Synthesis of Diospongins A and B
Optical rotations were measured with a JASCO P1030 digital pola-
formed at r.t. after standing overnight, and were collected by suc-
rimeter at the sodium D-line (589 nm). EI-MS spectra were ob- tion, washed with ice-cold EtOH (0.5 mL) and dried in vacuo to
tained with a JEOL JMS-FABmate spectrometer. FAB-MS spectra
were obtained with a JEOL JMS-700TZ spectrometer. Analytical
high performance liquid chromatography (HPLC) was performed
with a JASCO PU-1580 intelligent HPLC pump and a JASCO UV-
1575 intelligent UV/Vis detector (detection at 254 nm). A Chiralcel
OD-H (0.46 cmϫ 25 cm) column, purchased from Daicel, was
used. Retention times (tR) and peak ratios were determined with a
JASCO-ChromNAV analysis system. All non-aqueous reactions
were carried out in flame-dried glassware under an argon atmo-
sphere unless otherwise noted. Reagents and solvents were purified
by standard means. Dehydrated, stabilizer-free CH2Cl2 and THF
were purchased from Kanto Chemical Co., Inc.
give optically pure 4 (100 mg, 85%); m.p. 73.5–74.0 °C. [α]2D2
=
–16.1 (c = 1.12, CHCl3). The enatiopurity of 4 was determined to
be Ͼ99% ee by comparison of the HPLC trace with that of a race-
mic sample.
Diospongin B (2): To a solution of diketone 4 (60 mg, 0.21 mmol,
Ͼ99% ee) in THF (2 mL), was added a solution of K-Selectride®
(1.0 m in THF, 0.21 mL, 0.21 mmol) at –78 °C. After stirring at
–78 °C for 2 h, the reaction was quenched by the addition of satu-
rated aq. NaHCO3 (0.1 mL) and the mixture was partitioned be-
tween EtOAc (30 mL) and water (5 mL). The organic layer was
washed with water (4 mL) and brine (2ϫ4 mL), and dried with
anhydrous Na2SO4. Filtration and evaporation in vacuo, followed
by column chromatography (silica gel; toluene/EtOAc, 2:1) pro-
vided 2 (51.2 mg, 86%) as a white amorphous solid, along with 12
(5.5 mg, 7%) as a colorless amorphous solid, and diketone 4
(2.9 mg, 5%); TLC Rf = 0.36 (toluene/EtOAc, 2:1); Rf = 0.32 (hex-
(3S,7S)-3-(1-Oxo-1-phenylethyl)-7-phenyltetrahydropyran-5-one (4):
To a solution of dihydropyranone (S)-6[7b] (98% ee, 200 mg,
1.2 mmol) and silyl enol ether 5[9] (270 mg, 1.4 mmol) in CH2Cl2
(5 mL), was added TMSOTf (27 mg, 0.12 mmol, 10 mol-%) at
–78 °C. After stirring at –78 °C for 1 h, trifluoroacetic acid (10%
in CH2Cl2, ca. 0.2 mL) was added and the mixture was stirred for
an additional 1 h. The mixture was partitioned between EtOAc
(25 mL) and saturated NaHCO3 (5 mL), and the organic layer was
washed with water (5 mL) and brine (2ϫ 5 mL), and dried with
anhydrous Na2SO4. Filtration and evaporation in vacuo followed
by column chromatography (silica gel; hexane/EtOAc, 3:1) gave 4
(300 mg, 89%) as a pale-yellow solid; m.p. 70.5–72.0 °C; TLC Rf
ane/EtOAc, 1:1). [α]2D3 = +23.3 (c = 0.63, CHCl3) {ref.[1] [α]D
=
–23.4 (c = 0.6, CHCl3); ref.[17] [α]D = +23.4 (c = 0.6, CHCl3)}. IR:
1
ν = 3406, 1686, 1598, 1495, 1450, 1052 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 1.50 (ddd, J = 9.7, 9.7, 12.6 Hz, 1 H, C4-H), 1.92
(ddd, J = 4.0, 9.7, 13.2 Hz, 1 H, C6-H), 2.05 (ddd, J = 2.9, 5.1,
12.6 Hz, 1 H, C4-H), 2.51 (ddd, J = 4.0, 4.0, 13.2 Hz, 1 H, C6-H),
3.17 (dd, J = 6.3, 16.0 Hz, 1 H, C2-H), 3.45 (dd, J = 6.9, 16.0 Hz,
1 H, C2-H), 4.02 (dddd, J = 4.0, 5.1, 9.7, 9.7 Hz, 1 H, C5-H), 4.23
(dddd, J = 2.9, 6.3, 6.9, 9.7 Hz, 1 H, C3-H), 5.19 (dd, J = 4.0,
4.0 Hz, 1 H, C7-H), 7.23 (t, J = 6.9 Hz, 1 H, ArH), 7.32 (m, 2 H,
ArH), 7.35 (m, 2 H, ArH), 7.47 (t, J = 7.4 Hz, 2 H, ArH), 7.58 (t,
J = 7.4 Hz, 1 H, ArH r), 7.99 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 36.6 (CH2), 40.1 (CH2), 44.6 (CH2),
64.1 (CH), 66.9 (CH), 72.3 (CH), 126.3 (CH), 127.0 (CH), 128.2
(CH), 128.5 (CH), 128.6 (CH), 133.2 (CH), 137.1 (C), 140.1 (C),
198.4 (C=O) ppm. HRMS (EI): m/z calcd. for C19H20O3 [M]+
296.1413; found 296.1399.
= 0.20 (hexane/EtOAc, 2:1). [α]2D2 = –16.0 (c = 1.17, CHCl ). IR: ν
˜
3
= 3061, 2906, 1720, 1681, 1597, 1449 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 2.49 (ddd, J = 1.1, 8.0, 14.9 Hz, 1 H, C4-H), 2.70
(ddd, J = 1.1, 4.0, 14.9 Hz, 1 H, C4-H), 2.84 (ddd, J = 1.1, 5.7,
14.9 Hz, 1 H, C6-H), 2.92 (ddd, J = 1.1, 5.7, 14.9 Hz, 1 H, C6-H),
3.14 (dd, J = 6.3, 16.0 Hz, 1 H, C2-H), 3.39 (dd, J = 6.3, 16.0 Hz,
1 H, C2-H), 4.60 (m, 1 H, C3-H), 5.29 (dd, J = 5.4, 5.4 Hz, 1 H,
C7-H), 7.26–7.35 (m, 5 H, ArH), 7.44–7.47 (m, 2 H, ArH), 7.56–
7.60 (m, 1 H, ArH), 7.91–7.93 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 43.5 (CH2), 45.4 (CH2), 46.5 (CH2), 68.3
(CH), 74.0 (CH), 126.6 (CH), 127.8 (CH), 127.9 (CH), 128.3 (CH),
128.4 (CH), 133.1 (CH), 136.5 (C), 139.2 (C), 196.6 (C=O), 206.1
(C=O) ppm. HRMS (EI): m/z calcd. for C19H18O3 [M]+ 294.1256;
found 294.1248. C19H18O3 (294.34): calcd. C 77.53, H 6.16; found
C 77.31, H 6.23.
Diol 12:[19] TLC Rf = 0.22 (toluene/EtOAc, 2:1); Rf = 0.27 (hexane/
1
EtOAc, 1:1). IR: ν = 3389, 2943, 1603, 1494, 1448, 1063 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 1.25 (m, 0.6 H, C4-H), 1.45 (m, 0.4
H, C4-H), 1.73 (dt, J = 2.3, 14.3 Hz, 0.6 H, C2-H), 1.81–1.94 (m,
2.4 H, C4-H, C6-H, C2-H, C4-H, and C6-H), 2.03 (m, 0.4 H, C2-
H), 2.13 (m, 0.6 H, C2-H), 2.48 (m, 0.4 H, C6-H), 2.53 (m, 0.6 H,
C6-H), 3.77–3.81 (m, 1 H, C3-H and C3-H), 3.90–3.94 (m, 1 H,
C5-H and C5-H), 4.89 (dd, J = 2.3, 9.2 Hz, 0.6 H, C1-H), 5.04 (dd,
J = 1.7, 9.1 Hz, 0.4 H, C1-H), 5.22 (m, 0.4 H, C7-H), 5.28 (m, 0.6
H, C7-H), 7.21–7.43 (m, 10 H, ArH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 36.0 (CH2), 36.5 (CH2), 40.3 (CH2), 41.2 (CH2), 44.1
(CH2), 45.0 (CH2), 63.6 (CH), 64.1 (CH), 67.3 (CH), 70.7 (CH),
70.8 (CH), 72.6 (CH), 73.1 (CH), 74.2 (CH), 125.5 (CH), 125.7
(CH), 126.4 (CH), 126.5 (CH), 127.30 (CH), 127.31 (CH), 127.2
(CH), 128.29 (CH), 128.31 (CH), 128.47 (CH), 128.53 (CH), 128.7
(CH), 139.7 (C), 140.2 (C), 144.1 (C), 144.6 (C) ppm. HRMS
(FAB): m/z calcd. for C19H22O3Na [M + Na]+ 321.14612; found
321.14569.
One-Pot Sequential HDA/Mukaiyama–Michael Reaction. Prepara-
tion of 4 from Benzaldehyde (7): To a solution of benzaldehyde (7;
150 mg, 1.4 mmol) and [Rh2(S-BPTPI)4]·3H2O (3; 20 mg,
0.014 mmol, 1 mol-%) in CH2Cl2 (1.8 mL), was added a solution
of Danishefsky-type diene 8b (300 mg, 1.4 mmol) in CH2Cl2
(1.0 mL) at 23 °C. After stirring at this temperature for 15 h,
TMSOTf (31 mg, 0.14 mmol, 10 mol-%) was added at –78 °C and
the mixture was stirred for an additional 0.5 h. A solution of silyl
enol ether 5 (320 mg, 1.7 mmol) in CH2Cl2 (0.2 mL) was added at
–78 °C and, after stirring at this temperature for 1 h, TFA (10% in
CH2Cl2, 0.2 mL) was added and the mixture was stirred for an
additional 1 h. The mixture was partitioned between EtOAc
(25 mL) and saturated NaHCO3 (5 mL), and the organic layer was
washed with water (5 mL) and brine (2ϫ5 mL), and dried with
anhydrous Na2SO4. Filtration and evaporation in vacuo, followed
by column chromatography (silica gel; hexane/EtOAc, 3:1) afforded
4 (345 mg, 85%) as a pale-yellow solid. The enantiomeric excess of
4 was determined to be 95% by HPLC analysis with a Chiralcel
OD-H column (hexane/iPrOH, 9:1; 1.0 mL/min): tR (major) =
20.2 min for (2S,6S)-4; tR (minor) = 33.2 min for (2R,6R)-4.
Diospongin A (1): To a solution of (+)-diospongin B (2; 29.6 mg,
0.1 mmol) in THF (2 mL), was added aqueous HCl (30%, 0.5 mL)
at 0 °C. After stirring at 23 °C for 6 h, the reaction was quenched
by addition of saturated NaHCO3 (3 mL), and the mixture was
extracted with EtOAc (20 mL). The organic layer was washed with
water (4 mL) and brine (2ϫ4 mL), and dried with anhydrous
Na2SO4. Filtration and evaporation in vacuo, followed by column
Recrystallization was performed by dissolving
0.41 mmol, 95% ee) in hot EtOH (2 mL). The colorless plates
4
(120 mg,
chromatography (silica gel; hexane/EtOAc, 3:1) furnished
1
(26.8 mg, 90%) as a white solid; m.p. 100–101 °C [ref.[1] m.p. 102–
Eur. J. Org. Chem. 2010, 6850–6854
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6853