Total syntheses of (±)-cyclophellitol and (1R°,6S°)-cyclophellitol

Article abstract of DOI:10.1021/jo962276o

A stereodivergent synthesis of (+)-cyclophellitol (1) and its unnatural diastereoisomer (1R*6S*)-cyclophellitol (2), starting from the Diels-Alder adduct of furan and acrylic acid, is reported. The stereochemistry of the key step, the epoxidation of alkene 7, is controlled by the nature of the hydroxyl protecting groups.

Full text of DOI:10.1021/jo962276o

3360
J . Org. Chem. 1997, 62, 3360-3364
Tota l Syn th eses of (()-Cyclop h ellitol a n d (1R*,6S*)-Cyclop h ellitol
J ose´ Luis Acen˜a, Odo´n Arjona,* and J oaqu´ın Plumet*
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040 Madrid, Spain
Received December 6, 1996X
A stereodivergent synthesis of (()-cyclophellitol (1) and its unnatural diastereoisomer (1R*,6S*)-
cyclophellitol (2), starting from the Diels-Alder adduct of furan and acrylic acid, is reported. The
stereochemistry of the key step, the epoxidation of alkene 7, is controlled by the nature of the
hydroxyl protecting groups.
In tr od u ction
Glycosidase inhibitors have been recognized as poten-
tial therapeutic agents against HIV infection and me-
tastasis.1 In this way, some cyclohexene oxides2 may act
as specific inhibitors of glycosidases because of their
resemblance to true sugars and by the irreversible
formation of bonds at the active site of the enzyme.3 In
this context, the naturally occurring carbasugar deriva-
tive (+)-cyclophellitol (1) (Figure 1), isolated from a
Phellinus sp. of mushroom inhibits almond â-glucosidase
with higher potency (IC50 ) 0.8 µg/mL) than that of other
well-known inhibitors such as castanospermine or nojiri-
mycin.4 The â-equatorial orientation of the C1-O bond
as in â-glucose and its half-chair conformation may be
crucial for its strong activity.3 Several analogues of
cyclophellitol have been synthesized and biologically
evaluated in order to establish a structure-inhibition
relationship.5 For instance, (1R,6S)-cyclophellitol (2) is
a weaker inhibitor of R-glucosidase as well as â-glucosi-
dase and inhibits experimental metastasis.5a,6
F igu r e 1.
Sch em e 1
The synthetic approaches to cyclophellitol described
thus far employ two different strategies for the construc-
tion of the oxirane ring: an intramolecular nucleophilic
substitution7 or the epoxidation of a suitable alkene
precursor.8 However, the latter is the only way for the
divergent preparation of 1 and 2 without significant
modifications in the common synthetic route. In this
manner, the selective access to each diastereoisomer
could be achieved from the same intermediate by choos-
ing the appropriate protecting groups for the hydroxyl
substituents in order to control the stereochemistry of
the epoxidation process.
In recent years we have prepared some members of
the carbasugar family such as 5a-carba-R-glucopyranose9a
and validamine and three of its diastereoisomers9b using
as a pivotal intermediate the cyclohexenyl sulfone 4,
available from the endoadduct of furan and acrylic acid
310 (Scheme 1). Within this project, the next targets we
selected were compounds 1 and 2 which we hoped to
prepare through the isomerization of the double bond in
4 to the allylic position11 and subsequent oxidative
desulfonylation12 of 5 to the enone 6. Transformation of
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) (a) Karpas, A.; Fleet, G. W. J .; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsdem, N. G.; J acob, G. S.; Rademacher, T. W.
Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229-9233. (b) Ganem, B. Acc.
Chem. Res. 1996, 29, 340-347.
(2) (a) Thebtaranonth, C.; Thebtaranonth, Y. Acc. Chem. Res. 1986,
19, 84-90. (b) Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetrahedron 1990,
46, 3715-3742.
(3) (a) Lale´gerie, P.; Legler, G.; Yon, J . M. Biochimie 1982, 64, 977-
1000. (b) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319-
384. (c) Sinnott, M. L. Chem. Rev. 1990, 90, 1171-1202.
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H.; Iitaka, Y.; Takeuchi, T. J . Antibiot. 1990, 43, 49-53.
(5) (a) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata,
M. J . Antibiot. 1991, 44, 456-458. (b) Tatsuta, K.; Niwata, Y.;
Umezawa, K.; Toshima, K.; Nakata, M. J . Antibiot. 1991, 44, 912-
914. (c) Nakata, M.; Chong, C.; Niwata, Y.; Toshima, K.; Tatsuta, K.
J . Antibiot. 1993, 46, 1919-1922. (d) Tai, V. W.-F.; Fung, P.-H.; Wong,
Y.-S.; Shing, T. K. M. Tetrahedron: Asymmetry 1994, 5, 1353-1362.
(6) Atsumi, S.; Nosaka, C.; Ochi, Y.; Iinuma, H.; Umezawa, K.
Cancer Res. 1993, 53, 4896-4899.
(7) (a) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata,
M. Tetrahedron Lett. 1990, 31, 1171-1172. (b) Akiyama, T.; Ohnari,
M.; Shima, H.; Ozaki, S. Synlett 1991, 831-832. (c) Moritz, V.; Vogel,
P. Tetrahedron Lett. 1992, 33, 5243-5244. (d) McDevitt, R. E.; Fraser-
Reid, B. J . Org. Chem. 1994, 59, 3250-3252. (e) Schlessinger, R. H.;
Bergstrom, C. P. J . Org. Chem. 1995, 60, 16-17.
(8) (a) Shing, T. M. K.; Tai, V. W.-F. J . Chem. Soc., Chem. Commun.
1993, 995-997. (b) Sato, K.; Bokura, M.; Moriyama, H.; Igarashi, T.
Chem. Lett. 1994, 37-40. (c) J ung, M. E.; Choe, S. W. T. J . Org. Chem.
1995, 60, 3280-3281. Protected derivatives of cyclophellitol have been
prepared as synthetic intermediates; see the following: (d) Ogawa, S.;
Chida, N.; Suami, T. J . Org. Chem. 1983, 48, 1203-1207. (e) Letellier,
P.; Ralainirina, R.; Beaupe`re, D.; Uzan, R. Tetrahedron Lett. 1994, 35,
4555-4558.
(9) (a) Acen˜a, J . L.; Arjona, O.; Ferna´ndez de la Pradilla, R.; Plumet,
J .; Viso, A. J . Org. Chem. 1992, 57, 1945-1946. (b) Acen˜a, J . L.; Arjona,
O.; Ferna´ndez de la Pradilla, R.; Plumet, J .; Viso, A. J . Org. Chem.
1994, 59, 6419-6424.
(10) (a) Moore, J . A.; Partain, E. M., III. J . Org. Chem. 1983, 48,
1105-1106. (b) Ogawa, S.; Iwasaga, Y.; Nose, T.; Suami, T.; Ohba, S.;
Ito, M.; Saito, Y. J . Chem. Soc., Perkin Trans. 1 1985, 903-906.
S0022-3263(96)02276-1 CCC: $14.00 © 1997 American Chemical Society

Total Syntheses of (()- and (1R*,6S*)-Cyclophellitol
J . Org. Chem., Vol. 62, No. 10, 1997 3361
Sch em e 2
F igu r e 2.
dienes17 or by SO2 extrusion of (arylsulfonyl)sulfolenes18
and used as synthetic intermediates on the basis of their
dienic properties.17a Moreover, the double bonds are able
to be differentiated in epoxidation or cyclopropanation
reactions, depending on the conditions employed.19 The
synthetic exploitation of these processes is now under
investigation in our laboratory.
The failure of the isomerization reaction in our syn-
thetic plan led us to design an alternative way to the
enone 6. Thus, the R-bromo ketone 12a was prepared
from sulfone 4a by nucleophilic epoxidation followed by
reaction with MgBr2‚OEt29b (Scheme 3). The subsequent
dehydrohalogenation reaction in the presence of CaCO3
in DMF gave the desired enone 6a . The stereoselective
carbonyl reduction under Luche’s conditions20 yielded the
related diol 7a . Finally, the epoxidation of 7a controlled
by the free allylic hydroxy group21 using m-chloro-
peroxybenzoic acid (m-CPBA) followed by debenzylation
by catalytic hydrogenation afforded (1R*,6S*)-cyclophel-
litol (2), which was isolated and characterized as its
tetraacetyl derivative 14.8a
6 into the related allylic alcohol 7 followed by epoxidation
controlled by the free hydroxy groups could lead selec-
tively to either cyclophellitol 1 or its unnatural diaste-
reoisomer 2.13 Although the sequence reported here has
been carried out using racemic compounds, it should be
possible to obtain the final products in enantiomerically
pure form since the optical resolution of 3 has been
described.10b
In order to invert the selectivity of the epoxidation
process, our initial attempts included changing the
protecting groups in diol 7a using a protection-debenz-
ylation sequence. However, the preparation of diol 15
was unsuccessful using several debenzylation conditions
(Na/NH3, BF3‚OEt2/EtSH,22 TMSCl/NaI,23 PhSSiMe3/
Resu lts a n d Discu ssion
Sulfones 4a -c were prepared as previously reported9
(Scheme 2). Starting from compounds 4, none of the
conditions tested to achieve the isomerization led us to
the corresponding allyl sulfone. However, several prod-
ucts were obtained in synthetically useful yields. For
instance, reaction of 4c with MeLi at -78 °C afforded a
85:15 mixture of compounds 8 and 9, arising from the
SN2′ addition of the organolithium reagent. Both prod-
ucts were obtained in varying amounts depending on the
conformation of the starting material as determined by
the protecting groups.14 Thus, when hydroxy sulfone 4a
was treated with MeLi, followed by silylation (TBSOTf,
Et3N) of the crude mixture, a 40:60 ratio of 8 and 9 was
obtained.15 The stereochemistry of the methyl group in
8 was deduced by observation of two axial-axial coupling
constants (13.4 and 10.6 Hz) in the adjacent H-5 axial
ZnI2/TBAI,24 BCl3‚SMe2 ) due to partial losses and
25
migrations of the protecting groups employed (TBS and
acetyl) (Scheme 4). In the search for suitable protecting
groups, we found that treatment of 7a with HNa and
MeOCH2Cl in refluxing THF produced the bicyclic acetal
16 in good yield. Its epoxidation with m-CPBA gave 17
as a single diastereoisomer due to the steric hindrance
of the â-face of the double bond by the methylene acetal
moiety. The orientation of the oxirane ring was con-
firmed by NOE measurements (Figure 2). Unfortunately,
(16) For other examples of 1,4-elimination in â′-heterosubstituted
cyclic vinyl sulfones, see: a) Saddler, J . C.; Fuchs, P. L. J . Am. Chem.
Soc. 1981, 103, 2112-2114. b) Hardinger, S. A.; Fuchs, P. L. J . Org.
Chem. 1987, 52, 2739-2749. See also ref 15.
(17) (a) Ba¨ckvall, J . E.; J untunen, S. K. J . Am. Chem. Soc. 1987,
109, 6396-6403. (b) Ba¨ckvall, J . E.; Na´jera, C.; Yus, M. Tetrahedron
Lett. 1988, 29, 1445-1448.
(18) Chou, T.-S.; Lee, S.-J .; Peng, M.-L.; Sun, D.-J .; Chou, S.-S. P.
J . Org. Chem. 1988, 53, 3027-3031.
(19) (a) Ba¨ckvall, J . E.; Ericsson, A. M.; J untunen, S. K; Na´jera, C.;
Yus, M. J . Org. Chem. 1993, 58, 5221-5225. (b) Lo¨fstro¨m, C. M. G.;
Ericsson, A. M.; Bourrinet, L.; J untunen, S. K.; Ba¨ckvall, J .-E. J . Org.
Chem. 1995, 60, 3586-3591.
(20) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
1
proton in its H NMR spectra. On the other hand, the
use of non-nucleophilic bases gave rise to the isomeriza-
tion with concomitant elimination of the â′-benzyloxy
group. Thus, the reaction of 4c with LDA or t-BuOK
yielded the diene 10.16 It should be noted that related
dienyl systems have been previously prepared from
(11) This strategy has been successfully applied on â′-methylcyclo-
hexenyl sulfones in the synthesis of small polypropionate fragments;
see the following: Acen˜a, J . L.; Arjona, O.; Leo´n, M.; Plumet, J .
Tetrahedron Lett. 1996, 37, 8957-8960.
(12) (a) Little, R. D.; Myong, S. O. Tetrahedron Lett. 1980, 21, 3339-
3342. (b) Hwu, J . R. J . Org. Chem. 1983, 48, 4432-4433.
(13) For a preliminary communication of this work, see: Acen˜a. J .
L.; de Alba, E.; Arjona, O.; Plumet, J . Tetrahedron Lett. 1996, 37,
3043-3044.
(14) The change of conformation on sulfones 4 was also used for their
selective nucleophilic epoxidation with LiOO-t-Bu; see ref 9b.
(15) For a mechanistic study of the related SN2′ addition of orga-
nometallic reagents to â′-aminocyclohexenyl sulfones or their quater-
nary ammonium salts, see: Pan, Y.; Hardinger, S. A.; Fuchs, P. L.
Synth. Commun. 1989, 19, 403-416.
(21) (a) Henbest, H. B.; Wilson, R. A. L. J . Chem. Soc. 1957, 1958-
1965. (b) Kocovsky, P. J . Chem. Soc., Perkin Trans. 1 1994, 1759-
1763.
(22) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J . Org. Chem. 1979,
44, 1661-1664.
(23) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J .
Org. Chem. 1979, 44, 1247-1251.
(24) Hanessian, S.; Guindon, Y. Tetrahedron Lett. 1980, 21, 2305-
2308.
(25) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A.
B.; Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett 1993, 663-664.

3362 J . Org. Chem., Vol. 62, No. 10, 1997
Acen˜a et al.
Sch em e 3
Sch em e 4
Sch em e 5
the deprotection of 17 was not possible due to the lability
of the epoxide under the harsh conditions required for
the acetal cleavage.
In view of the problems encountered in the removal of
the benzyl groups in 7a , we decided to repeat the
sequence with protecting groups that were easier to
remove. Thus, diol 7b was prepared in an identical
manner as before, replacing the benzyl groups by PMB
functionalities. Acetylation of this compound to 18a or
silylation to 18b followed by clean deprotection with
DDQ26 produced diols 15a and 15b, respectively (Scheme
5). Epoxidation of the acetyl derivative 15a with m-
CPBA followed by acetylation afforded a mixture of
tetraacetyl-(()-cyclophellitol and its diastereoisomer in
a 60:40 ratio. A totally stereoselective epoxidation could
be achieved using a bulkier substituent at the allylic
position. Thus, treatment of 15b with m-CPBA gave 19
as a single product. Final desilylation with tetrabutyl-
ammonium fluoride (TBAF) yielded (()-cyclophellitol (1)
which was isolated as its tetraacetate 20.8a
In summary, (()-cyclophellitol has been prepared in
14 steps starting from furan. This synthesis constitutes
the shortest route developed to date with the exception
of Vogel’s synthesis.7c Moreover, the unnatural isomer
(1R*,6S*)-cyclophellitol is also accessible in 12 steps via
the common intermediate 7, providing the best way
known to obtain both inhibitors through a divergent
synthetic sequence.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
positive pressure of dry argon using freshly distilled solvents
under anhydrous conditions. Reagents and solvents were
handled by using standard syringe techniques. Tetrahydro-
furan (THF) and diethyl ether were distilled from sodium and
benzophenone; dichloromethane, toluene, triethylamine, di-
isopropylamine, N,N,N′,N′-tetramethylethylene diamine (TME-
DA), pyridine, and N,N-dimethylformamide (DMF) were dis-
tilled from CaH2. Lithium diisopropylamide (LDA) was
purchased from Aldrich (2.0 M solution in heptane, THF and
ethylbenzene). Commercial methyllithium (1.6 M, low halide
solution in ether) and n-butyllithium (1.6 M solution in hexane)
were purchased from Aldrich. m-Chloroperoxybenzoic acid (m-
CPBA) was washed with a 5% aqueous solution of NaHCO3
prior to use. Flash chromatography was performed using E.
Merck 230-400 mesh silica gel. Analytical TLC was carried
out on 0.20 mm Merck precoated silica gel plates (60F-254),
with detection by UV light, acidic vanillin solution, and a 10%
solution of phosphomolybdic acid in ethanol. Melting points
are uncorrected. 1H NMR and 13C NMR spectra were recorded
at 250 or 300 MHz with CDCl3 as solvent. The following
abbreviations are used to describe peak patterns when
appropriate: br, broad; s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet. Elemental analyses were performed at
the Universidad Complutense de Madrid.
(3R*,4R*,6R*)-4-((Ben zyloxy)m et h yl)-3-((ter t-b u t yld i-
m eth ylsilyl)oxy)-6-m eth yl-1-(p h en ylsu lfon yl)cycloh ex-1-
en e, 8. To a cold (-78 °C) solution of 39 mg (0.07 mmol) of
(26) Treatment of 18a with DDQ in CH2Cl2/H2O caused migrations
of the acetyl groups. The reaction was carried out in anhydrous
conditions instead.

Total Syntheses of (()- and (1R*,6S*)-Cyclophellitol
J . Org. Chem., Vol. 62, No. 10, 1997 3363
4c9b in 0.5 mL of THF was added 0.13 mL (0.21 mmol) of MeLi.
After the mixture was stirred at -78 °C for 2 h, a saturated
aqueous solution of NH4Cl was added. The crude mixture was
extracted with Et2O, dried over MgSO4, concentrated under
reduced pressure, and purified by column chromatography on
silica gel (hexane:EtOAc, 2:1) to give 25 mg of an inseparable
mixture of 8 and 9 in an 85:15 ratio determined by integration
of the methyl signals at 1.11 and 1.17 ppm, respectively, in
the 1H NMR spectra (76% overall yield). Data for 8: Rf ) 0.26
(hexane:EtOAc, 5:1). 1H NMR (300 MHz): δ 0.04 (s, 3 H), 0.05
(s, 3 H), 0.86 (s, 9 H), 1.11 (d, 3 H, J ) 6.8 Hz), 1.37 (td, 1 H,
J ) 13.4, 10.6 Hz), 1.67-1.77 (m, 1 H), 1.99 (ddd, 1 H, J )
13.7, 5.4, 2.6 Hz), 2.55-2.60 (m, 1 H), 3.50 (d, 2 H, J ) 4.6
Hz), 4.31 (ddd, 1 H, J ) 9.4, 3.2, 1.7 Hz), 4.42 (d, 1 H, J )
11.9 Hz), 4.52 (d, 1 H, J ) 11.9 Hz), 6.62 (br s, 1 H), 7.29-
7.35 (m, 5 H), 7.54 (t, 2 H, J ) 7.7 Hz), 7.62 (t, 1 H, J ) 7.2
Hz), 7.88 (d, 2 H, J ) 7.0 Hz). 13C NMR (75 MHz): δ -5.0,
-4.5, 18.0, 20.3, 25.7, 30.6, 34.6, 42.3, 68.6, 70.3, 73.2, 89.2,
127.6, 128.0, 128.4, 129.0, 133.2, 138.3, 140.2, 142.5, 144.6.
IR (CHCl3): 2950, 1480 cm-1. Anal. Calcd for C27H38O4SSi:
C, 66.76; H, 7.88. Found: C, 66.65; H, 7.72.
yl)cycloh ex-4-en e-1,3-d iol, 7a . To a cold (-78 °C) solution
of 373 mg (1.00 mmol) of CeCl3‚7H2O in 2 mL of MeOH was
added 23 mg (0.60 mmol) of NaBH4. After the mixture was
stirred for 30 min, a solution of 170 mg (0.50 mmol) of 6a in
3 mL of MeOH was added. The mixture was slowly warmed
up to room temperature and stirred for 2.5 h. A 0.5 N HCl
solution was added, and the crude mixture was extracted with
Et2O, dried over MgSO4, concentrated under reduced pressure,
and purified by column chromatography on silica gel (CH2Cl2:
hexane:EtOAc, 10:1:1) to give 141 mg of 7a as a white solid
(83% yield). Data for 7a : Rf ) 0.12 (hexane:EtOAc, 2:1).
Mp: 156-157 °C. 1H NMR (300 MHz): δ 1.97 (d, 1 H, J )
4.8 Hz), 2.55-2.65 (m, 1 H), 3.12 (d, 1 H, J ) 1.3 Hz), 3.47
(dd, 1 H, J ) 9.9, 7.7 Hz), 3.57 (dd, 1 H, J ) 8.8, 6.6 Hz), 3.63
(dd, 1 H, J ) 8.9, 5.4 Hz), 3.79 (td, 1 H, J ) 10.1, 1.3 Hz),
4.27-4.32 (m, 1 H), 4.55 (s, 2 H), 4.87 (d, 1 H, J ) 11.7 Hz),
4.96 (d, 1 H, J ) 11.7 Hz), 5.51 (dt, 1 H, J ) 10.1, 2.1 Hz),
5.61 (dt, 1 H, J ) 10.1, 2.4 Hz), 7.31-7.40 (m, 10 H). 13C NMR
(75 MHz): δ 44.4, 71.9, 72.2, 72.4, 73.4, 74.8, 85.6, 126.9, 127.6,
127.7, 127.9, 128.0, 128.4, 128.6, 129.2, 137.8, 138.6. IR
(CHCl3): 3600-3200 cm-1
. Anal. Calcd for C21H24O4: C,
74.09; H, 7.11. Found: C, 73.99; H, 7.03.
(5R*,6R*)-5-((Ben zyloxy)m eth yl)-6-((ter t-bu tyld im eth -
ylsilyl)oxy)-2-(p h en ylsu lfon yl)cycloh exa -1,3-d ien e, 10. To
a cold (-78 °C) solution of 107 mg (0.19 mmol) of 4c9b in 1.6
mL of THF was added 0.28 mL (0.57 mmol) of LDA. After
the mixture was stirred at -78 °C for 1 h, a saturated aqueous
solution of NH4Cl was added. The crude mixture was ex-
tracted with Et2O, dried over MgSO4, concentrated under
reduced pressure, and purified by column chromatography on
silica gel (hexane:EtOAc, 5:1) to give 68 mg of 10 as a white
solid (77% yield). Data for 10: Rf ) 0.25 (hexane:EtOAc, 5:1).
Mp: 59-60 °C. 1H NMR (300 MHz): δ 0.06 (s, 3 H), 0.11 (s,
3 H), 0.88 (s, 9 H), 2.62-2.72 (m, 1 H), 3.39 (dd, 1 H, J ) 9.1,
5.4 Hz), 3.45 (dd, 1 H, J ) 9.1, 5.4 Hz), 4.43 (d, 1 H, J ) 12.1
Hz), 4.53 (d, 1 H, J ) 12.1 Hz), 4.70 (dd, 1 H, J ) 11.4, 3.0
Hz), 5.98 (dd, 1 H, J ) 10.1, 3.4 Hz), 6.08 (d, 1 H, J ) 10.1
Hz), 6.75 (br s, 1 H), 7.25-7.28 (m, 5 H), 7.52 (t, 2 H, J ) 7.7
Hz), 7.61 (t, 1 H, J ) 7.4 Hz), 7.87 (d, 2 H, J ) 7.7 Hz). 13C
NMR (75 MHz): δ -5.0, -4.3, 17.9, 25.7, 43.1, 67.6, 68.7, 73.1,
118.4, 127.6, 127.7, 127.9, 128.4, 129.2, 132.9, 133.4, 136.6,
137.8, 137.9, 139.3. IR (CHCl3): 1160 cm-1. Anal. Calcd for
C27H38O4SSi: C, 66.35; H, 7.28. Found: C, 66.08; H, 7.05.
(4R*,5R*,6S*)-6-(Ben zyloxy)-4-((ben zyloxy)m eth yl)-5-
h yd r oxycycloh ex-2-en -1-on e, 6a . To a solution of 310 mg
(0.74 mmol) of 12a 9b in 3.7 mL of DMF was added 370 mg
(3.7 mmol) of CaCO3. After the mixture was stirred at 150 °C
for 2.5 h, H2O was added. The crude mixture was extracted
with Et2O, dried over MgSO4, concentrated under reduced
pressure, and purified by column chromatography on silica gel
(hexane:EtOAc, 2:1) to give 175 mg of 6a as a colorless oil (70%
yield). Data for 6a : Rf ) 0.23 (hexane:EtOAc, 2:1). 1H NMR
(300 MHz): δ 2.74-2.80 (m, 1 H), 2.81 (br s, 1 H), 3.67 (dd, 1
H, J ) 9.0, 6.0 Hz), 3.79 (dd, 1 H, J ) 9.2, 4.3 Hz), 3.93-4.01
(m, 2 H), 4.55 (s, 2 H), 4.66 (d, 1 H, J ) 11.4 Hz), 5.17 (d, 1 H,
J ) 11.4 Hz), 6.07 (dd, 1 H, J ) 10.1, 3.0 Hz), 6.86 (dd, 1 H,
J ) 10.1, 2.0 Hz), 7.29-7.45 (m, 10 H). 13C NMR (75 MHz):
δ 44.9, 69.2, 71.4, 73.5, 74.2, 84.6, 127.6, 127.8, 128.1, 128.3,
128.5, 128.6, 128.9, 137.8, 137.9, 148.8, 197.5. IR (CHCl3):
3600-3300, 1700 cm-1. Anal. Calcd for C21H22O4: C, 74.54;
H, 6.55. Found: C, 74.35; H, 6.49.
(4R*,5R*,6S*)-5-Hyd r oxy-6-((p-m eth oxyben zyl)oxy)-4-
(((p-m eth oxyben zyl)oxy)m eth yl)cycloh ex-2-en -1-on e, 6b.
According to the procedure described for the synthesis of 6a ,
from 276 mg (0.58 mmol) of 12b, 134 mg of 6b was obtained
as a colorless oil (65% yield). Data for 6b: Rf ) 0.27 (hexane:
EtOAc, 1:1). 1H NMR (300 MHz): δ 2.71-2.78 (m, 1 H), 2.76
(s, 1 H), 3.62 (dd, 1 H, J ) 8.9, 6.0 Hz), 3.75 (dd, 1 H, J ) 9.0,
4.2 Hz), 3.81 (s, 6 H), 3.90-3.95 (m, 2 H), 4.47 (s, 2 H), 4.59
(d, 1 H, J ) 10.9 Hz), 5.09 (d, 1 H, J ) 10.9 Hz), 6.06 (dd, 1 H,
J ) 10.2, 3.0 Hz), 6.83 (d, 1 H, J ) 10.2 Hz), 6.87 (d, 2 H, J )
8.1 Hz), 6.90 (d, 2 H, J ) 7.7 Hz), 7.23 (d, 2 H, J ) 8.6 Hz),
7.36 (d, 2 H, J ) 8.4 Hz). 13C NMR (75 MHz): δ 44.7, 55.3,
68.8, 71.2, 73.0, 73.7, 84.0, 113.8, 113.9, 128.9, 129.2, 130.1,
148.9, 159.5, 197.8. IR (CHCl3): 3600-3200, 1700 cm-1. Anal.
Calcd for C23H26O6: C, 69.33; H, 6.58. Found: C, 69.20; H,
6.39.
(1R*,2R*,3S*,6R*)-2-((p-Meth oxyben zyl)oxy)-6-(((p-m eth -
oxyben zyl)oxy)m eth yl)cycloh ex-4-en e-1,3-d iol, 7b. Ac-
cording to the procedure described for the synthesis of 7a , from
740 mg (1.86 mmol) of 6b, 595 mg of 7b was obtained as a
white solid (80% yield). Data for 7b: Rf ) 0.17 (hexane:EtOAc,
1:1). Mp: 124-125 °C. 1H NMR (300 MHz): δ 2.12 (br s, 1
H), 2.49-2.61 (m, 1 H), 3.15 (br s, 1 H), 3.43 (dd, 1 H, J ) 9.7,
7.9 Hz), 3.53 (t, 1 H, J ) 8.9 Hz), 3.58 (dd, 1 H, J ) 8.9, 5.5
Hz), 3.72 (t, 1 H, J ) 9.5 Hz), 3.79 (s, 6 H), 4.20-4.27 (m, 1
H), 4.47 (s, 2 H), 4.78 (d, 1 H, J ) 11.2 Hz), 4.86 (d, 1 H, J )
11.2 Hz), 5.47 (br d, 1 H, J ) 10.1 Hz), 5.58 (br d, 1 H, J )
10.2 Hz), 6.87 (d, 2 H, J ) 8.4 Hz), 6.89 (d, 2 H, J ) 8.2 Hz),
7.21 (d, 2 H, J ) 8.6 Hz), 7.32 (d, 2 H, J ) 8.4 Hz). 13C NMR
(75 MHz): δ 44.3, 55.2, 71.7, 72.1, 72.5, 73.0, 74.5, 85.2, 113.8,
114.0, 126.9, 129.2, 129.2, 129.6, 129.9, 130.7, 159.2, 159.3.
IR (CHCl3): 3600-3300 cm-1. Anal. Calcd for C23H28O6: C,
68.98; H, 7.05. Found: C, 68.75; H, 6.64.
(1R*,2R*,3S*,4R*,5R*,6S*)-3-(Ben zyloxy)-5-((ben zyloxy)-
m eth yl)-7-oxa bicyclo[4.1.0]h ep ta n e-2,4-d iol, 13. To a so-
lution of 36 mg (0.11 mmol) of 7a in 1.5 mL of CH2Cl2 was
added 46 mg (0.26 mmol) of m-CPBA. The reaction was stirred
for 36 h. A 5% aqueous solution of NaHCO3 was added, and
the crude mixture was extracted with CH2Cl2, dried over
MgSO4, concentrated under reduced pressure, and purified by
column chromatography on silica gel (hexane:EtOAc, 2:1) to
give 27 mg of 13 as a white solid (71% yield). Data for 13: Rf
) 0.27 (hexane:EtOAc, 1:1). Mp: 116-117 °C. 1H NMR (300
MHz): δ 2.11 (d, 1 H, J ) 6.7 Hz), 2.24 (dt, 1 H, J ) 9.6, 4.9
Hz), 2.63 (d, 1 H, J ) 2.0 Hz), 3.17 (d, 1 H, J ) 4.0 Hz), 3.37
(dd, 1 H, J ) 4.5, 2.1 Hz), 3.40 (dd, 1 H, J ) 10.0, 8.1 Hz),
3.54 (td, 1 H, J ) 9.9, 2.0 Hz), 3.70 (m, 2 H), 4.00 (ddd, 1 H,
J ) 8.4, 6.6, 2.1 Hz), 4.55 (s, 2 H), 4.78 (d, 1 H, J ) 11.4 Hz),
4.90 (d, 1 H, J ) 11.4 Hz), 7.29-7.38 (m, 10 H). 13C NMR (75
MHz): δ 42.6, 54.7, 56.9, 69.4, 70.3, 72.7, 73.5, 75.4, 82.8,
127.6, 127.8, 128.0, 128.1, 128.5, 128.7, 137.9, 138.3. IR
(CHCl3): 3600-3200 cm-1
. Anal. Calcd for C21H24O5: C,
70.77; H, 6.79. Found: C, 70.68; H, 6.64.
(1R *,2R *,3S *,4R *,5R *,6S *)-2,3,4-Tr ia ce t oxy-5-(a ce -
toxym eth yl)-7-oxa bicyclo[4.1.0]h ep ta n e (Tetr a -O-a cetyl-
(1R*,6S*)-cyclop h ellitol), 14. To a solution of 17 mg (0.05
mmol) of 13 in 2 mL of MeOH was added 51 mg of 10% Pd-C.
The mixture was stirred for 24 h in a Parr hydrogenator at 60
psi. The crude was filtered through a sort pad of silica gel
with MeOH. The residue was acetylated with 1 mL of Ac2O,
1 mL of pyridine and a catalytic amount of DMAP. After 12
h the crude mixture was concentrated under reduced pressure,
and purified by column chromatography on silica gel (hexane:
Et2O, 1:2) to give 13 mg of 14 (80% yield). Its spectral features
were identical to those reported in the literature.8a
(1R*,2R*,3S*,6R*)-2-(Ben zyloxy)-6-((b en zyloxy)m et h -
yl)cycloh ex-4-en e-1,3-d iol 1,3-O-(Meth ylen e a ceta l), 16.
To a solution of 75 mg (0.22 mmol) of 7a in 2.2 mL of THF
were added 26 mg (0.66 mmol) of HNa (60% in mineral oil)
and 0.05 mL (0.66 mmol) of MeOCH2Cl. After the mixture
was stirred at 60 °C for 24 h, a 5% aqueous solution of NaHCO3
(1R*,2R*,3S*,6R*)-2-(Ben zyloxy)-6-((b en zyloxy)m et h -

3364 J . Org. Chem., Vol. 62, No. 10, 1997
Acen˜a et al.
131.6, 158.3, 159.1. IR (CHCl3): 1520, 1250 cm-1
. Anal.
Calcd for C35H56O6Si2: C, 66.83; H, 8.97. Found: C, 66.65; H,
8.82.
was added. The crude mixture was extracted with Et2O, dried
over MgSO4, concentrated under reduced pressure, and puri-
fied by column chromatography on silica gel (hexane:EtOAc,
5:1) to give 50 mg of 16 as a colorless oil (64% yield). Data for
16: Rf ) 0.34 (hexane:EtOAc, 2:1). 1H NMR (300 MHz): δ
2.73 (tt, 1 H, J ) 7.8, 2.9 Hz), 3.52 (d, 2 H, J ) 7.7 Hz), 3.97
(td, 1 H, J ) 3.7, 0.9 Hz), 4.34 (d, 1 H, J ) 4.0 Hz), 4.42-4.45
(m, 1 H), 4.46 (d, 1 H, J ) 12.1 Hz), 4.47 (s, 2 H), 4.55 (d, 1 H,
J ) 12.1 Hz), 4.63 (d, 1 H, J ) 6.3 Hz), 5.01 (d, 1 H, J ) 6.3
Hz), 5.78 (ddd, 1 H, J ) 10.0, 6.1, 3.1 Hz), 6.38 (ddd, 1 H, J )
10.0, 3.4, 1.2 Hz), 7.20-7.36 (m, 10 H). 13C NMR (75 MHz):
δ 41.1, 66.5, 68.7, 70.6, 70.9, 71.4, 72.8, 81.9, 120.2, 127.3,
127.5, 127.6, 128.3, 136.2, 137.8, 138.0. IR (CHCl3): 1110
cm-1. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86. Found:
C, 74.77; H, 6.75.
(1R*,2S*,5R*,6R*)-2,6-Dia cetoxy-5-(h yd r oxym eth yl)cy-
cloh ex-3-en -1-ol, 15a . To a solution of 56 mg (0.12 mmol) of
18a in 2.3 mL of CH2Cl2 was added 79 mg (0.35 mmol) of DDQ.
After the mixture was stirred for 6 h at room temperature,
brine was added. The crude mixture was extracted with CH2-
Cl2, dried over MgSO4, concentrated under reduced pressure,
and purified by column chromatography on silica gel (hexane:
EtOAc, 1:1) to give 15 mg of 15a as a colorless oil (60% yield).
Data for 15a : Rf ) 0.13 (hexane:EtOAc, 1:2). 1H NMR (300
MHz): δ 2.14 (s, 3 H), 2.18 (s, 3 H), 2.44-2.51 (m, 1 H), 3.00-
3.20 (m, 2 H), 3.59 (dd, 1 H, J ) 11.8, 4.2 Hz), 3.68 (dd, 1 H,
J ) 11.8, 3.0 Hz), 3.96 (dd, 1 H, J ) 10.2, 7.7 Hz), 5.06 (dd, 1
H, J ) 10.1, 9.8 Hz), 5.42 (br d, 1 H, J ) 7.7 Hz), 5.65 (br d,
1 H, J ) 9.9 Hz), 5.75 (br d, 1 H, J ) 10.2 Hz). 13C NMR (75
MHz): δ 21.0, 21.1, 44.1, 61.7, 72.0, 73.1, 75.6, 126.4, 130.2,
(1S*,2R*,3S*,4R*,5R*,6R*)-3-(Ben zyloxy)-5-((ben zyloxy)-
m eth yl)-7-oxa bicyclo[4.1.0]h ep ta n e-2,4-d iol 2,4-O-(Meth -
ylen e a ceta l), 17. According to the procedure described for
the synthesis of 13, from 56 mg (0.16 mmol) of 16, 35 mg of
17 was obtained as a colorless oil (60%). Data for 17: Rf )
0.26 (hexane:EtOAc, 2:1). 1H NMR (300 MHz): δ 2.73 (td, 1
H, J ) 7.6, 4.5 Hz), 3.32 (t, 1 H, J ) 3.4 Hz), 3.56 (t, 1 H, J )
4.0 Hz), 3.60 (dd, 1 H, J ) 9.1, 7.9 Hz), 3.83 (dd, 1 H, J ) 9.1,
7.6 Hz), 3.90 (t, 1 H, J ) 3.5 Hz), 3.99 (d, 1 H, J ) 3.9 Hz),
4.42-4.52 (m, 4 H), 4.57 (d, 1 H, J ) 11.9 Hz), 4.65 (d, 1 H, J
) 6.4 Hz), 5.31 (d, 1 H, J ) 6.5 Hz), 7.24-7.36 (m, 10 H). NOE
between H-1 and H-acetal-ax, 14%; H-5 and H-acetal-ax, 21%;
H-6 and H-acetal-ax, 12%; H-acetal-eq and H-acetal-ax, 52%.
13C NMR (75 MHz): δ 39.3, 48.9, 51.7, 66.8, 68.1, 69.4, 71.5,
73.3, 73.6, 83.7, 127.5, 127.6, 127.7, 127.7, 128.4, 128.4, 137.9,
138.3. IR (CHCl3): 1110 cm-1. Anal. Calcd for C22H24O5: C,
71.72; H, 6.57. Found: C, 71.55; H, 6.38.
171.6, 172.2. IR (CHCl3): 3600-3300, 1740 cm-1
. Anal.
Calcd for C11H16O6: C, 54.09; H, 6.60. Found: C, 53.95; H,
6.48.
(1R*,2S*,5R*,6R*)-2,6-Bis((ter t-bu tyldim eth ylsilyl)oxy)-
5-(h yd r oxym eth yl)cycloh ex-3-en -1-ol, 15b. According to
the procedure described for the synthesis of 15a , from 150 mg
(0.24 mmol) of 18b in 4.5 mL of CH2Cl2 and 0.25 mL of H2O,
70 mg of 15b was obtained as a colorless oil (75% yield). Data
for 15b: Rf ) 0.22 (hexane:EtOAc, 5:1). 1H NMR (300 MHz):
δ 0.10 (s, 3 H), 0.10 (s, 3 H), 0.12 (s, 3 H), 0.14 (s, 3 H), 0.89
(s, 18 H), 1.56 (s, 1 H), 2.19 (s, 1 H), 2.38-2.48 (m, 1 H), 3.52
(t, 1 H, J ) 8.9 Hz), 3.68 (t, 1 H, J ) 9.4 Hz), 3.72-3.78 (m, 2
H), 4.15 (br d, 1 H, J ) 8.7 Hz), 5.49 (br d, 1 H, J ) 10.4 Hz),
5.58 (br d, 1 H, J ) 10.1 Hz). 13C NMR (75 MHz): δ -4.8,
-4.5, -4.4, -3.6, 18.2, 18.3, 25.9, 26.0, 47.2, 62.3, 71.5, 73.6,
77.9, 127.0, 131.6. IR (CHCl3): 3600-3300 cm-1. Anal. Calcd
for C19H40O4Si2: C, 58.71; H, 10.37. Found: C, 58.55; H, 10.29.
(1S*,2R*,3S*,4R*,5R*,6R*)-2,4-Bis((ter t-bu tyld im eth yl-
silyl)oxy)-5-(h yd r oxym eth yl)-7-oxa bicyclo[4.1.0]h ep ta n -
3-ol, 19. According to the procedure described for the syn-
thesis of 13, from 45 mg (0.11 mmol) of 15b, 38 mg of 19 was
obtained as a white solid (81% yield). Data for 19: Rf ) 0.36
(hexane:EtOAc, 2:1). Mp: 79-80 °C. 1H NMR (300 MHz): δ
0.09 (s, 6 H), 0.14 (s, 3 H), 0.15 (s, 3 H), 0.88 (s, 9 H), 0.91 (s,
9 H), 1.96-2.04 (m, 1 H), 3.02 (d, 1 H, J ) 4.0 Hz), 3.30 (dd,
1 H, J ) 9.4, 8.4 Hz), 3.37 (br d, 1 H, J ) 3.7 Hz), 3.43 (t, 1 H,
J ) 9.4 Hz), 3.75 (d, 1 H, J ) 8.1 Hz), 3.84 (dd, 1 H, J ) 10.7,
6.4 Hz), 3.99 (dd, 1 H, J ) 10.7, 3.4 Hz). 13C NMR (75 MHz):
δ -4.7, -4.7, -4.5, -3.7, 18.2, 18.3, 25.8, 26.0, 44.9, 55.8, 56.0,
(3S*,4R*,5R*,6R*)-3,5-Dia cetoxy-4-((p-m eth oxyben zyl)-
oxy)-6-(((p-m eth oxyben zyl)oxy)m eth yl)cycloh exen e, 18a .
To a solution of 59 mg (0.15 mmol) of 7b in 1.5 mL of CH2Cl2
were added 0.06 mL (0.59 mmol) of Ac2O, 0.05 mL (0.59 mmol)
of pyridine, and a catalytic amount of DMAP. After the
mixture was stirred for 1 h at room temperature, the crude
mixture was concentrated under reduced pressure, and puri-
fied by column chromatography on silica gel (hexane:EtOAc,
2:1) to give 69 mg of 18a as a white solid (97% yield). Data
for 18a : Rf ) 0.21 (hexane:EtOAc, 2:1). Mp: 78-79 °C. 1H
NMR (300 MHz): δ 1.97 (s, 3 H), 2.00 (s, 3 H), 2.58-2.70 (m,
1 H), 3.31 (dd, 1 H, J ) 9.1, 6.5 Hz), 3.46 (dd, 1 H, J ) 9.1, 4.9
Hz), 3.77 (dd, 1 H, J ) 9.7, 7.7 Hz), 3.79 (s, 6 H), 4.40 (s, 2 H),
4.59 (s, 2 H), 5.19 (t, 1 H, J ) 9.6 Hz), 5.49 (br d, 1 H, J ) 7.6
Hz), 5.56 (br d, 1 H, J ) 10.2 Hz), 5.72 (br d, 1 H, J ) 10.1
Hz), 6.85 (d, 2 H, J ) 8.6 Hz), 6.86 (d, 2 H, J ) 8.7 Hz), 7.19
(d, 2 H, J ) 8.6 Hz), 7.24 (d, 2 H, J ) 8.4 Hz). 13C NMR (75
MHz): δ 21.0, 21.1, 42.6, 55.2, 70.0, 71.3, 73.0, 73.8, 74.2, 79.4,
113.7, 125.5, 129.0, 129.1, 129.4, 130.0, 130.4, 159.1, 159.1,
170.2, 170.2. IR (CHCl3): 1740, 1710, 1520 cm-1. Anal. Calcd
for C27H32O8: C, 66.93; H, 6.66. Found: C, 66.77; H, 6.50.
62.1, 68.4, 72.6, 77.8. IR (CHCl3): 3600-3300 cm-1
. Anal.
Calcd for C19H40O5Si2: C, 56.39; H, 9.96. Found: C, 56.08; H,
9.40.
Tetr a -O-a cetyl-(()-cyclop h ellitol, 20. To a solution of
14 mg (0.03 mmol) of 19 in 0.2 mL of THF was added 0.1 mL
(0.10 mmol) of TBAF (1 M solution in THF). After the mixture
was stirred for 30 min at room temperature, a few drops of
H2O were added and the crude mixture was concentrated
under reduced pressure. The residue was acetylated with 1
mL of Ac2O, 1 mL of pyridine, and a catalytic amount of
DMAP. After 12 h the crude mixture was concentrated under
reduced pressure, and purified by column chromatography on
silica gel (hexane:Et2O, 1:2) to give 9 mg of 20 (75% yield). Its
spectral features were identical to those reported in the
literature.8a
(3S*,4R*,5R*,6R*)-3,5-Bis(ter t-bu tyld im eth ylsilyl)oxy)-
4-((p -m et h oxyb en zyl)oxy)-6-(((p -m et h oxyb en zyl)oxy)-
m eth yl)cycloh exen e, 18b. To a cold (-78 °C) solution of 168
mg (0.42 mmol) of 7b in 4 mL of THF were added 0.23 mL
(1.68 mmol) of Et3N and 0.39 mL (1.68 mmol) of TBSOTf. After
the mixture was stirred for 1 h at -78 °C, a saturated aqeuous
solution of K2CO3 was added. The crude mixture was ex-
tracted with Et2O, dried over MgSO4, concentrated under
reduced pressure, and purified by column chromatography on
silica gel (hexane:EtOAc, 10:1) to give 264 mg of 18b as a
colorless oil (100% yield). Data of 18b: Rf ) 0.41 (hexane:
EtOAc, 5:1). 1H NMR (300 MHz): δ -0.09 (s, 3 H), 0.01 (s, 3
H), 0.03 (s, 3 H), 0.10 (s, 3 H), 0.85 (s, 9 H), 0.87 (s, 9 H), 2.42-
2.51 (m, 1 H), 3.40-3.48 (m, 2 H), 3.56 (dd, 1 H, J ) 8.7, 3.4
Hz), 3.73 (t, 1 H, J ) 9.4 Hz), 3.81 (s, 6 H), 4.36 (d, 1 H, J )
11.8 Hz), 4.36-4.42 (m, 1 H), 4.53 (d, 1 H, J ) 12.1 Hz), 4.74
(d, 1 H, J ) 11.4 Hz), 4.89 (d, 1 H, J ) 11.4 Hz), 5.53 (br d, 1
H, J ) 10.4 Hz), 5.60 (br d, 1 H, J ) 10.4 Hz), 6.85 (d, 2 H, J
) 8.7 Hz), 6.89 (d, 2 H, J ) 8.4 Hz), 7.26 (d, 2 H, J ) 8.7 Hz),
7.27 (d, 2 H, J ) 8.4 Hz). 13C NMR (75 MHz): δ -5.0, -4.5,
-4.3, -3.5, 18.0, 18.2, 25.9, 26.0, 46.1, 55.1, 55.2, 69.2, 71.1,
72.6, 74.3, 86.0, 113.1, 113.7, 127.9, 128.0, 129.2, 129.9, 130.4,
Ack n ow led gm en t. This research was supported by
D.G.I.C.Y.T. (Ministerio de Educacio´n y Ciencia, Grant
no. PB93-0077, and a doctoral fellowship to J .L.A.). We
also thank the European COST Chemistry D2 program.
Su p p or tin g In for m a tion Ava ila ble: Available charac-
terization data and experimental procedures for the synthesis
of 12b and their synthetic precursors (4 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O962276O