Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3+2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most signifcantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously

The [4+2]‐Cycloaddition of α‐Nitrosoalkenes with Thiochalcones as a Prototype of Periselective Hetero‐Diels–Alder Reactions—Experimental and Computational Studies

The [4+2]‐cycloadditions of α‐nitrosoalkenes with thiochalcones occur with high selectivity at the thioketone moiety of the dienophile providing styryl‐substituted 4H‐1,5,2‐oxathiazines in moderate to good yields. Of the eight conceivable hetero‐Diels–Alder adducts only this isomer was observed, thus a prototype of a highly periselective and regioselective cycloaddition has been identified. Analysis of crude product mixtures revealed that the α‐nitrosoalkene also adds competitively to the thioketone moiety of the thiochalcone dimer affording bis‐heterocyclic [4+2]‐cycloadducts. The experiments are supported by high‐level DFT calculations that were also extended to related hetero‐Diels–Alder reactions of other nitroso compounds and thioketones. These calculations reveal that the title cycloadditions are kinetically controlled processes confirming the role of thioketones as superdienophiles. The computational study was also applied to the experimentally studied thiochalcone dimerization, and showed that the 1,2‐dithiin and 2H‐thiopyran isomers are in equilibrium with the monomer. Again, the DFT calculations indicate kinetic control of this process

Mechanism, reactivity, and selectivity of nickel-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes.

Density functional theory (DFT) calculations with B3LYP and M06 functionals elucidated the reactivities of alkynes and Z/E selectivity of cyclodecatriene products in the Ni-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes. The Ni-mediated oxidative cyclization of butadienes determines the Z/E selectivity. Only the oxidative cyclization of one s-cis to one s-trans butadiene is facile and exergonic, leading to the observed 1Z,4Z,8E-cyclodecatriene product. The same step with two s-cis or s-trans butadienes is either kinetically or thermodynamically unfavorable, and the 1Z,4E,8E- and 1Z,4Z,8Z-cyclodecatriene isomers are not observed in experiments. In addition, the competition between the desired cooligomerization and [2 + 2 + 2] cycloadditions of alkynes depends on the coordination of alkynes. With either electron-deficient alkynes or alkynes with free hydroxyl groups, the coordination of alkynes is stronger than that of dienes, and alkyne trimerization prevails. With alkyl-substituted alkynes, the generation of alkyne-coordinated nickel complex is much less favorable, and the [4 + 4 + 2] cycloaddition occurs

Development of a Novel Epoxide-Containing Trimethylenemethane Precursor for Palladium-Catalyzed Cycloadditions

Pd(0)-catalyzed trimethylenemethane (TMM) cycloaddition reactions have been used extensively to generate disubstituted 5-membered rings with high levels of regioselectivity, chemoselectivity, and stereoselectivity. We aim to improve upon existing methodologies by introducing an epoxide into the TMM precursor, which should yield more highly functionalized products. A three step synthesis of a TMM precursor has been achieved in 20% overall yield. Efforts are underway to determine the reactivity of this precursor in Pd(0)-catalyzed cycloaddition reactions with substituted alkenes

Isomeric triazines exhibit unique profiles of bioorthogonal reactivity.

Expanding the scope of bioorthogonal reactivity requires access to new and mutually compatible reagents. We report here that 1,2,4-triazines can be tuned to exhibit unique reaction profiles with biocompatible strained alkenes and alkynes. Computational analyses were used to identify candidate orthogonal reactions, and the predictions were experimentally verified. Notably, 5-substituted triazines, unlike their 6-substituted counterparts, undergo rapid [4 + 2] cycloadditions with a sterically encumbered strained alkyne. This unique, sterically controlled reactivity was exploited for dual bioorthogonal labeling. Mutually orthogonal triazines and cycloaddition chemistries will enable new multi-component imaging applications

Phosphoramidite Gold(I)-Catalyzed Diastereo- and Enantioselective Synthesis of 3,4-Substituted Pyrrolidines

In this article the utility of phosphoramidite ligands in enantioselective AuI catalysis was explored in the development of highly diastereo- and enantioselective AuI-catalyzed cycloadditions of allenenes. A Au^I-catalyzed synthesis of 3,4-disubstituted pyrrolidines and γ-lactams is described. This reaction proceeds through the enantioselective AuI-catalyzed cyclization of allenenes to form a carbocationic intermediate that is trapped by an exogenous nucleophile, resulting in the highly diastereoselective construction of three contiguous stereogenic centers. A computational study (DFT) was also performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was demonstrated through the formal synthesis of (−)-isocynometrine

Concerted [4 + 2] and Stepwise (2 + 2) Cycloadditions of Tetrafluoroethylene with Butadiene: DFT and DLPNO-UCCSD(T) Explorations.

Tetrafluoroethylene and butadiene form the 2 + 2 cycloadduct under kinetic control, but the Diels-Alder cycloadduct is formed under thermodynamic control. Borden and Getty showed that the preference for 2 + 2 cycloaddition is due to the necessity for syn-pyramidalization of the two CF2 groups in the 4 + 2 transition state. We have explored the full potential energy surface for the concerted and stepwise reactions of tetrafluoroethylene and butadiene with density functional theory, DFT (B3LYP and M06-2X), DLPNO-UCCSD(T), and CASSCF-NEVPT2 methods and with the distortion/interaction-activation strain model to explain the energetics of different pathways. The 2 + 2 cycloadduct is formed by an anti-transition state followed by two rotations and a final bond formation transition state. Energetics are compared to the reaction of maleic anhydride and ethylene

Orthogonal, metal-free surface modification by strain-promoted azide–alkyne and nitrile oxide–alkene/alkyne cycloadditions

In this article we present a fast and efficient methodology for biochemical surface patterning under extremely mild conditions. Micropatterned azide/benzaldoxime-surfaces were prepared by microcontact printing of a heterobifunctional cyclooctyne oxime linker on azide-terminated self-assembled monolayers (SAMs). Strain-promoted azide–alkyne cycloaddition (SPAAC) in combination with microcontact printing allows fast and effective surface patterning. The resulting bifunctional azide/oxime substrates could successfully be used for metal-free, orthogonal immobilization of various biomolecules by 1,3-dipolar cycloadditions at room temperature. Azide-decorated areas were modified by reaction with a cyclooctyne-conjugate using SPAAC, while benzaldoxime-decorated areas were activated by in situ oxidation to the reactive nitrile oxides and subsequent nitrile oxide cycloaddition with alkene- and alkyne-functionalized bioconjugates. In addition, orthogonal double immobilization was achieved by consecutive and independent SPAAC and nitrile oxide cycloadditions