Synthesis of polyhydroxycyclohexanes and relatives from (-)-quinic acid

Article abstract of DOI:10.1021/jo026692m

An efficient and versatile strategy for the synthesis of polyhydroxycyclohexanes and related compounds 3-6 is reported. The successful synthesis of these analogues has been achieved from a common intermediate, quinic acid derived lactone 2, rapidly access

Full text of DOI:10.1021/jo026692m

Syn th esis of P olyh yd r oxycycloh exa n es a n d Rela tives fr om
(-)-Qu in ic Acid †
Concepcio´n Gonza´lez,* Montserrat Carballido, and Luis Castedo
Departamento de Quı´mica Orga´nica y Unidad Asociada al C.S.I.C., Facultad de Qu´ımica,
Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
cgb1@lugo.usc.es
Received November 12, 2002
An efficient and versatile strategy for the synthesis of polyhydroxycyclohexanes and related
compounds 3-6 is reported. The successful synthesis of these analogues has been achieved from a
common intermediate, quinic acid derived lactone 2, rapidly accessible from cheap and commercially
available (-)-quinic acid (1) as a chiral template. A practical route involving stereocontrolled epoxide
formation and hydrolysis has been developed for the synthesis of 2,3-trans analogues 3 and 4. The
preparation of the 2,3-cis analogues 5 and 6 has been realized by diasteroselective oxidation of a
5,6-double bond.
SCHEME 1
In tr od u ction
Structural entities having polyhydroxylated cyclohex-
anoid cores are found in many biologically important
molecules and natural products.1 This fact has aroused
widespread synthetic interest because of the diverse
biological activity exhibited by them ranging from gly-
cosidase inhibition to mediation of cellular communita-
tion.2 In addition, these compounds may have therapeutic
application for the treatment of, among others, viral
infections, HIV, cancer, and hyperglycemias and disor-
ders related to these conditions, such as obesity and
diabetes mellitus.3 Carba-sugars (or pseudo-sugars) are
an important type of polyhydroxylated cyclohexanoids
that have been proved to be potent glycomimics. Carba-
sugars are carbocyclic analogues of naturally occurring
carbohydrates.4 As a consequence of this substitution,
† In memory of the late Prof. Antonio Gonza´lez, a great organic
chemist pioneer in Spain.
* Corresponding author. Fax: +34 981 595012.
(1) (a) Ogawa, S. In Carbohydrates in Drug Design; Witczak, Z. J .,
Nieforth, K. A., Eds.; Dekker: New York, 1997; p 433. (b) Carbohydrate
Mimics: Concepts and Methods; Chapteur, Y., Ed.; Wiley-VCH: Wein-
heim, 1998.
(2) (a) Lillelund, V. H.; J ensen, H. H.; Liang, X. F.; Bols, M. Chem.
Rev. 2002, 102, 515. (b) Potter, B. V. L.; Lampe, D. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1933. (c) Suami, T. Pure Appl. Chem. 1987,
59, 1509. (d) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem.
1990, 48, 21. (e) Suami, T. Top. Curr. Chem. 1990, 154, 257. (f) Ferrier,
R. J .; Middleton, S. Chem Rev. 1993, 93, 2779. (g) Mart´ınez-Grau, A.;
Marco-Contelles, J . Chem. Soc. Rev. 1998, 27, 155. (h) Fleet, G. W. J .;
Fellows, L. E. In Natural Products Isolation; Wagman, G. H., Cooper,
R., Eds.; Elsevier: Amsterdam, 1988, p 540.
(3) (a) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K.
Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1752. (b) Fleet, G. W. J .; Karpas,
A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.; Namgoong,
S. K.; Ramsden, N. G.; Smith, P. W.; Son, J . C.; Wilson, F.; Witty, D.
R:; J acob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128. (c)
Montefoiori, D. C.; Robinson, W. E.; Mitchell, W. M. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9248. (d) Truscheit, E.; Frommer, W.; J unge, B.;
Mu¨ller, L.; Schmidt, D. D.; Wingender, W. Angew. Chem., Int. Ed. Engl.
1992, 31, 288. (e) Arends, J .; Willims, B. H. L. Horm. Metab. Res. 1986,
18, 761.
carba-sugars are hydrolytically stable analogues of their
parent sugars toward degradation of glycosidases.
As part of our ongoing research directed toward the
synthesis of structurally diverse carba-sugar entities, we
became interested in the synthesis of a variety of poly-
hydroxylated analogues. Herein, we disclose the synthe-
sis of four carba-sugars, 3a , 4a , 5a , and 6a , as well as
their corresponding acids, 3b, 4b, 5b, and 6b (Scheme
1). Our approach involves modification of a common key
intermediate, the 5-cyclohexene derivative 2, to access a
wide range of polyhydroxylated derivatives. This inter-
mediate can be obtained in three steps from (-)-quinic
(4) Berecibar, A.; Grandjean, C.; Sinwardena, A. Chem. Rev. 1999,
99, 779.
10.1021/jo026692m CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003
2248
J . Org. Chem. 2003, 68, 2248-2255

Synthesis of Polyhydroxycyclohexanes
SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (i) ref 6; (ii) K2CO3, MeOH, 60 °C
[7 (65%) and 8 (17%)] or rt [7 (39%) and 8 (55%)]; (iii) KCN, MeOH,
rt [7 (8%) and 8 (89%)]; (iv) NaH, THF, 0 °C (83%).
acid (1). The rich functionality present in (-)-quinic acid,
as well as its relatively low cost, make it an attractive
optically active precursor for the synthesis of substituted
cyclohexane skeletons.5
a
Reagents and conditions: (i) MCPBA, NaHCO3, DCM, ∆; (ii)
LiBH4, MeOH, THF, ∆; (iii) TFA (aq, 50%), 80 °C.
Com p ou n d s 3 and 4 with trans-hydroxyl groups in
positions 2 and 3 were synthesized by disateroselective
epoxidation of a double bond and subsequent hydrolysis.
The synthesis of compounds 5 and 6, which have cis-
hydroxyl groups in C2 and C3, was achieved by cis-
hydroxylation of the allyl alcohol derivative of 2.
confirmed by NOE experiments. Irradiation of H-4 led
to enhancement of the signal for H-3 (5%). The epoxida-
tion occurs from the less hindered face, opposite to the
lactone, also due to the orientating effect of the allylic
hydroxyl group.7
The desired polyhydroxycyclohexanes 3a and 4a were
obtained by a two-step reaction sequence. First, reduction
of the carbolactone 9 with lithium borohydride in metha-
nol afforded alcohol 10 in 88% yield, which underwent a
1,2-migration of the silyl group from the tertiary to the
primary hydroxyl group. This fact was confirmed by NOE
experiments. Irradiation of methyl groups led to enhance-
ment of the methylene group in C1 (2%). This migration
process was not surprinsing, since it is known that silyl
ethers with a cis vicinal hydroxyl group, specially under
basic conditions, can undergo migration to the most
stable compound.8 The reduction reaction was attempted
using other reducing agents such as sodium borohydride
and lithium aluminum hydride, but a lower yield or
decomposition was obtained. Finally, ring-opening hy-
drolysis of the epoxide 10 with concomitant deprotection
of the primary hydroxyl group was achieved by reflux in
aqueous trifluoroacetic acid to afford a chromatographi-
cally separable mixture of diastereoisomers 3a (42%) and
4a (58%). The hydrolysis reaction was also attempted
using Nafion-H, but lower yield and longer reaction times
were required.
Resu lts a n d Discu ssion
The strategy used for making compounds 3-6 involved
the initial preparation of the allyl alcohol 7 (Scheme 2).
This was made from benzoate 2, which was synthesized
in three steps from (-)-quinic acid (1) using previously
reported protocols.6 Treatment of benzoate 2 with potas-
sium carbonate in methanol afforded a chromatographi-
cally separable mixture of the hydroxycarbolactone 7 and
the methyl ester 8, which can be converted into 7 with
sodium hydride. The relative ratio of compounds 7 and
8 depends on the reaction temperature. At room temper-
ature the ratio 7:8 is approximately 1:1.4, but at 60 °C
the proportion of hydroxycarbolactone 7 increases to be
approximately a 3.8:1 mixture. The reaction can be also
carried out with potassium cyanide in methanol, and
under these conditions the relative ratio between com-
pounds 7:8 at room temperature is approximately 1:11.1.
Syn th esis of tr a n s-2,3-Dih yd r oxy An a logu es 3
a n d 4. The introduction of the trans-2,3-dihydroxy group
into the cyclohexane ring was achieved by a ring-opening
hydrolysis of an epoxide. The treatment of allylic alcohol
7 with m-chloroperbenzoic acid and sodium bicarbonate
afforded the epoxy alcohol 9 as the sole diastereoisomer
(Scheme 3). The sterochemistry of the epoxidation was
A similar strategy was used for making acids 3b and
4b. Whereas almost no diasteroselectivity was obtained
(7) (a) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis;
Morrison, J . D., Ed.; Academic Press: New York, 1985; Vol. 5, Chapter
8. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 116, 2483.
(8) Manthey, M. K.; Gonza´lez-Bello, C.; Abell, C. J . Chem. Soc.,
Perkin 1 1997, 625.
(5) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedon: Asymmetry 1997, 8, 3515.
(6) Bartlett, P. A.; Maitra, U.; Chouinard, P. M. J . Am. Chem. Soc.
1986, 108, 8068.
J . Org. Chem, Vol. 68, No. 6, 2003 2249

Gonza´lez et al.
SCHEME 4a
SCHEME 5a
a
Reagents and conditions: (i) TFA (aq, 50%), 80 °C; (ii) MeOH,
HCl(c) cat., ∆; (iii) (1) LiOH, rt, (2) Amberlite IR-120.
in the hydrolytic ring-opening step of epoxide 10 to
analogues 3a and 4a , the results proved to be completely
opposite when C1 has a carboxyl group. We have found
that treatment of epoxycarbolactone 9 with aqueous
trifluoroacetic acid at 80 °C afforded mainly acid 3b
(Scheme 4). Traces of acid 4b were only detected by NMR.
Although acid 3b can be directly obtained from epoxy-
decarbolactone 9, as was indicated above, product puri-
fication proved to be difficult, even by ion-exchange
chromatography. To avoid this problem, conversion of
crude acid 3b to the methyl ester 11 was achieved by
reflux in methanol in the presence of catalytic amount
of concentrated hydrochloric acid to afford a chromato-
graphically purifiable methyl ester 11 in 95% overall
yield from 9. The 1H NMR spectrum of 11 shows that
H-2 and H-3 are now at the axial position (J 2,3 ) 9.6 Hz,
J 3,4 ) 9.2 Hz). X-ray diffraction confirmed the structure
of methyl ester 11.9 Finally, basic hydrolysis, followed
by treatment with Amberlite IR-120 (H) ion-exchange
resin and lyophilization, gave the desired acid 3b in
excellent yield.
Having in mind the fact that hydrolysis of epoxycar-
bolatone 9 occurs diasteroselectively from the less hin-
dered side of the epoxide, C-3, to afford the 2R,3S isomer,
the opposite 2,3-epoxide would afford the desired 2S,3R
isomer. Indeed, treatment of epoxide 13 with aqueous
trifluoroacetic acid at 80 °C afforded exclusively carbo-
lactone 14 in excellent yield (Scheme 5). The sterochem-
istry of the ring-opening hydrolysis was confirmed by
NOE experiments. Irradiation of H-4 led to enhancement
of the signal for H-3 (9%). Irradiation of H-6axial led to
enhancement of the signal for H-2 (6%). The structure
of carbolactone 14 is also consistent with a diaxial
constant coupling between H-2 and H-3 (J 2,3 ) 8.8 Hz).
The synthesis of epoxide 13 was carried out by protection
of the trans-diol in 8 to give 1,2-dimethoxyacetal 12 in
88% yield, which then by treatment with MCPBA and
sodium bicarbonate in dichloromethane under reflux
afforded epoxide 13 in 66% yield (73% considering the
recovered starting material). This transformation was
particularly difficult due to the low reactivity of the
alkene. We found that in order to get successful results
it is crucial, first, to use fresh recrystallizated MCPBA
and, second, to add after 24 h more fresh MCPBA and
a
Reagents and conditions: (i) MeCOCOMe, CH(OMe)3, MeOH,
CSA cat., ∆; (ii) MCPBA, NaHCO3, DCM, ∆; (iii) TFA (aq, 50%),
80 °C; (iv) (1) LiOH, rt, (2) Amberlite IR-120.
sodium bicarbonate. The stereochemistry of the epoxide
13 was confirmed by NOE experiments. Irradiation of
H-5 led to enhancement of H-3 (1%), and irradiation of
H-2 led to enhacement of methyl groups in TBS group
in C1 (2%). Finally, treatment of carbolactone 14 with
lithium hydroxide, followed by ion exchange, gave the
desired acid 4b in excellent yield.
Syn th esis of cis-2,3-Dih yd r oxy An a logu es 5 a n d
6. The synthesis of analogues 5 and 6 was achieved by
cis-hydroxylation of the 5-cyclohexene derivative 7 using
catalytic osmium tetroxide (Scheme 6). Hydroxylation of
the allylic alcohol 7 gave a mixture of two hydroxylated
products, 15 and 16, resulting from reaction from the si
and re faces, respectively, as we have reported before.10
When the addition occurs from the re face, migration of
the carbolactone from the 1,5- to the 1,3-position was also
observed. Hydroxylated lactone 15 was the major dia-
stereoisomer in the OsO4/NMO oxidation. In contrast,
hydroxylated lactone 16 was the major diastereoisomer
in the OsO4/NaIO4 oxidation.
Osmylation of alkene 8 takes place diasteroselectively
on the olefin face opposite to the allylic oxygen, giving a
sole diastereoisomer 19 in high yield (Scheme 7).
The desired polyhydroxycyclohexane 5a was obtained
from lactone 15, by a two-step reaction sequence (Scheme
6). First, reduction of the carbolactone 15 with lithium
borohydride in methanol afforded alcohol 17 in 75% yield,
which by treatment with aqueous acetic acid at 40 °C
gave quantitatively polyhydroxycyclohexane 5a . Similar
strategy was used for the synthesis of acid 6a . Then, the
reduction of carbolactone 16 gave a mixture of difficult
to separate alcohols, the expected alcohols 18a and 18b,
resulting from the migration of the silyl group from the
tertiary to the primary hydroxyl group in C1. The relative
ratio of alcohols 18a and 18b depends on the reaction
(10) Carballido, M.; Castedo, L.; Gonza´lez, C. Tetrahedron Lett.
2001, 42, 3973.
(9) See Supporting Information.
2250 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Polyhydroxycyclohexanes
SCHEME 6a
a
Reagents and conditions: (i) OsO4 cat., NMO, dioxane-H2O, rt [15 (61%) and 16 (18%)]; (ii) OsO4 cat., NaIO4, dioxane-H2O, rt [15
(12%) and 16 (55%)]; (iii) LiBH4, MeOH, THF, ∆; (iv) AcOH (80%), 40 °C.
SCHEME 7
lactone 20 under basic conditions produced the derivative
6b in quantitative yield.
In conclusion, quinic acid derived lactone 2 can be used
as the starting point for the efficient synthesis of poly-
hydroxycyclohexanes and related compounds 3-6. Func-
tionalities at C1 and C4 positions have been successfully
utilized to control the facial selectivity in the formation
of diols and the epoxides as well as to direct the
regioselectivity in the opening epoxides.
SCHEME 8a
Exp er im en ta l Section
Gen er a l P r oced u r es. All organic solvents were purified
and freshly distilled prior to use according to the methods of
Armarego et al.12 FT-IR spectra were measured as NaCl plates,
Nujol mulls, or KBr disks. [R]D values are given in 10-1 deg
cm2 g-1 1H NMR spectra (250, 300, and 500 mHz) and 13C
.
NMR spectra (63, 75, and 500 MHz) were measured in
deuterated solvents. J values are given in hertz. NMR assign-
ments were made by a combination of 1 D, COSY, DEPT-135,
and NOE experiments. All procedures involving the use of ion-
exchange resins were carried out at room temperature and
used Mili-Q deionized water. Amberlite IR-120 (H) (cation
exchanger) was washed alternately with water, 10% HCl,
water, 10% sodium hydroxide, water, 10% HCl, and finally
water before use.
(1R,3R,4R)-1-(ter t-Bu tyld im eth ylsilyloxy)-4-h yd r oxy-
cycloh ex-5-en -1,3-car bolacton e (7) an d Meth yl (1R,3R,4R)-
1-(ter t-Bu tyld im eth ylsilyloxy)-3,4-d ih yd r oxycycloh ex-5-
en -1-ca r boxyla te (8). K2CO3/MeOH Meth od . A stirred
suspention of the benzoate 26 (2.12 g, 5.67 mmol) and anhy-
drous K2CO3 (118 mg, 0.85 mmol) in dry methanol (20 mL)
was heated at 60 °C for 1 h. The solvent was removed under
reduced pressure and the crude reaction was purified by flash
chromatography eluting with a gradient of diethyl ether-
hexane (50:50 to 100:0) to yield carbolactone 7 (988 mg, 65%)
and diol 8 (295 mg, 17%), both as white needles.
a
Reagents and conditions: (i) AcOH-THF-H2O (4:1:1), 40 °C;
(ii) (1) LiOH, rt, (2) Amberlite IR-120.
time. Longer reaction time favors the proportion of 18b.
Both silyl ethers 18a or 18b were deprotected individu-
ally or as mixture to the desired polyhydroxycyclohexane
6a in excellent yield.
Finally, the desired acids 5b and 6b were obtained
from lactones 15 and 16, respectively (Scheme 8). Treat-
ment of carbolactone 15 with aqueous acetic acid at 80
°C gave directly the acid 5b in 64% yield. The acid 5b
was purified by extraction into water and washing with
diethyl ether to remove impurities, followed by lyo-
philization. Under the same reaction conditions, lactone
16 afforded lactone 2011 in 91% yield. Hydrolysis of
KCN/MeOH Meth od . To a stirred suspention of the ben-
zoate 26 (2.30 g, 6.15 mmol) in dry methanol (65 mL) was
added potassium cyanide (439 mg, 6.76 mmol). The resultant
(11) Crystallographic data have been deposited in the Cambridge
Crystallographic Data Centre (CCDC no. 157890).
(12) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals; Butterworth Heinemann: Oxford, 1996.
J . Org. Chem, Vol. 68, No. 6, 2003 2251

Gonza´lez et al.
solution was stirred at room temperature for 1 h. Dichloro-
methane was added and then water. The organic layer was
separated and the aqueous layer was extracted twice with
dichloromethane. All the combined organic extracts were dried
(anhydrous Na2SO4), filtered, and evaporated. The obtained
residue was purified by flash chromatography eluting with a
gradient of diethyl ether-hexane (50:50 to 100:0) to yield
carbolactone 7 (140 mg, 8%) and diol 8 (1.65 g, 89%).
water (3 mL) were added. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (4 ×
3 mL). The combined organic extracts were dried (anhydrous
Na2SO4) and concentrated under reduced pressure. The crude
reaction was purified by flash cromatography eluting with
ethyl acetate to yield the triol 10 as white needles (125 mg,
1
88%): mp 102-104 °C; [R]20 -23° (c 1.6 in CHCl3); H NMR
D
(500 MHz, (CD3)3CO) δ (ppm) 4.35 (d, 1H, J 5.1), 3.97 (d, 1H,
J 4.5), 3.93 (s, 1H), 3.75 (m, 1H), 3.56 (d, 1H, J 9.7), 3.54 (m,
1H), 3.45 (d, 1H, J 9.7), 3.27 (dd, 1H, J 4.0 and 1.6), 3.08 (m,
1H), 1.59 (d, 1H, J 10.5), 1.57 (m, 1H), 0.85 (s, 9H), and 0.04
(s, 6H); 13C NMR (125 MHz, (CD3)3CO) δ (ppm) 75.2, 72.1, 70.4,
67.5, 59.9, 59.3, 41.7, 26.5, 19.1, -5.0, and -5.0; υmax (Nujol)/
cm-1 3540 (O-H) and 3389 (O-H); MS (CI) m/z (%) 273
(MH+ - H2O); HRMS calcd for C13H25O4Si, MH+, 273.1522;
found, MH+, 273.1520. Anal. Calcd for C13H26O5Si: C, 53.76;
H, 9.02. Found: C, 54.14; H, 9.31.
Data for carbolactone 7: mp 89-90 °C (hexane); [R]20
D
1
-170° (c 1.7 in CHCl3); H NMR (250 MHz, CDCl3) δ (ppm)
6.09 (d, 1H, J 9.7), 5.72 (ddd, 1H, J 9.7, 3.3 and 2.2), 4.61 (q,
1H, J 2.7), 4.25 (t, 1H, J 3.0), 2.76 (br. s, 1H), 2.40-2.31 (m,
2H), 0.91 (s, 9H), 0.16 (s, 3H), and 0.14 (s, 3H); 13C NMR (63
MHz, CDCl3) δ (ppm) 176.1, 138.1, 126.8, 76.1, 75.2, 64.9, 37.2,
25.6, 18.0, -3.0, and -3.1; υmax (NaCl)/cm-1 3430 (O-H) and
1760 (CdO); MS (FAB+) m/z (%) 271 (MH+); HRMS calcd for
C
13H23O4Si, MH+, 271.1366; found, MH+, 271.1365. Anal.
Calcd for C13H22O4Si: C, 57.75; H, 8.21. Found: C, 57.64; H,
8.16.
(1S,2S,3R,4S,5R)-1,2,3,4,5-P en t a h yd r oxy-1-h yd r oxy-
m eth ylcycloh exa n e (3a ) a n d (1S,2R,3S,4S,5R)-1,2,3,4,5-
P en ta h yd r oxy-1-h yd r oxym eth ylcycloh exa n e (4a ). A so-
lution of the epoxide 10 (57 mg, 0.20 mmol) in 2 mL of aqueous
TFA (50%) was stirred under reflux for 11 h. After cooling to
room temperature, the solvent was evaporated. The crude
reaction was purified by flash cromatography [eluent: (1) ethyl
acetate, (2) acetone-methanol-acetic acid (83:15:2)] to yield
16 mg of 3a (42%) and 22 mg of 4a (58%) both as colorless
Data for methyl ester 8: mp 50-51 °C (hexane); [R]20 -4°
D
1
(c 1.5 in CHCl3); H NMR (250 MHz, CDCl3) δ (ppm) 5.78 (d,
1H, J 14.8), 5.76 (d, 1H, J 14.8), 4.04 (m, 1H), 3.89 (m, 1H),
3.72 (s, 3H), 3.49 (d, 1H, J 4.9), 3.43 (d, 1H, J 3.8), 2.16 (ddd,
1H, J 11.9, 3.6 and 1.2), 1.95 (t, 1 H, J 12.5), 0.85 (s, 9H), 0.08
(s, 3H), and 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
174.0, 132.4, 128.7, 75.8, 73.4, 70.3, 52.4, 40.9, 25.7, 18.2, -2.9,
and -3.3; υmax (NaCl)/cm-1 3392 (O-H) and 1741 (CdO); MS
(CI) m/z (%) 287 (MH+); HRMS calcd for C13H23O5Si, MH+,
287.1315; found, MH+, 287.1316.
La cton iza tion of 8. To a stirred solution of the diol 8 (4.25
g, 14.07 mmol) in dry THF (50 mL) at 0 °C and under argon
was added sodium hydride (280 mg, 7.10 mmol, ca. 60% in
mineral oil). The resultant suspention was stirred for 15 min.
Diethyl ether and then water were added. The organic layer
was separated and the aqueous layer was extracted with
diethyl ether (3 × 30 mL). All combined organic layers were
dried (anhydrous Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by flash chromatog-
raphy eluting with 50% diethyl ether-hexane to afford car-
bolactone 7 (3.17 g, 83%).
oils.
1
Data for 3a : [R]20 -19° (c 1.2 in CH3OH); H NMR (500
D
MHz, CD3OD) δ (ppm) 3.79 (m, 1H), 3.61 (d, 1H, J 11.0), 3.58
(t, 1H, J 9.8 and 9.0), 3.44 (d, 1H, J 9.8), 3.40 (d, 1H, J 11.0),
3.19 (t, 1H, J 9.7 and 9.0), 1.94 (dd, 1H, J 13.8 and 5.1), and
1.57 (t, 1H, J 11.9 and 13.8); 13C NMR (125 MHz, CD3OD) δ
(ppm) 79.3, 75.6, 74.7, 74.6, 70.1, 67.5, and 38.6; υmax (Nujol)/
cm-1 3446 (O-H); MS (CI) m/z (%) 195 (MH+); HRMS calcd
for C7H15O6, MH+, 195.0869; found, MH+, 195.0875.
1
Data for 4a : [R]20 -41° (c 1.1 in CH3OH); H NMR (500
D
MHz, CD3OD) δ (ppm) 3.85 (m, 1H), 3.47 (d, 1H, J 11.0), 3.40
(dd, 1H, J 3.9 and 1.7), 3.66 (dd, 1H, J 8.2 and 1.7), 3.56 (d,
1H, J 11.0), 3.26 (dd, 1H, J 3.9 and 1.3), 1.68 (ddd, 1H, J 13.8,
4.2 and 1.3), and 1.61 (dd, 1H, J 13.8 and 11.6); 13C NMR (125
MHz, CD3OD) δ (ppm) 74.9, 72.2, 69.2, 67.7, 59.5, 59.4, and
41.5; υmax (Nujol)/cm-1 3420 (O-H); MS (CI) m/z (%) 195
(MH+); HRMS calcd for C7H15O6, MH+, 195.0869; found, MH+,
195.0865.
(1R,2S,3S,4S,5R)-1-(ter t-Bu tyld im eth ylsilyloxy)-2,3-ep -
oxy-4-h yd r oxycycloh exa n -1,5-ca r bola cton e (9). A stirred
suspention of the alkene 7 (50 mg, 0.19 mmol), sodium
bicarbonate (40 mg, 0.48 mmol), and m-chloroperbenzoic acid
(50 mg, 0.28 mmol) in dry dichloromethane (4 mL) and under
argon was heated under reflux for 24 h. The reaction mixture
was cooled to room temperature and diluted with diethyl ether
and water. The aqueous layer was separated and the organic
layer was washed with water (2 × 3 mL), saturated NaHCO3
(3 × 3 mL), and brine (2 × 3 mL). The organic extract was
dried (anhydrous Na2SO4) and concentrated under reduced
pressure. The crude reaction was purified by flash cromatog-
raphy eluting with 60% diethyl ether-hexane and recrystal-
lizalled from hexane to yield the epoxide 9 as white needles
Met h yl (1R,2S,3R,4S,5R)-1,2,3,4-Tet r a h yd r oxycyclo-
h exa n -1-ca r boxyla te (11). A stirred solution of the epoxide
9 (100 mg, 0.35 mmol) in 3.5 mL of aqueous TFA (50%) was
heated under reflux for 18 h. After cooling at room tempera-
ture, the solvent was evaporated. The obtained residue was
redisolved in 4 mL of dry methanol with a catalytic amount
of concentrated hydrochloric acid (2 drops). The resultant
mixture was heated under reflux for 6 h. After cooling at room
temperature, the solvent was removed at reduced pressure and
the residue was purified by flash cromatography eluting with
acetone-methanol-acetic acid (87:12:1) to yield methyl ester
(41 mg, 78%): mp 85-86 °C (hexane); [R]20 -92° (c 3.5 in
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ (ppm) 4.38 (dt, 1H,
J 6.4 and 2.9), 4.02 (br. t, 1H, J 2.9), 3.51 (dd, 1H, J 4.2 and
1.1), 3.40 (ddd, 1H, J 4.2, 2.1, and 0.5), 2.55 (d, 1H, J 11.8),
2.10 (d, 1H, J 11.8 and 6.4), 0.90 (s, 9H), 0.17 (s, 3H), and
0.16 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 174.0, 75.7,
75.0, 64.1, 57.7, 52.0, 32.2, 25.4, 17.8, and -3.3; υmax (KBr)/
cm-1 3432 (O-H) and 1767 (CdO); MS (FAB+) m/z (%) 287
(MH+); HRMS calcd for C13H23O5Si, MH+, 287.1315; found,
MH+, 287.1322. Anal. Calcd for C13H22O5Si: C, 54.52; H, 7.74.
Found: C, 54.13; H, 7.65.
11 (74 mg, 95%) as a colorless oil, which solidifies on stand-
1
ing: [R]20 -20° (c 1.2 in CH3OH); H NMR (250 MHz, CD3-
D
OD) δ (ppm) 3.81 (s, 3H), 3.79-3.72 (m, 1H), 3.72 (d, 1H,
J 9.6), 3.54 (t, 1H, J 9.6 and 9.2), 3.26 (t, 1H, J 9.2), 2.01 (dd,
1H, J 13.4 and 5.0), and 1.79 (dd, 1H, J 11.7 and 13.4); 13C
NMR (62.5 MHz, CD3OD) δ (ppm) 175.9, 79.1, 78.0, 76.6, 75.0,
70.0, 53.1, and 39.5; υmax (Nujol)/cm-1 3446 (O-H) and 1734
(CdO); MS (CI) m/z (%) 205 (MH+ - H2O); HRMS calcd for
C8H13O6, MH+, 205.0712; found, MH+, 205.0712.
(1R,2S,3R,4S,5R)-1,2,3,4-Tet r a h yd r oxycycloh exa n -1-
ca r boxylic Acid (3b). A solution of the methyl ester 11 (9
mg, 0.04 mmol) in aqueous lithium hydroxide (0.2 mL, 0.5M)
was stirred at room temperature for 1 h. The resultant solution
was washed with diethyl ether. The aqueous extract was
diluted with water and treated with Amberlite IR-120 until
pH 6. The resin was filtered and washed with water. The
filtrate was lyophilized to afford acid 3b (8 mg, 95%) as a
(1S,2S,3S,4S,5R)-2,3-E p oxy-1,4,5-t r ih yd r oxy-1-[(ter t-
bu t yld im et h ylsilyloxy)m et h yl]cycloh exa n e (10). To a
stirred solution of the lactone 9 (140 mg, 0.49 mmol), under
argon and at 0 °C, in 5 mL of a dry solution of methanol in
tetrahydrofuran (1/20 v/v), was added lithium borohydride (20
mg, 0.42 mmol). The reaction mixture was stirred at room
temperature for 20 min, and then ethyl acetate (1 mL) and
2252 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Polyhydroxycyclohexanes
1
colorless oil: [R]20 -25° (c 0.8 in H2O); H NMR (250 MHz,
1H, J 11.9), and 2.35 (dd, 1H, J 11.9 and 5.9); 13C NMR (62.5
MHz, CDCl3) δ (ppm) 177.5, 77.4, 76.8, 75.7, 73.9, 68.7, and
36.2; υmax (Nujol)/cm-1 3446 (O-H) and 1772 (CdO); MS (CI)
m/z (%) 191 (MH+); HRMS calcd for C7H11O6, MH+, 191.0556;
found, MH+, 191.0556.
D
D2O) δ (ppm) 3.90 (d, 1H, J 7.1), 3.86 (m, 1H), 3.70 (t, 1H,
J 6.9), 3.58 (t, 1H, J 6.8), 2.62 (dd, 1H, J 10.1 and 3.6), and
2.47 (t, 1H, J 9.3); 13C NMR (75 MHz, D2O) δ (ppm) 177.8,
77.1, 76.9, 74.8, 73.6, 68.8, and 37.9; υmax (NaCl)/cm-1 3432
(O-H) and 1728 (CdO); MS (CI) m/z (%) 209 (MH+); HRMS
calcd for C7H13O7, MH+, 209.0661; found, MH+, 209.0652.
(1R,2R,3S,4S,5R)-1,2,3,4-Tet r a h yd r oxycycloh exa n -1-
ca r boxyla te (4b). To a solution of the lactone 14 (22 mg, 0.12
mmol) in 1 mL of water was added aqueous lithium hydroxide
(0.6 mL, 0.5 M). The resultant solution was stirred at room
temperature for 1 h. Water was added and the solution was
treated with Amberlite IR-120 until pH 6. The resin was
filtered and washed with water. The filtrate was lyophilized
to afford acid 4b (25 mg, 99%) as a colorless oil: [R]20D +16° (c
Meth yl (1R,3S,4S,6R,9R)-9-(ter t-Bu tyldim eth ylsilyloxy)-
3,4-d im eth oxy-3,4-d im eth yl-2,5-d ioxa bicyclo[4.4.0]d ec-7-
en e-9-ca r boxyla te (12). A stirred solution of the diol 8 (1.65
g, 5.45 mmol), camphorsulfonic acid (63 mg, 0.27 mmol),
trimethyl orthoformate (3 mL, 27.27 mmol), and 2,3-butadione
(0.72 mL, 8.18 mmol) in dry methanol (50 mL) was heated
under reflux for 12 h. After cooling at room temperature,
powdered sodium bicarbonate was added and the solvent was
removed under reduced pressure. The crude product was
redisolved in a mixture of water and diethyl ether. The organic
layer was separated and the aqueous layer was extracted twice
with diethyl ether. All the combined organic extracts were
dried (anhydrous Na2SO4), filtered, and evaporated to give an
oil, which was purified by flash cromatography eluting with
diethyl ether-hexane (20:80) to yield diacetal 12 (2 g, 88%)
as a colorless oil, which solidifies on standing: mp 68-69 °C;
1
1.1 in H2O); H NMR (250 MHz, D2O) δ (ppm) 4.09 (dd, 1H,
J 5.4 and 2.3), 4.00-3.91 (m, 3H), and 2.61 (m, 2H); 13C NMR
(62.5 MHz, D2O) δ (ppm) 178.0, 77.8, 73.5, 72.5, 71.0, 67.4,
and 35.0; υmax (NaCl)/cm-1 3417 (O-H) and 1724 (CdO); MS
(CI) m/z (%) 191 (MH+ - H2O); HRMS calcd for C7H11O6, MH+,
191.0556; found, MH+, 195.0558.
Gen er a l P r oced u r e of Cis-Hyd r oxyla tion . To a stirred
solution of the alkene 7 (1 equiv) and the cooxidant (1.2 equiv)
in 1:1 dioxane-water at room temperature was added 0.15
equiv of a freshly made aqueous solution of osmium tetroxide
(0.12 M). After stirring for between 4 and 6 h, ethyl acetate
was added and then saturated Na2SO3. The reaction mixture
was stirred for 20 min. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate. All
combined organic layers were dried (anhydrous Na2SO4) and
concentrated in vacuo. The crude residue was crystallized and/
or purified by flash cromatography.
Meth od A. The reaction was carried out as described above
with alkene 7 (400 mg, 1.48 mmol), sodium periodate (380 mg,
1.78 mmol), osmium tetroxide (1.9 mL), and dioxane-water
(14 mL) and a reaction time of 6 h. The crude residue was
purified by crystallization from 25% ethyl acetate-hexane to
yield (1R,2R,3R,4S,5R)-1-(tert-butyldimethylsilyloxy)-2,4,5-tri-
hydroxycyclohexan-1,3-carbolactone (16) as white needles (203
mg, 45%). The mother waters were purified by flash cromatog-
raphy eluting with 60% dichloromethane-diethyl ether to
yield (1R,2S,3S,4S,5R)-1-(tert-butyldimethylsilyloxy)-2,3,4-tri-
hydroxycyclohexan-1,5-carbolactone (15) as white needles (52
mg, 12%).
Meth od B. The reaction was carried out as described above
with alkene 7 (1 g, 3.70 mmol), N-methylmorpholine oxide (560
mg, 4.81 mmol), osmium tetroxide (5.7 mL), and dioxane-
water (30 mL) and a reaction time of 4 h. The crude residue
was purified by crystallization from 25% ethyl acetate-hexane
to yield alcohol 16 (203 mg, 18%). The mother waters were
purified by flash cromatography eluting with 60% dichloro-
methane-diethyl ether to yield diol 15 (687 mg, 61%).
Data for 1,3-carbolactone 15: mp 176-178 °C (25% ethyl
acetate-hexane); [R]20D -329° (c 2.0 in CH3OH); 1H NMR (500
MHz, CD3OD) δ (ppm) 4.47 (d, 1H, J 4.5), 4.41 (s, 1H), 4.10
(dd, 1H, J 4.5 and 1.0), 3.98 (dd, 1H, J 5.0 and 1.0), 2.31 (dd,
1H, J 14.0 and 5.0), 2.10 (d, 1H, J 14.0), 0.96 (s, 9H), 0.18 (s,
3H), and 0.18 (s, 3H); 13C NMR (125 MHz, CD3OD) δ (ppm)
179.6, 84.8, 78.1, 76.1, 71.7, 71.5, 41.6, 26.3, 19.2, -4.4, and
-4.8; υmax (Nujol)/cm-1 3413 (O-H), 3282 (O-H), and 1775
(CdO); MS (CI) m/z (%) 305 (MH+); HRMS calcd for C13H25O6-
Si, MH+, 305.1420; found, MH+, 305.1414.
[R]20 +67° (c 1.8 in CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
(ppm) 5.80 (dd, 1H, J 10.0 and 1.5), 5.67 (ddd, 1H, J 10.0, 2.5
and 1.6), 4.16 (ddd, 1H, J 9.2, 1.6 and 2.5), 3.96 (ddd, 1H,
J 9.2, 2.9 and 4.2), 3.72 (s, 3H), 3.26 (s, 3H), 3.25 (s, 3H), 2.11
(d, 1H, J 13.0), 2.06 (ddd, 1H, J 13.0, 4.2 and 1.6), 1.33 (s,
3H), 1.31 (s, 3H), 0.87 (s, 9H), 0.09 (s, 3H), and 0.08 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 168.0, 130.2, 129.0, 100.4,
100.0, 76.4, 69.4, 65.7, 52.4, 47.9, 47.9, 38.3, 25.7, 18.3, 17.9,
-2.9, and -3.3; υmax (CHCl3)/cm-1 1735 (CdO); MS (ESI) m/z
(%) 439 (MNa+); HRMS calcd for C20H36O7SiNa, MNa+,
439.2122; found, MNa+, 439.2108.
Meth yl (1R,3S,4S,6R,7R,8R,9R)-9-(ter t-Bu tyld im eth yl-
silyloxy)-7,8-ep oxy-3,4-d im et h oxy-3,4-d im et h yl-2,5-d i-
oxa bicyclo[4.4.0]d eca n e-9-ca r boxyla te (13). To a stirred
solution of the alkene 12 (82 mg, 0.20 mmol) in dry dichloro-
methane (2 mL) were added sodium bicarbonate (42 mg, 0.50
mmol) and freshly recrystallized MCPBA (51 mg, 0.30 mmol).
The resultant solution was heated under reflux. After 24 h,
more sodium bicarbonate (42 mg, 0.50 mmol) and MCPBA (51
mg, 0.30 mmol) were added, and the reaction mixture was
heated under reflux for an additional 24 h. After cooling to
room temperature, saturated sodium bicarbonate was added
and the organic layer was separated. The organic extract was
washed twice with saturated sodium bicarbonate. The organic
extract was dried (anhydrous Na2SO4), filtered, and evaporated
to give a white solid, which was purified by flash cromatog-
raphy eluting with acetone-hexane (10:90) to yield 57 mg of
epoxide 13 (66%) as a colorless oil, which solidifies on standing,
and 10 mg of starting material (12%): mp 82-83 °C; [R]20
D
+89° (c 2.1 in CHCl3); 1H NMR (250 MHz, (CD3)2CO) δ (ppm)
3.85 (ddd, 1H, J 11.7, 10.0 and 4.1), 3.78 (s, 3H), 3.53 (dd, 1H,
J 0.6 and 10.0), 3.28 (dt, 1H, J 3.3 and 1.1), 3.25 (s, 3H), 3.20
(s, 3H), 3.15 (d, 1H, J 3.3), 1.76 (ddd, 1H, J 11.7, 1.1 and 4.1),
1.70 (d, 1H, J 11.7) 1.27 (s, 3H), 1.21 (s, 3H), 0.92 (s, 9H), and
0.14 (s, 6H); 13C NMR (63 MHz, CDCl3) δ (ppm) 171.6, 100.3,
99.9, 76.3, 69.0, 64.4, 56.5, 55.7, 52.4, 48.2, 48.0, 33.4, 25.6,
18.2, 17.7, 17.7, -3.4, and -3.9; υmax (CHCl3)/ cm-1 1745
(CdO); MS (CI) m/z (%) 433 (MH+); HRMS calcd for C20H37
-
Data for 1,5-carbolactone 16: mp 110-112 °C (hexane);
O8Si, MH+, 433.2258; found, MH+, 433.2276.
[R]20 +42° (c 1.25 in CH3OH); 1H NMR (500 MHz, CD3OD) δ
D
(ppm) 4.75 (t, 1H, J 6.0 and 5.0), 4.04 (t, 1H, J 5.0), 3.85 (dd,
1H, J 4.15 and 1.5), 3.61 (t, 1H, J 5 and 4.15), 3.04 (d, 1H,
J 11.7), 2.14 (ddd, 1H, J 11.7, 1.5, and 6.0), 0.95 (s, 9H), 0.21
(s, 3H), and 0.19 (s, 3H); 13C NMR (125 MHz, CD3OD) δ (ppm)
178.3, 80.0, 77.4, 74.9, 67.8, 67.7, 32.4, 26.2, 19.1, -3.0, and
-3.0; υmax (Nujol)/cm-1 3521 (O-H), 3390 (O-H), and 1779
(CdO); MS (CI) m/z (%) 305 (MH+); HRMS calcd for C13H25O6-
Si, MH+, 305.1420; found, MH+, 305.1411.
(1R,2R,3S,4S,5R)-1,2,3,4-Tetr a h yd r oxycycloh exa n -1,5-
ca r bola cton e (14). A stirred solution of the epoxide 13 (84
mg, 0.19 mmol) in 2 mL of aqueous TFA (50%) was stirred
under reflux for 6 h. After cooling at room temperature the
solvent was evaporated. The crude reaction was purified by
flash cromatography eluting with methanol-ethyl acetate (15:
85) to yield lactone 13 (36 mg, 99%) as colorless oil, which
1
solidifies on standing: [R]20 -2° (c 1.7 in CH3OH); H NMR
D
(250 MHz, CDCl3) δ (ppm) 4.70 (t, 1H, J 5.3), 4.16 (t, 1H,
J 4.7), 3.77 (d, 1H, J 8.8), 3.52 (dd, 1H, J 8.8 and 4.9), 2.51 (d,
Meth yl (1R,2R,3R,4S,5R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
2,3,4,5-tetr a h yd r oxycycloh exa n e-1-ca r boxyla te (19). The
J . Org. Chem, Vol. 68, No. 6, 2003 2253

Gonza´lez et al.
reaction was carried out as described above with alkene 8 (50
mg, 0.17 mmol), trimethylamine N-oxide (23 mg, 0.20 mmol),
osmium tetroxide (0.21 mL), and dioxane-water (2 mL) and
a reaction time of 20 h. The crude residue was purified by
recrystallization from dichloromethane to yield 38 mg of
methyl ester 19 as white prisms, and the mother waters were
purified by flash cromatography eluting with methanol-ethyl
acetate (5:95) to afford 13 mg of alcohol 19 (89%): mp 177-
178 °C (DCM); [R]20D +6° (c 1.9 in CH3OH);1H NMR (250 MHz,
CD3OD) δ 3.77 (dd, 1H, J 3.0 and 1.1), 3.53 (s, 3H), 3.52-3.42
(m, 2H), 3.32 (t, 1H, J 9.3), 1.97-1.80 (m, 2H), 0.71 (s, 9H),
-0.10 (s, 3H), and -0.13 (s, 3H); 13C NMR (63 MHz, CD3OD)
δ 173.8, 80.1, 76.2, 75.8, 72.8, 70.6, 52.5, 37.0, 26.3, 19.2, -3.2,
and -4.0; υmax (KBr)/cm-1 3377 (O-H) and 1738 (CdO); MS
(CI) m/z (%) 337 (MH+); HRMS calcd for C14H29O7Si, MH+,
337.1683; found, MH+, 337.1690.
1.3), 1.66 (dd, 1H, J 13.0 and 11.6), 0.96 (s, 9H), 0.21 (s, 3H)
and 0.19 (s, 3H); 13C NMR (125 MHz, CD3OD) δ (ppm) 79.4,
76.9, 74.6, 73.3, 71.0, 67.7, 37.2, 26.7, 19.5, -2.4, and -2.4;
υmax (NaCl)/cm-1 3417 and 3215; MS (CI) m/z (%) 309 (MH+);
HRMS calcd for C13H29O6Si, MH+, 309.1733; found, MH+,
309.1729; Anal. Calcd for C13H28O6Si: C, 50.62; H, 9.15.
Found: C, 50.95; H, 9.26.
Data for 18b: mp 133-134 °C; [R]20D +1° (c 1.2 in CH3OH);
1H NMR (500 MHz, CD3OD) δ (ppm) 3.79 (m, 3H), 3.74 (d,
1H, J 10.0), 3.59 (t, 1H, J 9.3 and 10.9), 3.55 (d, 1H, J 10.0),
1.80 (m, 1H), 1.65 (dd, 1H, J 13.1 and 11.8), 0.96 (s, 9H), and
0.08 (s, 6H); 13C NMR (125 MHz, CD3OD) δ (ppm) 77.0, 75.1,
73.9, 73.4, 70.8, 69.5, 36.2, 26.5, 19.3, -5.4, and -5.4; υmax
(NaCl)/cm-1 3417 and 3209; MS (CI) m/z (%) 309 (MH+);
HRMS calcd for C13H29O6Si, MH+, 309.1733; found, MH+,
309.1735
(1S,2S,3S,4S,5R)-1-(ter t-Bu tyld im eth ylsilyloxy)-2,3,4,5-
tetr a h yd r oxy-1-h yd r oxym eth ylcycloh exa n e (17). To a
stirred solution of the lactone 15 (100 mg, 0.33 mmol), under
argon and at 0 °C, in 4.2 mL of a dry solution of methanol in
tetrahydrofuran (1/20 v/v), was added lithium borohydride (22
mg, 1.01 mmol). The resultant reaction mixture was refluxed
for 10 h. After cooling to room temperature, ethyl acetate (1
mL) and then water (3 mL) were added. The solvent was
evaporated and the crude reaction was purified by flash
cromatography [eluent: (1) ethyl acetate, (2) methanol-ethyl
acetate-acetic acid (14:85:1)] to yield the alcohol 17 as white
(1S,2R,3R,4S,5R)-1,2,3,4,5-P en t a h yd r oxy-1-h yd r oxy-
m eth ylcycloh exa n e (6a ). A stirred solution of the silyl
ethers 18a and 18b (14 mg, 0.05 mmol) in 0.5 mL of aqueous
acetic acid (80%) was heated at 40 °C for 17 h. The crude
mixture was diluted with water and diethyl ether. The organic
layer was separated and the aqueous layer was washed with
diethyl ether (2 × 2 mL). The aqueous extract was freeze-dried
to afford polyhydroxycyclohexane 6a as colorless oil (8 mg,
1
91%): [R]20 -2° (c 0.7 in CH3OH); H NMR (500 MHz, CH3-
D
OD) δ (ppm) 3.76 (m, 3H), 3.64 (s, 2H), 3.45 (d, 1H, J 11.2),
1.77 (dd, 1H, J 13.1 and 4.7) and 1.66 (dd, 1H, J 13.1 and 11.8);
13C NMR (125 MHz, CH3OD) δ (ppm) 86.8, 84.2, 82.6, 81.7,
78.4, 75.1, and 31.7; υmax (Nujol)/cm-1 3423 (O-H); MS (+FAB)
m/z (%) 195 (MH+); HRMS calcd for C7H15O6, MH+, 195.0869;
found, MH+, 195.0875.
needles (70 mg, 75%): mp 126-128 °C; [R]20 -22° (c 1.1 in
D
CH3OH); 1H NMR (250 MHz, CD3OD) δ (ppm) 4.10 (t, 1H,
J 3.0), 4.09-3.99 (m, 1H), 3.80 (d, 1H, J 9.3), 3.63 (d, 1H,
J 3.0), 3.29 (dd, 1H, J 9.5 and 3.0), 3.27 (d, 1H, J 9.3), 1.90
(dd, 1H, J 13.7 and 5.1), 1.67 (dd, 1H, J 13.7 and 11.8), 0.97
(s, 9H), 0.16 (s, 3H), and 0.15 (s, 3H); 13C NMR (62.5 MHz,
CD3OD) δ (ppm) 77.9, 77.0, 76.5, 69.2, 67.9, 67.3, 39.9, 26.3,
19.1, and -5.4; υmax (NaCl)/cm-1 3454 (O-H); MS (CI) m/z (%)
309 (MH+); HRMS calcd for C13H29O6Si, MH+, 309.1733; found,
MH+, 309.1744.
(1R,2S,3S,4S,5R)-1,2,3,4,5-P en ta h yd r oxycycloh exa n -1-
ca r boxylic Acid (5b). A stirred solution of the carbolactone
15 (150 mg, 0.49 mmol) in 5 mL of aqueous acetic acid (80%)
was heated at 40 °C for 5.5 days. The crude mixture was
diluted with water and ethyl acetate. The organic layer was
separated and the aqueous layer was washed with ethyl
acetate (5 × 1 mL). The aqueous extract was freeze-dried and
crystallized from 20% ethyl acetate-methanol to afford acid
5b as an amorphous solid (69 mg, 64%): mp 210-212 °C [20%
ethyl acetate-methanol (lit.13 mp 221 °C, 25% aqueous etha-
nol)]; [R]20 -17° (c 2.6 in H2O) [lit.13 [R]20 -16° (c 1.0 in 50%
(1S,2S,3S,4S,5R)-1,2,3,4,5-P en t a h yd r oxy-1-h yd r oxy-
m eth ylcycloh exa n e (5a ). A stirred solution of the silyl ether
17 (43 mg, 0.14 mmol) in 1.5 mL of aqueous acetic acid (80%)
was heated at 40 °C for 5 h. The crude mixture was diluted
with water and diethyl ether. The organic layer was separated
and the aqueous layer was washed with diethyl ether (2 × 2
mL). The aqueous extract was freeze-dried to afford polyhy-
droxycyclohexane 5a as colorless oil (30 mg, 99%): [R]20D -20°
D
D
1
aqueous ethanol)]; H NMR (300 MHz, CD3OD) δ (ppm) 4.07
(t, 1H, J 3.0), 3.97 (m, 2H), 3.41 (dd, 1H, J 3.0 and 9.9), 2.10
(dd, 1H, J 13.1 and 4.9), and 1.81 (t, 1H, J 13.1); υmax (KBr)/
cm-1 3430 (O-H), 3313 (O-H), and 1734 (CdO); MS (CI) m/z
(%) 209 (MH+).
1
(c 1.1 in CH3OH); H NMR (250 MHz, CD3OD) δ (ppm) 4.12
(t, 1H, J 3.0), 4.05 (m, 1H), 3.66 (m, 2H), 3.64 (s, 2H), 3.32 (m,
1H), 1.98 (dd, 1H, J 13.6 and 4.9), and 1.56 (dd, 1H, J 13.6
and 11.7); 13C NMR (63 MHz, CD3OD) δ (ppm) 78.1, 77.1, 76.8,
70.4, 68.2, 67.5, and 39.8; υmax (Nujol)/cm-1 3423 (O-H); MS
(+FAB) m/z (%) 195 (MH+); HRMS calcd for C7H15O6, MH+,
195.0869; found, MH+, 195.0875.
(1R,2R,3R,4S,5R)-1,2,4,5-Tetr a h yd r oxycycloh exa n -1,3-
ca r bola cton e (20). A stirred solution of the silyl ether 16 (140
mg, 0.46 mmol) in 5 mL of aqueous acetic acid (80%) was
heated at 40 °C for 76 h. The crude mixture was diluted with
water and ethyl acetate. The organic layer was separated and
the aqueous layer was washed with ethyl acetate (5 × 1 mL).
The aqueous extract was freeze-dried and crystallizated from
water to afford carbolactone 20 as white prisms (67 mg, 77%):
(1S,2R,3R,4S,5R)-1-(ter t-Bu tyld im eth ylsilyloxy)-2,3,4,5-
tetr a h yd r oxy-1-h yd r oxym eth ylcycloh exa n e (18a ) a n d
(1S,2R,3R,4S,5R)-1-[(ter t-Bu tyld im eth ylsilyloxy)m eth yl]-
1,2,3,4,5-p en ta h yd r oxycycloh exa n e (18b). To a stirred
solution of the lactone 16 (55 mg, 0.18 mmol), under argon
and at 0 °C, in 0.8 mL of a dry solution of methanol in
tetrahydrofuran (1/20 v/v), was added lithium borohydride (10
mg, 0.46 mmol). The resultant reaction mixture was refluxed
for 7 h. After cooling at room temperature, ethyl acetate (0.7
mL) and then water (1.5 mL) were added. The solvent was
evaporated and the crude reaction was purified by flash
cromatography [eluent: (1) ethyl acetate, (2) methanol-ethyl
acetate (15:85), and (3) methanol-ethyl acetate-acetic acid
(14:85:1)] to yield 31 mg (55%) of 18a and 22 mg (39%) of 18b
both as white needles.
mp 286 °C (dec) (H2O); [R]20 -21° (c 2.2 in H2O); 1H NMR
D
(500 MHz, CD3OD) δ (ppm) 4.52 (dd, 1H, J 4.5 and 1.0), 4.29
(br. s, 1H), 4.09 (m, 1H), 3.98 (m, 1H), 2.61 (dd, 1H, J 13.9
and 5.1), and 2.09 (dt, 1H, J 13.9 and 1.6); 13C NMR (63 MHz,
D2O) δ (ppm) 181.0, 84.3, 76.7, 75.8, 71.1, 70.6, and 40.7; υmax
(KBr)/cm-1 3360 (O-H) and 1761 (CdO); MS (CI) m/z (%) 191
(MH+); HRMS calcd for C7H11O6, MH+, 191.0556; found, MH+,
191.0554.
(1R,2R,3R,4S,5R)-1,2,3,4,5-P en ta h yd r oxycycloh exa n -1-
ca r boxylic Acid (6b). A solution of the lactone 20 (19 mg,
0.10 mmol) in aqueous lithium hydroxide (0.2 mL, 0.2 M) was
stirred at room temperature for 2 h. The resultant solution
was diluted with water and treated with Amberlite IR-120
Data for 18a : mp 131-132 °C; [R]20D -2° (c 1.5 in CH3OH);
1H NMR (500 MHz, CD3OD) δ (ppm) 3.82 (dd, 1H, J 3.0 and
9.6), 3.78 (m, 1H), 3.76 (d, 1H, J 1.3), 3.67 (d, 1H, J 11.3), 3.59
(d, 1H, J 11.3), 3.57 (m, 1H), 1.79 (ddd, 1H, J 13.0, 4.8 and
(13) Adlersberg, M.; Bondinell, W. E.; Sprinson, D. B. J . Am. Chem.
Soc. 1973, 95, 887.
2254 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Polyhydroxycyclohexanes
until pH 6. The resin was filtered and washed with water. The
Ack n ow led gm en t. Financial support from the Xun-
ta de Galicia under project PGIDIT02RAG20901PR is
gratefully acknowledged. M.C. thanks the Xunta de
Galicia for a scholardship.
filtrate was concentrated to afford acid 6b (20 mg, 96%) as a
1
colorless oil: [R]20 -12° (c 0.7 in H2O); H NMR (250 MHz,
D
D2O) δ (ppm) 3.59 (d, 1H, J 3.0), 3.41 (dd, 1H, J 3.0 and 9.5),
3.33 (m, 1H), 3.22 (t, 1H, J 9.5), and 1.70 (m, 2H); 13C NMR
(63 MHz, D2O) δ (ppm) 177.5, 76.0, 74.5, 73.2, 71.2, 69.1, and
34.7; υmax (Nujol)/cm-1 3351 (O-H) and 1721 (CdO); MS (CI)
m/z (%) 209 (MH+); HRMS calcd for C7H13O7, MH+, 209.0661;
found, MH+, 209.0658.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for compound 11. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026692M
J . Org. Chem, Vol. 68, No. 6, 2003 2255