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Fernando Albericio

A Symphony of Coupling Reagents for Solid-Phase Synthesis of Azathiocoraline. Fernando Albericio. Bruce Merrifield The Nobel Prize in Chemistry 1984. I WONDER IF TRYING TO SYNTHESIZE THE POLYSATURATED POLYPEPTIDE CYCUTRINE TURNS 0UT TO BE A STUPID WASTE OF TIME. .

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Fernando Albericio

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  1. A Symphony of Coupling Reagents for Solid-Phase Synthesis of Azathiocoraline Fernando Albericio

  2. Bruce Merrifield The Nobel Prize in Chemistry 1984

  3. I WONDER IF TRYING TO SYNTHESIZE THE POLYSATURATEDPOLYPEPTIDECYCUTRINE TURNS 0UT TO BE A STUPID WASTE OF TIME. YOU SHOULD HAVE THOUGHT ABOUT THAT 20 YEARS AGO...MAN

  4. Solid-Phase Peptide Synthesis is a proper combination of solid supports protecting groups (handles/linkers) and coupling reagents

  5. SPPS Solid Supports PEG-PS/TentaGel CLEAR PS ChemMatrix® F. García-Martín et al J. Comb. Chem., 8, 213 (2006) F. García-Martín et al Biopolymers (Peptide Sci) in press

  6. Boc Trt H Fmoc Base, Nu Protecting Groups/Handles-Linkers + CTC, Barlos Resin Others Alloc Troc pNZ Resin is swelled in DCM (10 mL/g) for 10 min. Next, SOCl2 (0.26 mL/g) is added dropwise and the mixture turns darker. Consecutively, DMF (5% w/w SOCl2) (10 mL/g) is added and the dark color lightens slightly. The mixture is stirred under Ar atmosphere for 4 hours at 38 ºC, and then washed

  7. Coupling Reagents EDC Cl-HOBT HOBt PyAOP CDI TCTU dipcdi TCT HOAt PyClocK TMUCl Cl HOSu HATU

  8. TMUCl Cl, a reagent for SPS of Anilides TMUCl-Cl CDI M. Vendrell,et al.Tetrahedron Lett., 46, 5383 (2005).

  9. TMUCl Cl, a reagent for SPS of Anilides [±]-2-[N-phenylethyl-N-propyl]amino- 5-hydroxytetralin ([±]-PPHT) TCT 15% of racemization M. Vendrell,et al.Tetrahedron Lett., 46, 5383 (2005).

  10. Thiocoraline Family Azathiocoraline

  11. Solid-Phase Peptide Chain Elongation • Disulfide Bridge (S-Acm)Formation on Solid-Phase • If possible, Macrolactamization on Solid-Phase • Incorporation of the Heterocycle in the last step Azathiocoraline Solid-Phase Synthetic Strategy

  12. NH2 COOH Y NH2 Y NH NH NH NH NH NH HN NH HN NH NH S HN HN HN HN HN HN S Y S SH S SX Y Y NH NH2 Y SH NH2 COOH SX COOX Y S S S SH S S S XS SX Y Y Y NH2 XS S NH2 S Y Azathiocoraline: Two Synthetic Strategies Macrolactamization on Solution: Convergent Synthesis Barlos resin Macrolactamization on Solid-Phase: Stepwise Synthesis

  13. Synthesis of 3-Hydroxyquinaldic Acid E. Riego, et al. Tetrahedron, 61, 1407(2005).

  14. N-Methyl Amino Acid as Amino Component 9 Hindered MeCys as Acid Component 9 Racemization Choose of the Cyclization Point

  15. Scheme 1. a) Boc-D-Dap(Fmoc)-OH, DIEA, CH2Cl2; b) MeOH; c) piperidine-DMF (1:4), piperidine-DBU-toluene-DMF (1:1:4:14); d) Fmoc-AA-OH/HATU/DIEA, DMF; e) piperidine -DMF (1:4); f) TFA/CH2Cl2 (1:99); g) PyAOP/DIEA, CH2Cl2; h) I2, DMF; i) EDC·HCl/HOAt/DIEA, CH2Cl2 (1mM); j) TFA-H2O (19:1); k) 3-hydroxyquinaldic acid/EDC·HCl/HOSu/DIEA, CH2Cl2.

  16. Azathiocoraline: Peptide Elongation (c) piperidine-DMF (1:4), piperidine-DBU-toluene-DMF(1:1:4:14) d) Fmoc-AA-OH/HATU/DIEA, DMF e) piperidine -DMF (1:4) d)

  17. Azathiocoraline: Cleavage, Convergent Approach 1/3 2/3 piperidine-DMF (1:4) TFA/CH2Cl2 (1:99)

  18. HATU/DIEA Azathiocoraline: Coupling, Convergent Approach + g) PyOAP/DIEA, DMF, 24 h e) piperidine -DMF (1:4)

  19. Azathiocoraline: On resin disulfide formation h) I2 (2.5 eq/Acm), DMF, 10 min f) TFA/CH2Cl2 (1:99); Solution Disulfide Formation gave clearly worse results

  20. Azathiocoraline: Macrolactamization Crude Byclic Peptide i) EDC·HCl/HOAt/DIEA, CH2Cl2 (1mM), 2 h Other conditions PyAOP/DIEA, it is fast but with byproduct formation DIPCDI/HOBt, it is slow (> 3 d) DIPCDI/HOAt (2 h), but purification is required

  21. Azathiocoraline: Incorporation of 3-Hydroxyquinaldic Acid Other conditions EDC·HCl/HOAt over incorporation EDC·HCl/HOBt less over incorporation j) TFA-H2O (19:1); k) 3-hydroxyquinaldic acid/EDC·HCl/ HOSu/DIEA, CH2Cl2

  22. Azathiocoraline: Final Product EDC·HCl / HOAt EDC·HCl / HOSu a) c) EDC·HCl / HOBt Azathiocoraline b) Azathiocoraline + 3HQA [M+H]+

  23. Scheme 1. a) Boc-D-Dap(Fmoc)-OH, DIEA, CH2Cl2; b) MeOH; c) piperidine-DMF (1:4), piperidine-DBU-toluene-DMF (1:1:4:14); d) Fmoc-AA-OH/HATU/DIEA, DMF; e) piperidine -DMF (1:4); f) TFA/CH2Cl2 (1:99); g) PyAOP/DIEA, CH2Cl2; h) I2, DMF; i) EDC·HCl/HOAt/DIEA, CH2Cl2 (1mM); j) TFA-H2O (19:1); k) 3-hydroxyquinaldic acid/EDC·HCl/HOSu/DIEA, CH2Cl2.

  24. Scheme 2. a) H-D-Dap(Fmoc)-OAllyl, DIEA, CH2Cl2; b) MeOH; c) piperidine-DMF (1:4), piperidine-DBU/toluene/DMF (1:1:4:14); d) Fmoc-AA-OH/HATU/DIEA, DMF; e) piperidine-DMF (1:4); f) Boc-D-Dap(Fmoc)-OH/HATU/DIEA, DMF; g) [Pd(PPh3)4], PhSiH3, CH2Cl2; h) I2, DMF; i) DIPCDI/HOAt, DMF; j) TFA-CH2Cl2 (1:99); k) TFA-H2O (19:1); l) 2-hidroxyquinaldic acid/EDC·HCl/HOSu/DIEA, CH2Cl2 Azathiocoraline: Double Cyclization on Solid-Phase

  25. Figure 2. HPLC cromatograms of purified Azathiocoraline. Reverse-phase C18 columns was used for the analysis with elution by linear gradient over 15 min of 0.036% TFA in CH3CN and 0.045% TFA in H2O from 5:5 to 9:1. [M+H]+

  26. Conclusions • PEG resins as ChemMatrix are highly appropriate for the synthesis of peptides with structure and/or exhibiting interchain interaction • Barlos (CTC) resin is an excellent temporal protecting group for the preparation of protected amino acids • Cyclization on solid-phase is an efficient strategy. Even double cyclization gives good results • The most active reagent is not always the best

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