Radicals in natural product synthesis

Abstract

Free radical intermediates have intrigued chemists since their discovery, and an ever-increasing appreciation for their unique reactivity has resulted in the widespread utilization of these species throughout the field of chemical synthesis. This is most evident from the recent surge in the application of intermolecular radical reactions that feature in complex molecule syntheses. This tutorial review will discuss the diverse methods utilized for radical generation and reactivity to form critical bonds in natural product total synthesis. In particular, stabilized (e.g. benzyl) and persistent (e.g. TEMPO) radicals will be the primary focus.

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

“…Therefore, the minimal diastereoselectivity observed for 5 – 20 is in agreement with prior methods for preparing these materials, as is the excellent diastereoselectivity observed for 23 and 24 . The influence of additional stereocenters present in 23 / 24 presumably has a greater impact on the orientation in which the persistent radicals recombine, resulting in an increase in diastereoselectivity when moving from the dimer to the tetramer system . Importantly, the preparation of tert ‐butylated dimers ( 5 – 7 , 10 – 20 , 23 ) did not require chromatographic purification, which is highly advantageous for multi‐step syntheses and provides an attractive alternative to stoichiometric dimerization methods.…”

Vitamin B12 Enables Consecutive Generation of Acyl and Alkyl Radicals from One Reagent

“…[8][9][10][11][12][13][14] Of particular importance are Co complexes that mimic native reactivity of vitamin B 12 (1, cobalamin) (Figure 1, Scheme 1). [15][16][17][18] These are represented by cobaloxime (2) [19] and heptamethyl cobyrinate ((CN)(H 2 O)Cby(OMe) 7, 3) which is a derivative of vitamin B 12 that have been already successfully applied to radical-processes. [15,20] Catalytic activity of these compounds is inherently connected with the central Co(III) ion and its ability to access +1 Mechanistic studies reveal that alkyl corrins forms at much higher rate than the respective acyl derivatives enabling selective reactions with activated olefins.…”

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

“…To determine whether the desired dimerization would be feasible under anodic oxidation conditions,w einterrogated the oxidation potential of various 4-hydroxystilbene substrates using cyclic voltammetry (see page S38 of the Supporting Information). [5d] It was apparent that both electron-withdrawing and electron-donating groups were tolerated at each position of this aromatic ring as reactions proceeded with aw ide variety of electronically distinct substrates in excellent yields (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). With this information in hand (see page S43 of the Supporting Information for complete details), we developed conditions where anodic oxidation in the presence of 2,6-lutidine enables phenoxyl radical dimerization ( Figure 2).…”

“…[19] Importantly,t he preparation of tertbutylated dimers (5-7, 10-20, 23)d id not require chromatographic purification, which is highly advantageous for multistep syntheses and provides an attractive alternative to stoichiometric dimerization methods. [19] Importantly,t he preparation of tertbutylated dimers (5-7, 10-20, 23)d id not require chromatographic purification, which is highly advantageous for multistep syntheses and provides an attractive alternative to stoichiometric dimerization methods.…”

“…[5d] Therefore,t he minimal diastereoselectivity observed for 5-20 is in agreement with prior methods for preparing these materials,a si s the excellent diastereoselectivity observed for 23 and 24.The influence of additional stereocenters present in 23/24 presumably has agreater impact on the orientation in which the persistent radicals recombine,r esulting in an increase in diastereoselectivity when moving from the dimer to the tetramer system. [19] Importantly,t he preparation of tertbutylated dimers (5-7, 10-20, 23)d id not require chromatographic purification, which is highly advantageous for multistep syntheses and provides an attractive alternative to stoichiometric dimerization methods.…”