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

Abstract

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D 2 -symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Transition Metal Catalysis Controlled by Hydrogen Bonding in the Second Coordination Sphere

“…More recent examples from the Zhang group revealed that four-membered cyclic ketones also can be constructed in an enantioselective manner by a metalloradical catalyzed HAA and rebound sequence as shown in Scheme a . The related radical cascade reaction also allows for the enantioselective synthesis of bicyclic compounds illustrated in Scheme b . The enantioselectivities of these reactions again seem to be largely controlled by the hydrogen bonding interactions between the substrate(s) and chiral HB donors in the second coordination sphere of the catalyst.…”

“…453 The related radical cascade reaction also allows for the enantioselective synthesis of bicyclic compounds illustrated in Scheme 56b. 454 The enantioselectivities of these reactions again seem to be largely controlled by the hydrogen bonding interactions between the substrate(s) and chiral HB donors in the second coordination sphere of the catalyst.…”

Enantioselective radical cascade cyclization via Ti-catalyzed redox relay

“…Regarding substation on the alkyne group, electron-neutral and -rich aryl groups were compatible, delivering the corresponding bicyclic products in excellent yield with high enantioselectivity (8, 12, 13, 14). Substrates bearing haloarenes successfully participated in the reaction (6,7,11), producing a series of products that could be readily further functionalized via cross-coupling. Electron-poor aryl groups were also compatible (10,11), albeit giving marginally decreased yield and enantioselectivity.…”

“…For example, in a cobaltcatalyzed asymmetric radical cascade cyclization of 1,6-enynes with diazo compounds reported by Zhang and coworkers, precise selectivity control was achieved through fine-tuning of the structure of D2symmetric chiral amidoporphyrin ligands, enabling the construction of multisubstituted cyclopropane-fused tetrahydrofurans with excellent stereoselectivity. [6] Despite these advances, the development of new and highly effective metal-based chiral catalysts for controlling the stereoselectivity of radical cascade cyclization reactions remains an important objective in organic synthesis.…”

Computational insights into different regioselectivities in the Ir-porphyrin-catalyzed C–H insertion reaction of quinoid carbene

“…The prominent catalytic performance of Cytochrome P450 enzyme has prompted the development of a vast number of biomimetic metalloporphyrin catalysts, 1 which can react with the carbene precursor to form metalloporphyrin carbene complexes. 2 Metalloporphyrin carbene complexes can undergo C–H insertion, 3 cyclopropanation, 4 etc . to generate C–C products.…”