Allenation of Terminal Alkynes with Aldehydes and Ketones.

So far, over 150 natural products and pharmaceuticals containing an allene moiety have been identified. During the last two decades, allenes have also been demonstrated as synthetically versatile starting materials in organic synthesis. In comparison to alkenes and alkynes, allenes are unique unsaturated hydrocarbons due to their axial chirality, which could be transformed to central chirality via chirality transfer to provide an irreplaceable entry to chiral molecules. Thus, methods for allene synthesis from readily available chemicals are of great interest. In 1979, Crabbé et al. reported the first CuBr-mediated allenation of terminal alkynes (ATA) reaction to form monosubstituted allenes from 1-alkynes and paraformaldehyde in the presence of diisopropylamine. During the following 30 years, the ATA reactions were limited to paraformaldehyde. This Account describes our efforts toward the development of ATA reactions in the last ten years. First, we improved the yields and scope greatly for the synthesis of monosubstituted allenes by modifying the original Crabbé recipe. Next we developed the ZnI-promoted or CuI-catalyzed ATA reactions for the synthesis of 1,3-disubstituted allenes from terminal alkyne and normal aldehydes. Furthermore, we first realized the CdI-promoted ATA reaction of ketones with pyrrolidine as the matched amine for the preparation of trisubstituted allenes. Due to the toxicity of CdI, we also developed two alternative approaches utilizing CuBr/ZnI or CuI/ZnBr/Ti(OEt). The asymmetric version of ATA reactions for the synthesis of optically active 1,3-disubstituted allenes has also been achieved in this group with two strategies. One is called "chiral ligand" strategy, using terminal alkynes, aldehydes, and nonchiral amine with the assistance of a proper chiral ligand. The other is the "chiral amine" strategy, applying terminal alkynes, aldehydes, and chiral amines such as ( S)- or ( R)-α,α-diphenylprolinol or ( S)- or ( R)-α,α-dimethylprolinol. Optically active 1,3-disubstituted allenes containing different synthetically useful functionalities such as alcohol, amide, sulfamide, malonate, carboxylate, and carbohydrate units could be prepared without protection with the newly developed CuBr-catalyzed chiral amine strategy. Recently, we have applied these enantioselective allenation of terminal alkyne (EATA) reactions to the syntheses of some natural allenes such as laballenic acid, insect pheromone, methyl ( R)-8-hydroxyocta-5,6-dienoate, phlomic acid, and lamenallenic acid, as well as some non-allene natural γ-butyrolactones such as xestospongienes (E, F, G, and H), ( R)-4-tetradecalactone, ( S)-4-tetradecalactone, ( R)-γ-palmitolactone, and ( R)-4-decalactone.