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. 2016 Nov 28:7:13491.
doi: 10.1038/ncomms13491.

Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation

Shinichiro Fuse  1 , Yuto Mifune  1 , Hiroyuki Nakamura  1 , Hiroshi Tanaka  2
Affiliations

Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation

Shinichiro Fuse et al. Nat Commun. .

Abstract

Feglymycin is a naturally occurring, anti-HIV and antimicrobial 13-mer peptide that includes highly racemizable 3,5-dihydroxyphenylglycines (Dpgs). Here we describe the total synthesis of feglymycin based on a linear/convergent hybrid approach. Our originally developed micro-flow amide bond formation enabled highly racemizable peptide chain elongation based on a linear approach that was previously considered impossible. Our developed approach will enable the practical preparation of biologically active oligopeptides that contain highly racemizable amino acids, which are attractive drug candidates.

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Figures

Figure 1
Figure 1. Synthetic strategy for feglymycin (1).
Our linear synthetic approach and Süssmuth's convergent synthetic approaches. Süssmuth concluded that the linear approach for oligopeptides 2 and 3 containing D-Dpgs was not possible.
Figure 2
Figure 2. Micro-flow synthesis of dipeptide 20.
Dipeptide 20 was prepared by micro-flow amide bond formation. The obtained dipeptide was readily purified via simple aqueous workup and recrystallization.
Figure 3
Figure 3. Synthesis of C-terminal hexapeptide 2 using micro-flow amidation.
Conditions: (a) Pd(PPh3)4, PhSiH3, CH2Cl2/MeOH, r.t., 1–1.5 h, batch. (b) PS-Ph3P-Pd, PhSiH3, CH2Cl2/MeOH/H2O, r.t., 1 h, batch.
Figure 4
Figure 4. Synthesis of N-terminal heptapeptide 3 using micro-flow amidation.
Conditions: (a) Pd(PPh3)4, PhSiH3, CH2Cl2/MeOH/H2O, r.t., 40 min, batch. (b) PS-Ph3P-Pd, PhSiH3, CH2Cl2/MeOH/H2O, r.t., 1.5–2.5 h, batch.
Figure 5
Figure 5. Total synthesis of feglymycin (1).
Conditions: (a) Me3SnOH, 1,2-dichloroethane; 85 °C, 3.5 h; (b) PS-Ph3P-Pd, PhSiH3, CH2Cl2/MeOH/H2O, r.t., 50 min; (c) DEPBT, NaHCO3, DMF, 0 °C, 24 h, then 25 °C, 11 h, 2 steps 44% from heptapeptide 3. (d) H2, Pd/C, MeOH, r.t., 3 h, quant.
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References

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