Sammet et al.
JOCArticle
C12H17N3O6Naþ [M þ Na]þ 322.10096, found 322.10116; IR
[M þ Na]þ 965.20716, found 965.20486; IR (neat, cm-1) 2981,
2359, 2103, 1736, 1502.
(neat, cm-1) 2979, 2103, 1732, 1131, 923.
(S)-2-(3-Azido-2,2-dimethylpropanoyloxy)-4-methylpentanoic
acid (18b). A solution of tert-butyl ester 17b (667 mg, 2.13 mmol)
in CH2Cl2 (20 mL) is cooled to 0 °C. TFA (10.5 mL) is added
within 15 min. The reaction mixture is allowed to reach rt and
stirred for overall 3.5 h. The volatile material is removed in
vacuo. The crude product is coevaporated with toluene several
times. Carboxylic acid 18b is obtained as a yellow oil (623 mg,
quant): [R]24D =-25 (c=1.0 in CHCl3); 1H NMR (500 MHz,
CDCl3) δ [ppm] = 0.95 (d, J = 6.5 Hz, 3H, uD-CγH(CH3)A-
(CH3)B), 0.98 (d, J = 6.5 Hz, 3H, uD-CγH(CH3)A(CH3)B), 1.26
(s, 6H, uC-CR(CH3)2), 1.72 (m, 1H, uD-CβHAHB), 1.80 (m, 1H,
uD-CγH), 1.88 (m, 1H, uD-CβHAHB), 3.46 (s, 2H, uC-CβH2),
5.07 (dd, J = 9.8, 3.7 Hz, 1H, uD-CRH), 10.73 (s, 1H, uD-COOH);
13C NMR (126 MHz, CDCl3) δ [ppm]=21.4 (uD-CγH(CH3)A-
(CH3)B), 22.7 (uC-CR(CH3)A(CH3)B), 22.9 (uC-CR(CH3)A-
(CH3)B), 23.0 (uD-CγH(CH3)A(CH3)B), 24.8 (uD-CγH(CH3)A-
(CH3)B), 39.5 (uD-CβH2), 43.6 (uC-C(CH3)2), 59.4 (uC-CβH2),
70.8 (uD-CRCH), 175.3 (uC-CO2CH), 176.5 (uD-CO2H); ESI-
MS m/z 256.0 [M - Hþ]-; HR-ESI calcd for C11H18N3O4 [M -
H]- 256.13028, found 256.13031; IR (neat, cm-1) 2960, 2101,
1721, 1471, 1125.
seco-Depsipeptide 19a. Unit CD precursor 18a (85 mg, 0.28
mmol), unit AB precursor 16 (126 mg, 0.189 mmol), and DMAP
(6 mg, 0.05 mmol) are dissolved in THF (2 mL), and the solution
is cooled to 0 °C. NEt3 (53 μL, 39 mg, 0.38 mmol) is added,
followed by dropwise addition of 2,4,6-trichlorobenzoyl chlo-
ride (46 μL, 72 mg, 0.30 mmol) within 15 min. The reaction
mixture is stirred for 1 h at 0 °C. After addition of 10% aqueous
citricacid(3mL), themixtureisextractedwithEtOAc (3ꢀ 30 mL)
and the combined organic phases are washed with saturated
aqueous NaHCO3 (1 ꢀ 20 mL). After drying over MgSO4, the
crude product is purified by column chromatography (hexane/
EtOAc 7:3). seco-Depsipeptide 19a is obtained as a colorless
resin (0.14 g, 81%): Rf (hexane/EtOAc 7:3)=0.17; [R]24D=-34
(c=0.91 in CHCl3); 1H NMR (500 MHz, CDCl3) δ [ppm]=1.09
(d, J = 7.0 Hz, 3H, uA-CεCH3), 1.17 (s, 3H, uC-CR(CH3)A-
(CH3)B), 1.18 (s, 3H, uC-CR(CH3)A(CH3)B), 1.46 (s, 3H, uA-
C(CH3)A(CH3)B), 1.53 (s, 3H, uA-C(CH3)A(CH3)B), 1.94 (m,
1H, uA-CεH), 2.28-2.45 (m, 2H, uA-CγH2), 2.84-2.92 (m, 2H,
uD-CβH2), 3.08 (dd, J = 14.2, 6.3 Hz, 1H, uB-CβHAHB), 3.19
(dd, J = 14.2, 5.8 Hz, 1H, uB-CβHAHB), 3.33 (d, J = 12.0 Hz,
1H, uC-CβCHAHB), 3.40 (d, J = 12.0 Hz, 1H, uC-CβCHAHB),
3.81 (dd, J = 8.8, 2.8 Hz, 1H, uA-CζH), 3.87 (s, 3H, uB-OCH3),
4.53-4.65 (m, 2H, uD-CHAHBCHdCH2), 4.68 (d, J = 8.8 Hz,
1H, uA-CηH), 4.72 (d, J = 11.9 Hz, 1H, uB-CHAHBCCl3), 4.78
(d, J = 11.9 Hz, 1H, uB-CHAHBCCl3), 4.98-5.08 (m, 2H, uA-
CδH and uB-CRH), 5.27 (dd, J = 10.4, 1.1 Hz, 1H, uD-
CdCHcisHtrans), 5.31-5.39 (m, 2H, uD-CdCHcisHtrans and
uD-CRH), 5.56 (d, J = 15.6 Hz, 1H, uA-CRH), 5.91 (m, 1H,
seco-Depsipeptide 19b. Carboxylic acid 18b (117 mg, 0.455
mmol) and DMF (one drop) are dissolved in CH2Cl2 (2 mL).
Oxalyl chloride (48 μL, 71 mg, 0.56 mmol) is added over 10 min
at 0 °C, and the reaction mixture is stirred for 3 min at 0 °C and
for 2 h at rt. The solvent is removed under reduced pressure,
and the crude acid chloride is dried in high vacuum. Unit AB
precursor 16 (150 mg, 0.225 mmol), NEt3 (72 μL, 52 mg, 0.52
mmol), and DMAP (63 mg, 0.52 mmol) are dissolved in CH2Cl2
(3 mL) and cooled to 0 °C. The crude acid chloride in CH2Cl2
(2 mL) is added over 10 min. After stirring for 1 h at 0 °C, satu-
rated aqueous NaHCO3 (20 mL) is added. The aqueous phase is
extracted with Et2O (4 ꢀ 30 mL). The combined organic phases
are washed with 5% aqueous KHSO4 (10 mL) and brine (10 mL).
After drying over MgSO4, the solvent is removed under vacuum
and the crude product is purified by column chromatography
(hexane/EtOAc 7:3). seco-Depsipeptide 19b is obtained as a
colorless solid (160 mg, 79%): Rf (hexane/EtOAc 7:3) = 0.3;
[R]24D=-35 (c=0.50 in CHCl3); 1H NMR (500 MHz, CDCl3) δ
[ppm]=0.90 (d, J = 6.5 Hz, 3H, uD-CγH(CH3)A(CH3)B), 0.96
(d, J = 6.3 Hz, 3H, uD-CγH(CH3)A(CH3)B), 1.10 (d, J = 6.9
Hz, 3H, uA-CεCH3), 1.21 (s, 6H, uC-C(CH3)2), 1.46 (s, 3H, uA-
C(CH3)A(CH3)B), 1.52 (s, 3H, uA-C(CH3)A(CH3)B), 1.56-
1.63 (m, 1H, uD-CβHAHB), 1.70-1.83 (m, 2H, uD-CγH and uD-
CβHAHB), 1.96 (m, 1H, uA-CεHCH3), 2.25-2.48 (m, 2H, uA-
CγH2), 3.07 (dd, J = 14.1, 6.7 Hz, 1H, uB-CβHAHB), 3.19 (dd,
J = 14.1, 5.7 Hz, 1H, uB-CβHAHB), 3.32 (d, J = 12.1 Hz, 1H,
uC-CβHAHB), 3.42 (d, J = 12.1 Hz, 1H, uC-CβHAHB), 3.80 (dd,
J = 8.8, 3.0 Hz, 1H, uA-CζH), 3.86 (s, 3H, uB-OCH3), 4.70 (d,
J = 8.7 Hz, 1H, uA-CηH), 4.74 (d, J = 12.0 Hz, 1H, uB-
CHAHBCCl3), 4.78 (d, J = 12.0 Hz, 1H, uB-CHAHBCCl3), 4.87
(dd, J = 9.8, 3.5 Hz, 1H, uD-CRH), 4.95-5.08 (m, 2H, uB-CRH
and uA-CδH), 5.61 (d, J = 15.7 Hz, 1H, uA-CRH), 6.45 (d, J =
8.0 Hz, 1H, uB-NH), 6.57 (dt,0 J = 15.7, 6.3 Hz, 1H, uA-CβH),
6.83 (d, J = 8.8 Hz, 1H, uB-C5 H), 7.05 (dd, J = 8.4, 2.1 Hz, 1H,
0
0
uB-C6 H), 7.17 (d, J = 2.1 Hz, 1H, uB-C2 H), 7.30-7.40 (m,
5H, uA-CarH); 13C NMR (126 MHz, CDCl3) δ [ppm] = 9.5
(uA-CεHCH3), 21.4 (uD-CγH(CH3)A(CH3)B), 22.72 (uC-Cβ-
(CH3)A(CH3)B), 22.79 (uC-Cβ(CH3)A(CH3)B), 23.2 (uD-Cγ-
(CH3)A(CH3)B), 24.8 (uD-CγH), 27.1 (uA-C(CH3)A(CH3)B),
27.2 (uA-C(CH3)A(CH3)B), 32.1 (uA-CγH2), 36.1 (uA-CεH),
36.6 (uB-CβH2), 39.3 (uD-CβH2), 43.6 (uC-Cβ(CH3)2), 53.2
(uB-CRH), 56.1 (uB-OCH3), 59.1 (uC-CβH2N3), 71.5 (uD-CRH),
74.7 (uB-CH2CCl3), 75.1 (uA-CδH), 80.6 (uA-CηH), 82.3 (uA-
0
CζH), 94.3 (uB-CCl3), 109.0 (uA-C(CH3)2), 112.1 (uB-C5 H),
0
122.2 (uB-C3 ), 125.0 (uA-CRH), 126.9/128.6/128.820 (5 ꢀ uA-
0
0
CarH and uB-C6 H), 128.86 (uB-C1 ) 131.3 (uB-C2 H), 137.5
0
(uA-Car) 139.2 (uA-CβH), 154.1 (uB-C4 ), 165.3 (uA-CONH),
169.9 (uD-CO2), 170.0 (uB-CO2), 175.8 (uC-CO2); ESI-MS m/
z 925.2 [M þ Na]þ; HR-ESI calcd for C41H52N4O10Cl4 [M þ
H]þ 901.25103, found 901.25140; IR (neat, cm-1) 2958, 2359,
2102, 1734, 1502.
uD-CHdCH2), 6.33 (d, J = 7.9 Hz, 1H, NH), 6.57 (dt, J = 15.6,
0
6.4 Hz, 1H, uA-CβH), 6.86 (d, J = 8.4 Hz, 1H, uB-C5 H), 7.04
0
(dd, J = 8.4, 2.1 Hz, 1H, uB-C6 H), 7.18 (d, J = 2.1 Hz, 1H, uB-
cyclo-Depsipeptide 20a. Azide 19a (79 mg, 0.083 mmol) is dis-
solved in THF (970 μL). H2O(57μL) and PPh3 (66 mg, 0.25 mmol)
are added. After stirring for 10 min at rt, the reaction mixture is
stirred for 4 h at 40 °C. Then H2O (25 μL) is added, and the
stirring is continued for 45 min at 40 °C. Toluene is added, and
the solvents are removed in vacuo. After drying in high vacuum
for a few hours, the residue is dissolved in toluene (4.3 mL) and
2-hydroxypyridine (16 mg, 0.17 mmol) is added. After stirring
overnight at rt in the dark, the solvent is removed under reduced
pressure. The residue is purified by column chromatography
(hexane/EtOAc 3:7). Macrolactam 20a is obtained as a colorless
solid (21 mg, 32%): Rf (hexane/EtOAc 3:7) = 0.40; analytical
0
C2 H), 7.29-7.49 (m, 5H, uA-CarH); 13C NMR (126 MHz,
CDCl3) δ [ppm] = 9.6 (uA-CεHCH3), 22.7 (2 ꢀ uC-CβCH3),
27.1 (uA-C(CH3)A(CH3)B), 27.2 (uA-C(CH3)A(CH3)B), 32.4
(uA-CγH2), 35.6 (uD-CβH2), 35.9 (uA-CεH), 36.5 (uB-CβH2),
43.6 (uC-CR), 53.2 (uB-CRH), 56.1 (uB-OCH3), 59.0 (uC-CβH2),
65.9 (uD-CH2dCH), 68.6 (uD-CRH), 74.7 (uB-CH2CCl3), 75.8
(uA-CδH), 80.6 (uA-CηH), 82.2 (uA-CζH), 94.3 (uB-CCl3),
0
109.1 (uA-C(CH3)2), 112.1 (uB-C5 H), 118.9 (uD-CHdCH2),
0
122.3 (uB-C3 ), 125.2 (uA-CRH), 127.0/1028.61/128.62 (5 ꢀ uA-
0
0
CarH), 128.74 (uB-C1 ), 128.82 (uB-C6 H), 131.2 (uB-C2 H),
131.6 (uD-CHdCH2), 137.4 (uA-Car), 139.2 (uA-CβH), 154.2
0
(uB-C4 ), 165.1 (uA-C=O), 167.9 (uD-CdO), 168.6 (uD-
CO2CHdCH2), 170.0 (uB-CdO), 174.9 (uC-CdO); ESI-MS
m/z 966.9 [M þ Na]þ; HR-ESI calcd for C42H50N4O12Cl4Naþ
HPLC 27.8 min; [R]24D =þ9.5 (c=0.93 in CHCl3); H NMR
1
(500 MHz, CDCl3) δ [ppm] = 1.10 (s, 3H, uC-CR(CH3)A-
(CH3)B), 1.13 (d, J = 6.9 Hz, 3H, uA-CεCH3), 1.20 (s, 3H,
6958 J. Org. Chem. Vol. 75, No. 20, 2010