6. Consider the following orthogonal protecting groups than can be utlized in th

Question

6. Consider the following orthogonal protecting groups than can be utlized in the synthesis of a complex and branched peptide Protecting group Deprotection Boc, tBu |90% TFA to Alloc, ivDde Alloc vDde Mtt Fmoc |Pd(PPh3)4 e, Boc, tBu,ivDde, Boc, tBu, Alloc, Alloc, ivDde, Boc, tBu, Alloc. Hydrazine 3% TFA Piperidine reagents: Stable removal of: Mtt, Fmoc Mtt, Fmoc Mtt, Fmoc Mtt Using any of these protecting groups, propose a step-by-step SPPS of the given peptide sequence below. You need to clearly identify the resin of your choice and protected amino acid reagents HN H O ?? 0

Explanation / Answer

The given peptide can be synthesized using SPPS method as follows:

The choice of resin would be 2-Chloro Trityl Chloride because the final peptide required should have an acid functional group.

Step 1: The covalent linking of the free amino acid which is Fmoc-D-Lys(ivDde)-OH onto the resin using HBTU as coupling agent.

Step 2: Once the linkage is established the unreacted resin sites should be capped by uisng Methanol and DIPEA in Dichloromethane.

Step 3: The deprotection of ivDde group uisng hydrazine results in the formation of Resin-D-Lys(NH2)-Fmoc.

Step 4: Resin-D-Lys(NH2)-Fmoc Coupling reaction with Boc-Ala-OH results in formation of Resin-D-Lys(NHCO-Boc-Ala)-Fmoc.

Step 4: Fmoc deprotection with piperidine results in Resin-D-Lys(NHCO-Boc-Ala)-NH2.

Step 5: Resin-D-Lys(NHCO-Boc-Ala)-NH2 is then coupled with Fmoc-Ala-OH results in the formation of Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-Fmoc.

Step 6: Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-Fmoc is subjected to deprotection of Fmoc with piperidine results in formation of Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NH2

Step 7: Coupling reaction of Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NH2 with Fmoc-Ser(OTBDMS)-OH results in the formation of Resin-D-Lys(NHO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-Fmoc.

Step 8: Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-Fmoc subjected to deprotection with piperidine to remove Fmoc, this gives  Resin-D-Lys(NHO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-NH2.

Step 9: Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-NH2 reaction with alloc-Lys(ivDe)-OH results in Resin-D-Lys(NHO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-NHCO-Lys(ivDe)-alloc.

Step 10: Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-NHCO-Lys(ivDe)-alloc is subjected to removal of alloc with palladium tetrakis.

Step 11: Resin-D-Lys(NHCO-Boc-Ala)-NHCO-Ala-NHCO-Ser(OTBDMS)-NHCO-Lys(NH2)-NH2 is subjected to removal of ivDe group by using hydrazine.

Step 12: Global deprotection with TFA gives OH-D-Lys(NHCO-Ala)-NHCO-Ala-NHCO-Ser(OH)-NHCO-Lys(NH2)-NH2

STEP 13: ACETYLATION OF FREE AMINE GROUPS GIVES FINAL PEPTIDE

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