Regio‐ and Stereoselective Synthesis of Tri‐ and Tetrasubstituted Alkenes by Introduction of CO 2 and Alkylzinc Reagents into Alkynes

Carbon dioxide (CO 2 ) is a useful C‐1 unit resource in synthetic organic chemistry. It was known that a low‐valent nickel complex could coordinate to CO 2 to form an oxanickelacyclopropane, which reacts with a terminal alkyne to form an oxanickelacyclopentene. Transmetalation of the oxanickelacyclopentene with an alkylzinc reagent gives a trisubstituted alkene in high yield after hydrolysis. A novel synthetic method for heterocycles from terminal alkynes containing suitably positioned heteroatoms was developed, using this alkylative carboxylation followed by a hetero‐Michael reaction. Using this procedure, the synthesis of erythrocarine, one of the erthrina alkaloids, the total synthesis of which had not previously been achieved, was developed. Additionally, a regioselective synthesis of tetrasubstituted alkenes from disubstituted alkynes was also examined. A silylated alkyne was used and a tetrasubstituted alkene was obtained regioselectively. This reaction was further developed into a nickel‐catalyzed reaction, and the effects of substituents on the alkyne were also examined. It was found that an alkyne containing a tert ‐butyl or a phenyl group predominantly gave one tetrasubstituted alkene. The results indicated that conjugation of the carboxyl group with the substituent in the oxanickelacyclopentene is important for the formation of oxanickelacycles, and that the thermodynamically more stable oxanickelacycle should be formed. Thus, thermodynamically more stable alkenes are formed; that is, an electron‐donating group on the alkene would conjugate with the carboxyl group. Using this procedure, it was possible to synthesize tamoxifen, which is effective for the treatment of metastatic breast cancer and contains a tetrasubstituted alkene in its skeleton.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)