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Scalable Enantioselective Synthesis of Fmoc‐β 2 ‐Serine and Fmoc‐β 2 ‐Threonine by an Organocatalytic Mannich Reaction
Author(s) -
Meyer Daniel,
Marti Roger,
Seebach Dieter
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500636
Subject(s) - chemistry , enantioselective synthesis , mannich reaction , iminium , diastereomer , threonine , organocatalysis , organic chemistry , combinatorial chemistry , serine , catalysis , stereochemistry , enzyme
The diastereoselective Mannich reaction of functionalized aldehydes, using a phenethylamine‐derived iminium precursor, by activation with prolines and prolinol derivatives have been studied. Optimized reaction conditions have been developed, allowing for scale‐up and preparation of γ‐amino alcohol derivatives on multi‐gram scale from β‐hydroxypropanal and ‐butanal, with diastereoselectivites of typically >73:27 and yields of >60 %. After chromatographic diastereoisomer separation, hydrogenolytic debenzylation, enantiomerically pure Fmoc‐β 2 ‐Ser( t Bu)‐OH and Fmoc‐β 2 ‐Thr( t Bu)‐OH were thus prepared on multi‐gram scale in 6 steps and with overall yields of 24 % and 10 %, respectively, starting from commercially available starting compounds.