The Journal of Organic Chemistry
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3H, OMe), 2.63 (dd, 1H, J = 14.8, 5.0 Hz, CαH(pro‑R)-2), 2.49 (dd, 1H,
J = 14.8, 4.3 Hz, CαH(pro‑S)-2), 1.54 (s, 3H, Me), 1.44 (s, 9H, Boc),
1.39 (d, 3H, J = 7.1 Hz, CH3-3), 1.36 (d, 3H, J = 7.2 Hz, CH3-1), 1.35
(s, 3H, Me); 13C NMR (150 MHz, CDCl3, 298 K): δ 173.1, 172.7,
170.5, 155.2, 113.2, 103.7, 83.0, 80.0, 77.2(2C), 58.0, 52.5, 50.4, 49.2,
48.1, 36.9, 28.3(3C), 26.7, 26.5, 18.4, 17.9; HRMS (ESI+): m/z [M+ +
H] calculated for C23H40N3O10 518.2713, found 518.2697.
mmol) and stirred at room temperature for 1 h and was worked up as
described for 29 to give 32 (0.75 g, 95%) as a white solid, mp 210 °C.
A solution of 32 (0.15 g, 0.2 mmol), HOBt (0.04 g, 0.3 mmol) and
EDCI (0.05 g, 0.3 mmol) in CH2Cl2 (2 mL) was stirred at 0 °C under
a N2 atmosphere for 15 min, treated sequentially with 28 [prepared
from 27 (0.1 g, 0.22 mmol) and CF3COOH (0.1 mL) in dry CH2Cl2
(0.9 mL) at 0 °C] and DIPEA (0.08 mL, 0.6 mmol) and stirred for 8
h. Worked up as described for 27 and purified the residue by column
chromatography (60−120 mesh Silica gel, 2.8% MeOH in CHCl3) to
afford 8 (0.07 g, 32%) as a white solid; mp 240 °C; [α]20D = +147.77
(c 0.3, CHCl3); IR (KBr): 3377, 3291, 2984, 2925, 2855, 1726, 1650,
1537, 1374, 1237, 1169, 1086, 1025 cm−1; 1H NMR (600 MHz,
CDCl3, 283 K): δ 7.49 (d, 1H, J = 8.9 Hz, NH-4), 7.25 (d, 1H, J = 10.2
Hz, NH-6), 7.14 (d, 1H, J = 5.4 Hz, NH-5), 7.03 (d, 1H, J = 5.3 Hz,
NH-3), 6.91 (d, 1H, J = 8.9 Hz, NH-2), 5.79 (d, 2H, J = 3.3 Hz, C1H-
2, 4), 5.74 (d, 1H, J = 3.5 Hz, C1H-6), 4.98 (d, 1H, J = 4.2 Hz, NH-1),
4.72 (t, 1H, J = 3.9 Hz, C2H-2), 4.71 (t, 1H, J = 3.9 Hz, C2H-4), 4.64
(t, 1H, J = 3.8 Hz, C2H-6), 4.47 (m, 1H, CβH-6), 4.44 (m, 1H, CβH-
2), 4.30 (m, 1H, CαH-5),4.25 (m, 2H, CαH-3, CβH-4), 4.23 (m, 1H,
CαH-1), 4.18 (t, 1H, J = 8.7 Hz, C4H-4), 3.97 (m, 1H, C4H-2), 3.95
(m, 1H, C4H-6), 3.79 (dd, 1H, J = 8.0, 4.0 Hz, C3H-6), 3.70 (s, 3H,
COOMe), 3.58 (m, 1H, C3H-4), 3.57 (m, 1H, C3H-2), 3.49 (s, 3H,
OMe), 3.37 (s, 6H, 2 × OMe), 2.83 (dd, 1H, J = 15.8, 4.9 Hz,
CαH(pro‑S)-6), 2.79 (dd, 1H, J = 15.8, 9.1 Hz, CαH(pro‑R)-6), 2.67 (dd,
1H, J = 13.8, 1.7 Hz, CαH(pro‑S)-4), 2.60 (dd, 1H, J = 13.8, 10.0 Hz,
CαH(pro‑R)-4), 2.54 (dd, 1H, J = 13.6, 1.8 Hz, CαH(pro‑S)-2), 2.16 (dd,
1H, J = 13.6, 10.0 Hz, CαH(pro‑R)-2), 1,59 (s, 3H, Me), 1.56 (s, 3H,
Me), 1.55 (s, 3H, Me), 1.45 (s, 9H, Boc), 1.43 (m, 3H, CH3-5), 1.42
(m, 6H, CH3-3, Me), 1.42 (m, 3H, Me), 1.41 (m, 3H, Me), 1.36 (d,
3H, J = 7.0 Hz, CH3-1), 1.35 (m, 3H, Me); 13C NMR (150 MHz,
CDCl3, 298 K): δ 173.1, 172.7, 172.6, 171.9, 171.0, 170.7, 155.6,
113.1, 112.8 (2C), 103.9 (2C), 103.8, 83.9, 83.0, 82.6, 80.7, 79.2, 78.9,
78.3, 77.7 (2C), 58.1, 58.0, 57.9, 51.9, 51.2, 51.1, 50.6, 50.5, 49.3, 49.2,
39.6, 39.1, 36.7, 29.7, 28.3 (3C), 27.0 (2C), 26.7 (3C), 26.5, 17.8, 17.7,
17.4; HRMS (ESI+): m/z [M+ + Na] calculated for C48H78N6O21
1097.5117, found 1097.5075.
Boc-L-Ala-(R)-β-Caa(r)- L-Ala-(R)-β-Caa(r)-OMe (6). A solution of
acid 29 (0.15 g, 0.34 mmol), HOBt (0.05 g, 0.41 mmol), and EDCI
(0.08 g, 0.41 mmol) in CH2Cl2 (10 mL) was stirred at 0 °C under a
N2 atmosphere for 15 min. It was treated sequentially with amine 28
[prepared from 27 (0.17 g, 0.38 mmol) and CF3COOH (0.3 mL) in
dry CH2Cl2 (0.9 mL) at 0 °C] and DIPEA (0.11 mL, 0.81 mmol) and
stirred for 8 h and was worked up as described for 27 and purified the
residue by column chromatography (60−120 mesh Silica gel, 2.2%
MeOH in CHCl3) to afford 6 (0.09 g, 38%) as a white solid; mp 180−
184 °C; [α]20D = +84.33 (c 0.1, CHCl3); IR (KBr): 3377, 3291, 2984,
2925, 2855, 1726, 1650, 1537, 1374, 1237, 1169, 1086, 1025 cm−1; 1H
NMR (600 MHz, CDCl3, 298 K): δ 7.06 (d, 1H, J = 6.3 Hz, NH-2),
6.92 (d, 1H, J = 9.1 Hz, NH-4), 6.73 (d, 1H, J = 6.3 Hz, NH-3), 5.74
(d, 1H, J = 3.5 Hz, C1H-2), 5.73 (d, 1H, J = 3.5 Hz, C1H-4), 5.02 (d,
1H, J = 5.7 Hz, NH-1), 4.70 (t, 1H, J = 4.2 Hz, C2H-4), 4.69 (t, 1H, J
= 4.2 Hz, C2H-2), 4.46 (m, 1H, CβH-4), 4.36 (m, 1H, CαH-3), 4.33
(m, 1H, CβH-2), 4.16 (m, 1H, CαH-1), 4.00 (t, 1H, J = 7.6 Hz, C4H-
2), 3.95 (t, 1H, J = 8.4 Hz, C4H-4), 3.69 (m, 1H, C3H-4), 3.66 (s, 3H,
COOMe), 3.63 (m, 1H, J = 8.7, 4.3, C3H-2),, 3.44 (s, 3H, OMe), 3.39
(s, 3H, OMe), 2.76 (dd, 1H, J = 14.8, 4.2 Hz, CαH(pro‑S)-4), 2.70 (dd,
1H, J = 14.8, 7.0 Hz, CαH(pro‑R)-4), 2.55 (dd, 1H, J = 15.7, 4.7 Hz,
CαH(pro‑R)-2), 2.44 (dd, 1H, J = 15.7, 6.8 Hz, CαH(pro‑S)-2), 1.56 (s, 6H,
2 × Me), 1.44 (s, 9H, Boc), 1.37 (m, 3H, CH3-3), 1.35 (m, 9H, CH3-1,
2 × Me); 13C NMR (150 MHz, CDCl3, 298 K): δ 172.8, 172.0, 171.9,
170.4, 155.5, 113.2, 113.3, 103.9, 103.8, 83.1, 82.9, 80.4, 78.6, 78.5,
77.4(2C), 58.1, 58.0, 51.9, 50.9, 49.6, 49.2, 48.8, 38.0, 36.0, 28.3(3C),
26.9, 26.8, 26.6, 26.5, 18.2, 18.0.; HRMS (ESI+): m/z [M+ + H]
calculated for C34H57N4O15 761.3820, found 761.3800.
Boc-L-Ala-(R)-β-Caa(r)-L-Ala-(R)-β-Caa(r)-L-Ala-OMe (7). A solu-
tion of acid 29 (0.23 g, 0.53 mmol), HOBt (0.10 g, 0.79 mmol), and
EDCI (0.15 g, 0.79 mmol), in CH2Cl2 (5 mL) was stirred at 0 °C
under a N2 atmosphere for 15 min, treated sequentially with 31
[prepared from 5 (0.26 g, 0.58 mmol) and CF3COOH (0.5 mL) in dry
CH2Cl2 (2 mL) at 0 °C] and DIPEA (0.27 mL, 1.59 mmol) and
stirred for 8 h and was worked up as described for 27 and purified the
residue by column chromatography (60−120 mesh Silica gel, 2.3%
MeOH in CHCl3) to afford 7 (0.22 g, 50%) as a white solid; mp 190
1H NMR (CD3CN, 313 K, 600 MHz): δ 7.16 (d, 1H, J = 8.9 Hz,
NH-4), 7.04 (d, 1H, J = 8.6 Hz, NH-2), 7.02 (d, 1H, J = 9.1 Hz, NH-
6), 6.98 (d, 1H, J = 5.2 Hz, NH-5), 6.84 (d, 1H, J = 5.3 Hz, NH-3),
5.75 (d, 1H, J = 3.6 Hz, C1H-4), 5.76 (d, 1H, J = 3.6 Hz, C1H-2), 5.70
(d, 1H, J = 3.6 Hz, C1H-6), 5.60 (bs, 1H, NH-1), 4.74 (t, 2H, J = 4.0
Hz, C2H-2, 4), 4.71 (t, 1H, J = 4.0 Hz, C2H-6), 4.39 (m, 1H, CβH-6),
4.34 (m, 1H, CβH-2), 4.27 (m, 1H, CβH-4), 4.19 (m, 1H, CαH-3,),
4.14 (m, 1H, CαH-5), 4.08 (m, 1H, CαH-1), 3.97 (dd, 1H, J = 8.4, 7.0
Hz, C4H-2), 3.92 (dd, 1H, J = 8.7, 6.1 Hz, C4H-4), 3.88 (dd, 1H, J =
8.6, 7.0 Hz, C4H-6), 3.64 (s, 3H, COOMe), 3.63 (dd, 1H, J = 8.4, 4.3
Hz, C3H-6), 3.57 (dd, 1H, J = 8.6, 4.3 Hz, C3H-4), 3.56 (dd, 1H, J =
8.4, 4.3 Hz, C3H-2), 3.38 (s, 3H, OMe), 3.35 (s, 3H, OMe), 3.33 (s,
3H, OMe), 2.65 (dd, 1H, J = 15.5, 5.1 Hz, CαH(pro‑S)-6), 2.57 (dd, 1H,
J = 15.5, 8.6 Hz, CαH(pro‑R)-6), 2.52 (dd, 1H, J = 14.1, 8.7 Hz,
CαH(pro‑R)-4), 2.51 (dd, 1H, J = 14.8, 3.2 Hz, CαH(pro‑S)-2), 2.44 (dd,
1H, J = 14.1, 3.3 Hz, CαH(pro‑S)-4), 2.35 (dd, 1H, J = 14.8, 8.5 Hz,
CαH(pro‑R)-2), 1,50 (s, 3H, Me), 1.49 (s, 3H, Me), 1.48 (s, 3H, Me),
1.46 (s, 9H, Boc), 1.34 (m, 9H, CH3-3, 2 × Me), 1.33(m, 3H, Me),
1.32 (m, 3H, Me), 1.30 (d, 3H, J = 7.0 Hz, CH3-1).
°C; [α]20 = +115.3 (c 0.15, CHCl3); IR (KBr): 3291, 2984, 2932,
D
1649, 1543, 1377, 1225, 1167, 1026 cm−1; 1H NMR (600 MHz,
CDCl3, 283 K): δ 7.31 (d, 1H, J = 9.3 Hz, NH-4), 7.07 (d, 1H, J = 8.5
Hz, NH-2), 6.81 (d, 1H, J = 6.9 Hz, NH-3), 6.74 (d, 1H, J = 6.9 Hz,
NH-5), 5.76 (d, 1H, J = 3.5 Hz, C1H-2), 5.75 (d, 1H, J = 3.4 Hz, C1H-
4), 5.15 (d, 1H, J = 6.0 Hz, NH-1), 4.71 (t, 1H, J = 3.5 Hz, C2H-2),
4.69 (t, 1H, J = 3.9 Hz, C2H-4), 4.51 (m, 1H, CαH-5), 4.38 (m, 1H,
CαH-3), 4.32 (m, 2H, CβH-2, 4), 4.15 (m, 1H, CαH-1), 4.01 (t, 1H, J
= 7.8 Hz, C4H-2), 4.00 (t, 1H, J = 8.5 Hz, C4H-4), 3.73 (s, 3H,
COOMe), 3.70 (dd, 1H, J = 8.5, 4.2 Hz, C3H-4), 3.63 (dd, 1H, J = 8.5,
3.9 Hz, C3H-2), 3.45 (s, 3H, OMe), 3.38 (s, 3H, OMe), 2.71 (dd, 1H,
J = 14.1, 8.1 Hz, CαH(pro‑R)-4), 2.63 (dd, 1H, J = 14.1, 3.9 Hz,
CαH(pro‑S)-4), 2.58 (dd, 1H, J = 14.8, 2.6 Hz, CαH(pro‑S)-2), 2.38 (dd,
1H, J = 14.8, 8.1 Hz, CαH(pro‑R)-2), 1.57 (s, 3H, Me), 1.55 (s, 3H, Me),
1.43 (s, 9H, Boc), 1.42 (d, 3H, J = 7.2 Hz, CH3-5), 1.38 (d, 3H, J = 7.3
Hz, CH3-3), 1.36 (s, 3H, Me), 1.35 (s, 3H, Me), 1.34 (d, 3H, J = 7.2
Hz, CH3-1); 13C NMR (150 MHz, CDCl3, 298 K): δ 173.4, 173.1,
172.5, 170.7, 170.6, 155.6, 113.2, 113.0, 103.9(2C), 83.3, 82.9, 80.3,
78.6, 78.4, 77.5(2C), 58.2(2C), 52.4, 50.8, 49.9, 49.8, 49.5, 48.3, 38.6,
37.9, 28.3(3C), 26.8(2C), 26.6, 26.5, 18.2, 17.8, 17.6; HRMS (ESI+):
m/z [M+ + Na] calculated for C37H61N5O16 854.4011, found
854.3984.
1H NMR (CD3OH, 293 K, 700 MHz): δ 8.02 (d, 1H, J = 5.1 Hz,
NH-3), 7.97 (d, 1H, J = 9.2 Hz, NH-6), 7.95 (d, 1H, J = 6.0 Hz, NH-
5), 7.92 (d, 1H, J = 8.8 Hz, NH-2), 7.81 (d, 1H, J = 8.5 Hz, NH-4),
5.76 (d, 1H, J = 3.6 Hz, C1H-2), 5.75 (d, 1H, J = 3.5 Hz, C1H-4), 5.72
(d, 1H, J = 3.5 Hz, C1H-6), 6.81 (d, 1H, J = 5.6 Hz, NH-1), 4.76 (m,
1H, C2H-4), 4.75 (m, 1H, C2H-2), 4.74 (m, 1H, C2H-6), 4.45 (m, 1H,
CβH-2), 4.43 (m, 1H, CβH-6), 4.32 (m, 1H, CβH-4), 4.24 (m, 1H,
CαH-3,), 4.21 (m, 1H, CαH-5), 4.06 (m, 1H, CαH-1), 4.02 (t, 1H, J ≈
8.0 Hz, C4H-4), 3.92 (dd, 1H, J = 8.6, 6.6 Hz, C4H-2), 3.84 (dd, 1H, J
= 8.5, 7.2 Hz, C4H-6), 3.65 (s, 3H, COOMe), 3.63 (m, 2H, C3H-2, 6),
3.62 (m, 1H, C3H-4), 3.39 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.35 (s,
3H, OMe), 2.71 (dd, 1H, J = 15.5, 4.6 Hz, CαH(pro‑S)-6), 2.59 (m, 1H,
CαH(pro‑S)-2), 2.56 (m, 1H, CαH(pro‑S)-4), 2.55 (m, 1H, CαH(pro‑R)-6),
2.52 (dd, 1H, J = 14.8, 8.5 Hz CαH(pro‑R)-4), 2.42 (dd, 1H, J = 15.3, 9.0
Hz, CαH(pro‑R)-2), 1.49 (s, 3H, Me), 1.48 (s, 6H, 2 × Me), 1.44 (s, 9H,
Boc-L-Ala-(R)-β-Caa(r)-L-Ala-(R)-β-Caa(r)-L-Ala-(R)-β-Caa(r)-OMe
(8). A cooled (0 °C) solution of 6 (0.08 g, 0.1 mmol) in THF/
MeOH/H2O (3:1:1) (0.5 mL) was treated with LiOH (0.005 g, 0.2
6846
dx.doi.org/10.1021/jo300865d | J. Org. Chem. 2012, 77, 6834−6848