Copper-chelating azides for efficient click conjugation reactions in complex media.

The concept of chelation-assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper-chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.

Iridium-catalyzed cycloaddition of azides and 1-bromoalkynes at room temperature.

Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.

Total synthesis of auripyrone B using a non-aldol aldol-cuprate opening process.

A non-aldol aldol-cuprate opening generates the polypropionate 11 from the epoxy ether 14 in eight steps as a single diastereomer. A highly stereoselective aldol reaction of 8 with 9 gives the aldol product 7 in high yield and excellent diastereoselectivity, due to double stereodifferentiation. This compound was used for an efficient synthesis of the natural product auripyrone B 2 in only 20 steps and 8% overall yield from 14 using a late-stage spiroketalization onto a stable hemiketal as the final key step.

Cycloadditions of 1,1-disubstituted benzocyclobutenes obtained by C(sp3)-H activation.

An efficient synthesis of polycyclic molecules has been performed by a sequence involving palladium-catalyzed C-H activation and [4 + 2] cycloaddition. The intermediate benzocyclobutenes underwent a microwave-enhanced electrocyclic ring-opening/cycloaddition process with complete torquoselectivity and diastereoselectivity.

Synthesis of benzocyclobutenes by palladium-catalyzed C-H activation of methyl groups: method and mechanistic study.

An efficient catalytic system has been developed for the synthesis of benzocyclobutenes by C-H activation of methyl groups. The optimal conditions employed a combination of Pd(OAc) 2 and P ( t )Bu 3 as catalyst, K 2CO 3 as the base, and DMF as solvent. A variety of substituted BCB were obtained under these conditions with yields in the 44-92% range, including molecules that are hardly accessible by other methods. The reaction was found limited to substrates bearing a quaternary benzylic carbon, but benzocyclobutenes bearing a tertiary benzylic carbon could be obtained indirectly from diesters by decarboxylation. Reaction substrates bearing a small substituent para to bromine gave an unexpected regioisomer that likely arose from a 1,4-palladium migration process. The formation of this "abnormal" regioisomer could be suppressed by introducing a larger subsituent para to bromine. DFT(B3PW91) calculations on the reaction of 2-bromo-tert-butylbenzene with Pd(P ( t )Bu 3) with different bases (acetate, bicarbonate, carbonate) showed the critical influence of the coordination mode of the base to induce both an easy C-H activation and to allow for a pathway for 1,4-palladium migration. Carbonate is shown to be more efficient than the two other bases because it can abstract the proton easily and at the same time maintain kappa (1)-coordination without extensive electronic reorganization.