Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived dehydroalanines

Abstract A three-step synthesis of cyclopropyl peptides is reported. The protocol involves a consecutive Ugi-4CR/elimination reaction to prepare dehydroalanines followed by a Corey-Chaykovsky cyclopropanation reaction. Peptide-like molecules that resemble some pharmacologically active compounds with a variety of substituents in the cyclopropane ring were prepared. When (2-ethoxy-2-oxoethyl) dimethyl sulfonium ylide was used the reaction exclusively gives the cis -diastereoisomer cyclopropanes in good yields from readily prepared starting materials. A collection of 26 highly substituted cyclopropyl peptides were obtained.

[1]  Hui-Sheng Huang,et al.  Bradykinin B1 receptor antagonists as potential therapeutic agents for pain. , 2010, Journal of medicinal chemistry.

[2]  R. Cox,et al.  Efficient synthesis of protected cyclopropyl β-aspartylphosphates , 2004 .

[3]  M. Bock,et al.  Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists. , 2007, Journal of medicinal chemistry.

[4]  J. Reibenspies,et al.  Three-step synthesis of cyclopropyl peptidomimetics. , 2011, Organic letters.

[5]  A. de Meijere,et al.  Natural occurrence, syntheses, and applications of cyclopropyl-group-containing alpha-amino acids. 1. 1-aminocyclopropanecarboxylic acid and other 2,3-methanoamino acids. , 2007, Chemical reviews.

[6]  K. Naumann,et al.  1-Aminocyclopropane-l-carboxylic Acid - An Intermediate of the Ethylene Biosynthesis in Higher Plants , 1979 .

[7]  L. D. Miranda,et al.  Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation. , 2015, The Journal of organic chemistry.

[8]  I. Ugi,et al.  Multicomponent Reactions with Isocyanides. , 2000, Angewandte Chemie.

[9]  J. Ciaccio,et al.  “Instant Methylide” Modification of the Corey–Chaykovsky Cyclopropanation Reaction , 2006 .

[10]  R. Orru,et al.  Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics , 2014, Beilstein journal of organic chemistry.

[11]  K. Ochiai,et al.  Belactosin A, a novel antitumor antibiotic acting on cyclin/CDK mediated cell cycle regulation, produced by Streptomyces sp. , 2000, The Journal of antibiotics.

[12]  D. Straeten,et al.  1-aminocyclopropane-1-carboxylic acid (ACC) in plants: more than just the precursor of ethylene! , 2014, Front. Plant Sci..

[13]  E. Flórez-López,et al.  A two-step practical synthesis of dehydroalanine derivatives , 2011 .

[14]  Robert M. Williams,et al.  Asymmetric syntheses of 1-aminocyclopropane-1-carboxylic acid derivatives , 1991 .

[15]  M. Calmès,et al.  Asymmetric synthesis of cis and trans 2-methyl and 2-ethyl 1-amino cyclopropanecarboxylic acids , 1991 .

[16]  T. Yamazaki,et al.  Synthesis and taste properties of L-aspartyl-methylated 1-aminocyclopropanecarboxylic acid methyl esters , 1992 .

[17]  Alexander Dömling,et al.  Recent developments in isocyanide based multicomponent reactions in applied chemistry. , 2006, Chemical reviews.

[18]  R. Ortuño,et al.  Highly efficient and stereocontrolled synthetic route to enantiopure ACC derivatives , 1994 .

[19]  L. D. Miranda,et al.  Ugi-derived dehydroalanines as a pivotal template in the diversity oriented synthesis of aza-polyheterocycles. , 2015, Chemical communications.

[20]  C. Cativiela,et al.  A simple synthesis of (−)-(1S,2R)-allocoronamic acid in its enantiomerically pure form , 1995 .

[21]  Shangfa Yang,et al.  Ethylene biosynthesis: Identification of 1-aminocyclopropane-1-carboxylic acid as an intermediate in the conversion of methionine to ethylene. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[22]  K. Burgess,et al.  Asymmetric syntheses of protected derivatives of carnosadine and its stereoisomers as conformationally constrained surrogates for arginine , 1994 .

[23]  M. Dwyer,et al.  Cyclopropane-derived peptidomimetics. Design, synthesis, and evaluation of novel enkephalin analogues. , 2000, The Journal of organic chemistry.

[24]  A. Herrero,et al.  Enantioselective synthesis of (+)-(1R,2S)-allocoronamic acid , 1992 .

[25]  T. Ye,et al.  Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides , 1998 .

[26]  C. Cativiela,et al.  New α,β-didehydroamino acid derivatives as precursors in the synthesis of 1-aminocyclopropanecarboxylic acids , 1994 .

[27]  G. Hynd,et al.  Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound. , 2001, Angewandte Chemie.

[28]  J. Erickson,et al.  Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder , 2008, Neuropsychopharmacology.

[29]  R. Cox,et al.  Diastereoselective synthesis of cyclopropane amino acids using diazo compounds generated in situ. , 2003, The Journal of organic chemistry.