropyl substituted ketone 1 is the key to the catalytic radical process. This transformation starts with a reversible SET from Sm(II) to the substrate 1 to produce a ketyl radical 2 which fragments, by cyclopropyl-ring opening, to give an enolate radical 3. Subsequent intramolecular cyclisation, with the pendant alkyne or alkene acting as a radical trap, generates a new radical 4, which rebounds by addition to the Sm(III)-enolate, thus generating a new ketyl radical 5. Back electron transfer to Sm(III) regenerates the SmI₂ catalyst and liberates the product 6. Furthermore, dearomatizing radical cyclisations were also successful using heteroarene substrates as the radical acceptor.

A more challenging intermolecular cross-coupling of cyclopropyl ketones 7 and alkynes 8, using the SmI₂-catalysed radical-relay approach, was successfully performed for the construction of decorated cyclopentenes 9.³

More recently, applying the SmI₂-catalysed approach to spring-loaded bicyclo[1.1.0]butyl ketones 10 and electron-deficient alkenes 11 allowed for the synthesis of bicyclo[2.1.1]hexanes 12, with a high-profile role as saturated bioisosteres of substituted benzenes in medicinal chemistry.⁴

References

1. H.-M. Huang, J. J. W. McDouall, D. J. Procter, Nature Catalysis 2019, 2, 211-218.
2. H.-M. Huang, Q. He, D. J. Procter, Synlett 2020, 31, 45-50.
3. S. Agasti, N. A. Beattie, J. J. W. McDouall, D. J. Procter, J. Am. Chem. Soc. 2021, 143, 3655-3661.
4. S. Agasti, F. Beltran, E. Pye, N. Kaltsoyannis, G. E. M. Crisenza, D. J. Procter, Nature Chemistry 2023, 15, 535-541.