10.1002/chem.201901069
Chemistry - A European Journal
FULL PAPER
(R,4E,6E)-3-Acetoxy-7-iodo-2,2,4-trimethylhepta-4,6-dienoic
Acid
concentrated to give the corresponding tetrahydroxy acid 26 (128 mg).
The crude tetrahydroxy acid 26 (128 mg) was dissolved in THF (4.5 mL)
and HATU (115 mg, 302 µmol) and diisopropylethylamine (74 µL, 603
mmol) were added at 0 oC. After being stirred at room temperature for 10
h in the dark, the mixture was diluted with brine and extracted with AcOEt.
The extract was washed with brine, dried, and concentrated. The residue
was purified by preparative TLC (AcOEt:MeOH = 20:1) to give 2 (27 mg)
and the activated intermediate (28 mg). The activated intermediate (28
mg) was dissolved in THF (2.0 mL) and diisopropylethylamine (74 µL,
603 mmol) was added at 0 oC. The mixture was stirred at room
temperature for 10 h in the dark and concentrated. The residue was
purified by preparative TLC (AcOEt:MeOH = 20:1) to give 2 (14.3 mg).
After all, compound 2 (41.3 mg, 44%) was obtained in total: [α]D22 –3.7 (c
0.20, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 14.2, 11.2 Hz,
1H), 6.31 (d, J = 14.4 Hz, 1H), 6.27 (dd, J = 2.8, 10.2 Hz, 1H), 6.20 (t, J =
13.6 Hz, 1H), 6.17-6.13 (m, 1H), 5.92 (d, J = 11.6 Hz, 1H), 5.71-5.63 (m,
2H), 4.71 (d, J = 6.6 Hz, 1H), 4.39 (d, J = 6.6 Hz, 1H), 3.97-3.88 (m, 4H),
3.61-3.57 (m, 2H), 3.42 (s, 3H), 2.92 (s, 3H), 2.46 (q, J = 6.8 Hz, 1H),
2.08-2.02 (m, 1H), 1.89-1.81 (m, 1H), 1.70 (s, 3H), 1.45-1.37 (m, 1H),
1.30 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H), 1.06 (s, 3H), 0.99 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 177.6, 174.8, 170.2, 141.1, 138.5,
134.1, 131.5, 131.1, 129.7, 129.8, 128.4, 86.0, 83.5, 82.4, 79.9, 79.6,
65.6, 57.1, 44.8, 42.2, 41.1, 38.6, 37.1, 32.8, 26.2, 25.5, 21.6, 17.5, 13.7;
FTIR (CDCl3) 3371, 2936, 1823, 1688, 1631, 1528, 1389 cm-1; HRMS
(FAB) calcd for C29H43IN2O8 (M+) 674.2177, found 674.2187.
(24). To an ice-cooled solution of hydroxy ester 3 (800 mg, 2.47 mmol) in
THF-MeOH-H2O (3:1:1, 25 mL) was added LiOH·H2O (259 mg, 6.17
mmol), and the mixture was stirred at room temperature for 16 h. The
mixture was acidified with 0.5 M HCl (10 mL) at 0 °C and extracted with
AcOEt. The extract was washed with brine, dried, and concentrated to
give the corresponding carboxylic acid (784 mg) as a pale yellow oil. The
crude carboxylic acid (784 mg) was dissolved in pyridine (2.0 mL) and
Ac2O (2.0 mL, 21.1 mmol) was added at 0 °C. The mixture was stirred at
room temperature for 20 h. A solution of NaHCO3 (600 mg, 7.14 mmol) in
MeOH (10 mL) was added to the mixture and stirring was continued at
room temperature for 1 h. The mixture was extracted with AcOEt,
washed with brine, dried, and concentrated to give 24 (870 mg, 100%) as
a yellow oil: [α]D22 +5.2 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.21
(dd, J = 11.2, 14.0 Hz, 1H), 6.35 (d, J = 14.0 Hz, 1H), 5.95 (d, J = 11.2
Hz, 1H), 5.33 (s, 1H), 2.04 (s, 3H), 1.73 (s, 3H), 1.21 (s, 3H), 1.16 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 181.7, 169.6, 140.7, 134.0, 129.1,
81.0, 80.8, 46.7, 22.2, 20.8, 20.5, 15.4; FTIR (neat) 3152, 2985, 1742,
1705, 1370, 1232, 1031 cm-1; HRMS (EI) calcd for C12H17O4I (M+)
352.0171, found 352.0168.
(4aS,7R,7aR)-((Triisopropylsilyl)oxy)methyl 7a-((1S,3R,4R,5E,7E)-4-
Acetoxy-9-((R,4E,6E)-3-acetoxy-7-iodo-2,2,4-trimethylhepta-4,6-
dienamido)-1-methoxy-3-methylnona-5,7-dien-1-yl)-2,2-diisopropyl-
5,7-dimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4a-
carboxylate (25). A solution of 4 (48.0 mg, 49.9 mmol) and DBU (11.0
µL, 72.7 mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature for 30
min to afford the corresponding free amine. To a solution of 24 (36.5 mg,
99.6 mmol) in CH2Cl2 (1 mL) were added BOPCl (31.7 mg, 125 µmol)
and triethylamine (35 µL, 249 mmol). The mixture was stirred at room
temperature for 2.5 h. To this solution was added the above mixture
prepared from 4, and the resulting mixture was stirred at room
temperature for 1.5 h. The mixture was extracted with AcOEt, washed
with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated.
The residue was purified by preparative TLC (AcOEt:hexane = 1:1) to
give 25 (33.0 mg, 62%) as a colorless oil: [α]D24 +18.9 (c 0.63, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 11.2, 14.0 Hz, 1H), 6.33 (d, J =
14.0 Hz, 1H), 6.20 (dd, J = 11.2, 14.4 Hz, 1H), 6.12 (t, J = 14.4 Hz, 1H),
5.92 (d, J = 11.6 Hz, 1H), 5.85 (brt, J = 6.8 Hz, 1H), 5.65 (dt, J = 7.6, 14.4
Hz, 1H), 5.55 (dd, J = 7.8, 15.0 Hz, 1H), 5.50 (d, J = 4.0 Hz, 1H), 5.41 (d,
J = 4.0 Hz, 1H), 5.25 (s, 1H), 5.16 (t, J = 7.2 Hz, 1H), 4.71 (d, J = 13.2 Hz,
1H), 4.14 (d, J = 13.2 Hz, 1H), 3.89 (m, 2H), 3.60 (m, 1H), 3.36 (m, 1H),
3.29 (s, 3H), 2.77 (s, 3H), 2.70 (q, J = 7.2 Hz, 1H), 2.06 (s, 3H), 2.05 (s,
3H), 1.87 (m, 1H), 1.71 (s, 3H), 1.55-1.45 (m, 2H), 1.25-0.78 (m, 47H);
13C NMR (100 MHz CDCl3) δ 176.5, 174.6, 170.0, 169.3, 169.0, 140.8,
134.5, 133.2, 131.3, 130.5, 129.2, 128.9, 85.5, 84.9, 83.0, 81.9, 80.8,
77.8, 77.3, 72.1, 61.0, 58.7, 46.2, 44.3, 43.2, 41.4, 34.6, 32.9, 27.2, 25.8,
22.7, 21.7, 22.2, 21.0, 17.7, 17.0, 17.0, 16.8, 16.7, 16.4, 15.3, 13.8, 13.3,
11.8, 8.1; FTIR (CDCl3) 3372, 2945, 2868, 1738, 1701, 1658, 1525, 1464,
1372, 1237, 1174, 1129 cm-1; HRMS (FAB) calcd for C49H84N2O12Si2I
[(M+H)+] 1075.4607, found 1075.4597.
Lajollamycin B (27). To a solution of 1 (43.4 mg, 104 µmol) and 2 (35
mg, 51.9 µmol) in degassed DMF (1.0 mL) were added CuI (1.0 mg, 5.19
µmol), CsF (1.58 mg, 10.4 µmol), and Pd(PPh3)4 (3.0 mg, 2.60 µmol) at
room temperature. After the mixture was stirred at room temperature for
30 min in the dark, the reaction was quenched with water (5 mL), and the
mixture was extracted with AcOEt. The extract was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
reverse phase column chromatography (ODS 4 g, MeOH:H2O = 2:1),
preparative TLC (AcOEt), and HPLC (ODS, 45% aq MeCN) to give
lajollamycin B (27) (7.8 mg, 22 %) and the isomer 28 (8.4 mg, 24%).
24
Lajollamycin B (27), a yellow powder: [α]D –14.4 (c 0.10, MeOH) {lit.[3]
[α]D25 +70 (c 0.1, MeOH)}; 1H NMR (500 MHz, CDCl3) δ 6.74 (d, J = 15.4
Hz, 1H), 6.62 (dd, J = 11.0, 15.4, 1H), 6.59 (dd, J = 11.0, 15.0, 1H), 6.36
(t, J= 5.5 Hz, 1H), 6.30 (dd, J = 11.0, 15.0 Hz, 1H), 6.22 (dd, J = 10.5,
14.0 Hz, 1H), 6.18 (dd, J = 10.5, 14.0 Hz, 1H), 6.06 (d, J = 11.0 Hz, 1H),
5.69 (m, 2H), 4.71 (d, J = 6.5 Hz, 1H), 4.39 (d, J = 6.5 Hz, 1H), 4.25 (brs,
1H), 4.01 (s, 1H), 3.95 (dd, J = 14.0, 7.0 Hz, 1H), 3.92 (m, 2H), 3.60 (t, J
= 4.6 Hz, 1H), 3.59 (s, 1H), 3.39 (s, 3H), 2.92 (s, 3H), 2.46 (q, J = 7.5 Hz,
1H), 2.30 (s, 3H), 2.05 (m, 1H), 1.99 (s, 3H), 1.85 (m, 1H), 1.78 (s, 3H),
1.40 (m, 1H), 1.31 (s, 3H), 1.22 (d, J= 7.5 Hz, 3H), 1.11 (s, 3H), 0.98 (d, J
= 6.8 Hz, 3H); 13C NMR (125 MHz CDCl3) δ 177.6, 174.8, 170.2, 144.5,
140.4, 135.4, 134.0, 132.9, 132.8, 132.0, 131.5, 131.1, 129.8, 128.6,
127.6, 86.0, 83.8, 82.4, 79.6, 76.7, 65.6, 57.1, 45.0, 42.2, 41.2, 37.1,
32.8, 26.2, 25.7, 21.6, 17.5, 17.0, 15.2, 13.7, 10.1; FTIR (neat) 3352,
2928, 1825, 1691, 1512, 988, 892, 752 cm-1; CD (1.4 µM, MeOH) (Δε)
209 (5.12) nm [lit.[3] CD (1.4 µM, MeOH) (Δε) 216 (1.26) nm]; HRMS
(FAB) calcd for C35H52N3O10, [(M+H)+] 674.3653, found 674.3649.
(R,4E,6E)-3-Hydroxy-N-((2E,4E,6R,7R,9S)-6-hydroxy-9-((4S,7R,8S)-8-
hydroxy-5,7-dimethyl-1,6-dioxo-2-oxa-5-azaspiro[3.4]octan-8-yl)-9-
methoxy-7-methylnona-2,4-dien-1-yl)-7-iodo-2,2,4-trimethylhepta-
4,6-dienamide (2). To a solution of 25 (149 mg, 139 µmol) in THF (10
mL) was added HF·pyridine (1 mL) at 0 oC, and the mixture was stirred at
room temperature for 4 h in the dark. The mixture was diluted with AcOEt,
washed with saturated NaHCO3, dried, and concentrated. The resulting
carboxylic acid (140 mg) was dissolved in THF-H2O (4:1, 5.0 mL) and
LiOH·H2O (63.4 mg, 1.51 mmol) was added at 0 °C. After being stirred at
room temperature for 6 h in the dark, the mixture was acidified to pH 4-5
by the addition of Amberlite IRC-76 at room temperature and filtered, and
the resin was washed with THF. The filtrate and washings were
23
Isomer 28, a yellow powder: [α]D –11.7 (c 0.20, MeOH); 1H NMR (500
MHz, CDCl3) δ 6.73 (dd, J = 11.0, 15.1 Hz, 1H), 6.64 (dd, J = 11.0, 14.8
Hz, 1H), 6.42 (d, J = 15.1 Hz, 1H), 6.36 (dd, J = 11.0, 14.8 Hz, 1H), 6.32
(t, J = 5.6 Hz, 1H), 6.22 (dd, J = 10.5, 14.0 Hz, 1H), 6.17 (dd, J = 10.5,
14.0 Hz, 1H), 6.08 (d, J = 11.0 Hz, 1H), 5.68 (m, 2H), 4.71 (d, J = 6.6 Hz,
1H), 4.39 (d, J = 6.6 Hz, 1H), 4.33 (d, J = 4.5 Hz, 1H), 4.03 (d, J = 4.5 Hz,
1H), 3.93 (m, 3H), 3.60 (t, J = 4.5 Hz, 1H), 3.57 (s, 1H), 3.40 (s, 3H), 2.92
(s, 3H), 2.46 (q, J= 7.3 Hz, 1H), 2.41 (brs, 1H), 2.31 (q, J = 1.2 Hz, 3H),
2.05 (q, J = 1.2 Hz, 3H), 2.04 (m, 1H), 1.83 (m, 1H), 1.79 (s, 3H), 1.41 (m,
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