Helmchen synthesis
The Helmchen synthesis is a name reaction from the field of organic chemistry . It is used to synthesize α- chiral carboxylic acids or β-chiral alcohols . The reaction is named after its developer, the German chemist Günter Helmchen .
Helmet auxiliary
The Helmchen synthesis makes use of a chiral auxiliary , which is also referred to as the Helmchen auxiliary . This can be obtained in several reaction steps from commercially available camphor . Since both enantiomers of camphor are available, both enantiomers of the auxiliary can be obtained in this way. The auxiliary has sterically demanding phenyl and dimethylphenyl residues . This means that one side of the molecule is effectively shielded during a reaction and a reaction can only take place in the second half-space. This forms the basis of the enantioselectivity that this auxiliary induces. The auxiliary can be coupled to the carboxylic acid on which the reaction is to take place by esterification .
Reaction mechanism
The present ester is a CH-acidic compound which is deprotonated with a base in the first step , whereby an enolate is formed. Lithium amides such as lithium diisopropylamide (LDA) are suitable as bases . However, better results are obtained with amide bases which have a sterically more demanding radical than the isopropyl group , for example with lithium cyclohexylisopropylamide . If only the base is used for enolate formation, the trans -enolate is obtained according to the Ireland model ; when hexamethylphosphoric acid triamide (HMPT) is added, the cis -enolate is produced, since the HMPT prevents the lithium-containing base from complexing with the enolate during the transition state. This is now made to react with the connection to be coupled. For this purpose, this compound must have a leaving group which the compound can leave in the event of a nucleophilic attack by the enolate in the sense of a substitution reaction . The bromides , which are usually easily accessible, are suitable for this purpose . In this step, an ester substituted in the α-position with high diastereoselectivity is obtained. The pure diastereomer can be obtained by subsequent chromatographic work-up. A subsequent reduction with lithium aluminum hydride (LAH) leads to the formation of the desired chiral alcohol with cleavage of the auxiliary.
With the help of the Helmchen auxiliary, for example, the enantioselective synthesis of the α- tocopherol side chain was achieved.
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- ↑ a b c Reinhard Brückner: reaction mechanisms . 3rd edition, Spektrum Akademischer Verlag, Munich 2004, ISBN 3-8274-1579-9 , pp. 549-552.
- ↑ a b M. Christmann, S. Bräse, D. Seebach : Asymmetric Synthesis . 2nd edition, Wiley-VCH, Weinheim, 2007, ISBN 978-3-527-32093-6 , pp. 3-9.
- ↑ Günter Helmchen, Roland Schmierer: A Total Synthesis of Enantiomerically Pure Vitamin E Side Chain Using a Chiral Propionate Synthon . In: Tetrahedron Letters . tape 24 , no. 12 , 1983, p. 1235-1238 , doi : 10.1016 / S0040-4039 (00) 81623-8 .