Schöllkopf method
Encyclopedia
The Schöllkopf method or Schöllkopf Bis-Lactim Amino Acid Synthesis is a method in organic chemistry
for the asymmetric synthesis of chiral amino acid
s. The method was established in 1981 by Ulrich Schöllkopf
. In it glycine is a substrate, valine a chiral auxiliary
and the reaction taking place an alkylation.
and chiral (R-)valine
are converted to a cyclic dipeptide
(a dioxopiperazine). A twofold methylation
forms the bis-lactim. A proton is then abstracted from the prochiral
position on glycine with the aid of BuLi. The next step decides the stereoselectivity
of the method: One face of the carbanion
ic center is shielded by steric hindrance from the isopropyl
residue on valinine. The reaction of the anion with an alkyl iodide will form the alkylated product with a strong preference for just one enantiomer
. In the final step the dipeptide is cleaved by acidic hydrolysis
in two amino acid methyl esters which can be separated from each other.
With valine Schöllkopf selected the natural proteinogenic amino acid
with the largest non-reactive and nonchiral residue in order to achieve the largest possible stereoselectivity, generally speaking enantiomeric excess
of over 95% ee is feasible.
With the Schöllkopf method all amino acids can be synthesised when a suitable R-I reagent is available. R does not need to be an alkyl group but can also be more complicated. The method is limited to the laboratory for the synthesis of exotic amino acids. Industrial applications are not known. One disadvantage is limited atom economy
.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
for the asymmetric synthesis of chiral amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. The method was established in 1981 by Ulrich Schöllkopf
Ulrich Schöllkopf
Ulrich Schöllkopf was a German chemist and together with Georg Wittig discovered the Wittig reaction in 1956. Later in 1981 he published the synthesis method for amino acids known as the Bislactimether method or Schöllkopf method....
. In it glycine is a substrate, valine a chiral auxiliary
Chiral auxiliary
A chiral auxiliary is a chemical compound or unit that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers...
and the reaction taking place an alkylation.
Reaction mechanism
GlycineGlycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
and chiral (R-)valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
are converted to a cyclic dipeptide
Dipeptide
A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond.Dipeptides are produced from polypeptides by the action of the hydrolase enzyme dipeptidyl peptidase. Dietary proteins are digested to dipeptides and amino acids, and the dipeptides are absorbed more rapidly...
(a dioxopiperazine). A twofold methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
forms the bis-lactim. A proton is then abstracted from the prochiral
Prochiral
In stereochemistry, prochiral molecules are those that can be converted from achiral to chiral in a single step.If two identical substituents are attached to a sp3-hybridized atom, the descriptors pro-R and pro-S are used to distinguish between the two...
position on glycine with the aid of BuLi. The next step decides the stereoselectivity
Stereoselectivity
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one...
of the method: One face of the carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...
ic center is shielded by steric hindrance from the isopropyl
Isopropyl
In organic chemistry, isopropyl is a propyl with a group attached to the secondary carbon. If viewed as a functional group an isopropyl is an organic compound with a propyl group attached at its secondary carbon.The bond is therefore on the middle carbon....
residue on valinine. The reaction of the anion with an alkyl iodide will form the alkylated product with a strong preference for just one enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
. In the final step the dipeptide is cleaved by acidic hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
in two amino acid methyl esters which can be separated from each other.
With valine Schöllkopf selected the natural proteinogenic amino acid
Proteinogenic amino acid
Proteinogenic amino acids are those amino acids that can be found in proteins and require cellular machinery coded for in the genetic code of any organism for their isolated production. There are 22 standard amino acids, but only 21 are found in eukaryotes. Of the 22, 20 are directly encoded by...
with the largest non-reactive and nonchiral residue in order to achieve the largest possible stereoselectivity, generally speaking enantiomeric excess
Enantiomeric excess
The enantiomeric excess of a substance is a measure of how pure it is. In this case, the impurity is the undesired enantiomer .-Definition:...
of over 95% ee is feasible.
With the Schöllkopf method all amino acids can be synthesised when a suitable R-I reagent is available. R does not need to be an alkyl group but can also be more complicated. The method is limited to the laboratory for the synthesis of exotic amino acids. Industrial applications are not known. One disadvantage is limited atom economy
Atom economy
Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved . In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted...
.