Chemoselective Suzuki Cross-Coupling Reactions of Chiral Pyrrolizines

摘要

Pyrrolizines have potent cytostatic effects and are thus potentially useful for the development of antitumor and antiviral agents. In particular, chiral trifluoromethylated pyrrolizines would play a unique and significant role in medicinal chemistry because the introduction of a trifluoromethyl group into pharmaceuticals often enhances their physical and/or chemical properties. Recently, we reported that the enantio- and diastereo-selective organocatalytic cascade conjugate addition-aldol reactions of a series of 2-trifluoroacetylpyrroles to α,β-unsaturated aldehydes afford highly functionalized chiral pyrrolizines that bear a trifluoromethyl group at the stereogenic center in good yields, high enantioselectivities, and excellent diastereoselec-tivities. Using the chiral pyrrolizines as the cascade products, we planned the development of an efficient synthesis of un-symmetrically diarylsubstituted chiral pyrrolizines via two sequential Suzuki cross-coupling reactions with different aryl-boronic acids in a highly chemoselective controlled manner. Specifically, in these two sequential Suzuki couplings of multiple halogenated heterocycles, the use of pyrrolizines remains unexplored, in spite of the importance of pyrrolizines as pharmacophores in biologically active compounds. Here, we report the development of the efficient synthetic route of a series of unsym-metrically 5,6-diarylsubstituted chiral pyrrolizines via chemoselective Suzuki cross-coupling reactions of chiral 6-bromo-5-iodopyrrolizines, followed by the sequential 2nd Suzuki cross-coupling reaction (Scheme 1).