The advantage of tagging organic compounds or biomolecules with perfluoroalkane groups has led to the publication of several research articles by many. Extending this to the chiral auxillaries is no exception. Several such fluorous oxazolidinone based chiral auxillaries have been synthesized and sucessfully demonstrated to be viable alternatives in asymmetric alkylations, aldol reactions, Michael additions etc. The non-interference of fluorous chains in further chemical modification coupled with ease of their recovery by F-SPE continues to draw the attention of many more in the scientific community. In one such communication, a group at Novartis have prepared perfluoro-tagged 5,5-diphenyl-2-oxazolidinone (DIOZ) and used it to stereoselectively synthesize beta-amino acids (ARKIVOC 2008 (xv) 210-214).
Synthesis of perfluoroalkane tagged DIOZ auxiliary 6 (Rf = C2H4C6F13)
In a two-step one pot synthesis, DIOZ was made from Boc-protected L and D-valine ester and perfluoroalkyl-arylithium (from corresponding bromide) with ~50% overall yield. Even though this method has lower overall yield than earlier methods, it is more convenient and does not involve the use of Grignard reactions. Grignard reactions have not been very successful when dealing with fluorous compounds.
These perfluoro derivatized chiral auxillaries were then put to use for the synthesis of beta-N-Fmoc-phenylalanine. The acylation of the auxillary with 2-benzylacrylic acid followed by stereoselective conjugate additon of O-benzylhydroxylamine and F-SPE purification resulted in 8.3:1 distereomeric excess of the adduct in decent yields (~ 70%). It was observed that the recovery of the fluorous auxillary by F-SPE is efficient (96%). Upon the completion of subsequent deprotection and protection steps, Fmoc-beta-phenylalanine was obtained with 95% ee. The authors have also tested the efficacy at multi-gram scale and found it to be satisfactory.
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