A Short and Scalable Synthesis of Orthogonally Protected Bis(aminomethyl)malonic Acid: Access to Bioactive Macrocyclic Peptides

Abstract

A short and scalable process for the preparation of multi-gram quantities of orthogonally protected bis(aminomethyl)malonic acid in good yield from readily available starting material is described. These orthogonally protected amino acids are important building blocks to make peptides based drugs, glycoconjugates, and in the total synthesis of peptide natural products. The newly developed route has only six steps with an overall yield of 27%, which involves nucleophilic attack of a malonate on an imide as one of the key steps.

Key words

macrocyclic peptides - orthogonally protected amino acid - gram scale synthesis - improved process - benzyl ethyl malonate

• References

• 1a Driggers EM. Hale SP. Lee J. Terret NK. Nat. Rev. Drug Discov. 2008; 7: 608
• 1b Mallinson J. Collins I. Future Med. Chem. 2012; 4: 1409
• 1c Marsault E. Peterson ML. J. Med. Chem. 2011; 54: 1961
• 1d Yu X. Sun DQ. Molecules 2013; 18: 6230
• 1e Virta P. Rosenberg J. Karskela T. Heinonen P. Lönnberg H. Eur. J. Org. Chem. 2001; 18: 3467
• 1f Johnson AM. Anslyn EV. Org. Lett. 2017; 19: 1654
• 2a White CJ. Yudin AK. Nat. Chem. 2011; 3: 509
• 2b Johnson B. Anker H. Meleney F. Science 1945; 102: 376
• 2c Gause GF. Brazhnikova MG. Nature 1944; 154: 703
• 2d Hollstein U. Chem. Rev. 1974; 74: 625
• 2e Safiulina D. Veksler V. Zharkovsky A. Kaasik A. J. Cell. Physiol. 2006; 206: 347
• 2f Lichtiger S. Present DH. Kornbluth A. Gelernt I. Bauer J. Galler G. Michelassi F. Hanauer S. N. Engl. J. Med. 1994; 330: 1841
• 3 Qian Z. Liu T. Liu YY. Briesewitz R. Barrios AM. Jhiang SM. Pei D. ACS Chem. Biol. 2013; 8: 423
• 4a Katajisto J. Karskela T. Heinonen P. Lönnberg H. J. Org. Chem. 2002; 67: 7995
• 4b Guzaev A. Salo H. Azhayev A. Lönnberg H. Bioconjugate Chem. 1996; 7: 240
• 4c Heinonen P. Rosenberg J. Lönnberg H. Eur. J. Org. Chem. 2000; 3647
• 4d Virta P. Leppänen M. Lönnberg H. J. Org. Chem. 2004; 69: 2008
• 4e Heinonen P. Virta P. Lönnberg H. Tetrahedron 1999; 55: 7613
• 4f Guzaev AP. Manoharan M. Tetrahedron Lett. 2001; 42: 4769
• 4g Olivier KS. Van Nieuwenhze MS. Org. Lett. 2010; 12: 1680
• 4h Shen Y. Schottelius M. Zelenka K. De Simone M. Pohle K. Kessler K. Wester HJ. Schmutz P. Alberto R. Bioconjugate Chem. 2013; 24: 26
• 5a Muller D. Zelster I. Bitan G. Gilon C. J. Org. Chem. 1997; 62: 411
• 5b Gellerman G. Elgavi A. Salitra Y. Kramer M. J. Peptide Res. 2001; 57: 277
• 5c Katajisto J. Heinonen P. Lönnberg H. J. Org. Chem. 2004; 69: 7609
• 5d Fletcher S. Jorgensen MR. Miller AD. Org. Lett. 2004; 6: 4245
• 5e Virta P. Karskela M. Lönnberg H. J. Org. Chem. 2006; 71: 1989
• 5f Avan I. Hall CD. Katritzky AR. Chem. Soc. Rev. 2014; 43: 3575
• 5g Mann E. Kessler H. Org. Lett. 2003; 5: 4567
• 5h Orain D. Hintermann S. Pudelko M. Carballa D. Jedrzejczak A. Synlett 2015; 26: 1815
• 5i Silva DR. C. Maria EJ. Suarez OR. M. Thierry J. Cariou K. Dodd RH. Synlett 2017; 28: 815
• 5j Chen PT. Lin CK. Tsai CJ. Huang DY. Nien FY. Lin WW. Cheng WC. Chem. Asian J. 2015; 10: 474
• 5k Tokairin Y. Maita K. Takeda S. Konna H. Synthesis 2015; 47: 351
• 6 Sikriwal D. Kant R. Maulik PR. Dikshit DK. Tetrahedron 2010; 66: 6167
• 7 Nejman M. Sliwinska A. Zwierzak A. Tetrahedron 2005; 61: 8536
• 8 Leandro dos Santos J. Lanaro C. Lima LM. Gambero S. Franco-Penteado CF. Alexandre-Moreira MS. Wade M. Yerigenahally S. Kutlar A. Meiler SE. Costa FF. Chung M.-C. J. Med. Chem. 2011; 54: 5811
• 9 Genet JP. Uziel J. Port M. Touzin AM. Roland S. Thorimbert S. Tanier S. Tetrahedron Lett. 1992; 33: 77
• 10 Cumpstey I. Gehrke S. Erfen S. Cribiu R. Carbohydr. Res. 2008; 343: 1675
• 11 Tekale SU. Kauthale SS. Pawar RP. J. Clin. Chem. Sci. 2013; 58: 1619