Forging C(sp³)–C(sp³) Bonds with Carbon-Centered Radicals in the Synthesis of Complex Molecules

Abstract

Radical fragment coupling reactions that unite intricate subunits have become an important class of transformations within the arena of complex molecule synthesis. This Perspective highlights some of the early contributions in this area, as well as more modern applications of radical fragment couplings in the preparation of natural products. Additionally, emphasis is placed on contemporary advances that allow for radical generation under mild conditions as a driving force for the implementation of radical fragment couplings in total synthesis.

Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

“…Subsequent irradiation with blue LEDs resulted in a successful spirocyclization that returned heteroclitin J (3) 14 in an isolated yield of 88% on 250 mg scale. Based on previous studies of similar photocatalytic reactions, 27 we believe that Et 3 N reduces photo-excited Ru-(II) to Ru-(I), which in turn reduces the N-phthalimidoyl ester of 16 to trigger fragmentation. This would release phthalimide anion, carbon dioxide (CO 2 ) and the phenoxy-methyl radical 18, before installation of the quaternary stereocenter by 5-exo-trig spirocyclization.…”

“…25 Therefore, we considered more recently developed photoredox mediated conditions, 26 in which carbon centered radicals are formed by one electron reduction of an (N-acyloxy)-phthalimide (NHPI) redox-active ester (Scheme 2C). 27 By generating the phenoxy methyl radical catalytically under redox neutral conditions, we hoped to approximate the biosynthetic environment of the oxygenase's active site, under the assumption that it prolongs radical lifetime without necessarily influencing its innate reactivity. This led us to identify radical progenitors 16 and 17 as strategic molecules from which to explore this hypothesis.…”

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

“…When we initiated studies to develop a chemical synthesis of macfarlandin C ( 2 ), only the related structural archetypes cheloviolene A ( 3 ) and cheloviolene B having the hydrocarbon fragment positioned on the convex face of the cis ‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one unit had been synthesized . The approach employed in these syntheses to access the 6‐substituted cis ‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one moiety relied on the coupling of a tertiary radical with a 5‐alkoxy butenolide . Although this approach allowed for facile access to diterpenoids bearing the C‐6 hydrophobic fragment on the convex face of the cis ‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one unit, we were unable to tune this coupling to access the alternate stereoisomer .…”

“…[8] The approach employed in these syntheses to access the 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety relied on the coupling of a tertiary radical with a 5-alkoxy butenolide. [9] Although this approach allowed for facile access to diterpenoids bearing the C-6 hydrophobic fragment on the convex face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit, we were unable to tune this coupling to access the alternate stereoisomer. [8b] We report herein the development of a synthetic approach to cis-2,8-dioxabicyclo[3.3.0]octan-3-ones attached at C-6 to a quaternary carbon of a bulky hydrophobic fragment that allows for the divergent synthesis of either C-6 substituted stereoisomeric from the product of fragment coupling (Scheme 1).…”

Total Synthesis of 1‐Hydroxytaxinine

“…Radical reactions are compatible with diverse oxygen functionalities and applicable to the formation of sterically hindered CÀCbonds,thereby serving as methods to forge the complex architectures of highly oxygenated terpenoids. [9] In this context, we developed as eries of powerful coupling reactions of a-alkoxy carbon radicals. [10,11] Our continued interest in these reactions motivated us to devise an efficient radical-based convergent route to 1 from chiral 5 and achiral 6 (Scheme 1).…”