Fráter-Seebach alkylation

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The Fráter-Seebach alkylation is a name reaction in organic chemistry . This was first described in 1979 by Georg Fráter (1941–2019). In 1980 Dieter Seebach reported a similar reaction with a malate . This synthesis serves to alkylate β-hydroxy esters stereospecifically in the α-position.

Overview reaction

A β-hydroxy ester can be alkylated diastereoselectively in the α-position with the aid of a strong base and a haloalkane . R 2 and R 3 are hydrocarbon radicals . R 1 can also correspond to a hydrogen.

Frater Seebach alkylation ÜV5.svg

General

The Fráter-Seebach alkylation is about the asymmetric alkylation of chiral β-hydroxyesters. The synthesis requires a temperature between −78 ° C and 10 ° C, depending on the reaction step. Tetrahydrofuran (THF) is a very suitable solvent . A very strong base is also required for the reaction. Lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LHMDS) are preferably used for this purpose .

The anti product is produced with high stereoselectivity; only a very small proportion of syn product is produced.

Reaction mechanism

The reaction mechanism of the Fráter-Seebach alkylation is believed to be as follows. In the first step, the hydroxy group of the β-hydroxyester 1 is deprotonated by a strong lithium base. The alcoholate ester 2 is formed . In the next step, an acidic hydrogen at the α-position is eliminated by a strong lithium base. The dianion 3 is created . With the addition of a haloalkane, alkylation takes place in the anti position to the alcoholate . The alcoholate ester 4 is formed . The β-hydroxy ester 5 is formed by protolysis .

Frater Seebach alkylation RM6.svg

Variations

Synthesis processes according to the Fráter-Seebach alkylation can not only be carried out with haloalkanes. The reaction can also be used for the allylation and arylation of β-hydroxyesters.

application

Due to the diastereoselectivity and the high yield, the Fráter-Seebach alkylation is still used. The yield is significantly lower in the case of alkylations with longer-chain haloalkanes. Furthermore, the yield is not only dependent on R 2 , but also strongly on the nature of R 1 . The reaction is mainly used for the production of natural substances and inhibitors .

Individual evidence

  1. a b c Dieter Seebach, Daniel Wasmuth: Production of erythro-2-hydroxysuccinic acid derivatives from malic acid esters. Preliminary communication . In: Helvetica Chimica Acta . tape 63 , no. 17 , 1980, pp. 197-200 , doi : 10.1002 / hlca.19800630118 .
  2. a b c d G. Fráter, U. Müller, W. Günther: The stereoselective α-alkylation of chiral β-hydroxy esters and some applications thereof . In: Tetrahedron . tape 40 , no. 8 , 1984, pp. 1269-1277 , doi : 10.1016 / S0040-4020 (01) 82413-3 .
  3. Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro: Name reactions and reagents in organic synthesis . 2nd Edition. John Wiley & Sons, New Jersey 2005, ISBN 0-471-22854-0 , pp. 252-253 .
  4. Jessie H. Bird, Ashna A. Khan, Naoya Nishimura, Sho Yamasaki, Mattie SM Timmer, and Bridget L. Stocker: Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity . In: The Journal of Organic Chemistry . tape 83 , no. 15 , 2018, p. 7593-7605 , doi : 10.1021 / acs.joc.7b03269 .