Differential use of anhydropyranosides for enantiopure routes to bis-γ-butyrolactones: A new approach to the frameworks of antibiotic and anticancer agents isoavenaciolide and ethisolide

Article abstract of DOI:10.1021/jo900192a

(Chemical Equation Presented) Regio- and chemoselective syntheses of enantiopure bis-furanoids are described. These compounds are chirons for several families of bioactive natural products, including isoavenaciolide and ethisolide. Reaction of a 3,4-epoxy

Full text of DOI:10.1021/jo900192a

Differential Use of Anhydropyranosides for Enantiopure Routes to
Bis-γ-butyrolactones: A New Approach to the Frameworks of
Antibiotic and Anticancer Agents Isoavenaciolide and Ethisolide
Taleb H. Al-Tel,*,† Raed A. Al-Qawasmeh,‡ Salim S. Sabri,† and Wolfgang Voelter*,§
College of Pharmacy, UniVersity of Sharjah, P.O. Box 27272, Sharjah, UAE, Chemistry Department,
UniVersity of Jordan, Amman, Jordan, and Physiologisch-Chemisches Institut der UniVersita¨t Tu¨bingen,
Hoppe-Seyler Strasse 4, D-72076 Tu¨bingen, Germany
taltal@sharjah.ac.ae
ReceiVed January 30, 2009
Regio- and chemoselective syntheses of enantiopure bis-furanoids are described. These compounds are
chirons for several families of bioactive natural products, including isoavenaciolide and ethisolide. Reaction
of a 3,4-epoxy pyran with ꢀ-ketoester dianions delivers substituted pyranosides in high yield. Cyclization
then yields fused furan-pyran intermediates. Oxidation, deprotection, and rearrangement lead to bis-
furanoids that bear the essential framework and stereochemistry of ethisolide and isoavenaciolide.
Introduction
Modern carbohydrate chemistry is a diverse discipline
strongly connected with organic and medicinal chemistry.1
These polyhydroxylated natural products offer a valuable
platform for enantioselective synthesis of stereochemically
robust and biologically important molecules. We report herein
the synthesis of a set of bis-γ-lactones that utilizes the rich
opportunities embodied in the carbohydrates. These synthetic
routes yield products with the essential stereochemistry present
in many biologically important natural products such as, among
others, isoavenaciolide 1 and ethisolide 2 (Figure 1).
FIGURE 1. Natural products containing the R-methylene-bis-γ-lactone
Isoavenaciolide 1 and ethisolide 2 are secondary metabolites
isolated from Aspergillus and Penicillium fermentation broths.
Both compounds inhibit fungal growth and have antibiotic
activity.1 Recently, it has been found that (-)-isoavenaciolide
is a potent irreversible inhibitor of a dual-specificity protein
phosphatase (VHR) involved in growth factor signaling, making
skeleton.
these targets and their derivatives candidates for cancer che-
motherapy.2 Because of their biological activity and structurally
interesting bis-γ-lactone framework, many synthetic methods
have been developed to access this family of natural products.3,4
In this regard, a few enantioselective approaches to this class
of natural products have been reported.3,4e,f While previous
† University of Sharjah.
‡ University of Jordan.
§ Universita¨t Tu¨bingen.
(1) (a) Arjona, O.; Gomez, A. M.; Lopez, J. C; Plumet, J. Chem. ReV. 2007,
107, 1919. (b) Gruner, A. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem.
ReV. 2002, 102, 491.
(2) Ueda, K.; Usui, T.; Nakayama, H.; Ueki, M.; Takio, K.; Ubukata, M.;
Osada, H. FEBS Lett. 2002, 525, 48.
4690 J. Org. Chem. 2009, 74, 4690–4696
10.1021/jo900192a CCC: $40.75  2009 American Chemical Society
Published on Web 05/21/2009

IsoaVenaciolide and Ethisolide Frameworks
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Furan Annulation and Control of C-3
Stereochemistry
synthetic methods appear to be very selective for one particular
core structure and in many cases required chirally pure reagents
that are expensive and fairly toxic and difficult to handle
reagents (e.g., bromine or stannyl compounds) and did not give
perfect selectivity,4a-d the route described herein can be used
to generate several enantiomerically analogous structures utiliz-
ing relatively nontoxic and cheap reagents.
The stereochemistry of these bis-γ-lactone natural product
targets seemed to be well-suited for carbohydrate-based routes
developed in our laboratories.5 In this regard, we sought to
control all of the stereocenters of the target molecules, taking
advantage of the inherent chirality and steric bias of the
pyranoside architecture. Previous work has demonstrated that
nucleophilic ring opening of epoxypyrans can lead to both
chemo- and regioselective annulation of new and enantiopure
heterocylic ring systems.5,6
ester dianion, opening the epoxide at C-3 in a trans-diaxial
manner.5,6 Cyclization by O-alkylation of the ꢀ-keto ester
substituted sugar followed by oxidative cleavage would then
yield the oxa-bicyclic furanoid II.
Retrosynthetic analysis of isoavenaciolide 1 and ethisolide 2
(Scheme 1) suggested that the oxa-bicyclic furanoid framework
I would be suitable building block for such natural products,
such that all the crucial stereocenters could be stereospecifically
derived from the furanoid precursor II. Following deprotections
at C-4 and C-1, rearrangement of the pyranoside ring would
yield the desired bis-furanoid I, from which the ultimate targets
and analogues could be derived (see Scheme 1).7,8 In order to
arrive at II, we would rely upon the demonstrated reactivity of
the anhydropyranoside III that selectively accepts the ꢀ-keto
Results and Discussion
Synthesis of Alkylidene Tetrahydrofurans. As previously
reported,5d arrival at 4 was achieved through nucleophilic ring
opening of the epoxide in 3 by the dianion derived from tert-
butyl acetoacetate. Subsequent mesylation, followed by the
kinetically preferred O-alkylation of the ꢀ-keto ester anion
following NaH deprotonation, delivered the furanoids (E)-6a
and (Z)-6b in 20% and 75% yields, respectively (Scheme 2).
The ketone oxygen anion is presumably able to reach a collinear
transition state with the trans mesylate leaving group to afford
(3) (a) For a Review, see: Martin, S. V.; Rodriguez, C. M.; Martin, T. Org.
Prep. Proced. Int. 1998, 30, 291. (b) For enantiopure syntheses using
carbohydrates, see: Anderson, R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50,
4781. (c) Anderson, R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4786.
(4) For recent publications, see: (a) Mondal, S.; Ghosh, S. Tetrahedron 2008,
64, 2359. (b) Hon, Y.-S.; Chen, H.-F. Tetrahedron Lett. 2007, 48, 8611. (c)
Hon, Y.-S.; Hsieh, C.-H. Tetrahedron 2007, 62, 9713. (d) Hon, Y.-S.; Hsieh,
C.-H. Tetrahedron 2006, 62, 9713. (e) Yu, C.-M.; Youn, J.; Jung, J. Angew.
Chem., Int. Ed. 2006, 45, 1553. (f) Liu, H.-M.; Zhang, F.; Zou, D.-P. J. Chem.
Soc., Chem. Commun. 2003, 2044. (g) Sharma, G. V. M.; Gopinath, T.
Tetrahedron Lett. 2001, 42, 6183. (h) Alcazar, E.; Kassou, M.; Matheu, I.;
Castillon, S. Eur. J. Org. Chem. 2000, 65, 2285. (i) Chen, M.-J.; Narkunan, K.;
Liu, R.-S. J. Org. Chem. 1999, 64, 8311. (j) Rodriguez, C. M.; Martin, T.; Martin,
V. S. J. Org. Chem. 1996, 61, 8448.
(5) (a) Naz, N.; Al-Tel, T. H.; Al-Abed, Y.; Voelter, W.; Ficker, R.; Hiller,
W. J. Org. Chem. 1996, 61, 3250. (b) Al-Tel, T. H.; Voelter, W. J. Chem. Soc.
Chem. Commun. 1995, 239. (c) Al-Tel, T. H.; Al-Abed, Y.; Voelter, W. J. Chem.
Soc. Chem. Commun. 1994, 1735. (d) Al-Tel, T. H.; Voelter, W. Tetrahedron
Lett. 1995, 36, 523.
(6) (a) Al-Tel, T. H.; Meisenbach, M.; Voelter, W. Liebigs Ann. 1995, 689.
(b) Al-Qawasmeh, R. A.; Al-Tel, T. H.; Abdel-Jalil, R.; Voelter, W. Chem. Lett.
1999, 541.
1
compounds 6a and 6b. By inspection of the H NMR spectra
of 6a and 6b, the Z and E configurations were confirmed by
the homoallylic coupling constant between H-6 and the exo-
alkylidene proton H-8 (6a: J6,8 ) 1.7 Hz and 6b: J6,8 ) 0.0
Hz).9,10 Oxidation of the alkylidene mixture (6a and 6b) by
ozonolysis at -78 °C followed by reductive workup with Ph3P,
delivered the γ-lactone 8 in 95% yield. Next, we turned our
attention to incorporation of a methyl group on the newly
annulated furan ring, as a precursor of the exo-methylene moiety
in both natural products (vide infra).
Control of Stereochemistry around the Furanoid Ring.
Following the same synthetic strategy, we diastereoselectively
obtained the exo-methyl derivative 7. Addition of the dianion
from methyl propionyl acetate to the epoxy sugar 3 produced
the substituted sugar 5 (Scheme 2). Mesylation and sodium
hydride mediated ring closure delivered compound 7 in 87%
(7) (a) Al-Abed, Y.; Al-Tel, T. H.; Voelter, W. Tetrahedron 1993, 49, 9295,
and references therein. (b) Grieco, P. A. Synthesis 1975, 67, 564 and relevant
references therein.
(8) (a) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V. Tetrahedron Lett. 1994,
35, 1205. (b) Honda, T.; Kobayoshi, Y.; Tsubuki, M. Tetrahedron 1993, 49,
1211. (c) Burke, S. D.; Pacofsky, G. J.; Piscopio, A. D. J. Org. Chem. 1992, 57,
2228, and references therein. (d) Nakunan, K.; Liu, R.-S. J. Chem. Soc. Chem.
Commun. 1998, 1521 and relevant references therein.
(9) Similar findings in relation to the geometry of the exo-alkylidene
tetrahydrofuran derivatives have been reported by Prof. Trost: (a) Trost, B. M.;
Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7550. (b) Trost, B. M.; Runge,
T. A. J. Am. Chem. Soc. 1981, 103, 7559.
(10) The adopted numbering scheme is only for the purpose of NMR
interpretation (see refs 3b and 3c).
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Al-Tel et al.
SCHEME 3. Furan Annulation from r-Epoxide 10
SCHEME 4. Half-Chair Conformations of Ribopyranoside
Diastereoisomers
SCHEME 5. Formation of Bis-furanoids by Rearrangement
of the Pyrans
overall yield. Notably, only one epimer (HPLC and NMR) was
produced at C-6 (exo-methyl) of the new furan ring; this
outcome is likely due to the thermodynamic equilibrium of the
enolate ester formed during the cyclization process, steering the
stereochemistry on the furan ring.5,6
The preferential formation of the Z-isomer 7 without the
alternative E-isomer may be attributable to the steric clash of
the ester group with the C-6 methyl group. The Z configuration
of the exo-alkylidene moiety is consistent with the J6,8 ) 0.0
Hz coupling.9,10 The cis ring fusion in 7 was readily identified
by the coupling of H-2, a doublet of doublet with J1,2 ) 4.8 Hz
and J2,3 ) 7.7 Hz. The trans relationship between H-3 and H-6
was also indicated from the coupling constant J3,6 ) 12.7 Hz.
Further confirmation of the stereochemistry around 7 was
deduced from extensive NOE experiments. Proton H-3 showed
a strong reciprocal NOE interaction with both H-2 and H-4,
confirming the cis relationship. A very weak interaction was
observed between H-3 and H-6 consistent with trans relation-
ship, while a strong reciprocal NOE was found between H-3
and the furan methyl substituent. Ozonolysis of 7 delivered 9
in 90% yield. The unambiguous confirmation of the stereo-
chemistry in 9 was determined by extensive NOE experiments
and from the coupling constant between H-3 and H-6 (12.8
Hz).10
Having these results in hand, we directed our efforts toward
extending the scope of this strategy to the synthesis of the other
isomers of 6, thereby providing access to other natural products,
such as avenaciolide and canadensolide. Thus, the cis-alkoxy-
epoxide 10 (Scheme 3) was treated with the dianion derived
from tert-butyl acetoacetate. In contrast to the reaction of 3,
this alkylation delivered two regioisomers, 11 and 12, in 75%
and 20% yield, respectively.
from 11 and 12 (Scheme 3). Surprisingly, only E-isomers are
produced. This was evident from the coupling between H-8 and
H-6 (J ≈ 1.5 Hz).9 It is worthwhile mentioning that the bicyclic
furanoids 13 and 14 have the proper stereochemistry for
synthesis of the naturally occurring enantiomers of avenaciolide
and canadensolide (Figure 1), respectively.
Synthesis of Bis-furanoids. To elaborate our synthons to
more advanced building blocks, we pursued the conversion of
the pyran ring to the bis-furanoids suitable for the total synthesis
of the isoavenaciolide and ethisolide natural products. Standard
protocols were used to remove the protecting groups at both
C-4 and C-1 to deliver compounds 17 and 18 (Scheme 5).
Treatment of 8 and 9 with BF3 ·OEt2 at -78 °C removed the
MOM protecting group, furnishing 15 and 16, respectively.
Removal of the benzyl moiety was carried out over Pd/C in
EtOAc to deliver compounds 17 and 18 in 90% and 95% yields,
respectively. The assignment of methyl group stereochemistry
The lower selectivity of the nucleophilic epoxide opening for
10, in contrast to epoxide 3 that gave a single ring-opening
product (Scheme 2), is most readily explained by considering
that the relative energies of the two half-chair conformation of
R-D-ribopyranoside allowed for nucleophilic attack at C-2
(Scheme 4) of the oxirane ring. This attack was not observed
in the case of ꢀ-L-ribopyranoside, where C-2 is sterically blocked
and the thermodynamic equilibrium favors the attack at C-3 of
the epoxide ring (Scheme 4). Therefore, one regioisomer is
obtained to the complete exclusion of the other.
1
for compound 16 was unambiguously confirmed by the H
NMR: coupling between H-3 and H-6 was 12.8 Hz, consistent
with a trans disposition. Having arrived at 17 and 18, ring
contraction of the pyranoside skeleton was carried out using a
freshly prepared solution of 6% HCl in MeOH at 0 °C for 30
Following the same strategy as described for the synthesis
of 6a, b and 7, compounds 13 and 14 were easily produced
4692 J. Org. Chem. Vol. 74, No. 13, 2009

IsoaVenaciolide and Ethisolide Frameworks
min to produce 19 and 20, respectively.11 The stereochemistry
of the anomeric methoxy groups in both 19 and 20 was inferred
from the coupling constants of the anomeric protons (J ) 0.0
Hz),12 indicating an R-disposition. Furthermore, the 13C NMR
spectra of compounds 19 and 20 showed a downfield shift of
the anomeric carbons to ca. 105 ppm, indicative of ring
contraction to the furanoid framework, whereas the chemical
shifts for the anomeric carbon in the pyranoside skeleton are
found at ca. 100 ppm.12 Unambiguous confirmation of the
stereochemistry for 19 and 20 utilized extensive NOE analysis.
The protons H-3 and H-2 showed strong reciprocal NOE
interactions, indicative of a cis relationship between these
bridgehead methine protons. Derivatization of 20 by conven-
tional tosylation of the hydroxyl residue led to the bis-furanoid
21. Substitution of the tosyl group in 21 by iodide, using NaI/
Benzyl 2,3-Anhydro-4-O-methoxymethyl-ꢀ-L-ribopyranoside (3).
To a suspension of NaH (399 mg, 10.4 mmol, 65% dispersion in
mineral oil) in THF (10 mL) at 0 °C was added under argon benzyl
2,3-anhydro-ꢀ-L-ribopyranoside (2.22 g, 10 mmol) in 5 mL of THF.
The mixture was stirred at 0 °C for 20 min followed by the addition
of methoxymethyl chloride (0.78 mL, 10.2 mmol). The mixture
was allowed to warm to rt and stirred for an additional 4 h. Workup
with saturated NH4Cl and extraction with EtOAc produced after
crystallization from EtOAc/pet ether 2.12 g (80%) of 3 as a white
1
solid: mp 64-66 °C; [R]D +220.5 (c 0.23, CH2Cl2); H NMR
20
(400 MHz, CDCl3) δ 7.39-7.22 (5H, m), 5.11 (1H, dd, J ) 2.1,
4.9 Hz), 4.80 (1H, d, J ) 11.9 Hz), 4.64 (2H, s), 4.60 (1H, d, J )
11.9 Hz), 5.14 (1H, s), 4.00 (1H, dd, J ) 2.4, 13.0 Hz), 3.67 (1H,
d, J ) 13.0 Hz), 3.43 (2H, br. s), 3.27 (3H, s); 13C NMR (75 MHz,
CDCl3, GASPE) δ 137.2, 129.1, 128.4, 128.1, 100.0, 92.8, 76.7,
69.5, 62.0, 55.5, 51.8, 49.3; FD-MS m/z ) 267 (M+ + 1). Anal.
Calcd for C14H18O5 (266.29): C, 63.15; H, 6.81. Found: C 63.20,
H 6.87.
1
acetone, produced compound 22. A salient feature of the H
NMR spectrum of compound 22 was the coupling constant
between H-3 and H-6 of 13.3 Hz, indicating a trans relationship.
This feature further confirmed the stereochemistry around the
γ-lactone ring. Extensive NOE experiments unambiguously
confirmed the stereochemistry around 22. Conventional chem-
istry, using 20, 21 or 22, should allow for the total synthesis of
isoavenaciolide 1 and ethisolide 2.7,8
Phenylmethyl 3-Deoxy-3-[4-(1,1-dimethylethoxy)-2,4-dioxobu-
tyl]-4-O-(methoxymethyl)-ꢀ-L-xylopyranoside (4). A suspension of
NaH (174 mg, 4.4 mmol, 65% dispersion in mineral oil) in 10 mL
of THF at 0 °C was cautiously treated with tert-butyl acetoacetate
(0.66 mL, 4 mmol) under argon over a 15 min period. After stirring
at this temperature for 30 min, a solution of n-BuLi (2.75 mL, 4.4
mmol, 1.6 M in n-hexane) was added dropwise over 10 min. The
mixture was stirred at 0 °C for 30 min. To the resultant milky
solution was added compound 3 (1 mmol, 266 mg in 2 mL of THF).
The reaction was then stirred at rt for 5 h, after which the mixture
was quenched with a saturated solution of NH4Cl (5 mL), extracted
with EtOAc (3 × 20 mL), dried over Na2SO4 and concentrated
under vacuum to give a yellowish crude oil. The crude was purified
through a short silica gel column using DCM/ EtOAc (9:1) as eluent
Conclusions
In summary, we have developed a new route from pyranoside
3 to advanced optically active bis-furanoid building blocks
19-22, which should be readily elaborated to the antibiotics
isoavenaciolide 1 and ethisolide 2 using chemistry described
by other laboratories.3-8 Further, compounds 21 and/or 22 could
serve as important “chirons”, replacing the nucleofuge and
potentially producing more potent or selective irreversible
inhibition of VHR.2 The scope of this methodology was also
tested with the isomeric oxirane 10 to deliver two alkylidene
tetrahydrofuran compounds 13 and 14 which are building blocks
with clear application to the synthesis of enantiomers of
avenaciolide and canadensolide natural products.
to afford compound 4 as a yellowish oil (407 mg, 96% yield): [R]D
20
-85.1 (c 0.31, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.32-7.24
(5H, m, arom. H), 4.83 (1H, d, J ) 11.3 Hz, OCHHPh), 4.68 (2H,
dd, J ) 7.0, 8.3 Hz, OCH2O), 4.48 (1H, d, J ) 11.3 Hz, OCHHPh),
4.46 (1H, d, J ) 7.1 Hz, 1-H), 4.34 (1H, t, J ) 11.3 Hz, 5-H),
4.13 (1H, dd, J ) 4.9, 11.3 Hz, 5-H), 3.69 (1H, m, 4-H), 3.31 (1H,
m, 2-H), 3.26 (3H, s, OMe), 2.90 (1H, dd, J ) 4.6, 17.1 Hz, 6-H),
2.80 (2H, br. s, 8-H), 2.73 (1H, dd, J ) 5.2, 17.1 Hz, 6-H), 2.24
(1H, m, 3-H), 1.39 (9H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3,
GASPE) δ 200.0 (C-7), 166.5 (CO2C(CH3)3), 137.5, 128.6, 128.4,
128.3 (Ph), 100.5 (C-1), 97.2 (OCH2O), 81.5 (C(CH3)3), 77.6 (C-
4), 74.9 (C-2), 71.0 (OCH2Ph), 67.1 (C-5), 55.8 (OMe), 50.9 (C-
8), 39.9 (C-6), 38.7 (C-3), 27.9 (C(CH3)3); FD-MS m/z ) 425 (M+
+ 1). Anal. Calcd for C22H32O8 (424.21): C 62.25, H 7.60. Found:
C 62.31, H 7.54.
Experimental Section
All reactions were performed under argon using anhydrous
solvents. Column chromatography was carried out with silica gel
(60-120 mesh). 1H and 13C NMR spectra were recorded on a 500
or 400 MHz spectrometer in CDCl3 with TMS as internal standard
in ppm. Elemental analysis was performed on elemental analyzer.
The EI, FD, and FAB mass spectra were recorded using a mass
spectrometer connected to a PDO 11/34 (DEC) computer system.
Optical rotations were obtained with a polarimeter at 546 nm. All
chemical used are of commercial grades.
Phenylmethyl 3-Deoxy-4-O-(methoxymethyl)-3-(4-methoxy-1-
methyl-2,4-dioxobutyl)-ꢀ-L-xylopyranoside (5). Following proce-
dure similar to the conversion of oxirane 3 to 4, a suspension of
NaH (4.4 mmol, 174 mg, 65% dispersion in mineral oil) in 10 mL
of THF at 0 °C was cautiously treated with methyl propionyl acetate
(0.5 mL, 4 mmol) under argon over a 15 min period. After stirring
at this temperature for 30 min, a solution of n-BuLi (2.75 mL, 4.4
mmol of 1.6 M in n-hexane) was added dropwise over 10 min.
Stirring at 0 °C was continued for an additional 30 min, after which
oxirane 3 (1 mmol, 266 mg) was added. Following workup/
purification procedure as employed for 4, a diastereomeric mixture
For the purpose of NMR interpretation, the following numbering
schemes have been adopted (see refs 3b and 3c):
1
(1:1 as indicated from the 13C and H NMR spectra) of the long
chain pyranoside 5 (376 mg, 95% yield) was obtained as a yellowish
oil: [R]D20 -63.2 (c 0.43, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
7.32-7.24 (10H, m, arom. H), 4.81 (1H, d, J ) 7.8 Hz, 1-H), 4.77
(1H, d, J ) 8.0 Hz, 1-H), 4.61 (5H, m), 4.34-4.27 (3H, m),
4.10-4.02 (2H, m), 3.64-3.60 (5H, m), 3.52-3.20 (9H, m),
(11) Motawia, M. S.; Pedersen, E. B. Liebigs Ann. 1990, 599.
(12) (a) Thibaudeau, C.; Foldesi, A.; Chattopadhyaya, J. Tetrahedron 1998,
54, 1867. (b) Plavec, J.; Tong, W.; Chattopadhyaya, J. J. Am. Chem. Soc. 1993,
115, 9734.
J. Org. Chem. Vol. 74, No. 13, 2009 4693

Al-Tel et al.
2.97-2.91 (3H, m), 2.30-2.21 (2H, m), 1.08-0.97 (6H, m); 13C
NMR (75 MHz, CDCl3, GASPE) δ 205.1, 204.5 (CO), 168.3
(CO2C(CH3)3), 137.2, 137.1, 128.5, 128.4, 128.2, 128.1, 127.9,
127.6 (Ph), 103.4, 103.1 (C-1), 97.2, 96.4 (OCH2O), 72.5, 72.2
(C-4), 70.7, 70.0 (OCH2Ph), 69.1, 68.2 (C-2), 66.9, 66.0 (C-5), 55.8,
55.7 (OMe), 52.2, 52.1 (OMe), 46.9, 46.8 (2C-8), 44.1, 43.8 (C-
3), 47.5, 46.7 (C-6), 9.6, 8.9 (Me); FD-MS m/z ) 397 (M+ + 1).
Anal. Calcd for C20H28O8: C, 60.59; H, 7.12. Found: C, 60.23; H,
6.98.
tetrahydrofuran 7 (346 mg, 92%) as a yellowish oil: [R]D20 +150.0
(c 0.50, CH2Cl2); significant NMR NOEs are 2-H to 3-H, 32%;
3-H to 6-CH3, 37%; 3-H to 6-CH3, 28%; 8-H to 6-CH3, 33%. H
1
NMR (400 MHz, CDCl3) δ 7.27-7.21 (5H, m, arom. H), 5.06 (1H,
d, J ) 4.8 Hz, 1-H), 4.84 (1H, s, 8-H), 4.80 (1H, dd, J ) 4.8, 7.7
Hz, 2-H), 4.69 (1H, d, J ) 12.4 Hz, OCHHPh), 4.68 (2H, br. s,
OCH2O), 4.52 (1H, d, J ) 12.4 Hz, OCHHPh), 3.86 (1H, dd, J )
1.6, 13.0 Hz, 5-H), 3.71 (1H, bs, 4-H), 3.68 (3H, s, OMe), 3.65
(1H, dt, J ) 1.5, 13.0 Hz, 5-H), 3.36 (3H, s, OMe), 2.93 (1H, dd,
J ) 6.7, 12.7 Hz, 6-H), 2.20 (1H, dd, J ) 7.7, 12.7 Hz, 3-H), 1.15
(3H, d, J ) 6.7 Hz, 6-CH3); 13C NMR (75 MHz, CDCl3, GASPE)
δ 175.9, 166.4 (CO2CH3), C-7), 137.4, 128.4, 127.6, 127.1 (Ph),
95.8 (C-1), 95.1 (OCH2O), 88.1 (C-8), 76.7 (C-2), 70.8 (C-4), 70.2
(OCH2Ph), 57.3 (C-5), 55.6 (OMe), 50.8 (OMe), 45.7 (C-6), 39.8
(C-3), 16.5 (6-CH3); FD-MS m/z ) 379 (M+ + 1). Anal. Calcd for
C20H26O7: C, 63.48; H, 6.93. Found: C, 63.50; H 6.90.
[3aR-(2E,3ar,4r,7ꢀ,7ar)]-Acetic Acid-[hexahydro-4-(methoxy-
methoxy)-7-(phenylmethoxy)-2H-furo[2,3-c]pyran-2-ylidene]-1,1-
dimethylethyl Ester (6a). Semisolid, (81 mg, 20%); [R]D20 +112.6
1
(c 0.26, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.25-7.19 (5H,
m, arom. H), 5.30 (1H, t, J ) 1.7 Hz, 8-H), 4.82 (1H, d, J ) 4.0
Hz, 1-H), 4.73 (1H, d, J ) 12.5 Hz, OCHHPh), 4.62 (2H, dd, J )
7.1, 9.8 Hz, OCH2O), 4.50 (1H, d, J ) 12.5 Hz, OCHHPh), 4.43
(1H, dd, J ) 4.0, 7.0 Hz, 2-H), 4.34 (1H, dd, J ) 2.7, 12.3 Hz,
5-H), 3.67 (1H, dd, J ) 3.9, 6.8 Hz, 4-H), 3.47 (1H, dd, J ) 3.8,
12.3 Hz, 5-H), 3.31 (3H, s, OMe), 3.16 (1H, ddd, J ) 1.7, 8.5,
17.5 Hz, 6-H), 2.97 (1H, ddd, J ) 1.8, 9.8, 17.5 Hz, 6′-H), 2.53
(1H, m, 3-H), 1.38 (9H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3,
GASPE) δ 174.3, 166.5 (CO2C(CH3)3, C-7), 137.5, 128.4, 127.6,
127.2 (Ph), 95.9 (C-1), 95.6 (OCH2O), 92.9 (C-8), 79.1 (C(CH3)3),
76.4 (C-2), 69.7 (OCH2Ph), 71.9 (C-4), 59.5 (C-5), 55.6 (OMe),
39.6 (C-3), 33.8 (C-6), 28.4 (C(CH3)3); FD-MS m/z ) 407 (M+ +
1). Anal. Calcd for C22H30O7: C, 65.01; H, 7.44. Found: C, 65.16;
H, 7.39.
(3aR,4R,7aR)-7-(Benzyloxy)-4-(methoxymethoxy)hexahydro-2H-
furo[2,3-c]pyran-2-one (8). A solution of 6a,b (1 mmol, 404 mg)
in 20 mL of DCM was cooled to -78 °C. A stream of O3/O2 was
then bubbled through this mixture until the blue color of the excess
O3 appeared (ca. 10-15 min). Reductive workup with PPh3 (1.4
mmol, 371 mg) led (after 30 min stirring at rt) to the corresponding
lactone. The mixture was concentrated under vacuum and purified
via column chromatography (50% v/v pet ether/DCM eluent) to
produce 8 (293 mg, 95%) as colorless oil: [R]D +85.1 (c 0.198,
20
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.32-7.23 (5H, m, arom.
H), 5.00 (1H, d, J ) 4.5 Hz, 1-H), 4.85 (1H, d, J ) 12.1 Hz,
OCHHPh), 4.70 (1H, d, J ) 7.2 Hz, OCH2O), 4.65 (1H, d, J )
7.2 Hz, OCH2O), 4.64 (1H, dd, J ) 4.5, 7.6 Hz, 2-H), 4.56 (1H, d,
J ) 12.1 Hz, OCHHPh), 3.94 (1H, dd, J ) 2.3, 12.6 Hz, 5-H),
3.781 (1H, dd, J ) 2.3, 6.0 Hz, 4-H), 3.62 (1H, dd, J ) 3.7, 12.6
Hz, 5-H), 3.36 (3H, s, OMe), 2.84 (1H, m, 3-H), 2.55 (1H, dd, J
) 12.1, 17.1 Hz, 6-H), 2.48 (1H, dd, J ) 7.5, 17.1 Hz, 6-H); 13C
NMR (75 MHz, CDCl3, GASPE) δ 175.9 (C-7), 136.7, 128.4,
127.8, 127.4 (Ph), 95.2 (C-1), 95.3 (OCH2O), 71.2 (C-2), 72.9 (C-
4), 69.7 (OCH2Ph), 57.8 (C-5), 55.6 (OMe), 31.6 (C-6), 38.0 (C-
3); FD-MS m/z ) 309 (M+ + 1). Anal. Calcd for C16H20O6
(308.33): C, 63.33; H, 6.54. Found: C, 62.48; H, 6.43.
[3aR-(2Z,3ar,4r,7ꢀ,7ar)]-Acetic Acid-[hexahydro-4-(methoxy-
methoxy) (phenylmethoxy)-2H-furo[2,3-c]pyran-2-ylidene]-1,1-
dimethylethyl Ester (6b). To a solution of the branched chain sugar
2 (1 mmol, 424 mg) in 10 mL of DCM at 0 °C was added Et3N
(0.17 mL, 1.2 mmol) and DMAP (0.1 mmol, 12 mg) followed by
the dropwise addition of MsCl (0.1 mL in 10 DCM, 1.2 mmol).
The resulting mixture was stirred at 0 °C for 2 h, after which TLC
analysis showed no starting material. The mixture was diluted with
10 mL of DCM and 5 mL of saturated NaHCO3, and the organic
layer was washed with brine, dried over Na2SO4, and concentrated
under vacuum. The crude mesylate product was used in the next
step without further purification. The mesylated derivative of
compound 4 (424 mg, 1 mmol) was dissolved in 10 mL of THF
and added dropwise to a cooled suspension of NaH (47.5 mg, 1.2
mmol, 65% dispersion in mineral oil) in 10 mL of THF. The
mixture was warmed to rt and stirred overnight. It was then diluted
with 5 mL of saturated NH4Cl, extracted with EtOAc (3 × 20 mL),
dried over Na2SO4 and concentrated under high vacuum to give
compounds 6a and 6b as a yellowish oil. The crude was purified
via column chromatography using EtOAc/DCM (1:9) as eluent to
(3S,3aR,4R,7aR)-7-(Benzyloxy)-4-(methoxymethoxy)-3-methyl-
hexahydro-2H-furo[2,3-c]pyran-2-one (9). Following procedure for
preparation of compound 8, a solution of 7 (1 mmol, 376 mg, 20
mL of DCM) was cooled to -78 °C, after which a stream of O3/
O2 was bubbled through this mixture until the blue color of the
excess O3 appeared (about 10-15 min). Reductive workup with
PPh3 (1.4 mmol, 371 mg) led after 30 min of stirring at rt to the
corresponding lactone 9 in 87% (280 mg) as colorless oil: [R]D
20
+156.6 (c 0.144, CH2Cl2); significant NMR NOEs are 2-H to 3-H,
29%; 3-H to 6-CH3, 34%; 3-H to 6-CH3, 35%. 1H NMR (400 MHz,
CDCl3) δ 7.28-7.19 (5H, m, arom. H), 4.98 (1H, d, J ) 4.7 Hz,
1-H), 4.67 (1H, d, J ) 7.0 Hz, OCH2O), 4.66 (1H, d, J ) 11.9 Hz,
OCHHPh), 4.63 (1H, d, J ) 7.0 Hz, OCH2O), 4.55 (1H, dd, J )
4.7, 7.2 Hz, 2-H), 4.47 (1H, d, J ) 11.9 Hz, OCHHPh), 3.88 (1H,
dd, J ) 3.9, 12.8 Hz, 5-H), 3.69 (1H, m, 4-H), 3.67 (1H, dd, J )
1.8, 12.8 Hz, 5-H), 3.33 (3H, s, OMe), 2.63 (1H, m, 3-H), 2.40
(1H, dq, J ) 7.7, 12.8 Hz, 6-H), 1.14 (3H, d, J ) 7.7 Hz, 6-CH3);
13C NMR (75 MHz, CDCl3, GASPE) δ 178.8 (C-7), 136.7, 128.5,
128.0, 127.4 (Ph), 95.0 (C-1), 94.9 (OCH2O), 70.9 (C-2), 70.4 (C-
4), 70.1 (OCH2Ph), 57.1 (C-5), 55.6 (OMe), 45.6 (C-6), 36.3 (C-
3), 14.5 (6-CH3); FD-MS m/z ) 323 (M+ + 1). Anal. Calcd for
C17H22O6 (322.35): C, 63.34; H, 6.88. Found: C, 63.30; H, 6.29.
Benzyl 2,3-Anhydro-4-O-methoxymethyl-r-D-ribopyranoside (10).
To a suspension of NaH (399 mg, 10.4 mmol, 65% dispersion in
mineral oil) in THF (10 mL) at 0 °C was added under argon benzyl
2,3-anhydro-R-D-ribopyranoside (2.22 g, 10 mmol) in 5 mL of THF.
The mixture was stirred at 0 °C for 20 min followed by the addition
of methoxymethyl chloride (0.78 mL, 10.2 mmol). The mixture
was allowed to warm to rt and stirred for an additional 4 h. Workup
with saturated NH4Cl and extraction with EtOAc produced after
crystallization from EtOAc/pet ether 2.00 g (75%) of 10 as a white
produce compound 6b (303 mg, 75%): [R]D +98.1 (c 0.22,
20
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.25-7.15 (5H, m, arom.
H), 5.02 (1H, d, J ) 4.6 Hz, 1-H), 4.78 (1H, s, 8-H), 4.74 (1H, dd,
J ) 4.6, 7.0 Hz, 2-H), 4.67 (1H, d, J ) 12.4 Hz, OCHHPh), 4.64
(2H, dd, J ) 7.0, 8.3 Hz, OCH2O), 4.50 (1H, d, J ) 12.4 Hz,
OCHHPh), 4.34 (1H, dd, J ) 2.0, 12.6 Hz, 5-H), 3.73 (1H, bd, J
) 2.1 Hz, 4-H), 3.55 (1H, dd, J ) 1.8, 12.6 Hz, 5-H), 3.33 (3H, s,
OMe), 2.82 (3H, m, 3-H, 6-H), 1.42 (9H, s, C(CH3)3); 13C NMR
(75 MHz, CDCl3, GASPE) δ 170.4, 165.2 (CO2C(CH3)3, C-7),
137.5, 128.3, 127.5, 127.1 (Ph), 96.1 (C-1), 95.4 (OCH2O), 90.7
(C-8), 78.9 (C(CH3)3), 77.9 (C-2), 70.1 (OCH2Ph), 71.7 (C-4), 57.8
(C-5), 55.8 (OMe), 38.3 (C-3), 34.8 (C-6), 28.4 (C(CH3)3); FD-
MS m/z ) 407 (M+ + 1). Anal. Calcd for C22H30O7: C, 65.01; H,
7.44. Found: C, 65.22; H, 7.32.
[3S-(2Z,3r,3ar,4r,7ꢀ,7ar)]-Acetic Acid-[hexahydro-4-(meth-
oxymethoxy)-3-methyl-7-(phenylmethoxy)-2H-furo[2,3-c]pyran-2-
ylidene]-methyl Ester (7). Following the procedure for the conver-
sion of long chain pyranoside 4 to 6a, b, compound 7 was
synthesized accordingly. Compound 5 (1 mmol, 396 mg, 10 mL
of DCM), Et3N (0.17 mL, 1.2 mmol), DMAP (12 mg, 0.1 mmol)
and MsCl (0.1 mL, 1.2 mmol) then NaH (47.5 mg, 1.2 mmol, 65%
dispersion in mineral oil) gave one epimer of the alkylidene
4694 J. Org. Chem. Vol. 74, No. 13, 2009

IsoaVenaciolide and Ethisolide Frameworks
solid: mp 84-85 °C; [R]D20 +104.1 (c 1.8, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.41-7.28 (5H, m), 5.11 (1H, dd, J ) 1.7, 5.4
Hz), 4.80 (1H, d, J ) 12.2 Hz), 4.68 (2H, s), 4.60 (1H, d, J ) 12.2
Hz), 4.49 (1H, s), 4.00 (1H, dd, J ) 1.7, 13.0 Hz), 3.66 (1H, d, J
) 13.0 Hz), 3.41 (2H, br. s), 3.24 (3H, s); 13C NMR (75 MHz,
CDCl3, GASPE) δ 137.0, 128.6, 128.1, 128.0, 97.1, 93.6, 76.2,
69.3, 61.7, 55.4, 51.9, 48.8; FD-MS m/z ) 267 (M+ + 1). Anal.
Calcd for C14H18O5 (266.29): C, 63.15; H, 6.81. Found: C 63.12,
H 6.86.
Phenylmethyl 3-Deoxy-3-[4-(1,1-dimethylethoxy)-2,4-dioxobu-
tyl]-4-O-(methoxymethyl)-r,D-xylopyranoside (11). Following the
procedure used for 4, compounds 11 (318 mg, 75%) and 12 (85
mg, 20%) were produced from 10 utilizing NaH (174 mg, 4.4 mmol,
65% dispersion in mineral oil) in 10 mL of THF, tert-butyl
acetoacetate (0.66 mL, 4 mmol), and n-BuLi (2.75 mL, 4.4 mmol,
1.6 M in n-hexane). The mixture was stirred at 0 °C for 30 min.
Next, compound 10 (1 mmol, 266 mg in 2 mL of THF) was added
and the reaction stirred at rt for 5 h: [R]D20 +77.2 (c 0.320, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (5H, m, arom. H), 4.73
(1H, d, J ) 3.5 Hz, 1-H), 4.70 (1H, d, J ) 11.8 Hz, OCHHPh),
4.68 (2H, s, OCH2O), 4.43 (1H, d, J ) 11.8 Hz, OCHHPh), 3.70
(1H, dd, J ) 5.0, 10.6 Hz, 5-H), 3.47 (1H, t, J ) 5.3 Hz, 4-H),
3.27 (4H, m, 2-H, 5-H, H-8,8′), 3.24 (3H, s, OMe), 2.68 (1H, dd,
J ) 6.3, 16.3 Hz, 6-H), 2.63 (1H, dd, J ) 5.4, 16.3 Hz, 6-H), 2.37
(1H, m, 3-H), 1.38 (9H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3,
GASPE) δ 203.3 (C-7), 166.6 (CO2C(CH3)3), 137.2, 128.5, 128.0,
127.9 (Ph), 96.4 (C-1), 97.1 (OCH2O), 81.7 (C(CH3)3), 76.0 (C-4),
69.3 (C-2), 69.1 (OCH2Ph), 61.8 (C-5), 55.7 (OMe), 50.9 (C-8),
42.4 (C-6), 41.2 (C-3), 28.0 (C(CH3)3); FD-MS m/z ) 425 (M+ +
1). Anal. Calcd for C22H32O8: C, 62.25; H, 7.60. Found: C, 62.34;
H, 7.51.
(CO2C(CH3)3), 137.8, 128.5, 127.7, 127.3 (Ph), 93.5 (C-1), 95.8
(OCH2O), 93.5 (C-8), 79.7 (C(CH3)3), 78.3 (C-2), 71.2 (OCH2Ph),
70.7 (C-4), 60.5 (C-5), 54.6 (OMe), 38.0 (C-3), 29.8 (C-6), 28.1
(C(CH3)3); FD-MS m/z ) 407 (M+ + 1). Anal. Calcd for C22H30O7:
C, 65.01; H 7.44. Found: C, 65.31; H, 7.11.
(2E)-Acetic Acid-2-[(3aR,4R,7S,7aS)-Tetrahydro-7-(methoxy-
methoxy)-4-(phenylmethoxy)-4H-furo[3,2-c]pyran-2(3H)-ylidene]-
1,1-dimethylethyl Ester (14). ꢀ-Keto ester derivative 12 (424 mg,
1 mmol, 10 mL of DCM), Et3N (0.17 mL, 1.2 mmol), DMAP (12
mg, 0.1 mmol), MsCl (1.2 mmol, in 10 DCM). The mesylated
derivative of compound 12 (1 mmol) was dissolved in 10 mL of
THF and added dropwise to a cooled suspension of NaH (47.5 mg,
1.2 mmol, 65% dispersion in mineral oil) in 10 mL of THF. The
mixture was warmed up to rt and stirred overnight. Following the
same procedure described for the synthesis of compounds 6a, b,
compound 11 was prepared from 9a in 88% (355 mg) yield as
colorless oil after column chromatography (EtOAc/DCM, 25%):
1
[R]D +78.7 (c 0.27, CH2Cl2); H NMR (400 MHz, CDCl3) δ
20
7.36-7.27 (5H, m, arom. H), 4.62 (1H, d, J ) 1.8 Hz, 1-H), 5.33
(1H, d, J ) 1.6 Hz, 8-H), 4.19 (1H, dd, J ) 7.8, 10.9 Hz, 3-H),
4.67 (1H, d, J ) 11.7 Hz, OCHHPh), 4.68 (1H, d, J ) 7.2 Hz,
OCHHO), 4.61 (1H, d, J ) 7.8 Hz, OCHHO), 4.50 (1H, d, J )
11.7 Hz, OCHHPh), 4.63 (1H, dd, J ) 4.4, 11.6 Hz, 5-H), 3.65
(1H, m, 4-H), 3.75 (1H, dd, J ) 3.8, 11.6 Hz, 5-H), 3.38 (3H, s,
OMe), 2.91 (1H, dd, J ) 4.7, 14.6 Hz, 6-H), 2.91 (1H, m, 2-H),
2.73 (1H, dd, J ) 3.2, 14.6 Hz, 6-H), 1.25 (9H, s, C(CH3)3); 13C
NMR (75 MHz, CDCl3, GASPE)
δ 171.4 (C-7), 166.3
(CO2C(CH3)3), 137.5, 128.1, 127.3, 127.1 (Ph), 99.2 (C-1), 95.3
(OCH2O), 92.3 (C-8), 80.3 (C(CH3)3), 77.6 (C-3), 70.1 (OCH2Ph),
70.4 (C-4), 61.2 (C-5), 53.8 (OMe), 38.5 (C-2), 29.6 (C-6), 28.3
(C(CH3)3); FD-MS m/z ) 407 (M+ + 1). Anal. Calcd for C22H30O7:
C, 65.01; H, 7.44. Found: C, 65.11; H 7.23.
Phenylmethyl 2-Deoxy-2-[4-(1,1-dimethylethoxy)-2,4-dioxobu-
tyl]-4-O-(methoxymethyl)-r-D-arabinopyranoside (12). [R]D20 +98.1
(3aR,4R,7aR)-7-(Benzyloxy)-4-hydroxyhexahydro-2H-furo[2,3-
c]pyran-2-one (15). To a - 78 °C solution of MOM derivative 8
(1 mmol, 308 mg) in 10 mL of DCM and thiophenol (1.1 mmol,
121 mg) was added under argon BF3 ·OEt2 (2 mL, 2 mmol, 1 M
solution). The temperature was maintained with stirring (10 min);
the solution was then warmed to 0 °C and stirred for additional
1 h. Workup was effected by extraction of the organic layer (3 ×
10 mL of EtOAc) resulting from addition of 10 mL of saturated
NH4Cl to the extraction mixture. The combined organic extracts
were dried over Na2SO4 and concentrated under vacuum. The crude
oil was loaded on a short column (25% EtOAc/DCM) delivering
1
(c 0.13, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.30-7.20 (5H,
m, arom. H), 4.75 (1H, d, J ) 11.7 Hz, OCHHPh), 4.68 (2H, s,
OCH2O), 4.43 (1H, d, J ) 11.7 Hz, OCHHPh), 4.25 (1H, d, J )
7.3 Hz, 1-H), 4.00 (1H, dd, J ) 3.6, 12.4 Hz, 5-H), 3.60 (1H, dd,
J ) 3.0, 5.8 Hz, 4-H), 3.42 (1H, dd, J ) 2.0, 12.4 Hz, 5-H), 3.37
(3H, s, OMe), 3.35 (1H, dd, J ) 2.0, 5.8 Hz, 3-H), 3.25 (2H, d, J
) 15.7 Hz, 8,8-H), 2.58 (1H, dd, J ) 5.4, 17.3 Hz, 6-H), 2.65
(1H, dd, J ) 6.6, 17.3 Hz, 6-H), 2.43 (1H, m, 2-H), 1.38 (9H, s,
C(CH3)3); 13C NMR (75 MHz, CDCl3, GASPE) δ 202.4 (C-7),
166.5 (CO2C(CH3)3), 137.1, 128.5, 128.1, 127.9 (Ph), 101.2 (C-1),
96.6 (OCH2O), 81.8 (C(CH3)3), 74.7 (C-4), 71.4 (C-3), 70.3
(OCH2Ph), 63.9 (C-5), 55.8 (OMe), 50.9 (C-8), 40.8 (C-6), 41.5
(C-2), 27.9 (C(CH3)3); FD-MS m/z ) 425 (M+ + 1). Anal. Calcd
for C22H32O8: C, 62.25; H 7.60. Found: C, 62.21; H, 7.57.
alcohol 15 as a colorless oil (251 mg, 95% yield): [R]D +114.9
20
(c 0.100, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.23-7.08 (5H,
m, arom. H), 4.75 (1H, d, J ) 4.7 Hz, 1-H), 4.55 (1H, d, J ) 12.2
Hz, OCHHPh), 4.42 (1H, dd, J ) 4.7, 7.2 Hz, 2-H), 4.35 (1H, d,
J ) 12.2 Hz, OCHHPh), 3.73 (1H, br. d, J ) 12.5 Hz, 5-H), 3.63
(1H, bd, J ) 1.5 Hz, 4-H), 3.29 (1H, dd, J ) 1.5, 12.5 Hz, 5-H),
2.54 (1H, m, 3-H), 2.30 (1H, dd, J ) 11.2, 16.8 Hz, 6-H), 2.20
(1H, dd, J ) 9.4, 16.8 Hz, 6-H); 13C NMR (75 MHz, CDCl3,
GASPE) δ 176.7 (C-7), 136.8, 129.1, 128.6, 127.8 (Ph), 95.3 (C-
1), 73.1 (C-2), 65.7 (C-4), 69.9 (OCH2Ph), 60.2 (C-5), 31.7 (C-6),
40.0 (C-3); FD-MS m/z ) 265 (M+ + 1). Anal. Calcd for C14H16O5
(264.27): C, 63.62; H 6.10. Found: C, 63.69; H, 6.25.
(2E)-AceticAcid-[(3aS,4S,7S,7aS)-hexahydro-4-(methoxymethoxy)-
7-(phenylmethoxy)-2H-furo[2,3-c]pyran-2-ylidene]-1,1-dimethyl-
ethyl Ester (13). Mesylation of compound 11 (424 mg, 1 mmol,
10 mL of DCM), Et3N (0.17 mL, 1.2 mmol), DMAP (12 mg, 0.1
mmol), MsCl (0.1 mL, 1.2 mmol in 10 mL of DCM). The mesylated
derivative of compound 9 (1 mmol) was dissolved in 10 mL of
THF and added dropwise to a cooled suspension of NaH (47.5 mg,
1.2 mmol, 65% dispersion in mineral oil) in 10 mL of THF. The
mixture was allowed to reach rt and stirred overnight. Following
the procedure described for synthesis of 6a, b, R-methylene-furanyl
annelated 13 was produced from 11 in 84% yield (339 mg) as a
(3S,3aR,4R,7aR)-7-(Benzyloxy)-4-hydroxy-3-methylhexahydro-
2H-furo[2,3-c]pyran-2-one (16). Preparation of 16 is analogous to
MOM-cleavage procedure for15; MOM-protected 9 (1 mmol, 322
mg, 10 mL of DCM), thiophenol (1.1 mmol, 121 mg) and BF3 ·OEt2
(2 mL, 2 mmol, 1 M solution). The resulting mixture was stirred
at -78 °C for 10 min before warming to 0 °C with continued
stirring for an additional 1 h. Deprotected alcohol 16 was produced
in 95% (264 mg) as a white solid: mp 151-153 °C; [R]D20 +97.6
(c 0.0171, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (5H,
m, Ph), 5.40 (1H, d, J ) 4.8 Hz, 1-H), 4.65 (1H, dd, J ) 4.8, 7.6
Hz, 2-H), 4.45 (1H, d, J ) 12.1 Hz, OCHHPh), 4.21 (1H, d, J )
12.1 Hz, OCHHPh), 3.90 (1H, bd, J ) 1.7 Hz, 4-H), 4.05 (1H, dd,
J ) 1.7, 12.8 Hz, 5-H), 3.57 (1H, dt, J ) 1.7, 12.8 Hz, 5-H), 2.46
(1H, ddd, J ) 1.7, 7.6, 12.8 Hz, 3-H), 2.66 (1H, dq, J ) 7.0, 12.8
colorless oil following column chromatography using EtOAc/DCM
1
(25%) as eluent: [R]D +153.7 (c 0.32, CH2Cl2); H NMR (400
20
MHz, CDCl3) δ 7.35-7.32 (5H, m, arom. H), 4.92 (1H, d, J ) 3.6
Hz, 1-H), 5.12 (1H, d, J ) 1.4 Hz, 8-H), 4.34 (1H, dd, J ) 3.6, 7.3
Hz, 2-H), 4.57 (1H, d, J ) 12.6 Hz, OCHHPh), 4.67 (1H, d, J )
7.0 Hz, OCHHO), 4.59 (1H, d, J ) 7.0 Hz, OCHHO), 4.50 (1H,
d, J ) 12.6 Hz, OCHHPh), 4.44 (1H, dd, J ) 5.6, 11.6 Hz, 5-H),
3.53 (1H, m, 4-H), 3.65 (1H, dd, J ) 3.8, 11.6 Hz, 5-H), 3.27 (3H,
s, OMe), 2.82 (1H, dd, J ) 4.5, 15.3 Hz, 6-H), 2.81 (1H, m, 3-H),
2.73 (1H, dd, J ) 3.2, 15.3 Hz, 6-H), 1.15 (9H, s, C(CH3)3); 13C
NMR (75 MHz, CDCl3, GASPE)
δ 172.4 (C-7), 165.1
J. Org. Chem. Vol. 74, No. 13, 2009 4695

Al-Tel et al.
Hz, 6-H), 1.24 (3H, d, J ) 7.0 Hz, 6-CH3); 13C NMR (100 MHz,
CDCl3, GASPE) δ 177.0 (C-7), 95.1 (C-1), 70.6 (C-2), 70.3
(OCH2Ph), 66.0 (C-4), 59.4 (C-5), 47.7 (C-3), 36.5 (C-6), 14.7 (6-
CH3).); FD-Ms m/z 278 (M+). Anal. Calcd for C14H16O5 (278.30):
C, 64.74; H, 6.52. Found: C, 64.53; H, 6.29.
(3S,3aR,4R,7aR)-4,7-Dihydroxy-3-methylhexahydro-2H-furo[2,3-
c]pyran-2-one (17). A solution of 15 (1 mmol, 264 mg) in 15 mL
of EtOAc and 10% w/w of Pd/C (26.5 mg, 25% w/w) was shaken
under positive pressure of H2 at rt for overnight. Mixture was filtered
(3H, s, OMe), 3.65 (1H, m, 3-H), 2.78 (1H, m, 6-H), 1.25 (3H, d,
J ) 7.4 Hz, 6-CH3); 13C NMR (100 MHz, CDCl3, GASPE) δ 179.3
(C-7), 105.8 (C-1), 85.6 (C-2), 78.9 (C-4), 61.1 (C-5), 54.8 (OMe),
47.3 (C-6), 34.7 (C-3), 17.2 (Me-6); FD-MS m/z ) 203 (M+ + 1).
Anal. Calcd for C9H14O5 (202.20): C, 53.46; H, 6.98. Found: C,
53.55; H, 6.75.
((3S,3aR,4R,6S,6aR)-6-Methoxy-3-methyl-2-oxohexahydrofuro[3,4-
b]furan-4-yl)methyl-4-methylbenzenesulfonate (21). To a solution
of bifuranoid 20 (1 mmol, 202 mg) in 15 mL of DCM containing
1 mL of pyridine at 0 °C was added p-toluenesulfonyl chloride (5
mmol, 935 mg). The mixture was maintained at 0 °C for 2 h and,
then at rt for another 12 h. Ice water was added, followed by 5 mL
of a saturated solution of NaHCO3. The mixture was extracted with
EtOAc (3 × 10 mL), dried over Na2SO4, and evaporated to dryness
to afford a white solid. Crystallization from EtOAc/petroleum ether
gave 338 mg (95%) of compound 21: mp 83-85 °C; [R]D20 -80.60
(c 0.0475, DCM); 1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J )
8.3 Hz, Ts), 7.31 (2H, d, J ) 8.3 Hz, Ts), 4.86 (1H, s, 1-H), 4.73
(1H, d, J ) 7.4 Hz, 2-H), 4.32 (1H, dd, J ) 6.1, 12.2 Hz, 4-H),
4.16 (1H, dd, J ) 6.0, 10.5 Hz, 5-H), 4.05 (1H, dd, J ) 6.6, 10.4
Hz, 5-H), 3.25 (3H, s, OMe), 2.44(1H, ddd, J ) 7.4, 8.3, 13.0 Hz,
3-H), 2.75 (1H, dd, J ) 7.4, 13.0 Hz, 6-H), 2.43 (3H, s, Ts-Me),
1.21 (3H, d, J ) 7.4 Hz, 6-CH3); 13C NMR (100 MHz, CDCl3,
GASPE) δ 178.3 (C-7), 145.4, 132.1, 130.0, 127.9 (Ts), 106.6 (C-
1), 84.8 (C-2), 75.2 (C-4), 67.0 (C-5), 54.9 (OMe), 47.3 (C-6), 33.7
(C-3), 21.6 (Ts-Me), 19.9 (Me-6); FD-MS m/z ) 357 (M+ + 1).
Anal. Calcd for C16H20O7S (356.39): C, 53.92; H, 5.65. Found: C,
54.13; H, 5.55.
over Celite and concentrated to afford 157 mg (90%) of the lactol
1
17 as colorless oil: [R]D -78.8 (c 0.054, EtOH); H NMR (400
20
MHz, CDCl3) δ 5.38 (1H, s, 1-H), 4.72 (1H, d, J ) 4.4 Hz, 2-H),
4.13 (1H, dd, J ) 7.3, 13.2 Hz, 4-H), 4.34 (1H, dd, J ) 7.3, 11.5
Hz, 5-H), 3.82 (1H, dd, J ) 6.2, 11.5 Hz, 5-H), 3.75 (1H, dd, J )
4.4, 6.2, 11.8 Hz, 3-H), 2.75 (2H, m, 6-H); 13C NMR (75 MHz,
CDCl3, GASPE) δ 179.2, 100.6, 81.0, 66.8, 61.9, 40.5, 29.7; FD-
MS m/z ) 175 (M+ + 1). Anal. Calcd for C7H10O5 (174.15): C,
48.28; H, 5.79. Found: C, 48.43; H, 5.92.
(3S,3aR,4R,7aR)-4,7-Dihydroxy-3-methylhexahydro-2H-furo[2,3-
c]pyran-2-one (18). Following procedure for synthesis of compound
17, a solution of 16 (1 mmol, 277 mg) in 15 mL of EtOAc and
10% w/w of Pd/C (27.7 mg, 25% w/w) was shaken under positive
pressure of H2 at rt overnight. Compound 10 was formed in 95%
yield (178.6 mg) as a colorless oil: [R]D20 -42.6 (c 0.101, MeOH);
1H NMR (400 MHz, CDCl3) δ 5.48 (1H, s, 1-H), 4.83 (1H, d, J )
6.7 Hz, 2-H), 4.05 (1H, dd, J ) 7.1, 14.3 Hz, 4-H), 4.40 (1H, dd,
J ) 4.6, 11.2 Hz, 5-H), 3.82 (1H, dd, J ) 4.2, 11.2 Hz, 5-H), 3.71
(1H, dd, J ) 4.4, 6.7, 12.8 Hz, 3-H), 2.75 (1H, m, 6-H), 1.26 (3H,
d, J ) 7.4 Hz, 6-CH3); 13C NMR (100 MHz, CDCl3, GASPE) δ
181.0 (C-7), 100.1 (C-1), 85.6 (C-2), 78.6 (C-4), 61.3 (C-5), 34.4
(C-3), 37.4 (C-6), 17.3 (6-CH3).); FD-Ms m/z 189 (M+ + 1). Anal.
Calcd for C8H12O5 (188.18): C, 51.06; H, 6.43. Found: C, 50.92;
H, 6.50.
(3aR,4R,6S,6aR)-4-(Hydroxymethyl)-6-methoxytetrahydrofuro[3,4-
b]furan-2(3H)-one (19). The lactol 17 (1 mmol, 174 mg) was
dissolved in 10 mL of dry MeOH to which was also added a freshly
prepared solution of 6% HCl (10 mL) at 0 °C. The mixture was
stirred at 0 °C for 2 h until TLC indicated no starting material.
Workup involved neutralization with solid NaHCO3, gravity
filtration and evaporation under reduced pressure to yield a
yellowish oily material which was purified over a short silica gel
column (25% EtOAc/DCM). Colorless oil, 169 mg (90% yield):
[R]D20 -46.12 (c 0.600, EtOH); significant NMR NOEs are 1-H to
2-H, 42%; 2-H to 3-H, 32%; 3-H to 4-H, 32%. 1H NMR (400 MHz,
CDCl3) δ 5.04 (1H, s, 1-H), 4.82 (1H, d, J ) 6.2 Hz, 2-H), 4.23
(1H, dd, J ) 3.5, 7.7 Hz, 4-H), 3.86 (1H, dd, J ) 4.0, 12.2 Hz,
5-H), 3.74 (1H, dd, J ) 4.0, 12.2 Hz, 5-H), 3.35 (3H, s, OMe),
3.18 (1H, m, Hz, 3-H), 2.74 (1H, dd, J ) 3.1, 18.4 Hz, 6-H), 2.56
(1H, dd, J ) 10.3, 18.4 Hz, 6-H); 13C NMR (75 MHz, CDCl3,
GASPE) δ 176.2 (C-7), 105.4 (C-1), 86.4 (C-2), 78.5 (C-4), 61.2
(C-5), 54.7 (OMe), 38.5 (C-3), 29.1 (C-6); FD-MS m/z ) 189 (M+
+ 1). Anal. Calcd for C8H12O5 (188.18): C, 51.06; H, 6.43. Found:
C, 51.12; H, 6.40.
(3S,3aS,4R,6S,6aR)-4-(Iodomethyl)-6-methoxy-3-methyltetrahy-
drofuro[3,4-b]furan-2(3H)-one (22). To a solution of tosylate 21
(1 mmol, 356 mg) in 20 mL of dry acetone was added NaI (3 mmol,
447 mg). The mixture was refluxed under argon for 5 h, allowed
to reach rt, concentrated to 3 mL, and partitioned between H2O (5
mL) and DCM (3 × 5 mL). Combined organic layers were dried
over Na2SO4, evaporated and purified on a short silica gel column
eluting with DCM. Product appeared as a yellowish oil (249.6 mg,
80% yield): [R]D -44.30 (c 0.2113, DCM); significant NMR
20
NOEs are 1-H to 2-H, 38%; 2-H to 3-H, 38%; 3-H to 4-H, 34%;
3-H to 6-CH3, 39%; 1H NMR (400 MHz, CDCl3) δ 4.79 (1H, d, J
) 7.4 Hz, 2-H), 4.75 (1H, s, 1-H), 4.38 (1H, ddd, J ) 5.7, 8.9,
11.5 Hz, 4-H), 3.32 (1H, dd, J ) 6.1, 13.3 Hz, 5-H), 3.31 (3H, s,
OMe), 3.01 (1H, dd, J ) 8.9, 13.3 Hz, 5-H), 2.86 (1H, ddd, J )
5.7, 7.4, 13.3 Hz, 3-H), 2.53 (1H, dd, J ) 7.4, 13.3 Hz, 6-H), 1.35
(3H, d, J ) 7.4 Hz, 6-CH3); 13C NMR (100 MHz, CDCl3, GASPE)
δ 178.5 (C-7), 107.0 (C-1), 85.5 (C-2), 79.0 (C-4), 67.6 (C-5), 55.0
(OMe), 48.2 (C-6), 33.6 (C-3), 17.7 (Me-6); FD-MS m/z ) 312
(M+ + 1). Anal. Calcd for C9H13IO4 (312.10): C, 34.64; H, 4.66;
I, 40.66. Found: C, 34.73; H, 4.43; I, 40.32.
Acknowledgment. We thank Professor Scott McN Sieburth
(Temple University) and Professor Gary Hiel (Ferris University)
for their valuable comments and suggestions. We are also
grateful to the College of Research and Graduate Studies at the
University of Sharjah-UAE for their generous financial as-
sistance (research grant number 52219).
(3S,3aR,4R,6S,6aR)-4-(Hydroxymethyl)-6-methoxy-3-methyltet-
rahydrofuro[3,4-b]furan-2(3H)-one (20). Methyl ketal 20 was
prepared as per the procedure for 19 using lactol 18 (1 mmol, 188
mg, 10 mL of MeOH) and 6% HCl (10 mL) at 0 °C. Compound
20 was isolated in 90% yield (172 mg) as a colorless oil: [R]D
Supporting Information Available: Experimental proce-
dures and spectral data of compounds 3-22. Copies of 1H and
13C NMR spectra for compounds 4-22. This material is
available free of charge via the Internet at http://pubs.acs.org.
20
-35.88 (c 0.0171, DCM); significant NMR NOEs are 1-H to 2-H,
39%; 2-H to 3-H, 36%; 3-H to 4-H, 33%; 3-H to 6-CH3, 41%; 1H
NMR (400 MHz, CDCl3) δ 4.98 (1H, s, 1-H), 4.75 (1H, d, J ) 6.6
Hz, 2-H), 4.21 (1H, dd, J ) 4.7, 10.9 Hz, 4-H), 3.83 (1H, dd, J )
4.4, 13.7 Hz, 5-H), 3.65 (1H, dd, J ) 4.3, 13.7 Hz, 5-H), 3.31
JO900192A
4696 J. Org. Chem. Vol. 74, No. 13, 2009