Journal of Natural Products
Article
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89%): TLC (hexane/EtOAc, 10/1, UV) Rf = 0.55; H NMR (850
MHz, CDCl3) δ 7.34 (m, 10H, Bn), 6.49 (d, J = 2.7, 1H, H-5), 6.40 (d,
J = 2.7, 1H, H-3) 5.33 (s, 1H, OH), 5.03 (s, 2H, H-4 CH2) 4.97 (s,
2H, H-2 CH2), 2.60 (t, J = 7.7, 2H, H-7), 1.60 (m, 2H, H-8), 1.33(m,
2H, H-9; 2H, H-10), 0.89 (t, J = 6.9, 3H, H-11); 13C NMR (214 MHz,
CDCl3) δ 151.8 (C-4), 145.8 (C-2), 137.9 (C-1), 137.3 (Bn), 136.3
(Bn), 128.9−127.6 (C-6; Bn), 107.6 (C-5), 89.9 (C-3), 71.2 (C4
CH2), 70.8 (C-2 CH2), 31.7 (C-7), 30.0 (C-8), 29.4 (C-9), 22.6 (C-
10), 14.1 (C-11); HRESIMS m/z 377.2131 [M + H]+ (calcd for
C25H29O3, 377.2116).
resulting solid were added anhydrous DMF (3 mL) and benzyl
bromide (14 μL, 0.121 mmol), and then the reaction mixture was
stirred at rt for 18 h. After filtering the white solid, the filtrate was
concentrated in a rotary evaporator. Purification by flash column
chromatography on C18 resin (H2O/CH3CN) afforded compound 23
(50 mg, 83%) as a white solid: TLC (hexane/EtOAc, 2/1, with 0.1%
formic acid, UV) Rf = 0.44; 1H NMR (600 MHz, CDCl3) δ 7.44−7.33
(m, 5H, Bn), 6.61 (d, J = 1.8 1H, H-5), 6.51 (s, 1H, H-3′), 6.03 (d, J =
1.8, 1H, H-3), 5.33 (d, J = 7.7, 2H, H-7′ CH2), 3.76 (s, 3H, OMe),
2.73−2.40 (m, 2H, H-8′), 2.15−1.98 (m, 2H, H-9), 1.29 (m, 2H, H-
10; 2H, H-11), 1.15−1.03 (m, 2H, H-9′), 0.91 (m, 2H, H-10), 0.84 (t,
J = 7.1, 3H, H-12), 0.78 (m, 2H, H-11′), 0.62 (t, J = 7.4, 3H, H-12′);
13C NMR (150 MHz, CDCl3) δ 170.9 (C-7′), 167.7 (C-7), 162.8 (C-
4), 157.4(C-2′), 154.7 (C-2), 153.6 (C-4′), 139.6 (C-6′), 134.7 (Bn),
132.3 (C-5′), 129.2−128.7 (Bn), 107.4 (C-8), 106.4 (C-1), 104.8 (C-
3′), 103.5 (C-1′), 101.7 (C-3), 100.6 (C-5), 67.8 (C-7′ CH2), 56.1
(OMe), 37.8 (C-9), 31.9 (C-9′), 30.2 (C-10′), 28.6 (C-8′), 25.0 (C-
10), 22.3 (C-11), 22.0 (C-11′), 13.8 (C-12), 13.7 (C-12′); HRESIMS
m/z 564.2360 [M + H]+ (calcd for C32H36O9, 564.2359).
Benzyl 4,6-Bis (benzyloxy)-3-((1-butyl-1-hydroxy-6-me-
thoxy- 3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)-2-pentyl
Benzoate (22). A sealed tube equipped with a magnetic stir bar
was charged with CuI (53 mg, 0.28 mmol), picolinic acid (53 mg, 0.55
mmol), 2-iodo-4-methoxy-6-pentanoylbenzoic acid (10) (500 mg,
1.38 mmol), benzyl-4,6-bis(benzyloxy)-3-hydroxy-2-pentyl benzoate
(16) (704 mg, 1.38 mmol), and K3PO4 (880 mg, 4.14 mmol). The
tube was then evacuated and backfilled with argon. The evacuation
backfill sequence was repeated two additional times. Then the reaction
mixture was dissolved in DMSO (20 mL). The tube was placed in a
preheated oil bath at 110 °C, and the reaction mixture was stirred
vigorously for 12 h. The reaction mixture was cooled to rt. Ethyl
acetate (50 mL) and H2O (50 mL) were added, and the mixture was
stirred. The mixture was separated into two layers, and the aqueous
phase was extracted with EtOAc three times (3 × 50 mL). The organic
layer was dried over Na2SO4 and filtered through the pad of silica gel.
The filtrate was concentrated in a rotary evaporator. Purification by
flash column chromatography on C18 resin (H2O/CH3CN) afforded
compound 22 as a white powder (596 mg, 58%): TLC (hexane/
Lobaric Acid (1). To a solution of DMAP (15 mg, 0.133 mmol)
and compound 23 (60 mg, 0.106 mmol) in CH2Cl2 (10 mL) was
slowly added DCC (24 mg, 0.117 mmol) in CH2Cl2 (10 mL) through
a syringe pump over 30 min. After the addition was completed, the
mixture was stirred for another 12 h. The mixture was concentrated in
a rotary evaporator. Purification by flash column chromatography on
C18 resin (H2O/CH3CN) afforded an intermediate protected lactone
(45 mg, 78%). To a round-bottom flask charged with the lactone
compound (45 mg, 0.082 mmol) in MeOH (10 mL) was added
palladium on carbon (10%, 4.5 mg). The mixture was stirred under a
hydrogen atmosphere (1 atm, hydrogen ballon) for 12 h. Upon
completion, the reaction mixture was filtered through a pad of Celite.
The filtrate was concentrated in a rotary evaporator. Purification by
flash column chromatography on C18 resin (H2O/CH3CN) afforded
compound 1 (34 mg, 90%): TLC (hexane/EtOAc, 2/1, with 0.1%
formic acid, UV) Rf = 0.8; 1H NMR (400 MHz, CD3OD) δ 6.92 (d, J
= 2.4, 1H, H-6), 6.89 (d, J = 2.4, 1H, H-4), 6.68 (s, 1H, H-5′), 3.92 (s,
3H, OMe), 3.13 (m, 2H, H-8′), 2.82 (t, J = 7.3, 2H, H-9), 1.57 (m,
2H, H-10; 2H, H-9′), 1.48 (m, 2H, H-10′), 1.41 (m, 2H, H-11; 2H, H-
11′), 0.94 (m, 3H, H-12; 3H, H-12′); 13C NMR (101 MHz, CD3OD)
δ 205.9 (C-7), 172.8 (C-7′), 166.3 (C-5), 164.5 (C-3), 163.9 (C-8),
159.4 (C-6′), 150.6 (C-1), 148.6 (C-4′), 142.8 (C-3′), 139.2 (C-2′),
115.6 (C-1′), 112.8 (C-2), 112.5 (C-6), 107.9 (C-5′), 107.3 (C-4),
57.1 (OMe), 43.0 (C-9), 33.5 (C-10′), 32.3 (C-9′), 29.0 (C-8′), 27.2
(C-10), 23.7 (C-11′), 23.3 (C-11), 14.5 (C-12), 14.4 (C-12′);
HRESIMS m/z 457.1846 [M + H]+ (calcd for C25H29O8, 457.1862).
Lobarstin (4). A flame-dried 250 mL round-bottom flask equipped
with a magnetic stir bar was charged with lobaric acid (1) (100 mg,
0.22 mmol) in anhydrous DMF (5 mL), and the mixture was cooled to
0 °C. NaHMDS (48 mg, 0.26 mmol) in DMF (5 mL) was added
dropwise over 5 min. The reaction mixture was stirred for 10 min at 0
°C, and the cooling bath was removed. The reaction mixture was
stirred for 2 h at rt, and then 1 N HCl (20 mL) was added. The
mixture was extracted with EtOAc three times (3 × 10 mL). The
organic phase was washed with brine, dried over Na2SO4, and
concentrated in a rotary evaporator. Purification by flash column
chromatography on C18 resin (H2O/CH3CN) afforded compound 4
(90 mg, 90%) as a white powder: TLC (hexane/EtOAc (2/1) with
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EtOAc, 2/1, with 0.1% formic acid, UV) Rf = 0.62; H NMR (400
MHz, CDCl3) δ 7.29−7.11 (m, 10H, Bn), 6.55 (d, J = 1.8, 1H, H-5),
6.48 (s, 1H, H-3), 6.09 (d J = 1.8, 1H, H-3), 5.30 (s, 2H, H-1′ CH2),
5.00 (s, 2H, H-4′, CH2), 4.95 (s, 2H, H-2′ CH2), 3.73 (s, 3H, OMe),
2.48 (m, 2H, H-8′), 2.06 (m, 2H, H-9), 1.31 (m, 2H, H-9′; 2H, H-10′;
2H, H-10), 1.13 (m, 2H, H-11; 2H, H-11′), 0.86 (t, J = 7.3, 3H, H-12),
0.75 (t, J = 6.7, 3H, H-12′); 13C NMR (101 MHz, CDCl3) δ 167.2 (C-
7′), 166.7 (C-7), 165.1 (C-4), 158.2 (C-2), 153.9 (C-4′), 153.4 (C-2′),
151.9 (C-5′), 136.3 (Bn), 136.1 (Bn), 135.5 (Bn), 135.0 (C-6′),
128.7−127.0 (Bn; C-6), 117.7 (C-1), 106.9 (C-8), 105.0 (C-5), 102.1
(C-3), 99.7 (C-1′), 98.9 (C-3′), 71.1 (C-4′ CH2), 71.0 (C-2′ CH2),
67.2 (C-7′ CH2), 56.0 (OMe), 38.5 (C-8′), 31.9 (C-9), 29.9 (C-10′),
28.2 (C-9′), 25.2 (C-10), 22.4 (C-11), 22.1 (C-11′), 13.8 (C-12′),
13.7 (C-12); HRESIMS m/z 745.3374 [M + H]+ (calcd for C46H49O9,
745.3377).
Lobarin (3). To a 100 mL round-bottom flask charged with
compound 22 (100 mg, 0.211 mmol) in MeOH (20 mL) was added
palladium on carbon (10%, 10 mg). The mixture was stirred under a
hydrogen atmosphere (1 atm, hydrogen ballon) for 12 h. Upon
completion the reaction mixture was filtered through a pad of Celite.
The filtrate was concentrated in a rotary evaporator. Purification by
flash column chromatography on C18 resin (H2O/CH3CN) afforded
compound 3 as a yellow solid (57 mg, 90%): TLC (hexane/EtOAc, 2/
1, with 0.1% formic acid, UV) Rf = 0.15; 1H NMR (400 MHz,
CD3OD) δ 6.71 (d, J = 1.8, 1H, H-5), 6.37 (s, 1H, H-3′), 6.04 (d, J =
1.8, 1H, H-3), 3.77 (s, 3H, OMe), 2.92−2.74 (m, 2H, H-8′), 2.18−
2.01 (m, 2H, H-9), 1.54 (m, 2H, H-10), 1.34 (m, 2H, H-11; 2H, H-
9′), 1.22 (m, 2H, H-10; 2H, H-11′), 0.88 (t, J = 6.7, 3H, H-12), 0.80
(m, 3H, H-12′); 13C NMR (101 MHz, CD3OD) δ 174.5 (C-7′), 168.8
(C-7), 168.7 (C-4), 163.7 (C-2′), 156.7 (C-2), 156.6 (C-4′), 155.9 (C-
6), 141.6 (C-6′), 134.3 (C-5′), 108.1 (C-8), 106.2 (C-1), 103.2 (C-3′),
102.6 (C-1′), 101.2 (C-3), 101.1 (C-5), 56.8 (OMe) 39.8 (C-9), 33.6
(C-9′), 31.5 (C-10′), 29.4 (C-8′), 26.9 (C-10), 23.7 (C-11), 23.3 (C-
11′), 14.5 (C-12), 14.4 (C-12′); HRESIMS m/z 475.1960 [M + H]+
(calcd for C25H31O9, 475.1968).
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0.1% formic acid, UV) Rf = 0.21; H NMR (400 MHz, CD3OD) δ
6.94 (d, J = 1.2, 1H, H-5), 6.37 (s, 1H, H-3′), 6.01 (d, J = 1.2, 1H, H-
3), 5.81 (t, J = 7.9, 1H, H-9), 3.79 (s, 3H, OMe), 2.92 (m, 2H, H-8′),
2.41 (dd, J = 7.9, 7.3, 2H, H-10), 1.57 (dq, J = 14.6, 7.3, 2H, H-9′),
1.19 (m, 2H, H-11; 2H, H-10′; 2H, H-11′), 1.01 (t, J = 7.3, 3H, H-12),
0.75 (t, J = 7.3, 3H, H-12′); 13C NMR (101 MHz, CD3OD) δ
174.6(C-7′), 168.8 (C-4), 166.7 (C-7), 163.7 (C-2), 159.8 (C-4′),
156.6 (C-2′), 147.2 (C-8), 145.4 (C-6′), 141.6 (C-6), 134.3 (C-5′),
110.8 (C-1), 106.3 (C-9), 106.2 (C-1′), 103.2(C-5), 103.0 (C-3), 97.8
(C-3′), 56.8 (OMe), 33.5 (C-9′), 34.5 (C-10′), 29.4 (C-10), 29.0 (C-
8′), 23.6 (C-11), 23.3 (C-11′), 14.4 (C-12), 14.3 (C-12′); HRESIMS
m/z 457.1853 [M + H]+ (calcd for C25H29O8, 457.1862).
Benzyl 3-((1-Butyl-1-hydroxy-6-methoxy-3-oxo-1,3-dihy-
droisobenzofuran-4-yl)oxy)-4,6-dihydroxy-2-pentylbenzoate
(23). To a solution of lobarin (3) (50 mg, 0.11 mmol) in MeOH (5
mL) was added cesium carbonate (17 mg, 0.053 mmol), and the
solution was stirred at rt for 10 min. After concentrating the solution, it
was azotroped with toluene to remove remaining water. To the
F
J. Nat. Prod. XXXX, XXX, XXX−XXX