An Alkoxide-Directed Intermolecular [2+2+1] Annulation

An Alkoxide-Directed Intermolecular [2+2+1] Annulation: A Three-Component Coupling Reaction for the Synthesis of Tetrasubstituted alpha,beta-Unsaturated gamma-Lactams

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Martin McLaughlin, Masayuki Takahashi, Glenn C. Micalizio*

Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520-8107, USA

This is a method to make 1,5-unsaturated amino alcohol and alpha,beta-unsaturated gamma-lactams employing [2+2+1] annulation catalyzed by titanium complex. The type of coupling is presented in the general scheme below.

The coupling relied on the ability of the homopropagylic hydroxyl group of alkyne to coordinate to titanium and direct the addition of the alkyne to the imine partner. This methodology was found to work well as illustrated with the alkyne substrates in Table 1.

It should be noted in entry 4 that the coupling of internal alkyne substituted with TMS group occurred at the alpha carbon. This was in contrast to a typical coupling of TMS-substituted alkynes where the TMS group directed the reaction to occur at the beta carbon. This effect was only possible because of the directing effect of the hydroxyl group on the titanium center which overrode the effect of the TMS group.

In a Pauson-Khand type coupling in the presence of CO2, alpha,beta-unsaturated gamma lactams could be synthesized as illustrated between various alkyne and imine substrates in Table 2.

It should be noted in entry 5 that when ortho-substituted aromatic group of imine 21 was used, the reaction occurred diastereoselectively to give a 4:1 atropisomeric mixture.

When the imine coupling partner carried a stereogenic center, the reaction was also found to occur stereoselectively both in the syntheses of 1,5-amino alcohols and gamma-lactam (Scheme 2). As for the synthesis of the amino alcohols 28 and 29, the diastereoselectivity seemed to depend on the size of the R group on the alkyne coupling partners.