Leighton’s Chiral Allylation Reagents

Daniel Weibel, Ph.D.

Merck KGaA, Darmstadt, Germany

The asymmetric allylation of carbonyl compounds remains one of the most important and fundamental addition reactions for the synthesis of optically active chiral building blocks homoallylic alcohols.

In 2002, Leighton and co-workers developed strained silacycle compounds as versatile reagents for the practical enantioselective allylation of aldehydes.1

A newly developed chiral auxiliary based on the cyclohexane-1,2- diamine scaffold successfully allylated a broad range of aldehydes highly enantioselectively (Scheme 1).2

Leighton’s silacycle reagent for the enantioselective allylation of aldehydes

Scheme 1.Leighton’s silacycle reagent for the enantioselective allylation of aldehydes

The development of practical enantioselective syntheses of chiral amines is of great importance to synthetic organic and medicinal chemists. In 2003, Leighton and co-workers successfully used a pseudoephedrine-derived, five-membered-ring strained silacycle reagent for the enantioselective allylation of acylhydrazones (Scheme 2).3

Practical, enantioselective allylation of acylhydrazones using strained silacycles

Scheme 2.Practical, enantioselective allylation of acylhydrazones using strained silacycles

The reaction scope of these silacycles was extended to a practical method for the enantioselective synthesis of tertiary carbinamines based on the addition of this chiral allylsilane reagent to a structurally diverse array of ketone-derived benzoylhydrazones (Scheme 3).4 While many methods for the synthesis of quaternary α-amino acids have been published, far fewer reports have dealt with the synthesis of tertiary carbinamines.

Practical synthesis of tertiary carbinamines by enantioselective allylation of ketone-derived benzoylhydrazones

Scheme 3.Practical synthesis of tertiary carbinamines by enantioselective allylation of ketone-derived benzoylhydrazones

The free amines are easily accessed in good yields by subjecting the different hydrazones to reduction with SmI2 (409340).

Materials
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References

1. Leighton, J. L. Aldrichimica Acta 2010, 43, 3.

2. Kinnaird JWA, Ng PY, Kubota K, Wang X, Leighton JL. 2002. Strained Silacycles in Organic Synthesis: A New Reagent for the Enantioselective Allylation of Aldehydes. J. Am. Chem. Soc.. 124(27):7920-7921. http://dx.doi.org/10.1021/ja0264908

3. Kubota K, Leighton JL. 2003. A Highly Practical and Enantioselective Reagent for the Allylation of Aldehydes. Angew. Chem. Int. Ed.. 42(8):946-948. http://dx.doi.org/10.1002/anie.200390252

4. Berger R, Rabbat PMA, Leighton JL. 2003. Toward a Versatile Allylation Reagent: Practical, Enantioselective Allylation of Acylhydrazones Using Strained Silacycles. J. Am. Chem. Soc.. 125(32):9596-9597. http://dx.doi.org/10.1021/ja035001g

5. Berger R, Duff K, Leighton JL. 2004. Enantioselective Allylation of Ketone-Derived Benzoylhydrazones: Practical Synthesis of Tertiary Carbinamines. J. Am. Chem. Soc.. 126(18):5686-5687. http://dx.doi.org/10.1021/ja0486418

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