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.

Mechanism of the Helmchen synthesis; Y = auxiliary, HMPT = hexamethylphosphoric acid triamide

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 .

[brueckner-1] Reinhard Brückner: reaction mechanisms . 3rd edition, Spektrum Akademischer Verlag, Munich 2004, ISBN 3-8274-1579-9 , pp. 549-552.

[braese-2] M. Christmann, S. Bräse, D. Seebach : Asymmetric Synthesis . 2nd edition, Wiley-VCH, Weinheim, 2007, ISBN 978-3-527-32093-6 , pp. 3-9.

[3] 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 .