Brian Gold

Alkenes as alkyne equivalents in radical cascades terminated by fragmentations: overcoming stereoelectronic restrictions on ring expansions for the preparation of expanded polyaromatics.

Chemoselective interaction of aromatic enynes with Bu3Sn radicals can be harnessed for selective cascade transformations, yielding either Sn-substituted naphthalenes or Sn-indenes. Depending on the substitution at the alkene terminus, the initial regioselective 5-exo-trig cyclizations can be intercepted at the 5-exo stage via either hydrogen atom abstraction or C-S bond scission or allowed to proceed further to the formal 6-endo products via homoallylic ring expansion. Aromatization of the latter occurs via β-C-C bond scission, which is facilitated by 2c,3e through-bond interactions, a new stereoelectronic effect in radical chemistry. The combination of formal 6-endo-trig cyclization with stereoelectronically optimized fragmentation allows the use of alkenes as synthetic equivalents of alkynes and opens a convenient route to α-Sn-substituted naphthalenes, a unique launching platform for the preparation of extended polyaromatics.

Rerouting Radical Cascades: Intercepting the Homoallyl Ring Expansion in Enyne Cyclizations via C–S Scission

The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C-S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu3Sn-functionalized naphthalenes.

Alkynyl Crown Ethers as a Scaffold for Hyperconjugative Assistance in Noncatalyzed Azide–Alkyne Click Reactions: Ion Sensing through Enhanced Transition-State Stabilization

Our recent work has provided an alternative strategy for acceleration of azide/alkyne cycloadditions via selective transition state (TS) stabilization. Optimization of hyperconjugative assistance, provided by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, is predicted to relieve strain in cyclooctynes while providing large acceleration to the cycloaddition. The present work investigates this strategy in alkynyl crown ethers, where propargylic C-O bonds contained within the macrocycle are constrained close to proper alignment for hyperconjugative assistance. Preorganization of σ-acceptors into the optimal arrangement for hyperconjugative interactions may alleviate a portion of the entropic penalty for reaching the TS. Optimal alignment can be reinforced, and transition-state stabilization can be further amplified by binding positively charged ions to the crown ether core, highlighting the potential for applications in ion sensing.

1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

The diazo group has untapped utility in chemical biology. The tolerance of stabilized diazo groups to cellular metabolism is comparable to that of azido groups. However, chemoselectivity has been elusive, as both groups undergo 1,3-dipolar cycloadditions with strained alkynes. Removing strain and tuning dipolarophile electronics yields diazo group selective 1,3-dipolar cycloadditions that can be performed in the presence of an azido group. For example, diazoacetamide but not its azido congener react with dehydroalanine residues, as in the natural product nisin.

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.

1,3-Dipolar Cycloaddition with Diazo Groups: Noncovalent Interactions Overwhelm Strain

Like azides, diazoacetamides undergo 1,3-dipolar cycloadditions with oxanorbornadienes (OND) in a reaction that is accelerated by the relief of strain in the transition state. The cycloaddition of a diazoacetamide with unstrained ethyl 4,4,4-trifluoro-2-butynoate is, however, 35-fold faster than with the analogous OND because of favorable interactions with the fluoro groups. Its rate constant (k = 0.53 M(-1) s(-1) in methanol) is comparable to those of strain-promoted azide-cyclooctyne cycloadditions.