Amino acid N-carboxyanhydride

Amino acid N-carboxyanhydrides, also called Leuchs' anhydrides, are a family of heterocyclic organic compounds derived from amino acids. They are white, moisture-reactive solids. They have been evaluated for applications the field of biomaterials.[1][2][3]

Amino acid N-carboxyanhydride
N-Carboxyanhydrides

Preparation
Glycine N-carboxyanhydride is the parent member of the amino acid N-carboxyanhydrides.

NCAs are typically prepared by phosgenation of amino acids:[4]

They were first synthesized by Hermann Leuchs by heating an N-ethoxycarbonyl or N-methoxycarbonyl amino acid chloride in a vacuum at 50-70 °C:[5][6]

A moisture-tolerant route to unprotected NCAs employs epoxides as scavengers of hydrogen chloride.[7]

This synthesis of NCAs is sometimes called the Leuchs method. The relatively high temperatures necessary for this cyclization results in the decomposition of several NCAs. Of several improvements, one notable procedure involves treating an unprotected amino acid with phosgene or its trimer.[8][9][10]

Reactions

NCAs are prone to hydrolysis to the parent amino acid:

RCHNHC(O)OC(O) + H2O → H2NCH(R)CO2H + CO2

Some derivatives however tolerate water briefly.[7]

NCAs convert to homopolypeptides ( [N(H)CH(R)CO)]n) through ring-opening polymerization:[1][2][3][11][12][13][14]

n RCHNHC(O)OC(O) → [N(H)CH(R)CO)]n + n CO2

Poly-L-lysine has been prepared from N-carbobenzyloxy-α-N-carboxy-L-lysine anhydride, followed by deprotection with phosphonium iodide.[15] Peptide synthesis from NCAs does not require protection of the amino acid functional groups. N-Substituted NCAs, such as sulfenamide derivatives have also been examined.[16] The ring-opening polymerization of NCAs is catalyzed by metal catalysts.[17][3][6][11]

The polymerization of NCA’s have been considered as a prebiotic route to polypeptides.[3][18] [19]

Further reading
  • Grazon C, Salas-Ambrosio P, Ibarboure E, Buol A, Garanger E, Grinstaff MW, et al. (January 2020). "Aqueous Ring-Opening Polymerization-Induced Self-Assembly (ROPISA) of N-Carboxyanhydrides" (PDF). Angewandte Chemie. 59 (2): 622–626. doi:10.1002/ange.201912028. PMID 31650664. S2CID 241302007.
  • iang J, Zhang X, Fan Z, Du J (2019-10-15). "Ring-Opening Polymerization of N-Carboxyanhydride-Induced Self-Assembly for Fabricating Biodegradable Polymer Vesicles". ACS Macro Letters. 8 (10): 1216–1221. doi:10.1021/acsmacrolett.9b00606. PMID 35651173. S2CID 203135939.
  • Barrett SE, Burke RS, Abrams MT, Bason C, Busuek M, Carlini E, et al. (June 2014). "Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates". Journal of Controlled Release. 183: 124–37. doi:10.1016/j.jconrel.2014.03.028. PMID 24657948.
  • Kramer JR, Onoa B, Bustamante C, Bertozzi CR (October 2015). "Chemically tunable mucin chimeras assembled on living cells". Proceedings of the National Academy of Sciences of the United States of America. 112 (41): 12574–9. Bibcode:2015PNAS..11212574K. doi:10.1073/pnas.1516127112. PMC 4611660. PMID 26420872.

See also

References
  1. Kramer J, Deming TJ (2020). Polypeptide Nanomaterials. Vol. 1–4. Soft Matter and Biomaterials on the Nanoscale: World Scientific. pp. 115–180. Bibcode:2020smb3.book..115K.
  2. Whitesides GM, Grzybowski B (March 2002). "Self-assembly at all scales". Science. 295 (5564): 2418–21. Bibcode:2002Sci...295.2418W. doi:10.1126/science.1070821. PMID 11923529. S2CID 40684317.
  3. Kricheldorf HR (September 2006). "Polypeptides and 100 years of chemistry of alpha-amino acid N-carboxyanhydrides". Angewandte Chemie. 45 (35): 5752–84. doi:10.1002/anie.200600693. PMID 16948174.
  4. Lyndon C. Xavier, Julie J. Mohan, David J. Mathre, Andrew S. Thompson, James D. Carroll, Edward G. Corley, and Richard Desmond (1997). "(S)-Tetrahydro-1-methyl-3,3-diphenyl-1h,3h-pyrrolo-[1,2-c] [1,3,2]oxazaborole-borane Complex". Organic Syntheses. 74: 50. doi:10.15227/orgsyn.074.0050.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. Leuchs H (1906). "Ueber die Glycin-carbonsäure" [About the glycine-carboxylic acid]. Berichte der Deutschen Chemischen Gesellschaft (in German). 39: 857–61. doi:10.1002/cber.190603901133.
  6. Deming TJ (2007). "Synthetic polypeptides for biomedical applications". Prog. Polym. Sci. 32 (8–9): 858–875. doi:10.1016/j.progpolymsci.2007.05.010.
  7. Tian ZY, Zhang Z, Wang S, Lu H (October 2021). "A Moisture-Tolerant Route to Unprotected α/β-Amino acid N-Carboxyanhydrides and Facile Synthesis of Hyperbranched Polypeptides". Nature Communications. 12 (1): 5810. Bibcode:2021NatCo..12.5810T. doi:10.1038/s41467-021-25689-y. PMC 8490447. PMID 34608139.
  8. Montalbetti CA, Falque V (2005). "Amide bond formation and peptide coupling". Tetrahedron. 61 (46): 10827–52. doi:10.1016/j.tet.2005.08.031.
  9. Xavier LC, Mohan JJ, Mathre DJ, Thompson AS, Carroll JD, Corley EG, Desmond R (1997). "(S)-Tetrahydro-1-methyl-3,3-diphenyl-1h,3h-pyrrolo-[1,2-c] [1,3,2]oxazaborole-borane Complex". Org. Synth. 74: 50. doi:10.15227/orgsyn.074.0050.
  10. Gibson MI, Hunt GJ, Cameron NR (September 2007). "Improved synthesis of O-linked, and first synthesis of S- linked, carbohydrate functionalised N-carboxyanhydrides (glycoNCAs)". Organic & Biomolecular Chemistry. 5 (17): 2756–7. doi:10.1039/b707563d. PMID 17700840.
  11. Dimitrov I, Schlaad H (December 2003). "Synthesis of nearly monodisperse polystyrene-polypeptide block copolymers via polymerisation of N-carboxyanhydrides". Chemical Communications (23): 2944–2945. doi:10.1039/b308990h. PMID 14680253.
  12. Song Z, Han Z, Lv S, Chen C, Chen L, Yin L, Cheng J (October 2017). "Synthetic Polypeptides: from Polymer Design to Supramolecular Assembly and Biomedical Application". Chemical Society Reviews. 46 (21): 6570–6599. doi:10.1039/C7CS00460E. PMID 28944387.
  13. Kopecek J (September 2003). "Smart and genetically engineered biomaterials and drug delivery systems". European Journal of Pharmaceutical Sciences. 20 (1): 1–16. doi:10.1016/S0928-0987(03)00164-7. PMID 13678788.
  14. Lu H, Wang J, Song Z, Yin L, Zhang Y, Tang H, et al. (January 2014). "Recent Advances in Amino Acid N-Carboxyanhydrides and Synthetic Polypeptides: Chemistry, Self-Assembly and Biological Applications". Chemical Communications. 50 (2): 139–55. doi:10.1039/c3cc46317f. PMID 24217557.
  15. Katchalski-Katzir E (April 2005). "My contributions to science and society". The Journal of Biological Chemistry. 280 (17): 16529–41. doi:10.1074/jbc.X400013200. PMID 15718236.
  16. Katakai R (September 1975). "Peptide synthesis using o-nitrophenylsulfenyl N-carboxy alpha-amino acid anhydrides". The Journal of Organic Chemistry. 40 (19): 2697–2702. doi:10.1021/jo00907a001. PMID 1177065.
  17. Deming TJ (1998). "Amino Acid Derived Nickelacycles: Intermediates in Nickel-Mediated Polypeptide Synthesis". Journal of the American Chemical Society. 120 (17): 4240–4241. doi:10.1021/ja980313i.
  18. Taillades J, Beuzelin I, Garrel L, Tabacik V, Bied C, Commeyras A (February 1998). "N-carbamoyl-alpha-amino acids rather than free alpha-amino acids formation in the primitive hydrosphere: a novel proposal for the emergence of prebiotic peptides". Origins of Life and Evolution of the Biosphere. 28 (1): 61–77. Bibcode:1998OLEB...28...61T. doi:10.1023/A:1006566810636. PMID 11536856. S2CID 22189268.
  19. Ferris JP, Hill AR, Liu R, Orgel LE (May 1996). "Synthesis of long prebiotic oligomers on mineral surfaces". Nature. 381 (6577): 59–61. Bibcode:1996Natur.381...59F. doi:10.1038/381059a0. hdl:2060/19980119839. PMID 8609988. S2CID 4351826.
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