Synthesis of Salicylihalamides A and B
Alk en e 15. A solution of the vinyl stannane 5 (126 mg, 212
µmol) in 1-methyl-2-pyrrolidinone (1 mL) was freeze-pump-
thawed twice. Tris(dibenzylideneacetone)dipalladium(0) (9.45
mg, 10.3 µmol) and tri-2-furylphosphine (9.77 mg, 42.3 µmol)
were then added, the mixture was stirred for 15 min at room
temperature, and the bromide 4 (68.9 mg, 254 µmol) was then
added. The reaction mixture was stirred at room temperature
for 15 h after which time water and ether were added. The
organic extract was washed with aqueous ammonia, water,
and brine, dried (MgSO4), and concentrated, and the residue
was purified on silica gel using 20% EtOAc/petrol as eluant
to afford the alkene 15 (74.7 mg, 73%) as a colorless oil: Rf
trifluoromethanesuflonate (77.4 µL, 337 µmol) dropwise. The
reaction mixture was stirred at 0 °C for 1 h, and then ether
and saturated NaHCO3 were added. The crude product was
isolated by extraction with ether, and the organic fraction was
washed with water, saturated CuSO4, water, saturated NaH-
CO3, and brine, dried (MgSO4), and concentrated. The residue
produced was purified on silica gel using 2.5% EtOAc/petrol
as eluant to afford the bis TBS ether 17 (47.94 mg, 78%) as a
colorless oil: Rf 0.33 (2.5% EtOAc/petrol); [R]16D ) -1.2 (c 1.13,
CH2Cl2); IR υmax (film) 1726, 1643 cm-1 1H NMR δ 0.11 (s,
;
3H), 0.16 (s, 3H), 0.19 (s, 3H), 0.22 (s, 3H), 0.83 (d, J ) 6.3
Hz, 3H), 0.91 (s, 9H), 0.97 (s, 9H), 1.65 (m, 1H), 1.78 (m, 2H),
2.27 (m, 2H), 2.46 (t, J ) 6.8 Hz, 2H), 3.32 (m, 1H), 3.66 (dd,
J ) 16.4, 8.6 Hz, 1H), 4.27 (m, 1H), 5.12 (m, 2H), 5.23 (m,
1H), 5.36-5.41 (m, 2H), 5.79 (m, 1H), 6.72 (d, J ) 7.2 Hz, 1H),
6.74 (d, J ) 7.2 Hz, 1H), 7.11 (t, J ) 7.2 Hz, 1H); 13C NMR δ
-4.5, -4.4 (2C), -4.2, 18.0, 18.3, 25.7 (3C), 25.9 (3C), 30.3,
35.9, 37.2, 38.2, 40.1, 71.9, 73.9, 117.8, 117.9, 123.2, 127.5,
128.3, 129.4, 131.4, 133.7, 138.7, 152.7, 168.3; HRMS (ESI)
calcd for C31H52O4Si2Na [M + Na+] 567.3302, found 567.3311.
0.24 (20% EtOAc/petrol); [R]22 ) +16.6 (c 0.90, CH2Cl2); IR
D
1
υmax (film) 3467, 1641, 1608 cm-1; H NMR δ 0.83 (d, J ) 7.3
Hz, 3H), 1.57 (ddd, J ) 11.3, 7.3, 2.9 Hz, 1H), 1.68 (s, 6H),
1.81-1.98 (m, 2H), 2.14 (m, 1H), 2.19 (t, J ) 6.8 Hz, 2H), 2.71
(s, 1H), 3.55 (m, 1H), 3.78 (s, 3H), 3.84 (m, 2H), 3.89 (m, 1H),
4.44 (AB, J ) 11.1 Hz, 2H), 5.08 (m, 2H), 5.42 (dt, J ) 15.0,
6.6 Hz, 1H), 5.63 (dt, J ) 15.0, 6.6 Hz, 1H), 5.80 (m, 1H), 6.81
(d, J ) 7.9 Hz, 1H), 6.85 (d, J ) 8.7 Hz, 2H), 6.95 (d, J ) 7.9
Hz, 1H), 7.24 (d, J ) 8.7 Hz, 2H), 7.41 (t, J ) 7.9 Hz, 1H); 13
C
Acid 18. To a solution of acrylic acid (6.16 µL, 115 µmol) in
CH2Cl2 (0.3 mL) was added a solution of tricyclohexylphos-
phine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-
ylidene][benzylidine]ruthenium(IV) dichloride (2.41 mg, 2.88
µmol) in CH2Cl2 (0.3 mL) dropwise via cannula. A solution of
the alkene 17 (31.5 mg, 57.8 µmol) in CH2Cl2 (0.3 mL) was
then added dropwise via cannula. The reaction mixture was
then heated at reflux for 72 h after which time it was
concentrated and purified by flash chromatography silica gel
using 20% EtOAc/petrol as eluant and then by preparative
HPLC (25 mm × 10 mm 5 µm silica; solvent 30% EtOAc/petrol/
1% TFA; flow rate 2 mL min-1) to afford the acid 18 (12.7 mg,
NMR δ 14.2, 25.6, 35.0, 36.3, 37.1, 42.1, 55.2, 67.8, 71.1, 79.4,
105.0, 111.9, 113.7, 115.3, 117.4, 124.7, 129.5 (2C), 129.6 (2C),
130.3, 130.4, 135.0, 135.2, 146.0, 156.9, 159.1, 160.2; HRMS
(ESI) calcd for C30H38O6 [M + H+] 495.2746, found 495.2743.
Ma cr ola cton e 3. A solution of the acetonide 15 (40.3 mg,
81.5 µmol) in THF (2.8 mL) was added dropwise via cannula
to sodium hydride (220 mg, 5.54 mmol) in THF (4.4 mL). The
reaction mixture was stirred at room temperature for 6 h after
which time ether was added. The solution was cooled to 0 °C,
and the pH was adjusted to 3 by the addition of cold 5%
hydrochloric acid. Water was then added, and the crude
product was extracted into ether, washed with water and
brine, dried (MgSO4), and concentrated. The residue was
purified on silica gel using 20% EtOAc/petrol as eluant, which
provided the macrolactone 3 (22.7 mg, 64%) as a colorless oil:
37%) as a colorless oil: Rf 0.14 (10% EtOAc/petrol); [R]21
)
D
+5.9 (c 0.24, CHCl3); lit.6c [R]20 ) +2.0 (c 1.84, CHCl3); lit.7e
D
[R]20 ) +6.9 (c 0.3, CHCl3); IR υmax (film) 2957, 1728 cm-1
;
D
1H NMR δ 0.11 (s, 3H), 0.14 (s, 3H), 0.20 (s, 3H), 0.22 (s, 3H),
0.83 (d, J ) 6.3 Hz, 3H), 0.90 (s, 9H), 0.96 (s, 9H), 1.40 (m,
1H), 1.81 (m, 2H), 2.27 (m, 2H), 2.60 (t, J ) 6.8 Hz, 2H), 3.32
(d, J ) 16.8 Hz, 1H), 3.65 (dd, 1H, J ) 16.7, 8.0 Hz, 1H), 4.27
(d, J ) 8.7 Hz, 1H), 4.70 (s, 1H), 5.30-5.45 (m, 3H), 5.94 (d, J
) 15.6 Hz, 1H), 6.72 (d, J ) 8.1 Hz, 1H), 6.75 (d, J ) 8.1 Hz,
1H), 7.04 (dt, J ) 14.8, 7.5 Hz, 1H), 7.13 (t, J ) 8.1 Hz, 1H);
13C NMR δ -4.6, -4.5 (2C), -4.1, 13.0, 18.0, 18.3, 25.6 (3C),
25.8 (3C), 29.7, 36.2, 37.9, 38.1, 38.4, 71.9, 72.3, 117.8, 123.2,
127.3, 128.3, 129.6, 131.4, 138.7, 146.2, 152.7, 168.2, 170.1;
HRMS (ESI) calcd for C32H52O6Si2Na [M + Na+] 611.3200,
found 611.3206.
Rf 0.24 (20% EtOAc/petrol); [R]22 ) +71.6 (c 1.23, CH2Cl2);
D
1
IR υmax (film) 3494, 1725, 1651 cm-1; H NMR δ 0.92 (d, J )
7.2 Hz, 3H), 1.46 (dd, J ) 14.0, 8.9 Hz, 1H), 1.90 (m, 2H), 2.18
(ddd, J ) 14.1, 7.1, 3.2 Hz, 1H), 2.33 (m, 1H), 2.43 (dd, J )
13.4, 6.8 Hz, 2H), 3.36 (m, 2H), 3.77 (m, 1H), 3.71 (s, 3H), 4.33
(AB, J ) 10.8 Hz, 2H), 5.12 (m, 1H), 5.14 (m, 2H), 5.44-5.54
(m, 2H), 5.82 (m, 1H), 6.71 (d, J ) 7.7 Hz, 1H), 6.86 (d, J )
8.6 Hz, 2H), 6.91 (d, J ) 7.7 Hz, 1H), 7.26 (d, J ) 8.6 Hz, 2H),
7.31 (t, J ) 7.7 Hz, 1H), 11.24 (s, 1H); 13C NMR δ 14.0, 31.5,
38.4, 39.1, 39.5, 55.2, 71.1, 74.3, 78.0, 112.9, 113.7 (2C), 116.7,
118.4, 123.5, 126.2, 129.6 (2C), 130.6, 133.0, 133.2, 134.0,
142.6, 159.1, 162.9, 170.8; HRMS (ESI) calcd for C27H32O5Na
[M + Na+] 459.2148, found 459.2143.
TIP S Eth er 19. To a solution of the phenol 3 (56.3 mg, 129
µmol) and 2,6-lutidine (52 µL, 0.44 mmol) in CH2Cl2 (1.6 mL)
at 0 °C was added dropwise triisopropylsilyltrifluoromethane-
sulfonate (90 µL, 0.33 mmol). The reaction mixture was stirred
for 2 h at room temperature after which time saturated
NaHCO3 was added and the crude TIPS ether was isolated
by extraction with ether. The organic extracts were washed
with water and brine, dried (MgSO4), and concentrated. The
residue was purified on silica gel using 10% EtOAc/petrol as
eluant to yield the TIPS ether 19 (76.5 mg, 94%) as a colorless
oil: Rf 0.82 (20% EtOAc/petrol); [R]21D ) +2.3 (c 1.06, CH2Cl2);
IR υmax (film) 2948, 1727 cm-1; 1H NMR δ 0.84 (d, J ) 6.6 Hz,
3H), 1.08 (d, J ) 7.5 Hz, 9H), 1.13 (d, J ) 7.5 Hz, 9H), 1.30
(m, 3H), 1.56 (m, 1H), 1.70 (m, 2H), 2.07 (m, 1H), 2.29 (m,
1H), 2.42 (m, 2H), 3.35 (dd, J ) 16.1, 3.8 Hz, 1H), 3.70 (dd, J
) 16.2, 7.8 Hz, 1H), 3.81 (s, 3H), 4.11 (m, 1H), 4.59 (s, 2H),
5.09 (m, 2H), 5.36-5.43 (m, 3H), 5.80 (m, 1H), 6.73 (d, J ) 7.9
Hz, 1H), 6.76 (d, J ) 7.9 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 2H),
7.11 (t, J ) 7.9 Hz, 1H), 7.37 (d, J ) 8.6 Hz, 2H); 13C NMR δ
12.2, 13.0 (2C), 13.3, 17.7 (2C), 17.91, 17.94 (2C), 30.9, 37.7,
38.1, 40.0, 55.2, 71.4, 73.7, 79.6, 113.6, 116.6, 117.8, 122.7,
127.1, 128.5, 129.3, 129.4, 131.2, 131.8, 133.5, 138.6, 153.0,
158.9, 168.3; HRMS (ESI) calcd for C36H53O5Si [M + H+]
593.3662, found 593.3663.
Alcoh ol 16. To a solution of the PMB ether 3 (52.4 mg, 12.0
µmol) in CH2Cl2 (3.1 mL) and water (171 µL) was added 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (30.0 mg, 133 µmol).
The reaction mixture turned green and was stirred at room
temperature for 1 h open to the atmosphere. It was then
filtered through a plug of filter aid, washed with CH2Cl2, dried
(MgSO4), and concentrated. The residue was purified on silica
gel using 20% EtOAc/petrol as eluant to give the diol 16 (35.5
mg, 94%) as a colorless low melting crystalline solid: Rf 0.28
(20% EtOAc/petrol); [R]24 ) +37.3 (c 1.77, CH2Cl2); IR υmax
D
1
(film) 3494, 1732, 1653 cm-1; H NMR δ 0.92 (d, J ) 6.6 Hz,
3H), 1.38 (dd, J ) 15.5, 11.6 Hz, 2H), 1.74 (s, 1H), 1.86 (m,
2H), 2.35 (m, 1H), 2.46 (t, J ) 6.8 Hz, 2H), 3.41 (d, J ) 16.5
Hz, 1H), 3.66-3.77 (m, 2H), 5.13-5.18 (m, 3H), 5.38 (dt, J )
15.5, 4.5 Hz, 1H), 5.68 (dt, J ) 10.5, 5.6 Hz, IH), 5.83 (m, 1H),
6.70 (d, J ) 8.1 Hz, 1H), 6.88 (d, J ) 8.1 Hz, 1H), 7.29 (t, J )
8.1 Hz, 1H), 10.80 (s, 1H); 13C NMR δ 13.7, 35.4, 37.4, 38.3,
39.0, 39.7, 70.5, 74.2, 113.5, 116.6, 118.6, 123.5, 126.6, 132.7,
133.2, 133.9, 142.4, 162.2, 170.6; HRMS (ESI) calcd for
C
19H24O4Na [M + Na+] 339.1573, found 339.1574.
Bis TBS Eth er 17. To a solution of the diol 16 (35.5 mg,
112 µmol) in dry CH2Cl2 (0.6 mL) at 0 °C was added 2,6-
lutidine (52.2 µL, 487 µmol) followed by tert-butyldimethylsilyl
J . Org. Chem, Vol. 68, No. 6, 2003 2203