An Alternative Synthetic Route to (3R,5S,1 ' S)-5-{1 '-[(tert-Butyloxycarbonyl)amino]-3 '-methylbutyl}-3-methyldihydrofuran-2(3H)-one, a Precursor of a Leu-Ala Hydroxyethylene Isostere

An improved synthetic route to (3R, 5S, 1' S)-5-{1'-[(tert-butyloxycarbonyl) amino]-3'-methylbutyl}-3-methyldihydrofuran-2(3H)-one, a lactone precursor of the Leu-Ala (2R, 4S, 5S) hydroxyethylene isostere found in many peptidomimetic aspartyl protease inhibitors of Alzheimer's di...

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Bibliographic Details
Published inSynthesis (Stuttgart) Vol. 47; no. 19; pp. 3009 - 3012
Main Authors Vila-Real, Helder, Ventura, M. Rita, Maycock, Christopher, Iranzo, Olga, Simplicio, Ana
Format Journal Article
LanguageEnglish
Published STUTTGART Thieme Medical Publishers 01.10.2015
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
aspartyl proteases
inhibitors
lactones
DESIGN
hydroxyethylene isostere
peptides
BETA-SECRETASE INHIBITORS
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Summary:An improved synthetic route to (3R, 5S, 1' S)-5-{1'-[(tert-butyloxycarbonyl) amino]-3'-methylbutyl}-3-methyldihydrofuran-2(3H)-one, a lactone precursor of the Leu-Ala (2R, 4S, 5S) hydroxyethylene isostere found in many peptidomimetic aspartyl protease inhibitors of Alzheimer's disease, is devised. Alkylation of N-Boc-leucinal with the lithium salt of benzyl propargyl ether instead of ethyl propiolate is the key toward a more reproducible and efficient route to obtain the title lactone from N-Boc-L-leucine in six steps, and an overall yield of 16%.
Bibliography:FCT
ISSN:0039-7881
1437-210X
DOI:10.1055/s-0034-1381036