Leighton’s Strained Silacycles: Powerful Enantioselective Allylation Reagents

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. Prof. James L. Leighton from Columbia University has developed a powerful method making use of silicon in constrained five-membered ring systems benefiting of an increased reactivity. These five-membered silacycles consisting of allylsilanes and a simple chiral 1,2-diol, diamine or aminoalcohol showed profound practical implications acting as chiral silicon-based Lewis acids in allylation reactions.

Enantioselective allylation of aldehydes

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.2

leighton-silacycles

Practical, enantioselective allylation of acylhydrazones

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.3

leighton-silacycles0

Enantioselective allylation of ketimines: synthesis of tertiary carbinamines

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

leighton-silacycles1

Friedel-Crafts Alkylation with Acylhydrazones

Addition of electron-rich arenes to glyoxylate-derived imines, in an overall Friedel-Crafts-like alkylation reaction, provides access to valuable arylglycine derivatives. Silacycle smoothly promotes the additions of anilines to the benzoylhydrazone of isopropyl glyoxylate.

leighton-silacycles2

Acylhydrazone-Alkene [3+2] Cycloaddition Reactions

A variety of aliphatic and aromatic aldehyde-derived benzoylhydrazones may be reacted with tert-butyl vinyl ether to give pyrazolidines with excellent levels of enantioselectivity. This reaction was easily carried out on a larger scale (5g of hydrazone) to demonstrate the true practicality and scalability of this method.

leighton-silacycles4

References

1.
Leighton JL. 2010. Powerful and versatile silicon Lewis acids for Asymmetric chemical synthesis.. Aldrichimica Acta.. 43:3-12.
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.
Shirakawa S, Berger R, Leighton JL. 2005. Enantioselective Friedel?Crafts Alkylations with Benzoylhydrazones Promoted by a Simple Strained Silacycle Reagent. J. Am. Chem. Soc.. 127(9):2858-2859. http://dx.doi.org/10.1021/ja042522a
6.
Shirakawa S, Lombardi PJ, Leighton JL. 2005. J. Am. Chem. Soc.. 127:9974-9975. https://doi.org/10.1021/ja052307+