Rhodium-Catalyzed Enantioselective Cycloaddition Route to Indolizidines

indolizidines - alkenyl isocyanates - alkynes - cycloaddition - rhodium catalysis

Significance

<P>Described herein is a synthesis of indolizidines by an asymmetric Rh(I)-catalyzed [2+2+2] cycloaddition of 1,1-disubstituted alkenyl isocyanates to terminal alkynes. The reaction proceeds in moderate to high yields with a high level of enantio- and regioselectivity in the presence of the phosphoramidite ligands. Aliphatic alkynes gave lactams A as major products whereas vinylogous amides B predominated with aryl alkynes. The formation of 2-pyridones E as the major byproduct was suppressed under high dilution reaction conditions (typically 0.04 M). The isolated yields were low with sterically demanding substituents (e.g., R¹ = i-Pr, Cy) and in such reactions an increase in the 2-pyridone byproduct was observed, presumably due to a slow rate of coordination-insertion of the alkene with Rh.</P>

Comment

<P>The indolizidine and quinolizidine framework are present in many biologically important natural products (J. R. Linddell Nat. Prod. Rep. 2002, 773; J. P. Michael Nat. Prod. Rep. 2007, 191), for example, marine alkaloids cylindricine A-F (see review below). This present work constitutes an extension of the methodology previously applied by the Rovis group in the synthesis of the natural product (+)-lasubine II demonstrating the use of this methodology (J. Am. Chem. Soc. 2006, 128, 12370). The scope of the reaction was reasonably well established.</P>

Review

<P>S. M. Weinreb Chem. Rev. 2006, 106, 2531-2549.</P>