A short synthesis of (+)-cyclophellitol

Article abstract of DOI:10.1021/jo051645q

A new synthesis of (+)-cyclophellitol, a potent β-glucosidase inhibitor, has been completed in nine steps from D-xylose. The key transformations involve a zinc-mediated fragmentation of benzyl-protected methyl 5-deoxy-5-iodo-xylofuranoside followed by a h

Full text of DOI:10.1021/jo051645q

A Short Synthesis of (+)-Cyclophellitol
Flemming Gundorph Hansen, Eva Bundgaard, and
Robert Madsen*
Center for Sustainable and Green Chemistry, Building 201,
Department of Chemistry, Technical University of Denmark,
DK-2800 Lyngby, Denmark
rm@kemi.dtu.dk
Received August 5, 2005
FIGURE 1. Retrosynthesis for (+)-cyclophellitol.
bocyclization reaction is either a Ferrier reaction, a
cycloaddition, a radical cyclization, or a ring-closing olefin
metathesis reaction.
Olefin metathesis has now become one of the most
popular tools for forming carbo- and heterocyclic ring
systems in organic chemistry.8 We have recently de-
scribed several strategies for converting carbohydrates
into functionalized carbocycles by the use of ring-closing
metathesis.9,10 During this work, a metal-mediated tan-
dem reaction has been a key transformation to generate
dienes from carbohydrates. In this procedure, methyl
iodoglycosides are subjected to a reductive fragmentation
to produce unsaturated aldehydes, which are then al-
kylated by unsaturated organometallics (e.g., allylic
reagents).11 This tandem reaction combined with olefin
metathesis has been applied in the synthesis of several
natural products, including the inositols12 and the calys-
tegines.13
Herein, we describe a nine-step synthesis of (+)-
cyclophellitol from D-xylose by the use of these organo-
metallic transformations. To date, this represents the
shortest method for the preparation of enantiopure
cyclophellitol.
The epoxide can be introduced at a late stage in the
synthesis from the corresponding olefin. This strategy has
been used in several previous syntheses of cyclophellitol,
but the epoxidation only occurs with good stereocontrol
when it is directed by the primary hydroxy group.3 Thus,
we embarked on a strategy where the epoxide is gener-
ated from cyclohexene A, which will be prepared by ring-
closing metathesis from diene B (Figure 1). This diene
can arise from unsaturated aldehyde C by a metal-
A new synthesis of (+)-cyclophellitol, a potent â-glucosidase
inhibitor, has been completed in nine steps from D-xylose.
The key transformations involve a zinc-mediated fragmenta-
tion of benzyl-protected methyl 5-deoxy-5-iodo-xylofurano-
side followed by a highly diastereoselective indium-mediated
coupling with ethyl 4-bromocrotonate. Subsequent ring-
closing olefin metathesis, ester reduction, olefin epoxidation,
and deprotection then afford the natural product. This
constitutes the shortest synthesis of (+)-cyclophellitol re-
ported to date.
(+)-Cyclophellitol was isolated in 1990 from the culture
filtrates of a mushroom Phellinus sp. and shown to be a
strong and specific inhibitor of almond â-glucosidase.1,2
It is a carbocyclic analogue of D-glucopyranose with an
epoxide ring on the â-face of the molecule. The inhibition
of â-glucosidase is irreversible, which is presumably due
to protonation and ring opening of the epoxide by a
carboxylate in the active site of the enzyme.3,4 (+)-
Cyclophellitol has been the target for a number of total
syntheses starting from either a carbohydrate,5 a natu-
rally occurring cyclitol,6 or a synthetic cyclohexene
derivative.7 In the former case, the carbohydrate car-
(1) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.; Nakamura,
H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990, 43, 49.
(2) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K. J. Antibiot.
1990, 43, 1579.
(3) For a review on the chemistry and biochemistry of (+)-cyclo-
phellitol, see: Marco-Contelles, J. Eur. J. Org. Chem. 2001, 1607.
(4) Withers, S. G.; Umezawa, K. Biochem. Biophys. Res. Commun.
1991, 177, 532.
(5) (a) Kireev, A. S.; Breithaupt, A. T.; Collins, W.; Nadein, O. N.;
Kornienko, A. J. Org. Chem. 2005, 70, 742. (b) Ishikawa, T.; Shimizu,
Y.; Kudoh, T.; Saito, S. Org. Lett. 2003, 5, 3879. (c) Ziegler, F. E.; Wang,
Y. J. Org. Chem. 1998, 63, 7920. (d) Takahashi, H.; Iimori, T.; Ikegami,
S. Tetrahedron Lett. 1998, 39, 6939. (e) Letellier, P.; Ralainairina, R.;
Beaupe`re, D.; Uzan, R. Synthesis 1997, 925. (f) Ohba, K.; Suzuki, K.;
Nakata, M. Carbohydr. Lett. 1996, 2, 175. (g) Jung, M. E.; Choe, S. W.
T. J. Org. Chem. 1995, 60, 3280. (h) McDevitt, R. E.; Fraser-Reid, B.
J. Org. Chem. 1994, 59, 3250. (i) Sato, K.; Bokura, M.; Moriyama, H.;
Igarashi, T. Chem. Lett. 1994, 37. (j) Tatsuta, K.; Niwata, Y.; Umezawa,
K.; Toshima, K.; Nakata, M. Carbohydr. Res. 1991, 222, 189.
(6) (a) Shing, T. K. M.; Tai, V. W.-F. J. Chem. Soc., Perkin Trans. 1
1994, 2017. (b) Akiyama, T.; Shima, H.; Ohnari, M.; Okazaki, T.; Ozaki,
S. Bull. Chem. Soc. Jpn. 1993, 66, 3760.
(7) (a) Trost, B. M.; Patterson, D. E.; Hembre, E. J. Chem.-Eur. J.
2001, 7, 3768. (b) Schlessinger, R. H.; Bergstrom, C. P. J. Org. Chem.
1995, 60, 16.
(8) For recent reviews, see: (a) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199. (b) Schrock, R. R.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 4592. (c) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900.
(9) (a) Poulsen, C. S.; Madsen, R. J. Org. Chem. 2002, 67, 4441. (b)
Jørgensen, M.; Iversen, E. H.; Paulsen, A. L.; Madsen, R. J. Org. Chem.
2001, 66, 4630. (c) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000,
122, 8444.
(10) For a review, see: Jørgensen, M.; Hadwiger, P.; Madsen, R.;
Stu¨tz, A. E.; Wrodnigg, T. M. Curr. Org. Chem. 2000, 4, 565.
(11) Hyldtoft, L.; Poulsen, C. S.; Madsen, R. Chem. Commun. 1999,
2101.
(12) Andresen, T. L.; Skytte, D. M.; Madsen, R. Org. Biomol. Chem.
2004, 2, 2951.
(13) Skaanderup, P. R.; Madsen, R. J. Org. Chem. 2003, 68, 2115.
10.1021/jo051645q CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/19/2005
J. Org. Chem. 2005, 70, 10139-10142
10139

SCHEME 1a
SCHEME 2
a Reagents and conditions: (a) MeOH, HCl, 5 °C. (b) I2, PPh3,
imidazole, THF, 65 °C. (c) BnOC(NH)CCl3, TfOH, dioxane, rt. (d)
Zn, THF/H2O, ultrasound, 40 °C.
promoted reaction with a substituted allylic halide.
Aldehyde C is available from a protected derivative of
methyl 5-iodoxylofuranoside D by a zinc-mediated reduc-
tive fragmentation. The alkylation introduces two new
stereogenic centers, and controlling the stereochemistry
in this reaction is crucial.
The required starting material for the reductive frag-
mentation was prepared in three steps from D-xylose.
First, this cheap pentose was converted into the furanose
form by a Fischer glycosylation with methanol under
kinetic conditions (Scheme 1). The crude product consist-
ing of a 1:1 mixture of the R- and the â-furanoside was
treated with iodine and triphenylphosphine. The obtained
methyl 5-iodofuranoside 1 was separated from tri-
phenylphosphine oxide on a reverse-phase column and
isolated in 74% overall yield from D-xylose.14 The 2- and
3-hydroxy groups were then protected as benzyl ethers
by reaction with benzyl trichloroacetimidate under acidic
conditions. The resulting dibenzyl ether 2 was sonicated
with zinc to afford unsaturated aldehyde 3.9c With this
compound in hand, the pivotal alkylation was then
examined under Barbier conditions.
Two allylic bromides were selected for these studies:
4-bromobut-2-en-1-ol (4) and ethyl 4-bromocrotonate (5).
Alcohol 4 is available from ester 5 by reduction with
DIBAL-H.15 Treatment of 3 and 4 with indium metal in
a 10:1 THF/water mixture at room temperature gave the
desired allylation product 6, but unfortunately the reac-
tion was not stereoselective and yielded a mixture of
three stereoisomers in the ratio 3:2:2 (Scheme 2). The
allylic bromide was then changed to ester 5. The indium-
mediated addition reaction with this reagent gave diene
7 in 55% yield as a 1:1 mixture of two diastereomers.
The reaction was slow and required 2 days at room
temperature. We attempted to carry out the reaction as
a tandem sequence where the same metal performs the
reductive fragmentation of iodide 2 and the alkylation
of intermediate 3 in the same pot. Unfortunately, these
experiments were not successful. When a mixture of 2
and 5 was reacted with zinc metal, the major product
obtained was aldehyde 3, while no reaction occurred with
indium metal. Apparently, zinc would not promote the
coupling between aldehyde 3 and ester 5, while indium
would not mediate the fragmentation of iodide 2.
Increased rates and selectivities have previously been
observed in indium-mediated allyl addition reactions
when lanthanide triflates are added.16 Accordingly, the
reaction between 3 and 5 was repeated in the presence
of 2 equiv of La(OTf)3. Notably, only one diastereomer
was formed in this case, although the reaction was still
slow and only afforded a 36% yield after 24 h. This isomer
was shown to be the desired diastereomer after complet-
ing the synthesis (vide infra). Incomplete conversion and
decomposition of aldehyde 3 seemed to be the main
reason for the low yield, and several experiments with
added La(OTf)3 were performed to improve the yield.
Changing the solvent to pure water gave essentially the
same yield, while the addition proceeded poorly in
saturated ammonium chloride solution. We also at-
tempted to use a more reactive reagent, ethyl 4-iodocro-
tonate, which was prepared from 5 by a Finkelstein
reaction. However, in aqueous solution no indium-medi-
ated coupling occurred between this iodide and aldehyde
3. It was then decided to change the indium source to a
more finely dispersed indium powder. All the experi-
ments so far had been conducted with indium powder
containing 1% magnesium as anticaking agent. Hence,
the coupling between 3 and 5 was repeated in the
presence of a 60 mesh indium powder (99.999% pure).
Gratifyingly, this now provided the desired product 7 in
85% yield as a single diastereomer. The reaction was
performed in water with 2 equiv of La(OTf)3 and required
about 48 h for complete conversion of aldehyde 3. A
slower conversion was observed in the absence of La-
(OTf)3, but the reaction still furnished only one dia-
stereomer. The stereochemical outcome can be explained
by invoking a chelated intermediate such as 8 (Scheme
2). Chelation to flanking heteroatoms has previously been
observed in indium-mediated allylations in water.17
Diene 7 was converted into the corresponding cyclo-
hexene 9 by ring-closing metathesis with Grubbs second
generation catalyst18 (Scheme 3). The highly colored
ruthenium catalyst was removed in the workup by
treating the reaction mixture with tris(hydroxymethyl)-
phosphine.19 The ester functionality was then reduced
with DIBAL-H to afford diol 10. This reduction was quite
sluggish and afforded minor amounts of the intermediate
(16) (a) Loh, T.-P.; Cao, G.-Q.; Pei, J. Tetrahedron Lett. 1998, 39,
1453. (b) Diana, S.-C. H.; Sim, K.-Y.; Loh, T.-P. Synlett 1996, 263. (c)
Wang, R.; Lim, C.-M.; Tan, C.-H.; Lim, B.-K.; Sim, K.-Y.; Loh, T.-P.
Tetrahedron: Asymmetry 1995, 6, 1825.
(14) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M.
R.; Madsen, R. Synthesis 2002, 1721.
(15) Kinoshita, M.; Takami, H.; Taniguchi, M.; Tamai, T. Bull.
Chem. Soc. Jpn. 1987, 60, 2151.
(17) Paquette, L. A. Synthesis 2003, 765.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(19) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137.
10140 J. Org. Chem., Vol. 70, No. 24, 2005

SCHEME 3a
trichloroacetimidate (4.1 mL, 22.0 mmol) in dioxane (20 mL,
dried over 4 Å molecular sieves) was added triflic acid (0.45 mL,
5.12 mmol). The mixture was cooled in an ice bath for 1 min,
followed by stirring at room temperature for 5 min. The reaction
was quenched with saturated aqueous NaHCO3 and extracted
with EtOAc. The organic phase was concentrated, and the
residue was purified by dry column chromatography (EtOAc/
heptane ) 1:9 f 2:8) to give 2 (2.94 g, 90%) as a 1:1 mixture of
anomers. Clear oil. Rf 0.19 and 0.29 (heptane/EtOAc ) 5:1). 1H
NMR (CDCl3, 300 MHz): δ 7.40-7.30 (m, 20H), 5.00 (d, J ) 1.1
Hz, 1H), 4.90 (d, J ) 4.0 Hz, 1H), 4.70-4.40 (m, 10H), 4.20 (m,
2H), 4.10-4.00 (m, 2H), 3.44 (s, 3H), 3.42 (s, 3H), 3.40-3.30 (m,
4H). 13C NMR (CDCl3, 75 MHz): δ 137.6, 137.6, 137.4, 129.2,
128.7, 128.6, 128.6, 128.6, 128.5, 128.3, 128.3, 128.2, 128.1, 128.1,
128.0, 127.9, 127.9, 127.9, 108.4, 101.0, 86.8, 83.9, 82.1, 82.0,
81.8, 77.7, 72.9, 72.8, 72.7, 72.2, 56.0, 55.4, 4.4, 2.9. HRMS calcd
for C20H23IO4Na [M + Na]+ m/z 477.0533, found m/z 477.0532.
(2R,3S)-2,3-Bis(benzyloxy)pent-4-enal (3). To a solution
of iodide 2 (1.04 g, 2.29 mmol) in THF/H2O (30 mL, 9:1) was
added activated zinc dust9c (1.52 g, 23.2 mmol). The reaction
was sonicated at 40 °C for 2.5 h, whereupon the mixture was
filtered through Celite, which was rinsed with Et2O. The filtrate
was concentrated and purified by flash chromatography (EtOAc/
heptane ) 3:17) to give 3 (530.6 mg, 78%) as a clear oil. Rf 0.29
(EtOAc/heptane ) 1:3). [R]D +68.7 (c 1.0, CHCl3). IR (KBr):
3029, 1733, 1072, 737, 698 cm-1. 1H NMR (CDCl3, 300 MHz): δ
9.70 (d, J ) 1.5 Hz, 1H), 7.41-7.26 (m, 10H), 5.96 (ddd, J ) 7.7,
10.5, 17.2 Hz, 1H), 5.42-5.32 (m, 2H), 4.78 (d, J ) 12.2 Hz, 1H),
4.69-4.61 (m, 2H), 4.37 (d, J ) 12.1 Hz, 1H), 4.19 (dd, J ) 4.1,
7.6 Hz, 1H), 3.85 (dd, J ) 1.4, 4.1 Hz, 1H). 13C NMR (CDCl3, 75
MHz): δ 202.7, 137.6, 137.1, 133.9, 128.6, 128.5, 128.3, 128.3,
128.1, 127.9, 120.1, 85.2, 80.0, 73.6, 70.7. HRMS calcd for
C19H20O3Na [M + Na]+ m/z 319.1305, found m/z 319.1305.
Ethyl (2S,3R,4S,5S)-4,5-Bis(benzyloxy)-3-hydroxy-2-vi-
nylhept-6-enoate (7). To a solution of aldehyde 3 (134.4 mg,
0.45 mmol) in H2O (2 mL) were added ethyl 4-bromocrotonate
(282 mg, 1.46 mmol), La(OTf)3 (548 mg, 0.94 mmol), and indium
(60 mesh, 120.5 mg, 1.05 mmol). After being stirred for 47 h at
room temperature, the mixture was filtered through Celite,
which was rinsed with Et2O. The filtrate was concentrated and
purified by flash chromatography (EtOAc/heptane ) 3:17) to
afford 7 (157.7 mg, 85%) as a clear oil. Rf 0.23 (EtOAc/heptane
) 1:3). [R]D -12.1 (c 1.0, CHCl3). IR (KBr): 1734, 1064, 928,
a Reagents and conditions: (a) (PCy3)(C3H4N2Mes2)Cl2RudCHPh,
CH2Cl2, 40 °C. (b) DIBAL-H, THF, 0 °C f rt, then NaBH4, H2O,
rt. (c) FeCl3, CH2Cl2, rt. (d) m-CPBA, CH2Cl2, 40 °C. (e) H2,
Pd(OH)2/C, MeOH, rt.
aldehyde as a byproduct. Using a larger excess of
DIBAL-H or a higher reaction temperature did not solve
the problem. Instead, water and sodium borohydride
were added in the workup to drive the reaction to
completion. Deprotection of diol 10 with ferric chloride
in dichloromethane20 gave tetrol 11, which is an olefin
analogue of cyclophellitol. Several carbasugars have
previously shown good inhibition of glycosidases,21 and
we speculated if 11 would be a reversible inhibitor. Thus,
compound 11 was tested against yeast R-glucosidase,
almond â-glucosidase, green coffee bean R-galactosidase,
Escherichia coli â-galactosidase, and Jack bean R-man-
nosidase.22 However, it showed no inhibition of these
enzymes, which underlines the importance of the epoxide
ring for the inhibition by cyclophellitol.
This epoxide was then installed by treating diol 10 with
m-CPBA to give the desired product 12. The epoxidation
was completely stereoselective, and none of the other
isomer was observed. Finally, epoxide 12 was deprotected
by hydrogenolysis to afford (+)-cyclophellitol, mp 150-
151 °C, [R]D +100.0 (c 1.0, H2O), with spectral and
physical data in excellent agreement with those reported
for the natural product.1,5
In conclusion, we have developed a concise synthesis
of enantiopure cyclophellitol. The strategy requires nine
steps from D-xylose and gives rise to the natural product
in 14% overall yield. The key steps are three consecutive
organometallic reactions: zinc-mediated fragmentation
of 2, indium-mediated coupling between 3 and 5, and
ruthenium-catalyzed ring-closing metathesis of 7. The
synthesis highlights the usefulness of these organo-
metallic reactions in the development of more efficient
synthetic routes from carbohydrates.
734, 699 cm-1 1H NMR (CDCl3, 300 MHz): δ 7.40-7.17 (m,
.
10H), 5.82 (ddd, J ) 7.9, 10.3, 17.5 Hz, 1H), 5.71 (ddd, J ) 9.4,
10.1, 17.1 Hz, 1H), 5.38-5.28 (m, 2H), 5.19-5.08 (m, 2H), 5.01
(d, J ) 11.5 Hz, 1H), 4.62 (d, J ) 11.8 Hz, 1H), 4.58 (d, J ) 11.5
Hz, 1H), 4.33 (d, J ) 11.5 Hz, 1H), 4.11 (t, J ) 7.5 Hz, 1H), 4.03
(q, J ) 7.1 Hz, 2H), 3.90 (t, J ) 9.5 Hz, 1H), 3.47 (d, J ) 7.6 Hz,
1H), 3.21 (t, J ) 9.3 Hz, 1H), 2.64 (d, J ) 10.0 Hz, 1H), 1.15 (t,
J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 172.6, 138.5,
138.4, 135.0, 133.0, 128.5, 128.5, 128.1, 127.9, 127.9, 127.7, 120.2,
120.1, 83.0, 79.4, 74.7, 72.2, 70.9, 61.0, 55.3, 14.2. HRMS calcd
for C25H30O5Na [M + Na]+ m/z 433.1985, found m/z 433.1975.
Ethyl (1S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-hydroxycyclo-
hex-2-enecarboxylate (9). To a solution of diene 7 (105.1 mg,
0.26 mmol) in CH2Cl2 (10 mL) was added Grubbs second
generation catalyst (23.9 mg, 0.028 mmol), and the mixture was
stirred at 40 °C in the dark for 50 h. A 1.5 M solution of P(CH2-
OH)3 in 2-propanol (0.6 mL) was added, and the solution was
refluxed for another 25 h. The mixture was then washed with
H2O, evaporated to dryness, and purified by flash chromatog-
raphy (EtOAc/heptane ) 3:17) to give 9 (89.3 mg, 91%) as a
yellow oil. Rf 0.21 (EtOAc/heptane ) 1:3). [R]D +127.5 (c 1.1,
Experimental Section
CHCl3). IR (KBr): 3492, 1733, 1180, 1055, 737, 698 cm-1 1H
.
Methyl 2,3-Di-O-benzyl-5-deoxy-5-iodo-D-xylofuranoside
(2). To a solution of iodide 114 (1.97 g, 7.22 mmol) and benzyl
NMR (CDCl3, 300 MHz): δ 7.37-7.28 (m, 10H), 5.81 (dt, J )
2.1, 10.3 Hz, 1H), 5.67 (dt, J ) 2.1, 10.3 Hz, 1H), 4.97 (d, J )
11.3 Hz, 1H), 4.79 (d, J ) 11.3 Hz, 1H), 4.71 (d, J ) 11.4 Hz,
1H), 4.66 (d, J ) 11.4 Hz, 1H) 4.23-4.11 (m, 4H), 3.66 (dd, J )
7.7, 10.0 Hz, 1H), 3.29-3.23 (m, 1H), 2.96 (d, J ) 2.0 Hz, 1H),
1.28 (t, J ) 7.3 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 172.1,
(20) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477.
(21) For some recent examples, see: (a) Ogawa, S.; Fujieda, S.;
Sakata, Y.; Ishizaki, M.; Hisamatsu, S.; Okazaki, K. Bioorg. Med.
Chem. Lett. 2003, 13, 3461. (b) Ogawa, S.; Aoyama, H.; Sato, T.
Carbohydr. Res. 2002, 337, 1979. (c) Mehta, G.; Ramesh, S. S. Chem.
Commun. 2000, 2429.
(22) For details of the enzymatic assays, see: Andersen, S. M.;
Ekhart, C.; Lundt, I.; Stu¨tz, A. E. Carbohydr. Res. 2000, 326, 22.
J. Org. Chem, Vol. 70, No. 24, 2005 10141

138.5, 138.1, 128.6, 128.6, 128.3, 128.0, 128.0, 128.0, 128.0 124.2,
82.6, 79.3, 75.0, 72.0, 70.5, 61.4, 50.1, 14.3. Anal. Calcd for
C23H26O5: C, 72.23; H, 6.85. Found: C, 71.98; H, 6.61.
(1R,2R,3R,4S,5R,6S)-4,5-Bis(benzyloxy)-2-(hydroxy-
methyl)-7-oxa-bicyclo[4.1.0]heptan-3-ol (12). To a solution
of diol 10 (103 mg, 0.30 mmol) in CH2Cl2 (5 mL) was added
m-CPBA (85 mg, 0.45 mmol). The mixture was heated at reflux
for 60 h and then concentrated and purified by flash chroma-
tography (EtOAc/heptane ) 2:3) to give 12 (60.1 mg, 56%) as a
clear oil. Rf 0.33 (EtOAc). [R]D +45.9 (c 0.23, MeOH). IR (KBr):
3467, 1100, 1049, 734, 696 cm-1. 1H NMR (CDCl3, 300 MHz): δ
7.46-7.25 (m, 10H), 4.96 (d, J ) 11.3 Hz, 1H), 4.82 (d, J ) 11.3
Hz, 1H), 4.68 (d, J ) 11.4 Hz, 1H), 4.66 (d, J ) 11.4 Hz, 1H),
4.05-3.88 (m, 2H), 3.82 (d, J ) 8.1 Hz, 1H), 3.49 (t, J ) 9.9 Hz,
1H), 3.42-3.36 (t, J ) 9.9 Hz, 1H), 3.29-3.26 (m, 1H), 3.17 (dd,
J ) 0.9, 3.6 Hz, 1H), 2.79 (br s, 2H), 2.21-2.13 (m, 1H). 13C
NMR (CDCl3, 75 MHz): δ 138.2, 137.4, 128.8, 128.7, 128.3, 128.1,
128.1, 128.0, 83.5, 79.5, 75.0, 72.7, 68.8, 64.3, 55.0, 53.0, 43.4.
Anal. Calcd for C21H24O5: C, 70.77; H, 6.79. Found: C, 70.48;
H, 6.80.
(1R,2R,5S,6S)-5,6-Bis(benzyloxy)-2-(hydroxymethyl)cy-
clohex-3-enol (10). DIBAL-H (0.78 mL, 4.38 mmol) was added
slowly to a solution of ester 9 (186.6 mg, 0.49 mmol) in THF (15
mL) at 0 °C. After being stirred for 35 min at 0 °C, the reaction
was warmed to room temperature and stirred for 2 h. The
mixture was cooled to 0 °C again, and EtOAc (1 mL) was added
slowly. Then, H2O (2 mL) and NaBH4 (120 mg, 3.17 mmol) were
added, and the mixture was allowed to warm to room temper-
ature and was stirred for 19 h. The organic layer was separated,
and the aqueous phase was extracted with EtOAc. The combined
organic phases were concentrated, and the residue was purified
by flash chromatography (EtOAc/heptane ) 3:7 f 1:1) to give
10 (106.6 mg, 64%) as a clear oil. Rf 0.39 (EtOAc). [R]D +104.7
(c 1.0, CHCl3). IR (neat): 3407, 1454, 1097, 1055, 735, 698 cm-1
.
1H NMR (CDCl3, 300 MHz): δ 7.30-7.20 (m, 10H), 5.70 (dt, J
) 2.9, 10.2 Hz, 1H), 5.40 (dt, J ) 1.7, 10.3 Hz, 1H), 5.02 (d, J )
11.3 Hz, 1H), 4.71 (d, J ) 11.3 Hz, 1H), 4.71 (d, J ) 11.4 Hz,
1H), 4.63 (d, J ) 11.4 Hz, 1H), 4.20-4.10 (m, 1H), 3.70-3.50
(m, 4H), 2.55-2.46 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 138.6,
138.3, 128.8, 128.7, 128.2, 128.2, 128.1, 128.1, 127.7, 127.5, 83.5,
80.4, 75.1, 73.0, 71.7, 65.7, 45.4. Anal. Calcd for C21H24O4: C,
74.09; H, 7.11. Found: C, 73.93; H, 7.27.
(1S,2R,3S,4R,5R,6R)-5-(Hydroxymethyl)-7-oxa-bicyclo-
[4.1.0]heptane-2,3,4-triol ((+)-Cyclophellitol). To a solution
of dibenzyl ether 12 (59.4 mg, 0.17 mmol) in MeOH (2 mL) was
added 20% Pd(OH)2/C (10.0 mg). The mixture was stirred
vigorously at room temperature under an atmosphere of H2 for
22 h and was then filtered through cotton and rinsed with
MeOH. The filtrate was concentrated, and the product was
isolated as white crystals without further purification (29.5 mg,
quant). Rf 0.38 (MeOH/CH2Cl2 ) 1:3). [R]D +100.0 (c 1.0, H2O)
(lit.1 [R]27D +103.0 (c 0.5, H2O)). mp 150-151 °C (EtOAc/MeOH)
(1R,2R,3S,6R)-6-(Hydroxymethyl)cyclohex-4-ene-1,2,3-
triol (11). To an ice-cold solution of dibenzyl ether 10 (96.8 mg,
0.28 mmol) in CH2Cl2 (2 mL) was added anhydrous FeCl3 (459
mg, 2.83 mmol). After being stirred for 1.5 h at room tempera-
ture, the reaction was stopped by addition of H2O, and the
mixture was evaporated to dryness. The residue was dissolved
in MeOH and poured through a mixture of two ion-exchange
resins (Amberlite IR-120 (H+) (20 mL) and Amberlite IRA-420
(OH-) (10 mL)) eluting with MeOH. The eluent was treated with
activated charcoal, filtered through Celite, and concentrated to
give compound 11 as a clear oil (41.3 mg, 91%). Rf 0.23 (EtOAc).
1
(lit.1 mp 149-151 °C). H NMR (D2O, 300 MHz): δ 4.00 (dd, J
) 4.0, 11.3 Hz, 1H), 3.82 (dd, J ) 7.5, 11.0 Hz, 1H), 3.78 (d, J )
8.5 Hz, 1H), 3.55 (m, 1H), 3.41-3.36 (m, 1H), 3.26 (d, J ) 3.8
Hz, 1H), 3.25 (t, J ) 10.2 Hz, 1H), 2.12 (m, 1H). 13C NMR (D2O,
75 MHz): δ 78.5, 72.8, 68.8, 62.5, 57.4, 56.0, 45.9. NMR data
are in accordance with literature values.1,5
Acknowledgment. Financial support from the Lund-
beck Foundation and the Holm Foundation is gratefully
acknowledged.
[R]D -13.4 (c 1.1, MeOH). IR (KBr): 3333, 1652, 1083, 725 cm-1
.
1H NMR (CD3OD, 300 MHz): δ 5.60-5.51 (m, 2H), 4.02-3.94
(m, 1H), 3.74 (dd, J ) 10.6, 3.9 Hz, 1H), 3.55 (dd, J ) 10.5, 6.0
Hz, 1H), 3.41-3.34 (m, 2H), 2.25-2.17 (br s, 1H). 13C NMR (CD3-
OD, 75 MHz): δ 131.0, 128.6, 78.8, 73.6, 71.9, 63.4, 47.7. HRMS
calcd for C7H12O4Na [M + Na]+ m/z 183.0628, found m/z
183.0626.
Supporting Information Available: General experimen-
tal methods and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO051645Q
10142 J. Org. Chem., Vol. 70, No. 24, 2005