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. 2017 Jun 1;4(6):995-1004.
doi: 10.1039/C7QO00052A. Epub 2017 Feb 9.

Synthesis and Structure Revision of Symplocin A

Lu-Ping Shao  1 , Chang-Mei Si  1 , Zhuo-Ya Mao  1 , Wen Zhou  1 , Tadeusz F Molinski  2 , Bang-Guo Wei  1 , Guo-Qiang Lin  1
Affiliations

Synthesis and Structure Revision of Symplocin A

Lu-Ping Shao et al. Org Chem Front. .

Abstract

Symplocin A, a linear peptide possessing N-terminal N,N-dimethylisoleucine, statine, and valic acid residues, has been synthesized for the first time employing our previously established 'one-pot intramolecular tandem protocol'. Moreover, the stereochemistry of natural symplocin A was unambiguously revised through the confirmation by 1D NMR, 2D NMR, and HPLC comparisons with authentic natural product.

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Figures

Figure 1.
Figure 1.
The Structures of DMAA Linear Peptides.
Figure 2.
Figure 2.
Retrosynthetic analysis of 3a.
Scheme 1.
Scheme 1.
Preparation of Tetrapeptide Fragment 8. Reagents and conditions: (a) NaH, MeI, THF; (b) L-Pro-OMe, HATU, DIPEA, DCM, 62% (2 steps); (c) (1) TFA, DCM; (2) Boc-Gly, HATU, DIPEA, DCM, 80% (2 steps); (d) (1) TFA, DCM; (2) Boc-Val-OH, HOBt, EDCI, DMF, 62% (2 steps).
Scheme 2.
Scheme 2.
Preparation of (3R,4S)-Statine Subunit 7. Reagents and conditions: (a) TBAF, THF, 50%; (b) LiOH•H2O, H2O2, THF/H2O, 100%.
Scheme 3.
Scheme 3.
Preparation of Depsipeptide Fragment 19. Reagents and conditions: (a) DCC, DMAP, DCM, 76%; (b) (1) TFA, DCM; (2) HCHO, NaBH3(CN), CH3CN, 64% (2 steps); (c) (1) Pd(PPh3)4, N-methylaniline, NMA, THF; (2) 5, HATU, HOAt, DIPEA, DCM, 45% (2 steps); (d) H2, 1 atm, Pd/C, MeOH, 100%.
Scheme 4.
Scheme 4.
Preparation of Symplocin A (3a). Reagents and conditions: (a) (1) TFA, DCM; (2) 7, HATU, HOAt, DIPEA, DMF, 59% (2 steps); (b) (1) TFA, DCM; (2) 6, HOBt, EDCI, NMM, DMF, 70% (2 steps); (c) (1) TFA, DCM; (2) 19, HOBt, EDCI, NMM, DCM, 38% (2 steps).
Scheme 5.
Scheme 5.
Preparation of (50S, 51S)-Symplocin A (3b). Reagents and conditions: (a) (1) 16, DCC, DMAP, DCM; (2) TFA, DCM; (3) HCHO, NaBH3(CN), CH3CN, 37% (3 steps); (b) (1) Pd(PPh3)4, N-methylaniline, NMA, THF; (2) 5, HATU, HOAt, DIPEA, DCM, 31% (2 steps); (c) (1) H2, 1 atm, Pd/C; (2) free amine of 21, HOBt, EDCI, NMM, DCM, 26% (2 steps).
Scheme 6.
Scheme 6.
Preparation of (26S, 50S, 51S)-Symplocin A (3c). Reagents and conditions: (a) (1) (COCl)2, DMSO, DCM; (2) NaBH4, MeOH, 67% (2 steps); (b) LiOH•H2O, H2O2, THF/H2O, 100%; (c) free amine of 8, HATU, HOAt, DIPEA, DMF, 87%; (d) (1) TFA,DCM; (2) 6, HOBt, EDCI, NMM, DMF, 37% (2 steps); (3) TFA,DCM; (4) (2S,3S)-19, HOBt, EDCI, NMM, DCM, 21% (2 steps).
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