Site-Selectivity Control in Organic Reactions: A Quest To Differentiate Reactivity among the Same Kind of Functional Groups

Abstract

On our path to the perfection of organic synthesis lies the challenge of controlling site selectivity, which is the differentiation of reactivity among the same kind of functional groups. Overcoming this challenge would significantly enhance synthetic efficiency and minimize waste production, which in turn calls for the development of new catalysts, reagents, tactics, and innovative strategies.

Radical Cyclization of Alkene‐Tethered Ketones Initiated by Hydrogen‐Atom Transfer

“…Communications example of in situ selectivity dictated by the radical stability of HATreactions with respect to isolated alkenes. [27] Similarly, the analogous dialkene 3d gave clean cyclization of the methylene group onto the carbonyl, thus leading to the alcohol 6.T oevaluate whether our cyclization reaction could compete with radical cross-coupling reactions,weperformed the reaction of 1 in the presence of methyl vinyl ketone. [10a] Although intramolecular reactions are normally much faster, we wondered whether the formation of 7 might be favored by the potential reversibility of the reaction or by acompetitive process.Indeed, amixture of 2 and 7 (3:1) was isolated from the reaction mixture.…”

Catalyst‐Enabled Site‐Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

“…[1] This advantage stems from the fact that the siteselective reaction leaves other reactive functional groups intact and the product could be directly subjected to subsequent transformations.However,site-selectivity primarily depends on the intrinsic reactivity preference of the substrates,t hus leading to the formation of am ixture of isomers,e specially when the molecule of interest has several similar functional groups.T his common trend causes an inherent difficulty in not only enhancing the substratecontrolled selectivity but also overriding it by ac atalyst with recognition elements capable of differentiating the subtle steric and electronic differences between potential reactive sites. [1] This advantage stems from the fact that the siteselective reaction leaves other reactive functional groups intact and the product could be directly subjected to subsequent transformations.However,site-selectivity primarily depends on the intrinsic reactivity preference of the substrates,t hus leading to the formation of am ixture of isomers,e specially when the molecule of interest has several similar functional groups.T his common trend causes an inherent difficulty in not only enhancing the substratecontrolled selectivity but also overriding it by ac atalyst with recognition elements capable of differentiating the subtle steric and electronic differences between potential reactive sites.…”

“…We then thoroughly explored the scope with repsepct to the azlactones 3 in the 2i-catalyzed asymmetric 1,6-addition to 4.T he results listed in Table 2show that the incorporation of various alkyl and aryl groups onto the 4-position of 3 was tolerated and 1,6-g-Z,E-5 products were predominantly obtained with high stereoselectivities (entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. It should be noted that lowering the temperature to À40 8 8C was crucial for the additions of N-Ts-tryptophan-and phenylglycine-derived azlactones 3h and 3i,respectively,toproceed with rigorous enantiocontrol (entries 13 and 14).…”

“…Selective modification of either specific sites or functional groups of an organic compound, which has multiple sites of reactivity (site-selective reaction), is ap owerful tool for rapidly increasing molecular complexity,thereby allowing the design of astraightforward synthetic route to access complex targets. [1] This advantage stems from the fact that the siteselective reaction leaves other reactive functional groups intact and the product could be directly subjected to subsequent transformations.However,site-selectivity primarily depends on the intrinsic reactivity preference of the substrates,t hus leading to the formation of am ixture of isomers,e specially when the molecule of interest has several similar functional groups.T his common trend causes an inherent difficulty in not only enhancing the substratecontrolled selectivity but also overriding it by ac atalyst with recognition elements capable of differentiating the subtle steric and electronic differences between potential reactive sites.…”

“…At the outset, we examined the intrinsic reactivity of the enynyl N-acyl pyrazole 4 [12] as aM ichael acceptor toward an enolate of the alanine-derived azlactone 3a [13] using several common achiral bases as catalysts ( Table 1, entries [1][2][3][4]. While the treatment of 4 with 3a under the influence of KOtBu (1 equiv) in Et 2 Oat08 8Cpreferably gave adiastereomeric mixture of the 1,4-adduct, 1,4-5a[type (i a )and (i b )],the use of ac atalytic quantity of relatively strong organic bases resulted in the formation of complex mixtures containing all the expected adducts except for the allene isomer [1,6-adiastereomers (ii)].…”