The application of the Diels-Alder approach to biaryls (DAB) is described for the synthesis of tetra-ortho-substituted biaryl compounds containing orthogonally functionalized substituents. The syntheses of phosphorus-containing, disubstituted alkynes and carbonyl-containing, disubstituted alkynes were accomplished in two to three steps from commercially available reagents. Subsequent Diels-Alder cycloadditions with a range of oxygenated dienes yielded the target biaryls. Further functionalization through palladium-couplings is demonstrated on the phosphorus-containing biaryls. In addition, selective manipulation of each of the remaining ortho substituents on the phosphorus-containing biaryls is demonstrated. One of these phosphorus-containing derivatives is utilized as a highly active catalyst for Suzuki coupling. For the carbonyl-containing series, a wide range of dienophile substituents were screened including esters, ketones, and amides. The key Diels-Alder cycloadditions proceeded smoothly with the commercially available 1-methoxy-1,3-cyclohexadiene to yield the resultant tetra-ortho-substituted biaryls with excellent regioselectivity. The scope of the cycloaddition process was also explored on the carbonyl-containing dienophiles with a series of cyclic dienes. Acyclic dienes were also screened; however, they did not prove effective in the Diels-Alder process with the carbonyl-containing acetylenes. The ability to isolate enantiomerically pure biaryl atropisomers using a benzyl oxazolidinone is disclosed. Finally, the subsequent conversion to an axially chiral anilino alcohol is also reported.
A rapid Diels-Alder approach to halogenated biaryl templates is described. These biaryl templates are available in two steps from the corresponding aromatic aldehydes. The scope of subsequent Suzuki couplings on the biaryl chlorides is explored. Good tolerance for both electron-donating and electron-withdrawing groups in the coupling process can be achieved. Further functionalization of the biaryl templates is described. Hydrogenation of the nitro moiety with concomitant removal of the benzyl ether yields the o-anilino, o-phenolic polyaryls. Selective reduction of the nitro group can be accomplished. Alternatively, the benzyl ether can be selectively removed under Lewis acidic conditions. The utilization of the Diels-Alder adducts for the synthesis of a series of chlorinated carbazoles via the Cadogan cyclization is also demonstrated. Finally, application of this technology to the total synthesis of siamenol, an anti-HIV agent, is reported.
An unusual organocatalytic asymmetric cyclization of a ketoazirine that is accompanied by a kinetic resolution leads to 4-hydroxy-3-oxo-1,2,3,6-tetrahydropyridine-2-carboxylates in >99/1 er.
Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regioselectivity of these cycloadditions. Several new substrates were predicted that would either give enhanced regiocontrol or invert the regiochemical preference. Experimentally, the alkynes were screened in the [3 + 2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition process and their subsequent orthogonal modification was demonstrated.
The dipolar cycloadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated. A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated.
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