Seebach Hydroxy ester alkylation

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

Chiral P-hydroxy esters and l,3-dioxan-4-ones are well-known substrates for diaster-oselective a-alkylation reactions developed by Frater [20] and Seebach [21]. These chiral compounds are available in both enantiomeric forms, and have been also ami-nated at the a-carbon with high stereoselectivity. 

P-Hydroxy esters may be alkylated via their dilithium dianions. Deprotonation of the hydroxy group by the base prevents its elimination to form an a,P-unsaturated system. Two recent publications by Prater et alP and by Seebach et al ° provide summaries of the results of the alkylations of nonracemic... 

Butanoic acid, 3-hydroxy-, esters pr, 176 Frater-Seebach 2-alkylation, 27 —, 3-oxo-, esters (acetoacetic esters) pr., 176 carbon acidity, 10 carboxymethyl da-synthon, 19, 207 dianion 4-alkylation, 24, 207,325-326... 

Seebach completed the first synthesis of optically active 9 as depicted in Scheme 4.2. ° Protected alcohol 10, available from an optically active p-hydroxy butyric ester, was alkylated with 2-lithio-1,3-dithiane. Deprotonation of this material followed by formylation with DMF then afforded 11. Chain extension to the unsaturated ester was accomplished via a Wittig condensation and deprotection to produce the monomeric unit 12 in 57% overall yield from 10. Double lactonization under Mitsunobu conditions (DEAD-PhjP) afforded a 60%... 

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