Intercepting fleeting cyclic allenes with asymmetric nickel catalysis

Abstract

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity 1 . The considerable ring strain (30-50 kilocalories per mole) 2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products 4 . Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents 5,6 , catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“…Our laboratory has since developed two variants of asymmetric transition metal-catalyzed annulations of cyclic allenes, as shown in Figure . It was found that, under nickel-catalyzed annulation conditions, cyclic allene precursor 136 and benzotriazinone 137 afforded tricycle 139 in 85% yield and 94% ee . More recently, we demonstrated that reaction of silyl triflate 140 and iodopyridine 141 under palladium-catalyzed annulation conditions afforded tricycle 143 in 64% yield and 90% ee .…”

“…It was found that, under nickel-catalyzed annulation conditions, 200 cyclic allene precursor 136 and benzotriazinone 137 afforded tricycle 139 in 85% yield and 94% ee. 201 More recently, we demonstrated that reaction of silyl triflate 140 and iodopyridine 141 under palladium-catalyzed annulation conditions afforded tricycle 143 in 64% yield and 90% ee. 202 These transformations are thought to proceed via the reaction of an in situ generated, racemic cyclic allene and a transient metallocycle formed by oxidative addition.…”

“…These transformations are thought to proceed via the reaction of an in situ generated, racemic cyclic allene and a transient metallocycle formed by oxidative addition. Mechanistic details, including how absolute stereochemistry is introduced, have been proposed for the nickel-catalyzed annulation based on computations . As such, these methodologies not only provide an advance in strained cyclic allene chemistry but also are some of the few catalytic asymmetric reactions across the larger family of transiently generated cyclic intermediates (e.g., arynes, cyclic alkynes, cyclic allenes).…”

Recent Advances in Nonprecious Metal Catalysis

“…Consequently, catalytic asymmetric approaches remain a challenging task. Garg, Houk, and co-workers reported a Ni-catalyzed asymmetric approach based on utilizing an intermediate π-allylnickel complex as depicted in Scheme . A reactive Ni metallacycle is rapidly formed by an irreversible oxidative addition into benzotriazinone.…”

Origins of Endo Selectivity in Diels–Alder Reactions of Cyclic Allene Dienophiles

“…A diverse range of stereochemically‐rich products can be accessed via highly endo selective Diels–Alder cycloadditions to strained cyclic allenes, as shown by cycloadducts 1 – 4 (Figure 1 a). [2b–e] Our groups [2c,d,f–i] and others [2j,k] have generated strained cyclic allenes from silyl triflates, 5 , and have found that in situ generated heterocyclic allenes, such as unsubstituted allenes 7 and 8 , participate in highly endo selective Diels–Alder reactions to provide adducts 13 – 22 (Figure 1 b). [2c,d] …”