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Chemical Synthesis

Leighton’s Strained Silacycles

Leighton’s Strained Silacycles: Powerful Enantioselective Allylation Reagents

    Enantioselective allylation of aldehydes
    Practical, enantioselective allylation of acylhydrazones
    Enantioselective allylation of ketimines: synthesis of tertiary carbinamines
    Friedel-Crafts Alkylation with Acylhydrazones
    Acylhydrazone-Alkene [3+2] Cycloaddition Reactions
    Products

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.

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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 (Aldrich Prod. No. 704725) based on the cyclohexane-1,2-diamine scaffold successfully allylated a broad range of aldehydes highly enantioselectively.2

Leighton Silacycles - 1

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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 (Aldrich Prod. No. 706671) for the enantioselective allylation of acylhydrazones.3

Leighton Silacycles - 2

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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 (Aldrich Prod. No. 409340).

Leighton-Silacycles - 3

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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 720380 smoothly promotes the additions of anilines to the benzoylhydrazone of isopropyl glyoxylate.

Leighton-Silacycles - 4

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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-Silacycles - 5

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Products

Prod. No. Product Name Structure
704725 (R,R)-1,3-Bis[(4-bromophenyl)methyl]-2-chlorooctahydro-2-allyl-1H-1,3,2-benzodiazasilole  
705098 (S,S)-2-Allyl-1,3-bis-(4-bromobenzyl)-2-chlorooctahydro-2-1H-1,3,2-benzodiazasilole  
706671 (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-1-oxa-3-aza-2-silacyclopentane  
719056 (4R,5R)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-1-oxa-3-aza-2-silacyclopentane 719056 Structure 
720380 (4S,5S)-2-Chloro-3,4-dimethyl-2,5-diphenyl-1-oxa-3-aza-2-silacyclopentane  
720380 (4R,5R)-2-Chloro-3,4-dimethyl-2,5-diphenyl-1-oxa-3-aza-2-silacyclopentane  

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Reference:

  1. Review: Leighton, J. L. Aldrichimica Acta 2010, 31, 3-12.
  2. Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X., Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920.
  3. Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 42, 946.
  4. Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596.
  5. Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858.
  6. Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974.

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