PAPER
Formal Synthesis of (R)-(+)-Lasiodiplodin
19F NMR (376 MHz, CDCl3): d = 51.49.
HRMS (ESI+): m/z [M]+ calcd for C16H21FO3: 303.1367; found:
303.1364.
1057
tane, 4.60 mL, 7.36 mmol) at –78 °C. After 30 min, 9-methoxy-9-
borabicyclo[3.3.1]nonane (1 M in hexanes, 9.20 mL, 9.20 mmol)
was added. The resulting solution was stirred for 10 min at –78 °C
and then allowed to warm to r.t. for 1.5 h. Cs2CO3 (4.80 g,
14.7 mmol) was added, followed by the addition of iodide 10 (1.07
g, 3.68 mmol) in DMF (20 mL). [PdCl2(dppf)] [150 mg, 0.184
mmol, dppf = 1,1¢-bis(diphenylphosphino)ferrocene] was added,
followed by H2O (1.59 mL) and AsPh3 (169 mg, 0.55 mmol). The
resulting solution was stirred for 16 h at r.t., then Et2O (20 mL) was
added and the organic solution was washed with H2O (10 mL). The
aqueous layer was extracted with Et2O (3 × 30 mL), and the com-
bined organic layers were dried over Na2SO4, filtered, concentrated,
and purified by flash chromatography (pentane–Et2O, 10:1) to give
(–)-(R)-But-3-en-2-yl 6-(Hept-6-en-1-yl)-2,4-dimethoxyben-
zoate (6)
To a stirred solution of ester 4 (138 mg, 0.78 mmol, 97% ee) in H2O
(4 mL), was added KOH (439 mg, 7.8 mmol). The resulting mixture
was stirred overnight, extracted with Et2O (3 × 5 mL), and the com-
bined organic layers were dried over Na2SO4 and filtered. The crude
alcohol 8 was used for the next step without complete removal of
the solvent in order to avoid loss due to evaporation of the volatile
alcohol.
1H NMR (400 MHz, CDCl3): d = 5.92 (ddd, J = 17.2, 10.4, 5.8 Hz,
1 H), 5.24–5.19 (m, 1 H), 5.12–4.97 (m, 1 H), 4.40–4.17 (m, 1 H),
1.57 (br, 1 H), 1.28 (d, J = 6.4 Hz, 3 H).
11 as a colorless oil with traces of 9-BBN residues visible in the 13
NMR spectrum, which were removed in the next step.
C
Yield: 500 mg (1.91 mmol, 52%).
1H NMR (400 MHz, CDCl3): d = 10.45 (s, 1 H), 6.31 (s, 2 H), 5.80
(ddt, J = 16.9, 10.1, 6.7 Hz, 1 H), 4.99–4.89 (m, 1 H), 4.93–4.89 (m,
1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.95–2.92 (m, 2 H), 2.41–2.38 (m,
2 H), 1.89–1.83 (m, 2 H), 1.59–1.50 (m, 2 H), 1.41–1.38 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 190.4, 165.6, 164.7, 149.8, 139.4,
117.0, 114.4, 108.2, 95.9, 56.0, 55.6, 34.8, 34.0, 31.3, 29.5, 29.0.
To a stirred solution of alcohol 8 (0.78 mmol) in THF (2 mL), was
added NaHMDS (1 M in THF, 0.78 mL, 0.78 mmol) at 0 °C, and
the solution was stirred for 10 min. A solution of acid fluoride 7
(30.0 mg, 0.10 mmol) in THF (2 mL) was added slowly, and the
mixture was warmed to r.t. and stirred overnight. The reaction was
quenched with aq. sat. NH4Cl (20 mL) and extracted with Et2O
(3 × 10 mL), and the combined organic layers were dried over
Na2SO4, filtered, concentrated, and purified by flash chromatogra-
phy (pentane–Et2O, 20:1) to give 6.
HRMS (ESI+): m/z [M + H]+ calcd for C16H23O3: 263.1642; found:
263.1643.
6-(Hept-6-en-1-yl)-2,4-dimethoxybenzoic Acid (12)
Yield: 30.2 mg (0.09 mmol, 90%); colorless oil; [a]D –7.4 (c 1.1,
To a stirred solution of aldehyde 11 (420 mg, 1.61 mmol) in t-
BuOH–H2O (5:1, 30 mL) was added NaH2PO4 (0.34 g, 2.87 mol),
NaClO2 (0.69 g, 7.64 mol), and 2-methyl-2-butene (806 mg, 1.21
mL, 11.5 mmol). The resulting solution was stirred for 4 h and the
solvent was removed. The resulting mixture was extracted with
CH2Cl2 (3 × 30 mL) and the combined organic layers were dried
over Na2SO4, filtered, concentrated, and purified by flash chroma-
tography (heptane–EtOAc, 1:2) to give 12.
CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.31 (s, 2 H), 5.92 (ddd, J = 16.7,
10.6, 5.9 Hz, 1 H), 5.85–5.72 (m, 1 H), 5.63–5.59 (m, 1 H), 5.36 (d,
J = 17.3 Hz, 1 H), 5.18 (d, J = 10.5 Hz, 1 H), 5.04–4.88 (m, 2 H),
3.79 (s, 3 H), 3.78 (s, 3 H), 2.58–2.53 (m, 2 H), 2.04–2.02 (m, 2 H),
1.63–1.56 (m, 2 H), 1.42 (d, J = 6.5 Hz, 3 H), 1.48–1.18 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 162.8, 156.5, 153.2, 137.9, 134.2,
132.9, 111.9, 111.3, 109.5, 101.0, 91.5, 66.9, 51.0, 50.6, 29.0, 28.9,
26.4, 24.3, 24.0, 15.2.
Yield: 360 mg (1.29 mmol, 80%); brown oil.
1H NMR (400 MHz, CDCl3): d = 10.03 (br, 1 H), 6.38 (d,
J = 2.2 Hz, 1 H), 6.35 (d, J = 2.2 Hz, 1 H), 5.79 (ddt, J = 16.9, 10.2,
6.7 Hz, 1 H), 5.01–4.90 (m, 2 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 2.79–
2.75 (m, 2 H), 2.06–2.01 (m, 2 H), 1.66–1.58 (m, 2 H), 1.44–1.36
(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 171.6, 162.2, 159.1, 146.1, 139.3,
114.5, 114.0, 107.3, 96.6, 56.4, 55.6, 34.8, 33.9, 31.5, 29.3, 28.9.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO4: 355.1880;
found: 355.1862.
(+)-(R)-12,14-Dimethoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-
1H-benzo[c][1]oxacyclododecin-1-one (5)
To a stirred solution of compound 6 (13.0 mg, 0.04 mmol) in
toluene (30 mL), was added Hoveyda–Grubbs second-generation
catalyst {[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]di-
chloro(o-isopropoxyphenylmethylene)ruthenium; 1.30 mg, 2.00
mmol, 5 mol%}. The resulting solution was heated to reflux for 10
min under N2. The solvent was removed and the product was puri-
fied by flash chromatography (pentane–Et2O) to give 13 as a green
oil (9.50 mg, 32.0 mmol, 80%; E/Z = 1:2), which was difficult to pu-
rify, so was used immediately for the next step.
HRMS (ESI+): m/z [M + H]+ calcd for C16H23O4: 279.1591; found:
279.1594.
6-(Hept-6-en-1-yl)-2,4-dimethoxybenzoyl Fluoride (7)
To a stirred solution of acid 12 (100 mg, 0.36 mmol) in CH2Cl2 (4
mL) was added cyanuric fluoride (72.9 mg, 46.0 mL, 0.54 mmol)
and pyridine (85.4 mg, 87.0 mL, 1.08 mmol) at 0 °C. The resulting
mixture was stirred for 4 h and then quenched with H2O (20 mL).
The aqueous mixture was extracted with CH2Cl2 (3 × 30 mL) and
the combined organic layers were dried over Na2SO4, filtered, con-
centrated, and purified by flash chromatography (heptane–EtOAc,
1:1) to give 7.
To a stirred solution of compound 13 (9.50 mg, 0.03 mmol) in
EtOAc (2 mL), was added Pd/C (10.0 mg) and the resulting solution
was exposed to H2 (1 atm). The mixture was stirred overnight and
the solvent was removed. Purification by flash chromatography
(pentane–Et2O, 10:1) gave 5.
Yield: 77 mg (0.27 mmol, 76%); colorless oil.
Yield: 9.6 mg (0.03 mmol, 100%); colorless oil; [a]D +10.5 (c 0. 1,
CHCl3) [Lit.4i +8.7 (c 1.63, CHCl3); Lit.4d +9 (c 1.0, CHCl3); Lit.4g
+4.2 (c 0.18, CHCl3)].
1H NMR (400 MHz, CDCl3): d = 6.30 (d, J = 2.2 Hz, 1 H), 6.32 (d,
J = 2.2 Hz, 1 H), 5.31–5.25 (m, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H),
2.77–2.67 (m, 1 H), 2.58–2.49 (m, 1 H), 1.98–1.88 (m, 1 H), 1.74–
1.61 (m, 4 H), 1.36–1.60 (m, 5 H), 1.32 (d, J = 6.5 Hz, 3 H), 1.28–
1.24 (m, 2 H). The NMR data are in agreement with those reported
previously.4i
1H NMR (400 MHz, CDCl3): d = 6.37 (d, J = 2.2 Hz, 1 H), 6.34 (d,
J = 2.2 Hz, 1 H), 5.80 (ddt, J = 17.0, 10.2, 6.7 Hz, 1 H), 5.02–4.95
(m, 1 H), 4.95–4.89 (m, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 2.76–2.64
(m, 2 H), 2.09–1.98 (m, 2 H), 1.66–1.51 (m, 2 H), 1.46–1.29 (m,
4 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 161.2 (d, J = 2 Hz), 159.1,
155.6, 147.7 (d, J = 3 Hz), 139.2, 114.5, 107.2, 96.5, 56.2, 55.7,
34.8, 33.9, 31.6, 29.2, 28.9.
Synthesis 2011, No. 7, 1055–1058 © Thieme Stuttgart · New York