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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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Presentation Transcript
slide2

Bruce Merrifield

The Nobel Prize in Chemistry 1984

slide3

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

slide4

Solid-Phase Peptide Synthesis

is a proper combination of

solid supports

protecting groups (handles/linkers)

and coupling reagents

slide5

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

slide6

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

slide7

Coupling Reagents

EDC

Cl-HOBT

HOBt

PyAOP

CDI

TCTU

dipcdi

TCT

HOAt

PyClocK

TMUCl Cl

HOSu

HATU

slide8

TMUCl Cl, a reagent for SPS of Anilides

TMUCl-Cl

CDI

M. Vendrell,et al.Tetrahedron Lett., 46, 5383 (2005).

slide9

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).

slide10

Thiocoraline Family

Azathiocoraline

slide11

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

slide12

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

slide13

Synthesis of 3-Hydroxyquinaldic Acid

E. Riego, et al. Tetrahedron, 61, 1407(2005).

slide14

N-Methyl Amino Acid as Amino Component 9 Hindered

MeCys as Acid Component 9 Racemization

Choose of the Cyclization Point

slide15

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.

slide16

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)

slide18

Azathiocoraline: Cleavage, Convergent Approach

1/3

2/3

piperidine-DMF (1:4)

TFA/CH2Cl2 (1:99)

slide20

HATU/DIEA

Azathiocoraline: Coupling, Convergent Approach

+

g) PyOAP/DIEA, DMF, 24 h

e) piperidine -DMF (1:4)

slide22

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

slide24

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

slide25

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

slide26

Azathiocoraline: Final Product

EDC·HCl / HOAt

EDC·HCl / HOSu

a)

c)

EDC·HCl / HOBt

Azathiocoraline

b)

Azathiocoraline + 3HQA

[M+H]+

slide27

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.

slide28

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

slide29

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]+

slide30

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