Scholars of Chinese NSF (81125021), National Science and
Technology Major Project on ‘Key New Drug Creation and
Manufacturing Program’, China (Numbers: 2012ZX09103-101-
0
35). Support from Shanghai Commission of Science and Tech-
nology (10410702600, 10JC1417100, 10dz1910104) was also
appreciated.
Notes and references
1
L. A. Salvador, J. S. Biggs, V. J. Paul and H. Luesch, J. Nat. Prod., 2011,
74, 917–927.
1
13
Fig. 2 H and C NMR comparison between synthetic 1 and natural
product.
2 E. Mevers, W. T. Liu, N. Engene, H. Mohimani, T. Byrum, P. A. Pevzner,
P. C. Dorrestein, C. Spadafora and W. H. Gerwick, J. Nat. Prod., 2011,
74, 928–936.
3
D. J. Edwards, B. L. Marquez, L. M. Nogle, K. McPhail, D. E. Geoger,
M. A. Roberts and W. H. Gerwick, Chem. Biol., 2004, 11, 817–833.
slightly different from that reported for natural product: −44
1
(
c 0.44, MeOH) by Luesch and −14.7 (c 0.22, CH Cl ) by
2
2
4 R. C. Elgersma, T. Meijneke, G. Posthuma, D. T. Rijkers and
2
1
13
Gerwick. However, both the H and C NMR spectra of our
synthetic product were not in agreement with that reported for
the natural product. The major difference between our synthetic
product 1 and the natural veraguamide A came from both the
proton and carbon signals of the tertiary carbon centers (C-2,
C-19) in the two N-methyl valine fragments. As shown in Fig. 2,
R. M. Liskamp, Chem.–Eur. J., 2006, 12, 3714–3725.
S. Yu, X. Pan and D. Ma, Chem.–Eur. J., 2006, 12, 6572–6584.
D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2
5
6
127–2130.
7 H. Sugiyama, A. Watanabe, T. Teruya and K. Suenaga, Tetrahedron Lett.,
009, 50, 7343–7345.
2
8
H. Kigoshi, K. Suenaga, T. Mutou, T. Ishigak, T. Atsumi, H. Ishiwata,
A. Sakakura, T. Ogawa, M. Ojika and K. Yamada, J. Org. Chem., 1996,
6
1
in the H NMR spectra, the two protons on the C-2 and C-19 of
1, 5326–5351.
9 P. V. Reddy, V. Bajpai, B. Kumar and A. K. Shaw, Eur. J. Org. Chem.,
011, 1575–1586.
our synthetic 1 showed two doublets with chemical shifts of
2
5
.09 and 5.19 ppm, respectively, whereas two doublets with
1
0 (a) H. Kigoshi, K. Suenaga, T. Mutou, T. Ishigak, T. Atsumi, H. Ishiwata,
A. Sakakura, T. Ogawa, M. Ojika and K. Yamada, J. Org. Chem., 1996,
61, 5326–5351; (b) B. Zou, K. Long and D. Ma, Org. Lett., 2005, 7,
4237–4240.
chemical shifts of 3.94 and 4.15 ppm were reported for the
natural product. Therefore, the two protons on the C-2 and C-19
were ∼1.0 ppm downfield-shifting in our synthetic product.
Meanwhile, significant difference was also observed in the corre-
11 S. Li, S. Liang, W. Tan, Z. Xu and T. Ye, Tetrahedron, 2009, 65, 2695–
702.
2
13
sponding C NMR spectra. The C-2 and C-19 in our synthetic
product 1 displayed chemical shifts of 60.9 and 61.4 ppm,
respectively, much upfield-shifting than that for natural product
12 Preparation of natural product 1. To a solution of peptide 20 (125 mg,
0.135 mmol) in CH Cl (7 mL) at 0 °C, was added [Pd(PPh3)4]
2
2
(
31.2 mg, 0.027 mmol) and NMA (0.04 mL, 0.405 mmol). The reaction
was stirred at rt for 10 h and then quenched with water. The mixture was
extracted with CH Cl , and the combined organic phase was washed with
brine and dried over Na SO . After evaporation of the solvents, the
residue was purified by flash chromatography to give the carboxyl acid
intermediate as yellow oil, which was then dissolved in CH Cl (6 mL).
(65.0 and 66.1 ppm, respectively). The signals for the rest
2
2
protons and carbons were comparable between our synthetic 1
and the natural product.
2
4
2
2
In conclusion, we have developed a practical method to facili-
tate the total synthesis of the proposed structure of natural
product veraguamide A (1) by first preparing the three key frag-
ments followed by optimizing the macrocyclization site.
Although the synthetic product gave similar optical rotation to
To the solution just obtained, TFA (0.13 mL) was added at 0 °C. The
resulting solution was stirred for 6 h, and then concentrated in vacuo to
give the N-deprotected intermediate. To the solution of the N-deprotected
intermediate in CH
0
0
2
Cl
.306 mmol), HOAt (42 mg, 0.306 mmol) and DIPEA (0.11 mL,
.612 mmol) at 0 °C. The reaction mixture was stirred at rt for 3 d, then
O and extracted with CH Cl . The combined organic
phase was washed with brine, dried over Na SO , and evaporated. The
2
(100 mL), was added HATU (116 mg,
1
that reported for natural product, significant difference in the H
diluted with H
2
2
2
1
3
and C NMR spectra was observed, especially the proton and
carbon signals in the two N-MeVal amino acid residues. Syn-
thesis of other analogues with different stereo-configurations of
the corresponding amino acids, together with biological screen-
ing on a panel of cancer cell lines are currently being
undertaken.
2
4
residue was purified by column chromatography on silica gel (petroleum
ether–ethyl acetate) to give cyclic peptide 1 (32.1 mg, 31% yield for 3
20
1
steps) as a colorless amorphous solid. [α]
D
−33.0 (c 0.27, MeOH); H
NMR (300 MHz, CDCl ) δ 9.02 (d, J = 9.8 Hz, 1H), 5.20 (d, J = 10.1
3
Hz, 1H), 5.05 (dd, J = 16.9, 8.7 Hz, 3H), 4.89 (d, J = 8.3 Hz, 1H), 4.80
(t, J = 8.6 Hz, 1H), 3.86 (m, 1H), 3.71 (m, 1H), 3.01 (s, 6H), 2.69 (s,
1
1
H), 1.85–2.31 (m, 12H), 1.58 (m, 4H), 1.14 (d, J = 6.3 Hz, 3H),
.05–0.93 (m, 13H), 0.90–0.76 (m, 11H); C NMR (125 MHz, CDCl )
3
13
δ 174.1, 173.8, 172.6, 170.6, 170.2, 167.9, 80.2, 76.2, 75.7, 61.4, 60.8,
Acknowledgements
5
2
6.9, 53.1, 47.3, 44.6, 37.7, 36.6, 32.3, 32.0, 31.9, 31.7, 28.7, 27.9, 26.9,
5.1, 24.7, 24.0, 20.6, 20.4, 19.6, 19.5, 19.5, 18.3, 18.1, 16.4, 13.5, 10.7;
This work was supported by grants from Chinese National
Science Foundation (81072528), the Distinguished Young
4 8
ESI-MS m/z 789 (M + Na); HRMS Calcd for C37H59BrN NaO (M +
Na): 789.3414, found 789.3411.
7030 | Org. Biomol. Chem., 2012, 10, 7027–7030
This journal is © The Royal Society of Chemistry 2012