Radical asymmetric intramolecular α-cyclopropanation of aldehydes towards bicyclo[3.1.0]hexanes containing vicinal all-carbon quaternary stereocenters

Abstract

The development of a general catalytic method for the direct and stereoselective construction of cyclopropanes bearing highly congested vicinal all-carbon quaternary stereocenters remains a formidable challenge in chemical synthesis. Here, we report an intramolecular radical cyclopropanation of unactivated alkenes with simple α-methylene group of aldehydes as C1 source via a Cu(I)/secondary amine cooperative catalyst, which enables the single-step construction of bicyclo[3.1.0]hexane skeletons with excellent efficiency, broad substrate scope covering various terminal, internal alkenes as well as diverse (hetero)aromatic, alkenyl, alkyl-substituted geminal alkenes. Moreover, this reaction has been successfully realized to an asymmetric transformation, providing an attractive approach for the construction of enantioenriched bicyclo[3.1.0]hexanes bearing two crucial vicinal all-carbon quaternary stereocenters with good to excellent enantioselectivity. The utility of this method is illustrated by facile transformations of the products into various useful chiral synthetic intermediates. Preliminary mechanistic studies support a stepwise radical process for this formal [2 + 1] cycloaddition.

Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover

“…Single-electron approaches for the cyclopropanations of alkenes are much less well-developed. Leading methods rely on the use of diazo compounds, prefunctionalized substrates, or methods that require large excesses of reagents and multiple additives . Thus, these methods are not easily employed in late-stage functionalization of complex molecules.…”

Theoretical Study of Ni-Catalyzed C–N Radical–Radical Cross-Coupling

“…Development of methods to stabilize one of the reactive radicals could prevent two transient radicals from homocoupling. Fortunately, the transition metal can be considered to be a radical shuttle to selectively combine with the transient radicals and protect it from being quenched, thereby leading to the selective radical coupling reactions . Recently, a variety of radical–radical cross-coupling reactions have been realized by this strategy …”

Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures

“…Considering the versatility of the formyl functionality, (−)- 4a may serve as a valuable intermediate for further transformations. For instance, treatment of (−)- 4a with Bestmann reagent under basic conditions led to high-yielding production of bicyclic compound (−)- 5a bearing a terminal alkyne, which is a popular motif in click chemistry for bioconjugation applications (Scheme , eq 1) . As another example, the aldehyde functionality in (−)- 4a could undergo reductive amination with different amines by using sodium triacetoxyborohydride, as shown by its productive reaction with secondary amine morpholine to generate bicyclic compound (−)- 6a in good yield (Scheme , eq 2) .…”

“…For instance, treatment of (−)-4a with Bestmann reagent under basic conditions led to high-yielding production of bicyclic compound (−)-5a bearing a terminal alkyne, which is a popular motif in click chemistry for bioconjugation applications (Scheme 4, eq 1). 12 As another example, the aldehyde functionality in (−)-4a could undergo reductive amination with different amines by using sodium triacetoxyborohydride, 13 as shown by its productive reaction with secondary amine morpholine to generate bicyclic compound (−)-6a in good yield (Scheme 4, eq 2). 12 Furthermore, the trisubstituted alkene in (+)-3a could be productively reduced with dihydrogen on Pd/C to give αcyanoacetate-containing compound 7a, which could undergo decarboxylation to afford bicyclic compound (−)-8a bearing propanenitrile in good yield with almost full preservation of the original optical purity (Scheme 4, eq 3).…”