Facile syntheses of (+)-gabosines A, D, and e

Article abstract of DOI:10.1039/b911810a

(+)-Gabosines A (12), D (4), and E (5), which share the same trihydroxycyclohexenone skeleton, were synthesized from enone 11 as the common intermediate. The key building block 11 was accessed by an intramolecular aldol cyclization of a diketone derived f

Full text of DOI:10.1039/b911810a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile syntheses of (+)-gabosines A, D, and E†‡
Tony K. M. Shing* and Hau M. Cheng
Received 17th June 2009, Accepted 16th September 2009
First published as an Advance Article on the web 16th October 2009
DOI: 10.1039/b911810a
(+)-Gabosines A (12), D (4), and E (5), which share the same trihydroxycyclohexenone skeleton, were
synthesized from enone 11 as the common intermediate. The key building block 11 was accessed by an
intramolecular aldol cyclization of a diketone derived from D-glucose (8).
Introduction
Gabosines belong to a family of multi-hydroxylated cyclo-
hexenones and hexanones that may be classified as pseudo-
or carba-sugars (Fig. 1).1 They have been shown to display
antibiotic,1b anticancer,2 and weak DNA binding properties.1c
A
total of 14 gabosines have been identified since the first isolation of
gabosine C (1) and its crotonyl ester COTC (2) from Streptomyces
strains in 1974.1a The structures and the absolute configurations
have been established for gabosines A–G, I, L, N, and O. Syntheses
of the gabosines have been achieved by the construction of the
carbocyclic framework from carbohydrates3–8 or by a Diels–Alder
reaction.9,10 Other syntheses employed starting materials with the
carbocyclic ring already present,11–16 e.g. (–)-quinic acid.
Construction of (–)-gabosine A (3) has been accomplished
by a chemoenzymatic synthesis from iodobenzene14 and an
enantiospecific synthesis from (–)-quinic acid.13 The most concise
route was conducted by R. Madsen et al. using a ring-closing olefin
metathesis as the key step from D-ribose with 13.9% overall yield
in 9 steps.7
(+)-Gabosine D (4) has been synthesized by T. Shinada et al.
from (–)-quinic acid in 11 steps with 13.3% overall yield.13
(+)-Gabosine E (5) has also been prepared from (–)-quinic acid13
and D-ribose via an intramolecular nitrile-oxide cycloaddition as
the key step.3 The former synthesis, which was also achieved by
T. Shinada et al., afforded (+)-gabosine E (5) in 11 steps with
11.7% overall yield.13
Fig. 1 The gabosine family.
Our previous endeavors have already furnished enantiospe-
cific syntheses of COTC (2) from (–)-quinic acid,11 as well as
(–)-gabosines G (6) and I (7) from d-D-gluconolactone via an
intramolecular Horner–Wadsworth–Emmons olefination.8 In this
paper, the enone 11, constructed from D-glucose (8) via an
intramolecular aldol cyclization of a diketone 9, was further
elaborated to other gabosines (Scheme 1).17,18
The present study was inspired by the structure/chirality
similarity between (+)-gabosines A (12), D (4) and E (5), all of
which share the same trihydroxycyclohexenone framework. We
Department of Chemistry and Center of Novel Functional Molecules, The
Chinese University of Hong Kong, Shatin NT, Hong Kong, China. E-mail:
tonyshing@cuhk.edu.hk; Fax: +852 2603 5057; Tel: +852 2609 6344
† This work was supported by a Strategic Investments Scheme admin-
istered by the Center of Novel Functional Molecules of The Chinese
University of Hong Kong.
Scheme 1 Preparation of enone 11 from D-glucose (8).17,18
‡ Electronic supplementary information (ESI) available: General experi-
1
mental; H, 13C and DEPT NMR spectra of 4, 5, 12–15 and 17–22. See
recognized that the advanced intermediate 11 was well suited for
their syntheses (Scheme 2).
DOI: 10.1039/b911810a
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Scheme 4 Synthesis of (+)-gabosine D (4). Reagents and conditions: i
AcCl, 2,4,6-collidine, CH2Cl2, -78 ◦C; ii PDC, 3A MS, CH2Cl2; iii TFA,
˚
H2O, CH2Cl2.
Scheme 2 Retrosynthetic analysis.
then underwent PDC oxidation to produce enone 20. Acid
hydrolysis of enone 20 then furnished (+)-gabosine D (4) without
incident. The number of steps and the overall yield for the synthesis
of (+)-gabosine D (4) from D-glucose (8) was 14 and 15.8%,
respectively. The physical constant (specific rotation) and the
spectral data (1H and 13C NMR) of synthetic (+)-gabosine D (4)
were consistent with those reported for the natural compound.1b
Scheme 5 shows the synthesis of (+)-gabosine E (5). Regios-
elective silylation of the primary alcohol in diol 15 gave disilyl
ether 21 which was oxidized with PDC to generate enone 22. Acid
hydrolysis of the enone 22 provided (+)-gabosine E (5) in 87%
yield. (+)-Gabosine E (5) was thus harvested from D-glucose (8) in
14 steps with 17.5% overall yield. The specific rotation and spectral
data (1H and 13C NMR) of synthetic 5 were in accord with those
reported previously.1b
Results and discussion
The synthesis of (+)-gabosine A (12) from enone 11 is shown
in Scheme 3. Diastereoselective 1,2-reduction of the enone
11 with K-selectride resulted in the exclusive production of
a-alcohol 13, which was protected with TBSCl and imidazole to
give silyl ether 14. The isopropylidene blocking group in 14 was
selectively removed with 80% aqueous acetic acid to afford diol 15.
Regioselective mesylation of the primary hydroxy group19 in diol
15 was realized with methanesulfonyl chloride and 2,4,6-collidine
at -78 ◦C to generate mesylate 16 which was displaced with Super
R
hydrideꢀ (LiEt3BH)20 to give alcohol 17 in 84% overall yield from
the diol 15. PDC oxidation of the alcohol 17 in CH2Cl2 afforded
enone 18 in a high yield. (+)-Gabosine A (12), produced after acid
hydrolysis of 18, was thus constructed from D-glucose (8) in 15
steps with 14.4% overall yield with the optical rotation, H and
13C NMR spectral data in accord with the literature values.1b
1
Scheme 5 Synthesis of (+)-gabosine E (5). Reagents and conditions: i
˚
TBSCl, imidazole, CH2Cl2; ii PDC, 3A MS, CH2Cl2; iii TFA, H2O, CH2Cl2.
Conclusions
Scheme 3 Synthesis of (+)-gabosine A (12). Reagents and conditions: i
K-selectride, THF, -78 ◦C; ii TBSCl, imidazole, DMF; iii 80% AcOH; iv
MsCl, 2,4,6-collidine, CH2Cl2, -78 ◦C; v LiEt3BH, THF, -78 ◦C; vi PDC,
In summary, the syntheses of (+)-gabosines A (12), D (4) and
E (5) have been accomplished from cheap starting material
D-glucose (8) in better overall yields than those reported previ-
ously. The common intermediate enone 11, readily available from
D-glucose (8), demonstrates the versatility of intramolecular direct
aldol cyclization of carbohydrates in the enantiospecific synthesis
of biologically interesting polyhydroxylated carbocyclic natural
˚
3A MS, CH2Cl2; vii TFA, H2O, CH2Cl2.
The synthesis of (+)-gabosine D (4) is shown in Scheme 4.
The primary alcohol in diol 15 was selectively masked by acetyl
◦
chloride and 2,4,6-collidine21 at -30 C to give acetate 19 which
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products. Application of this strategy to the construction of other
cyclohexa(e)noid natural products is in progress.
in THF (35 mL) at -78 ◦C was added 1M THF solution of
K-selectride (9 mL, 9 mmol) over 30 min and the mixture was
stirred for 12 h at room temperature. The reaction was quenched
with saturated NH4Cl solution (20 mL). The aqueous layer was
extracted with EtOAc (3 ¥ 30 mL). The combined organic extracts
were washed with brine (2 ¥ 10 mL), dried over MgSO4 and filtered.
Concentration of the filtrate followed by flash chromatography
(hexane:EtOAc, 1:1) gave a-alcohol 13 (2 g, 99%) as a colorless
Experimental
General experimental procedures are described in the ESI‡
(+)-Gabosine D (4)
20
oil; [a]D –118 (c 1.51 in CHCl3); Rf = 0.33 (hexane:EtOAc, 1:1);
To a solution of the enone 20 (54.2 mg, 0.122 mmol) in CH2Cl2
(3 mL) were added trifluoroacetic acid (TFA) (0.2 mL) and H2O
(0.05 mL) and the mixture was stirred at room temperature for
20 h. The solvent was removed under reduced pressure and flash
chromatography (CHCl3:MeOH, 20:1) of the residue afforded (+)-
v
max (film)/cm-1 3469, 2994, 2950, 1645, 1455, 1376, 1140 and 754;
d
H (300 MHz; CD3OD) 1.33 (6H, s, 2 ¥ Me), 1.38 (3H, s, Me), 1.49
(3H, s, Me), 3.27 (6H, s, 2 ¥ Me), 3.62 (1H, dd, J = 11.1, 4.2 Hz),
4.06 (1H, dd, J = 11.1, 8.1 Hz), 4.14–4.22 (2H, m), 4.38–4.43 (2H,
m), 5.59 (1H, d, J = 4.2 Hz); dC (75 MHz; CDCl3) 18.1 (CH3),
18.2 (CH3), 20.8 (CH3), 28.3 (CH3), 48.4 (CH3), 48.6 (CH3), 63.2
(CH2), 65.6 (CH), 67.2 (CH), 68.3 (CH), 70.3 (CH), 99.4 (C), 99.7
(C), 100.1 (C), 119.6 (CH), 136.8 (C); HRMS (ESI, [M+Na]+)
Found: 353.1579, Calcd for C16H26O7 353.1571; m/z (ESI): 353
([M+Na]+, 100%).
20
gabosine D (4) (23.4 mg, 89%) as a colorless oil; [a]D +71.2
(c 0.54 in MeOH) {lit.1b [a]D +86.2 (c 1.0 in MeOH)}; Rf 0.5
20
(tBuOH:AcOH:H2O 4:1:5, upper phase);1b dH (300 MHz; CD3OD)
2.06 (3H, s, Me), 3.78 (1H, dd, J = 9.6, 3.9 Hz), 4.32 (1H, d, J =
9.6 Hz), 4.48 (1H, t, J = 4.2 Hz), 4.73 (2H, d, J = 0.9 Hz), 6.91–
6.93 (1H, m); dC (75 MHz; CD3OD) 20.6 (CH3), 61.6 (CH2), 67.0
(CH), 73.8 (CH), 75.1 (CH), 135.1 (C), 144.8 (CH), 172.2 (C),
198.8 (C); HRMS (ESI, [M+Na]+) Found 239.0524, Calcd for
C9H12O6 239.0526; m/z (ESI): 239 ([M+Na]+, 100%).
(1S,2R,3S,4R)-1-O-tert-Butyldimethylsilyl-5-(hydroxymethyl)-
4,6-di-O-isopropylidene-2,3-[(2R,3R)-2,3-dimethoxybutan-2,3-di-
oxy]-5-cyclohexene-1,2,3,4-tetraol 14. A solution of the alcohol
13 (506 mg, 1.53 mmol), imidazole (312 mg, 4.58 mmol) and tert-
butyl dimethyl silyl chloride (TBSCl) (345 mg, 2.30 mmol) in dry
DMF (5 mL) was stirred at room temperature for 24 h. The mixture
was quenched with saturated NaHCO3 solution and the aqueous
phase was extracted with Et2O (3 ¥ 20 mL). The combined organic
extracts were washed with brine, dried over anhydrous MgSO4, and
filtered. The filtrate was concentrated under reduced pressure and
the residue was purified by flash chromatography (hexane:Et2O,
1:1) to afford silyl ether 14 (649 mg, 95%) as a white solid; mp
(+)-Gabosine E (5)
To a solution of the enone 22 (99.7 mg, 0.193 mmol) in CH2Cl2
(3 mL) were added trifluoroacetic acid (TFA) (1 mL) and H2O
(0.05 mL) and the mixture was stirred at room temperature for
19 h. The solvent was removed under reduced pressure and flash
chromatography (CHCl3:MeOH, 10:1) of the residue afforded
20
(+)-gabosine E (5) (29 mg, 87%) as a colorless oil; [a]D +136
(c 0.46 in MeOH) {lit.1b [a]D +148 (c 0.95 in MeOH)}; Rf 0.33
20
83–85 ◦C (from EtOAc); [a]D -46.9 (c 0.79 in CHCl3); Rf 0.5
20
(tBuOH:AcOH:H2O 4:1:5, upper phase);1b dH (300 MHz; CD3OD)
3.76 (1H, dd, J = 9.9, 3.9 Hz), 4.20 (1H, d, J = 15.9 Hz), 4.26 (1H,
d, J = 15.3 Hz), 4.34 (1H, d, J = 9.9 Hz), 4.81 (1H, t, J = 4.5 Hz),
6.91 (1H, dt, J = 5.4, 1.8 Hz); dC (75 MHz; CD3OD) 59.5 (CH2),
67.1 (CH), 73.9 (CH), 75.1 (CH), 139.9 (C), 141.8 (CH), 199.7
(C); HRMS (ESI, [M+Na]+) Found 197.0425, Calcd for C7H10O5
197.0420; m/z (ESI): 197 ([M+Na]+, 100%).
(hexane:Et2O, 1:1); vmax (film)/cm-1 2990, 2947, 1463, 1374, 1131
and 836; dH (300 MHz; CDCl3) 0.07 (3H, s, Me), 0.09 (3H, s, Me),
0.89 (9H, s, 3 ¥ Me), 1.28 (3H, s, Me), 1.30 (3H, s, Me), 1.40 (3H, s,
Me), 1.50 (3H, s, Me), 3.24 (6H, s, 2 ¥ Me), 3.48 (1H, dd, J = 10.8,
3.6 Hz), 4.06–4.14 (2H, m), 4.17 (1H, t, J = 4.2 Hz), 4.37–4.42
(2H, m), 5.44 (1H, d, J = 5.1 Hz); dC (75 MHz; CDCl3) -4.2
(CH3), -4.1 (CH3), 18.1 (CH3), 18.3 (CH3), 18.9 (C), 20.6 (CH3),
26.3 (CH3), 28.7 (CH3), 48.2 (CH3), 48.3 (CH3), 63.5 (CH2), 66.7
(CH), 67.4 (CH), 68.5 (CH), 71.0 (CH), 98.9 (C), 99.6 (C), 121.6
(CH), 133.9 (C); HRMS (ESI, [M+Na]+) Found 467.2440, Calcd
for C22H40O7Si1 467.2436; m/z (ESI): 467 ([M+Na]+, 100%).
(+)-Gabosine A (12)
To a solution of the enone 18 (36.2 mg, 0.0936 mmol) in CH2Cl2
(3 mL) were added trifluoroacetic acid (TFA) (0.2 mL) and H2O
(0.05 mL) and the mixture was stirred at room temperature for
48 h. The solvent was removed under reduced pressure and flash
chromatography (CHCl3:MeOH, 20:1) of the residue afforded
(1S,2R,3S,4R)-1-O-tert-Butyldimethylsilyl-5-(hydroxymethyl)-
2,3-[(2R,3R)-2,3-dimethoxybutan-2,3-dioxy]-5-cyclohexene-1,2,3,
4-tetraol 15. A solution of the silyl ether 14 (361 mg, 0.812 mmol)
in 80% aqueous AcOH (5 mL) was stirred at room temperature
for 1 h. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (hexane:EtOAc,
1:1) to afford diol 15 (289 mg, 88%) as a white solid; mp 123–
20
(+)-gabosine A (12) (13.3 mg, 90%) as a colorless oil; [a]D +146
(c 0.64 in MeOH) {lit.1b enantiomer of 12 had [a]D -132 (c 1.0
20
in MeOH)}; Rf 0.51 (tBuOH:AcOH:H2O 4:1:5, upper phase);1b
dH (300 MHz; CD3OD) 1.80 (3H, d, J = 0.9 Hz, Me), 3.72 (1H,
dd, J = 9.9, 3.9 Hz), 4.31 (1H, d, J = 9.9 Hz), 4.38 (1H, t, J =
4.8 Hz), 6.73–6.75 (1H, m); dC (75 MHz; CD3OD) 15.6 (CH3),
67.4 (CH), 73.9 (CH), 75.1 (CH), 136.9 (C), 143.0 (CH), 200.4
(C); HRMS (ESI, [M+Na]+) Found 181.0477, Calcd for C7H10O4
181.0471; m/z (ESI): 181 ([M+Na]+, 100%).
125 ◦C (from EtOAc); [a]D -37.2 (c 0.46 in CHCl3); Rf 0.28
20
(hexane:EtOAc, 1:1); vmax (film)/cm-1 3474, 2928, 2854, 1645, 1462,
1126 and 1037; dH (300 MHz; CDCl3) 0.07 (3H, s, Me), 0.10 (3H, s,
Me), 0.88 (9H, s, 3 ¥ Me), 1.28 (3H, s, Me), 1.31 (3H, s, Me, 2.33
(1H, brs), 2.75 (1H, brs), 3.24 (3H, s, Me), 3.26 (3H, s, Me), 3.43
(1H, dd, J = 11.1, 3.9 Hz), 4.06 (1H, dd, J = 11.1, 8.1 Hz), 4.18–
4.28 (3H, m), 4.34 (1H, d, J = 8.1 Hz), 5.70 (1H, d, J = 4.5 Hz);
dC (75 MHz; CDCl3) -4.2 (CH3), -4.1 (CH3), 18.1 (CH3), 18.3
(1S,2S,3S,4R)-2,3-[(2R,3R)-2,3-Dimethoxybutan-2,3-dioxy]-5-
(hydroxymethyl)-4,6-di-O-isopropylidene-5-cyclohexene-1,2,3,4-
tetraol 13. To a solution of the enone 11 (2.01 g, 6.12 mmol)
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(CH3), 18.8 (C), 26.3 (CH3), 48.2 (CH3), 48.4 (CH3), 64.7 (CH2),
66.5 (CH), 68.4 (CH), 69.8 (CH), 72.7 (CH), 99.1 (C), 99.6 (C),
125.3 (CH), 139.8 (C); HRMS (ESI, [M+Na]+) Found 427.2119,
Calcd for C19H36O7Si1 427.2123; m/z (ESI): 427 ([M+Na]+, 100%).
Found 409.2013, Calcd for C19H34O6Si1 409.2017; m/z (ESI): 409
([M+Na]+, 100%).
(1S,2R,3S,4R)-5-Acetoxymethyl-1-O-tert-butyldimethylsilyl-
2,3-[(2R,3R)-2,3-dimethoxybutan-2,3-dioxy]-5-cyclohexene-1,2,3,
4-tetraol 19. To a solution of the diol 15 (87.6 mg, 0.216 mmol)
and 2,4,6-collidine (0.086 mL, 0.649 mmol) in dry CH2Cl2
(3 mL) at -78 ◦C was added acetyl chloride (AcCl) (0.018 mL,
0.253 mmol) slowly. The reaction mixture was stirred for 18 h at
(1S,2R,3S,4R)-1-O-tert-Butyldimethylsilyl-2,3-[(2R,3R)-2,3-
dimethoxybutan-2,3-dioxy]-5-methyl-5-cyclohexene-1,2,3,4-tetraol
17. To a solution of the diol 15 (55.8 mg, 0.138 mmol) and
2,4,6-collidine (0.05 mL, 0.378 mmol) in dry CH2Cl2 (4 mL) at
-78 ◦C was added methanesulfonyl chloride (MsCl) (0.012 mL,
0.155 mmol) slowly. The resultant solution was allowed to warm
to 0 ◦C slowly. The reaction mixture was stirred for 6 h at 0 ◦C and
then quenched with saturated NaHCO3 solution. The aqueous
phase was extracted with EtOAc (3 ¥ 10 mL). The combined
organic extracts were washed with brine, dried over anhydrous
MgSO4, and filtered. The filtrate was concentrated under reduced
pressure to afford 16 as a colorless oil. To a solution of 16 in
THF (5 mL) was added a 1M THF solution of LiEt3BH (1.2 mL,
1.2 mmol) dropwise at -30 ◦C under N2. The reaction mixture was
stirred for 6 h at room temperature. Water was then added slowly
at 0 ◦C to destroy the excess of hydride and the aqueous phase was
extracted with EtOAc (2 ¥ 30 mL). The combined organic extracts
were dried over anhydrous MgSO4, and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified
by flash chromatography (hexane:Et2O, 3:1) to afford alkene 17
(45 mg, 84%) as a white solid; mp 91–92 ◦C (from EtOAc);
◦
-78 C and quenched with water (3 mL). The resultant solution
was allowed to warm to room temperature. The aqueous phase was
extracted with EtOAc (3 ¥ 10 mL). The combined organic extracts
were then washed with cold 1 N HCl (2 ¥ 5 mL), cold deionized
water (5 mL) and cold diluted NaHCO3 (5 mL). The organic layer
was washed with brine (2 ¥ 5 mL), dried (MgSO4), and filtered.
Concentration of the filtrate followed by flash chromatography
(hexane:Et2O, 1:1) gave acetate 19 (90.4 mg, 94%) as a colorless
20
oil; [a]D -44.2 (c 0.71 in CHCl3); Rf 0.66 (hexane:EtOAc, 1:1); vmax
(film)/cm-1 3486, 2948, 2892, 1742, 1130 and 835; dH (300 MHz;
CDCl3) 0.06 (3H, s, Me), 0.09 (3H, s, Me), 0.87 (9H, s, 3 ¥ Me),
1.28 (3H, s, Me), 1.31 (3H, s, Me), 2.06 (3H, s, Me), 2.76 (1H, brs),
3.24 (3H, s, Me), 3.26 (3H, s, Me), 3.46 (1H, dd, J = 10.8, 3.6 Hz),
4.06 (1H, dd, J = 10.8, 8.1 Hz), 4.17–4.20 (2H, m), 4.48 (1H, d,
J = 12.9 Hz), 4.90 (1H, d, J = 12.6 Hz), 5.77 (1H, d, J = 5.1 Hz);
dC (75 MHz; CDCl3) -4.3 (CH3), -4.2 (CH3), 18.1 (CH3), 18.3
(CH3), 18.8 (C), 21.4 (CH3), 26.2 (CH3), 48.1 (CH3), 48.4 (CH3),
64.6 (CH2), 66.3 (CH), 68.3 (CH), 69.7 (CH), 70.7 (CH), 99.1 (C),
99.6 (C), 127.9 (CH), 136.6 (C), 171.6 (C); HRMS (ESI, [M+Na]+)
Found 469.2230, Calcd for C21H38O8Si1 469.2228; m/z (ESI): 469
([M+Na]+, 100%).
20
[a]D -40.4 (c 0.6 in CHCl3); Rf 0.53 (hexane: EtOAc, 2:1); vmax
(film)/cm-1 3457, 2952, 2891, 1460, 1085 and 834; dH (300 MHz;
CDCl3) 0.06 (3H, s, Me), 0.08 (3H, s, Me), 0.88 (9H, s, 3 ¥ Me),
1.28 (3H, s, Me), 1.31 (3H, s, Me), 1.79 (3H, s, Me), 3.24 (3H, s,
Me), 3.25 (3H, s, Me), 3.43 (1H, dd, J = 10.2, 3.6 Hz), 3.97–4.07
(2H, m), 4.11 (1H, t, J = 4.8 Hz), 5.46 (1H, dt, J = 5.7, 1.5 Hz);
dC (75 MHz; CDCl3) -4.2 (CH3), -4.1 (CH3), 18.1 (CH3), 18.3
(CH3), 18.8 (C), 19.1 (CH3), 26.3 (CH3), 48.1 (CH3), 48.3 (CH3),
66.8 (CH), 68.6 (CH), 70.0 (CH), 73.6 (CH), 99.0 (C), 99.5 (C),
124.4 (C), 137.9 (CH); HRMS (ESI, [M+Na]+) Found 411.2177,
Calcd for C19H36O6Si1 411.2173; m/z (ESI): 411 ([M+Na]+, 100%).
(4S,5R,6R)-2-Acetoxymethyl-4-O-tert-butyldimethylsilyl-5,6-
[(2R,3R)-2,3-dimethoxybutan-2,3-dioxy]-2-cyclohexen-1-one 20.
˚
A mixture of 3A molecular sieves (ca. 121 mg) and pyridinium
dichromate (PDC) (93 mg, 0.247 mmol) was added to a solution
of the alcohol 19 (73.9 mg, 0.165 mmol) in dry CH2Cl2 (5 mL)
under N2 at 0 ◦C. The mixture was stirred for 24 h at room
temperature. The mixture was then filtered through a pad of celite
and the residue was washed with EtOAc until no product was
observed in the eluent (checked with TLC). Concentration of
the filtrate followed by flash chromatography (hexane:Et2O, 1:1)
(4S,5R,6R)-4-O-tert-Butyldimethylsilyl-5,6-[(2R,3R)-2,3-dime-
thoxybutan-2,3-dioxy]-2-methyl-2-cyclohexen-1-one 18. A mix-
˚
ture of 3A molecular sieves (ca. 82 mg) and pyridinium dichromate
20
yielded enone 20 (66.5 mg, 91%) as a colorless oil; [a]D -11.6 (c
(PDC) (72 mg, 0.191 mmol) was added to a solution of the alcohol
17 (50.1 mg, 0.129 mmol) in dry CH2Cl2 (3 mL) under N2 at 0 ◦C.
The mixture was stirred for 12 h at room temperature. The mixture
was then filtered through a pad of celite and the residue was
washed with EtOAc until no product was observed in the eluent
(checked with TLC). Concentration of the filtrate followed by flash
chromatography (hexane:Et2O, 5:1) yielded enone 18 (45.8 mg,
92%) as a white solid; mp 79–80 ◦C (from EtOAc); [a]D20 +11.2 (c
1.45 in CHCl3); Rf 0.24 (hexane:Et2O, 3:1); vmax (film)/cm-1 2952,
2933, 1703, 1462, 1381, 1131 and 980; dH (300 MHz; CDCl3) 0.10
(3H, s, Me), 0.14 (3H, s, Me), 0.89 (9H, s, 3 ¥ Me), 1.29 (3H, s,
Me), 1.36 (3H, s, Me), 1.80 (3H, d, J = 0.6 Hz, Me), 3.21 (3H, s,
Me), 3.24 (3H, s, Me), 3.82 (1H, dd, J = 10.8, 3.3 Hz), 4.35 (1H,
dd, J = 5.7, 3.3 Hz), 4.73 (1H, d, J = 11.1 Hz), 6.53 (1H, dd,
J = 6, 1.2 Hz); dC (75 MHz; CDCl3) -4.3 (CH3), -4.2 (CH3), 16.1
(CH3), 18.0 (CH3), 18.1 (CH3), 18.8 (C), 26.2 (CH3), 48.3 (CH3),
48.5 (CH3), 66.3 (CH), 69.2 (CH), 69.9 (CH), 99.6 (C), 100.1
(C), 136.6 (C), 140.3 (CH), 195.6 (C); HRMS (ESI, [M+Na]+)
0.51 in CHCl3); Rf 0.34 (hexane: Et2O, 1:1); vmax (film)/cm-1 2932,
2855, 1764, 1704, 1377, 1124 and 835; dH (300 MHz; CDCl3)
0.12 (3H, s, Me), 0.16 (3H, s, Me), 0.89 (9H, s, 3 ¥ Me), 1.30
(3H, s, Me), 1.37 (3H, s, Me), 2.08 (3H, s, Me), 3.22 (3H, s, Me),
3.26 (3H, s, Me), 3.86 (1H, dd, J = 11.1, 3.6 Hz), 4.44 (1H, dd,
J = 5.7, 3.6 Hz), 4.70–4.81 (3H, m), 6.74 (1H, d, J = 6 Hz);
dC (75 MHz; CDCl3) -4.3 (CH3), -4.2 (CH3), 17.9 (CH3), 18.0
(CH3), 18.8 (C), 21.3 (CH3), 26.2 (CH3), 48.4 (CH3), 48.6 (CH3),
61.0 (CH2), 65.9 (CH), 69.0 (CH), 69.8 (CH), 99.8 (C), 100.2
(C), 134.9 (C), 142.0 (CH), 170.9 (C), 193.9 (C); HRMS (ESI,
[M+Na]+) Found 467.2078, Calcd for C21H36O8Si1 467.2072; m/z
(ESI): 467 ([M+Na]+, 100%).
(1S,2R,3S,4R)-1-O-tert-Butyldimethylsilyl-5-(tert-butyldime-
thylsilyloxymethyl)-2,3-[(2R,3R)-2,3-dimethoxybutan-2,3-dioxy]-
5-cyclohexene-1,2,3,4-tetraol 21. A solution of the diol 15
(102 mg, 0.252 mmol), imidazole (51.2 mg, 0.752 mmol) and tert-
butyl dimethyl silyl chloride (TBSCl) (46.1 mg, 0.306 mmol) in
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dry CH2Cl2 (3 mL) was stirred at room temperature for 12 h. The
mixture was quenched with saturated NaHCO3 solution and the
aqueous phase was extracted with Et2O (3 ¥ 20 mL). The combined
organic extracts were washed with brine, dried over anhydrous
MgSO4, and filtered. The filtrate was concentrated under reduced
pressure and the residue was purified by flash chromatography
(hexane:Et2O, 4:1) to afford silyl ether 21 (127 mg, 97%) as a
Acknowledgements
This work was supported by a Strategic Investments Scheme
administrated by the Center of Novel Functional Molecules, The
Chinese University of Hong Kong.
Notes and references
20
colorless oil; [a]D -32.1 (c 0.53 in CHCl3); Rf 0.21 (hexane:Et2O,
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3:1); vmax (film)/cm-1 3474, 2951, 2933, 1464, 1130 and 840; dH
(300 MHz; CDCl3) 0.06 (3H, s, Me), 0.07 (3H, s, 2 ¥ Me), 0.09
(3H, s, Me), 0.88 (9H, s, 3 ¥ Me), 0.90 (9H, s, 3 ¥ Me), 1.28
(3H, s, Me), 1.32 (3H, s, Me), 2.67 (1H, brs), 3.24 (3H, s, Me),
3.26 (3H, s, Me), 3.45 (1H, dd, J = 11.1, 3.6 Hz), 4.07 (1H, dd,
J = 11.1, 8.1 Hz), 4.18 (1H, t, J = 4.2 Hz), 4.22–4.35 (3H, m),
5.69–5.72 (1H, m); dC (75 MHz; CDCl3) -4.9 (CH3), -4.3 (CH3),
-4.1 (CH3), 18.1 (CH3), 18.3 (CH3), 18.8 (C), 26.2 (CH3), 26.3
(CH3), 48.1 (CH3), 48.3 (CH3), 64.1 (CH2), 66.4 (CH), 68.5 (CH),
69.9 (CH), 71.9 (CH), 99.0 (C), 99.6 (C), 123.1 (CH), 140.5 (C);
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541.2987; m/z (ESI): 541 ([M+Na]+, 100%).
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20
yielded enone 22 (116 mg, 100%) as a colorless oil; [a]D +3.6 (c
0.89 in CHCl3); Rf 0.33 (hexane:Et2O, 3:1); vmax (film)/cm-1 2951,
2933, 1700, 1464, 1382, 1126 and 840; dH (300 MHz; CDCl3) 0.06
(3H, s, Me), 0.07 (3H, s, Me), 0.12 (3H, s, Me), 0.15 (3H, s, Me),
0.89 (9H, s, 3 ¥ Me), 0.90 (9H, s, 3 ¥ Me), 1.29 (3H, s, Me), 1.37
(3H, s, Me), 3.22 (3H, s, Me), 3.25 (3H, s, Me), 3.85 (1H, dd, J =
10.8, 3.3 Hz), 4.29 (1H, dd, J = 16.2, 1.8 Hz), 4.37–4.47 (2H,
m), 4.76 (1H, d, J = 10.8 Hz), 6.81 (1H, dt, J = 6, 2.1 Hz); dC
(75 MHz; CDCl3) -4.9 (CH3), -4.9 (CH3), -4.3 (CH3), -4.2 (CH3),
18.0 (CH3), 18.1 (CH3), 18.7 (C), 18.8 (C), 26.1 (CH3), 26.3 (CH3),
48.3 (CH3), 48.5 (CH3), 60.0 (CH2), 65.8 (CH), 69.3 (CH), 70.0
(CH), 99.7 (C), 100.2 (C), 138.7 (CH), 139.4 (C), 194.9 (C); HRMS
(ESI, [M+Na]+) Found 539.2835, Calcd for C25H48O7Si2 539.2831;
m/z (ESI): 539 ([M+Na]+, 100%).
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5102 | Org. Biomol. Chem., 2009, 7, 5098–5102
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©