Synthesis of the epimer of pericosine B from (-)-quinic acid

Article abstract of DOI:10.1248/cpb.52.1130

Synthesis of the epimer of pericosine B from (-)-quinic acid was achieved. This synthesis involves some regioselective and stereoselective processes. The desired product showed lower cytotoxic activity in comparison with natural pericosine B against the P

Full text of DOI:10.1248/cpb.52.1130

1130
Notes
Chem. Pharm. Bull. 52(9) 1130—1133 (2004)
Vol. 52, No. 9
Synthesis of the Epimer of Pericosine B from (ꢀ)-Quinic Acid
Yoshihide USAMI,* Chikage HATSUNO, Hiroe YAMAMOTO, Manabu TANABE, and Atsushi NUMATA
Osaka University of Pharmaceutical Sciences; 4–20–1, Nasahara, Takatsuki, Osaka 569–1094, Japan.
Received April 12, 2004; accepted May 27, 2004
Synthesis of the epimer of pericosine B from (ꢀ)-quinic acid was achieved. This synthesis involves some re-
gioselective and stereoselective processes. The desired product showed lower cytotoxic activity in comparison
with natural pericosine B against the P388 leukemia cell line. The result implies that the stereocenter of C-6 in
natural pericosine B plays an important role in this activity.
Key words epimer; pericosine B; selectivity; synthesis; cytotoxicity
Cyclohexanoids with multifunctional groups, called carba- secondary hydroxyl group of 4 was protected as tert-butyl-
sugars,1—4) have been reported to have various biological ac- dimethylsilyl ether (5) in 84% yield. When 5 was treated
tivities, such as antifungal, antibacterial, antiviral and anti- with POCl3, the desired a,b-unsaturated ester (6) was ob-
cancer activities. They are thus attractive synthetic targets for tained as a minor product (39% yield) with chloride (7: 54%
chemists.
yield). Treatment of 5 with SOCl2 led to a similar result.
In the course of our continuing study of new antitumor When Martin’s sulfrane dehydrating reagent9) (bis[a,a-
drug candidates, we isolated pericosin B (1), which has cyto- bis(trifluoromethyl)benzyloxy]diphenylsulfur) was applied to
toxic activity against P388 lymphocytic leukemia cells, as a the reaction, the desired 6 was obtained in 71% yield as the
metabolite of Periconia sp. originally separated from the sea sole product. Compound 6 was treated with a catalytic
hare.5) So far only the total synthesis of 1 has been reported amount of osmium tetroxide and trimethylamine N-oxide to
by Donohoe and coworkers.6) We have been interested in the give a mixture of diols (8: 30% and 9: 10%) with recovery of
synthesis of pericosins and related compounds7) because they 6 (33%) (Chart 1). The prolonged reaction time and the
are thought to be a class of carbasugars. In this paper we re- stereoselectivity7) of this dihydroxylation should be affected
port the stereoselective synthesis of the epimer of pericosine by the steric a-tert-butyldimethylsilyloxy group at C-3.
B (2) from commercially available (ꢀ)-quinic acid (3). The Changing the cooxidant to morpholin N-oxide10) gave a simi-
cytotoxic activity of 2 is also described (Fig. 1).
lar result. O-Methylation of major diol (8) occurred in a re-
gioselective manner to afford monomethylether (10) as a sin-
gle product. Cross peaks at H-6/H-4 and H-6/H-2b observed
Results and Disscusion
(ꢀ)-Quinic acid (3) was converted into methyl ester (4) in the NOESY spectra of 10 confirmed the stereochemistry,
according to the method reported in the literature.8) The C-3 and cross peaks at MeO/C-2 and H-2/MeO in the HMBC
spectra of 10 confirmed the position of the methylated hy-
droxyl group. In the case of O-methylation of minor diol (9),
bis methyl ether (11) and monomethyl ether (12) were ob-
tained in low yield. The structure of 12 was confirmed by
analysis of the 2D-NMR spectra.
Conversion of 10 into 2 is summarized in Chart 2. Methyl
ether (10) was treated with tetrabutylammonium fluoride to
Fig. 1.
Chart
1
* To whom correspondence should be addressed. e-mail: usami@gly.oups.ac.jp
© 2004 Pharmaceutical Society of Japan

September 2004
1131
Chart
2
400.2279; Found 400.2279.
afford alcohol (13) in quantitative yield, which was then oxi-
dized with Dess-Martin periodinane to give b-hydroxyketone
(14) quantitatively. Compound 14 was dehydrated with
(CF3CO)2O and pyridine to give an unstable enone (15),
Methyl (3R,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclohexylinene-
3,4,5-trihydroxy-1-cyclohexene-1-carboxylate 6; Methyl 3-O-tert-Butyl-
dimethylsilyl-4,5-O-cyclohexylidene-1-chloro-3,4,5-trihydroxycyclohexa-
necarboxylate 7 Dehydration with POCl3: Phosphoryl chloride (1 ml,
which was reduced with NaBH4 immediately to give allyl al- 4 mmol) and pyridine (2.5 ml) were dissolved in 20 ml of CH2Cl2. Methyl
cohol (16) stereoselectively.11) Compound 16 was depro-
tected with trifluoroacetic acid in methanol to give 2 in 68%
yield.
ester 5 (932.3 mg) in 10 ml of CH2Cl2 was added gradually to the solution at
ꢀ10 °C under an argon atmosphere. After stirring at room temperature for
3 h, the reaction mixture was treated with water carefully, then extracted
with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered,
The cytotoxic activity test of 2 against P388 lymphocytic
cells resulted in an ED50 value of 17.8 mg/ml, although the
value of natural pericosine B was 4.0 mg/ml. It is thus appar-
ent that the stereochemistry of C-6 in natural pericosine B
has an important role in its activity.
In conclusion, we achieved stereoselective synthesis of the
C-6 epimer of pericosine B (2) from (ꢀ)-quinic acid. The
lower cytotoxic activity against P388 cells of 2 than that of
natural pericosine B (1) indicates that the stereochemistry of
C-6 influences its activity.
and the solvent was removed under reduced pressure to afford a crude
residue that was further purified over silica gel column chromatography (elu-
ent, 1% MeOH–CH2Cl2) to give 6 (346.6 mg, 38.7%) and 7 (523.2 mg,
53.6%).
Dehydration with Martin’s Sulfrane: To a 10-ml CH2Cl2 solution of 5
(192.1 mg) Martin’s sulfrane (484.5 mg) in CH2Cl2 (10 ml) was added at
room temperature under an argon atmosphere. After stirring for 2 h, the re-
action mixture was treated with aqueous NaHCO3, then extracted with
CH2Cl2. The organic layer was separated, dried over MgSO4, filtered, and the
solvent was removed under reduced pressure to afford a crude residue that
was further purified over silica gel column chromatography (eluent, 1%
MeOH–CH2Cl2) to afford 6 (131.6 mg, 71.4%).
6: Oil; [a]D22 ꢀ28.0° (cꢁ0.856, CH3Cl); IR (liquid film) nmax 1724
1
(CꢁO), 1655 (CꢁC) cmꢀ1; H-NMR (CDCl3) d: 0.07 (3H, s, SiMe), 0.10
Experimental
IR spectra were obtained with Perkin Elmer FT-IR spectrometer 1720X.
EI-MS was determined using a Hitachi 4000H mass spectrometer. NMR
spectra were recorded at 27 °C on Varian UNITY INOVA-500, Gemini-
2000, and Murcury-300 spectrometers in CDCl3 with tetramethylsilane
(TMS) as an internal reference. Melting points were determined on a Yana-
gimoto micromelting point apparatus and are uncorrected. Liquid column
chromatography was conducted over silica gel (Nakalai Tesque, silica gel
60, mesh 70—230 or 230—400). Analytical TLC was performed on pre-
coated Merck aluminium sheets (DC-Alufolien Kieselgel 60 F254), and com-
pounds were viewed by spraying with an ethanol solution of phosphomolib-
dic acid, followed by heating. Dry THF was distilled over sodium-benzophe-
none ketyl under an argon atmosphere.
Methyl (1S,3R,4R,5R)-3-O-tert-Butyldimethylsilyl-4,5-O-cyclohexyli-
dene-1,3,4,5-tetrahydroxycyclohexanecarboxylate 5 To a CH2Cl2 solu-
tion (20 ml) of 4 (835.4 mg), TBDMSCl (552.0 mg), imidazole (415.3 mg),
and a catalytic amount of DMAP (50 mg) were added at room temperature.
After stirring overnight the reaction mixture was treated with saturated aque-
ous NaHCO3, then extracted with CH2Cl2. The organic layer was dried over
MgSO4, filtered, and the solvent was removed under reduced pressure to
give a crude residue, which was purified with silica gel column chromatog-
raphy (eluent, 1% MeOH–CH2Cl2) to afford 5 (1.02 g, 84%).
(3H, s, SiMe), 0.87 (9H, s, tBu), 1.3—1.7 (10H, m), 2.21 (1H, dd, Jꢁ16.5,
1.4 Hz, H-6A), 2.58 (1H, br d, Jꢁ16.5 Hz, H-6B), 3.77 (3H, s, COOMe), 4.06
(2H, m), 4.70 (1H, m), 6.87 (1H, m, H-2); 13C-NMR (CDCl3) d: ꢀ4.71 (q),
ꢀ4.59 (q), 18.11 (s), 23.90 (t), 24.14 (t), 25.15 (t), 25.81 (q), 29.59 (t), 35.51
(t), 37.83 (t), 52.01 (q), 68.86 (d), 71.89 (d), 76.46 (d), 109.94 (s), 128.97
(s), 134.71 (d), 166.90 (s); HR-MS Calcd for C20H34O5Si (Mꢂ), 382.2179;
Found, 382.2175.
7: Colorless crystals (CH2Cl2); mp 45—47 °C; [a]D22 ꢀ34.7° (cꢁ0.467,
1
CH3Cl); IR (KBr) nmax 1744 (CꢁO) cmꢀ1; H-NMR (CDCl3) d: 0.120 (3H,
s, SiMe), 0.123 (3H, s, SiMe), 0.91 (9H, s, tBu), 1.54 (10H, m), 1.90 (1H,
dd, Jꢁ14.0, 9.9 Hz), 2.29 (1H, dd, Jꢁ14.8, 3.6 Hz), 2.73 (1H, ddd, Jꢁ14.0,
4.4, 2.2 Hz), 3.11 (1H, dt, Jꢁ14.8, 2.5 Hz), 3.78 (3H, s, COOMe), 3.87 (1H,
t, Jꢁ5.8 Hz), 3.96 (1H, m), 4.29 (1H, m); 13C-NMR (CDCl3) d: ꢀ4.67 (q),
ꢀ4.52 (q), 18.06 (s), 23.74 (t), 24.03 (t), 25.09 (t), 25.86 (q), 34.84 (t), 37.15
(t), 37.56 (t), 41.96 (t), 52.96 (q), 62.63 (s), 70.69 (d), 72.91 (d), 78.92 (d),
109.47 (s), 170.38 (s); HR-MS Calcd for C20H35O5SiCl (Mꢂ), 418.1940;
Found, 418.1940.
Methyl
(1S,2R,3S,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclo-
hexylidene-1,2,3,4,5-pentahydroxycyclohexanecarboxylate 8; Methyl
(1R,2S,3S,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclohexylidene-
1,2,3,4,5-pentahydroxycyclohexanecarboxylate 9 Olefin (6: 799.6 mg)
was dissolved in 10 ml of solvent (tBuOH : pyridine : H2Oꢁ20 : 5 : 1). OsO4
(30 mg: catalytic amount) and trimethylamine N-oxide (333.0 mg) were
added to the solution at room temperature and then the reaction mixture was
refluxed for 6 h. After cooling, 30 ml of EtOAc and small amount of satu-
rated aqueous Na2S2O3 were added to the reaction mixture, which was ex-
tracted with EtOAc. The organic layer was dried over MgSO4, filtered, and
the solvent was removed under reduced pressure to give a crude residue,
which was purified with silica gel column chromatography (eluent, 2%
MeOH–CH2Cl2) to afford 8 (209.0 mg, 24.0%) and 9 (86.1 mg, 10.0%), with
5: Colorless crystals (CH2Cl2–MeOH); mp 45—47 °C; [a]D221 ꢀ46.8°
(cꢁ1.71, CH3Cl); IR (KBr) nmax 3468 (OH), 1731 (CꢁO) cmꢀ1; H-NMR
(CDCl3) d: 0.08 (3H, s, SiMe), 0.12 (3H, s, SiMe), 0.88 (9H, s, tBu), 1.83
(1H, dd, Jꢁ13.4, 10.6 Hz, H-2A), 2.00 (1H, dd, Jꢁ13.4, 4.9 Hz, H-2B), 2.25
(2H, m, H-6), 3.78 (3H, s, COOMe), 3.93 (1H, br t, Jꢁ6.2 Hz, H-5), 4.10
(1H, ddd, Jꢁ10.6, 6.2, 4.9 Hz, H-3), 4.45 (1H, m, H-4); 13C-NMR (CDCl3)
d: ꢀ4.25 (q), ꢀ3.92 (q), 18.08 (s), 24.07 (t), 24.41 (t), 25.41 (t), 26.14 (q),
34.58 (t), 35.26 (t), 38.38 (t), 40.94 (t), 52.96 (q), 69.81 (d), 73.56 (d), 74.29
(s), 79.97 (d), 109.34 (s), 174.02 (s); HR-MS Calcd for C20H36O6Si (Mꢂ),

1132
Vol. 52, No. 9
recovery of 6 (263.8 mg, 33.0%).
35.09 (t), 37.72 (t), 39.16 (t), 52.78 (q), 57.37 (q), 69.18 (d), 72.51 (d), 76.86
(s), 77.77 (d), 80.32 (d), 110.47 (s), 174.16 (s); HR-MS Calcd for
C21H38O7Si (Mꢂ), 430.2384; Found 430.2395.
8: Colorless crystals (CH2Cl2–MeOH); mp 85—88 °C; [a]D22 ꢂ118.2°
(cꢁ0.044, CH3Cl); IR (KBr) nmax 3530 (OH), 3430 (OH), 1736 (CꢁO)
cmꢀ1
;
1H-NMR (CDCl3) d: 0.13 (3H, s, SiMe), 0.14 (3H, s, SiMe), 0.91
Methyl (1S,2R,3S,4S,5R)-3,4-O-Cyclohexylidene-2-O-methyl-1,2,3,4,5-
(9H, s, tBu), 1.60—1.80 (10H, m), 1.95 (1H, dd, Jꢁ14.8, 6.0 Hz, H-6A), pentahydroxycyclohexanecarboxylate 13 To a THF solution (3 ml) of 10
2.30 (1H, dd, Jꢁ14.8, 4.1 Hz, H-6B), 3.81 (3H, s, COOMe), 3.88 (1H, d,
Jꢁ7.4 Hz, H-2), 4.17 (2H, m), 4.29 (2H, m); 13C-NMR (CDCl3) d: ꢀ4.92
(q), ꢀ4.85 (q), 18.05 (s), 23.73 (t), 24.08 (t), 25.09 (t), 25.77 (q), 35.12 (t),
(85.9 mg), tetrabutylammonium fluoride 1 M in THF (0.2 ml) was added at
room temperature and stirred 3 h. The reaction mixture was treated with sat-
urated aqueous NH4Cl and extracted with EtOAc. The organic layer was
36.55 (t), 37.81 (t), 52.99 (q), 69.05 (d), 74.59 (d), 77.06 (s), 77.47 (d), dried over MgSO4, filtered, and the solvent was removed under reduced pres-
78.26 (d), 110.25 (s), 173.56 (s); HR-MS Calcd for C20H36O7Si (Mꢂ),
sure to give a crude residue, which was purified with silica gel column chro-
416.2230; Found, 416.2234. Anal. Calcd for C20H36O7Si·1/4H2O: H, 8.74; matography (eluent, 2% MeOH–CH2Cl2) to afford 13 (63.0 mg, 100%).
C, 57.05. Found: H, 8.76; C, 57.05.
13: Oil; [a]D24 ꢂ78.1° (cꢁ0.548, CH3Cl); IR (liquid film) nmax 3476 (OH),
9: Colorless crystals (CH2Cl2–MeOH); mp 140—145 °C; [a]D22 ꢀ14.5° 1747 (CꢁO) cmꢀ1; 1H-NMR (CDCl3) d: 1.38—1.80 (10H, m), 2.03 (1H, dd,
(cꢁ0.704, CH3Cl); IR (KBr) nmax 3512 (OH), 3447 (OH), 1731 (CꢁO) Jꢁ14.8, 1.9 Hz, H-6A), 2.27 (1H, dd, Jꢁ14.8, 5.1 Hz, H-6B), 3.51 (3H, s,
cmꢀ1
;
1H-NMR (CDCl3) d: 0.06 (3H, s, SiMe), 0.10 (3H, s, SiMe), 0.87
OMe), 3.54 (1H, d, Jꢁ7.1 Hz, H-2), 3.64 (1H, br s, OH), 3.83 (3H, s,
COOMe), 3.87 (1H, d, Jꢁ10.2 Hz, OH), 4.20 (1H, m), 4.32 (1H, dd, Jꢁ7.4,
5.2 Hz), 4.36 (1H, m); 13C-NMR (CDCl3) d: 23.76 (t), 24.12 (t), 25.10 (t),
(9H, s, tBu), 1.32—1.75 (10H, m), 1.83 (1H, dd, Jꢁ14.0, 9.9 Hz, H-6A),
1.94 (1H, dd, Jꢁ14.0, 4.7 Hz, H-6B), 3.82 (3H, s, COOMe), 4.01 (2H, m),
4.21 (1H, d, Jꢁ4.7 Hz), 4.48 (1H, t, Jꢁ4.9 Hz); 13C-NMR (CDCl3) d: ꢀ4.53 34.43 (t), 35.57 (t), 38.31 (t), 53.20 (q), 59.82 (q), 67.26 (d), 78.50 (s), 78.84
(q), ꢀ4.50 (q), 18.02 (s), 23.65 (t), 24.11 (t), 25.13 (t), 25.85 (q), 35.26 (t),
(d), 82.91 (d), 109.68 (s), 173.80 (s); HR-MS Calcd for C15H24O7 (Mꢂ),
36.97 (t), 38.00 (t), 53.25 (q), 65.87 (d), 74.23 (d), 76.24 (d), 76.58 (s), 316.1520; Found 316.1527.
79.09 (d), 110.31 (s), 174.42 (s); HR-MS Calcd for C20H36O7Si (Mꢂ),
Methyl (1S,2R,3S,4R)-3,4-O-Cyclohexylidene-2-O-methyl-5-oxo-1,2,3,4-
416.2228; Found, 416.2235. Anal. Calcd for C20H36O7Si·1/4H2O: H, 8.74; tetrahydroxycyclohexanecarboxylate 14 To a suspension of Dess-Martin
C, 57.05. Found: H, 8.69; C, 57.12.
periodinane (182.8 mg) in 2 ml of CH2Cl2, 13 (64.2 mg) in 1 ml of CH2Cl2
Methyl (1S,2R,3S,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclohex was added at room temperature. After stirring overnight, the reaction mix-
ylidene-2-O-methyl-1,2,3,4,5-pentahydroxycyclohexanecarboxylate 10 ture was diluted with tbutyl methyl ether, then treated with aqueous Na2S2O3
To a suspension of NaH (30.8 mg, 60% oil dispersion) in 4 ml of dry THF,
160.0 mg of 8 in 1 ml of THF was added at 0 °C with stirring. After 30 min,
MeI (60 ml) was added to the reaction flask. Then the reaction mixture was
and aqueous NaHCO3. The organic layer was washed with brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure to
give a crude residue, which was purified with silica gel column chromatog-
stirred for 80 min, treated with saturated aqueous NaHCO3, and extracted raphy (eluent, 1% MeOH–CH2Cl2) to afford 14 (64.0 mg, 100%).
with CH2Cl2. The organic layer was dried over MgSO4, filtered, and the sol-
vent was removed under reduced pressure to give a crude residue, which was
purified with silica gel column chromatography (eluent, 1% MeOH–CH2Cl2) Jꢁ18.0 Hz, H-6A), 2.89 (1H, d, Jꢁ18.0 Hz, H-6B), 3.52 (3H, s, Me), 3.61
14: Oil [a]D24 ꢀ30.0° (cꢁ0.36, CH3Cl); IR (liquid film) nmax 3474 (OH),
1
1740 (CꢁO) cmꢀ1; H-NMR (CDCl3) d: 1.40—1.80 (10H, m), 2.61 (1H, d,
to give 10 (109.6 mg, 66%).
(1H, br s, OH), 3.69 (1H, d, Jꢁ5.5 Hz, H-2), 3.85 (3H, s, COOMe), 4.57
10: Oil; [a]D22 ꢂ85.0° (cꢁ0.753, CH3Cl); IR (liquid film) nmax 3503 (OH),
(1H, dd, Jꢁ7.7, 5.5 Hz, H-3), 4.75 (1H, d, Jꢁ7.7 Hz, H-4); 13C-NMR
1751 (CꢁO) cmꢀ1 1H-NMR (CDCl3) d: 0.11 (3H, s, SiMe), 0.13 (3H, s, (CDCl3) d: 23.84 (t), 24.03 (t), 25.02 (t), 34.90 (t), 37.04 (t), 45.74 (t), 53.45
;
SiMe), 0.90 (9H, s, tBu), 1.4—1.8 (10H, m), 1.84 (1H, dd, Jꢁ14.6, 7.7 Hz, (q), 58.56 (t), 77.11 (s), 77.71 (d), 78.63 (d), 83.22 (d), 111.79 (s), 172.32
H-6A), 2.29 (1H, dd, Jꢁ14.6, 4.4 Hz, H-6B), 3.51 (3H, s, OMe), 3.60 (1H, d, (s), 203.50 (s); HR-MS Calcd for C15H22O7 (Mꢂ), 314.1364; Found,
Jꢁ8.0 Hz, H-2), 3.81 (3H, s, COOMe), 3.92 (1H, s, –OH), 4.16 (2H, m),
4.33 (1H, dd, Jꢁ8.0, 5.9 Hz, H-3); 13C-NMR (CDCl3) d: ꢀ4.90 (q), ꢀ4.78
(q), 18.04 (s), 23.73 (t), 24.06 (t), 25.13 (t), 25.75 (q), 34.97 (t), 37.81 (t),
314.1363.
Methyl (4R,5R,6R)-4,5-O-Cyclohexylidene-6-O-methyl-3-oxo-1,2,3,4-
tetrahydroxy-1-cyclohex-1-enecarboxylate 15 To CH2Cl2 solution
a
37.95 (t), 52.77 (q), 59.7 (q), 69.02 (d), 76.97 (d), 78.69 (d), 82.79 (d), (2 ml) of 14 (64.0 mg), pyridine (0.25 ml) and (CF3CO)2O (0.1 ml) were
109.67 (s), 174.17 (s); HR-MS Calcd for C21H38O7Si (Mꢂ), 430.2384; added at ꢀ10 °C, and after stirring for 30 min the reaction mixture was
Found, 430.2391.
treated with saturated aqueous NaHCO3, then extracted with CH2Cl2. The
Methyl (1R,2S,3S,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclohex organic layer was dried over MgSO4, filtered, and the solvent was removed
ylidene-1,2-O-dimethyl-1,2,3,4,5-pentahydroxycyclohexanecarboxylate under reduced pressure to give a crude residue, which was purified with sil-
11; Methyl (1R,2S,3S,4R,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclo- ica gel column chromatography (eluent, 1% MeOH–CH2Cl2) to afford 15
hexylidene-2-O-methyl-1,2,3,4,5-pentahydroxycyclohexanecarboxylate (47.3 mg, 78%).
12 To a suspension of NaH (18.4 mg, 60% oil dispersion) in 4 ml of dry
THF, 95.4 mg of 9 in 1 ml of THF was added at 0 °C with stirring. After 30
min, MeI (400 ml: excess) was added to the reaction flask with stirring. After
15: Oil; [a]D22 ꢂ24.4° (cꢁ0.32, CH3Cl); IR (liquid film) nmax 1728
1
(CꢁO), 1694 (CꢁO), 1590 (CꢁC) cmꢀ1; H-NMR (CDCl3) d: 1.35—1.70
(10H, m), 3.53 (3H, s, OMe), 3.89 (3H, s, COOMe), 4.43 (1H, d, Jꢁ5.0 Hz,
2 d, the reaction mixture was treated with saturated aqueous NaHCO3, then H-6), 4.64 (1H, d, Jꢁ2.3 Hz, H-4), 4.67 (1H, d, Jꢁ5.0, 2.3 Hz, H-5), 6.83
extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, (1H, s, H-2); 13C-NMR (CDCl3) d: 23.67 (t), 23.77 (t), 24.85 (t), 35.19 (t),
and the solvent was removed under reduced pressure to give a crude residue
(75.1 mg), which was purified with column chromatography using ICN Alu-
37.07 (t), 52.94 (q), 58.95 (q), 71.47 (d), 73.73 (d), 74.64 (d), 111.20 (s),
132.68 (d), 143.49 (s), 165.89 (s), 196.48 (s); HR-MS Calcd for C15H20O6
mina B AktI as the stationary phase (eluent, 0.5% MeOH–CH2Cl2) to give (Mꢂ), 296.1259; Found 296.1258.
11 (20.8 mg, 20.4%) and 12 (15.3 mg, 15.5%).
11: Colorless crystals (CH2Cl2–MeOH); mp 66—68 °C; [a]D26 ꢀ5.7° hydroxy-1-cyclohex-1-enecarboxylate 16 To a suspension of NaBH4
(cꢁ2.43, CH3Cl); IR (KBr) nmax 1754 (CꢁO) cmꢀ1 1H-NMR (CDCl3) d: (4.7 mg, 0.12 mmol) in 7 ml of MeOH, 15 (36.8 mg) in 1 ml of MeOH was
0.06 (3H, s, SMe), 0.12 (3H, s, SMe), 0.88 (9H, s, tBu), 1.37—1.80 (11H, added dropwise at ꢀ10 °C. After stirring for 1 h, the reaction mixture was
Methyl (3S,4S,5R,6R)-4,5-O-Cyclohexylidene-6-O-methyl-3,4,5,6-tetra-
;
m), 2.02 (1H, dd, Jꢁ14.0, 4.6 Hz, H-6), 3.46 (3H, s, OMe), 3.49 (3H, s,
treated with saturated aqueous NH4Cl, then extracted with CH2Cl2. The or-
ganic layer was dried over MgSO4, filtered, and the solvent was removed
OMe), 3.79 (3H, s, COOMe), 3.94 (2H, m, H-2, H-4), 4.04 (1H, m, H-5),
4.59 (1H, dd, Jꢁ5.5, 4.3 Hz, H-3); 13C-NMR (CDCl3) d: ꢀ4.90 (q), ꢀ4.42 under reduced pressure to give a crude residue, which was purified with sil-
(q), 17.96 (s), 23.78 (t), 24.04 (t), 25.15 (t), 25.77 (q), 35.40 (t), 37.76 (t),
ica gel column chromatography (eluent, 1% MeOH–CH2Cl2) to afford 16
38.10 (t), 52.30 (q), 54.62 (q), 58.35 (q), 68.80 (d), 72.14 (d), 80.34 (d), (26.3 mg, 71%).
80.94 (d), 81.61 (s), 110.54 (s), 173.08 (s); HR-MS Calcd for C22H40O7Si
(Mꢂ), 444.2541; Found 444.2539.
16: Oil; [a]D22 ꢂ56.5° (cꢁ0.602, CH3Cl); IR (liquid film) nmax 3453 (OH),
1720 (CꢁO), 1648 (CꢁC) cmꢀ1 1H-NMR (CDCl3) d: 1.40—1.80 (10H,
;
12: Colorless crystals (CH2Cl2–MeOH); mp 66—70 °C; [a]D301 ꢂ67.0° m), 3.21 (3H, s, OMe), 3.72 (3H, s, COOMe), 4.40 (2H, m), 4.53 (1H, dd,
(cꢁ1.06, CH3Cl); IR (KBr) nmax 3523 (OH), 1724 (CꢁO) cmꢀ1; H-NMR Jꢁ7.1, 2.5 Hz), 4.56 (1H, m), 7.04 (1H, d, Jꢁ1.6 Hz, H-2); 13C-NMR
(CDCl3) d: 0.06 (3H, s, SMe), 0.10 (3H, s, SMe), 0.88 (9H, s, tBu), 1.35— (CDCl3) d: 23.64 (t), 23.98 (t), 25.18 (t), 29.78 (t), 33.98 (t), 35.76 (t), 52.11
1.80 (10H, m), 1.79 (1H, dd, Jꢁ14.0, 10.8 Hz, H-6A), 2.01 (1H, dd, Jꢁ14.0, (q), 57.02 (q), 66.85 (d), 71.95 (d), 74.78 (d), 75.07 (d), 77.00 (s), 109.81
4.8 Hz, H-6B), 3.47 (3H, s, OMe), 3.80 (3H, s, COOMe), 3.94 (1H, d, (s), 129.89 (s), 148.03 (d), 165.80 (s); HR-MS Calcd for C15H22O6 (Mꢂ),
Jꢁ4.3 Hz, H-2), 3.99 (1H, dd, Jꢁ6.6, 5.5 Hz, H-4), 4.08 (1H, ddd, Jꢁ10.8, 298.1415; Found 298.1406.
6.6, 4.8 Hz, H-5), 4.63 (1H, dd, Jꢁ5.5, 4.3 Hz, H-3); 13C-NMR (CDCl3)
d: ꢀ4.89 (q), ꢀ4.53 (q), 17.93 (s), 23.68 (t), 23.97 (t), 25.03 (t), 25.62 (q),
Methyl (3S,4S,5R,6R)-6-O-Methyl-3,4,5,6-tetrahydroxy-1-cyclohex-1-
enecarboxylate 2 Compound 16 (12.5 mg) was dissolved in 1 ml of

September 2004
1133
MeOH, and then TFA (1 ml) was added with stirring at room temperature.
After 2 h, the solvent was removed from the reaction mixture under reduced
pressure to afford a residue, which was purified with silica gel column chro-
matography (eluent, 5% MeOH–CH2Cl2) to afford 2 (6.2 mg, 68.1%).
6) Donohoe T. J., Blades K., Helliwell M., Waring M. J., Newcombe N.
J., Tetrahedron Lett., 39, 8755—8758 (1998).
7) Usami Y., Numata A., Chem. Pharm. Bull., 52, 1125—1129 (2004).
8) Shing T. K. M., Tang Y., Tetrahedron, 46, 6575—6584 (1990).
9) Arhart R. J., Martin J. C., J. Am. Chem. Soc., 94, 5003—5010 (1972).
2: Oil; [a]D22 ꢂ35.1° (cꢁ0.285, EtOH); IR (liquid film) nmax 3338 (OH),
1
1733 (CꢁO), 1684 (CꢁC) cmꢀ1; H-NMR (acetone-d6) d: 3.49 (3H, s, 6- 10) Carballido M., Castedo L., Gonzalez C., Tetrahedron Lett., 42, 3973—
OMe), 3.77 (3H, s, COOMe), 3.94 (1H, br dd, Jꢁ3.7, 2.0 Hz, H-4), 3.98
(1H, dd, Jꢁ4.8, 2.0 Hz, H-5), 4.22 (1H, d, Jꢁ4.8 Hz, H-6), 4.31 (1H, br t,
Jꢁ3.7 Hz, H-3), 6.75 (1H, d, Jꢁ3.7 Hz, H-2); 13C-NMR (acetone-d6) d:
52.29 (q), 59.61 (q), 67.46 (d), 70.62 (d), 73.10 (d), 79.11 (d), 131.48 (s),
140.80 (d), 167.93 (s); HR-MS Calcd for C9H15O6 (MꢂHꢂ), 219.0867;
Found, 219.0863.
3976 (2001).
11) Formation of a mixture of acetonides (17, 18) from 2 confirmed the
stereochemistry of C-3 of 16. Cross peaks between one of the methyl
groups of acetonide and both H-3 and H-4 in the NOESY spectra of
17 also supported the stereochemistry.
Acknowledgments We are grateful to Mr. K. Minoura, Mrs. M. Fuji-
take, and Mrs. S. Okabe of this university for the NMR, MS measurement,
and elemental analyses, respectively. This work was supported in part by a
Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Data for Mixture of 17 and 18: IR (liquid film) nmax 3473 (OH), 1724
(CꢁO), 1651 (CꢁC) cmꢀ1; EI-MS m/z 258 (Mꢂ); 1H-NMR (CDCl3) d
17: 1.43 (3H, s, acetonide-Me), 1.50 (3H, s, acetonide-Me), 3.46 (3H,
s, OMe), 3.81 (3H, s, COOMe), 4.19 (1H, dd, Jꢁ4.3, 3.9 Hz, H-5),
4.53 (1H, d, Jꢁ4.3 Hz, H-6), 4.53 (1H, dd, Jꢁ7.1, 3.9 Hz, H-4), 4.72
(1H, dd, Jꢁ7.1, 3.0 Hz, H-3), 7.07 (1H, d, Jꢁ3.0 Hz, H-2); 18: 1.29
(3H, s, acetonide-Me), 1.40 (3H, s, acetonide-Me), 3.29 (3H, s, OMe),
3.80 (3H, s, COOMe), 4.47 (1H, dd, Jꢁ3.4, 2.5 Hz, H-6), 4.50 (1H,
dd, Jꢁ4.6, 1.6 Hz, H-3), 4.61 (1H, dd, Jꢁ7.1, 2.5 Hz, H-5), 4.66 (1H,
ddd, Jꢁ7.1, 4.6, 1.6 Hz, H-4), 7.13 (1H, dt, Jꢁ3.4, 1.6 Hz, H-2).
References and Notes
1) For a review: Suami T., Pure Appl. Chem., 59, 1509—1520 (1987).
2) For a review: Suami T., Ogawa S., Adv. Carbohydr. Chem. Biochem.,
48, 21—90 (1990).
3) For a review: Suami T., Topics Curr. Chem., 154, 257—283 (1990).
4) For a review: Berecibar A., Grandjean C., Sinwardena A., Chem. Rev.,
99, 779—844 (1999).
5) Numata A., Iritani M., Yamada T., Minoura K., Matsumura E., Yamori
T., Tsuruo T., Tetrahedron Lett., 38, 8215—8218 (1997).