PAPER
Stereoselective Total Synthesis of Leiocarpin C and (+)-Goniodiol
3009
IR (neat): 3448, 2925, 2855, 1455, 1374, 1249, 1214, 1153, 1072,
1027, 918, 895, 762, 703, 632 cm–1.
IR (neat): 3453, 2928, 1640, 1452, 1214, 1152, 1034, 917, 764, 702
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.29 (m, 5 H), 4.64 (d,
J = 3.5 Hz, 1 H), 4.51 (s, 2 H), 4.15–4.05 (m, 1 H), 3.88–3.82 (m, 1
H), 3.6–3.5 (m, 2 H), 3.36 (s, 3 H), 1.94–1.80 (m, 1 H), 1.76–1.63
(m, 1 H), 1.32 (s, 3 H), 1.27 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.42–7.28 (m, 5 H), 5.84–5.68 (m,
1 H), 5.12–4.98 (m, 2 H), 4.71–4.49 (m, 5 H), 4.17–4.07 (m, 1 H),
3.88–3.70 (m, 2 H), 3.36 (s, 3 H), 3.33 (s, 3 H), 2.30–2.22 (m, 2 H),
1.70–1.40 (m, 2 H), 1.33 (s, 3 H), 1.20 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.8, 128.3, 128.1, 127.6, 109.2,
13C NMR (75 MHz, CDCl3): d = 137.9, 134.4, 128.1, 128.0, 127.8,
117.3, 108.9, 95.7, 94.2, 83.5, 77.9, 77.1, 73.9, 55.8, 39.7, 39.2,
27.5, 26.7.
94.3, 85.5, 77.9, 60.8, 55.9, 36.5, 26.8.
HRMS (ESI): m/z [M + Na] calcd for C16H24NaO5: 319.1521;
found: 319.1519.
HRMS (ESI): m/z [M + Na] calcd for C21H32O6Na: 403.2085;
found: 403.2096.
(4S,6R,7S,8R)-6,7-(Isopropylidenedioxy)-8-(methoxymethoxy)-
8-phenyloct-1-en-4-ol (12)
Methyl (3R,5R,6S,7R)-5,6-(Isopropylidenedioxy)-3,7-bis(meth-
oxymethoxy)-7-phenylheptanoate (14)
To a stirred soln of IBX (11.3 g, 40.2 mmol) in DMSO (5.7 mL,
80.5 mmol) at r.t. was added alcohol 11 (6 g, 20.1 mmol) dropwise
in anhyd CH2Cl2 (100 mL) and stirring was continued at r.t. for 4 h.
When the reaction was complete it was extracted with Et2O (3 × 100
mL) and filtered through a Celite pad. The filtrate was washed with
sat. aq NaHCO3 and brine, dried (Na2SO4), and concentrated under
reduced pressure. The resulted crude aldehyde was directly used for
next reaction.
The soln of 13 (2.5 g, 6.52 mmol) in anhyd CH2Cl2 (15 mL) and 2.5
M NaOH in MeOH (13 mL) was stirred at –78 °C and ozone was
passed through the soln at the same temperature till the mixture ac-
quired the blue characteristic color of ozone and a yellow precipi-
tate had formed. The mixture was diluted with Et2O (100 mL) and
H2O (20 mL). The resulting mixture was allowed to warm to r.t. and
extracted with Et2O (3 × 100 mL). The combined organic layers
were dried (Na2SO4) and the solvent removed. Purification by col-
umn chromatography (silica gel, EtOAc–hexane, 2:8) afforded 14
(1.6 g, 60%) as a colorless product.
[a]D25 –25.8 (c 1.55, CHCl3).
IR (neat): 2895, 1745, 1230, 1050, 736 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.24 (m, 5 H), 4.65 (d,
J = 6.2 Hz, 1 H), 4.61–4.55 (m, 4 H), 4.12 (m, 1 H), 3.98–3.85 (m,
2 H), 3.84 (s, 3 H), 3.39–3.35 (d, J = 7.5 Hz, 6 H), 2.68–2.35 (m, 2
H), 1.82–1.47 (m, 2 H), 1.32 (s, 6 H).
To a stirred soln of MgBr2·OEt2 (8.72 g, 33.8 mmol) in anhyd
CH2Cl2 (100 mL) was added the aldehyde (5 g, 16.9 mmol) in anhyd
CH2Cl2 (80 mL) at 0 °C and stirring was continued at this tempera-
ture for 15 min. To the mixture was added allyltributyltin (7.8 mL,
25.3 mmol) dropwise at –78 °C and under inert atmosphere. The re-
sulted mixture was stirred at this temperature for a further 2 h. The
mixture was warmed to –20 °C and stirring was continued for 30
min. The mixture was quenched with sat. NH4Cl (20 mL) and ex-
tracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were washed with H2O and brine, dried (Na2SO4), and the solvent
removed. Column chromatography (silica gel, EtOAc–hexane, 2:8)
furnished the allylated product (4.58 g, 80%) as a colorless liquid as
a diastereomeric mixture. The pure diastereomers were separated by
column chromatography to obtained purified 1,3-anti-allylated
product 12 (4.31 g); 90% de.
13C NMR (75 MHz, CDCl3): d = 172.1, 128.1, 128.0, 127.8, 117.3,
108.9, 95.7, 94.2, 83.5, 77.9, 77.1, 73.9, 55.8, 39.7, 39.2, 27.5, 26.7.
HRMS (ESI): m/z [M + Na] calcd for C21H32NaO8: 435.1994;
found: 435.1995.
[a]D26 –34.4 (c 1, CHCl3).
Leiocarpin C [(4R,6R)-6-[(1R,2R)-1,2-Dihydroxy-2-phenyleth-
yl]-4-hydroxytetrahydro-2H-pyran-2-one]
IR (neat): 3453, 2926, 1638, 1454, 1377, 1250, 1214, 1154, 1074,
1029, 917, 764, 701 cm–1.
To a stirred soln of ester 14 (0.5 g, 1.20 mmol) in MeOH (2 mL)
was added PTSA (23 mg, 0.12 mmol) at r.t. The mixture was heated
under reflux for 2 h. The mixture was then cooled to r.t. and solvent
was removed under reduced pressure. The residue was subjected to
column chromatography (silica gel, EtOAc–hexane, 2:8) to afford
leiocarpin C (0.21 g, 70%) as needles.
[a]D29 –63.2 (c 0.5, MeOH).
IR (neat): 3450, 3180, 2885, 1720, 1460, 1150, 890 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.21 (m, 5 H), 5.42 (d,
J = 5.8 Hz, 1 H), 4.77 (dd, J = 2.4, 5.8 Hz, 1 H), 4.45–4.40 (m, 1 H),
4.35 (dt, J = 3.2, 7.0 Hz, 1 H), 3.35 (dd, J = 7.2, 14.8 Hz, 2 H), 2.38
(t, J = 4.1 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 5.82–5.65 (m,
1 H), 5.12–4.98 (m, 2 H), 4.68 (d, J = 6.0 Hz, 1 H), 4.54 (s, 2 H),
4.27 (td, J = 3.8, 7.5 Hz, 1 H), 4.16–4.05 (m, 1 H), 3.90–3.82 (m, 1
H), 3.83–3.74 (br s, 1 H), 3.36 (s, 3 H), 2.24–2.10 (m, 2 H), 1.67 –
1.49 (m, 2 H), 1.35 (s, 3 H), 1.32 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.3, 134.1, 127.8, 127.3, 127.1,
117.3, 108.9, 93.9, 82.8, 77.4, 77.3, 67.8, 55.5, 41.5, 39.9, 27.0,
26.4.
HRMS (ESI): m/z [M + Na] calcd for C19H28NaO5: 359.1834;
found: 359.1834.
13C NMR (75 MHz, CDCl3): d = 173.5, 141.2, 129.2, 128.4, 127.3,
74.5, 70.0, 68.8, 67.9, 41.5, 38.1.
(4S,6R,7S,8R)-6,7-(Isopropylidenedioxy)-4,8-bis(meth-
oxymethoxy)-8-phenyloct-1-ene (13)
To a well-stirred soln of 12 (3.48 g, 10.35 mmol) in anhyd CH2Cl2
(50 mL) was added DIPEA (4 mL, 20.7 mmol) dropwise at 0 °C and
stirring was continued for 30 min. MOMCl (1.06 mL, 13.3 mmol)
was then added and the mixture was stirred at r.t. for 15 h. The re-
action was quenched with ice flakes and the product was extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with H2O and brine, dried (Na2SO4), and the solvent re-
moved. Purification by column chromatography (silica gel, EtOAc–
hexane, 4:6) afforded pure 13 (3.542 g, 90%) as a colorless liquid.
HRMS (ESI): m/z [M + Na] calcd for C13H16NaO5: 275.0895;
found: 275.0895.
(2R,3R)-4-(tert-Butyldimethylsiloxy)-2,3-(isopropylidene-
dioxy)butan-1-ol (15)
To a stirred soln of [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl]methanol (11.7 g, 72 mmol) and NaH (3.4 g, 144
mmol) in anhyd THF (400 mL) was added TBSCl (10.8 g, 72 mmol)
in anhyd THF (200 mL) dropwise through a dropping funnel at 0 °C
over 60 min under an inert atmosphere. The mixture was stirred for
2 h and then it was allowed to warm up to r.t. The reaction was
[a]D26 –37.6 (c 1, CHCl3).
Synthesis 2010, No. 17, 3004–3012 © Thieme Stuttgart · New York