Ozonolysis of Protected Iridoid Glucosides
FULL PAPER
6,2Ј,3Ј,6Ј-Tetra-O-benzoylantirrhinoside 10: Antirrhinoside (0.78
tal 11 (1:1, 1.53 g, 67%) followed by more, impure (ca. 50%) 11
g, 2.15 mmol) was dissolved in dry pyridine/CH2Cl2 (3:2, 5 ml),
and BzCl (1.12 ml, 9.66 mmol) was added under cooling to 0°C. 50 ml) gave an analytical sample, m.p. 162Ϫ163°C, [α]D ϭ Ϫ5.8
Then additional dry CH2Cl2 (10 ml) was added and the mixture
(0.24 g, 5%). Recrystallization of the former (hexane/acetone 1:1,
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1
(c ϭ 0.2, MeOH). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.49 (s , 3
was kept at 4°C overnight when excess BzCl was hydrolyzed by H, 10-H), 2.84 (dd, J ϭ 9, 5 Hz, 1 H, 9-H), 3.52 (br. s, 1 H, 4-OH),
addition of water (1 ml) and standing for 0.5 h. Work-up gave a 3.69 (br. s, 1 H, 7-H), 3.74 (dd, J ϭ 9.5, 5 Hz, 1 H, 1a-H), 4.33 (t,
crude product (1.70 g). Chromatography on a VLC column (5 ϫ 5
cm) eluting first with hexane and then hexane/EtOAc (4:1 to 1:1) 1 H, 4-H), 7.44 (t, J ϭ 8 Hz, 2 H, 3Ј-H/5Ј-H), 7.57 (br. t, J ϭ 8
gave crude pentabenzoate (4:1, 0.20 g, 10%), crystalline tetrabenzo-
Hz, 1 H, 4Ј-H), 8.09 (br. d, J ϭ 8 Hz, 2 H, 2Ј-H/6Ј-H). Ϫ 13C
ate 10 (2.5:1, 0.91 g, 55%) followed by two tribenzoates: 6,3Ј,6Ј- NMR: See Table 3. Ϫ C15H16O6 (292.3): calcd. C 61.64, H 5.52;
J ϭ 9.5 Hz, 1 H, 1b-H), 5.29 (d, J ϭ 1 Hz, 1 H, 6-H), 5.52 (br. s,
tri-O-benzoylantirrhinoside (1.5:1, 0.15 g, 10%) and 6,2Ј,6Ј-tri-O-
found C 61.43, H 5.39.
benzoylantirrhinoside (1:1, 0.12 g, 8%); the latter two were charac-
terized only by H NMR.
Periodate Oxidation of Hemiacetal 11. Ϫ Monobenzoylated
Cyclopentanoid Synthon 14: Hemiacetal 11 (252 mg, 0.875 mmol)
in warm (55°C) acetone (20 ml) was treated with NaIO4 (206 mg,
0.962 mmol) in H2O (10 ml). The mixture was stirred at 55°C for
1 h. Ethylene glycol (10 µl) was added, and the acetone was evapo-
rated. The remaining aq. solution was diluted with brine (30 ml)
and extracted with EtOAc (3 ϫ 50 ml). The combined organic lay-
ers were dried (Na2SO4) and concentrated to yield the crude ketone
12 as a syrup (240 mg, 95% yield, purity > 95%). Ϫ 1H NMR (250
MHz, CDCl3): δ ϭ 1.60 (s, 3 H, 10-H), 2.79 (m, 1 H, 9-H), 3.90
(dd, J ϭ 1.5, 0.5 Hz, 1 H, 7-H), 4.42 (ddd, J ϭ 12, 3.5, 1 Hz, 1 H,
1a-H), 4.49 (ddd, J ϭ 12, 3.5, 1 Hz, 1 H, 1b-H), 5.81 (dd, J ϭ 1.5,
1 Hz, 1 H, 6-H), 7.45 (br. t, J ϭ 8 Hz, 2 H, 3Ј-H/5Ј-H), 7.59 (br.
t, J ϭ 8 Hz, 1 H, 4Ј-H), 8.08 (br. s, 1 H, OCHO), 8.10 (br. d, J ϭ
8 Hz, 2 H, 2Ј-H/6Ј-H).
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Tetrabenzoate 10: M.p. 221Ϫ223°C, [α]D ϭ Ϫ80 (c ϭ 0.5,
1
CHCl3). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.51 (s, 3 H, 10-H),
2.53 (d, J ϭ 7.5 Hz, 1 H, 9-H), 3.57 (br. s, 1 H, 7-H), 3.63 (d, J ϭ
4.5 Hz, 1 H, 4Ј-OH), 3.88 (ddd, J ϭ 10, 4, 2.5 Hz, 1 H, 5Ј-H), 3.97
(dt, J ϭ 2 ϫ 9.5, 4.5 Hz, 1 H, 4ЈЈ-H), 4.73 (dd, J ϭ 12, 2.5 Hz, 1
H, 6aЈ-H), 4.82 (d, J ϭ 6 Hz, 1 H, 4-H), 4.83 (dd, J ϭ 12, 4 Hz, 1
H, 6bЈ-H), 5.14 (d, J ϭ 1.5 Hz, 1 H, 6-H), 5.22 (d, J ϭ 8 Hz, 1 H,
1Ј-H), 5.25 (d, J ϭ 7.5 H, 1 H, 1-H), 5.46 (dd, J ϭ 10, 8 Hz, 1 H,
2Ј-H), 5.57 (t, J ϭ 9.5 Hz, 1 H, 3Ј-H), 6.10 (d, J ϭ 6 Hz, 1 H, 3-
H), 7.35Ϫ7.63 (m, 12 H, 4 ϫ 3ЈЈ-H, 4 ϫ 4ЈЈ-H and 4 ϫ 5ЈЈ-H),
7.98 (br. d, J ϭ 8 Hz, 4 H, 2 ϫ 2ЈЈ-H and 2 ϫ 6ЈЈ-H), 8.09, 8.13
(2 br. d, J ϭ 8 Hz, each 2 H, 2 ϫ 2ЈЈ-H and 2 ϫ 6ЈЈ-H). Ϫ 13C
NMR: See Table 3. Ϫ C43H38O14 (778.8): calcd. C 66.32, H 4.92;
found C 66.03, H 4.75.
Without purification, the above ketone (240 mg, 0.84 mmol) and
boric acid (104 mg, 1.68 mmol) were dissolved in MeOH (15 ml).
At 0°C, sodium cyanotrihydridoborate (53 mg, 0.84 mmol) in
MeOH (2 ml) was added. The mixture was stirred at 0°C for 45
min, followed by 45 min while the temp. was allowed to rise to
20°C. Acetone (1 ml) was added followed, after 10 min, by HOAc
(0.2 ml). Upon concentration, the resulting residue was partitioned
between EtOAc (50 ml) and 5% aq. HOAc/brine (1:1, 40 ml). The
aq. layer was extracted with EtOAc (2 ϫ 40 ml). The organic layers
were separately washed with satd aq. NaHCO3/brine (1:1, 40 ml).
The combined EtOAc phases were dried (Na2SO4) and concen-
trated to yield a crude product (250 mg), which was purified on a
VLC column (4.5 ϫ 3 cm). Elution first with hexane and then
hexane/acetone (10:1 to 5:1) yielded first a 2:1 mixture of 5α- and
5β-alcohols 13 (174 mg, 0.60 mmol, 69% overall) and next a frac-
tion containing deformylated diols 14/15 (29 mg, 13%).
6,3Ј,6Ј-Tri-O-benzoylantirrhinoside: 1H NMR (500 MHz,
CDCl3): δ ϭ 1.48 (s, 3 H, 10-H), 2.51 (d, J ϭ 9 Hz, 1 H, 9-H),
3.55 (br. s, 1 H, 7-H), 3.73 (dd, J ϭ 9.5, 8 Hz, 1 H, 2Ј-H), 3.76
(ddd, J ϭ 9.5, 4.5, 2.5 Hz, 1 H, 5Ј-H), 3.80 (t, J ϭ 9.5 Hz, 1 H,
4Ј-H), 4.68 (dd, J ϭ 12, 2.5 Hz, 1 H, 6aЈ-H), 4.72 (dd, J ϭ 12, 4.5
Hz, 1 H, 6bЈ-H), 4.93 (d, J ϭ 8 Hz, 1 H, 1Ј-H), 4.98 (d, J ϭ 6 Hz,
1 H, 4-H), 5.12 (d, J ϭ 9 Hz, 1 H, 1-H), 5.17 (d, J ϭ 1 Hz, 1 H,
6-H), 5.28 (t, J ϭ 9.5 Hz, 1 H, 3Ј-H), 6.30 (d, J ϭ 6 Hz, 1 H, 3-
H), 7.40Ϫ7.46 (m, 6 H, 3 ϫ 3ЈЈ-H and 3 ϫ 5ЈЈ-H), 7.53Ϫ7.58 (m,
3 H, 3 ϫ 4ЈЈ-H), 8.03, 8.07, and 8.10 (3 br. d, J ϭ 8 Hz, each 2 H,
3 ϫ 2ЈЈ-H and 3 ϫ 6ЈЈ-H).
6,2Ј,6Ј-Tri-O-benzoylantirrhinoside: 1H NMR (500 MHz,
CDCl3): δ ϭ 1.47 (s, 3 H, 10-H), 2.48 (br. d, J ϭ 7.5 Hz, 1 H, 9-
H), 3.51 (br. s, 1 H, 7-H), 3.68 (m, 2 H, 4Ј-H and 5Ј-H), 3.86 (m,
1 H, 3Ј-H), 4.64 (br. d, J ϭ 12 Hz, 1 H, 6aЈ-H), 4.75 (dd, J ϭ 12,
2.5 Hz, 1 H, 6bЈ-H), 4.81 (d, J ϭ 6 Hz, 1 H, 4-H), 5.04 (d, J ϭ 7.5
Hz, 1 H, 1Ј-H), 5.07 (t, J ϭ 8 Hz, 1 H, 2Ј-H), 5.10 (d, J ϭ 1 Hz,
1 H, 6-H), 5.18 (d, J ϭ 7.5 Hz, 1 H, 1-H), 6.12 (d, J ϭ 6 Hz, 1 H,
3-H), 7.42, 7.43, and 7.46 (3 br. t, J ϭ 8 Hz, each 2 H, 3 ϫ 3ЈЈ-H
and 3 ϫ 5ЈЈ-H), 7.53Ϫ7.59 (m, 3 H, , 3 ϫ 4ЈЈ-H), 8.04, 8.05, and
8.10 (3 br. d, J ϭ 8 Hz, each 2 H, 3 ϫ 2ЈЈ-H and 3 ϫ 6ЈЈ-H).
The above fraction of 13 was solely characterized by 13C NMR
(Table 3.). It was dissolved in MeOH (7 ml), and NaBH4 (23 mg,
0.60 mmol) was added. After stirring at room temp. for 15 min,
HOAc (0.2 ml) was added. The reaction mixture was concentrated
twice with MeOH, followed by chromatography on an MPLC col-
umn (size C). Gradient elution with H2O (2:1 and 1.75:1) afforded
successively the 5β-benzoate 16 (15 mg, 9%), the 1,5β-diol 15 (21
mg, 13%), and then the 1,5α-diol 14 (98 mg, 61%); the former two
proved to undergo partial interconversion due to benzoyl migration
and were therefore characterized only by NMR.
Ozonolysis of Tetrabenzoate 10. Ϫ Hemiacetal 11: Tetrabenzoate
10 (6.20 g, 7.97 mmol) in CH2Cl2/MeOH (4:1, 75 ml) was treated
with ozone as above. After purging with nitrogen, EtOH (40 ml)
and NaBH4 (0.90 g, 23.8 mmol) were added. The mixture was kept
at Ϫ78°C with vigorous stirring for 1 h. Cooling was stopped, and
stirring of the mixture at room temp. was continued for an ad-
1,5Ͱ-Diol 14: [α]D23 ϭ Ϫ155 (c ϭ 1.1, acetone). Ϫ 1H NMR (500
ditional 1 h. Neutralization of the reaction mixture with HOAc (4 MHz, [D6]acetone): δ ϭ 1.49 (s, 3 H, 10-H), 2.36 (ddd, J ϭ 7, 2 ϫ
ml) was followed by concentration with MeOH (twice). The ob- 3.5 Hz, 1 H, 9-H), 3.53 (d, J ϭ 1.5 Hz, 1 H, 7-H), 3.62 (t, J ϭ 4.5
tained residue was partitioned between EtOAc (150 ml) and satd Hz, 1 H, 1-OH), 3.84 (dt, J ϭ 11, 2 ϫ 3.5 Hz, 1 H, 1a-H), 4.01
aq. NaHCO3/brine (1:1, 150 ml). The aq. layer was extracted (ddd, J ϭ 11, 4.5, 3.5 Hz, 1 H, 1b-H), 4.24Ϫ4.28 (m, 2 H, 5-H and
further with EtOAc (2 ϫ 150 ml). The combined organic layers 5-OH), 5.39 (dd, J ϭ 6, 1.5 Hz, 1 H, 6-H), 7.53 (br. t, J ϭ 8.5 Hz,
were dried (Na2SO4) and concentrated to give a crude product 2 H, 3Ј-H/5Ј-H), 7.65 (br. t, J ϭ 8.5 Hz, 1 H, 4Ј-H), 8.07 (br. d, J ϭ
(5.98 g), which was chromatographed by MPLC (column size D). 8.5 Hz, 2 H, 2Ј-H/6Ј-H). Ϫ 13C NMR: See Table 3. Ϫ C14H16O5 ·
Elution with H2O/MeOH (3:1 to 1:1) afforded crystalline hemiace-
1/4 H2O (268.8): calcd. C 62.56, H 6.19; found C 62.72, H 6.37.
Eur. J. Org. Chem. 1998, 365Ϫ370
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