Direct synthesis of substituted tetrahydrofurans via regioselective dehydrative polyol cyclization cascades

Article abstract of DOI:10.1016/S0040-4020(02)00043-1

A one-pot procedure for the conversion of 1,2,4,5-tetraols into substituted tetrahydrofuran moieties has been developed. This involves the regioselective sulfonylation of the terminal hydroxyl of the polyol array followed by sequential oxirane and oxolane formation under basic conditions. A survey of reaction conditions has defined the use of N-(2,4,6-triisopropylbenzenesulfonyl)imidazole as sulfonylation reagent, potassium tert-butoxide as base, and tert-butanol as solvent to be optimal. Under these conditions, 8-O-benzyl-octan-1,2,4,5,8-pentaol was converted stereospecifically into tetrahydrofurans in 62% yield. Polyol substrates were derived from Sharpless asymmetric dihydroxylation of 1,4-dienes. Hence, substituted tetrahydrofurans could be obtained stereospecifically from diene substrates in two operations.

Full text of DOI:10.1016/S0040-4020(02)00043-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1865±1874
Direct synthesis of substituted tetrahydrofurans via regioselective
dehydrative polyol cyclization cascades
Amy B. Dounay,a Gordon J. Florence,a Akira Saitob and Craig J. Forsytha,p
aDepartment of Chemistry, University of Minnesota, 139 Smith Hall, 207 Pleasant Street, SE, Minneapolis, MN 55455, USA
bDepartment of Chemistry, Kyoto University, Kyoto 606-8502, Japan
Received 1 October 2001; accepted 17 November 2001
AbstractÐA one-pot procedure for the conversion of 1,2,4,5-tetraols into substituted tetrahydrofuran moieties has been developed. This
involves the regioselective sulfonylation of the terminal hydroxyl of the polyol array followed by sequential oxirane and oxolane formation
under basic conditions. A survey of reaction conditions has de®ned the use of N-(2,4,6-triisopropylbenzenesulfonyl)imidazole as sulfonyl-
ation reagent, potassium tert-butoxide as base, and tert-butanol as solvent to be optimal. Under these conditions, 8-O-benzyl-octan-1,2,4,5,8-
pentaol was converted stereospeci®cally into tetrahydrofurans in 62% yield. Polyol substrates were derived from Sharpless asymmetric
dihydroxylation of 1,4-dienes. Hence, substituted tetrahydrofurans could be obtained stereospeci®cally from diene substrates in two
operations. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
epoxide opening to provide substituted cyclic ethers.17
Reported here are the details of a direct synthesis of highly
functionalized tetrahydrofurans that employs a novel
dehydrative cyclization cascade of polyols that may avoid
the necessity of isolation or handling of activated alcohol or
epoxide intermediates.
Substituted cyclic ethers occur widely among various
classes of natural products.1±3 A common biogenetic
mechanism postulated for the formation of both oxolane
and oxane ring systems in compounds such as the emergent
marine toxin azaspiracid (1),4 the bis-THF acetogenin
motrilin (2),5,6 the ionophoric antibiotic monensin (3),1
and the squalenoid polyether thyrsiferol2 (4, Fig. 1) is the
isomerization of the precursor hydroxy epoxides.7 Hydroxy
epoxide intermediates, in turn, may be derived from the
enzymatic incorporation of molecular oxygen into polyene
systems.8,9 These tenets of cyclic ether biosynthesis,
combined with the widespread occurrence and potent
biological activities of cyclic ether containing natural
products have prompted the development of a variety of
laboratory methods for their synthesis.3,10±14 A conventional
strategy toward tetrahydrofuran construction involves the
isomerization of g-hydroxy epoxides via acid-catalyzed
5-exo-trig opening (Scheme 1), as suggested by biogenetic
considerations.15 In the seminal polyether total synthesis of
lasalocid A, Kishi demonstrated the stereoselective
hydroxyl-directed epoxidation of bishomoallylic alcohols
using VO(acac)2 to access g-hydroxy epoxides, which
could be cyclized in situ under acidic conditions to generate
the corresponding THF rings.16 We considered that the same
type of hydroxy epoxide intermediates could be obtained via
the direct regioselective dehydration of a polyol array, but
under basic conditions that could also promote in situ
The envisioned conversion of a polyol into a substituted
cyclic ether would involve selective sulfonylation of the
kinetically more reactive hydroxyl group, followed by
base-induced epoxide formation and intramolecular trans-
etheri®cation in an exo-mode (Scheme 2). Sharpless asym-
metric dihydroxylation (SAD)18,19 of the corresponding
polyene precursors would provide a facile entry to the
polyol cyclization precursors. Thus, the proposed cyclic
ether synthesis could be achieved in only two operations
from readily accessible polyenes. The use of SAD to access
the polyol systems would dictate both the enantio and dia-
stereoselectivity of the process.18 In principle, either cis or
trans substituted cyclic ether products may be obtained by
dihydroxylation of (E)- or (Z)-alkenes. To establish direc-
tionality of the dehydrative polyol cyclization cascade,
steric differentiation of the individual hydroxyl groups
may be exploited using a sterically discriminating activating
reagent. Hence, N-arylsulfonyl imidazole reagents were
selected for this purpose. N-p-(Toluenesulfonyl)imidazole
(N-TsIm)20 and N-(2,4,6-triisopropylbenzenesulfonyl)-
imidazole (N-TrisIm)21 have been used previously for the
in situ conversion of vicinal diols into the corresponding
epoxides in several cases.
Keywords: tetrahydrofurans; cyclization; 1,4-dienes.
Corresponding author. Tel.: 11-612-624-0218; fax: 11-612-626-7541;
e-mail: forsyth@chem.umn.edu
p
Rather than relying upon sequential protecting or functional
group manipulations, the regioselective formation of the
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00043-1

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A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
Figure 1. Representative tetrahydrofuran-containing natural products.
requisite hydroxy epoxides would be determined by the
relative reactivity of the individual alcohols in polyol
substrates. In addition to the inherent steric discrimination
of the sulfonyl imidazole reagents, the by-products of epox-
ide formation (arylsulfonate and imidazolide salts) may be
innocuous to subsequent transformations.22
2. Results and discussion
The direct conversion of a polyene to a cyclic ether via a
polyol intermediate was originally explored in the context
of tetraols derived from 1,4-dienes. Rapid synthetic access
to the D-ring tetrahydrofuran of azaspiracid (1, Fig. 1)4 was
speci®cally targeted via this approach (Scheme 3). Here, a
hydroxyl group at the 3-position and a hydroxymethyl group
at the 5-position of the THF ring 5 were required for subse-
quent elaboration. This oxygenation pattern resident in
tetraol 6 would derive from bis-dihydroxylation of 1,4-
diene 7.
Scheme 1. In situ generation and transetheri®cation of g-hydroxy-epoxides.
Scheme 2. Proposed synthesis of substituted cyclic ethers from dienes via one-pot conversion of a tetraol into a tetrahydrofuran.

A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
1867
chloride provided ester 9 (Scheme 4). Treatment of 9 with
KHMDS followed by TBSCl in THF at 2788C gave the
t-butyldimethylsilyl ketene acetal, which underwent
Ireland±Claisen rearrangement to provide the a-methyl
silyl ester in nearly quantitative yield upon warming to
room temperature.24 The silyl ester was then hydrolyzed
using an acidic workup to give carboxylic acid 10. Treat-
ment of 10 with lithium aluminum hydride provided the
primary alcohol 11. Benzylation of alcohol 11 under
standard conditions provided diene 7,25 which would serve
as the scaffold for examining the bis-dihydroxylation/
dehydrative cyclization cascade en route to the azaspiracid
D-ring.
Treatment of (^)-7 under standard SAD conditions con-
sistently provided a ,1.5:1 mixture of chromatographically
separable tetraols that were epimeric not only at the C14
methyl-bearing carbon (azaspiracid carbon numbering), but
also at the C19 carbinol center (Scheme 5).26
Scheme 3. Retrosynthesis of the azaspiracid D-ring.
Scheme 4. Synthesis of C13±C20 diene.
2.1. Two-step approach to cyclic ethers from dienes
(diene to tetrahydrofuran)
To investigate the unexpectedly low level of diastereo-
selectivity of the bis-dihydroxylation reaction, enantio-
merically enriched (R)-7 was subjected to a series of
experiments (Scheme 6). Diene 7 was ®rst oxidized using
3 equiv. of AD-mix-b to the regioisomeric diols 13 and 14.
Analysis of the diols by 1H NMR spectroscopy allowed for
2.1.1. Diene synthesis and hydroxylation. The synthesis of
7 began with the readily available allylic alcohol (^)-1,5-
hexadien-3-ol ((^)-8).23 Acylation of 8 with propionyl
Scheme 6. Attempts to enhance the diastereoselectivity of diene 7
dihydroxylation.
Scheme 5. Bis-dihydroxylation of diene 7.

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A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
Table 1. Ligand effects in diene to tetraol transformation according to
Scheme 6
Despite signi®cant efforts to optimize the SAD of diene 7,
no conditions were identi®ed under which bis-dihydroxyl-
ation could be achieved with a high level of diastereo-
selectivity at the terminal ole®n. Nevertheless, the C19-
epimeric tetraols could be chromatographically separated
and the high overall yield and brevity of this approach
allowed for facile synthetic access to tetraol 6 in ®ve steps
from the known 1,4-hexadien-3-ol.29
Ligand
dr 13
dr 14
(DHQD)2PHAL (AD-mix b)
(DHQD)2PYRp
.95:5
.95:5
.95:5
,1.5:1
,1.5:1
,2:1
(DHQD)2AQNp
Ligand was premixed with OsO4, K3Fe(CN)6, and K2CO3 in t-BuOH/H2O
prior to addition of 7. Note: tetraols were also formed to a minor degree
under the reaction conditions; therefore, the diastereomeric ratios are only
approximate.
2.1.2. One-pot tetraol to THF transformation. Initial
attempts toward the conversion of tetraol 6 to tetrahydro-
furan 5 (Scheme 8) involved treatment of 6 with excess KH
or NaH in THF, followed by addition of 0.95 equiv. of
N-TsIm. However, these conditions led only to bis-epoxide
17, which resulted from non-selective sulfonylation of the
tetraol. Treatment of 6 with excess KH or NaH in THF
followed by addition of 1.0 equiv. of the bulkier sulfonyl-
ation reagent N-TrisIm also resulted in formation of 17 as
the major product (Table 2, entries 1 and 2). Under the NaH
conditions, a small amount (,5±10%) of the THF product
(5) was generated, but none was observed under the KH
conditions.
determination that 13 was a single diastereomer, and 14 was
a ,1.5:1 mixture of diastereomers. This result demonstrated
that the con®guration at the C14 methyl-bearing center had
little effect on dihydroxylation diastereoselectivity. Further-
more, this indicated that the previously observed low levels
of diastereoselectivity in the bis-dihydroxylation were not a
result of intramolecular directing effects during the conver-
sion of the diol to the tetraol, because the low level of
stereocontrol is already evident during the dihydroxylation
to 14.
The modest stereoselectivity achieved with oxidation of the
terminal ole®n of 7 with AD-mix led to the examination of
other ligands for the SAD that might provide higher levels
of diastereoselectivity (Scheme 6, Table 1). However,
neither the (DHQD)2PYR ligand system, which was opti-
mized by Sharpless and co-workers speci®cally for
problematic terminal ole®ns,27 nor the (DHQD)2AQN
system28 provided any signi®cant improvement in diastereo-
selectivity for dihydroxylation of the terminal ole®n of 7.
To thoroughly examine the one-pot tetraol etheri®cation
cascade, simpli®ed desmethyl cyclization precursors (19
and 20) were synthesized following the previous route
toward tetraol 6 with the exception that the initial acylation
of 1,5-hexadien-3-ol was accomplished with acetic
anhydride rather than propionyl chloride. The cyclization
reactions of tetraols 6 and 12 and 19 and 20 were examined
using a series of bases and solvents.30 The preliminary
experiments with KH and NaH had suggested that control
of the base stoichiometry might be required for selective
sulfonylation of the primary alcohol of 6. To control this
parameter more easily, commercially available solutions of
KHMDS in toluene were used. After extensive experimen-
tation, it was found that treatment of tetraols 6 and 12 with
1 equiv. of KHMDS followed by slow addition of 1.0±
1.1 equiv. of N-TrisIm allowed for selective sulfonylation
of the primary alcohol, which underwent rapid conversion
to the diol-epoxide intermediate. Subsequent base-induced
tetrahydrofuran formation was effected by gradually adding
an additional ,2.5 equiv. of KHMDS to the reaction
mixture over the course of 3±4 h and allowing the reaction
to continue at room temperature for 12 h. This one-pot
protocol allowed for conversion of tetraols 6 and 12 to
To verify that the observations for the conversion of diene 7
to diols 13 and 14 were consistent with results for the
synthesis of the tetraols, diol 13 was further oxidized
using the (DHQD)2PYR ligand under Sharpless conditions
(Scheme 7). Once again, as in the one-pot bis-dihydroxyl-
ation, a 1.5:1 mixture of 15 and 16 was obtained.
Scheme 8. Initial attempts at one-pot conversion of tetraol to tetrahydro-
furan.
Scheme 7. Stepwise conversion to tetraols.

A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
1869
substituted tetrahydrofuran 5 and 14 in 50% combined
yield (entry 3). Reaction of the desmethyl tetraols
(19120) under the same conditions provided the corre-
sponding tetrahydrofurans in comparable yield (47±53%,
entry 4). The bis-epoxide by-product formed under these
reaction conditions was isolated in 22% yield.31 The use
of NaHMDS in the cyclization rather than KHMDS led to
reduced yields of the tetrahydrofuran (19%, entry 7) due to
increased formation of the bis-epoxide by-product. A vari-
ety of other bases were surveyed for this reaction in THF,
including Triton-B, i-PrMgBr, CsOH, K2CO3, and
BrMgHMDS, but none provided any improvement in
conversion to tetrahydrofuran products.
Optimal results for the one-pot tetraol to THF conversion
were achieved using potassium tert-butoxide in tert-butanol
(entry 8, Table 2). Under these conditions, a mixture of
tetraols 19 and 20 were converted into the corresponding
tetrahydrofurans 21 and 22 in 62% combined, isolated yield.
Only a minor amount of bis-epoxide byproducts (ca. 8%)
were formed under these reaction conditions. Best results
were obtained using solutions of potassium tert-butoxide
that were freshly prepared from solid KH and tert-butanol.
The use of the polar, protic solvent tert-butanol in conjunc-
tion with the portion-wise addition of potassium tert-butox-
ide (see Section 4) reduced the formation of bis-epoxide
resulting from over sulfonylation of the polylol substrates.
In an effort to further enhance the selectivity of primary
sulfonylation, the mixture of tetraols (19 and 20) were trea-
ted with 1 equiv. each of KHMDS and N-TrisIm at 2408C,
and the reaction was maintained at this temperature.
However, the sulfonylation was extremely slow at this
temperature, and virtually only starting material remained
after several hours at 2408C. Hence, a step-wise sulfonyla-
tion±etheri®cation cascade process was examined to deter-
mine whether enhanced regioselectivity via a discrete
sulfonylation step would translate into higher overall ef®-
ciency.
The tetraols 19 and 20 were also used in a brief study of
solvent effects in the cyclization cascade (Table 2, Scheme
9). To test the role of solvent polarity, solid KHMDS was
used instead of commercially available toluene solutions.
With KHMDS, the yield of tetrahydrofurans (21122) was
lower in THF solvent alone (entry 5), due to the formation of
slightly more bis-epoxide by-product. When the reaction
was performed in DMF (entry 6), the tetrahydrofurans
were isolated in yields comparable to those achieved in
THF/toluene. However, the major by-product formed in
DMF was the alternative tetrahydrofuran regioisomer
resulting from intramolecular 5-exo displacement of the
primary sulfonate. Less of the bis-epoxide was apparent
(TLC) when the reaction was performed in DMF.
2.2. Step-wise sulfonylation±dehydrative cyclization
cascade
Examination of a discrete step-wise approach to the dehy-
drative polyol cyclization cascade began with the selective
mono-sulfonylation of the primary alcohol of tetraols 19 and
20 (Scheme 10). 2,4,6-Triisopropylbenzenesulfonyl chlo-
ride (TrisCl) has previously been employed under standard
conditions (pyridine, 08C, 24 h)32 and lengthy reaction times
for such a purpose. Here, it was found that 19 and 20 could
be converted into the corresponding sulfonates 23 using
TrisCl and Et3N in CH2Cl2 at rt. In contrast to the one pot
sulfonylation±cyclization cascade, the pre-formed primary
sulfonate could be converted into the tetrahydrofurans in
very high yield upon treatment with K2CO3 in methanol at
room temperature (ca. 3 h). However, 23 was very sensitive
to puri®cation and handling, being obtained in 49% after
¯ash chromatography. That THF formation may proceed
through the in situ generation of epoxide 24 was demon-
strated in separate experiments by the isolation and charac-
terization of 24 followed by its resubmission to the K2CO3/
methanol reaction conditions to yield the cyclic ethers 21
and 22. Again, 24 was quite unstable. In this step-wise
approach, side reactions resulting from sulfonylation of
secondary alcohols were clearly avoided. However, dif®cul-
ties associated with the handling of sulfonate and epoxide
intermediates diminish the utility of this sequence compared
to the optimized one-pot procedure (entry 8, Table 2).
Table 2. Base and solvent effects in one-pot tetraol to tetrahydrofuran
transformation
Entry
R
Base
NaH
KH
KHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
KOt-Bu
Solvent
THF
THF
THF/toluene
THF/toluene
THF
DMF
THF
t-BuOH
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Me
Me
Me
H
H
H
2±3
2±3
8±22
8±22
6±22
22
5±10a
0a
50
47±53
28
39
H
H
8
16
19
62
a
Bis-epoxide 17 is formed rapidly under these reaction conditions.
2.3. Stereochemical assignment of tetraols and
tetrahydrofurans
To assign the relative con®gurations of the tetraols 6 and 12
and the resulting tetrahydrofuran products (5 and 18) of the
cyclization reactions, further studies of the one-pot tetraol to
tetrahydrofuran conversion were conducted using 6, which
had been chromatographically separated from its C19
Scheme 9. Survey of cyclization conditions summarized in Table 2.

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A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
Scheme 10. Step-wise vs. one-pot sulfonylation±dehydrative cyclization cascade.
epimer (12) using MPLC.29 The C19 con®gurations of 6 and
12 were initially assigned on the basis of the Sharpless
mnemonic.19 NOE experiments on the cyclization products
of 6 and 12 supported the initial C19 stereochemical assign-
ments. No NOE enhancement was observed between the
C16 and C19 protons of 5, suggesting that this was the
trans-substituted tetrahydrofuran expected to arise from
cyclization of 6 (Scheme 11).33 Likewise, NOE enhance-
ment was observed between the C16 and C19 protons of
tetrahydrofuran 18, as expected for a cis-substituted tetra-
hydrofuran (Scheme 12). These experiments provided
further support for the initial stereochemical assignments
of tetraols 6 and 12 and allowed the tentative assignments
of relative con®gurations of tetrahydrofurans 5 and 18.
Ultimately, these stereochemical assignments were veri®ed
via X-ray crystallography. THF 5 was converted into diol 25
via lactone B (Scheme 13) which was subjected to X-ray
crystallography to provide relative con®gurational assign-
ments for all of the stereocenters in this system.
Scheme 13. Assignment of relative stereochemistry based on derivatization
and X-ray crystallography.
3. Conclusions
The one-pot conversion of polyols to substituted tetra-
hydrofurans under the conditions de®ned here represents a
remarkably convenient and relatively ef®cient method for
construction of highly substituted cyclic ethers. Although
the overall yield for this transformation is moderate,
several reactions that might typically be accomplished in
multiple steps are taking place in this one-pot
procedure. In contrast, the step-wise alternative involving
the isolation of sensitive sulfonate and epoxide inter-
mediates provides considerably lower yields of tetrahydro-
furan products. The dehydrative polyol etheri®cation
cascade couples with the ready accessibility of stereo-
chemically enriched polyol arrays from the corresponding
dienes via SAD methodology18,19,27,28 to provide a two-
operation conversion of dienes to cyclic ethers. This
methodology compares favorably in yield and absolute
stereocontrol with direct metal-mediated oxidative cycliza-
tions of 1,4- and 1,5-dienes leading to substituted cyclic
ethers.14a Applications of this methodology to the total
synthesis of polyether natural products, including the
azaspiracids4,17 and bis-THF acetogenins,5,6 will be reported
in due course.
Scheme 11. Cyclization of tetraol 6 to tetrahydrofuran 5.
Scheme 12. Tentative assignment of C19 stereochemistry based on
observed NOE enhancement.

A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
1871
4. Experimental
vigorously at rt for 1 h to ensure complete hydrolysis of the
silyl ester intermediate, as indicated by TLC analysis.
Aqueous NaOH (15%) was added to adjust the aqueous
phase to pH 10. The aqueous layer was separated and acidi-
®ed to pH 2 with aqueous HCl (10%), then washed with
CH2Cl2 (8£75 mL). The combined organic fractions were
washed with saturated aqueous NaCl, dried over Na2SO4,
®ltered, and concentrated to provide (^)-10 (3.8 g,
25 mmol, 95%) as a pale yellow oil: Rf 0.11 (hexanes/
ethyl acetate, 5:1, v/v); IR (neat): 2978, 1708, 1638, 1463,
1417, 1241, 970, 914 cm21; 1H NMR (CDCl3, 500 MHz): d
11.2 (br. s, 1H), 5.81 (dddd, Jˆ16.5, 10.0, 6.0, 6.0 Hz, 1H),
5.52 (ddd, Jˆ15.5, 6.5, 6.5 Hz, 1H), 5.42 (ddd, Jˆ15.0, 7.5,
7.5 Hz, 1H), 5.04±4.98 (m, 2H), 2.76 (dd, Jˆ6.0, 6.0 Hz,
2H), 2.52 (dddd, Jˆ14.0, 7.0, 7.0, 7.0 Hz, 1H), 2.41 (ddd,
Jˆ13.5, 6.5, 5.5 Hz, 1H), 2.18 (ddd, Jˆ14.5, 8.0, 6.5 Hz,
1H), 1.18 (d, Jˆ7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 182.8, 136.9, 130.7, 127.7, 115.1, 39.5, 36.6, 36.3, 16.3;
Anal. Calcd for C9H14O2: C, 70.10; H, 9.15; Found: C,
70.19; H, 9.09; HRCIMS Calcd for C9H18NO2 [M1NH4]1
172.1336, found 172.1338.
4.1. General
Unless otherwise noted, all reactions were carried out under
an Ar or N2 atmosphere using oven dried glassware and
standard syringe, cannula, and septa techniques. Diethyl
ether, THF, and benzene were distilled from Na/benzo-
phenone under N2. Toluene was distilled from Na
under N2. CH2Cl2, CH3CN, Et3N, i-Pr2NH, and BF3´OEt2
were distilled from CaH2 under N2. AD-mix-a
[K2OsO2(OH)4, (DHQ)2-PHAL, K3FeCN6, K2CO3]19 and
b [K2OsO2(OH)4, (DHQD)2-PHAL, K3FeCN6, K2CO3],19
solutions of KHMDS in toluene, and solid KHMDS were
obtained from Aldrich Chemical Company. A 0.78 M
solution of KHMDS in toluene was purchased from
Lancaster Chemical Company. Flash chromatography was
performed using ICN silica gel 32±63 and the solvent
systems indicated. Analytical TLC was performed with
0.25 or 0.50 mm EM silica gel 60 F254 plates that were
analyzed by ¯uorescence upon 254 nm irradiation or by
staining upon heating with anisaldehyde reagent (450 mL
95% EtOH, 25 mL conc. H2SO4, 15 mL acetic acid, and
25 mL anisaldehyde). High resolution mass spectrometric
data were obtained by the University of Minnesota Mass
Spectrometry Laboratory using CI, FAB, and MALDI tech-
niques. Elemental analyses were performed by M-H-W
Laboratories (Phoenix, AZ).
4.1.3. (^)-(E)-2-Methyl-4,7-octadien-1-ol ((^)-11). To a
stirred 08C suspension of lithium aluminum hydride (1.6 g,
42 mmol) in diethylether (175 mL) under Ar was added a
solution of (^)-10 (3.85 g, 25 mmol) in diethylether
(75 mL) via cannula. After 30 min, H2O(1.6 mL) was
added, followed by 15% aqueous NaOH (1.6 mL), and an
additional portion of H2O(3.2 mL). The mixture was stirred
for 15 min, and then the white solid was removed by
vacuum ®ltration and washed with diethylether
(2£20 mL). The combined organic fractions were washed
with saturated aqueous NaCl, dried over Na2SO4, ®ltered,
and concentrated to provide (^)-11 (3.2 g, 23 mmol, 90%)
as a clear, colorless oil: Rf 0.28 (hexanes/ethyl acetate, 5:1,
v/v); IR (neat): 3338, 3079, 2957, 2913, 1638, 1456, 1037,
970, 912 cm21; 1H NMR (CDCl3, 500 MHz): d 5.82 (dddd,
Jˆ16.5, 10.0, 6.5, 6.5 Hz, 1H), 5.46 (m, 2H), 5.05±4.97 (m,
2H), 3.52 (dd, Jˆ10.5, 6.0 Hz, 1H), 3.44 (dd, Jˆ10.5,
6.0 Hz, 1H), 2.76 (m, 2H), 2.12 (m, 1H), 1.92 (m, 1H),
1.70 (dddd, Jˆ13.5, 6.5, 6.5, 6.5 Hz, 1H), 1.41 (s, 1H),
0.91 (d, Jˆ7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
137.2, 129.5, 129.4, 114.9, 68.0, 36.7, 36.5, 35.9, 16.4;
HRCIMS Calcd for C9H20NO[M 1NH4]1 158.1544,
found 158.1549.
4.1.1. (^)-3-Propanoyl-1,4-pentadiene ((^)-9). To a stir-
red 08C solution of (^)-1,5-hexadien-3-ol (10.0 g,
102 mmol) in CH2Cl2 (500 mL) under Ar was added pyri-
dine (10.7 mL, 133 mmol), followed by freshly distilled
propionyl chloride (11.7 mL, 133 mmol). After 1.5 h, satu-
rated aqueous NaHCO3 (150 mL) was added. The organic
layer was separated and washed again with saturated
aqueous NaHCO3 (150 mL). The separated organic layer
was washed with 5% aqueous HCl (2£100 mL) and satu-
rated aqueous NaCl (100 mL) and dried over Na2SO4. The
solution was ®ltered, concentrated, and puri®ed by silica gel
column chromatography (hexanes/ethyl acetate, 12:1!8:1,
v/v) to provide (^)-9 (15.0 g, 97.4 mmol, 95%) as a clear,
colorless oil: Rf 0.60 (hexanes/ethyl acetate, 5:1, v/v); IR
(neat): 2978, 1706, 1464, 1417, 1241, 971, 914 cm21; H
1
NMR (CDCl3, 300 MHz): d 5.84±5.66 (m, 2H), 5.33±5.04
(m, 5H), 2.37 (m, 2H), 2.32 (q, Jˆ7.5 Hz, 2H), 1.12 (t,
Jˆ7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 173.6,
136.0, 133.2, 117.9, 116.6, 73.4, 38.8, 27.8, 9.1; Anal.
Calcd for C9H14O2: C, 70.10; H, 9.15; Found: C, 70.28; H,
8.96; HRCIMS Calcd for C9H15O2 [M1H]1 155.1072,
found 155.1088.
4.1.4. (^)-(E)-1-Benzyloxy-2-methyl-4,7-octadiene ((^)-
7). To a stirred 08C solution of (^)-11 (10.7 g, 76 mmol) in
THF (500 mL) under Ar was added NaH (6.1 g of a 60%
dispersion in mineral oil, 0.15 mol). The reaction mixture
was allowed to warm to rt over a 1 h period. The mixture
was recooled to 08C and benzyl bromide (13.1 mL,
107 mmol) and tetra-n-butylammonium iodide (8.4 g,
24 mmol) were added. After stirring at rt for 15 h, the
mixture was cooled to 08C and anhydrous methanol
(13 mL) was added. The solution was allowed to warm to
rt, and after 1 h, saturated NH4Cl (150 mL) was added. The
mixture was diluted with ethyl acetate (200 mL), and the
aqueous phase was extracted with ethyl acetate
(3£150 mL). The combined organic extracts were washed
with saturated NaCl (200 mL), dried over Na2SO4, ®ltered,
and concentrated. Silica gel chromatography (pentane/
diethylether, 1:0!50:1!40:1, v/v) provided (^)-7
4.1.2. (^)-(E)-2-Methyl-4,7-octadienoic acid ((^)-10). To
a stirred 2788C solution of 9 (4.0 g, 26 mmol) in THF
(200 mL) under Ar, KHMDS (53 mL of a 0.78 M solution
in toluene, 42 mmol) was added via syringe over a 15 min
period. After an additional 20 min, a solution of TBSCl
(6.3 g, 42 mmol) in THF (60 mL) was added via cannula.
After an additional 30 min, the cooling bath was removed,
allowing the reaction to gradually warm to rt. The reaction
mixture was maintained at this temperature for 1.5 h. The
mixture was then cooled to 08C, and H2O(25 mL) and 10%
aqueous HCl (100 mL) were added. The mixture was stirred

1872
A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
(15.7 g, 68 mmol, 90%) as a clear, colorless oil: Rf 0.80
(hexanes/ethyl acetate, 5:1, v/v); IR (neat): 3063, 3029,
gel column chromatography (hexanes/ethyl acetate/
5
methanol, 1:1:0!0:1:0!0:20:1, v/v) to provide
2956, 2903, 1637, 1453, 1363, 1098 cm21
;
1H NMR
(455 mg, 1.6 mmol, 30%) and 18 (300 mg, 1.1 mmol,
20%) as colorless oils. 5: Rf 0.45 (ethyl acetate/methanol,
5:1, v/v); IR (neat): 3425, 2925, 2850, 1500, 1435, 1180,
(CDCl3, 300 MHz): d 7.36±7.25 (m, 5H), 5.83 (dddd,
Jˆ16.5, 10.2, 6.3, 6.3 Hz, 1H), 5.44 (m, 2H), 5.07±4.97
(m, 2H), 4.51 (s, 2H), 3.34 (dd, Jˆ9.0, 6.0 Hz, 1H), 3.27
(dd, Jˆ9.0, 6.3 Hz, 1H), 2.76 (m, 1H), 2.19 (m, 1H), 1.95±
1.79 (m, 2H), 0.94 (d, Jˆ6.6 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 138.8, 137.4, 129.5, 129.3, 128.3, 127.6, 127.5,
114.8, 75.3, 73.0, 36.8, 36.7, 33.7, 16.9; Anal. Calcd for
C16H22O: C, 83.42; H, 9.63; Found: C, 83.58; H, 9.80;
HRCIMS Calcd for C16H23O[M 1H]1 231.1749, found
231.1743.
1
745 cm21; H NMR (CDCl3, 500 MHz): d 7.36±7.26 (m,
5H), 4.52 (s, 1H), 4.50 (s, 1H), 4.33 (m, 0.5H), 4.29 (m,
0.5H), 4.25 (s, 0.5H), 4.21 (s, 0.5H), 3.89 (m, 1H), 3.65 (m,
1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.26 (t, Jˆ7.5 Hz, 0.5H),
3.12 (s, 0.5H), 2.54 (d, Jˆ5.0 Hz, 0.5H), 2.41 (br s, 0.5H),
2.06±1.95 (m, 1.5H), 1.91±1.84 (m, 1.5H), 1.77 (m, 1H),
1.52 (m, 1H), 0.98 (d, Jˆ6.0 Hz, 1.5H), 0.97 (d, Jˆ6.0 Hz,
1.5H); 13C NMR (CDCl3, 75 MHz): d 138.4, 137.8, 128.5,
128.4, 127.8, 127.6, 127.5, 81.8, 80.2, 77.7, 77.2, 75.8, 75.7,
73.6, 73.4, 73.0, 72.6, 64.5, 36.9, 36.2, 32.9, 32.6, 30.8,
30.6, 18.4, 17.2; HRCIMS Calcd for C16H25O4 [M1H]1
281.1753, found 281.1741. 18: Rf 0.55 (ethyl acetate/
4.1.5. (2S,3S,5R)-2-[(R,S)-3-(1-Benzyloxy-2-methyl)]pro-
pyl-3-hydroxy-5-(hydroxy)methyltetrahydrofuran (5)
and (2S,3S,5S)-2-[(R,S)-3-(1-benzyloxy-2-methyl)]pro-
pyl-3-hydroxy-5-(hydroxy)methyltetrahydrofuran (18).
A rt mixture of AD-mix-a (50 g) in tert-butanol (240 mL)
and H2O(240 mL) was stirred until both phases became
clear. Methanesulfonamide (2.27 g, 23.9 mmol) was
added, and the mixture was cooled to 08C. A solution of
(^)-7 (5.5 g, 24 mmol) in tert-butanol (10 mL) was added,
and the reaction mixture was stirred vigorously at 08C for
13 h. Sodium sul®te (,50 g) was added, and the mixture
was warmed to rt and stirred for 30 min. The mixture was
diluted with ethyl acetate (200 mL) and H2O(100 mL), and
the separated aqueous phase was extracted with ethyl
acetate (8£50 mL). The combined organic fractions were
washed with 20% aqueous KOH and saturated aqueous
NaCl (150 mL ea), dried over Na2SO4, ®ltered, and concen-
trated. The crude residue was puri®ed by silica gel column
chromatography (ethyl acetate/methanol, 1:0!20:1, v/v) to
provide a ca. 1.5±1.0:1.0 mixture of (2S,4S,5S,7R,S)-8-O-
benzyl-7-methyl-octan-1,2,4,5,8-pentaol (6) and (2R,4S,
5S,7R,S)-8-O-benzyl-7-methyl-octan-1,2,4,5,8-pentaol (12),
respectively (6.5 g combined, 23 mmol, 96%), as an oil. A
portion of this was used directly in the subsequent reaction.
To a 08C solution of a mixture of 6 and 12 (1.6 g, 5.4 mmol)
in THF (90 mL) under Ar was added KHMDS (11.8 mL of a
0.50 M solution in toluene, 5.9 mmol). After 15 min, the
cooling bath was removed, and the reaction mixture was
maintained at rt for 20 min. The reaction was cooled to
08C, and N-(2,4,6-triisopropylbenzenesulfonyl)imidazole
(2.16 g, 6.44 mmol) in THF (10 mL) was added slowly
via syringe over 1 h. The cooling bath was removed, and
the mixture was stirred at rt for an additional 1.3 h. The
mixture was cooled to 08C, and KHMDS (5.0 mL of a
0.50 M solution in toluene, 2.5 mmol) was added. The
reaction mixture was gradually warmed to rt, and after an
additional 1.6 h, it was again cooled to 08C and another
portion of KHMDS (5.0 mL of a 0.5 M solution in toluene,
2.5 mmol) was added. The reaction mixture was gradually
warmed to rt, and after an additional 1.6 h, it was cooled to
08C and another aliquot of KHMDS (12 mL of a 0.5 M
solution in toluene, 5.9 mmol) was added. The cooling
bath was removed, and the mixture was stirred at rt for an
additional 14 h. Saturated aqueous NH4Cl (15 mL) and
ethyl acetate (50 mL) were added, and the separated
aqueous phase was washed with ethyl acetate (3£50 mL).
The combined organic fractions were washed with H2Oand
saturated aqueous NaCl (75 mL ea), dried over Na2SO4,
®ltered, and concentrated. The residue was puri®ed by silica
1
methanol, 5:1, v/v); H NMR (CDCl3, 300 MHz): d 7.30
(m, 5H), 4.51 (s, 1H), 4.50 (s, 1H), 4.14±3.71 (m, 4H),
3.31±3.31 (m, 3H), 2.30 (m, 1H), 2.03±1.80 (m, 3H), 1.55
(m, 1H), 1.00 (d, Jˆ6.6 Hz, 1.5H), 0.98 (d, Jˆ6.6 Hz,
1.5H).
4.1.6. (2S,4S,5S)-8-O-Benzyl-octan-1,2,4,5,8-pentaol (19)
and (2R,4S,5S)-8-O-benzyl-octan-1,2,4,5,8-pentaol (20).
A rt mixture of AD-mix-a (29.2 g) in tert-butanol
(80 mL) and H2O(90 mL) was stirred until both phases
became clear. Methanesulfonamide (2.0 g, 21 mmol) was
added, and the mixture was cooled to 08C. A solution of
(E)-8-benzyloxy-1,4-octadiene (2.3 g, 10.6 mmol) in tert-
butanol (10 mL) was added, and the reaction mixture was
stirred vigorously at 08C for 7.5 h. Sodium sul®te (,50 g)
was added, and the mixture was warmed to rt and stirred for
30 min. The mixture was diluted with ethyl acetate
(100 mL) and H2O(25 mL), and the separated aqueous
phase was washed with ethyl acetate (8£50 mL). The
combined organic fractions were washed with saturated
aqueous NaCl (150 mL), dried over Na2SO4, ®ltered, and
concentrated. The crude residue was puri®ed by silica
gel column chromatography (ethyl acetate/methanol,
1:0!10:1, v/v) to provide a mixture of tetraols 19 and 20
(ca. 1.5:1.0, 19/20, 2.7 g, 9.5 mmol, 90%) as a white
amorphous solid which was used directly in the subsequent
reaction.
4.1.7. (2S,3S,5R)-2-[3-(1-Benzyloxy)]propyl-3-hydroxy-
5-(hydroxy)methyltetrahydrofuran (21) and (2S,3S,5S)-
2-[3-(1-benzyloxy)]propyl-3-hydroxy-5-(hydroxy)methyl-
tetrahydrofuran (22) using KHMDS and N-(2,4,6-triiso-
propylbenzenesulfonyl)imidazole. To a 08C solution of a
mixture of 19 and 20 (ca. 1.5:1.0, 19:20, 450 mg,
1.58 mmol) in THF (50 mL) under Ar was added KHMDS
(3.4 mL of a 0.50 M solution in toluene, 1.7 mmol). After
15 min, the cooling bath was removed, and the reaction
mixture was maintained at rt for 20 min. The mixture was
cooled to 08C, and a solution of N-(2,4,6-triisopropylbenzene-
sulfonyl)imidazole (584 mg, 1.74 mmol) in THF (4 mL)
was added slowly via syringe over 1.5 h. The cooling bath
was removed, and the mixture was stirred at rt for an addi-
tional 1.3 h. The mixture was re-cooled to 08C, and KHMDS
(3.4 mL of a 0.50 M solution in toluene, 1.7 mmol) was
added. The reaction mixture was gradually warmed to rt,
and after an additional 2 h, it was again cooled to 08C and

A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
1873
another portion of KHMDS (3.4 mL of a 0.5 M solution in
toluene, 1.7 mmol) was added. The cooling bath was
removed, and the mixture was stirred at rt for an additional
3 h. Saturated aqueous NH4Cl (20 mL) and ethyl acetate
(50 mL) were added, and the separated aqueous phase was
washed with ethyl acetate (3£50 mL). The combined
organic fractions were washed with H2Oand saturated
aqueous NaCl (75 mL ea), dried over Na2SO4, ®ltered,
and concentrated. The crude residue was puri®ed by silica
gel column chromatography (hexanes/ethyl acetate/
methanol, 2:1:0!0:1:0!0:10:1, v/v) to provide 21
(109 mg, 0.41 mmol, 26%) and 22 (87 mg, 0.33 mmol,
21%) as colorless oils in 47% combined yield. 21: Rf 0.38
(methanol/CH2Cl2, 1:9, v/v), Rf 0.22 (ethyl acetate/
was puri®ed by silica gel column chromatography (ethyl
acetate !CH2Cl2/methanol, 19:1, v/v) to provide 21
(51 mg, 0.19 mmol, 38%) and 22 (32 mg, 0.12 mmol,
24%) in 62% combined yield, and the corresponding
1,2,4,5-bis-epoxides (10 mg, 40 mmol, 8%).
4.1.9. (2R/S,4S,5S)-8-O-Benzyl-octan-1,2,4,5,8-pentaol-
1-(2,4,6-triisopropylbenzenesulfonate (23). To a stirred
solution of tetraols 19 and 20 (101 mg, 0.356 mmol) in
CH2Cl2 (5.0 mL) at rt was added triethylamine (198 mL,
1.42 mmol), and 2,4,6-triisopropylbenzenesulfonylchloride
(431 mg, 1.42 mmol). After 12 h, further triethylamine
(198 mL, 1.42 mmol) was added. After an additional 12 h,
the reaction mixture was partitioned between saturated
aqueous NaHCO3 (10 mL) and CH2Cl2 (3£15 mL). The
combined organic phases were dried (Na2SO4), ®ltered,
and concentrated in vacuo. Flash chromatography (ethyl
acetate/hexanes, 1:1, v/v) provided 23 as a diastereomeric
mixture (96 mg, 49%). Rf 0.26 (ethyl acetate/hexanes, 1:1,
v/v); IR (thin ®lm): 3404, 2959, 2869, 1600, 1563, 1496,
25
methanol, 10:1, v/v); [a]D ˆ11.4 (c 3.4, CHCl3); IR
(neat): 3401, 2930, 2863, 1495, 1453, 1097 cm21 1H
;
NMR (CDCl3, 500 MHz): d 7.36±7.26 (m, 5H), 4.50 (s,
2H), 4.32 (m, 1H), 4.25 (t, Jˆ3.5 Hz, 1H), 3.79 (ddd,
Jˆ7.5, 7.5, 3.0 Hz, 1H), 3.65 (dd, Jˆ12.0, 3.5 Hz, 1H),
3.56±3.44 (m, 3H), 2.50 (br s, 1H), 2.27 (br s, 1H), 1.98
(ddd, Jˆ13.5, 6.5, 1.0 Hz, 1H), 1.90 (ddd, Jˆ13.5, 9.0,
4.0 Hz, 1H), 1.78 (m, 3H), 1.63 (m, 1H); 13C NMR
(CDCl3, 75 MHz): d 138.3, 128.6, 127.9, 127.8, 82.9,
77.7, 73.2, 73.0, 70.2, 65.0, 36.8, 26.2, 25.6; HRCIMS
Calcd for C15H23O4 [M1H]1 267.1596, found 267.1612.
1
1454, 1425, 1364, 1346, 1274, 1178, 1103, 1010 cm21; H
NMR (CDCl3, 300 MHz): d 7.39±7.28 (m, 5H), 7.20 (s,
2H), 4.53 (s, 2H), 4.25±4.05 (m, 4H), 4.03 (m, 1H), 3.82±
3.66 (m, 1H), 3.58±3.50 (m, 1H), 3.49±3.39 (m, 1H), 3.13
(br s, 3H), 2.93 (septet, Jˆ6.9 Hz, 1H), 1.84±1.46 (m, 6H),
1.27 (d, Jˆ6.6 Hz, 1H); HRFABMS Calcd for C30H47O7S
[M1H]1 551.3043, found 551.3036.
25
22: Rf 0.47 (methanol/CH2Cl2, 1:9, v/v); [a]D ˆ122.2 (c
1.65, CHCl3); IR (thin ®lm): 3374, 2864, 1452, 1454, 1363,
1
1077 cm21; H NMR (CDCl3, 500 MHz): d 7.36±7.28 (m,
5H), 4.52 (s, 2H), 4.16 (dddd, Jˆ9.5, 3.0, 2.5, 2.5 Hz, 1H),
4.07 (dd, Jˆ5.0, 2.5 Hz, 1H), 3.83 (dd, Jˆ12.0, 2.5 Hz, 1H),
3.67 (ddd, Jˆ7.0, 6.5, 3.0 Hz, 1H), 3.53 (t, Jˆ6.0 Hz, 2H),
3.50 (dd, Jˆ11.5, 2.0 Hz, 1H), 2.76 (br s, 2H), 2.36 (ddd,
Jˆ14.5, 9.5, 5.0 Hz, 1H), 1.89 (dd Jˆ14.5, 3.5 Hz, 1H),
1.83±1.65 (m, 4H); 13C NMR (CDCl3, 75 MHz): d 138.4,
128.5, 127.8, 127.7, 84.3, 77.2, 71.5, 70.4, 64.3, 37.2, 26.4,
25.6; HRFABMS Calcd for C15H23O4 [M1H]1 267.1596,
found 267.1612.
4.1.10. Epoxide 24. To a stirred solution of sulfonate 23
(72 mg, 0.13 mmol) in methanol (2.0 mL) was added
K2CO3 (91 mg, 0.66 mmol) at 08C. After 30 min at rt, the
mixture was diluted with H2O(10 mL) and extracted with
CH2Cl2 (4£20 mL). The combined organic phases were
dried (Na2SO4), ®ltered, and concentrated in vacuo. Flash
chromatography (ethyl acetate/hexanes, 3:1, v/v) gave
epoxide 24 (20 mg, 57%). Rf 0.41 (ethyl acetate); IR (thin
®lm): 3422, 3030, 2922, 2862, 1654, 1601, 1560, 1496,
1
1453, 1410, 1364, 1276, 1206, 1099, 1072 cm21; H NMR
4.1.8. Tetrahydrofurans 21 and 22 using potassium
t-butoxide and N-(2,4,6-triisopropylbenzenesulfonyl)-
imidazole. To a solution of tetraols 19 and 20 (ca. 1.5:1,
19/20, 142 mg, 500 mmol) in THF (14 mL) was added
1.1 mL of a 0.50 M solution of potassium tert-butoxide in
tert-butanol/THF (0.55 mmol, 1:1, v/v) that was freshly
prepared using KH and tert-butanol. The resulting solution
was stirred at rt for 1 h. The solution was cooled to 08C and a
solution of N-(2,4,6-triisopropylbenzenesulfonyl)imidazole
(184 mg, 0.55 mmol) in THF (2 mL) was added dropwise
over 1 h. After warming to rt and stirring for 1.5 h, the
mixture was re-cooled to 08C and an additional 1.1 mL of
0.50 M potassium tert-butoxide in tert-butanol/THF
(0.55 mmol, 1:1, v/v) was added. The reaction mixture
was allowed to warm to rt and stir for 1 h before being
re-cooled to 08C. A third aliquot (1.1 mL of 0.50 M solution,
0.55 mmol) of potassium tert-butoxide in tert-butanol/THF
(1:1, v/v) was added and the reaction mixture allowed to
warm to rt and stir for 16 h. At this time, some amount of 19
and 20, as well as the corresponding primary sulfonates
remained in the reaction mixture (TLC). The mixture was
poured into saturated aqueous NH4Cl (20 mL) and extracted
with ethyl acetate (3£50 mL). The combined organic frac-
tion was washed with saturated aqueous NaCl (75 mL),
dried over Na2SO4, ®ltered, and concentrated. The residue
(CDCl3, 300 MHz): d 7.38±7.29 (m, 5H), 4.54 (s, 2H),
3.76±3.63 (m, 1H), 3.60±3.44 (m, 3H), 3.22 (br s, 1H),
3.21±3.11 (mobs, 1H), 2.86 (dd, Jˆ4.8, 4.2 Hz, 0.5H), 2.82
(dd, Jˆ4.8, 4.2 Hz, 0.5H), 2.74 (br s, 0.5H), 2.67 (br s,
0.5H), 2.61 (dd, Jˆ4.8, 2.7 Hz, 0.5H), 2.54 (dd, Jˆ4.8,
2.7 Hz, 0.5H), 2.02±1.87 (m, 1H), 1.85±1.51 (m, 5H); 13C
NMR (CDCl3, 75 MHz) d 138.0, 128.6, 127.9 (2C), 74.0,
73.2, 72.1, 70.5, 50.3, 47.4, 36.3, 31.0, 26.2; HRFABMS
Calcd for C15H23O4 [M1H]1 267.1596, found 267.1610.
4.1.11. Tetrahydrofurans 21 and 22 using epoxide 24. To
a stirred solution of epoxide 24 (44 mg, 0.165 mmol) in
methanol (2.0 mL) was added K2CO3 (228 mg,
1.65 mmol) at 08C. After 2.5 h at rt, the mixture was diluted
with saturated aqueous NH4Cl (5 mL) and extracted with
ethyl acetate (3£15 mL). The combined organic phases
were washed with brine (10 mL), dried (Na2SO4), ®ltered,
and concentrated in vacuo. Flash chromatography (ethyl
acetate/methanol/CH2Cl2, 1:0:0!0:1:19, v/v) gave
a
mixture of tetrahydrofurans 21 and 22 (43 mg, 99%).
4.1.12. Tetrahydrofurans 21 and 22 using 2,4,6-triiso-
propylbenzenesulfonate 23. To a stirred solution of
sulfonate 23. (67 mg, 0.12 mmol) in methanol (1.5 mL)
was added K2CO3 (169 mg, 1.22 mmol) at 08C. After 3 h

1874
A. B. Dounay et al. / Tetrahedron 58 (2002) 1865±1874
and references therein. (b) Narayan, R. S.; Sivakumar, M.;
Bouhlel, E.; Borhan, B. Org. Lett. 2001, 3, 2489±2492.
15. Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9328.
16. Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-
Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933.
17. Dounay, A. B.; Forsyth, C. J. Org. Lett. 2001, 3, 975.
18. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
at rt, the mixture was diluted with H2O(5 mL) and extracted
with CH2Cl2 (4£15 mL). The combined organic phases
were dried (Na2SO4), ®ltered and concentrated in vacuo.
Flash chromatography (methanol/CH2Cl2, 1:32!1:19, v/v)
provided 21 (20 mg, 62%) and 22 (12 mg, 37%).
Acknowledgements
19. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.;
Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57,
2768.
This publication was made possible by grant number
ES10615 from the National Institute of Environmental
Health Sciences (NIEHS), NIH, and generous unrestricted
grant support from Bristol±Myers Squibb (C. J. F.). Its
contents are solely the responsibility of the authors and do
not necessarily represent the of®cial views of the NIEHS,
NIH. A. B. D. gratefully acknowledges graduate fellowships
from the American Chemical Society Divisions of
Medicinal Chemistry (sponsored by Parke±Davis) and
Organic Chemistry (sponsored by Organic Syntheses), and
the University of Minnesota Stanwood Johnston Memorial
Fund. A. S. contributed while on leave from the Department
of Chemistry, Kyoto University, for which we thank
Professor K. Maruoka. We thank Dr V. Young and W.
Brennessel for X-ray analyses and Dr L. Yao for assistance
with NMR experiments (University of Minnesota).
20. Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
21. Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B.
J. Am. Chem. Soc. 1980, 102, 1439.
22. Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
23. Alcohol (^)-8 is commercially available from Aldrich
Chemical Company, Milwaukee, WI, USA. It can also be
synthesized on multi-gram scale using a Barbier±Grignard
addition of allyl magnesium bromide to acrolein: Dreyfuss,
M. P. J. Org. Chem. 1963, 28, 3269.
24. (a) Ireland, R. E.; Wipf, P.; Armstrong III, J. D. J. Org. Chem.
1991, 56, 650. (b) Ireland, R. E.; Thompson, W. J. J. Org.
Chem. 1979, 44, 3041. (c) Ireland, R. E.; Mueller, R. H.;
Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868.
25. Racemic 7 was used because, in this case, the stereochemistry
would be established at later stage via equilibration (see Ref.
17). For the synthesis of non-racemic diene, enantioenriched
allylic alcohol 8 could also be converted to enantioenriched
carboxylic acid via Ireland±Claisen rearrangement with
moderate stereochemical control.
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1
C13 (azaspiracid numbering) methyl doublet in the H NMR
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