Strain control in nucleophilic cyclizations: reversal of <i>exo</i>‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

Vasilevsky, S. F.; Gold, Brian; Mikhailovskaya, T. F.; Alabugin, Igor V.

doi:10.1002/poc.2990

Cited by 27 publications

(12 citation statements)

References 48 publications

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“…Cyclooctynes BT8O and IC8O possess RSE values higher than 3,4-MOBO for 2 and 1 kcal/mol, respectively. This trend coincides with the known fact of the increased RSE for structures with five-membered annulated rings compared to six-membered. ,− However, BT8S (14.6 kcal/mol) and BT9O (13.6 kcal/mol) possess significantly lower RSE values than 3,4-MOBO and similar RSE values to other known stable SPAAC reagents ( DIFO, COMBO, F ) (Figure ). Thus, RSE is not the only reason for the instability of all the target cyclooctynes and BT9O .…”

Section: Resuts and Discussionsupporting

confidence: 84%

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

et al. 2021

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In the search for fundamentally new, active, stable, and readily synthetically accessible cycloalkynes as strain-promoted azide–alkyne cycloaddition (SPAAC) reagents for bioorthogonal bioconjugation, we integrated two common approaches: the reagent destabilization by the increase of a ring strain and the transition state stabilization through electronic effects. As a result new SPAAC reagents, heterocyclononynes fused to a heterocyclic core, were created. These compounds can be obtained through a general synthetic route based on four crucial steps: the electrophile-promoted cyclization, Sonogashira coupling, Nicholas reaction, and final deprotection of Co-complexes of cycloalkynes from cobalt. Varying the natures of the heterocycle and heteroatom allows for reaching the optimal stability-reactivity balance for new strained systems. Computational and experimental studies revealed similar SPAAC reactivities for stable 9-membered isocoumarin- and benzothiophene-fused heterocycloalkynes and their unstable 8-membered homologues. We discovered that close reactivity is a result of the interplay of two electronic effects, which stabilize SPAAC transition states (πin* → σ* and π* → πin*) with structural effects such as conformational changes from eclipsed to staggered conformations in the cycloalkyne scaffold, that noticeably impact alkyne bending and reactivity. The concerted influence of a heterocycle and a heteroatom on the polarization of a triple bond in highly strained cycles along with a low HOMO–LUMO gap was assumed to be the reason for the unpredictable kinetic instability of all the cyclooctynes and the benzothiophene-fused oxacyclononyne. The applicability of stable isocoumarin-fused azacyclononyne IC9N-BDP-FL for in vitro bioconjugation was exemplified by labeling and visualization of HEK293 cells carrying azido-DNA and azido-glycans.

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Section: Resuts and Discussionsupporting

confidence: 84%

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

et al. 2021

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“…A variety of N -containing heterocycles, shown in Scheme 18, exhibit complete 6-endo-dig selectivity [64,65,66,67]. These observations are consistent with the role of strain on the competition between closely matched radical cyclization [55,68].…”

Section: Vinyl Ether Generation From Alkynessupporting

confidence: 54%

Alkynes as Synthetic Equivalents of Ketones and Aldehydes: A Hidden Entry into Carbonyl Chemistry

et al. 2019

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The high energy packed in alkyne functional group makes alkyne reactions highly thermodynamically favorable and generally irreversible. Furthermore, the presence of two orthogonal π-bonds that can be manipulated separately enables flexible synthetic cascades stemming from alkynes. Behind these “obvious” traits, there are other more subtle, often concealed aspects of this functional group’s appeal. This review is focused on yet another interesting but underappreciated alkyne feature: the fact that the CC alkyne unit has the same oxidation state as the -CH2C(O)- unit of a typical carbonyl compound. Thus, “classic carbonyl chemistry” can be accessed through alkynes, and new transformations can be engineered by unmasking the hidden carbonyl nature of alkynes. The goal of this review is to illustrate the advantages of using alkynes as an entry point to carbonyl reactions while highlighting reports from the literature where, sometimes without full appreciation, the concept of using alkynes as a hidden entry into carbonyl chemistry has been applied.

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“…We then analyzed in more detail the structural features of the transition states, some of them responsible for the exo / endo selectivity, and the intriguing finding was that the difference between the exo and endo cyclization becomes lower or even reversed for the Ni(II) species. In general, the transition states are early according to the C1–C2 bond forming distance (>2 Å, Table ), but at the same time, the M–C3 distance is in every case much shorter than M–C1, meaning that the stabilization of the developing negative charge at C3 by the metal is more important than the stabilization of the prior existing one at C1.…”

Section: Resultsmentioning

confidence: 99%

Baldwin-Type Rules for Metal-Controlled Intramolecular Migratory Insertions. A Computational Study of Ni, Pd, and Pt Case

2018

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Transition metal (Ni, Pd, Pt) promoted carbocyclizations of alkenes and alkynes have been computationally investigated to rationalize the easiness or difficulty of such processes depending on the size of the forming ring. Special emphasis has been placed on measuring the activation barriers and the exo versus endo selectivities of the processes. The study leads us to propose some qualitative rules for metal controlled ring closures, noting some discrepancies with the classical Baldwin’s rules for nonmetallic cyclizations. Also, some unexpected results were found, like the extremely low activation barriers for 3-exo-dig and 3-exo-trig closures, contrasting with the scarcity of such experimental procedures, which can be computationally interpreted by the reversibility and endergonicity of cyclopropane/cyclopropene ring formation in the presence of these metals. The consistency of the present rules has been further checked by introduction of selected structural variations in the substrates.

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Strain control in nucleophilic cyclizations: reversal of exo‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

Cited by 27 publications

References 48 publications

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

Alkynes as Synthetic Equivalents of Ketones and Aldehydes: A Hidden Entry into Carbonyl Chemistry

Baldwin-Type Rules for Metal-Controlled Intramolecular Migratory Insertions. A Computational Study of Ni, Pd, and Pt Case

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