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Organic & Biomolecular Chemistry
0.73H, Ala-NH), 6.78 (br, 0.72H, Cys-α-CH), 5.73 (t, J = 7.4 Hz, line), 8.00 (d, J = 8.6 Hz, 1H, quinoline), 7.97 (d, J = 8.6 Hz, 1H,
1.28H, Cys-α-CH), 5.22 (d, J = 10.3 Hz, 0.95H, Val-α-CH), quinoline), 7.90 (d, J = 8.0 Hz, 1H, quinoline), 7.86 (d, J = 8.0
5.15–5.00 (m, 1.19H + 1.16H, Ser-α-CH and Ala-α-CH), 4.97 (td, Hz, 1H, quinoline), 7.79–7.61 (m, 4H, quinoline), 6.94 (d, J =
J = 7.0, 1.3 Hz, 0.81H, Ser-α-CH), 4.79 (q, J = 6.5 Hz, 0.84H, Ala- 4.6 Hz, 1H, Ala-NH) 6.60 (t, J = 6.6 Hz, 1H, Cys-α-CH), 5.74 (t,
α-CH), 4.74 (dd, J = 11.5, 6.5 Hz, 1.23H, Ser-β-CH2), 4.64 (d, J = J = 7.4 Hz, 1H, Cys-α-CH), 5.18 (d, J = 10.3 Hz, 1H, Val-α-CH),
10.3 Hz, 0.84H, Ser-β-CH2), 4.59 (dd, J = 11.2, 1.4 Hz, 1.16H, 5.02 (t, J = 6.6 Hz, 1H, Ser-α-CH), 4.99–4.90 (m, 2H, Ser-α-CH,
Ser-β-CH2), 4.50 (dd, J = 11.2, 7.2 Hz, 0.77H, Ser-β-CH2), 4.27 Ala-α-CH), 4.85–4.63 (m, 3H, Ala-α-CH, Ser-β-CH2), 4.62–4.47
(d, J = 10.3 Hz, 1.05H, Val-α-CH), 3.45–3.25, 3.27–3.03 (m, 4H, (m, 2H, Ser-β-CH2), 4.29 (d, J = 10.3 Hz, 1H, Val-α-CH),
major and minor Cys-β-CH2), 3.32, 3.00 (s, 3H, major and 3.53–2.80 (m, 16H, Cys-β-CH2, N-Me, Val-N-Me), 2.51–2.22 (m,
minor Cys-N-Me), 3.13, 3.05 (s, 3H, minor and major Val-N- 2H, Val-β-CH), 1.41 (d, J = 6.9 Hz, 3H, Ala-β-CH3), 1.12 (d, J =
Me), 2.43–2.28 (m, 2H, Val-β-CH), 1.46 (d, J = 6.9 Hz, 2.48H, 6.9 Hz, 3H, Val-γ-CH3), 1.07 (d, J = 6.9 Hz, 3H, Val-γ-CH3), 1.06
Ala-β-CH3), 1.13 (d, J = 6.3 Hz, 3.47H, Val-γ-CH3), 1.09 (d, J = (d, J = 7.0 Hz, 3H, Val-γ-CH3), 0.91 (d, J = 6.9 Hz, 3H, Val-
6.9 Hz, 2.68H, Val-γ-CH3), 1.06 (d, J = 6.3 Hz, 3.41H, Val- γ-CH3), 0.62 (d, J = 6.3 Hz, 3H, Ala-β-CH3); 13C NMR (125 MHz,
γ-CH3), 0.88 (d, J = 6.9 Hz, 2.44H, Val-γ-CH3), 0.72 (d, J = 6.3 CDCl3) δ 172.8, 172.6 (Ala-CO), 170.74 (Cys-CO), 170.66 (Ser-CO),
Hz, 3.52H, Ala-β-CH3); 1H NMR (single conformer, 500 MHz, 170.1 (Val-CO), 169.5 (Cys-CO), 168.7 (Ser-CO), 168.2 (Val-CO),
DMSO-d6) δ 9.53 (s, 2H, Qx-C3), 8.52 (d, J = 9.7 Hz, 2H, Ser- 165.1, 165.0 (quinolinic acid CO), 148.8, 148.6, 146.4, 137.8,
NH), 8.25–8.21 (m, 2H, Qx-C5 and C8), 8.19 (d, J = 5.7 Hz, 2H, 137.5, 130.5, 130.3, 129.7, 129.6, 129.4, 129.3, 128.3, 127.9,
Ala-NH), 8.03–7.92 (m, 6H, Qx-C6 and C7), 6.16 (dd, J = 10.9, 127.7, 118.9, 118.8 (quinoline), 65.2 (Val-α-CH), 64.9, 64.7 (Ser-
3.4 Hz, 2H, Cys-α-CH), 4.92 (dd, J = 9.5, 3.7 Hz, 2H, Ser-α-CH), β-CH2), 62.2, 62.1 (Val-α-CH), 54.1 (Cys-α-CH), 53.74, 53.70 (Ser-
4.83 (d, J = 9.7 Hz, 2H, Val-α-CH), 4.66–4.49 (m, 4H, Ser-β-CH2 α-CH), 52.9 (Cys-α-CH), 51.90, 51.87 (Ser-α-CH), 46.76, 46.74,
and Ala-α-CH), 4.44 (dd, J = 10.9, 4.0 Hz, 2H, Ser-β-CH2), 3.61 44.79, 44.74 (Ala-α-CH), 40.1, 38.3 (Cys-β-CH2), 32.2, 31.6 (Cys-N-
(t, J = 12.3 Hz, 2H, Cys-β-CH2), 3.31 (s, 6H, Cys-N-Me), 2.86 (s, Me), 30.3, 30.0 (Val-N-Me), 29.8, 28.0 (Val-β-CH), 20.6, 20.2, 20.0,
6H, Val-N-Me), 2.43–2.33 (m, 2H, Val-β-CH), 2.31 (dd, J = 13.5, 18.9 (Val-γ-CH3), 17.24, 17.20 (Ala-β-CH3); HRMS (ESI) calcd for
3.2 Hz, 2H, Cys-β-CH2), 1.30 (d, J = 7.4 Hz, 6H, Ala-β-CH3), 0.99 C52H64N10NaO12S2 [M + Na]+ 1107.4039, found: 1107.4047; m.
+
(d, J = 7.0 Hz, 6H, Val-γ-CH3), 0.95 (d, J = 7.5 Hz, 6H, Val- p. 227.8–231.6 °C (dec.) (recrystallization from AcOEt/MeOH);
γ-CH3); 13C NMR (mixture of conformers, 125 MHz, CDCl3) [α]D28.0 −141.6° (c 0.1, CHCl3).
δ 172.9, 172.8 (major and minor Ala-CO), 170.6 (major Val-CO),
[N-(Naphthalene-2-carbonyl)-D-Ser-L-Ala-N-Me-L-Cys-N-Me-L-Val]2
170.4 (major Cys-CO), 170.2 (minor Val-CO), 169.3 (minor Cys- (serine-hydroxy)-dilactone disulfide 41 (Np). The reaction was
CO), 168.4 (major Ser-CO), 167.9 (minor Ser-CO), 163.9, 163.7 performed in almost the same way as the method of triostin
(major and minor Qx-CO), 144.2, 143.9, 143.8, 143.6, 142.7, A. 2-Naphthoic acid 39 33.0 mg (0.19 mmol, 4 equiv.) was used
142.6, 140.25, 142.22, 132.1, 132.0, 131.3, 131.0, 129.7, 129.61, instead of 2-quinoxalinecarboxylic acid 37. 35.8 mg of the
129.57, 129.48 (Qx), 65.6 (minor Ser-β-CH2), 65.2 (major Val- target compound 41 was obtained (0.033 mmol, 74% yield in 2
α-CH), 64.6 (major Ser-β-CH2), 61.9 (minor Val-α-CH), 53.8 steps) as a pale yellow solid: Rf = 0.5 (CH2Cl2 : MeOH = 10 : 1);
(minor Cys-α-CH), 53.4 (major Ser-α-CH), 53.2 (major Cys- 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 2H), 7.96–7.88 (m, 6H,
α-CH), 51.7 (minor Ser-α-CH), 47.2 (minor Ala-α-CH), 44.8 Ser-NH, Ala-NH, naphthalene C5 or C8), 7.87 (d, J = 8.6 Hz,
(major Ala-α-CH), 39.9 (major Cys-β-CH2), 38.5 (minor Cys- 2H, naphthalene C5 or C8), 7.85 (d, J = 8.5 Hz, 2H, naphtha-
β-CH2), 32.3 (major Cys-N-Me), 31.2 (minor Val-N-Me), 30.04 lene C4), 7.63 (dd, J = 8.6, 1.7 Hz, 2H, naphthalene C3),
(minor Cys-N-Me), 29.96 (major Val-N-Me), 29.71 (major Val- 7.62–7.52 (m, 4H, naphthalene C6, C7), 5.64 (t, J = 6.0 Hz, 2H,
β-CH), 27.4 (minor Val-β-CH), 20.5 (major Val-γ-CH3), 20.4 Ser-α-CH), 5.10 (dd, J = 8.0, 4.6 Hz, 2H, Cys-α-CH), 5.01–4.81
(minor Val-γ-CH3), 20.2 (major Val-γ-CH3), 18.4 (minor Val- (m, 4H, Ser-β-CH2, Ala-α-CH), 4.51 (d, J = 10.3 Hz, 2H, Ser-
γ-CH3), 17.7 (minor Ala-β-CH3), 17.3 (major Ala-β-CH3); HRMS β-CH2), 4.23 (d, J = 10.3 Hz, 2H, Val-α-CH), 3.41–3.30 (m, 4H,
+
(ESI) calcd for C50H63N12O12S2 [M + Na]+ 1109.3944, found: Cys-β-CH2), 3.29 (s, 6H, Cys-N-Me), 3.12 (s, 6H, Val-N-Me),
1109.3915; m.p. 220.4–222.9 °C (dec.) (recrystallization from 2.56–2.33 (m, 2H, Val-α-CH), 1.10 (d, J = 6.3 Hz, 6H, Val-γ-CH3),
AcOEt/MeOH) (lit. 245–248 °C (dec.));18 [α]2D6.5 −142.1° (c 0.108, 1.07 (d, J = 6.9 Hz, 6H, Val-γ-CH3), 0.35 (d, J = 6.3 Hz, 6H, Ala-
CHCl3) (lit. [α]2D5 −154° (c 1.0, CHCl3)).18
β-CH3); 13C NMR (125 MHz, CDCl3) δ 173.6 (Ala-CO), 171.2
[N-(Quinoline-2-carbonyl)-D-Ser-L-Ala-N-Me-L-Cys-N-Me-L-Val]2 (Val-CO), 170.4 (Cys-CO), 168.4 (Ser-CO), 167.4 (naphthoic acid
(serine-hydroxy)-dilactone disulfide 40 (Qn).41 The reaction was CO), 134.8, 132.4, 130.7 (naphthalene C2, C9, C10), 128.9
performed in almost the same way as the method of triostin (naphthalene C8), 128.4 (naphthalene C4), 127.99 (naphtha-
A. 2-Quinolinecarboxylic acid 38 32.9 mg (0.19 mmol, 4 equiv.) lene C6 or C7), 127.93 (naphthalene C1), 127.7 (naphthalene
was used instead of 2-quinoxalinecarboxylic acid 37. The target C5), 127.0 (naphthalene C6 or C7), 123.7 (naphthalene C3),
compound 40 was obtained 34.0 mg (0.031 mmol, 65% yield 65.3 (Ser-β-CH2), 64.9 (Val-α-CH), 53.8 (Ser-α-CH), 53.7, 53.6
1
in 2 steps) as a colorless solid: Rf = 0.1 (AcOEt only); H NMR (Cys-α-CH), 44.4 (Ala-α-CH), 39.7 (Cys-β-CH2), 32.5 (Cys-N-Me),
(500 MHz, CDCl3) δ 9.16 (d, J = 8.6 Hz, 1H, Ser-NH), 9.01 (d, J = 30.0 (Val-N-Me), 29.7 (Val-β-CH), 20.4, 19.9 (Val-γ-CH3), 17.1
8.0 Hz, 1H, Ser-NH), 8.39 (d, J = 9.2 Hz, 1H, Ala-NH), 8.35 (d, (Ala-β-CH3); HRMS (ESI) calcd for C54H66N8NaO12S2+ [M + Na]+
J = 8.0 Hz, 1H, quinoline), 8.29 (d, J = 5.2 Hz, 1H, quinoline), 1105.4134, found: 1105.4105; m.p. 170.4–174.3 °C;
8.28–8.24 (m, 1H, quinoline), 8.20 (d, J = 8.0 Hz, 1H, quino- [α]2D3.7 −80.7° (c 0.1, CHCl3).
Org. Biomol. Chem.
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