Tamadarin B Analogues
57.5, 60.7, 66.0, 69.3, 71.9, 79.6, 80.7, 126.3, 126.9 127.5, 127.8,
128.2, 128.5, 128.9, 132.8, 133.9, 135.9, 156.2, 169.0, 170.1, 170.9,
171.7, 172.0 173.2. IR (neat): 3339, 2962, 2872, 2248, 1742, 1665,
(3 mL) at 0 °C was added BOP (15 mg, 0.035 mmol) and NMM
(10 µL, 0.092 mmol). After 30 min at 0 °C, the mixture was stirred
at room temperature overnight. The reaction mixture was treated
with saturated NaCl solution (2 mL) and extracted with EtOAc
(2 × 10 mL). The organic layers were washed with 10% HCl
(5 mL), 5% NaHCO3 (5 mL), and NaCl (5 mL, saturated), dried
(Na2SO4), filtered, and concentrated. The crude oil (24 mg) was
purified by HPLC (C18, isocratic, CH3CN/H2O 85/15; flow 7 mL/
1635, 1529, 1451, 1167, 851 cm-1
.
[2-Naphthylala5]-Tamandarin B (17). To a solution of the Boc-
protected macrocycle 18 (28 mg, 0.032 mmol) in HPLC-grade
dioxane (3 mL) was added a solution of HCl in dioxane (3 mL).
The resulting solution was stirred at room temperature for 2 h. The
solution was concentrated and the residue diluted with CH2Cl2 and
concentrated again to yield the hydrochloride salt (quantitative yield)
as a white solid, which was used directly in the next step. To a
mixture of the macrocycle amine salt (25 mg, 0.031 mmol) and
side chain 15 (14.6 mg, 0.046 mmol) in CH2Cl2 (4 mL) at 0 °C
was added BOP (20.3 mg, 0.046 mmol) and NMM (14 µL,
0.12 mmol). After 30 min at 0 °C, the reaction was stirred at room
temperature overnight. The reaction mixture was treated with NaCl
solution (2 mL, saturated) and extracted with EtOAc (2 × 10 mL).
The organic layers were washed with 10% HCl (5 mL), 5%
NaHCO3 (5 mL), and NaCl (5 mL, saturated), dried (Na2SO4),
filtered, and concentrated. The crude oil (8 mg, 68%) was purified
by HPLC (HyperPrep PEP 100 C18, isocratic, CH3CN/H2O 85/
1
min, 270 nm) to obtain 34 as a white foam. H NMR (300 MHz,
CDCl3, δ): 0.82-0.96 (m, 24H), 1.09-1.28 (m, 14H), 1.39-1.43
(m, 3H), 1.64-1.67 (m, 2H), 1.88-1.98 (m, 2H), 2.10-2.15 (m,
2H), 2.58 (s, 3H), 2.90-2.65 (m, 1H), 3.05 (s, 3H), 3.09-3.12
(m, 1H), 3.35-3.43 (m, 1H), 3.43-3.82 (m, 5H), 3.79 (s, 3H),
3.98-4.05 (m, 1H), 4.12-4.17 (m, 1H), 4.45-4.50 (m, 1H), 4.62-
4.66 (m, 1H), 4.67-4.70 (m, 2H), 5.05 (d, J ) 5.3 Hz, 1H), 5.29-
5.32 (m, 2H), 6.80 (d, J ) 8.7 Hz, 2H), 7.02 (d, J ) 8.6 Hz, 2H),
7.65 (d, J ) 6.7 Hz, 1H), 8.09 (d, J ) 9.5 Hz, 1H), 8.45 (d, J )
8.9 Hz, 1H). HRMS: m/z calcd for C52H81N7O14Na (M + Na)+
1050.5739, found 1050.5731.
[Ala4]-Tamandarin B Macrocycle (42). To a solution of the
protected linear precursor (102 mg, 0.09 mmol) in MeOH (88 mL),
under argon, was added Pd(OH)2 (44 mg). The reaction mixture
was purged with H2 and stirred overnight under a H2 atmosphere
(1 atm). The mixture was filtered through Celite, and the filtrate
was concentrated to yield the free linear precursor (77 mg, 96%)
as a yellow oil. The crude amino acid linear precursor (77 mg,
0.91 mmol) was dissolved in CH3CN (20 mL) and cooled to 0 °C.
HATU (815 mg, 0.22 mmol) was added, followed by the dropwise
addition of NMM (20 µL, 1.82 mmol). The reaction mixture was
stirred at 0 °C for 1 h and then overnight at room temperature. The
reaction mixture was concentrated in vacuo, diluted with EtOAc
(15 mL), washed with 10% KHSO4 (15 mL), 5% NaHCO3
(15 mL), and NaCl (15 mL, saturated), dried (Na2SO4), filtered,
and concentrated. The crude oil was purified by column chroma-
tography (silica gel, EtOAc/Hex 2/1) to yield the protected
macrocycle 42 (45 mg, 60%) as a white foam. Rf ) 0.24 (AcOEt/
1
15; flow 7 mL/min, 270 nm) to afford 17 as a white foam. H
NMR (500 MHz, CDCl3, δ): 0.82-0.96 (m, 24H), 1.09-1. 28
(m, 14H), 1.31 (d, J ) 6.8 Hz, 3H), 1.39 (d, J ) 6.8 Hz, 3H), 1.64
(m, 3H), 2.10 (m, 4H), 2.48 (s, 3H), 3.10 (s, 3H), 3.09-3.15 (m,
2H), 3.35-3.41 (m, 2H), 3.43-3.82 (m, 5H), 4.29-4.33 (m, 1H),
4.42-4.47 (m, 1H), 4.65-4.70 (m, 1H), 4.72 (t, J ) 6.8 Hz, 1H),
4.87 (t, J ) 8.3 Hz, 1H), 5.02 (d, J ) 5.3 Hz, 1H), 5.29-5.32 (m,
2H), 7.24-7.27 (m, 1H), 7.45-7. 63 (m, 4H), 7.67-7.83 (m, 4H).
[Ser6]-Tamandarin B Macrocycle (33). To a solution of the
protected linear precursor 32 (206 mg, 0.19 mmol) in MeOH
(15 mL) under argon was added Pd(OH)2 (81 mg). The reaction
mixture was purged with H2 and stirred overnight under a H2
atmosphere (1 atm). The mixture was filtered through Celite. The
filtrate was concentrated to yield the free linear precursor (150 mg,
91%) as a yellow oil, which was used in the next step without
purification. The crude amino acid linear precursor (150 mg,
0.17 mmol) was dissolved in CH3CN (30 mL) and cooled to 0 °C.
HATU (160 mg, 0.42 mmol) was added, followed by the dropwise
addition of NMM (38 µL, 0.34 mmol). The reaction mixture was
stirred at 0 °C for 1 h and then overnight. The reaction mixture
was concentrated in vacuo, diluted with EtOAc (15 mL), washed
with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL), and NaCl
(10 mL, saturated), dried (Na2SO4), filtered, and concentrated. The
crude oil was purified by column chromatography (silica gel,
EtOAc/Hex 2/1) to yield the protected macrocycle 33 (130 mg,
89%) as a white foam. Rf ) 0.23 (AcOEt/Hex 1/2). [R]D20 ) -56.1
20
1
Hex 1/2). [R]D ) -33.09 (c ) 1, CHCl3). H NMR (500 MHz,
CDCl3, δ): 0.92-1.04 (m, 18H), 1.16 (d, J ) 6.8 Hz, 3H), 1.17-
1.30 (m, 3H), 1.49 (s, 9H), 1.51-1.61 (m, 1H), 1.73-1.75 (m,
1H), 1.83-1.86 (m, 1H), 1.93-1.97 (m, 1H), 2.30-2.40 (m, 1H),
2.57-2.39 (m, 1H), 3.00-3.05 (m, 1H), 3.08 (s, 3H), 3.19-3.21
(m, 1H), 3.49-3.51 (m, 1H), 3.82 (s, 3H), 3.98-4.00 (m, 1H),
5.01-5.06 (m, 2H), 5.27-5.30 (m, 1H), 5.56-5.66 (m, 1H), 6.67-
6.69 (m, 1H), 6.88 (d, J ) 7.9 Hz, 2H), 7.00-7.09 (m, 1H), 7.12
(d, 2H). 13C NMR (125 MHz, CDCl3, δ): 15.1, 18.4, 18.9, 20.9,
21.1, 23.2, 24.0, 24.8, 24.9, 25.5, 28.0, 28.1, 30.1, 33.7, 34.4, 39.01,
39.3, 45.4, 47.1, 51.2, 55.3, 69.3, 71.9, 79.5, 80.6, 114.1, 114.2,
129.9, 132.3, 156.1, 169.01, 170.9, 171.5, 172.3, 173.2. HRMS:
m/z calcd for C41H65N5O12Na (M + Na)+ 842.4527, found
842.4545.
1
(c ) 1, CHCl3). H NMR (500 MHz, CDCl3, δ): 0.89-1.05 (m,
18H), 1.45 (m, 9H), 1.62-1.74 (m, 1H), 2.00-2.20 (m, 4H), 2.55
(m, 3H), 2.81 (dd, 1H), 2.99(dd, 1H), 3.15 (dd, 1H), 3.36 (dd, 1H),
3.53 (m, 1H), 3.67 (m, 1H), 3.73 (m, 1H), 3.80 (s, 3H), 3,91 (m,
1H), 4.10 (m, 1H), 4.19 (m, 1H), 4.42 (td, 1H), 4.48 (m, 1H), 4.51
(dd, 1H), 4.59 (m, 1H), 4,91 (m, 1H), 5.06 (m, 2H), 6.84 (d, 2H),
7.01 (d, 2H), 7.77 (d, 2H), 8.55 (d, 2H). 13C NMR (125 MHz,
CDCl3, δ): 17.4, 17.8, 18.7, 20.2, 20.6, 21.4, 23.5, 24.9, 25.1, 26.0,
28.0, 28.1, 28.3, 28.6, 28.8, 30.2, 30.7, 34.1, 38.6, 46.1, 47.0, 48.7,
48.9, 52.4, 55.3, 57.2, 62.9, 63.7, 65.6, 68.7, 69.3, 78.7, 80.5, 114.1,
129.8, 130.3, 155.6, 158.6, 169.1, 170.8, 171.1, 171.2. IR (neat):
3314, 2924, 2359, 1742, 1630 cm-1. HRMS: m/z calcd for
C57H79N5O15Na (M + Na)+ 1096.5470, found 1096.5498.
[N-Ala4]-Tamandarin B (43). To a solution of the Boc-protected
macrocycle 42 (11 mg, 0.013 mmol) in HPLC-grade dioxane
(5 mL) was added a solution of HCl in dioxane (5 mL). The
resulting solution was stirred at room temperature for 4 h. The
solution was concentrated and the residue diluted with CH2Cl2 and
concentrated again to yield the hydrochloride salt (quantitative yield)
as a white solid, which was used directly in the next step. To a
mixture of the macrocycle amine salt (10 mg, 0.013 mmol) and
side chain (6.2 mg, 0.019 mmol) in CH2Cl2 (2 mL) at 0 °C was
added BOP (8.4 mg, 0.019 mmol) and NMM (6 µL, 0.052 mmol).
After 30 min at 0 °C, the reaction was stirred at room temperature
overnight. The reaction mixture was treated with NaCl solution (5
mL, saturated) and extracted with EtOAc (2 × 10 mL). The organic
layers were washed with 10% HCl (5 mL), 5% NaHCO3 (5 mL),
and NaCl (5 mL, saturated), dried (Na2SO4), filtered, and concen-
trated. The crude oil (10 mg, 77%) was purified by semipreparative
HPLC (C18, isocratic, CH3CN/H2O 85/15; flow 7 mL/min, 270
[N-Ser6]-Tamandarin B (34). To a solution of the Boc-protected
macrocycle 33 (20 mg, 0.024 mmol) in HPLC-grade dioxane
(10 mL) was added a solution of HCl in dioxane (10 mL). The
resulting solution was stirred at room temperature for 2 h. The
solution was concentrated and the residue diluted with CH2Cl2 and
concentrated again to yield the hydrochloride salt (18 mg, quantita-
tive yield) as a white solid, which was used directly in the next
step. To a mixture of the macrocycle amine salt (18 mg,
0.023 mmol) and side chain (11 mg, 0.035 mmol) in CH2Cl2
1
nm) to give 43 as a white foam. H NMR (300 MHz, CDCl3, δ):
0.82-1.46 (m, 32H), 1.46-2.10 (m, 12H), 2.16 (m, 4H), 2.65 (m,
J. Org. Chem, Vol. 72, No. 14, 2007 5137