Stereoselective synthesis of bishomo-inositols as glycosidase inhibitors

Article abstract of DOI:10.1021/jo801344f

(Chemical Equation Presented) For the synthesis of various bishomo-inositol derivatives, 1,3,3a,7a-tetrahydro-2-benzofuran was used as the key compound. For further functionalization of the diene unit, the diene was subjected to photooxygenation, epoxidat

Full text of DOI:10.1021/jo801344f

Stereoselective Synthesis of Bishomo-inositols as Glycosidase
Inhibitors
Arif Baran*,†,‡ and Metin Balci*,†
Department of Chemistry, Middle East Technical UniVersity, 06531 Ankara, Turkey, and
Department of Chemistry, Sakarya UniVersity, 54100 Sakarya, Turkey
baranarif@yahoo.com; mbalci@metu.edu.tr
ReceiVed June 25, 2008
For the synthesis of various bishomo-inositol derivatives, 1,3,3a,7a-tetrahydro-2-benzofuran was used as
the key compound. For further functionalization of the diene unit, the diene was subjected to
photooxygenation, epoxidation, and cis-hydroxylation reactions. The endoperoxide linkage was cleaved
by thiourea. The remaining double bond was subjected to epoxidation and cis-hydroxylation reactions.
The epoxide rings and tetrahydrofuran rings formed were opened by acid-catalyzed reaction with sulfamic
acid. The combination of these reactions resulted in the formation of various new inositol derivatives
such as bishomo-chiro-inositol, bishomo-myo-inositol, and two isomeric bishomo-allo-inositols.
Introduction
acts as a Ca2+-mobilizing intracellular second messenger, many
other inositol phosphates have been discovered, although it is
only in recent years that their physiological functions have begun
to be understood.2-4
Inositols (cyclohexanehexols) are sugar-like molecules. There
are nine stereoisomers, all of which may be referred to as
inositol.1 The most prominent naturally occurring form is myo-
inositol, cis-1,2,3,5-trans-4,6-cyclohexanehexol, and it is actively
involved in cellular events and processes. Other naturally
occurring isomers are scyllo-, chiro-, muco-, and neo-inositol.
It is assumed that these isomers may be made from myo-inositol
by inversion of the configuration (epimerization) of one or two
hydroxyl groups.5 Inositol 1,4,5-trisphosphate is a second
messenger molecule used in signal transduction in biological
cells. Since the discovery that myo-inositol 1,4,5-triphosphate
New synthetic methodologies for various inositols and their
derivatives have been developed.6 Motivated by the medical
value of certain cyclitol derivatives, we formulated a general
† Middle East Technical University.
‡ Sakarya University.
(1) Michell, R. H. Nat. ReV. Mol. Cell Biol. 2008, 9, 151–161. Inositol
Phosphates and DeriVatiVes: Synthesis, Biochemistry and Therapeutic Potential;
Reitz, A. B., Ed.; American Chemical Society: Washington, DC, 1991.
(2) Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315–321.
(3) Berridge, M. J. Nature 1993, 361, 315–325.
(4) Irvine, R. F.; Schell, M. J. Nat. ReV. Mol. Cell Biol. 2001, 2, 327–338.
(5) Hipps, P. P.; Sehgal, R. K.; Holland, W. H.; Sherman, W. R. Biochemistry
1973, 12, 4705–4712.
88 J. Org. Chem. 2009, 74, 88–95
10.1021/jo801344f CCC: $40.75 2009 American Chemical Society
Published on Web 12/03/2008

SCHEME 1
SCHEME 2
strategy of synthesis based on the photooxygenation of the
appropriate dienes.7 Our aim in the present work was to design
a synthesis of an analogue of this molecule, bishomo-inositols,
using simple starting materials.
the substituents play an important role in determining the
direction of the addition. We assume that the repulsive interac-
tion13 between the nonbonded electron pairs on the heteroatoms
present in the tetrahydrofuran ring and on the singlet oxygen
molecule is responsible for the exclusively anti addition.14
After successful isolation and characterization of the endop-
eroxide 6, we turned our attention to the reduction of the
peroxide linkage in 6. Selective reduction of the peroxide linkage
with thiourea under very mild conditions followed by acetylation
in pyridine afforded the diacetate 7 in 87% yield. Since only
the oxygen-oxygen bond breaks in this reaction, it preserves
the configuration at all carbon atoms. For further functional-
ization of the double bond, diacetate 7 was submitted to a cis-
hydroxylation reaction with OsO4-NMO15 followed by acety-
lation to give the tetraacetate 8. The spectral data confirmed
the formation of a single isomer. The stereochemical course of
the hydroxylation may be syn or anti with respect to the
tetrahydrofuran ring. NMR spectroscopic studies did not allow
the assignment of the configuration of the acetate groups. The
exact configuration of this tetraacetate 8 was later proven by
comparison of the spectral data of the tetraacetate 8 with those
obtained by cis-hydroxylation of the diene 5 with OsO4 (see
Scheme 4). We assume that the molecule 7 prefers mainly the
boat conformation in which the acetate groups are located in
the pseudoequatorial positions. syn-Face attack of OsO4 is
hindered by axial hydrogens as well as by the tetrahydrofuran
ring. Similar results have been observed recently by our research
group.16
Results and Discussion
The synthesis of the key compound 58 used in the synthesis
of bishomo-inositols began with readily available anhydride 1
and was followed by the sequence of steps outlined in Scheme
1. Treatment of the anhydride 1,9 obtained by the addition of
maleic anhydride to in situ generated butadiene, with LiAlH4
yielded the diol 2.10 The diol 2 was successfully converted to
the desired tetrahydrofuran derivative 3 by treatment of 2 with
tosyl chloride in pyridine.11 The resulting compound 3 was
brominated at low temperature to give only the trans-dibromo
compound 4 in high yield. Hydrogen bromide elimination with
1,8-biazabicyclo[5.4.0]undec-7-ene (DBU) in methylene chlo-
ride at 0 °C gave the diene 5.
Photooxygenation of 5 in methylene chloride (500 W,
projection lamp) at room temperature using tetraphenylporphyrin
as the sensitizer afforded the bicyclic endoperoxide 6 in a yield
1
of 85%. The H and 13C NMR spectra reveal the formation of
only one isomer. The four-line 13C NMR spectrum is in good
agreement with the structure 6, which possesses a symmetry
element. The diene unit in 5 is dissymmetric12 and can be
attacked from both sides of the diene. It is well established that
(6) (a) Azab, A. N.; He, Q.; Ju, S.; Li, G.; Greenberg, M. L. Mol. Microbiol.
2007, 63, 1248–1258. (b) Moris, M.-A.; Caron, A. Z.; Guillemette, G.; Rognan,
D.; Schmitt, M.; Schlewer, G. J. Med. Chem. 2005, 48, 1251–1255. (c) Freeman,
S.; Hudlicky, T. Bioorg. Med. Chem. Lett. 2004, 14, 1209–1212. (d) Podeschwa,
M.; Plettenburg, O.; vom Brocke, J.; Block, O.; Adelt, S.; Altenbach, H.-J. Eur.
J. Org. Chem. 2003, 1958–1972. (e) Mills, S. J.; Riley, A. M.; Liu, C.; Mahon,
M. F.; Potter, B. V. L. Chem.-Eur. J. 2003, 9, 6207–6214. (f) Cid, M. B.;
Bonilla, J. B.; Alfonso, F.; Martin-Lomas, M. Eur. J. Org. Chem. 2003, 3505–
3514. (g) Dinkel, C.; Schultz, C. Tetrahedron Lett. 2003, 44, 1157–1159. (h)
Praveen, T.; Shashidhar, M. S. Carbohyd. Res. 2001, 330, 409–411. (i) Chung,
S.-K.; Kwon, Y.-U.; Chang, Y.-T.; Sohn, K.-H.; Shin, J.-H.; Park, K.-H.; Hong,
B.-J.; Chung, I.-H. Bioorg. Med. Chem. 1999, 7, 2577–2589. (j) Riley, A. M.;
Jenkins, D. J.; Potter, B. V. L. Carbohydr. Res. 1998, 314, 277–281. (k) Brammer,
L. E., Jr.; Hudlicky, T. Tetrahedron: Asymmetry 1998, 9, 2011–2014.
(7) (a) Gultekin, M. S.; Celik, M.; Balci, M. Curr. Org. Chem. 2004, 13,
1159–1186. (b) Balci, M. Pure Appl. Chem. 1997, 69, 97–104. (c) Balci, M.;
Su¨tbeyaz, Y.; Secen, H. Tetrahedron 1990, 46, 3715–3742.
Sulfamic acid17 was used as an efficient catalyst in acetic
anhydride to promote the acetolysis reaction of the tetrahydro-
furan ring in 8 to produce the hexaacetate 9 in 84% yield
(Scheme 2). In particular, the 13C NMR spectrum consisting of
10 resonance signals was in agreement with the proposed
(13) (a) Gillard, J. R.; Burnell, D. J. J. Chem. Soc., Chem. Commun. 1989,
1439–1440. (b) Paquette, L. A.; Branan, B. M.; Rogers, R. D.; Bond, A. H.;
Lange, H.; Gleiter, R. J. Am. Chem. Soc. 1995, 117, 5992–6001.
(14) For anti-addition of singlet oxygen to similar systems see: (a) Kelebekli,
L.; Kara, Y.; Balci, M. Carbohydr. Res. 2005, 340, 1940–1948. (b) Secen, H.;
Sutbeyaz, Y.; Balci, M. Tetrahedron Lett. 1990, 31, 1323–1326. (c) Adam, W.;
Balci, M.; Rivera, J. Synthesis 1979, 10, 807–808. (d) Adam, W.; Balci, M.
J. Am. Chem. Soc. 1979, 101, 7542–7547. (e) Foster, C. H.; Berchtold, G. A. J.
Org. Chem. 1975, 40, 3743–3746.
(8) Ashkenazi, P.; Ginsburg, D.; Scharf, G.; Fuchs, B. Tetrahedron 1977,
33, 1345–1348.
(9) (a) Goodridge, R. J.; Hambley, T. W.; Ridley, D. D. Aust. J. Chem. 1986,
39, 591–604. (b) Hall, H. K., Jr.; Nogues, P.; Rhoades, J. W.; Sentman, R. C.;
Detar, M. J. Org. Chem. 1982, 47, 1451–1455.
(10) (a) Ochia., H.; Ishida, A. Eur. J. Med. Chem. 2004, 39, 555–571. (b)
Von Langen, D. J.; Tolman, R. L. Tetrahedron Asymmetry 1997, 8, 677–681.
(c) Ladbury, J. E.; Turner, E. E. J. Chem. Soc. 1954, 3885–3886.
(11) (a) Miyafuji, A.; I.; Katsuji, K., T. Heterocycles 2000, 52, 261–272.
(b) Henbest, H. B.; Jackson, W. R.; Robb, B. C. G. J. Chem. Soc. B 1966, 803–
807.
(15) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973–1976.
(16) (a) Kara, Y.; Balci, M. Tetrahedron 2003, 59, 2063–2066. (b) Kelebekli,
L.; Kara, Y.; Balci, M. Carbohydr. Res. 2005, 340, 1940–1948.
(17) (a) Gong, W. Z.; Wang, B.; Gu, Y. L.; Yan, L.; Yang, L. M.; Suo, J. S.
Chin. Chem. Lett. 2005, 16, 747–750. (b) Wang, B.; Gu, Y.; Gong, W.; Kang,
Y.; Yang, L.; Suo, J. Tetrahedron Lett. 2004, 45, 6599–6602.
(12) Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278–286.
J. Org. Chem. Vol. 74, No. 1, 2009 89

Baran and Balci
SCHEME 3
SCHEME 5
the basis of these findings we assigned a trans-trans-cis relation
to the acetate groups in 12. These configurational assignments
show that the epoxide ring in 11b undergoes a normal trans
ring-opening reaction. It is surprising to note that the neighboring
acetoxy groups are not involved (no anchimeric assistance) in
the ring-opening reaction. This can be attributed to the cis
configuration of the acetoxy groups with respect to the epoxide
ring. To support these observations chemically, acetate groups
were removed by treatment of 11b with ammonia in methanol
to give 11a. Acid-catalyzed ring opening of 11a followed by
acetylation afforded 12 that was identical to the compound
obtained from the ring-opening reaction of epoxy diacetate 11b
described above. Noninvolvement of the acetates in the ring-
opening reaction was further proven. Deacetylation of 13 with
ammonia gave hexol, bishomo-chiro-inositol 14, in 94%. The
asymmetry in the molecule was in complete in agreement with
the spectroscopic data.
SCHEME 4
The diene 5 is an ideal substrate for the synthesis of further
bishomo-inositol derivatives. For that reason, one of the double
bonds of diene 5 was cis-hydroxylated with OsO4-NMO
oxidation (Scheme 4). After acetylation of the reaction mixture,
only a single isomer 15 was isolated in 70% yield. The NMR
spectroscopic studies did not reveal the exact configuration of
the acetate groups in 15, which was later proven by chemical
reactions (see Scheme 6). Further reaction of diacetate 15 with
an additional 1 mol of OsO4 followed by acetylation with acetic
anhydride in pyridine resulted in the formation of two easily
separable tetraacetates (one with symmetrical configuration and
the other unsymmetrical configuration) 8 and 16. The spectral
data of the symmetrical tetraacetate was in complete agreement
with 8, which was obtained by cis-hydroxylation of 7 followed
by acetylation (see Scheme 2). The formation of the tetraacetate
8 from this reaction also establishes the exact configuration of
15. For the formation of this symmetrical tetraacetate 8, where
all acetoxy groups are in cis-position, the acetate groups in 15
must be in anti position with respect to the tetrahydrofuran ring.
Thus, the formed tetraacetate 16 was converted to the hexaac-
etate 17. Hexol 18 itself was readily and almost quantitatively
obtained by ammonolysis of the hexaacetate 17 in methanol.
structure. Deacetylation of 9 with ammonia was carried out in
methanol to give the free hexol, bishomo-allo-inositol 10, in
91% yield.
For the synthesis of other isomeric bishomo-inositol deriva-
tives, the diacetate 7 was reacted with m-CPBA to give 11b as
the sole isomer (Scheme 3). The exact configuration of the
1
epoxide was confirmed by H NMR spectroscopy. The most
conspicuous feature in the 1H NMR spectrum is the sharp singlet
arising from the epoxide proton-resonances at 3.43 ppm.
Geometry optimization calculations (AM1) for the syn- and anti-
epoxides with respect to the tetrahydrofuran ring show dihedral
angles of 128° and 82° for H1a-H2. The 82° angle in 11b is
consistent with our assignments. Furthermore, a similar result
(antihydroxylation) was obtained by OsO4 reaction (Scheme 2).
Epoxy diacetate 11b was subjected to an acid-catalyzed ring-
opening reaction in the presence of acetic anhydride. Treatment
of 11b with sulfuric acid for 7 h followed by acetylation gave
only the tetraacetate 12. However, the sulfamic acid catalyzed
reaction of 11b in acetic acid in the presence of acetic anhydride
for 24 h resulted in the opening of the epoxide ring as well as
the tetrahydrofuran ring to afford 13. To determine the exact
configuration of 12, first we made full assignments for the
acetoxy protons with the help of the COSY spectrum. The
acetoxy proton H4 in 12 resonates as a triplet with a coupling
constant of J ) 9.8 Hz, clearly indicating that the neighboring
protons H3 and H5 are in trans positions. The fact that the proton
H5 appears as a doublet of doublets with coupling constants of
J ) 9.8 and 9.3 Hz also support the trans relation of the protons
H5 and H6. The resonance signal of H6 appears as a doublet of
doublets with coupling constants of J ) 9.3 and 3.2 Hz, which
clearly supports the cis relation of the protons H6 and H7. On
FIGURE 1. AM1 optimized geometries for isomers 19 and 20.
90 J. Org. Chem. Vol. 74, No. 1, 2009

SCHEME 6
SCHEME 7
subjected to a hydrolysis reaction with sulfamic acid the
tetraacetate 12 and its further hydrolysis product 13 were not
formed; instead, the isomeric tetraacetate 25 was probably
formed as the intermediate, which underwent a further ring-
opening reaction of the tetrahydrofuran ring to give 26. It is
likely that there is neighboring group participation controlling
the mode of the reaction. Probably, the initially protonated
epoxide ring undergoes an attack by the adjacent acetoxy group
to form cyclic oxolonium ion 24, which can undergo ring
opening through attack by acetate ions. Two possible products
16 and 25 can be formed. We were not able to detect any
trace of the isomeric tetraacetate 16 (attack a), which was
formed by the cis-hydroxylation reaction of the diene 5 (see
Scheme 4). The sole formation of 25 can be attributed to the
attack from the less hindered site in 24. Hydrolysis of 25
with ammonia in MeOH resulted in the formation of the
bishomo-myo-inositol 26 in 95% yield.
Finally, the epoxy diacetate 20 was submitted to a sulfamic
acid catalyzed ring-opening reaction in the presence of acetic
anhydride (Scheme 7). The epoxide as well as the tetrahydro-
furan ring underwent a ring-opening reaction to give the
tetraacetate 9 that was identical to the compound obtained by
the hydrolysis of 8 (Scheme 2). The exclusive formation of this
isomer can be explained by the neighboring group participation
of the acetate group as discussed above.
Kinetic Resolution of 15. To test the inhibitory activities of
the individual enantiomers in assay, the racemic diacetate 15
was resolved. First, for the resolution of the racemic mixture
(()-15, PLE was used. Unfortunately, we were not able to obtain
satisfactory results. After this, we turned our attention to the
enantioselective esterification of the diol (()-28, which was
synthesized by hydrolysis of the diacetate (()-15 with ammonia
in methanol (Scheme 8). Lipases are able to catalyze asymmetric
hydrolysis18 as well as esterification.19 Among the lipases
studied, Candida antarctia (Novozyme) proved to be suitable
for the enantioselective esterification of substrate (()-28. To a
stirred solution of (()-28 in vinyl acetate was added C. antarctia
lipase in one portion, and reaction mixture was shaken at 30
°C. The conversion was monitored by TLC. After 24 h, about
50% conversiton was observed. The residue was purified on
silica gel to give (+)-28 in a 45% yield and a mixture of the
monoacetates 29 and 30, which were converted into the diacetate
(-)-15 in high yield. The diol (+)-28 was also converted in
the corresponding diacetate (+)-15. The analysis of the separated
enantiomers showed that the enantiomer (+)-15 was formed
with 89% ee, whereas the enantiomer (-)-15 with 80% ee,
respectively. After the successful synthesis of those enatomeri-
For the synthesis of further bishomo-inositols, the diacetate
15 was reacted with m-CPBA to give two isomers 19 and 20 in
51% and 26% yields in addition to the epoxide-opening products
21 and 22. The structures of 19 and 20 were assigned on the
1
basis of H NMR spectra. The most conspicuous features in
the 1H NMR spectra of these epoxides 19 and 20 are the epoxide
proton resonances. The epoxide protons (H1a and H6b) of 19
resonating at δ 3.39 (J ) 3.6 Hz) and 3.26 (J ) 3.6 Hz) as
triplets show further splitting with adjacent protons. However,
the epoxide protons of 20 appear at δ 3.44 (J ) 3.6 Hz) and
3.16 (d, J ) 3.6) as a triplet and a doublet, respectively. There
is no coupling between the epoxide protons H6b and H6a in 20.
Geometry optimization calculations (AM1) on the molecules
19 and 20 show a dihedral angle of 15° for H6b-H6a in 19 and
78° for H6b-H6a in 20, which are consistent with our assignments.
The positions of chlorine atoms in 21 and 22 were determined
with the help of the COSY spectra. The exact configuration of
the substituents was established by measuring the corresponding
coupling constants between the relevant protons. The acetoxy
proton H-5 in 21 resonates as a triplet with a coupling constant
of J ) 2.6 Hz, indicating the cis configuration of the neighboring
protons H-4 and H-6. Furthermore, the large coupling between
the protons H-6 and H-7 (J6,7 ) 11.2 Hz) shows the trans
relation between those protons. On the other hand, the triplet
resonance of the proton H-6 in 22 with a large coupling constant
(J5,6 ) J6,7 ) 10.7 Hz) indicates the trans configuration of the
neighboring protons. After correct assignment of the configura-
tions to the chlorine compounds 21 and 22 we assume that these
compounds are formed by HCl-catalyzed ring-opening reaction
of the isomer 20.
Next we studied the epoxide-opening reaction of 19. To
prevent any neighboring group participation by the acetate we
decided to remove the acetates before the ring-opening. For that
reason, the syn-epoxide 19 was subjected to hydrolysis with
ammonia in methanol to provide the epoxy-diol 23 (Scheme
6). The diol 23 was submitted to a ring-opening reaction with
sulfuric acid followed by acetylation with acetic anhydride in
pyridine. The formed tetraacetate 12 was identical to those
obtained from the ring-opening reaction of the epoxide 11. We
assume that the acetate anion prefers to attack the protonated
epoxide ring from the less crowded side to produce 12 as a
single isomer. However, when the epoxy-diacetate 19 was
(18) (a) Ladner, W. E.; Whitesides, G. M. J. Am. Chem. Soc. 1984, 106,
7250–7251. (b) Ozdemirhan, F. D.; Celik, M.; Atli, S.; Tanyeli, C. Tetrahedron:
Asymmetry 2006, 17, 287–291.
(19) (a) Zaks, A.; Klibanov, A. M. Science 1984, 224, 1249–1251. (b) Zaks,
A.; Klibanov, A. M. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 3192–3196. (c)
Sweers, H. M.; Wong, C.-H. J. Am. Chem. Soc. 1986, 108, 6421–6422. (d) C¸ elik,
M.; Gu¨ltekin, M. S.; Turkut, E.; Tanyeli, C.; Balci, M. Tetrahedron: Asymmetry
2004, 15, 453–456.
J. Org. Chem. Vol. 74, No. 1, 2009 91

Baran and Balci
TABLE 1. Inhibition of r-Glycosidases by 10, 14, (()-18, (+)-18,
(-)-18, and 27
SCHEME 8
cally enriched diacetates, they were converted into the corre-
sponding hexols (+)-18 and (-)-18 as described above (Scheme
8).
a Four experiments are performed for all compounds and in duplicate
in each experiment. b NI ) no inhibition (the compound was added in
the 5-200 µM range and did not show any inhibition). c Inhibition by
20 µM compound. d Inhibition by 10 µM compound. e Inhibition by 5
µM compound. f Concentration required for 50% inhibition of the
enzyme activity under the assay conditions. g NT ) not tested
r-Glycosidase Inhibition Assay. The inhibitory activities of
10, 14, (()-18, (+)-18, (-)-18, and 27 were screened against
R-glycosidase. The results are summarized in Table 1. Bishomo-
chiro-inositol 14 did not show inhibition for R-glycosidase even
for higher than 200 µM concentration. The other compounds
showed R-glycosidase inhibitions and inhibition rates were 57
( 0.96% for 10 µM, 13 ( 4% for 20 µM, and 26 ( 5.5% for
5 µM concentration for the compounds 10, 18, and 24,
respectively. The racemic hexol 18 was resolved, and individual
enantiomers were tested in the assay. We noticed that the
R-glycosidase inhibitions of the individual enantiyomers (+)-
18 and (-)-18 were increased compared with the racemic
mixture (()-18 (Table 1).
In summary, with relatively little synthetic effort, we achieved
the stereoselective synthesis of four isomeric bishomo-inositol
derivatives 10, 14, 18, and 27 starting from the diene 5 and
introduced the complex stereochemistry in a very simple way,
by combination of photooxygenation, epoxidation, and cis-
hydroxylation reactions. Some of the synthesized isomers
showed R-glycosidase inhibitions. In the case of 18, the
individual enantiomers showed increased inhibitions. Further
studies of the chemistry of the double bonds in 5 directed toward
the synthesis of bishomo-aminoinositols are currently in progress.
CDCl3) δ 5.69 (s, 2H), 3.89 (dd, A-part of AB-system, J ) 7.5
and 6.4 Hz, 2H), 3.54 (dd, B-part of AB-system, J ) 7.5 and 5.6
Hz, 2H), 2.36 (m, 2H), 2.26-2.22 (m, 2H), 1.95 (dd, J ) 16.0 and
3.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 124.9, 73.1, 35.3,
24.1; IR (KBr, cm-1) 3025, 2927, 2857, 1485, 1437, 1377, 1309,
1209, 1189, 1175, 1120, 1088, 1055, 1019, 968, 951, 899. Anal.
Calcd for C8H12O: C, 77.38; H, 9.74. Found: C, 77.4; H, 9.7.
3aR(S),5R(S),6S(R),7aS(R)-5,6-Dibromooctahydro-2-benzofu-
ran (4). To a magnetically stirred solution of 4 (10.0 g, 80,65 mmol)
in 300 mL of dry CH2Cl2 at 0 °C was added dropwise a solution
of bromine (13.0 g, 81.2 mmol) in 200 mL of CH2Cl2 over a period
of 1 h. The reaction mixture was stirred for an additional 2 h at
room temperature. The solvent was evaporated. Crystallization of
the residue from ether at 0 °C gave 17.87 g of pure 4 (78% after
1
crystallization) as white crystals. Mp 58-60 °C; H NMR (400
MHz, CDCl3) δ 4.42-4.37 (m, 1H), 4.29-4.24 (m, 1H), 3.92-3.81
(m, 3H), 3.69-3.65 (m, 1H), 2.61-2.46 (m, 3H), 2.42-2.36 (m,
1H), 2.25-2.15 (m, 1H), 2.12-2.05 (m, 1H); 13C NMR (100 Mhz,
CDCl3) δ 72.4, 70.2, 53.2 (2x), 38.3, 37.2, 34.5, 33.2; IR (KBr,
cm-1) 2926, 2871, 1306, 1286, 1246, 1169, 1158, 1118, 1069, 1041,
1029, 1013, 980, 942, 934, 903. Anal. Calcd for C8H12Br2O: C,
33.83; H, 4.26. Found: C, 34.00; H, 4.23.
3aR(S),7aS(R)-1,3,3a,7a-Tetrahydro-2-benzofuran (5). To a
solution of dibromide 4 (15.0 g, 52.82 mmol) in 400 mL of dry
benzene was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-
ene (36.0 g, 236 mmol) in 400 mL of dry benzene at room
temperature. The reaction mixture was refluxed for 6 h and then
Experimental Section
1R(S),3S(R)-1,3,3a,4,7,7a-Hexahydro-2-benzofuran (3). Hexahy-
drobenzofuran derivative 3 was prepared according to same
procedure as described in the literature.11 1H NMR (400 MHz,
92 J. Org. Chem. Vol. 74, No. 1, 2009

cooled to room temperature. The solid was filtered off. The benzene
phase was poured into water (1000 mL) and extracted with ether
(3 × 500 mL). The combined organic phase was washed with
saturated aqueous sodium bicarbonate (3 × 500 mL), dried
(Na2SO4), and evaporated in vacuum to give 4.51 g of 5 (70%) as
a colorless liquid.11 1H NMR (400 MHz, CDCl3) δ 5.86-5.80 (m,
2H), 5.62-5.59 (m 2H), 4.16-4.12 (m, 2H), 3.60-3.57 (m, 2H),
2.96 (bs, 2H); 13C NMR (100 MHz, CDCl3). 126.2, 122.3, 75.0,
37.8.
cedure for Sulfamic Acid Catalyzed Hydrolysis. To a stirred
solution of 2.0 g (5.62 mmol) of tetraacetate 8 in Ac2O/AcOH (15
mL 1:1) was added a catalytic amount of 100 mg (1.0 mmol) of
sulfamic acid at room temperature, followed by refluxing for 24 h.
The mixture was poured into water (100 mL), acidified with HCl
(2-3 drops), and extracted with dichloromethane. The organic phase
was washed with water (2 × 100 mL) and saturated NaHCO3 (2 ×
50 mL) and dried (MgSO4). Crystallization from EtOAc/hexane
(1:2) gave 2.17 g (84%) of 9 as colorless crystals, mp 154-156
°C. 1H NMR (400 MHz, in CDCl3) δ 5.38 (bs, 1H), 5.31 (bd, J )
3.7 Hz, 2H), 4.27 (dd, A-part of AB-system, J ) 11.9 and 6.0 Hz,
2H), 4.19 (dd, B-part of AB-system, J ) 11.9 and 4.8 HZ, 2H),
2.67 (bs, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.6, 170.0, 169.9, 68.5, 67.9, 61.8, 34.2,
21.00, 20.9, 20.8; IR (KBr, cm-1) 2970, 1734, 1469, 1433, 1373,
1233, 1174, 1128, 1035, 983, 965, 954. Anal. Calcd for C20H28O12:
C, 52.17; H, 6.13; O. Found: C, 52.12; H, 6.08.
1R(S),2R(S),6S(R),7S(R)-4,10,11-Trioxa-tricyclo[5.2.2.02,6]undec-
8-ene (6). A stirred solution of cyclohexadiene derivative 5 (10.0
g, 81.9 mmol) and 200 mg of tetraphenylporphyrine (TPP) in 250
mL of CH2Cl2 was irradiated with a projection lamp (500 W) while
oxygen was passed through the solution The reaction was completed
after 12 h. Evaporation of solvent (30 °C, 20 mmHg) and
crystallization of the residue from ether gave 10.7 g of pure
1
endoperoxide (85%) as colorless crystals. Mp 123-126 °C; H
NMR (400 MHz, CDCl3) δ 6.68 (quasi t, A-part of AA′XX′-system,
2H), 4.71 (m, X-part of AA′XX′-system, 2H), 3.73 (m, 2H), 3.50
(dd, J3,3′(5,5′) ) 9.3 and 2.6 Hz, 2H), 3.03 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 131.9, 72.4, 70.0, 39.9; IR (KBr, cm-1) 3079, 2958,
2923, 2861, 1475, 1465, 1377, 1277, 1198, 1129, 1075, 1040, 1029,
965, 950. Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C,
62.03; H, 6.59.
Synthesis of cis-5,6-Bis(hydroxymethyl)cyclohexane 1,2,3,4-
Tetraol (10). Tetraacetate 9 (1.0 g, 2.17 mmol) was dissolved in
75 mL of absolute methanol. While dry NH3(g) was passed through
solution, the mixture was stirred for 5 h. Evaporation of solvent
and formed acetamide gave hexol 10, which was crystallized from
EtOH to give colorless powder (0.37 g, 91%). Mp 142-144 °C;
1H NMR (400 MHz, in D2O at 60 °C) δ 4.71 (s, 6H, -OH),
4.39-4.27 (m, 4H), 4.22-4.1 (m, 4H), 2.8-2.7 (m, 2H)); 13C NMR
(100 MHz, in D2O at 60 °C) δ 70.2, 70.1 59.6, 38.9; IR (KBr,
cm-1) 3332, 2926, 2890, 2430, 1450, 1391, 1323, 1236, 1147, 1109,
1080, 1046, 982, 882. Anal. Calcd for C8H16O6: C, 46.15; H, 7.75.
Found: C, 45.82; H, 8.01.
3aS(R),4R(S),7S(R),7aR(S)-7-(Acetyloxy)-1,3,3a,4,7,7a-hexahy-
dro-2-benzofuran-4-yl Acetate (7). To a magnetically stirred slurry
of 2.96 g (39 mmol) of thiourea in 50 mL of methanol was added
a solution of 5.0 g (32.47 mmol) of endoperoxide 6 in 50 mL of
methanol at room temperature. After completion of the addition
(ca. 30 min), the mixture was stirred for 3 h at room temperature.
The solids were removed by filtration. Pyridine (10 mL) and Ac2O
(15 mL) were added to the formed viscose liquid residue followed
by stirring for 12 h at room temperature. Then the residue was
quenched with 2 × 30 mL of ice-cold HCl, after stirring for 5 min,
and the mixture was extracted with ether (3 × 100 mL). The
combined organic extracts were washed with NaHCO3 solution and
water and then dried (MgSO4). Removal of the solvent and
crystallization of the residue from EtOAc/n-hexane (1:3) gave 6.8 g
(87%) of diacetate 7 as colorless crystals. Mp 54-57 °C; 1H NMR
(400 MHz, CDCl3) δ 5.86 (s, 2H,) 5.14 (d, J3a4 ) 4.2 Hz, 2H),
3.95 (dd, J1,1′(3,3′) ) 8.6 and J3,3a(1,7a) ) 4.2 Hz, 2H), 3.68 (dd, J1,1′(3,3′)
1aR(S),2S(R),2aS(R),5aR(S),6R(S),6aS(R)-6-(Acetyloxy)oc-
tahydrooxireno[2,3-f][2]benzofuran-2-yl Acetate (11b). General
Procedure for Epoxidation. To 2.0 g (8.32 mmol) of diacetate 7
in 150 mL of CHCl3 was added 4.01 g (16.3 mmol, 70%) pf
m-chloroperbenzoic acid. The resulting mixture was refluxed for 3
weeks, then 15 mL 50% NaHSO3 solution was added, and the
mixture was stirred for 15 min. The organic layer was separated,
washed with saturated aqueous NaHCO3 (100 mL), dried (MgSO4),
and concentrated to give 1.72 g (6.75 mmol, 81%) f epoxide 11b,
which was crystallized from EtOAc. Colorless crystals, mp
1
148-150 °C; H NMR (400 MHz, CDCl3) δ 5.05 (quasi d, J )
7.8 Hz, 2H) 3.81 (dd, A-part of AB-system, J ) 9.2 and 6.7 Hz,
2H), 3.61 (dd, B-part of AB-system, J ) 9.2 and 4.3 Hz, 2H), 3.43
(s, 2H), 2.54 (ddd, J ) 9.2 and 6.6 and 4.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 170.6, 71.9, 71.7, 53.4, 39.4, 20.9; IR (KBr,
cm-1) 2995, 2961, 2870, 1722, 1480, 1430, 1369, 1349, 1309, 1245,
1159, 1108, 1079, 1033, 987, 930, 881. Anal. Calcd for C12H16O6:
C, 56.24; H, 6.29. Found: C, 56.24; H, 6.58.
) 8.6 and J3′,3a(1′,7a) ) 5.2 Hz, 2H), 2.52 (m, 2H), 2.19 (s, 6H); 13
C
NMR (100 MHz, CDCl3) 170.4, 128.6, 70.8, 67.4, 41.0, 21.0; IR
(KBr, cm-1) 2968, 1758, 1671, 1665, 1436, 1366, 1345, 1285, 1204,
1124, 1076, 1042, 948, 923, 889. Anal. Calcd for C12H16O5: C,
59.99; H, 6.71. Found: C, 59.62; H, 6.75.
3aS(R),4S(R),5S(R),6R(S),7R(S),7aR(S),-4,6,7-Tris(acetyloxy)
octahydro-2-benzofuran-5-yl Acetate (8). A General Procedure
for cis-Hydroxylation. To a stirred solution of 2.0 g (8.33 mmol)
of diacetate 7 in 10 mL of acetone/H2O (1:1) were added 1.0 g
(8.7 mmol) of NMO and 12.0 mg (0.048 mmol) of OsO4 at 0 °C.
The resulting mixture was stirred vigorously under nitrogen at room
temperature for 24 h. The reaction was stopped, and the pH of the
solution was adjusted to 2 with HCl. After evaporation of solvent,
pyridine (5 mL) and Ac2O (8 mL) were added to the residue,
followed by stirring for 25 h at room temperature. The product
was hydrolyzed with aqueous ice-cooled HCl (100 mL, 20%),
neutralized with aqueous NaHCO3, dried (Na2SO4), and filtered.
Evaporation of solvent gave 8 (2.18 g, 73%) as pure white crystals
from EtOAc. Mp 152-154 °C. 1H NMR (400 MHz, CDCl3) δ 5.33
1aR(S),2S(R),2aS(R),5aR(S),6R(S),6aS(R)-Octahydroox-
ireno[2,3-f][2]benzofuran-2,6-diol (11a). Epoxy diacetate 11b (1.0
g, 3.91 mmol) was hydrolyzed with ammonia in MeOH as described
above for the synthesis of 10. 11a: colorless crystals (645 mg, 96%)
1
from MeOH, mp 184-186 °C. H NMR (400 MHz, MeOH-d4) δ
4.79 (bs, 2H, -OH), 3.85-3.80 (m, 4H), 3.70 (dd, B-part of AB-
system, J ) 8.8 and 3.4 Hz, 2H), 3.30 (s, 2H), 2.35-2.26 (m, 2H).
13C NMR (100 MHz, MeOH-d4) δ 73.7, 70.8, 57.4, 43.5; IR (KBr,
cm-1) 3400, 2931, 2904, 1447, 1382, 1343, 1324, 1256, 1239, 1214,
1196, 1134. Anal. Calcd for C8H12O4: C, 55.81; H, 7.02. Found:
C, 56.08; H, 7.23.
3R(S),4R(S)5S(R),6S(R),7S(R),8S(R)-4,6,7-Tris(acetyloxy)oc-
tahydro-2-benzofuran-5-yl Acetate (12). One gram (3.91 mmol)
of epoxy diacetate 11b was hydrolyzed with ammonia in MeOH
as described above. Without any purification, the residue 11a was
dissolved in water (5 mL), and sulfuric acid (1 mL) was added.
The mixture was refluxed for 6 h. Evaporation of the solution gave
viscous residue. Pyridine (5 mL) and acetic anhydride (7 mL) were
added to the mixture, which was stirred at room temperature for
10 h. The mixture was acidified with cold HCl and washed with
water (2 × 100 mL) and saturated NaHCO3 (2 × 50 mL),
respectively. The organic phase was dried (NaSO4), and evaporation
(bs, 1H), 5.12 (bs, 1H), 3.92 (dd, A-part of AB-system, J1,1′(3,3′)
)
8.9 and J3,3a(1,7a) ) 6.6 Hz, 1H), 3.71 (dd, B-part of AB-system, J
) 8.9 and J3′,3a(1′,7a) ) 5.1 Hz, 1H), 2.75-2.69 (m, 2H), 2.07 (s,
12H); 13C NMR (100 MHz, CDCl3) δ 169.9, 169.7, 69.0, 67.4,
67.3 40.1, 20.7, 20.6; IR (KBr, cm-1) 2967, 2940, 2864, 1751, 1440,
1373, 1228, 1174, 1156, 1108, 1042, 978, 954. Anal. Calcd for
C16H22O9: C, 53.63; H, 6.19. Found: C, 53.58; H, 5.97.
3aS(R),4S(R),5S(R),6R(S),7R(S),7aR(S)2,3,4-Tris(acetyloxy)-
5,6-bis[(acetyloxy)-methyl]cyclohexyl Acetate (9). General Pro-
J. Org. Chem. Vol. 74, No. 1, 2009 93

Baran and Balci
of the solvent gave tetraacetate 12. Crystallization from hexane/
EtOAc 4:1 gave tetraacetate (12) (1,38 g, 77%). Pure white crystals,
mp 128-131 °C. H NMR (400 MHz, CDCl3) δ 5.39-5.35 (m,
3041, 2961, 2866, 1739, 1440, 1376, 1244, 1049. Anal. Calcd for
C12H16O5: C, 59.99; H, 6.71. Found: C, 59.87; H, 6.92.
1
cis-Hydroxylation of 5. 3aS(R),4S(R),5S(R),6R(S),7R(S),7aR(S),-
4,6,7-Tris(acetyloxy)octahydro-2-benzofuran-5-yl Acetate (8) and
3aS(R),4S(R),5S(R),6S(S),7S(S),7aR(S),-4,6,7-Tris(acetyloxy)octahy-
dro-2-benzofuran-5-yl Acetate (16). An 8.5 g (35.4 mmol) portion
of diacetate 15 was submitted to cis-hydroxylation reaction as
described above. Acetylation of the residue gave a crude mixture
consisting of 8 and 16 (10.63 g), which was separated by silica gel
chromatography eluting with EtOAc/hexane (1:1). The first fraction
was the symmetrical diacetate 8 (5.7 g, 45%). The second fraction
was identified as 16 (4.6 g, 36%). Colorless crystals from EtOAc/
2H), 5.16-5.11 (m, 2H), 4.01 (t, A-part of AB-system, J ) 9.1
Hz, 1H), 3.80 (d, A-part of AB-system, J ) 9.0 Hz, 1H), 3.72,
(dd, B-part of AB-system, J ) 9.1 and 5.2 Hz, 1H), 3.70 (t, B-part
of AB-system, J ) 9.0 Hz, 1H), 2.74-2.66 (m, 1H), 2.61-2.55
(m, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.0 (2C), 169.9, 169.7, 71.2, 71.0,
70.97, 69.6, 68.0, 67.9, 42.1, 41.8, 20,9, 20.7, 20.6, 20.55.
1H NMR (400 MHz, benzene-d6) δ 5.76 (dd, J ) 9.8 and 9.3
Hz, 1H), 5.54 (t, J ) 3.2 Hz, 1H), 5.44 (t, J ) 9.8 Hz, 1H), 5.37
(dd, J ) 9.3, J ) 3.2 Hz), 3.88 (d, A-part of AB-system, J ) 8.8
Hz, 1H) 3.57 (t, A-part of AB-system, J ) 9.1 Hz, 1H), 3.45 (m,
B-parts of AB-systems) 2H), 2.40-2.34 (m, 1H), 2.30-2.22 (m,
1H), 1.83 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz,
benzene-d6) δ 169.4, 169.3, 169.1 (2C), 71.5, 71.2, 70.7, 70.0, 68.1,
67.6, 42.14, 42.06. 20.11, 20.07, 20.00 (2C); IR (KBr, cm-1) 3014,
2943, 1753, 1442, 1375, 1232, 1043, 906. Anal. Calcd for C16H22O9:
C, 53.63; H, 6.19. Found: C, 53.58; H, 5.97.
1R(S),2R(S)3S(R),4S(R),5R(S),6S(R)-2,3,4-(Acetyloxy)-5,6-
bis[(acetyloxy)methyl]cyclohexyl Acetate (13). To a stirred solu-
tion of 2.0 g (7.81 mmol) of epoxydiacetate (11b) in AcOH/AcOH
(15 mL 1:1) was added 0.15 g (1.55 mmol) sulfamic acid at room
temperature, and then the mixture was refluxed for 24 h. The
reaction mixture was worked up as described above to give 13 as
colorless liquid, (3.19 g, 89%). 1H NMR (400 MHz, CDCl3) δ 5.41
(t, J ) 2.7 Hz, 1H), 5.32 (t, J ) 10.6 Hz, 1H), 5.24 (dd, J ) 10.6
and 10.1 Hz, 1H), 5.13 (dd, J ) 10.1 and 3.0 Hz, 1H), 4.27-4.17
(m, 3H), 3.93 (dd, J ) 11.7 and 3.8 Hz, 1H), 2.58-2.51 (m, 1H),
2.40-2.36 (m, 1H), 2.08 (s, 6H), 1.96 (s, 6H), 1.94 (s, 3H), 1.92
(s, 3H); 13C NMR (100-MHz, CDCl3) δ 170.36, 170.23, 170.03,
169.88, 169.79 169.6, 71.6, 70.1, 69.8, 69.6, 61.5, 61.1, 39.3, 36.8,
20.9, 20.8, 20.6, 20.58, 20.5 (2C); IR (KBr, cm-1) 2964, 1746,
1433, 1369, 1230, 1040, 952. Anal. Calcd for C20H28O12: C, 52.17;
H, 6.13; Found: C, 51.84; H, 6.09.
1
hexane (1:2), mp 94-96 °C. H NMR (400 MHz, CDCl3) δ 5.46
(dd, J ) 5.2 and 3.7 Hz, 1H), 5.34 (dd, J ) 6.8 and 2.8 Hz, 1H),
5.26 (m, 2H), 3.90 (dd, J ) 8.6 and 6.3 Hz, 1H) 3.83-3.80 (m,
2H), 3.46 (dd, J ) 8.3 and 5.6 Hz, 1H), 2.82-2.75 (m, 1H),
2.58-2.52 (m, 1H), 2.01 (s, 9H), 1.99 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 170.0, 169.6 (2C), 69.9, 69.3, 68.9, 68.4, 68.1,
67.6, 41.0, 39.5, 20.81 (2C), 20.7, 20.7; IR (KBr, cm-1) 2968, 2876,
1752, 1437, 1371, 1340, 1211, 1100, 1061. Anal. Calcd for
C16H22O9: C, 53.63; H, 6.19. Found: C, 53.68; H, 6.51.
1R(S),2R(S)3R(S),4R(S),5R(S),6S(R)-2,3,4-(Acetyloxy)-5,6-
bis[(acetyloxy)methyl]-cyclohexyl Acetate (19). The tetraacetate
16 (2.0 g, 5.58 mmol) was reacted with sulfamic acid as described
1
above to give 17: 2.14 g (83%), colorless liquid; H NMR (400
MHz, CDCl3) δ 5.57 (bd, 2H); 5.31 (dd, A-part of AB-system, J
) 10.7 and 2.8 Hz, 1H), 5.25 (dd, B-part of AB-system, J ) 10.7
and 3.0 Hz, 1H), 4.36 (dd, J ) 11.8 and 5.1 Hz, 1H), 4.19 (t, J )
10.7 Hz, 1H), 4.16-4.01 (m, 2H), 2.63-2.61 (m, 1H), 2.38-2.34
(m, 1H), 2.13 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H),
2.01(s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6,
170.5, 170.0, 169.9, 169.7, 169.6, 69.1, 68.4, 66.7, 61.6, 60.9, 60.3,
39.9, 35.4, 20.9, 20.8, 20.7 (2C), 20.65, 20.60; IR (KBr, cm-1
)
2970, 1736, 1373, 1234, 1174, 1094, 1036. Anal. Calcd for
C20H28O12: C, 52.17; H, 6.13. Found: C, 52.02; H, 6.05.
(1R(S),2R(S),3R(S),3R(S),5R(S),6S(R)-Bis(hydroxymethyl)cy-
clohexane-1,2,3,4-tetrol (18). One gram (2.17 mmol) pof hexaac-
etate 17 was hydrolyzed with ammonia as described above to give
the free hexol 18. The residue was crystallized from EtOH to give
0.4 g (88%) of 18 as a colorless powder, mp 156-158 °C. 1H NMR
(400 MHz, D2O) δ 4.7 (bs, 6H, -OH), 4.04 (bs, 1H), 3.92 (bs, 1H),
3.74 (dd, J ) 10.0 Hz, 1H), 3.67-3.42 (m, 5H), 2.07 (m, 1H),
2.03 (m, 1H); 13C NMR (100 MHz, D2O) δ 71.0 (2C), 69.3, 68.8,
60.1, 59.4, 44.1, 38.6; IR (KBr, cm-1) 3458, 2940, 2868, 1482,
1433, 1372, 1238, 1186, 1044. Anal. Calcd for C8H16O6: C, 46.15;
H, 7.75. Found: C, 46.53; H, 7.94.
Reaction of Diacetate 15 with m-Chloroperbenzoic Acid.
Diacetate 15 (1.5 g, 6.25 mmol) was dissolved in 200 mL of
chloroform, m-CPBA (3.0 g, 12 mmol, 70%) was added, and then
the reaction was stirred at reflux temperature for 3 weeks (every
2-3 days, small portions (200 mg) of m-CPBA were added). The
reaction mixture was worked up as described in the general
procedure. Evaporation of solvent under reduced pressure gave a
oily residue (1.5 g), which was treated with 0.5 mL of pyridine
and 1 mL of acetic anhydride. The resulting solution was stirred at
room temperature for 5 h. The mixture consisting of 19, 20, 21,
and 22 was chromatographed on a silica gel column (50 g) eluting
with hexane/EtOAc 3:1. Four compounds were isolates in the
following order: 21 (92 mg, 4.4%), 22 (50 mg, 2.4%), 19 (816
mg, 51%), 20 (416, 26%).
1R(S),2R(S)3S(R),4S(R),5R(S),6S(R)-Bis(hydroxymethyl)cy-
clohexane-1,2,3,4-tetrol (14). One gram (2.17 mmol) of hexaacetate
13 was dissolved in methanol (75 mL), NH3(g) was passed through
the solution for 5 h, and the solvent concentrated in vacuo to give
429 mg (2.04 mmol, 94%) white solid from EtOH, mp 175-
1
177 °C. H NMR (400 MHz, DMSO) δ 4.55 (bs, 1H), 4.43 (bs,
2H), 4.34 (bs, 1H), 4.27 (bs, 2H), 3.88 (bs, 1H), 3.703.67 (m, 1H),
3.53-3.50 (m, 1H), 3.46-3.43 (m, 1H), 3.37 (bs, 1H), 3.3 (bd, J
) 7.9 Hz, 1H), 3.27-3.17 (m, 2H), 2.01-1.94 (m, 2H). 13C NMR
(100 MHz, DMSO) 75.4, 71.9, 71.4, 70.2, 60.9, 58.6, 43.3, 40.1;
IR (KBr, cm-1) 3400, 2931, 2904, 1447, 1382, 1343, 1324, 1256,
1239, 1214, 1196. Anal. Calcd for C8H16O6: C, 46.15; H, 7.75.
Found: C, 46.52; H, 7.49.
3aS(R),4S(R),5S(R),7aR(S)-4-(Acetyloxy)-1,3,3a,4,5,7a-hexahy-
dro-2-benzofuran-5-yl Acetate (15). The diene 5 (8.0 g, 65.6
mmol), NMO (8.91 g, 77.5 mmol), and OsO4 (ca. 20 mg) in 30
mL of H2O and acetone (1:1) were reacted as described above.
The residue was dissolved in pyridine (10 mL) and Ac2O (15 mL)
and stirred for 25 h at room temperature. The product was
hydrolyzed with aqueous ice-cooled HCl (100 mL, 20%), neutral-
ized with aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated
to give colorless liquid (12.43 g). After filtration of over silica gel
(150 g) with EtOAc, evaporation of solvent and crystallization from
EtOAc/hexane (1:2) gave 11.02 g (70%) of colorless crystals, mp
1
98-100 °C. H NMR (400 MHz, CDCl3) δ 5.96 (dd, A-part of
Data for 4,6-Bis(acetyloxy)-7-chlorooctahydro-2-benzofuran-
5-yl Acetate (21). 1H NMR (400 MHz, CDCl3) δ 5.56 (t, J ) 2.6
Hz, 1H), 5.24 (dd, J ) 11.0 and 2.6 Hz, 1H), 4.96 (dd, J ) 11.0
and 2.2 Hz, 1H), 4.51 (dd, J ) 11.2 and 6.4 Hz, 1H), 4.09 (t, J )
9.2 Hz, 1H), 3.80-3.88 (m, 3H), 3.25-3.12 (m, 1H), 2.60-2.53
(m, 1H), 2.14 (s, 3H), 2.06 (s, 3H), 2.01(s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.1, 170.0, 169.7, 71.6, 70.6, 70.2, 68.7, 68.3,
55.6, 43.8, 41.0, 21.0, 20.9, 20.8; IR (KBr, cm-1) 2957, 2877, 1738,
AB-system, J ) 9.8 and 3.8 Hz, 1H), 5.83 (ddd, B-part of AB-
system, J ) 9.8, 5.4 and 1.6 Hz, 1H), 5.46 (dd, J ) 3.8 and 3.3
Hz), 5.01 (dd, J ) 10.7 and 3.3 Hz, 1H), 4.03 (t, J ) 8.5 Hz, 1H),
3.91 (dd, A-part of AB-system, J ) 9.3 and 6.5 Hz, 1H), 3.74 (dd,
B-part of AB-system, J ) 9.3 and 2.8 Hz, 1H), 3.48 (t, J ) 8.5
Hz, 1H), 3.09-3.04 (m, 1H), 2.79-2.72 (m, 1H), 2.07 (s, 3H),
2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.3, 132.1,
123.7, 71.8, 70.6, 70.1, 64.9, 40.4, 37.8, 20.9, 20.8; IR (KBr, cm-1
)
94 J. Org. Chem. Vol. 74, No. 1, 2009

1436, 1369, 1214, 1142, 1124, 1073, 1053. Anal. Calcd for
C14H19ClO7: C, 50.23; H, 5.72. Found: C, 50.64; H, 5.86.
Data for 3aS(R),4S(R),5R(S),6R(S),7R(S),7aR(S)rel-4,7-Bis-
(acetyloxy)-6-chlorooctahydro-2-benzofuran-5-yl Acetate (22).
1H NMR (400 MHz, CDCl3) δ 5.38 (t, J ) 2.9 Hz, 1H), 5.18 (t, J
) 10.3 Hz, 1H), 5.12 (dd, J ) 10.6 and 3.3 Hz, 1H), 4.22 (t, J )
10.7 Hz, 1H), 4.03 (dd, J ) 9.5 and 9.2 Hz, 1H), 3.85 (d, J ) 9.2
Hz, 1H), 3.70 (dd, J ) 9.2 and 7.0 Hz, 1H), 3.69 (d, J ) 9.5 Hz,
1H), 2.72-2.65 (m, 1H), 2.52-2.47 (m, 1H), 2.14 (s, 3H), 2.12
(s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 169.9,
169.8, 73.0, 71.3, 71.1, 67.8, 67.6, 59.0, 43.1, 42.9, 21.1, 21.0, 20.8;
IR (KBr, cm-1) 2951, 2838, 1743, 1519, 1451, 1371, 1224, 1038,
924, 894. Anal. Calcd for C14H19ClO7: C, 50.23; H, 5.72. Found:
C; 50.46; H, 5.94.
Data for 1aS(R),2R(S),3S(R),3aS(R),6aR(S),6bS(R)2-(Acety-
loxy)octahydrooxireno[2,3-e][2]benzofuran-3-yl Acetate (19).
Colorless crystals from ethylacetate/n-hexane, mp 108-110 °C.;
1H NMR (400 MHz, CDCl3) δ 5.67 (dd, J ) 3.6 and 2.8 Hz, 1H),
4.96 (dd, J ) 11.2 and 2.8 Hz, 1H), 4.09 (t, J ) 8.6, 1H), 3.84
(dd, J ) 9.2 and 6.6 Hz, 1H), 3.75 (t, J ) 8.6 Hz, 1H), 3.5 (dd, J
) 9.2 and 3.9 Hz, 1H), 3.39 (t, J ) 3.6 Hz, 1H), 3.26 (t, J ) 3.6
Hz, 1H), 2.87 (dq, J ) 8.6 and 3.6 Hz, 1H), 2.52-2.44 (m, 1H),
2.17 (s, 3H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.01,
169.96, 71.4, 70.2, 69.8, 66.6, 53.5, 51.1, 37.7, 36.7, 20.8 (2C); IR
(KBr, cm-1) 3016, 2980, 2857, 1737, 1441, 1376, 1246, 1093. Anal.
Cald for C12H16O6: C, 56.24; H, 6.29. Found: C, 56.26; H, 6.12.
Data for 1aR(S),2R(S),3S(R),3aS(R),6aR(S),6bR(S)2-(Acety-
loxy)octahydrooxireno[2,3-e][2]benzofuran-3-yl Acetate (20).
Colorless crystals from ethylacetate/n-hexane, mp 109-111 °C; 1H
NMR (400 MHz, CDCl3) δ 5.43 (t, J ) 4.2 Hz, 1H), 4.92 (dd, J
) 8.4 and 4.2 Hz, 1H), 4.05 (t, J ) 8.7 Hz, 1H), 3.84-3.77 (m,
1H), 3.72 (dd, J ) 9.3 and 3.6 Hz, 1H), 3.44 (t, J ) 3.6 Hz, 1H),
3.16 (d, J ) 3.6, 1H), 3.02 (q, J ) 7.7), 2.59-2.53 (m, 1H), 2.14
(s, 3H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.3,
70.1, 69.8, 67.6, 66.1, 53.2, 51.8, 37.9, 37.7, 20.9, 20.6; IR (KBr,
cm-1) 2993, 2939, 2874, 1742, 1429, 1374, 1246, 1174, 1122, 1070,
1050, 972, 950, 916, 891. Anal. Calcd for C12H16O6: C, 56.24; H,
6.29. Found: C, 56.07; H, 5.97.
) 10.1 and 2.8 Hz, 1H), 5.24 (dd, B-part of AB system, J ) 10.8
and 3.6 Hz, 1H), 4.24 (b, A-part of AB-system, J ) 11.8 Hz, 2H),
4.15 (bd, B-part of AB system, J ) 11.8 Hz, 2H), 4.1-4.05 (m,
2H), 2.65-2.58 (m, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H),
3
1.95 (s, 3H), 1.94 (s, 6H); C NMR (100 MHz, CDCl3) δ 170.4,
170.2, 170.1, 169.9, 169.7, 169.5, 69.7, 69.2, 68.2, 67.3, 61.7, 59.4,
36.5, 35.9, 21.0, 20.8, 20.7, 20.65, 20.58 (2C); IR (KBr, cm-1
)
2938, 2870, 1740, 1443, 1368, 1243, 1108, 1066, 965. Anal. Calcd
for C20H28O12: C, 52.17; H, 6.13 Found: C, 52.08; H, 6.23.
Bishomo-myoinositol 27. A 0.7 g (1.52 mmol) portion of
hexaacetate 26 was hydrolyzed with ammonia in MeOH as
described above to give the free hexol 27 (0.30 g, 95%) as a viscous
liquid. 1H NMR (400 MHz, D2O) δ 4.7 (bs, 6H, -OH), 3.99-3.73
(m, 8H), 2.28 (m, 1H), 2.14 (m, 1H); 13C NMR (100 MHz, D2O)
δ 70.6, 68.7 (2C), 60.9, 57.0 (2C), 40.8 (2C); IR (KBr, cm-1) 3342,
1661, 1397, 1032, 845. Anal. Calcd for C8H16O6: C, 46.15; H, 7.75.
Found: C, 45.87; H, 7.53.
Ring-Opening Reaction of the Epoxide 20. The epoxide 20
(0.7 g, 1.96 mmol) was submitted to hydrolysis reaction with
sulfamic acid in acetic acid (5 mL) and acetic anhydride (5 mL) at
room temperature as described above. The residue was chromato-
graphed of over silica gel (55 g) eluting with EtOAc/hexane (1:2).
Evaporation of solvent and crystallization from EtOAc/hexane (1:
2) gave 0.955 g (76%) of 9 as colorless crystals, which was identical
with that compound obtained by ring-opening reaction of 8.
(3aS,4S,5R,7aR)-1,3,3a,4,5,7a-Hexahydro-2-benzofuran-4,5-
diol (28). Diacetate 15 (2.0 g, 8.33 mmol) was dissolved in 100
mL of absolute methanol. While dry NH3(g) was passed through
solution, the mixture was stirred for 3 h. Evaporation of solvent
and formed acetamide gave diol 28 in quantitative yield (1.36 g).
Crystallization from EtOH gave colorless powder, mp 123-
128 °C. 1H NMR (400 MHz, in CDCl3) δ 5.85 (bs, 2H), 4.01 (bs,
1H, 3.99 (t, J ) 8.8 Hz, 1H), 3.96-3.89 (m, 2H), 3.70 (bd, J )
7.6 Hz, 1H), 3.43 (t, J ) 8.0 Hz, 1H), 3.27 (bs, 2H), 2.97-2.93
(m, 1H), 2.53-2.49 (m, 1H); 13C NMR (100 MHz, in CDCl3) δ
130.3, 127.3, 72.16, 70.74, 69.21, 65.3, 40.58, 39.94; IR (KBr,
cm-1) 3468, 3025, 2928, 2858, 1437, 1176, 1055, 655. Anal. Calcd
for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.45; H, 7.96.
Kinetic Resolution of (()-15. A solution of racemic diol (()-
15 (350m g, 2.24 mmol) in vinyl acetate (17.9 mL of solvent as
acyl donor) containing lipase from Candida antarctica (Novozyme
435) (161.5 mg) was stirred on a water bath shaker at 30 °C until
appropriate conversion (55%) of the starting material (24 h).
Afterward, the mixture was filtered, and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using ethyl acetate as eluent to give
the enantiomerically enriched monoacetates 29 and 30 in a 55%
yield and diol 28 in a 45% yield. The enantiomeric purity of the
products 29 and 30 as well as the diol 28 were determined by HPLC
analysis after conversion to diacetate 15 (OD-H, hexane/iPrOH 1:99,
flow rate ) 0.5 mL min-1, λ ) 254 nm), tR ) 9.2 min, tR ) 11.3.
(+)-15 as a white solid; [R]30D ) +226.5 (c 4.6, CH2Cl2) for 89%
1aS(R),2R(S),3S(R),3aS(R),6aR(S),6bS(R)-Octahydroox-
ireno[2,3-e][2]benzofuran-2,3-diol (23). One gram (3.91 mmol)
of epoxy diacetate 19 was hydrolyzed with ammonia in MeOH as
described above for the synthesis of 10 to give 23 as colorless
1
crystals (598 mg, 89%) from MeOH, mp 173-175 °C. H NMR
(400 MHz, CDCl3) δ 4.27 (bs, 1H), 4.04 (t, J ) 8.6 Hz, 1H), 3.83
(d, J ) 4.5 Hz, 2H), 3.75 (t, J ) 8.2 Hz, 1H), 3.6 (dd, J ) 10.8
and 2.6 Hz, 1H), 3.9-3.3 (m, 2H, -OH), 3.44 (t, J ) 3.2 Hz, 1H),
3.25 (T, J ) 3.7 Hz, 1H), 2.81 (dq, J ) 8.9 and 3.9 Hz, 1H),
2.30-2.23 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 71.4, 69.7,
68.7, 67.3, 56.2, 51.6, 38.6, 37.5; IR (KBr, cm-1) 3400, 2931, 2904,
1447, 1382, 1343, 1324, 1256, 1239, 1214, 1196, 1134. Anal. Calcd
for C8H12O4: C, 55.81; H, 7.02. Found: C, 55.45; H, 6.78.
3R(S),4R(S)5S(R),6S(R),7R(S),8S(R)-4,6,7-Tris(acetyloxy)oc-
tahydro-2-benzofuran-5-yl Acetate (12). Epoxydiol 23 (0.75 g,
4.36 mmol) was dissolved in a mixture of water (5 mL) and H2SO4
(three drops). The solution was stirred for 24 h at room temperature,
and then the water was evaporated. Without any purification, the
remaining residue was treated with pyridine (4 mL) and Ac2O (7
mL). This solution was then stirred for 12 h at room temperature.
EtOAc (100 mL) was added to the reaction mixture, and the product
was hydrolyzed with aqueous ice-cooled HCl (100 mL, 5%),
neutralized with aqueous NaHCO3, dried (Na2SO4), filtered, and
evaporated. After crystallization from hexane/EtOAc 3:1, tetraac-
etate (12) (0.98 g, 63%) was obtained.
ee. (-)-15 [R]30 ) -193.0 (c 3.7, CH2Cl2) for 80% ee.
D
Acknowledgment. The authors are indebted to TUBITAK
(Scientific and Technological Research Council of Turkey),
Department of Chemistry at Middle East Technical University
and TUBA (Turkish Academy of Sciences) for their financial
support of this work. Furthermore, we are grateful to Assis.
Prof. Dr. Aslihan Gu¨nel and Prof. Dr. Mahinur Akkaya (Middle
East Technical University) for their assistance with the biological
tests and Res. Assis. Serdar Sezer and Prof. Dr. Cihangir Tanyeli
(Middle East Technical University) for enzymatic resolution.
1S(R),2R(S),3R(S),4S(R),5S(R),6S(R)-2,3,4-(Acetyloxy)-5,6-
bis[(acetyloxy)methyl]cyclohexyl Acetate (26). The epoxide 19
(0.8 g, 3.13 mmol) was hydrolyzed with Ac2O/AcOH (1/1) and
sulfamic acid as described above to give 26 (1.10 g, 76%) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.5 (bs, 1H), 5.32
(dd, A-part of AB system, J ) 10.7 and 2.8 Hz, 1H), 5.27 (dd, J
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO801344F
J. Org. Chem. Vol. 74, No. 1, 2009 95