Stereoselective synthesis of 3-oxygenated-ds-dialkyl-2,5-substituted tetrahydrofurans from cyclohexadienediols

Article abstract of DOI:10.1021/jo800514k

(Chemical Equation Presented) The 3-oxygenated-cis-dialkyl-2,5-substituted tetrahydrofuran system, present in several natural products, was prepared with good selectivity by acidic cyclization of 5-alkene-1,2,4-triol derivatives. The starting alkenol was

Full text of DOI:10.1021/jo800514k

Stereoselective Synthesis of 3-Oxygenated-cis-dialkyl-2,5-substituted
Tetrahydrofurans from Cyclohexadienediols
Margarita Brovetto* and Gustavo Seoane
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de la Repu´blica, C.C. 1157,
MonteVideo, Uruguay
mbroVett@fq.edu.uy
ReceiVed March 5, 2008
The 3-oxygenated-cis-dialkyl-2,5-substituted tetrahydrofuran system, present in several natural products,
was prepared with good selectivity by acidic cyclization of 5-alkene-1,2,4-triol derivatives. The starting
alkenol was obtained in few steps from a chiral cis-diol resulting from microbial oxidation of
bromobenzene. The study of the cyclization allowed the rationalization of all experimental results by
assuming a complete ionization at the allylic position and a model close to the one proposed by Labelle
for homoallylic induction in five-membered ring closures.
Introduction
and epoxy alcohols;16–20 Ti-mediated coupling of acetylated
γ-lactols or lactones with chiral enolates;21,22 tandem 1,3-dipolar
cycloaddition/electrophilic cyclizations supported on a poly-
mer;23 asymmetric [3 + 2]-annulation of chiral ꢀ-silyloxyal-
lylsilanes;24 cyclization of 1,4-diols25,26 derived from several
chiral templates; oxidative cyclization of 1,5-dienes;27 etc. Many
of these procedures suffer from moderate stereoselectivity and
lengthy routes. In addition, only a few of the reported approaches
led to the formation of either cis-11,16,27 or trans-2,5-disubstituted
THF.9,13,15,21,22 Thus, the design and development of a simple
and stereocontrolled strategy to construct 2,5-disubstituted
2,5-Disubstituted tetrahydrofurans (THF) constitute important
structural and functional subunits in various bioactive natural
products including the group of cytotoxic polyethers,1,2 polyether
antibiotics,3,4 antitumor acetogenins,5–8 etc. As a result, the
stereoselective construction of both cis- and trans-2,5-disub-
stituted tetrahydrofurans has drawn considerable attention from
synthetic chemists. Several strategies have been described in
this pursuit, namely, cyclization of 4-alkenols,9–13 3-alkenols,14,15
(1) Kang, S. H.; Lee, S. B. Chem. Commun. 1998, 761–762.
(2) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett. 1995, 1043–1044.
(3) Bartlett, P. A. Tetrahedron 1980, 36, 3–72.
(4) O’Hagan, D. Nat. Prod. Rep. 1989, 6, 205–209.
(5) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–
540.
(15) Kang, S. H.; Lee, S. B. Tetrahedron Lett. 1993, 34, 1955–1958.
(16) Arista, L.; Gruttadauria, M.; Thomas, E. J. Synlett 1997, 627–628.
(17) Chattopadhyay, A.; Vichare, P.; Dhotare, B. Tetrahedron Lett. 2007,
48, 2871–2873.
(18) Nakata, T.; Kishi, Y. Tetrahedron Lett. 1978, 19, 2745–2748.
(19) Nakata, T.; Schmid, G.; Vranesic, M.; Okigawa, M.; Smith-Palmer, T.;
Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933–2935.
(20) Narayan, R. S.; Sivakumar, M.; Bouhlel, E.; Borhan, B. Org. Lett. 2001,
3, 2489–2492.
(6) Hoppe, R. S.; Scharf, H. D. Synthesis 1995, 1447–1464.
(7) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C. Pure Appl. Chem. 1997,
69, 423–430.
(8) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin,
J. L. Nat. Prod. Rep. 1996, 13, 275–308.
(21) Jalce, G.; Seck, M.; Franck, X.; Hocquemiller, R.; Figadere, B. J. Org.
Chem. 2004, 69, 3240–3241.
(9) Michael, J. P.; Ting, P. C.; Bartlett, P. A. J. Org. Chem. 1985, 50, 2416–
2423, and references therein.
(22) Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2, 53–56.
(23) Beebe, X.; Schore, N. E.; Kurth, M. J. J. Am. Chem. Soc. 1992, 114,
10061–10062.
(10) Miura, K.; Hondo, T.; Okajima, S.; Hosomi, A. Eur. J. Org. Chem.
2006, 3251–3258.
(11) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963–
3964.
(24) Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem. 2005, 70, 8035–
8046.
(12) Tanikaga, R.; Hosoya, K.; Kaji, A. J. Chem. Soc., Perkin Trans. 1 1987,
1799–1803.
(25) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819–4822.
(26) Sharma, G. V. M.; Punna, S.; Prasad, T. R.; Krishna, P. R.; Chorghade,
M. S.; Ley, S. V. Tetrahedron: Asymmetry 2005, 16, 1113–1123.
(27) Goksel, H.; Stark, C. B. W. Org. Lett. 2006, 8, 3433–3436, and
references therein.
(13) Zhang, H.; Mootoo, D. R. J. Org. Chem. 1995, 60, 8134–8135.
(14) Bew, S. P.; Barks, J. M.; Knighta, D. W.; Middletona, R. J. Tetrahedron
Lett. 2000, 41, 4447–4451.
5776 J. Org. Chem. 2008, 73, 5776–5785
10.1021/jo800514k CCC: $40.75 2008 American Chemical Society
Published on Web 06/27/2008

Synthesis of 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
SCHEME 1. Chemoenzymatic Route to 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
SCHEME 2. Synthesis of 8c
tetrahydrofurans (THF) has assumed considerable importance
in organic synthesis.28,29
followed by acetoxyiodination using acetyl hypoiodite as source
of halogen (Pre´vost reaction). The stereoselectivity of the
halohydrin-forming reaction was thoroughly studied, varying
the halonium donor, medium polarity, and temperature.37 Best
results were obtained under Pre´vost conditions, which afforded
iodoacetates 4a and 4b in excellent yields and selectivity (99:1
dr). The major isomers present a coupling pattern for the H
geminal to the iodine consisting of a triplet with 3JH-H 7.5-7.8
Hz, suggesting a trans-diaxial relationship with its neighbors.
Further radical dehalogenation using tributyltin hydride gave
acetates 5a and 5b in 95% yields, which were ozonized under
reductive conditions to give aldehyde-ester 6.
The excellent yield of the ozonolysis was obtained after some
experimentation, trying different solvent mixtures and bases.38
Best results were obtained in a 1:1 mixture of CH2Cl2/MeOH,
in the presence of NaHCO3 (3 equiv), using 8 equiv of DMS in
the reductive step, Scheme 3. In our synthetic design for the
C13-C21 fragment of Isolaulimalide, the aldehyde group in 6,
corresponding to C16 of the fragment, would react with a three
carbon residue to give a Z-olefin, which would then be
osmylated to give the requisite C13-C16 side chain. Owing to
the presence of a labile R-acetoxy group in 6, the mild conditions
reported by Boden were chosen for the olefination.39 Accord-
ingly, different phosphonium salts were tried for the Z-selective
Wittig-type olefination.40 In all cases the selectivity was
During our studies on the chemoenzymatic synthesis of
isolaulimalide30–34 starting from cyclohexadienediols of micro-
bial origin of type 1,35 we required a stereoselective route to
the 3-hydroxy-trans-2,5-dialkyl tetrahydrofuran 2 present in the
C13-C21 fragment, Scheme 1. However, during the manipulation
of protecting groups in the acyclic precursor aiming at an
intramolecular Williamson reaction, an unexpected cyclization
afforded cis-2,5-trisubstituted THF, 3, in good yields. Herein,
we present a chemoenzymatic route to 3-oxygenated-cis-2,5-
substituted tetrahydrofurans of type 3 starting from either chloro-
or bromobenzene, as well as mechanistic studies accounting for
the stereoselectivity of the cyclization.
Results and Discussion
The sequence started with the toluene dioxygenase-mediated
oxidation of halobenzenes to produce enantiopure cis-diols, 1,
using Pseudomonas putida 39/D, Scheme 2.35,36 From either
diol 1, acetylated halohydrins of type 4 were obtained in two
steps, through acetonide protection of the diol functionality
(28) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711–
1754.
(29) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
(30) Corley, D.; Herb, R.; Moore, R. E.; Sheuer, P. J. J. Org. Chem. 1988,
53, 3644–3646.
(31) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-
Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 77, 5–778.
(32) Jefford, C. W.; Bernardinelli, G.; Tanaka, J.; Higa, T. Tetrahedron Lett.
1996, 37, 159–162.
(37) Carrera, I.; Brovetto, M.; Seoane, G. Tetrahedron 2007, 63, 4095–4107.
(38) Brovetto, M. Cyclization studies of tetrahydrofuran rings as precursors
of isolaulimalide. Ph.D. Thesis, Universidad de la Repu´blica, 2006.
(39) Boden, R. M. Synthesis 1975, 784–784.
(33) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642–3644.
(34) Tanaka, J.; Higa, T.; Bernardinelli, G.; Jefford, C. Chem. Lett. 1996,
255–256.
(40) General Procedure for the Phosphonium Salt. Triphenylphosphine
(1.7 mmol) was added to a solution of alkyl halide (1.6 mmol) in dry solvent
(toluene or xylene) under a N2 atmosphere. The reaction mixture was heated to
reflux until consumption of the halide. When the reaction was complete, the
solvent was removed under reduced pressure, and the residue was washed several
times with dry hexanes until disappearance of triphenylphosphine by TLC. The
resulting syrup was crystallized from a mixture of CH2Cl2/ Hexanes.
(35) Brovetto, M.; Schapiro, V.; Cavalli, G.; Padilla, P.; Sierra, A.; Seoane,
G.; Suescum, L.; Mariezcurrena, R. New J. Chem. 1999, 23, 549–555.
(36) Vitelio, C.; Bellomo, A.; Brovetto, M.; Seoane, G.; Gonza´lez, D.
Carbohydr. Res. 2004, 339, 1773–1778.
J. Org. Chem. Vol. 73, No. 15, 2008 5777

Brovetto and Seoane
SCHEME 3. Optimization of Ozonolysis and Wittig Reactions
TABLE 1. Cyclization Studies of 8c in Acidic Conditions
product, yield (%)
cis/trans ratioa
entry
reaction conditions
3a,b
9a,b
10a,b
10a, 45; 10b, 14
3a, 14; 3b, 20 9a, 29; 9b, 20 10b, 33
3a, 40; 3b, 2 9a, 10; 9b, 2 10a, 44
11
a
b
overall yield (%)
1
2
3
4
5
6
Dowex (50WX8-200), MeOH:H2O (99:1), rt, 72 h
10% HCl, MeOH, rt, 24 h
CuCl2 ·2H2O (2eq), CH3CN, 0 °C to rt, 24 h
BF3.Et2O (2 eq), CH2Cl2, 0 °C, 72 h
BF3.Et2O (2 eq), CH2Cl2, rt, 24 h
8
67
89
98
80
7:1
4:1
9:1
3:2
3:2
1:1
1:1
1:1
1:1
1:1
3a, 52; 3b, 0.5 9a, 6; 9b, 0.5 10a, 13
3a, 11; 3b, 27 9a, 7; 9b, 27
3a, 33; 3b, 11 9a, 22; 9b, 11
8
72 (87)b
77
BF3.Et2O (2 eq), Toluene, -20 to 0 °C, 48 h
a The product distribution was determined by NMR on the crude of reaction, by integration of representative signals. The cis/trans isomers were not
successfully separated by column chromatography or by HPLC. Basic characterization was performed on a 9:1 mixture, entry 4. b An additional 15% of
a 7:3 cis/trans mixture of dihydropyranes 12 was also obtained (see structure in Scheme 4).
excellent; the E-isomer was not detected by NMR spectroscopy
in any of the reaction mixtures. The Z-geometry of the double
bond was assigned on the basis of the value of the corresponding
coupling constants and NOE data for the olefinic protons: a
3JH-H of 10.5-10.8 Hz and NOE enhancements of 11% were
found. The isolated yields were acceptable only for the
phosphonium salt 7c, and the corresponding compound 8c was
carried through, Scheme 3.
temperature;48 Candida antarctica lipase A, MeOH, 30 °C;
Candida antarctica lipase B, MeOH, phosphate buffer pH 7,
30 °C.49 None of the conditions used produced the desired
compounds in acceptable yields, the reactions being always
complicated by concomitant nonselective deprotection of the
remaining esters or other side reactions. In particular, under
acidic conditions, the products of the reaction were mainly THF
rings, Table 1.
With olefin 8c in hand, we were ready to perform some
functional group manipulations in order to investigate the
cyclization to the tetrahydrofuran ring. To this end, the allylic
acetate had to be removed and the acetonide on C2-C3 replaced
by a leaving group, thus allowing the allylic alcohol on C5 to
effect a displacement on C2 (see Scheme 3 for numbering in
8c). In this way the THF ring would be formed through an
intramolecular Williamson reaction.41 A number of acidic, basic,
and also enzymatic conditions were tested for the deprotection
of either the acetonide or the acetate group: Dowex resin
50WX8-200 (H+ form), MeOH/H2O (99:1), room temperature;36
CuCl2 · 2H2O, CH3CN, 0 °C to room temperature;42–44
BF3 ·Et2O, CH2Cl2, 0 °C to room temperature;45,46 K2CO3,
MeOH, room temperature; 47 Bu4NOH, CH2Cl2, room temper-
ature; guanidine hydrochloride, TEA, MeOH/CH2Cl2 (9:1) room
The use of a strongly acidic resin (entry 1) produced mostly
the deprotection of the acetonide giving the diol 10a, together
with some triol, 10b, which also lactonized to 11. On the other
hand, when using strong mineral or Lewis acids (entries 2-6),
the main products were always THF rings of type 3 and 9. It is
interesting to note that both types of THF rings present an
E-configuration of the double bond, thus suggesting a complete
isomerization of the Z-olefin in 8c along the reaction pathway
(see below for mechanistic details). We found that mineral acids
(entry 2) gave mostly THF rings with a free ꢀ-hydroxy group,
corresponding to the type b, whereas Lewis acids favor the
cyclization to form ꢀ-acetoxy THF rings of type a, except for
entry 5. By inspecting the cis/trans ratio of THF rings (ratio
3:9) a definite pattern is seen: the cis/trans ratio of acetylated
THF rings (type a) always favors the cis-isomer (compound
3a) in different proportions depending on the conditions used
(from 6:4 to 9:1 cis/trans, entries 2-6), whereas for the free
hydroxyl series (type b) the ratio is always 1:1, and remains
constant regardless of the conditions (entries 2-6). This suggests
(41) Koert, U. Synthesis 1995, 115–132.
(42) Aranda, G.; Corte´s, M.; Maurs, M.; Azerad, R. Tetrahedron: Asymmetry
2001, 12, 2013–2018.
(43) Ko, K.-Y.; Park, S.-T. Tetrahedron Lett. 1999, 40, 6025–6027.
(44) Saravanan, P.; Chadrasekhar, M.; Anand, R. V.; Singh, V. K. Tetra-
hedron Lett. 1998, 39, 3091–3092.
(45) Kinderman, S. S. AdV. Synth. Catal. 2002, 344, 736–748.
(46) Prestat, G.; Baylon, C.; Heck, M. P.; Mioskowski, C. Tetrahedron Lett.
2000, 41, 3829–3831.
(48) Kunesch, N.; Miet, C.; Poisson, J. Tetrahedron Lett. 1987, 28, 3569–
3572.
(49) (a) Berglund, Hult, K. In StereoselectiVe Biocatalysis; Patel, R. N., Ed.;
Marcel Dekker Inc.: New York. (b) Roberts, S. M. J. Chem. Soc., Perkin Trans.
1 2000, 611–633.
(47) Schapiro, V.; Cavalli, G.; Seoane, G.; Faccio, R.; Mombru´, A.
Tetrahedron: Asymmetry 2002, 13, 2453–2459.
5778 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
SCHEME 4. Stereochemistry of the a and b Series
SCHEME 5. Selective Deprotection of 8c and Synthesis of Epimer 14
that the cyclization to form THF rings of either type (a or b)
proceeded by different mechanisms.
pyranes (entry 5) and lactone 11 (entry 4). The formation of
dihydropyranes 12 (15% yield of a 7:3 cis/trans mixture)
involved the nucleophilic attack of the C3-alcohol on the distal
carbon of an allylic carbocationic species via an overall 6-endo-
cyclization (vide infra). Lactone 11 was produced through
removal of the acetonide protecting group and further lacton-
ization (vide infra). The use of the milder Lewis acid
CuCl2 ·2H2O afforded THF rings as the sole cyclic products
(entry 3).
The stereochemical assignments of all compounds were done
according to NOE experiments and J analysis performed on
different isomeric mixtures (Figure 1). The data obtained for
the cis and trans isomers agreed well with the NOE enhance-
ments50 and J values30,33 reported in the literature for these
systems.
Also, the stereochemistry of the deacetylated THF rings,
corresponding to the b series, was assigned in a similar way by
means of J analysis and NOE measurements. Moreover,
additional evidence for the proposed structures of THF 3b and
9b was obtained by acetylation of the free alcohol, giving
monoacetates of identical structure to 3a and 9a, Scheme 4.
Table 1 shows that, in addition to THF, other rings were
formed in some of the conditions tested (entries 1, 4, and 5). In
entry 1, the strongly acidic resin deprotected first the acetonide
giving 10a, which was identified by TLC in the reaction mixture.
Further removal of the acetate afforded 10b, which formed the
corresponding lactone 11. When using BF3 ·Et2O (entries 4-6)
different types of rings were formed, depending on the tem-
perature and polarity of the reaction medium. Whereas the
reaction in toluene afforded exclusively THF rings (entry 6),
the use of the more polar dichloromethane gave also dihydro-
In summary, by an adequate choice of the reaction conditions,
the acidic cyclization of 8c led exclusively to THF rings,
although variable cis/trans mixtures were produced. The highest
cis/trans ratio was achieved for compound 3a upon treatment
of the precursor 8c with BF3 ·Et2O (2 equiv) in CH2Cl2 at 0 °C
for 72 h, giving a 9:1 cis/trans mixture, representing a 52%
yield of 3a, entry 4. However, considering the long reaction
time (72 h) and the presence of other cyclic products (8% of
11), the reaction conditions chosen for preparative purposes
corresponded to entry 3, giving 50% of a 8:2 cis/trans mixture
in only 24 h (representing a 40% of 3a), together with 44%
deprotected diol 10a, which can be recycled.51
It was previously mentioned that the presence of either an
acetate or a free hydroxyl in the THF rings (corresponding to
(51) To establish the usefulness of the methodology, in one run the
deprotected diol was separated and recycled to give, after acetonization (95%),
an additional 17% of 3a, which was thus obtained in a 57% overall yield.
(50) Durand, T.; Guy, A.; Vidal, J.-P.; Rossi, J.-C. J. Org. Chem. 2002, 67,
3615–3624.
J. Org. Chem. Vol. 73, No. 15, 2008 5779

Brovetto and Seoane
TABLE 2. Cyclization of Selectively Protected 5-Alkene-1,2,4-triolsa
a Reaction conditions: CuCl2.2H2O (2 equiv), CH3CN, rt. All reactions were run until consumption of the starting material, except for entry 2.
compounds 3 and 9 of type a or b, respectively) caused a
significant shift in the cis/trans selectivity. In order to get some
insight into the reasons for this selectivity change, we studied
the acidic cyclization of selectively deprotected precursors,
namely, diol 10a, allylic alcohol 13, triol 10b, and the C5 epimer
of 8c, acetate 14.52 These precursors were prepared by selective
deprotection of 8c and, for epimer 14, through a Mitsunobu
inversion of the allylic acetate in 5b, Scheme 5.
product containing the acetate migrated to the C3 position, which
is consistent with an active participation of the acetate in the
cyclization process.
The protecting groups influence the cis/trans selectivity in a
differential way. Whereas the acetonide produces no effect in
the selectivity (compare entries 1 vs 2, and 3 vs 4), the acetate
has a profound effect in the cis/trans ratio and its absence causes
a total lack of selectivity (compare entries 1 vs 3, and 2 vs 4).
Additionally, the configuration of the carbon atom bearing the
acetate is determinant for the course of the reaction, giving high
yields of THF rings only when using 8c (for the epimer 14,
less than 10% of cyclized products are formed under the same
conditions).
The rate of cyclization is also dependent on the protecting
groups. It is much faster when both groups are present, giving
the highest yield of THF rings in the shortest time (24 h, entry
1). The rate decreases with the removal of both (entry 4) or
either one of the protecting group (entries 2 and 3).
For the allylic alcohol 13, the reaction gave mostly the product
of deprotection, triol 10b, together with lactone 11 and a 1:1
mixture of THF rings. In addition, when the reaction was left
to proceed until consumption of triol 10b, the final product
distribution was similar to entry 4. This separate experiment
was monitored by TLC-scanning densitometry, which allows
for rapid quantification of the different species using the UV
spectrum of the benzoate.
The cyclizations were run as already mentioned (entry 3 of
Table 1), using CuCl2 ·2H2O in acetonitrile, at room temperature,
until TLC analysis indicated completion, Table 2.42–44
Analysis by TLC of the reaction mixtures indicated that, when
both protecting groups were present (compounds 8c and 14),
the more labile was always the acetonide (the only deprotected
products found were 10a and 15, respectively). For compounds
containing an allylic acetate (8c, 10a, and 14), migration of this
group to the alcohol on C3 was observed in the cyclized
products, except for the epimeric acetate 14. In this case the
cyclic compounds were deacetylated, although they accounted
for less than 10% of the product distribution (3b and 9b). This
seems to indicate that the migration is heavily dependent on
conformational requirements (entries 1 vs 5). In addition, neither
1
the TLC nor the H NMR analysis of aliquots of the reaction
mixtures was able to detect the intermediacy of the acyclic
(52) The change of the acetate for other acyl protecting group, namely,
benzoate, was also performed. When the benzoate 10c (R ) PhCO) was submitted
to the cyclization conditions, clean deprotection of the acetonide was observed,
giving the corresponding diol as the sole product in 85% yield.
Compound 8c and its derivatives present multiple regio- and
stereochemical routes for reaction under acidic conditions,
5780 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
SCHEME 6. Mechanistic Proposal for THF Compounds
namely, cyclizations to form THF, lactones, or dihydropyranes,
and also simple deprotection of allylic alcohols and/or 1,2-diols.
Under the conditions tested all derivatives afforded THF rings
as the major cyclic products, although their reactions displayed
ample variations in product distribution, ratesm and selectivities.
However, based in the results presented in Tables 1 and 2,
several features can be noticed:
drolysis of six-membered ring orthoesters is governed by
stereoelectronic factors only, favoring the cleavage of the
C-O bond presenting two anti periplanar lone pairs. In this
case the reaction proceeds by cleavage of the exocyclic C-O
bond, to form the dioxonium ion 17. This species can form
a stabilized allylic carbocation by cleavage of another C-O
bond. In the acidic medium, the allylic carbocation can
equilibrate to the more stable isomer, 18, leading to the
E-olefin at the end. The driving force for this outcome could
be ascribed to the higher stability of the final cationic species
which, being acyclic, is able to accommodate the corre-
sponding orbitals for a better overlap than that achieved for
the cyclic dioxonium counterpart. In a related work, the
evolution of acyclic dioxonium cations to form tertiary
carbocations has been observed during the reaction of
orthoesters with olefins.56 The net result is the migration of
the acetate and concomitant formation of an allylic carboca-
tion suitably configured to afford an E-olefin, which can
proceed to form the cyclized products. Experimentally, only
products with an E-olefin are observed.
For the epimeric acetate, 14, the reaction is slower and there
is no migration of acetate. This is consistent with the proposal,
since in this case the formation of the corresponding hemi-
orthoester, epi-16, is prevented by severe 1,3-diaxial interaction
between the olefin and the hydroxyl, Scheme 6. As a result,
compound 14 gives mostly the free diol 15 (by removal of the
acetonide) and less than 10% of cyclic products (through
ionization of the acetate).
According to this proposal, the nonacetylated derivatives 10b
and 13 react through a different pathway not involving the
intermediacy of an hemiorthoester. However, since their cy-
clization produces mixtures of THF rings with the configuration
at C5 retained and inverted (3b and 9b, respectively), it is
assumed that the allylic carbocation is formed. This species then
proceeds to give the same type of THF products, although with
different stereoselectivity.
(a)
The rate of cyclization depends on the given arrangement
of protecting groups.
(b)
All detected products present the olefin of the side chain
exclusively as the E-isomer, suggesting the formation
of a fully developed carbocation, which can isomerize
to the more stable configuration during the reaction.
In all products the configurations of C2 and C3 are
preserved whereas the configuration at C5 is either
retained (in THF 3) or inverted (in THF 9), which is
consisting with a nucleophilic attack of the C2-hydroxyl
to C5. This reinforces the previous point and prevents
the consideration of competing mechanisms involving
an SN2-type attack on the allylic alcohol of C5 (which
would produce a different stereochemical outcome).
The cis/trans selectivity to form THF rings depends on
the reactions conditions (temperature, medium, and
catalyst, Table 1) and mainly on the presence of the
allylic acetate. It is noteworthy the effect on the
selectivity produced by the presence of an acetyl protect-
ing group on the allylic alcohol, suggesting the operation
of two mechanistic pathways for cyclization, depending
on the presence or absence of this functionality. On the
other hand, the fact that the nonacetylated products
(series b) can be converted into the products of series a
by simple acetylation is consistent with mechanisms of
similar type for both series.
(c)
(d)
All available data are consistent with the following
mechanistic proposal. To start, let us consider the reaction
of 8c. The first step involves the removal of the acetonide
group, freeing the 1,2-diol. In this event, the newly unmasked
alcohol on C3 reacts with the acetate on the allylic position
to form a cyclic hemiorthoester (2-hydroxy-m-dioxane), 16,
presenting the two side chains in equatorial position, Scheme
6. This intermediate in the hydrolysis of orthoesters can react
through acidic cleavage at different C-O bonds. According
to the work by Deslongchamps53,54 and others,55 the hy-
As already mentioned, when the homoallylic alcohol is
acetylated, the cyclization proceeds with good selectivity, which
is lost for the free alcohol, Table 2. Unlike allylic stereocontrol,
which has been frequently studied for electrophile-induced
cyclization of hydroxy-alkenes,57– examples of homoallylic
induction are scarce.15,56,70–6978 Unfortunately, the distance
between the involved centers in homoallylic stereocontrol turns
their interaction much weaker and ill-defined. The available
(53) Deslongchamps, P.; Dory, Y. L.; Li, S. Tetrahedron 2000, 56, 3533–
3537.
(54) Deslongchamps, P. Tetrahedron 1975, 31, 2463–2490.
(55) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754–1769.
(56) Perron-Sierra, F.; Promo, M. A.; Martin, V. A.; Albizati, K. F. J. Org.
Chem. 1991, 56, 6188–6199.
J. Org. Chem. Vol. 73, No. 15, 2008 5781

Brovetto and Seoane
SCHEME 7. Homoallylic Induction for Cyclization Reaction
Giving THF Rings, 3a and 9a
FIGURE 1. Selected NOE enhancements for compounds 3a and 9a.
SCHEME 8. Homoallylic Induction for Cyclization Reaction
Giving THF Rings, 3b and 9b
models for 5-exo cyclizations postulate a chairlike transition
state with the homoallylic alkyl substituent disposed in equatorial
position.70,71 For electronegative substituents (i.e. F, OH, OMe),
the axial position is preferred in the transition state.71 Further
substitution in other positions is not accounted for, constituting
a limitation of the model. This is especially important when
considering additional oxygenated substituents, which are able
to interact through hydrogen bonding.75,79 Another point is
related to the geometrical arrangement of the substituents in a
five-membered ring, where the positions are “quasi” equatorial
and axial.
In our case the homoallylic substituent is either an acetate
or a hydroxyl, and an explanation should be advanced for
the intriguing selectivity difference. The product distribution
we obtained may be rationalized using a model close to the
one proposed by Labelle et al. for homoallylic induction
cyclization reactions giving THF rings.71 A chairlike transi-
tion state is assumed and the stereochemical outcome is
controlled by the relative conformation of the vicinal
oxygenated substituents and the cationic moiety, Scheme 7.
The cationic moiety can adopt two conformations (either up,
18au, or down, 18ad), and the preferred one, 18au, results
from steric reasons to avoid the hindrance in the R-face (of
the type A1,3-strain, as indicated in Scheme 7), which is
absent in 18au. For the nucleophilic terminus, in turn, the
major product is consistent with the conformation 18au
having both substituents (carbomethoxy and acetate) in
equatorial positions. In this conformation, both oxygenated
polar groups (hydroxyl and acetate) are anti, which minimize
their dipolar interaction. Thus, the preferred arrangement of
the oxygenated functions is anti, based in electrostatic
considerations. In this conformation the attack on the
carbocation furnishes the cis-THF, 3a, Scheme 7. The minor
trans-THF, 9a, is obtained by hydroxyl attack in conforma-
tion 18ad.
This model may also explain other features of the cyclizations
of different derivatives, such as the deacetylated 10b and 13.
For the deacetylated compounds, the complete lack of stereo-
selection in the cyclizations may be the result of strong hydrogen
bonding between the hydroxyl groups, which is not favored in
the acetate 8c, Scheme 8. As a result of hydrogen bonding the
two hydroxyls are gauche (giving rise to the conformations 18g),
thus forcing the carbomethoxy group on C2 to adopt an axial
position. In this situation, the relative stability of the cationic
moiety changes. The cationic end can adopt the conformation
18gd (with the olefinic side chain down), in order to avoid the
steric hindrance produced by the axial substituent on C2 (of the
type A1,3 strain), which is present in 18gu. Again, during the
cyclization of the free diols, the presence of hydrogen bonding
causes the C2 substituent to adopt an axial position, which
hinders the ꢀ-face and destabilizes the conformation 18gu, and
thus attack can occur to an equal extent on both faces of the
cationic species, giving THF 3b and 9b in a 1:1 ratio, Scheme
(57) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C. J. Am.
Chem. Soc. 1983, 105, 5819–5825.
(58) Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. D.; Hehre, W. J.
J. Am. Chem. Soc. 1987, 109, 672–677.
(59) Labelle, M.; Guindon, Y. J. Am. Chem. Soc. 1989, 111, 2204–2210.
(60) Lipshutz, B. H.; Barton, J. C. J. Am. Chem. Soc. 1992, 114, 1084–
1086.
(61) Mihelich, E. D.; Hite, G. A. J. Am. Chem. Soc. 1992, 114, 7318–7319.
(62) Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc., Chem. Commun.
1981, 375–376.
(63) Reitz, A. B.; Nortey, S.; Maryanoff, B. E.; Liotta, D.; Monahan, R., III
J. Org. Chem. 1987, 52, 4191–4202.
(64) Reitz, A. B.; Nortey, S. O.; Maryuroff, B. E. Tetrahedron Lett. 1985,
26, 3915–3918.
(65) Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483–4485.
(66) Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yosbida, Z. J. Org.
Chem. 1987, 52, 4062–4072.
(67) Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron Lett.
1984, 25, 1063–1066.
(68) Tamaru, Y.; Kawamura, S.; Yoshida, Z. Tetrahedron Lett. 1985, 26,
2885–2888.
(69) Bartlett, P. A. Tetrahedron 1980, 36, 2–72.
(70) Andrey, O.; Landais, Y. Tetrahedron Lett. 1993, 34, 8435–8438.
(71) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J. P. J. Am. Chem.
Soc. 1988, 110, 4533–4540.
(72) Bravo, P.; Resnati, G.; Viani, F.; Amone, A. J. Chem. Soc., Perkin Trans.
1 1989, 839–840.
(73) Bartlett, P. A.; Richardson, D. P.; Myerson, J. Tetrahedron 1984, 40,
2317–2327.
(74) Bedford, S. B.; Fenton, G.; Knight, D. W.; Shaw, D. Tetrahedron Lett.
1992, 33, 6505–6506.
(75) Bennett, F.; Bedford, S. B.; Bell, K. E.; Fenton, G.; Knight, D. W.;
Shaw, D. Tetrahedron Lett. 1992, 33, 6507–6510.
(76) Bedford, S. B.; Bell, K. E.; Fenton, G.; Hayes, C. J.; Knight, D. W.;
Shaw, D. Tetrahedron Lett. 1992, 33, 6511–6514.
(77) Kang, S. H.; Hwang, T. S.; Kim, W. J.; Lim, J. K. Tetrahedron Lett.
1990, 31, 5917–5920.
(78) Adam, W.; Saha-Moller, C. R.; Schmid, K. S. J. Org. Chem. 2001, 66,
7365–7371.
(79) Byon, C.; Gut, M. J. Org. Chem. 1976, 41, 3716–3722.
5782 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
8. The presence of hydrogen-bonded conformations accounting
for the formation of THF of the series a (3a and 9a) can not be
completely ruled out.
Experimental Section
General Procedure for the Prevost Reaction. To a stirred
solution of cyclohexadienediol acetonide (1.9 mmol) and silver
acetate (657 mg, 3.9 mmol) in acetic acid (20 mL) was added iodine
(500 mg, 1.9 mmol) in small lots during 3 h. The mixture was
protected from light and stirred at ambient temperature for 3 h.
The precipitated silver iodide was filtered off, and the filtrate was
diluted with CH2Cl2 (50 mL), neutralized with saturated aqueous
NaHCO3 (2 × 30 mL,), washed with water (2 × 30 mL), 20%
aqueous solution of NaHSO3 (2 × 30 mL), again with water (2 ×
30 mL), and dried over Na2SO4. After filtration of the solids, the
solvent was removed in vacuo. The crude product was purified by
column chromatography on silica gel using hexanes/ethyl acetate
as eluant.
A particular case is compound 10a, which reacts very slowly
(80% starting material was recovered after 72 h of reaction).
This can be explained through the formation of a chelate with
the Lewis acid (Cu(II)), involving the two hydroxyl groups and
the acetate. In this way once the complex is formed its stability
makes it difficult to proceed with further reactions.
In summary several considerations on the mechanism of
the cyclizations of 5-alkene-1,2,4-triol derivatives emerge:
(i) The protecting groups determine the course of the reaction.
The acetate is actively involved not only in the cis/trans
selectivity (Schemes 7 and 8) but also in the reaction rate. For
the latter case, its participation in the formation of a cyclic
hemiorthoester favors the generation of the allylic carbocation
needed to cyclize (entries 1 vs 5). Also in this sense, the acetate
accelerates the ionization compared to the free allylic alcohol
(entries 1 vs 3). For the acetonide, even though this group is
the first to be removed, under certain circumstances its presence
seems to favor the cyclization (entries 1 vs 2), possibly through
interaction with the Lewis acid, thus altering the electrostatic
and steric environment.
(ii) Under the acidic conditions tried, the results are in agreement
with the intermediacy of an allylic carbocationic species, whose
formation is the rate determining step for the cyclization.
Evidence for this proposal is found in the stereochemical
outcome, the isomerization of the olefinic side chain, and the
occasional formation of mixtures of dihydropyranes of type 12
(Table 1, entry 5).
(iii) The nature of the acids is determinant for the product
distribution, operating on the relative reactivity of the different
groups, allowing for several reaction pathways.
(iv) The selectivity of the reaction depends on the interplay
between steric and stereoelectronic factors (Schemes 6, 7, and
8), among others, which determine the relative stability of
intermediate species and conformations and, therefore, the final
product distribution. The presence of conformations involving
active participation of the Lewis acid by complexation can not
be ruled out.
(1R,2S,5S,6S)-3-Chloro-6-iodo-1,2-isopropylidenedioxycyclohex-
3-ene-5-yl Acetate (4a). Yellow crystalline solid; mp 102.0-103.0
1
°C; H NMR (400 MHz, CDCl3) δ 1.45 (s,3H), 1.54 (s,3H), 2.13
(s,3H), 4.17 (t,1H, J 7.5 Hz), 4.61 (m, 2H), 5.54 (dd, 1H, J 3.2,
7.3 Hz), 5.99 (d, 1H, J 3.2 Hz); 13C NMR (100 MHz, CDCl3) δ
21.2 (CH3), 26.4 (HC-I), 26.6 (CH3), 28.4 (CH3), 72.6 (HC-O),
75.6 (HC-O), 79.2 (HC-O), 112.2 (C), 126.7 (CH), 133.8 (C), 170.3
(CdO); IR νmax (KBr)/cm-1 3000, 2920,1745, 1375; 1240, 1217;
CIMS m/z (%) 372 (1, M+), 357 (75, M+ - CH3), 313 (10, M+
-
OAc), 255 (63, M+ - Ac - C3H6O2), 146 (41), 128 (46), 43 (100,
Ac+); [R]25D +22° (c 0.8, CHCl3). Anal. required for C11H14O4ClI:
C, 35.54; H, 3.80%. Found: C, 35.93; H, 4.26%.
General Procedure for the Dehalogenation Reaction. Bu3SnH
(174 mg, 0.6 mmol) was added to a mixture of 1,1′-azobis(cyclo-
hexanecarbonitrile) (ABCC) (3 mg, 0.012 mmol) and compound
4a or 4b (0.4 mmol) in dry THF (15 mL) under an nitrogen
atmosphere. The reaction mixture was refluxed for 2 h. The solvent
was evaporated and the residue was purified by flash chromatog-
raphy (silica gel, ethyl acetate/hexanes, 15:85) to afford pure
products 5a or 5b.
(1S,2S,5R)-3-Chloro-1,2-isopropylidenedioxycyclohex-3-ene-5-
yl Acetate (5a). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.41
(s,3H), 1.50 (s,3H), 2.06 (s,3H), 2.13 (m,2H), 4.45 (m, 2H), 5.30
(qd, 1H, J 5.1 Hz), 6.08 (d, 1H, J 4.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.4 (CH3), 26.6 (CH3), 28.3 (CH3), 30.5 (CH2), 66.7
(HC-O), 72.8 (HC-O), 75.1 (HC-O), 111.0 (C), 127.1 (CH), 135.6
(C), 170.9 (CdO); IR νmax (KBr)/cm-1 2988, 2936, 2876,1740,
1240; 1078, 1023; CIMS m/z (%) 246 (0.8, M+), 231 (58, M+
-
CH3), 187 (100, M+ - OAc), 129 (79), 111 (26), 59 (24, OAc+),
43 (29, Ac+); HRMS (ESI) m/z calcd for C11H15ClO4 (M + Na)+
269.0551, obsd 269.0559; [R]25 +30° (c 0.1, CHCl3).
D
(1S,2S,5R)-3-Bromo-1,2-isopropylidenedioxycyclohex-3-ene-5-
yl Acetate (5b). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.39
(s,3H), 1.52 (s,3H), 2.08 (s,3H), 2.15 (m,2H), 4.44 (td, 1H, J 6.0,
6.2 Hz), 4.55 (d, 1H, J 5.8 Hz), 5.24 (td, 1H, J 4.5, 4.7 Hz), 6.33
(d, 1H, J 4.1 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4 (CH3),
26.6 (CH3), 28.2 (CH3), 30.4 (CH2), 67.2 (HC-O), 72.9 (HC-O),
76.3 (HC-O), 110.0 (C), 126.6 (C), 131.3 (HCd), 170.8 (CdO);
IR νmax (KBr)/cm-1 2986, 2936, 1736, 1647, 1238; 1078, 1032,
738; EIMS m/z (%) 290-292 (1, M+), 275-277 (36, M+ - CH3),
190-192 (10, M+ - OAc - C3H6), 173-175 (39, M+ - OAc -
C3H7O), 145-147 (9), 111 (7), 94 (12), 65 (14), 43 (29, Ac+);
HRMS (ESI) m/z calcd for C11H15BrO4 (M + Na)+ 313.0046, obsd
Conclusions
In this work we have shown the use of acidic conditions
for the cyclization of 5-alkene-1,2,4-triol derivatives to
produce 3-oxygenated-cis-dialkyl-2,5-substituted tetrahydro-
furans with good selectivity. The product distribution is
dependent on the choice of protecting groups and, to a minor
extent, on the reaction conditions. Higher selectivity and
shorter reaction time were obtained when using acetate and
acetonide as protecting groups of the allylic alcohol and the
diol, respectively.
313.0036, [R]25 +96° (c 2.7, CHCl3).
D
Methyl (2S,3S,5R)-5-Acetoxy-2,3-isopropylidenedioxy-6-oxohex-
anoate (6). A mixture of O2/O3 (60% O3 in O2) was bubbled through
a solution of compounds 5a or 5b (0.35 mmol) and NaHCO3 (88
mg, 1.05 mmol) in CH2Cl2 (4 mL) and MeOH (4 mL) at -78 °C,
until a blue color persisted. After removal of the excess of O3 at
-78 °C with N2, dimethyl sulfide (2.8 mmol, 0.2 mL) was added,
and the temperature was allowed to rise overnight until room
temperature, whereupon the solvent was removed at reduced
pressure. The residue was purified by column chromatography (10%
deactivated silica gel, hexanes/ethyl acetate, 1:1) to afford com-
The cyclization was studied by changing the protecting groups
and the stereochemistry of the allylic alcohol. The results were
rationalized assuming a complete ionization at the allylic
position and a model close to the one proposed by Labelle for
homoallylic induction in five-membered ring closures. It is
expected that these results could be used as a guide in
applications of these cyclizations, which are under way in our
laboratory.
J. Org. Chem. Vol. 73, No. 15, 2008 5783

Brovetto and Seoane
1
pound 6 as an oil (94 mg, 98%). H NMR (400 MHz, CDCl3) δ
until consumption of starting material. When the reaction was
complete, the solvent was removed under reduced pressure and
the residue purified by flash chromatography.
1.37 (s,3H), 1.57 (s,3H), 2.01 (m,1H), 2.11 (m,1H), 2.21 (s,3H),
3.79 (s,3H), 4.54 (m,1H), 4.68 (d, 1H, J 6.7 Hz), 5.23 (t, 1H, J 5.5
Hz), 9.53 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0 (CH3), 25.9
(CH3), 27.3 (CH3), 31.2 (CH2), 52.5 (CH3), 73.5 (HC-O), 75.7 (HC-
O), 77.4 (HC-O), 111.6 (C), 170.2 (CdO), 170.6 (CdO), 197
(CHO); IR νmax (KBr)/cm-1 3586, 3564,1755, 1738; 1439, 1373,
1242, 1221, 1093; CIMS m/z (%) 275 (0.1, M++1), 259 (100, M+
- CH3), 217 (57, M+ - CH3 - C3H6), 199 (10, M+ - CH3 -
C3H6 - H2O), 157 (95, (M++1) - OAc - COOMe), 127 (18), 97
Methyl (2S,3S,5R,6E)-3-Acetoxy-9-benzoyloxy-2,5-oxy-6-
nonenoate (3a). Oil, 1H NMR (400 MHz, CDCl3) δ 1.96
(ddd,1H, J 5.4, 10.6, 13.8 Hz), 2.11 (s,3H), 2.12 (ddd,1H, J
0.6, 5.8, 13.8 Hz), 2.54 (dt,2H, J 6.4, 6.5 Hz), 3.77 (s,3H), 4.38
(t,2H, J 6.6 Hz), 4.48 (d,1H, J 1.2 Hz), 4.67 (ddd,1H, J 5.4,
7.4, 10.6 Hz), 5.41 (ddd,1H, J 0.5, 1.2, 5.3 Hz), 5.75 (dd,1H, J
7.6, 15.5 Hz), 5.87 (td,1H, J 6.6, 15.4 Hz), 7.45 (t,2H, J 7.8
Hz), 7.56 (dt,1H, J 1.2, 7.6 Hz), 8.04 (dd,2H, J 1.2, 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ 21.3 (CH3), 32.0 (CH2), 38.5
(CH2), 52.8 (O-CH3), 64.2 (O-CH2), 77.9 (HC-O), 81.4 (HC-
O), 82.7 (HC-O), 128.7 (CHd), 128.7 (CHd), 129.9 (CHd),
129.9 (HCd), 130.4 (HCd), 130.7 (C), 132.4 (HCd), 133.3
(HCd), 166.8 (CdO), 170.4 (CdO), 171.1 (CdO); IR νmax
(KBr)/cm-1 2984, 2916, 1740, 1603, 1450, 1242, 1047, 715;
EIMS m/z (%) 303 (3, M+ - COOMe), 240 (3, M+ - C7H6O2),
198 (4, M+ - C7H5O2 - AcO), 180 (51, M+ - C7H6O2 -
AcOH), 148 (14), 122 (28, (C7H6O2)+), 121 (100, (C7H5O2)+),
105 (100, (C7H5O)+), 93 (31), 77 (88, φ+), 59 (16, AcO+,
COOMe+); HRMS (ESI) m/z calcd for C19H22O7 (M + Na)+
385.1258, obsd 385.1269.
(25), 73 (15), 59 (17, AcO+) 43 (95, Ac+); [R]25 +1° (c 0.5,
CHCl3). Anal. required for C12H18O7: C, 52.5; H, 6.6%. Found: C,
52.0; H, 7.0%.
D
General Procedure for the Wittig-Boden Reaction. A mixture
of phosphonium salt (0.15 mmol), K2CO3 (0.15 mmol) and catalytic
amounts of 18-Crown-6 in THF (12 mL) was refluxed under a N2
atmosphere for 1 h. After that time a solution of aldehyde (0.10
mmol) in the minimum amount of THF was added dropwise. The
system was kept under reflux until there was no more aldehyde by
TLC. The reaction mixture was then filtrated through a small pad
of silica gel and eluted with a 1:1 mixture of AcOEt/Hex. The
filtrate was concentrated under reduced pressure, and the residue
purified by flash chromatography.
Methyl (2S,3S,5R,6Z)-5-Acetoxy-9-benzoyloxy-2,3-isopropy-
lidenedioxy-6-nonenoate (8c). Oil, 1H NMR (400 MHz, CDCl3) δ
1.35 (s,3H), 1.62 (s,3H), 1.80 (m,2H), 2.03 (s,3H), 2.66 (dtd,1H, J
1.6, 6.8, 21 Hz), 2.78 (dtd,1H, J 1.4, 7.9, 21 Hz), 3.77 (s,3H), 4.31
(ddd,1H, J 4.0, 6.7, 9.5 Hz), 4.40 (ddd,2H, J 4.0, 6.8, 9.3 Hz),
4.58 (d,1H, J 6.7 Hz), 5.44 (dd,1H, J 9.8, 10.6 Hz), 5.76 (m,2H),
7.45 (t,2H, J 7.7 Hz), 7.57 (dt,1H, J 1.2, 7.4 Hz), 8.05 (dd,2H, J
1.2, 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5 (CH3), 25.9
(CH3), 27.3 (CH3), 27.8 (CH2), 35.2 (CH2), 52.3 (O-CH3), 64.4
(O-CH2), 68.1 (HC-O), 74.5 (HC-O), 77.7 (HC-O), 111.3 (C), 128.7
(CHd), 128.7 (CHd), 129.6 (CHd), 129.9 (HCd), 129.9 (HCd),
130.6 (C), 131.0 (HCd), 133.2 (HCd), 166.8 (CdO), 170.2
(CdO), 170.8 (CdO); IR νmax (KBr)/cm-1 2986, 2918, 2851, 1760,
1740, 1721, 1425, 1278, 1240, 1099, 713; EIMS m/z (%) 405 (10,
M+ - CH3), 361 (6, M+ - AcO), 302 (10, M+ - AcO - COOMe),
181 (31, M+ - AcO - COOMe - BzOH), 163 (40), 121 (38,
(C7H5O2)+), 105 (100, (C7H5O)+), 59 (6, AcO+), 43 (18, Ac+);
Methyl (2S,3S,5R,6E)-9-Benzoyloxy-3-hydroxy-2,5-oxy-6-
nonenoate (3b). Oil, 1H NMR (400 MHz, CDCl3) δ 1.89
(ddd,1H, J 5.5, 9.8, 13.3 Hz), 2.07 (ddd,1H, J 1.9, 5.7, 12.0
Hz), 2.19 (s,1H), 2.55 (dt,2H, J 6.3, 12.9 Hz), 3.78 (s,3H), 4.39
(t,2H, J 6.7 Hz), 4.40 (d,1H, J 1.7 Hz), 4.57 (m,1H), 4.70
(ddd,1H, J 6.7, 6.8, 6.8 Hz), 5.74 (dd,1H, J 7.5, 15.1 Hz), 5.84
(td,1H, J 8.5, 15.2 Hz), 7.45 (t,2H, J 7.8 Hz), 7.56 (dt,1H, J
1.2, 7.6 Hz), 8.04 (dd,2H, J 1.2, 8.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 31.9 (CH2), 40.8 (CH2), 52.6 (O-CH3), 64.2 (O-CH2),
76.3 (HC-O), 80.9 (HC-O), 85.3 (HC-O), 128.7 (CHd), 128.7
(CHd), 129.8 (CHd), 129.9 (HCd), 129.9 (HCd), 130.7 (C),
133.2 (HCd), 133.3 (HCd), 166.8 (CdO), 171.9 (CdO); IR
ν
max (KBr)/cm-1 3460 (broad), 2955, 2920, 1747, 1716, 1452,
1275, 1113, 713; EIMS m/z (%) 277 (5), 198 (27, M+
-
UV:λmax 232.0 nm; [R]25 -8.6° (c 2.5, CHCl3). Anal. required
D
C7H6O2), 180 (8, M+ - C7H6O2 - COOMe - H), 139 (33),
121 (54, (C7H5O2)+), 105 (100, (C7H5O)+), 96 (47), 77 (70,
φ+), 59 (31, AcO+, COOMe+), 51 (33); HRMS (ESI) m/z calcd
for C17H20O6 (M + Na)+ 343.1152, obsd 343.1147.
for C22H28O8: C, 62.86; H, 6.70%. Found: C, 62.80; H, 7.21%.
General Procedures for Deprotection of the Acetonide
Group. Method A: Using Dowex Resin (H+). Acetonide
compound (0.04 mmol) was dissolved in a mixture of MeOH/
H2O (99:1) and stirred at room temperature with Dowex resin
(H+) until reaction was complete. The mixture was filtered and
the solvent removed under reduced pressure. The residue was
purified by flash chromatography.
Methyl (2S,3S,5S,6E)-3-Acetoxy-9-benzoyloxy-2,5-oxy-6-non-
enoate (9a). Oil, 1H NMR (400 MHz, CDCl3) δ 1.81 (ddd,1H,
J 3.7, 6.3, 13.6 Hz), 2.08 (s,3H), 2.54 (m,3H), 3.78 (s,3H), 4.38
(t,2H, J 6.7 Hz), 4.57 (d,1H, J 2.3 Hz), 4.75 (ddd,1H, J 7.0,
7.1, 7.1 Hz), 5.43 (ddd,1H, J 2.3, 3.7, 4.0 Hz), 5.74 (d,1H, J
7.6 Hz), 5.87 (m,1H), 7.45 (t,2H, J 7.8 Hz), 7.56 (dt,1H, J 1.2,
7.6 Hz), 8.04 (dd,2H, J 1.2, 8.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.3 (CH3), 32.0 (CH2), 38.3 (CH2), 52.7 (O-CH3),
64.2 (O-CH2), 77.5 (HC-O), 80.7 (HC-O), 82.2 (HC-O), 128.7
(CHd), 128.7 (CHd), 129.5 (CHd), 129.9 (HCd), 129.9
(HCd), 130.7 (C), 132.7 (HCd), 133.3 (HCd), 166.8 (CdO),
170.6 (CdO), 171.3 (CdO); IR νmax (KBr)/cm-1 2984, 2916,
1740, 1603, 1450, 1242, 1047, 715; EIMS m/z (%) 303 (3, M+
- COOMe), 240 (3, M+ - C7H6O2), 198 (4, M+ - C7H5O2 -
AcO), 180 (51, M+ - C7H6O2 - AcOH), 148 (14), 122 (28,
(C7H6O2)+), 121 (100, (C7H5O2)+), 105 (100, (C7H5O)+), 93
(31), 77 (88, φ+), 59 (16, AcO+, COOMe+); HRMS (ESI) m/z
calcd for C19H22O7 (M + Na)+ 385.1258, obsd 385.1269.
Method B: Using Hydrochloric acid. Acetonide compound
(0.03 mmol) was dissolved in 10% methanolic HCl and stirred
at room temperature until reaction was complete. After neu-
tralization with Amberlyst 21 (basic resin), the mixture was
filtered and the solvent removed under reduced pressure. The
residue was purified by flash chromatography.
Method C: Using Cupric Chloride. Solid CuCl2 · 2H2O
(0.12 mmol) was added to the acetonide compound (0.06
mmol) dissolved in acetonitrile (5 mL) at 0 °C and stirred
until the resulting blue-green solution reached room temper-
ature. When the reaction was complete, the solvent was
removed under reduced pressure and the residue purified by
flash chromatography.
Method D: Using Boron Trifluoride Etherate. A 10% (v/
v) solution of BF3 ·Et2O (0.005 mL, 0.004 mmol) in CH2Cl2
was added dropwise to a solution of acetonide compound (0.04
mmol) in CH2Cl2. The reaction was stirred at room temperature
Methyl (2S,3S,5S,6E)-9-Benzoyloxy-3-hydroxy-2,5-oxy-6-
nonenoate (9b). Oil, 1H NMR (400 MHz, CDCl3) δ 1.83
(ddd,1H, J 5.3, 7.4, 12.8 Hz), 2.19 (s,1H), 2.42 (ddd,1H, J 6.3,
5784 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of 3-Oxygenated-cis-2,5-substituted Tetrahydrofurans
6.9, 13.3 Hz), 2.55 (td,2H, J 6.3, 12.9 Hz), 3.79 (s,3H), 4.39 (t,2H,
J 6.7 Hz), 4.45 (d,1H, J 3.6 Hz), 4.58 (m,1H), 4.74 (m,1H), 5.75
(m,1H), 5.82 (m,1H), 7.45 (t,2H, J 7.8 Hz), 7.56 (dt,1H, J 1.2, 7.6
Hz), 8.04 (dd,2H, J 1.2, 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
32.0 (CH2), 40.6 (CH2), 52.6 (O-CH3), 64.2 (O-CH2), 76.1 (HC-
O), 80.2 (HC-O), 84.4 (HC-O), 128.7 (CHd), 128.7 (CHd), 129.8
(CHd), 129.9 (HCd), 129.9 (HCd), 130.7 (C), 133.3 (HCd),
133.5 (HCd), 166.8 (CdO), 171.9 (CdO); IR νmax (KBr)/cm-1
3460 (broad), 2955, 2920, 1747, 1716, 1452, 1275, 1113, 713;
EIMS m/z (%) 277 (5), 198 (27, M+ - C7H6O2), 180 (8, M+ -
C7H6O2 - COOMe- H), 139 (33), 121 (54, (C7H5O2)+), 105 (100,
(C7H5O)+), 96 (47), 77 (70, φ+), 59 (31, AcO+, COOMe+), 51
(33); HRMS (ESI) m/z calcd for C17H20O6 (M + Na)+ 343.1152,
obsd 343.1147.
Acknowledgment. Support of this work from DINACYT
(PDT 54, Ministerio de Educacio´n y Cultura, Uruguay) is
gratefully acknowledged. The authors thank Professor T.
Hudlicky for providing the cultures of P. putida F39/D.
Supporting Information Available: Experimental details,
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800514K
J. Org. Chem. Vol. 73, No. 15, 2008 5785