Synthesis of cyclophellitol utilizing a palladium chloride mediated-ferrier-II rearrangement

Article abstract of DOI:10.3390/10080901

Cyclophellitol and its C3-epimer have been synthesized from 5-enoglucopyranoside and 5-enomannopyranoside, respectively. The carbocyclic skeleton was constructed through a Ferrier-II reaction meditated by PdCl ₂.

Full text of DOI:10.3390/10080901

Molecules 2005, 10, 901-911
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Cyclophellitol Utilizing a Palladium Chloride
Mediated-Ferrier-II Rearrangement
Hideyo Takahashi and Shiro Ikegami *,#
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan.
Tel. +81-426-85-3728, Fax. +81-426-85-1872
* Author to whom correspondence should be addressed; e-mail. shi-ike@pharm.teikyo-u.ac.jp
#
Dedicated to Professor K. K. Balasubramanian on the occasion of his sixty fifth birthday.
Received: 2 January 2005 / Accepted: 5 January 2005 / Published: 31 August 2005
Abstract: Cyclophellitol and its C3-epimer have been synthesized from
5-enoglucopyranoside and 5-enomannopyranoside, respectively. The carbocyclic skeleton
was constructed through a Ferrier-II reaction meditated by PdCl2.
Keywords: Glycosidase inhibitor, Ferrier-II reaction, palladium chloride.
Introduction
Since Ferrier developed a cyclization of saccharides using mercurate [Ferrier-II reaction] in 1979 [1],
the ring conversion of 6-membered rings using saccharides has been intensively studied [2, 3]. Because
naturally occurring and biologically active compounds often contain a ring structure with
multi-functional groups, stereochemical control of chiral centers on these rings becomes crucial in the
total synthesis of these compounds. The Ferrier-II reaction is remarkably useful for the total synthesis of
compounds with a complicated conformation such as cyclitols. Cyclophellitol is a β-D-glucosidase
inhibitor first isolated by Umezawa in 1990 [4]. It is known to have high activity, and its application has
been expected to range from an anti-virus and anti-HIV agent to an inhibitor of cancer metastasis. The
structure of cyclophellitol, an epoxy ring in the β-position on a multi-substituted cyclitol in the
glucose-conformation, resembles that of β-D-glucoside. We investigated synthetic methods of not only
cyclophellitol but also its epimers, ultimately aiming at the study of structure activity relationship [5].

Molecules 2005, 10
902
Results and Discussion
Figure 1 shows the strategy for the synthesis of cyclophellitol. Commercially available D-glucoside
is converted into a cyclohexane ring through Ferrier-II reaction, and then an epoxy ring is formed
stereoselectively.
Figure 1
C1 unit
OH
O
epoxide
OH
HO
HO
OBn
BnO
OH
OBn
O
Cyclophellitol
β-D-glucosidase inhibitor
IC50 < 0.8 µg / mL
For the introduction of a hydroxymethyl group as a C1 unit, regio- and stereoselective nucleophilic
addition to the epoxy ring is examined. Finally, an elimination reaction forms a β-epoxy ring to complete
the total synthesis of cyclophellitol.
Figure 2
O
O
a, b
d, e
BnO
BnO
c
BnO
BnO
BnO
BnO
OMe
1
HO
2
O
MPMO
BnO
BnO
BnO
BnO
BnO
BnO
3
4
Reagents and Conditions: a)PdCl2, dioxane - H2O, 60 °C, 3 h, 81%; b) MsCl,
Et3N, CH2Cl2, r.t., 9 h, 74%; c) CeCl3•7H2O, NaBH4, MeOH, 0 °C, 15 min,
87%; d) mCPBA, Na2HPO4, CH2Cl2, r.t., 4 days, quant.; e) NaH, MPMCl, DMF
- THF, r.t., 2 h, 93%.
In the beginning, 5-enoglucopyranoside 1 [6] was used in Ferrier-II reaction mediated by a catalytic
amount of palladium chloride. We have recently reported on the Ferrier-II reaction using palladium
chloride instead of mercury salt [7]. This reaction is more advantageous than the conventional methods
because it proceeds under very mild conditions, which especially suit the reaction of multi-substituted
carbohydrates [8]. In this case, the ring conversion was completed by using 0.05 equivalent of palladium
chloride and the obtained cyclohexanone was converted to an enone 2 [6] via an elimination reaction.
The enone 2 was reduced under Luche’s conditions [9] to provide a β-alcohol 3 [10]. Then β-form
epoxide was formed stereoselectively on the cyclohexane ring, and the hydroxyl group was protected by
an MPM group to provide an intermediate, the epoxide 4 (Figure 2).

Molecules 2005, 10
903
Figure 3
M
OR
5
2
O
chelation
O
3
OR
1
OR
1
4
OR
4
5
6
RO
6
RO
OR
Nu
2
3
Nu
OR
conformational change
The key reaction in this total synthetic pathway is the regioselective and nucleophilic attack of
hydroxymethyl group to the epoxide 4. Generally, a nucleophile predominantly attacks at the axial
position of epoxide in the ring opening reaction of cyclohexane. Therefore, we expected that the
nucleophilic substitution to this epoxide would occur at the axial position C5, and would not show the
desired regioselectivity (Figure 3) We then thought that if the conformation of the epoxide could be
changed, we would be able to introduce a hydroxymehyl group from the desired C6 position. As shown
in Figure 3, chelation between metals and oxygen atoms of the epoxide and an ether oxygen may
drastically change the conformation of the cyclohexane ring, resulting in the axial nucleophilic attack at
the C6 position. For induce such chelation, we used a boron reagent Mes2BCH2Li [11] and studied the
regio-selectivity of ring opening of the epoxide using substrates that are protected at the C1, a
coordinative position of chelation, with variation of the protecting groups (Table 1).
Table 1
OH
RO
RO
a, b
O
OH
OH
OBn
OR
BnO
BnO
BnO
BnO
BnO
BnO
BnO
9b~12b
BnO
9a~12a
4~8
OH
R
Epoxide Yield (%)
Regioselectivity
Entry
1
2
3
4
5
MPM c
Bn
4
78
60
65
83
0
9a : 9b > 99 : 1
10a : 10b > 99 : 1
11a : 11b = 94 : 6
12a : 12b < 1 : 99
–
5 [12]
BOM
6
7
8
TBDMS c
Ac
Reagents and Conditions: a) Mes2BCH2Li (10.0 eq), THF, rt, 6h; b) NaOH, H2O2,
THF-MeOH, rt; c) oxidation conditions: mCPBA (9.0 eq), Na2HPO4 (10.0 eq), rt,
30h.
Unfortunately, because acyl protective groups react with the boron reagent, we did not obtain the
hydroxymethylated products (entry 5). Hydroxymethyl addition, however, occurred smoothly in the
substrate with an ether protective group. Interestingly, the substrate protected with MPM, benzyl, and
BOM groups produced the hydroxymethyl products 9a~11a in which the nucleophile attacked at the

Molecules 2005, 10
904
opposite C6 position due to the chelation, but protection by a TBDMS groups resulted in only 12b in
which nucloephile attacked at the originally axial C5 position. Thus, a significant difference in the
selectivity was observed depending on the nature of the protecting group. Presumably, this change in
selectivity originated from differences in the coordinative power by the oxygen of the protected OH
group. As shown in Figure 3, chelation of the metal to the oxygens of both the oxirane and C1 alkoxy
group might change the conformation of the substrates to cause unusual regioselectivity. On the other
hand, the oxygen of the siloxy group might not coordinate to the metal because of bulkiness of the silyl
group. In this case, the usual selectivity was observed. Based on these results, we selected the MPM
group as the most appropriate protective group, and carried out the synthesis illustrated in Figure 4.
Figure 4
MPMO
BnO
BnO
OH
OH
RO
O
MPMO
BnO
BnO
OBn
OBn
g
BnO
BnO
f
BnO
BnO
BnO
13 R = MPM
14 R = H
4
9a
h
i
15 R = Ms
OH
O
OH
OH
MsO
OH
OH
j
k
HO
HO
HO
OH
HO
OH
OH
HO
O
16
Cyclophellitol
Reagents and Conditions: f) Mes2BCH2Li, THF, r.t., 6 h; NaOH, H2O2, THF –
MeOH, r.t., 1 day, 78%; g) NaH BnBr, DMF-THF, r.t., 4 days, 93%; h) DDQ,
CH2Cl2 – H2O, 0ºC, 1.5 h, 96%; 1) MsCl, Et3N, CH2Cl2, r.t., 12 h, 91%; j)
Pd(OH)2/C, MeOH, r.t., 1 day, 77%; k) 1.0M NaOH, 1 h, 82%.
Two hydroxy groups of the diol 9a obtained through the hydroxymethylation process were protected
by benzyl groups and the MPM group was converted to a mesyl group. Then, all the benzyl groups were
simultaneously deprotected by catalytic hydrogenation to obtain the pentaol 16. The pentaol readily
underwent epoxide cyclization under alkaline conditions, and cyclophellitol was thus synthesized from
1 in 14% total yield.
In this synthetic method, the initial D-glycosides readily give rise to various epimers depending on
the conformation of glycosides and types of protective groups. The same method could be successfully
applied to the synthesis of the epimer of cyclophellitol with a different configuration at C3 (Figure 5).
The Ferrier-II reaction of the 5-enomannoside 19 promoted by a catalytic amount of PdCl2 provided
the corresponding cyclohexanone, which was subjected to a dehydration with MsCl-pyridine to give
enone 20. Stereoselective reduction under Luche’s conditions afforded the β-alcohol 21. After
protection of the hydroxy group, debenzoylation and subsequent protection with TBDMSOTf-lutidine
afforded 23.

Molecules 2005, 10
905
Figure 5
OBz
O
OH
HO
OBz
O
O
OBz
I
f
d, e
a, b
O
c
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
20
OMe
OMe
OMe
18
17
19
HO
HO
MPMO
BnO
MPMO
BnO
OTBDMS
OBz
OTBDMS
OBz
h, i
j
g
BnO
BnO
BnO
BnO
BnO
BnO
24
22
23
m, n
21
OTBDMS
OTBDMS
O
OTBDMS
O
MPMO
HO
MPMO
o, p
k
l
OH
OH
BnO
BnO
BnO
BnO
BnO
BnO
25
27
26
OBn
OH
OBn
MsO
MPMO
BnO
MsO
t
q, r
s
OH
OH
OBn
OBn
OBn
OBn
HO
HO
BnO
BnO
BnO
30
28
29
OH
O
HO
HO
OH
OH
HO
HO
3
31 R
OH
OH
O
Reagents and Conditions: a) PPH3, imidazole, I2, toluene, 80ºC, 30 min., 80%; b) BzCl, Et3N,
DMAP, r.t., 21 h., 99%; c) AgF, Py, r.t., 20 h., 99%; d) PdCl2, dioxane – H2O, 60ºC, 3 h., 86%; e)
MsCl, Et3N, CH2Cl2, 0ºC, 5 min., 95%; f) CeCl3·7H2O, NaBH4, MeOH, 0ºC, 30 min., 97% (α:β =
1:5); g) CCl3C(=NH)OMPM, TfOH. Et2O, r.t., 10 min., 95%; h) 2N NaOH, MeOH, r.t., 12 h., 82%;
i) TBDMSOTf, lutidine, CH2Cl2, r.t., 10 min., 95%; j) DDQ, CH2Cl2 - H2O, 0ºC, 3 h., 95%; k)
m-CPBA, Na2HPO4, CH2Cl2, r.t., 14 h., 86%; l) MPMCl, NaH, DMF – THF, 0ºC, 2.5 h., 66%; m)
Mes2BCH2Li, THF, r.t., 1 h.; n) 5N NaOH, H2O2, r.t., 30 min., 76% (2 steps); o) TBAF, THF, r.t., 2
days; p) NaH, BnCl, DMF – THF, 60ºC, 4 h., 89% (2 steps); q) DDQ, CH2Cl2 – H2O, r.t., 3 h.,
quant.; r) MsCl, Et3N, ClCH2CH2Cl, 60ºC, 5 h., 61%; s) H2, Pd(OH)2/C, MeOH, r.t., 20 h., 73%; t)
1.0M NaOH, r.t., 20 h., quant.
Deprotection of the MPM ether of 23 provided the β-alcohol 24, which was oxidized with m-CPBA
to yield the epoxide 25 efficiently in a highly diastereoselective manner. The remaining hydroxy group
was protected as an MPM ether to give 26. The subsequent introduction of a hydroxymethyl group by
nucleophilic opening of the epoxide afforded the diol 27 in good yield. Deprotection of 27 and
successive benzylation afforded 28, which was deprotected with DDQ and then mesylation provided the
mesylate 29. The fully-benzylated mesylate 29 was subjected to hydrogenolysis using 1 atm of H2 and
Pd(OH) 2 in MeOH to generate the deprotected mesylate 30. Finally, treatment of 30 with aqueous
NaOH afforded the cyclophellitol C3- epimer.

Molecules 2005, 10
906
Conclusions
We have presented a facile synthesis of cyclophellitol and its C3-epimer utilizing Ferrier-II reaction
mediated by PdCl2. This method enables not only the synthesis of various diastereomers of
cyclophellitol but also application of the new strategy for the regioselective hydroxymethylation
reaction of highly oxygenated cyclohexanes.
Acknowledgements
We thank Misses J. Shimode, M. Kitsukawa, and A. Tonoki for spectroscopic measurements. The
generous financial support for this research from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, Fujisawa Foundation, Hayashi Memorial Foundation for Female Natural
Scientists, and Uehara Memorial Foundation are gratefully acknowledged.
Experimental
General
Melting points were determined with a Yanagimoto micro melting point apparatus and are
uncorrected. IR spectra were measured with a JASCO FT/IR-8000 spectrometer. HRFAB-MS were
1
13
recorded with a JEOL SX-102A. H-NMR and C-NMR spectra were recorded at 600 MHz with a
JEOL GSX-600 spectrometer using tetramethylsilane (TMS) as the internal standard. Chemical shifts
were reported in ppm downfield from TMS. Optical rotations were measured with a JASCO DIP-370 in
a 1-dm cell. Analytical and preparative TLC was conducted on precoated TLC plates (silica gel 60 F254,
Merck). Column chromatography was performed using Merck silica gel 60 N (100–210 µm). All
anhydrous solvents were purified according to standard methods.
Spectral Data
(1S,2R,3S,4S,5R,6R)-2,3,4-Tris(benzyloxy)-5-[(4-methoxybenzyl)oxy]-7-oxabicyclo[4.1.0]heptane (4):
1H-NMR (CDCl3) δ: 7.50-7.24 (m, 17H), 6.90-6.85 (m, 2H), 4.90-4.60 (m, 8H), 3.88 (m, 2H), 3.79 (s,
3H), 3.60 (dd, 1H, J=10.4, 8.5), 3.46 (dd, 1H, J=10.4, 7.9), 3.27 (m, 1H), 3.18 (d, 1H, J=3.7); 13C-NMR
(CDCl3) δ: 159.3, 138.6, 137.6, 130.32, 129.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5,
113.83, 79.0, 76.7, 75.9, 75.5, 73.3, 72.7, 55.2, 53.9; HRMS (EI) for C35H36O6 (M+): Calcd 552.2512;
Found 552.2512.; Mp.110°C
(1S,2R,3R,4S,5R,6S)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methoxy]-7-oxabicyclo[4.1.0]heptane (6):
1H-NMR (CDCl3) δ: 7.38-7.27 (m, 20H), 5.00 (d, 1H, J=7.0), 4.94 (d, 1H, J=7.0), 4.89-4.59 (m, 6H),
4.07 (1H, dd, J=10.4, 1.8), 3.89 (d, 1H, J=7.9), 3.56 (dd, 1H, J=10.4, 8.5), 3.49 (dd, 1H, J=10.4, 7.9),
3.43 (m, 1H), 3.22 (d, 1H, J=3.7); HRMS (CI) for C35H36O2 (M+): Calcd 552.2512; Found 552.2514.
tert-Butyl(dimethyl)[[(1S,2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-7-oxabicyclo[4.1.0]hept-2-yl]oxy]-
silane (7): 1H-NMR (CDCl3) δ: 7.38-7.19 (m, 15H), 4.85-4.64 (m, 6H), 4.09 (m, 1H), 3.90 (m, 1H), 3.46

Molecules 2005, 10
907
(m, 2H), 3.25 (m, 1H), 3.18 (d, 1H, J = 4.0), 0.93 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); 13C-NMR (CDCl3) δ:
138.8, 138.6, 137.7, 128.5, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5, 127.3, 83.4, 79.7, 79.4, 75.7, 75.5,
73.3, 57.6, 54.0, 25.8, 18.1, -4.5, -4.6; HRMS (EI) for C33H42O5Si (MH+): Calcd 546.2802; Found
546.2802.
(1S,2R,3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-7-oxabicyclo[4.1.0]hept-2-yl acetate (8): 1H-NMR (CDCl3)
δ: 7.40-7.21 (m, 15H), 5.28 (d, 1H, J=8.2), 4.78-4.70 (m, 5H), 4.60 (d, 1H, J=11.6), 3.90 (d, 1H, J=7.3),
3.66-3.56 (m, 2H), 3.40 (m, 1H), 3.23 (d, 1H, J=3.7), 2.02 (s, 3H); 13C-NMR (CDCl3) δ: 170.5, 138.3,
137.4, 128.5, 128.3, 128.0, 127.8, 127.6, 83.2, 78.9, 75.6, 75.5, 73.6, 73.2, 54.6, 54.0, 20.9l; HRMS (EI)
for C29H30O6 (M+): Calcd 474.2043; Found 474.2044.
(1R,2S,3R,4R,5S,6R)-2,3,4-Tris(benzyloxy)-6-(hydroxymethyl)-5-[(4-methoxybenzyl)oxy]cyclohexanol
1
(9a): H-NMR (CDCl3) δ: 7.38-7.26 (m, 15H), 7.21 (m, 2H), 6.85 (m, 2H), 4.98 (d, 1H, J=11.6),
4.93-4.81 (m, 5H), 4.68 (d, 1H, J=11.3), 4.56 (d, 1H, J=10.7), 3.89 (dd, 1H, J=10.7, 3.1), 3.77 (s, 3H),
3.74 (dd, 1H, J=10.7, 4.7), 3.63 (dd, 1H, J=9.2, 9.2), 3.49 (m, 2H), 3.39 (m, 2H), 1.65 (m, 1H); 13C-NMR
(CDCl3) δ:152.6, 138.7, 138.6, 138.5, 130.4, 130.1, 129.9, 128.9, 128.7, 128.2, 128.1, 128.0, 127.9,
127.8, 114.2, 80.9, 79.3, 77.6, 77.5, 76.0, 75.9, 75.7, 75.2, 61.0, 47.5, 40.9; HRMS (EI) for C36H40O7
(M+): Calcd 584.2774; Found 584.2771; Mp. 131°C
(1R,2S,3R,4R,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-(hydroxymethyl)cyclohexanol (10a): 1H-NMR
(CDCl3) δ: 7.36-7.26 (m, 20H), 5.01-4.84 (m, 6H), 4.70-4.62 (m, 2H), 3.91 (m, 1H), 3.75 (m, 1H), 3.66
13
(dd, 1H, J=9.5, 9.5), 3.51 (m, 2H), 3.40 (m, 2H), 1.68 (m, 1H); C-NMR (CDCl3) δ: 138.4, 138.3, 138.1,
128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 86.3, 85.1, 83.2, 77.5, 77.2, 75.7, 75.5,
75.3, 70.6, 60.5, 46.1; MS (EI) for C35H38O6 (M+) : Calcd 554.2668; Found 554.2654
(1R,2R,3R,4R,5S,6R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methoxy]-6-(hydroxymethyl)cyclohexanol
(11a): 1H-NMR (CDCl3) δ: 7.40-7.22 (m, 20H), 5.20-4.70 (m, 9H), 4.53 (d, 1H, J=11.9), 3.94 (m, 1H),
3.85 (m, 1H), 3.60-3.36 (m, 5H), 1.57 (m, 1H); 13C-NMR (CDCl3) δ: 138.5, 138.3, 137.0, 128.6, 128.4,
128.0, 127.9, 127.8, 127.7, 127.6, 97.1, 85.8, 85.5, 83.1, 76.5, 75.7, 75.6, 75.4, 70.7, 69.1, 58.0, 46.0;
HRMS (EI) for C29H33O7: Calcd 493.2226; Found 493.2226.
(1S,2S,3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-2-[(benzyloxy)methoxy]-6-(hydroxymethyl)cyclohexanol
(11b): 1H-NMR (CDCl3) δ: 7.40-7.22 (m, 20H), 5.05-4.55 (m, 10H), 4.18 (m, 1H), 4.00-3.50 (m, 6H),
2.58 (m, 1H); HRMS (EI) for C29H33O7: Calcd 493.2226; Found 493.2226.
(1S,2S,3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-2-{[tert-butyl(dimethyl)silyl]oxy}-6-(hydroxymethyl)cyclo-
hexanol (12b): 1H-NMR (CDCl3) δ: 7.40-7.21 (m, 15H), 4.86-4.64 (m, 6H), 4.11 (dd, 1H, J=8.8, 5.9),
3.87 (m, 2H), 3.80 (dd, 1H, J=8.8, 8.8), 3.75 (dd, 1H, J=8.8, 2.9), 3.69 (dd, 1H, J=8.8, 8.8), 3.60 (dd, 1H,
J=11.0, 4.8), 2.59 (dddd, 1H, J=8.1, 4.8, 5.9, 2.9), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C-NMR
(CDCl3) δ: 138.8, 138.7, 138.0, 131.4, 128.5, 128.3, 128.2, 127.9, 127.8, 127.5, 127.4, 125.8, 82.4, 82.3,
80.1, 76.7, 75.6, 73.9, 73.8, 72.9, 61.4, 43.0, 25.8, 15.6, -4.5, -4.8; HRMS (EI) for C34H46O6Si: Calcd
578.3064; Found 578.3063.

Molecules 2005, 10
908
(1S,2R,3S,4S,5R,6S)-2,3,4,5-Tetrakis(benzyloxy)-6-[(benzyloxy)methyl]cyclohexanol (14): 1H-NMR
(CDCl3+D2O) δ: 7.33-7.26 (m, 25H), 5.00-4.44 (m, 10H), 3.82 (dd, 1H, J=8.8, 2.2), 3.70 (m, 2H), 3.62
(m, 2H), 3.53 (m, 1H), 3.40 (dd, 1H, J=9.2, 9.2), 1.69 (m, 1H); HRMS (EI) for C42H44O6 (M+): Calcd
644.3138; Found 644.3130.
(1S,2S,3R,4S,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-[(benzyloxy)methyl]cyclohexylmethanesulfonate
1
(15): H-NMR (CDCl3) δ: 7.40-7.10 (m, 25H), 5.10-4.35 (m, 11H), 3.87 (m, 1H), 3.75 (m, 1H), 3.67 (m,
1H), 3.65-3.56 (m, 3H), 2.80 (s, 3H), 1.85 (m, 1H); HRMS (EI) for C36H39O8S (M+): Calcd 631.2366;
Found 631.2365.
(1S,2S,3R,4S,5R,6R)-2,3,4,5-Tetrahydroxy-6-(hydroxymethyl)cyclohexylmethanesulfonate (16): 1H-
NMR (D2O) δ: 4.70 (dd, 1H, J=9.9, 9.9), 3.98 (d, 1H, J=12.0), 3.79 (d, 1H, J=12.0), 3.67 (dd, 1H, J=9.2,
9.2), 1H), 3.34 (m, 4H), 1.82 (dd, 1H, J=11.0, 11.0); HRMS (CI) for C13H24NO6 (MH+): Calcd
290.160363; Found 290.160300.
1
Cyclophellitol: H-NMR (D2O) δ: 4.01 (dd, 1H, J=11.0, 4.0), .83 (dd, 1H, J=11.0, 7.3), 3.79 (d, 1H,
J=8.4), 3.56 (dd, 1H, J=4.0, 1.8), 1H), 3.38 (dd, 1H, J=10.3, 8.4), 3.27 (m, 2H), 2.13 (m, 1H); 13C-NMR
(D2O) δ: 77.0, 71.6, 67.5, 61.2, 57.0, 56.7l; MS (EI) for C7H12O5 (M+): 176, (M+-H2O): 158.
Methyl 2-O-benzoyl-3,4-di-O-benzyl-6-deoxy-6-iodo-α-D-mannopyranoside (18): 1H-NMR (CDCl3) δ:
8.18-8.14 (m, 2H), 7.70-7.23 (m, 13H), 5.62 (m, 1H), 4.96 (d, 1H, J=10.7), 4.83 (d, 1H, J=1.8), 4.77 (d,
1H, J=11.3), 4.69 (d, 1H, J=10.7), 4.55 (d, 1H, J=11.3), 4.11 (dd, 1H, J=9.5, 1.3), 3.82 (dd, 1H, J=9.5,
9.5), 3.59-3.46 (m, 3H), 3.42 (s, 3H); IR (thin film) cm-1: 2954 (broad), 1736, 1611, 1524, 1439, 1323,
1204; HRMS (EI) for C28H29O6I (M+): Calcd 588.1009; Found 588.1022.
1
Methyl 2-O-benzoyl-3,4-di-O-benzyl-6-deoxy -α-D-lyxo-hex-5-enopyranoside (19): H-NMR (CDCl3)
δ: 8.08-8.04 (m, 2H), 7.61-7.22 (m, 13H), 5.62 (dd, 1H, J=5.5, 3.0), 4.94 (brs, 1H ), 4.88 (brs, 1H),
4.84-4.61 (m, 5H, J=11.3), 4.36 (d, 1H, J=9.5), 4.05 (dd, 1H, J=9.5, 3.0); 13C-NMR (CDCl3) δ: 170.4,
166.0, 130.2, 130.1, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 106.3, 84.8, 81.2, 77.4, 77.2,
72.4, 60.4; HRMS (EI) for C28H28O6 (M+) : Calcd 460.1886; Found 460.1876.
(1R,5S,6R)-5,6-Bis(benzyloxy)-4-oxocyclohex-2-en-yl benzoate (20): 1H-NMR (CDCl3) δ: 8.02-8.00 (m,
2H), 7.65-7.21 (m, 13H), 6.90 (dd, 1H, J=10.4, 4.0), 6.17 (d, 1H, J=10.4 ),6.07 (dd, 1H, J=3.7, 3.7), 4.88
(d, 1H, J=11.9), 4.70 (m, 3H), 4.24 (d, 1H, J=7.6), 4.19 (dd, 1H, J=7.6, 3.4); 13C-NMR (CDCl3) δ: 165.7,
143.6, 138.6, 136.8, 133.2, 128.3, 127.7, 126.5, 125.6, 86.6, 77.0, 76.9, 71.4, 69.5; HRMS (EI) for
C27H24O5 (M+): Calcd 428.1624; Found 428.1639.
1
(1R,4S,5R,6R)-5,6-Bis(benzyloxy)-4-hydroxycyclohex-2-en-1-yl benzoate (21): H-NMR (CD3OD) δ:
7.95 (m, 2H), 7.56-7.11 (m, 13H), 5.89-5.80 (m, 3H), 4.78-4.50 (m, 4H), 4.15 (d, 1H, J=7.3), 3.84 (dd,
1H, J=10.3, 7.3), 3.69 (dd, 1H, J=10.3, 3.7); HRMS (CI) for C13H24NO6 (MH+): Calcd 290.160363;
Found 290.160300.

Molecules 2005, 10
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(1R,4S,5R,6R)-5,6-Bis(benzyloxy)-4-[(4-methoxybenzyl)oxy]cyclohex-2-en-1-yl benzoate (22): 1H-
NMR (CDCl3) δ: 7.95 (m, 2H), 7.40-7.10 (m, 12H), 6.85 (m, 2H), 5.86 (m, 1H), 5.80 (m, 2H), 4.90 (1H,
d, J=11.0), 4.76 (1H, d, J=11.0), 4.70 (1H, d, J=11.6), 4.63 (1H, d, J=11.0), 4.56 (2H,m), 4.39 (3H, s),
4.05 (1H,m), 3.70 (2H,m); 13C-NMR (CDCl3) δ: 166.0, 159.2, 138.8, 138.4, 131.4, 130.1, 129.8, 129.7,
129.5, 128.5, 128.3, 127.7, 114.1, 114.0, 79.2, 78.7, 75.4, 68.7, 67.2, 64.6, 62.9, 55.5; HRMS (CI) for
C13H24NO6 (MH+): Calcd 290.160363; Found 290.160300.
[[(1R,4S,5R,6S)-5,6-Bis(benzyloxy)-4-[(4-methoxybenzyl)oxy]cyclohex-2-en-1-yl]oxy](tert-butyl)-
dimethylsilane (23): 1H-NMR (CDCl3) δ: 7.40-7.20 (m, 12H), 6.85 (m, 2H), 5.77-5.67 (m, 2H), 4.92 (d,
1H, J=11.0 ), 4.79 (d, 1H, J=11.0), 4.73 (s, 2H), 4.59 (d, 1H, J=11.3), 4.54 (d, 1H, J=11.3), 4.32 (dd, 1H,
J=8.2, 4.9), 4.22-4.02 (m, 2H), 3.80 (s, 3H), 3.40 (dd, 1H, J=9.8, 4.4), 0.88 (s, 9H), 0.08 (3H,s), 0.05 (3H,
s); MS (EI) for C34H44O5Si (M+) 560, (M+-tBu) 503.
1
(1S,4R,5S,6R)-5,6-Bis(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]cyclohex-2-en-1-ol (24): H-NMR
(CDCl3) δ: 7.38-7.26 (m, 10H), 5.78 (dd, 1H, J=10.4, 3.4), 5.70 (dd, 1H, J=10.4, 3.1), 4.82 (d, 1H,
J=11.9 ), 4.74-4.61 (m, 3H), 4.52 (m, 1H), 4.01 (m, 1H), 3.86 (dd, 1H, J=6.7, 4.3), 3.64 (dd, 1H, J=6.7,
13
3.5), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (3H, s); C-NMR (CDCl3) δ: 159.3, 143.0, 138.5, 129.9, 128.9,
128.7, 128.6, 128.1, 128.0, 127.9, 123.7, 121.8, 79.2, 79.0, 78.1, 77.4, 73.5, 72.6, 69.4, 54.3, 26.1, 22.3,
-4.3; HRMS (EI) for C26H36O4Si (M+): Calcd 440.2383; Found 440.2383.
(1R,2R,3S,4S,5S,6R)-3,4-Bis(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-oxabicyclo[4.1.0]heptan-
1
2-ol (25): H-NMR (CDCl3) δ: 7.38-7.18 (m, 10H), 4.78 (d, 1H, J=11.9), 4.54 (m, 3H), 4.36 (dd, 1H,
J=4.0, 3.1), 3.96 (m, 1H), 3.65 (dd, 1H, J=4.0, 3.1), 3.56 (dd, 1H, J=4.0, 4.0), 3.48 (dd, 1H, J=4.0, 4.0),
2.86 (d, 1H, J=10.1), 0.96 (s, 9H), 0.15 (s, 3H), 0.13 (3H, s); 13C-NMR (CDCl3) δ:137.8, 128.6, 128.3,
128.1, 127.7, 127.5, 80.8, 76.8, 76.6, 73.6, 72.8, 67.8, 55.7, 54.3, 25.7, 19.6, -4.8; HRMS (EI) for
C26H36O5Si(M+): Calcd 456.2332; Found 456.2327.
[[(1R,2S,3S,4R,5R,6R)-3,4-Bis(benzyloxy)-5-[(4-methoxybenzyl)oxy]-7-oxabicyclo[4.1.0]hept-2-yl]-
1
oxy](tert-butyl)dimethylsilane (26): H-NMR (CDCl3) δ: 7.40-7.20 (m, 12H), 6.92-6.82 (m, 2H),
4.88-4.62 (m, 6H), 4.31 (dd, 1H, J=4.6, 4.6), 3.89 (dd, 1H, J=10.1, 8.2), 3.80 (s, 3H), 3.74 (dd, 1H, J=8.2,
2.1), 3.22 (dd, 1H, J=4.5, 2.1), 3.19 (dd, 1H, J=4.5, 4.5), 3.14 (dd, 1H, , J=10.1, 4.6), 0.94 (s, 9H), 0.13
(3H, s), 0.11 (3H, s); 13C-NMR (CDCl3) δ: 157.7, 137.9, 131.0, 129.5, 1283.2, 127.6, 127.4, 127.3, 125.9,
122.7, 122.3, 76.9, 76.8, 76.7, 76.6, 70.0, 65.9, 58.8, 57.5, 50.4, 25.8, 19.7, -4.5; HRMS (EI) for
C34H44O6Si (M+): Calcd 576.2907; Found 576.2907.
(1R,2R,3S,4R,5S,6R)-3,4-Bis(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-6-(hydroxymethyl)-5-[(4-
1
methoxybenzyl)oxy]cyclohexanol (27): H-NMR (CDCl3) δ: 7.40-7.20 (m, 12H), 6.90-6.83 (m, 2H),
4.98 (d, 1H, J=11.0), 4.84 (m, 2H), 4.70 (s, 2H), 4.55 (d, 1H, J=11.0), 4.15 (dd, 1H, J=2.1, 2.1), 3.94 (dd,
1H, J=9.8, 9.8), 3.87 (dd, 1H, J=10.7, 3.7), 3.81 (m, 4H), 3.43 (m, 1H), 3.31 (dd, 1H, J=11.0, 9.8), 3.25
13
(dd, 1H, J=9.8, 2.1), 2.05 (2H, brs), 1.96 (1H, m); C=NMR (CDCl3) δ: 159.6, 138.6, 133.2, 129.2,
128.6, 128.5, 128.2, 128.1, 128.0, 127.8, 127.7, 114.2, 111.2, 78.6, 78.1, 77.0, 75.6, 75.1, 73.6, 72.1,
69.9, 61.4, 44.7, 26.3, 18.7, -4.8; HRMS (EI) for C35H48O7Si(M+): Calcd 608.3169; Found 608.3169.

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1-Methoxy-4-[[(1S,2R,3R,4R,5R,6R)-2,3,4,5-tetrakis(benzyloxy)-6-[(benzyloxy)methyl]-2-cyclohexyl]-
1
oxymethyl]benzene (28): H-NMR (CDCl3) δ: 7.40-7.20 (m, 27H), 7.12 (d, 1H, J=8.5), 6.80 (d, 1H,
J=8.5), 4.96 (d, 1H, J=10.7), 4.82 (m, 4H), 4.64 (m, 2H), 4.49 (m, 2H), 4.38 (m, 2H), 4.07 (m, 2H), 3.76
(s, 3H), 3.63 (dd, 1H, J=9.2, 9.2), 3.47 (dd, 1H, J=11.6, 1.8), 3.32 (dd, 1H, J=9.8, 1.8), 2.31 (1H, m);
HRMS (EI) for C43H45O7 (M+): Calcd 673.3166; Found 673.3165.
(1S,2S,3R,4R,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-[(benzyloxy)methyl]cyclohexylmethanesulfonate
1
(29): H-NMR (CDCl3) δ: 7.40-7.16 (m, 25H), 5.09 (dd, 1H, J=11.3), 4.82 (dd, 1H, J=11.0, 11.0),
4.69-4.35 (m, 9H), 4.12 (dd, 1H, J=9.5, 9.5), 4.03 (brs, 1H), 3.88 (dd, 1H, J=9.5, 2.5), 3.65 (dd, 1H,
J=9.5, 1.5), 3.50 (dd, 1H, J=11.3, 2.1), 3.36 (dd, 1H, J=11.3, 2.1), 2.81 (s, 3H), 2.45 (m, 1H); HRMS
(EI) for C43H46O8S (M+): Calcd 722.2914; Found 722.2916.
(1S,2S,3R,4R,5R,6R)-2,3,4,5-Tetrahydroxy-6-(hydroxymethyl)cyclohexylmethanesulfonate (30): HRMS
(CI) for C13H24NO6 (MH+): Calcd 290.160363; Found 290.160300.
1
(1S,2R,3R,4R,5R,6R)-5-(Hydroxymethyl)-7-oxabicyclo[4.1.0]heptane-2,3,4-triol (31): H-NMR (D2O)
δ: 3.85 (m, 1H), 3.82 (m, 2H), 3.65 (m, 1H), 3.43 (bs, 1H), 3.28 (d, 1H, J=9.5), 3.07 (m, 1H), 2.14 (m,
13
1H); C-NMR (D2O) δ: 71.0, 67.4, 66.2, 60.5, 56.3, 55.4, 38.5; HRMS (CI) for C13H24NO6 (MH+):
Calcd 290.160363; Found 290.160300.
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synthesis of (+)-vittatine. Chem. Commun. 2004, 1086-1087.
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Production, isolation and structure determination of a novel β-glucosidase inhibitor, cyclophellitol,
from Phellinus sp. J. Antibiol. 1990, 43, 49-53.
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regioselectivity of oxirane ring opening with Mes2BCH2Li. Tetrahedron Letts. 1998, 39,
6939-6942.
6. Semeria, D.; Philippe, M.; Delaumeny, J-M.; Sepulchre, A-M.; Gero, S. D. A general synthesis of
cyclitols and aminocyclitols from carbohydrates. Synthesis 1983, 710-713.
7. Iimori, T.; Takahashi, H.; Ikegami, S. Palladium chloride mediated rearrangement of
6-deoxyhex-5-enopyranosides into cyclohexanones. Tetrahedron Letters 1996, 37, 649-652.
8. Takahashi, H.; Kittaka, H.; Ikegami, S. Novel synthesis of enantiomerically pure natural inositols
and their diastereoisomers. J. Org. Chem. 2001, 66, 2705-2716.
9. Gemal, A. L.; Luche, J. L. Lanthanoids in organic synthesis. 6. Reduction of α-enones by sodium
borohydride in the presence of lanthanoid chlorides: synthetic and mechanistic aspects. J. Am.
Chem. Soc. 1981, 103, 5454-5459.

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10. Jaramillo, C.; Chiara, J-L.; Martin-Lomas, M. An effective strategy for the synthesis of
6-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-D-chiro-and –D-myo-inositol 1-phosphate related to
putative insulin mimetics. J. Org. Chem. 1994, 59, 3135-3141.
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Samples Availability: Available from the authors.
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