acid (120 mg, 0.32 mmol) in ethanol-free chloroform (50 mL).
When the reaction was finished the reaction crude was purified by
flash column chromatography on silica gel using hexane and then
with 3% THF–hexane. In this way, oxacyclopentadecan-2-one was
obtained as white solid (69 mg, 90%).
with citric acid and extracted with ethyl acetate (2 ¥ 30 mL). The
combined organic layers were dried over Na2SO4 and concentrated
1
in vacuum to give white solid (1.09 g, 91%). H NMR (CDCl3):
d 7.27 (1H, d, J = 9 Hz), 6.13 (2H, s), 4.46 (1H, dd, J = 9, 4.8),
4.22 (1H, dd J = 9.3, 3.9 Hz), 2.26 (1H, m), 1.86 (1H, m), 1.59
(1H, ddd J = 13.8, 9.3, 6.6 Hz), 1.54 (1H, ddd J = 13.8, 6.6, 3.9
Hz), 0.98 (6H, d, J = 6.9 Hz) y 0.95 (6H, d, J = 6.9 Hz); 13C NMR
(CDCl3): d 176.4, 174.7, 71, 56.8, 43.56, 30.5, 24.6, 23.4, 21.4,
19, 17.5; IR (Pellet/KBr): 3381, 3211, 2961, 2874, 1747, 1636,
1536, 1391, 1144, 597, 497. HRMS (FAB) calcd for C11H22O4N1
232.1549, found 232.1548.
O-LeuValLeuOH 4. Following the general procedure, the re-
action was carried out starting from L-leucine methyl ester
hydrochloride (654 mg, 3.6 mmol), hydroxy carboxylic acid 3
(708 mg, 3 mmol), DIPEA (581 mg, 4.51 mmol), HOBT (459 mg,
3 mmol) and EDC (465 mg, 3 mmol), to give 957 mg of a white
solid (92%). 1H NMR (CDCl3): d 7.38 (1H, d, J = 9 Hz), 7.27 (1H,
d, J = 7.8 Hz), 4.47 (1H, ddd, J = 9,3, 7.8, 5.1 Hz), 4.35 (1H, dd,
J = 9, 6 Hz), 4.09 (1H, dd, J = 9.9, 3.3 Hz), 2.2 (1H, m), 1.87 (1H,
m), 1.73-1.42 (5H, m), 0.95 (3H, d, J = 6.9 Hz), 0.94 (3H, d, J = 6.6
Hz), 0.94 (6H, d, J = 6.3 Hz), 0.93 (3H, d, J = 6.6 Hz), 0.9 (3H, d,
J = 6.9 Hz); 13C NMR (CDCl3): d 176.9, 173.9, 170.7, 71.1, 56.9,
50.3, 43.4, 30.5, 24.6, 23.4, 21.4, 19, 17.5; IR (Pellet/KBr): 3281,
2961, 2879, 1724, 1645, 1467, 1240, 1144, 1078, 682, 580. HRMS
(FAB) calcd for C17H33O5N2 345.2389, found 345.2385.
Synthesis of oxacyclotridecan-2-one. Following the general
procedure, the reaction was carried out starting from HOBT
(64 mg, 0.42 mmol), EDC (206 mg, 0.42 mmol), BF3·Et2O (59 mg,
0.42 mmol) and 12-(tert-butyldimethylsilyoxy)-dodecanoic acid
(140 mg, 0.42 mmol) in ethanol-free chloroform (50 mL). When
the reaction was finished the reaction crude was purified by flash
column chromatography on silica gel using hexane and then
with 3% THF–hexane. In this way, oxacyclotridecan-2-one was
obtained as white solid (65 mg, 79%).
Synthesis of oxacycloundecan-2-one. Following the general
procedure, the reaction was carried out starting from HOBT
(50 mg, 0.33 mmol), EDC (63 mg, 0.33 mmol), BF3·Et2O
(46 mg, 0.33 mmol) and 10-(tert-butyldimethylsilyoxy)-decanoic
acid (100 mg, 0.33 mmol) in ethanol-free chloroform (50 mL).
When the reaction was finished the reaction crude was purified by
flash column chromatography on silica gel using hexane and then
with 3% THF–hexane. In this way, oxacycloundecan-2-one was
obtained as yellow oil (13 mg, 24%).
Synthesis of Sansalvamide A.
O-LeuValLeuPheOH 5. Following the general procedure, the
reaction was carried out starting from L-phenylalanine methyl
ester hydrochloride (719 mg, 3.33 mmol), hydroxy carboxylic acid
4 (957 mg, 2.78 mmol), DIPEA (538 mg, 4.17 mmol), HOBT
(425 mg, 2.78 mmol) and EDC (430 mg, 2.78 mmol), to give
2-Hydroxy-4-methyl-pentanoic acid 2. To stirred solution of L-
leucine (1 g, 7.62 mmol) in 0.5 mol H2SO4 (30 mL) was added
dropwise a solution of NaNO2 (3 g) in water (10 mL) over a
period of 3 h at 0 ◦C, after which it was left for 24 h at room
temperature. Then the solution was extracted with ethyl ether (2
¥ 50 ml). The combined extracts were washed with brine (2 ¥
50 ml), dried over Na2SO4, filtered and concentrated in vacuum.
The sticky solid residue was recrystall◦ized from hexane to give
white solid (754 mg, 75%, m.p. 78–80 C).1H NMR (CDCl3): d
7.6 (2H, br, s), 4.23 (1H, dd, J = 7.8, 5.4 Hz), 1.89 (1H, m), 1.62
(1H, ddd J = 13.8, 6.6, 5.4 Hz), 1.57 (1H, ddd, J = 13.8, 7.8, 6.6
Hz), 0.95 (6H, d, J = 6.6 Hz); 13C NMR (CDCl3): d 178.5, 68.7,
43, 24.3, 23, 21.3; IR (Pellet/KBr): 3426, 2958, 2702, 2627, 2486,
1710, 1269, 1227, 1138, 1082, 900, 688, 525 cm-1.
1
1.17 g of a white solid (86%). H NMR (CDCl3): d 7.42 (1H, d,
J = 8.4 Hz), 7.31 (1H, d, J = 9.9 Hz), 7.29-7.16 (5H, m), 7.02 (1H,
d, J = 7.5 Hz), 5.67 (2H, brs), 4.71 (1H, ddd, J = 7.5, 6.6, 5.4 Hz),
4.41 (1H, td, J = 8.4, 5.4 Hz), 4.32 (1H, dd, J = 9.3, 6 Hz), 4.09
(1H, dd, J = 9.6, 3.3 Hz), 3.19 (1H, dd, J = 14.1, 5.7 Hz), 3 (1H,
dd, J = 14.1, 6.6 Hz), 2.2 (1H, m), 1.6-1.5 (5H, m), 1.8 (1H, m),
0.92 (3H, d, J = 6.6 Hz), 0.91 (6H, d, J = 6.6 Hz), 0.9 (6H, d,
J = 6.3 Hz), 0.86 (3H, d, J = 6.6 Hz);13C NMR (CDCl3): d 175.2,
172.6, 171.4, 171.1, 136.3, 129.1, 128, 126.4, 70.4, 57.3, 53, 51.6,
43.3, 40.2, 37.1, 30.3, 24.3, 24.2, 23.2, 22.6, 21.4, 21.1, 19, 17.2;
IR (Pellet/KBr): 3366, 3281, 3095, 2961, 2879, 1724, 1645, 1535,
1467, 1389, 1276, 1240, 1144, 1078, 927, 682, 580, 466. HRMS
(FAB) calcd for C26H42O6N3 492.3074, found 492.3078.
O-LeuValOH 3. General procedure. A solution of L-valine
methyl ester hydrochloride (1.04 g, 6.24 mmol) and DIPEA (1 g,
7.8 mmol) in anhydrous CH2Cl2 (30 mL) was stirred at 0 ◦C under
an argon atmosphere. Then a solution of a-hydroxy carboxylic
acid 2 (680 mg, 5.2 mmol), HOBT (0.79 g, 5.2 mmol) and EDC
(1.07 g, 5.2 mmol) CH2Cl2 (30 mL) was added and stirred for 1 h
O-LeuValLeuPheLeuOH 6. Following the general procedure,
the reaction was carried out starting from L-leucine methyl ester
hydrochloride (521 g, 2.86 mmol), hydroxy carboxylic acid 5
(1.17 g, 2.39 mmol), DIPEA (463 mg, 3.58 mmol), HOBT (365 mg,
2.39 mmol) and EDC (370 mg, 2.39 mmol), to give 1.317 mg of
◦
at 0 C under argon atmosphere. After stirring for 18 h at room
temperature, the reaction mixture was filtered and evaporated.
The residue was dissolved in ethyl acetate (50 ml) and washed
successively with 10% citric acid solution (2 ¥ 25 mL), 10%
NaHCO3 solution (2 ¥ 25 mL), 10% K2CO3 solution (2 ¥ 25 mL)
and brine (2 ¥ 25 mL). The organic layer was dried over Na2SO4
and concentrated in vacuum to give crude hydroxy ester which was
used in the next reaction without further purification. To the crude
product in THF (25 mL) was added a 2.5 N aqueous solution of
LiOH (21.6 mL, 54 mmol) and the mixture was then stirred at
room temperature for 4 h. Solid CO2 was added to the separated
THF layer and the mixture was evaporated in vacuo to leave a
solid which was taken up in water (30 mL), then acidified to pH 3
1
a white solid (91%). H NMR (CD3OD): d 8.12 (1H d, J = 8.4
Hz), 8.00 (1H, d, J = 7.8. Hz), 7.9 (1H, d, J = 8.1 Hz), 7.5 (1H,
d, J = 9 Hz), 7.23-7.14 (5H, m), 4.54 (1H, td, J = 8.4, 4.8 Hz),
4.26 (ddd, 1H, J = 7.8, 6.9, 6.6 Hz), 4.26 (1H, ddd, J = 7.8, 6.9,
6.6 Hz) 4.17 (1H, dd, J = 9, 2.7 Hz), 3.85 (1H, td, J = 9, 4.2 Hz),
3.02 (1H, dd, J = 14.1, 4.8 Hz), 2.79 (1H, dd, J = 14.1, 8.7 Hz),
1.89 (1H, m), 1.73 (1H, m), 1.59 (3H, m), 1.52-1.32 (5H, m), 0.84
(6H, d, J = 6.6 Hz), 0.83 (6H, d, J = 6.6 Hz), 0.82 (3H, d, J = 6.6
Hz), 0.78 (3H, d, J = 6.6 Hz), 0.75 (3H, d, J = 6.6 Hz), 0.70 (3H,
d, J = 6.6 Hz); 13C NMR (CD3OD): d 174.4, 174.2, 171.5, 170.5,
137.6, 129.2, 128, 126.2, 69.7, 56.4, 53.2, 51.15, 50.7, 43.7, 40.9,
4946 | Org. Biomol. Chem., 2010, 8, 4940–4948
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The Royal Society of Chemistry 2010
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