8612
I.S. Marcos et al. / Tetrahedron 66 (2010) 8605e8614
(3Me, s each, Me-18, Me-19 and Me-20); 13C NMR (50 MHz, CDCl3)
: 195.3 (C-17), 153.1 (C-7), 144.6 (C-8), 142.7 (C-15), 138.9 (C-16),
126.0 (C-13), 111.5 (C-14), 50.4 (C-9), 49.6 (C-5), 42.2 (C-3), 39.1 (C-
1), 36.8 (C-10), 33.3 (C-18), 33.1 (C-4), 28.1 (C-12), 26.9 (C-11), 25.5
(C-6), 22.1 (C-19), 18.7 (C-2), 14.3 (C-20); EIHRMS: calcd for
C20H29O2 (MþHþ): 301.2065, found: 301.2061.
4.20.1. Methyl (8R)-15,16-epoxy-labda-6,13(16),14-trien-17-oate (24).
d
Rf 0.69 (n-Hex/EtOAc 8:2); [
a]
20 ꢁ56.9 (c 0.3, CHCl3); IR nmax (film):
D
2925, 2867, 1738, 1501, 1459, 1383, 1270, 1192, 1162, 1104, 1025, 974,
874, 783 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d: 7.32 (1H, s, H-15), 7.18
(1H, s, H-16), 6.24 (1H, s, H-14), 5.79 (1H, dt, J¼5.8 and 2.9 Hz, H-6),
5.59 (1H, dd, J¼5.8 and 2.9 Hz, H-7), 3.69 (3H, s, eCOOMe),
2.88e1.28 (12H, m), 2.84 (1H, dd, J¼9.5 and 2.9 Hz, H-8), 0.91, 0.87
and 0.83 (3Me, s each, Me-18, Me-19 and Me-20); 13C NMR
4.18. Reaction of 21 with NaClO2 to yield 22
(50 MHz, CDCl3) d: 175.9 (C-17), 142.8 (C-15), 138.8 (C-16), 130.5 (C-
7),125.5 (C-13),124.6 (C-6),111.1 (C-14), 54.0 (C-5), 52.2 (eCOOMe),
49.1 (C-9), 50.1 (C-8), 41.3 (C-3), 37.3 (C-1), 37.1 (C-10), 33.0 (C-18),
32.8 (C-4), 30.7 (C-12), 25.0 (C-11), 21.8 (C-19), 18.8 (C-2), 13.5 (C-
20). EIHRMS: calcd for C21H30O3Na (MþNaþ): 353.2093, found:
353.2091.
To a solution of 21 (35 mg, 0.12 mmol) in t-BuOH/2-methyl-2-
butene (1:1, 2.4 mL), was added a solution of NaH2PO4 (71.0 mg,
0.6 mmol) in water (0.46 mL) and NaClO2 (0.36 mL, 1.2 mmol). The
mixture was stirred for 21 h at room temperature. After that, the
reaction was quenched with water and HCl 5% (10 mL), extracted
with EtOAc (200 mL), followed by successive washing (10 mL each)
of the organic layer with water and brine, dried (Na2SO4), and the
solvent was evaporated to give 22 (33 mg, 87%).
4.21. Reaction of 24 with OsO4 to yield 25
Compound 24 (63 mg, 0.20 mmol) in t-BuOH/THF/H2O (7:2:1,
2 mL) was treated with 4-methylmorpholine N-oxide (NMO)
(26 mg, 0.19 mmol) and OsO4 (2.5% in t-BuOH, 0.2 mL, 0.02 mmol).
The solution was stirred and checked by TLC during 24 h.
Then, a saturated aqueous solution of Na2SO3 (15 mL) was added
and the mixture stirred for 30 min. The resulting solution was
diluted with Et2O (200 mL) followed by successive washing (30 mL
each) of the organic layer with HCl 7%, water, brine and dried over
Na2SO4. After evaporating the solvent a column chromatography
(n-Hex/EtOAc 8:2) was done to afford 24 (47 mg, 73%) and 25
(15 mg, 20%).
4.18.1. 15,16-Epoxy-labda-7,13(16),14-trien-17-oic acid (22). Rf 0.43
20
(n-Hex/EtOAc 8:2); [
a
]
ꢁ28.0 (c 0.1, CHCl3); IR nmax (film): 3000
D
(br), 2925, 2665, 1699, 1502, 1459, 1277, 1214, 1168, 1025, 974, 874,
780 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d: 7.28 (1H, s, H-15), 7.16 (1H,
s, H-16), 6.92e6.90 (1H, m, H-7), 6.23 (1H, s, H-14), 2.85 (1H, ddd,
J¼17.0, 11.4 and 4.6 Hz, HA-12), 2.37 (1H, ddd, J¼17.0, 11.4 and
4.6 Hz, HB-12), 2.21e1.46 (12H, m), 0.88, 0.85 and 0.81 (3Me, s each,
Me-18, Me-19 and Me-20); 13C NMR (50 MHz, CDCl3)
d: 174.5 (C-
17), 142.7 (C-15), 140.9 (C-7), 138.8 (C-16), 134.6 (C-8), 125.9 (C-13),
111.3 (C-14), 50.8 (C-9), 49.5 (C-5), 42.2 (C-3), 39.6 (C-1), 37.1 (C-10),
33.3 (C-18), 33.0 (C-4), 29.4 (C-11), 26.7 (C-12), 24.4 (C-6), 22.1 (C-
19), 18.7 (C-2), 14.4 (C-20); EIHRMS: calcd for C20H28O3Na
(MþNaþ): 339.1943, found: 339.1946.
4.21.1. Methyl (8S)-6
dien-17-oate (25). Rf 0.15 (n-Hex/EtOAc 7:3); [
CHCl3); IR nmax (film): 3447 (br), 2925, 2869, 1734, 1684, 1556, 1458,
1388, 1244, 1168, 1024, 977, 874, 779 cmꢁ1 1H NMR (200 MHz,
CDCl3) : 7.32 (1H, br s, H-15), 7.18 (1H, br s, H-16), 6.21 (1H, br s, H-
a,7a-dihydroxy-15,16-epoxy-labda-13(16),14-
20
a
]
þ9.5 (c 0.2,
D
;
4.19. Reaction of 22 with TMSCHN2 to yield 23
d
14), 4.04e4.02 (1H, m, H-7), 3.73 (3H, s, eCOOMe), 3.66e3.64 (1H,
m, H-6), 2.65 (1H, dd, J¼12.0 and 2.6 Hz, H-8), 2.48e1.46 (12H, m),
1.14, 1.01 and 0.84 (3Me, s each, Me-18, Me-19 and Me-20); 13C
To a solution of acid 22 (100 mg, 0.6 mmol) in MeOH/benzene
(1:1, 20 mL) was added TMSCHN2 2 M in hexane (0.3 mL). After
30 min the solvent was evaporated to give 23 (102 mg, 98%).
NMR (50 MHz, CDCl3) d: 176.4 (C-17), 143.0 (C-15), 138.7 (C-16),
125.3 (C-13), 111.5 (C-14), 72.1 (C-6), 70.8 (C-7), 54.3 (eCOOMe),
52.1 (C-5), 50.0 (C-8), 46.2 (C-9), 43.8 (C-3), 38.5 (C-10), 37.5 (C-1),
34.6 (C-18), 32.0 (C-4), 30.8 (C-12), 26.8 (C-11), 22.1 (C-19), 18.9 (C-
2), 14.6 (C-20); EIHRMS: calcd for C21H32O5Na (MþNaþ): 387.2138,
found: 387.2134.
4.19.1. Methyl 15,16-epoxy-labda-7,13(16),14-trien-17-oate (23). Rf
20
0.78 (n-Hex/EtOAc 8:2); [
a
]
ꢁ35.3 (c 1.0, CHCl3); IR nmax (film):
D
2925, 2851, 1716, 1646, 1558, 1501, 1458, 1388, 1244, 1214, 1104,
1024, 976, 874, 850 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d: 7.33 (1H, s,
H-15), 7.20 (1H, s, H-16), 6.69 (1H, s, H-7), 6.26 (1H, s, H-14), 3.72
(3H, s, eCOOMe), 2.74 (1H, ddd, J¼17.1, 11.6 and 5.6 Hz, HA-12), 2.37
(1H, ddd, J¼17.1, 11.6 and 5.6 Hz, HB-12), 2.48e1.46 (12H, m), 0.91,
0.87 and 0.83 (3Me, s each, Me-18, Me-19 and Me-20); 13C NMR
4.22. Reaction of 25 with (Cl3CO)2CO to yield 26
To a solution of pyridine (0.02 mL) in DCM (0.1 mL), (Cl3CO)2CO
(9.0 mg, 0.03 mmol) was added at ꢁ78 ꢀC, under argon and stirred
for 5 min, then compound 25 (6.0 mg, 0.02 mmol) in DCM (0.1 mL)
was added. The reaction mixture was allowed to warm to room
temperature. After 75 min 5 mL of a saturated NH4Cl solution was
added at 0 ꢀC, extracted with EtOAc (100 mL), washed with water
(10 mL) and brine (10 mL) and dried (Na2SO4). The solvent was
evaporated to yield 26 (6 mg, 98%).
(50 MHz, CDCl3) d: 169.9 (C-17), 142.8 (C-15), 138.8 (C-7), 137.6 (C-
16), 135.4 (C-8), 125.9 (C-13), 111.3 (C-14), 51.6 (eCOOMe), 51.0 (C-
9), 49.6 (C-5), 42.2 (C-3), 39.6 (C-1), 37.1 (C-10), 33.4 (C-18), 33.0 (C-
4), 29.3 (C-12), 26.6 (C-11), 24.2 (C-6), 22.2 (C-19), 18.7 (C-2), 14.5
(C-20); EIHRMS: calcd for C21H30O3Na (MþNaþ): 353.2093, found:
353.2091.
4.20. Reaction of 23 with NaOMe/MeOH to yield 24
4.22.1. Methyl(8S)-6
dien-17-oate (26). Rf 0.35 (n-Hex/EtOAc 7:3); [
CHCl3); IR nmax (film): 2962, 2925, 2851, 1806, 1738, 1462, 1367, 1261,
1124, 873, 800 cmꢁ1 1H NMR (200 MHz, CDCl3)
: 7.31 (1H, s, H-
15), 7.17 (1H, s, H-16), 6.20 (1H, s, H-14), 4.95 (1H, t, J¼6.5 Hz, H-7),
4.76 (1H, dd, J¼10.8 and 6.5 Hz, H-6), 3.75 (3H, s, eCOOMe), 2.80
(1H, dd, J¼11.5 and 6.5 Hz, H-8), 2.21e1.26 (12H, m), 1.05, 1.01 and
0.78 (3Me, s each, Me-18, Me-19 and Me-20); 13C NMR (50 MHz,
a,7a-carbonyldioxy-15,16-epoxy-labda-13(16),14-
20
A solution of NaOMe (2 N) in MeOH was prepared carefully
adding sodium metal (166 mg, 0.71 mmol) over MeOH (360 mL) at
a]
D
ꢁ2.5 (c 0.6,
0 ꢀC. Then, a solution of compound 23 (280 mg, 0.85 mmol) in
MeOH (0.2 mL) was added at room temperature. The solution was
left to stir at 85 ꢀC for 72 h. After that, the mixture was diluted with
Et2O (200 mL) followed by successive washing (30 mL each) of the
organic layer with saturated NH4Cl solution, H2O, brine and dried
over Na2SO4. The solvent was removed and the crude mixture was
chromatographed (Hex/EtOAc 8:2) and compounds 23 (73 mg,
26%) and 24 (174, 62%) were separated.
;
d
CDCl3) d: 170.9 (C-17), 153.9 (eOCOOe), 143.0 (C-15), 138.8 (C-16),
125.2 (C-13), 111.0 (C-14), 77.4 (C-7), 76.1 (C-6), 53.1 (C-5), 52.6
(eCOOMe), 47.6 (C-8), 46.0 (C-9), 42.8 (C-3), 38.3 (C-1), 37.5 (C-10),