Schöllkopf bis-lactim ether method

What is Schöllkopf bis-lactim ether method?

In 1979, Schöllkopf first reported a reaction that involves the synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid such as glycine, alanine, and valine. This process includes diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol condensation or Michael addition to an α,β-unsaturated molecule and subsequent acidic hydrolysis.

Schöllkopf bis-lactim ether method - general reaction scheme - Schöllkopf bis-lactim method - Schöllkopf methodology
Schöllkopf bis-lactim ether method
  • R’ = Me, Et, etc.
  • E = electrophile, e.g., alkyl halides, tosylates, ketones, aldehydes, α,β-unsaturated compounds (see list of acronyms)

The intermediate bis-lactim ether prepared from corresponding amino acids is referred to as the Schöllkopf bis-lactim ether, Schöllkopf chiral auxiliary, Schöllkopf reagent, or Schöllkopf bis-lactim ether chiral auxiliary.

The Schöllkopf bis-lactim ether method, Schöllkopf bis-lactim method, or Schöllkopf methodology is used for the Schöllkopf bis-lactim ether-mediated synthesis of chiral nonproteinogenic amino acids. The reaction between a lithiated Schöllkopf bis-lactim ether and an electrophile is termed the Schöllkopf alkylation, while the addition of such lithiated intermediate to an α,β-unsaturated compound is referred to as the Schöllkopf-type addition.

To prepare the Schöllkopf bis-lactim ether smoothly from an amino acid, it is crucial to add 2,6-di-tert-butylpyridine to the reaction system. The alkylation of the lithiated Schöllkopf bis-lactim ether in diethyl ether contains high levels of π-facial discrimination, where the tosylate or halide electrophile is introduced into the opposite side of the bulky group on the bis-lactim ether ring. Such a stereochemical outcome is known as the Schöllkopf’s rule or Schöllkopf’s observation. However, this rule is not always followed, and the reaction is likely controlled by both reagent and substrate. For example, the reaction between the Schöllkopf bis-lactim ether with a benzyl group at the 3-position and methyl iodide or deuterium chloride all give products in favor of trans isomers, with a trans/cis ratio of 4:1, whereas the alkylation with a triflate leads to the formation of a racemic mixture.

A small amount of THF is necessary to ensure a homogeneous reaction condition due to the low solubility of the lithiated Schöllkopf bis-lactim ether in diethyl ether.

In comparison, the conjugated addition of the lithiated Schöllkopf bis-lactim ether to the α,β-unsaturated compounds may yield products with high levels of stereochemical control at both the α- and β-positions. Moreover, the lithiated Schöllkopf bis-lactim ether can add to aldehydes or ketones to yield threo diastereomers. It is essential to use a higher concentration of HCl to ensure complete hydrolysis of the Schöllkopf bis-lactim ether, rather than a mild acidic condition.

The utility of Schöllkopf bis-lactim ether method lies in its ability to synthesize unconventional amino acids that are not found in proteins, which are then employed in the creation of biologically active molecules such as immunostimulants, hormones, synthetic enzymes, and peptide drugs possessing unique properties.

References

Schöllkopf, U.; Hartwig, W. and Groth, U., Angew. Chem. Int. Ed. Engl., 1979, 18, 863

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