Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

Abstract

Arynes, strained cyclic alkynes, and strained cyclic allenes were validated as plausible intermediates in the 1950s and 1960s. Despite initially being considered mere scientific curiosities, these transient and highly reactive species have now become valuable synthetic building blocks. This Perspective highlights recent advances in the field that have allowed access to structural and stereochemical complexity, including recent breakthroughs in asymmetric catalysis.

Access to and unexplored reactivity of nickel-bound 5-membered O- and N-heterocyclic arynes via computational insight

“…Having successfully isolated two new aryne complexes we next sought to access nickel-bound benzofuran-2,3-yne, a target sought after for over 120 years as it was the first ever proposed aryne intermediate but was later disproven. 7,14 Based on the necessary steric interactions needed for transmetallation to proceed, we anticipated that the benzofuran-2,3-yne complex would also need a larger bite angle ligand. Indeed, activation of complex 3c-dcpe with KO t Pent did not yield the desired aryne complex 5c-dcpe ( Fig.…”

Access to and unexplored reactivity of nickel-bound 5-membered O- and N-heterocyclic arynes via computational insight

“…Having successfully isolated two new aryne complexes we next sought to access nickel-bound benzofuran-2,3-yne, a target sought after for over 120 years as it was the first ever proposed aryne intermediate but was later disproven. 7,14 Based on the necessary steric interactions needed for transmetallation to proceed, we anticipated that the benzofuran-2,3-yne complex would also need a larger bite angle ligand. Indeed, activation of complex 3c-dcpe with KO t Pent did not yield the desired aryne complex 5c-dcpe ( Fig.…”

Highly Enantioselective Formal Synthesis of (+)‐Treprostinil Enabled by Rhodium‐Catalyzed Enyne Cycloisomerization

“…The chemoselectivity was probably attributed to the high electrophilicity of C1 position of benzyne Int1 as well as the less sterically hindered 1,1‐disubstituted olefin of 21 . [ 35‐38 ] Subsequently, a 1,5‐H transfer could furnish 23 as the sole product. Although the B ring of Treprostinil ( 1 ) was not obtained via this approach, a new type of interphenylene prostaglandin scaffold was accessed.…”

Alkenylthianthrenium Salts as Synthetic Equivalents of (Cyclo)alkynes in Azide Cycloaddition Reactions

“…[ 14 ] Other substituted cyclohexenylthianthrenium substrates furnished high yields, as demonstrated for triazoles 5i/5i’ (88% combined yield of regioisomers) and 5j/5j’ (71% combined yield). Tolerance of the free alcohol in thianthrenium 3j emphasizes the complementary advantages of this methodology alongside those that rely on in situ generation of the cycloalkyne, since the susceptibility of strained cycloalkynes toward nucleophilic addition [ 47 ] precludes substrates with pendant nucleophiles. Triazole 5k/5k’ was obtained in 63% combined yield from 3,6‐dihydropyran‐derived thianthrenium 3k/3k’ , and alkenylthianthrenium 3l , synthesized from 3,4‐dihydropyran as a single regioisomer, gave a single triazole product, 5l , in slightly higher yield at 57%.…”

Access to and unexplored reactivity of nickel-bound 5-membered O- and N-heterocyclic arynes via computational insight

“…Having successfully isolated two new aryne complexes we next sought to access nickel-bound benzofuran-2,3-yne, a target sought after for over 120 years as it was the first ever proposed aryne intermediate but was later disproven. 7,14 Based on the necessary steric interactions needed for transmetallation to proceed, we anticipated that the benzofuran-2,3-yne complex would also need a larger bite angle ligand. Indeed, activation of complex 3c-dcpe with KO t Pent did not yield the desired aryne complex 5c-dcpe ( Fig.…”

Highly Enantioselective Formal Synthesis of (+)‐Treprostinil Enabled by Rhodium‐Catalyzed Enyne Cycloisomerization

“…The chemoselectivity was probably attributed to the high electrophilicity of C1 position of benzyne Int1 as well as the less sterically hindered 1,1‐disubstituted olefin of 21 . [ 35‐38 ] Subsequently, a 1,5‐H transfer could furnish 23 as the sole product. Although the B ring of Treprostinil ( 1 ) was not obtained via this approach, a new type of interphenylene prostaglandin scaffold was accessed.…”

Alkenylthianthrenium Salts as Synthetic Equivalents of (Cyclo)alkynes in Azide Cycloaddition Reactions

“…[ 14 ] Other substituted cyclohexenylthianthrenium substrates furnished high yields, as demonstrated for triazoles 5i/5i’ (88% combined yield of regioisomers) and 5j/5j’ (71% combined yield). Tolerance of the free alcohol in thianthrenium 3j emphasizes the complementary advantages of this methodology alongside those that rely on in situ generation of the cycloalkyne, since the susceptibility of strained cycloalkynes toward nucleophilic addition [ 47 ] precludes substrates with pendant nucleophiles. Triazole 5k/5k’ was obtained in 63% combined yield from 3,6‐dihydropyran‐derived thianthrenium 3k/3k’ , and alkenylthianthrenium 3l , synthesized from 3,4‐dihydropyran as a single regioisomer, gave a single triazole product, 5l , in slightly higher yield at 57%.…”

Access to and unexplored reactivity of nickel-bound 5-membered O- and N-heterocyclic arynes via computational insight

“…Having successfully isolated two new aryne complexes we next sought to access nickel-bound benzofuran-2,3-yne, a target sought after for over 120 years as it was the first ever proposed aryne intermediate but was later disproven. 7,14 Based on the necessary steric interactions needed for transmetallation to proceed, we anticipated that the benzofuran-2,3-yne complex would also need a larger bite angle ligand. Indeed, activation of complex 3c-dcpe with KO t Pent did not yield the desired aryne complex 5c-dcpe ( Fig.…”

Highly Enantioselective Formal Synthesis of (+)‐Treprostinil Enabled by Rhodium‐Catalyzed Enyne Cycloisomerization

“…The chemoselectivity was probably attributed to the high electrophilicity of C1 position of benzyne Int1 as well as the less sterically hindered 1,1‐disubstituted olefin of 21 . [ 35‐38 ] Subsequently, a 1,5‐H transfer could furnish 23 as the sole product. Although the B ring of Treprostinil ( 1 ) was not obtained via this approach, a new type of interphenylene prostaglandin scaffold was accessed.…”

Alkenylthianthrenium Salts as Synthetic Equivalents of (Cyclo)alkynes in Azide Cycloaddition Reactions

“…[ 14 ] Other substituted cyclohexenylthianthrenium substrates furnished high yields, as demonstrated for triazoles 5i/5i’ (88% combined yield of regioisomers) and 5j/5j’ (71% combined yield). Tolerance of the free alcohol in thianthrenium 3j emphasizes the complementary advantages of this methodology alongside those that rely on in situ generation of the cycloalkyne, since the susceptibility of strained cycloalkynes toward nucleophilic addition [ 47 ] precludes substrates with pendant nucleophiles. Triazole 5k/5k’ was obtained in 63% combined yield from 3,6‐dihydropyran‐derived thianthrenium 3k/3k’ , and alkenylthianthrenium 3l , synthesized from 3,4‐dihydropyran as a single regioisomer, gave a single triazole product, 5l , in slightly higher yield at 57%.…”