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Synthesis 2011(6): 954-960  
DOI: 10.1055/s-0030-1258428
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Practical One-Pot Double Functionalizations of Proline

Peter Huy, Hans-Günther Schmalz*
Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax: +49(221)4703064; e-Mail: schmalz@uni-koeln.de;
Further Information

Publication History

Received 23 December 2010
Publication Date:
10 February 2011 (online)

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Abstract

Solubilization of proline as the triethylammonium salt allows N-protection (as the Boc, Cbz or Moc derivative) and subsequent esterification or amidation of the carboxy terminus to be performed in an efficient one-pot fashion. Based on this concept, highly practical protocols were developed to prepare a series of proline derivatives (including Pro-Ser dipetides, Weinreb amides and N-protected proline esters), which are important intermediates, for instance, for the synthesis of proline-derived peptides, chiral reagents and catalysts for asymmetric synthesis.

Key words

proline derivatives - peptides - carbamates - N-protecting groups - solvent effects - coupling reagents

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12

Protic solvents such as water or alcohols are rival nucleophiles.

13

The esterification step requires DMAP as a nucleophilic catalyst, which activates both Boc2O (to react with the carboxylate) and the resulting mixed anhydride (to react with t-BuOH); see ref. 9a.

16

DCC-mediated coupling of 10 in the presence of DMAP led to the isolation of 2e in only 48% yield, along with 21% of the tert-butyl ester 2b resulting from the reaction of 7a with tert-butyl alcohol.

19

Methyl ester 2j was synthesized in 93% yield with K2CO3 instead of Et3N.¹¹b

20

For example, the yield of tert-butyl ester 2k (Table  [²] , entry 9) dropped to 42% when MocCl was added undiluted.