A modular synthesis of the bis-tetrahydrofuran core of rolliniastatin from pyranoside precursors

Article abstract of DOI:10.1016/S0040-4020(00)00878-4

The iodoetherification of C6 allyllated 2,3-dideoxypyranosides has been shown to give cis-2,5-disubstituted tetrahydrofurans in high stereoselectivity. This result is applied to a modular synthesis of the bis-THF core of the acetogenin, rolliniastatin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00878-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9203±9211
A Modular Synthesis of the Bis-Tetrahydrofuran Core of
Rolliniastatin from Pyranoside Precursors
*
Zheming Ruan, Darrin Dabideen, Michael Blumenstein and David R. Mootoo
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021, USA
Received 4 August 2000; revised 20 September 2000; accepted 21 September 2000
AbstractÐThe iodoetheri®cation of C6 allyllated 2,3-dideoxypyranosides has been shown to give cis-2,5-disubstituted tetrahydrofurans in
high stereoselectivity. This result is applied to a modular synthesis of the bis-THF core of the acetogenin, rolliniastatin. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
ology to the adjacently linked bis-THF subunits of
the acetogenins is illustrated herein,6a by the synthesis of
the bis-THF core of rolliniastatin 3.9,10
The tetrahydrofuran (THF) containing acetogenins have
attracted attention because of their potent antitumor,
immunosuppressive and pesticidal activities.1 Their
structures are characterized by the presence of 2,5-bishy-
droxyalkyl-THF or 2,20-linked, 5-50-bis(hydroxyalkyl)bis-
THF subunits of variable stereochemistry. A number of
total and formal syntheses have been reported. These pro-
cedures highlight methodologies for stereoselective THF
formation, and strategies for enantioselective synthesis of
THF precursors.2±7 Among the more successful approaches
for THF formation are the cyclization of hydroxy epoxides,3
hydroxy alkenes4 and variations of the Williamson ether
synthesis.5 Protocols based on Sharpless epoxidation and
dihydroxylation,2±4 addition of chiral allenyltin reagents
to aldehydes,5b and elaboration of natural enantiopure
materials,6 have been employed for synthesis of the THF
precursors. We have previously reported that C6 allylated
pyranosides 1 are practical templates for cis-2,5-disubsti-
tuted THF's 2 (Scheme 1).8 The application of this method-
Our synthetic strategy was guided by observations on the
rate- and stereo- controlling effects of the aglycone sub-
stituent in the iodoetheri®cation reaction of C6 allylated
2,3-dideoxypyranosides. Substrates containing more elec-
tronegative aglycone substituents were less reactive than
systems with less electronegative aglycones. Systems with
sterically demanding aglycones showed a preference for the
cis-2,5-disubstituted THF. In particular, trityl glycosides
gave cis:trans stereoselectivities in the range of 8:1 to
20:1. These results were general with respect to the relative
con®guration of the vicinal carbinol centers (erythro or
threo), and the substitution pattern of the alkene (terminal,
and Z or E disubstituted alkenes). t-Butyl glycosides were
less selective but also displayed selectivities as high as 8:1
(Scheme 1).
Accordingly we envisaged a modular approach to the threo-
cis-threo-cis-erythro bis-THF subunit 4 of rolliniastatin.
The bis-THF 4 could be related to a bis-pyranoside-E-
alkene 5 or 6 in which one pyranoside contains a stereo-
directing t-butyl or trityl aglycone and the other a deacti-
vating tri¯uorethyl aglycone (Scheme 2). Regioselective
halocyclization involving the ring oxygen of the more
reactive, t-butyl or trityl pyranoside would give a cis-2,5-
disubstituted THF iodide, and subsequent iodide displace-
ment by the ring oxygen of the second pyranoside would
lead to the bis-THF 4. The key bis-pyranoside may be
assembled in a convergent fashion from allylated pyrano-
sides 7 and 8. In principle pyranoside subunits of variable
complexity and stereochemistry may be incorporated into
the bis-pyranoside precursor, thereby leading to a variety
of bis-THF systems. Furthermore, the stepwise liberation
of the aldehydic carbons would allow for attachment of
Scheme 1.
Keywords: carbohydrates; iodoetheri®cation; tetrahydrofuran; acetogenins.
* Corresponding author. Tel.: 11-212-772-4356; fax: 11-212-772-5332;
e-mail: dmootoo@shiva.hunter.cuny.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00878-4

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Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
Scheme 2.
different side chains to the central bis-THF core, an attrac-
tive feature because of the structural diversity of these
appendages.
the ozonolysis of the t-butyl alkene 18 (Scheme 4). The
tri¯uoroethyl alkene 15 was converted to the phosphonium
salt 7 over four straightforward steps: ozonolysis of the
alkene, reduction of the aldehyde product, iodination of
the resulting alcohol, and phosphonium salt formation.
Unfortunately, the Schlosser variation which is reported to
give high E selectivity with unstabilized ylides, led to poor
E/Z ratios.13 This problem was addressed by carrying out the
conventional Wittig procedure on 7 and 8, to produce the Z
alkene 20 in greater than 95% selectivity (as determined by
NMR analysis), and subsequently performing the two step
Vedejs protocol for stereospeci®c alkene inversion.14The
three step sequence from 7 and 8 to E-alkene 5 proceeded
in 66% overall yield. The stereochemistry of the Z and E
alkenes was established by comparison of the 13C chemical
shifts of the ole®nic carbons. The carbons of the Z isomer
are known to resonate up®eld relative to those of the E
isomer (d: 129.5 and 130.1 vs. 130.0 and 130.7 ppm).15
The trityl bispyranoside derivative was obtained as an
inseparable mixture 6a/b, via selective hydrolysis of the
t-butyl glycoside in 5, followed by silver tri¯ate mediated
tritylation of the resulting lactol.
Results and Discussion
The synthesis of the pyranoside precursors started with the
Ferrier reaction of tri-O-acetyl-d-glucal 9 and t-butanol
or tri¯uoroethanol (Scheme 3).11 The resulting 2,3-eno-
pyranosides 10 and 11 were individually converted to the
hydroxytosylate derivatives 12 and 13 over three straight-
forward operations: hydrogenation, acetate hydrolysis and
selective tosylation of the resulting primary alcohols.
Benzylation of 12 provided 14, which led to alkene 15 on
treatment with allylmagnesium bromide in diethyl ether
containing 10% TMEDA. The t-butyl 2,3-dideoxygluco
tosylate 13 was converted to its galacto epimer 16 via the
Mitsunobu reaction on the alcohol and hydrolysis of
the resulting benzoate.12 Application of the two step
benzylation-allylation sequence on 16 provided the t-butyl
2,3-dideoxy galacto alkene 18.
Our initial plan for the synthesis of the key bis-pyranoside-
E-alkenes 5 called for an E-selective coupling of Wittig
partners. The aldehyde component 8 was obtained from
Iodoetheri®cation of the t-butyl-tri¯uoroethyl bispyranoside
5 in wet dichloromethane with iodonium dicollidine
Scheme 3. (a) CF3CH2OH or t-BuOH, BF3´OEt2, CH2Cl2; (b) (i) H2, Pd/C. EtOAc; (ii) NaOMe, MeOH; (c) TsCl, py.; (d) BnBr, NaH, THF; Bu4Nl;
(e) CH2vCHCH2MgBr, TMEDA, Et2O; (f) (i) Ph3P, DEAD, PhCOOH, PhCH3; (ii) NaOMe, MeOH.

Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
9205
Scheme 4. (a) O3, CH2Cl2±MeOH, then Me2S; (b) NaBH4, MeOH; (c) Ph3P, I2, Imidazole, PhH; (d) Ph3P, CH3CN±PhCH3, (i-Pr)2NEt, 808C; (e) 7,
Na(NSiMe3)2, PhCH3, 2788C then 8; (f) m-CPBA, CH2Cl2, phosphate buffer; (g) Ph2PLi then Mel; (h) THF-HCi (3:1); (i) Ph3CCl, AgOOCF3, collidine,
CH2Cl2, MS.
perchlorate (IDCP) provided an inseparable mixture (ca 6:1)
of the desired cis THF-iodide 21 and a minor product, which
was not identi®able because of considerable overlap of
NMR signals in the mixture (Scheme 5). By comparison
the iodoetheri®cation of the trityl derivatives 6a/b led to
21 exclusively. In view of the relative stereoselectivities of
t-butyl and trityl aglycone substituents in the iodoetheri®-
cation of simpler pyranoside alkenes, it is probable that the
side product in the reaction of 5 is the trans THF isomer of
21. The cis stereochemistry of 21 was tentatively inferred
from the aforementioned stereoselectivity trends, and subse-
quently corroborated by careful NMR analysis of the bis-
THF system (vide infra).
lysis conditions.8b The lactol 23 was next treated with meth-
ylene triphenylphosphorane in THF at 2788C and the
reaction mixture warmed to room temperature. To our
pleasant surprise, these conditions resulted in both ole®na-
tion of the aldehyde and THF formation, leading to the
pseudo symmetrical bis-THF diene 24 in 68% overall
yield. For the eventual synthesis of rolliniastatin, it would
be necessary to use non-identical phosphoranes in order to
access a non-symmetrical bis-THF intermediate. The bis-
THF 24 was however important for stereochemical analysis.
Thus 24 was transformed under standard hydrogenolysis
conditions to the dibutylated bis-hydroxymethyl-bis-THF
diol 25.
Pyranoside-THF-iodoaldehydes like 21 are well suited for
elaboration into adjacently linked bis-THF subunits with
different appendages. In order to evaluate reactions which
could be used towards this goal, the aldehyde 21 was
converted to the alkene 22 by treatment with methylene
triphenylphosphorane at low temperature. Acid hydrolysis
of the glycosidic bond in 22 provided the lactol 23 in
preparation for a second Wittig ole®nation. There was
some concern that the acid hydrolysis conditions could
lead, through an intermediate iodonium ion, to isomeriza-
tion of the cis iodo-THF moiety to the trans-product.
However, we have shown in experiments on closely related
systems that no interconversion occurs when isomeric cis
and trans iodo-THF's are subjected to the identical hydro-
Our stereochemical analysis assumes that the iodoetheri®-
cation reaction proceeds with anti addition to the ole®n,16
and that formation of the second THF ring proceeds with
con®gurational inversion at the iodinated carbon. Thus two
possible bis-THF motifs are possible, er/c/th/c/th or er/tr/th/
tr/th depending on whether the initial iodoetheri®ction gave
the cis or the trans THF. The er/c/th/c/th motif was veri®ed
by comparison of the 13C chemical shifts of carbinol carbons
of the diol 25, and the corresponding carbons in rollinia-
statin 39 (er/c/th/c/th) and bullatacin 2617 (er/tr/th/tr/th)
(Table 1). Speci®c assignments were based on 1H±1H
COSY, HSQC and HMBC experiments and, or comparisons
with previously assigned spectra.18 Identi®cation based on
comparison of the proton data for 25-diacetate, rollinia-
statin triacetate (3-triacetate), and uvaracin diacetate
(27-diacetate), was also attempted using the method of
Hoye.19 However this was not conclusive because of the
similarity in the sums of the differences in chemical shifts
(SuDd 0su) for the oxymethine protons in 25-diacetate
relative to the corresponding protons in 3-triacetate and
27-diacetate (0.09 and 0.16 respectively).
It was also possible to assign the methylene carbons in the
THF rings of 25 by correlating the diagnostic methylenes of
the THF rings (d: 1.78, 1.9 ppm, both m, 4H ea.) to four
carbon resonances at d: 28.9, 28.6, 28.1 and 23.9 ppm. The
most up®eld of these signals does not ®t the assignment in
the original structural analysis of rolliniastatin. In this case
the methylenes were matched with three resonances at d:
28.7, 28.4 and 27.8 (two carbons) ppm.9 However, it should
be noted that these assignments were ambiguous. More
recently, in studies involving both mono- and bis-THF
Scheme 5. (a) IDCP, CH2Cl2±H2O; (b) Ph3PvCH2, THF; (c) BF3´OEt2,
THF-H2O; 9d) H2, Pd/C, MeOH, HCOOH.

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Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
Table 1. NMR correlation of 25 and 25-diacetate with known bis-THF's. (superscripts a, b, c, d, e, and f-assignments in each pair may be interchanged)
Carbon
C NMR of alcohols
H NMR of acetate derivatives
25
3
26
25-Diacetate
3-Triacetate
27-Diacetate
14
15
16
19
20
23
24
25
34.1
74.2
83.1e
81.3f
81.2f
83.3e
72.0
32.7
34.1
74.0
83.0
81.1
81.0
83.0
71.8
32.8
33.3
74.1
83.3
82.5
82.2
82.8
71.3
32.4
4.89a
3.98b
3.83c
3.86c
3.94b
4.92a
4.88
3.96
3.81
3.85
3.92
4.91
4.86
3.98
3.89
3.89
3.98
4.92
SuDduˆ0.09
SuDduˆ0.16
acetogenins, the methylene carbon which is proximal to a
vicinal erythro dioxy subunit has been observed to consist-
ently resonate at 3±4 ppm up®eld compared to the situation
in which a methylene is connected to a threo subunit.18
This trend supports our assignment and suggests that the
assignment of the C22 methylene in rolliniastatin should
be reexamined.
NMR spectra were recorded at 300 and 75.5 MHz respec-
tively, in CDCl3 solutions, with CHCl3 as internal standard.
Elemental analysis were performed by Schwarzkopf Micro-
analysis Laboratory. High resolution mass spectroscopy was
carried out at the Mass Spectral Facilities at PennState and
the University of Illinois at Urbana-Champaign.
Tri¯uoroethyl 4,6-di-O-acetyl-2,3-dideoxy-a-d-gluco-2-
enopyranoside (10). To a solution of tri-O-acetyl-d-glucal
9 (15.0 g, 55.0 mmol) in dry CH2Cl2 (400 mL) was added
CF3CH2OH (11.0 g, 110 mmol) and BF3´Et2O (0.93 mL,
7.3 mmol). The reaction was stirred at rt for 30 min. The
solution was then poured into saturated, aqueous NaHCO3
and the mixture extracted with ether. The organic phase was
dried (Na2SO4), ®ltered and evaporated in vacuo. Flash
chromatography of the residue afforded 10 (15.1 g, 90%).
Conclusion
In summary, the use of C6 allylated 2,3-dideoxypyranosides
as precursors for the modular synthesis of the adjacently
linked, bis-THF subunits of the acetogenins has been
demonstrated. Features of this methodology are the conver-
gent assembly of a bis-pyranoside-alkene THF precursor,
and a highly stereoselective, four step conversion of this
key intermediate to a bis-THF. A pivotal reaction in
this sequence is the iodoetheri®cation reaction of the
bis-pyranoside-alkene to a highly functionalized cis-2,5-
disubstituted THF. In principle, assembly of different
bis-pyranoside alkenes from C6 allylated partners of vary-
ing constitution and complexity would lead to a variety of
bis-THF systems.
1
Rfˆ0.76 (10% ethyl acetate/petroleum ether). H NMR d
2.15 (s, 6H), 4.00 (m, 2H), 4.13 (m, 1H), 4.24 (m, 2H), 5.15
(br s, 1H), 5.38 (dd, Jˆ1.5, 8.5 Hz, 1H), 5.90 (dt, Jˆ1.5,
8.5 Hz, 1H), 5.99 (bd, Jˆ8.5 Hz, 1H). 13C NMR: d 21.1,
21.4, 63.2, 65.5 (q, JCCFˆ34.0 Hz), 65.6, 68.2, 95.1, 124.4
(q, JCFˆ276 Hz), 126.9, 130.9, 170.6, 170.1. MS (ES) m/z
330 (M1NH14 ).
Tri¯uoroethyl 6-O-tosyl-2,3-dideoxy-a-d-gluco-pyrano-
side (12). A mixture of 10 (30.0 g, 0.100 mol) and 10%
Pd/C in ethyl acetate (400 mL) was stirred under a hydrogen
atmosphere (balloon) for 16 h. The suspension was then
®ltered through a short column of Celite and concentrated
in vacuo to give a clear syrup (29.3 g). This material was
dissolved in MeOH (200 mL) and treated with a solution of
NaOMe in MeOH (ca 1 M, 20 mL) for 2 h at rt. The solution
was then adjusted to pH 8 by dropwise addition of 10% HCl/
MeOH, and concentrated under reduced pressure. The
residue was partitioned between ether and saturated aqueous
Experimental
General
TLC was performed on aluminum sheets precoated with
silica gel 60 (HF-254, E. Merck) to a thickness of
0.25 mm. Flash column chromatography was performed
using Kieselgel 60 (230±400 mesh, E. Merck) and
employed a stepwise solvent polarity gradient, correlated
with TLC mobility. Unless otherwise stated, H and 13C
1

Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
9207
NaHCO3. The organic phase was washed with brine, dried
(Na2SO4), ®ltered and concentrated in vacuo. Flash chroma-
tography of the resulting gum provided tri¯uoroethyl 2,3-
dideoxy-a-d-gluco-pyranoside (18 g, 80%). Rfˆ0.20 (50%
NMR: d 23.6, 28.7, 29.7, 31.2, 63.8 (q, JCCFˆ34.4 Hz),
70.7, 71.8, 76.8, 96.7, 114.7, 124.3 (q, JCFˆ280 Hz),
127.8, 127.9, 128.5, 138.4, 138.7. Anal. Calcd for
C18H23O3F3: C, 63.04; H, 7.02. Found: C, 62.78; H, 6.70.
1
ethyl acetate/petroleum ether). H NMR: d 1.75±2.20 (m,
4H), 2.60 (br s, 1H, D2O ex), 2.85 (br s, 1H, D2O ex), 3.60
(m, 1H), 3.72 (m, 1H), 3.80±4.15 (m, 4H), 4.94 (br s, 1H).
t-Butyl 6-O-tosyl-2,3-dideoxy-a-d-galacto-pyranoside (16).
A solution of benzoic acid (3.68 g, 30 mmol) and DEAD
(4.72 mL, 30.0 mmol) in dry toluene (120 mL) was slowly
added, at 2158C, under an atmosphere of argon, to a
mixture of tosylate 1320 (7.38 g, 20.6 mmol) and triphenyl-
phosphine (6.61 g, 24.0 mmol) in dry toluene (120 mL).
The reaction mixture was allowed to warm to rt and stirred
for an additional 0.5 h at this temperature. The solution was
then concentrated under reduced pressure, neutralized by
addition of saturated aqueous NaHCO3, and extracted with
ether. The organic phase was dried (Na2SO4), ®ltered, and
evaporated in vacuo. For characterization purposes, a small
amount of the crude residue was puri®ed by ¯ash chroma-
tography to give 16-benzoate. Rfˆ0.45 (20% ethyl acetate/
petroleum ether). [a]D23ˆ1168 (cˆ0.39, CH2Cl2). IR (neat)
To a stirred solution of material obtained from the previous
step (7.45 g, 32.4 mmol) in dry pyridine (35 mL) was added
p-toluenesulfonyl chloride (8.00 g, 42.1 mmol) at 08C under
a nitrogen atmosphere. The reaction mixture was stirred for
2.5 h at rt. then quenched with MeOH. After concentration
of the solution, the residue was dissolved in ether and
washed with saturated aqueous NaHCO3 and brine. The
ethereal solution was dried (Na2SO4), ®ltered and evapo-
rated under reduced pressure. The crude residue was puri-
®ed by ¯ash chromatography to give product 12 (10.0 g,
84%). Rfˆ0.3 (20% ethyl acetate/petroleum ether).
1
[a]D23ˆ1678 (cˆ0.72, CHCl3). IR (neat) 3530 cm21. H
NMR: d 1.68±1.95 (m, 4H), 2.43 (s, 3H), 2.70 (br s, 1H,
D2O ex), 3.62 (m, 2H), 3.81 (m, 2H), 4.19±4.36 (m, 2H),
4.79 (br s, 1H), 7.34 (d, Jˆ8.0 Hz, 2H), 7.78 (d, Jˆ8.0 Hz,
2H). 13C NMR: d 21.7, 26.7, 28.6, 64.0 (q, JCCFˆ34.6 Hz),
65.3, 69.6, 72.3, 96.9, 123.8 (q, JCFˆ280 Hz), 128.0, 130.0,
132.9, 145.1. Anal. Calcd for C15H19O16SF3: C, 46.87; H,
4.98. Found: C, 46.53; H, 5.10.
1
1720 cm21. H NMR: d 1.23 (s, 9H), 1.40 (m, 1H), 1.80±
2.15 (m, 3H), 2.25 (s, 3H), 3.94±4.07 (m, 2H), 4.41
(dt, Jˆ0.9, 6.5 Hz, 1H), 5.06 (br s, 1H), 5.18 (br s, 1H),
7.12 (d, Jˆ8.1 Hz, 2H), 7.38 (t, Jˆ7.5 Hz, 2H), 7.53
(t, Jˆ7.4 Hz, 1H), 7.66 (d, Jˆ8.3 Hz, 2H), 7.92
(d, Jˆ7.2 Hz, 2H). Anal. Calcd for C24H30O7S: C, 62.32;
H, 6.54. Found: C, 62.04; H, 6.71.
Tri¯uoroethyl 4-O-benzyl-6-O-tosyl-2,3-dideoxy-a-d-
gluco-pyranoside (14). To a solution of 12 (8.90 g,
23.0 mmol) in dry THF (120 mL) at 08C was added NaH
(1.15 g, 60% in mineral oil, 28.8 mmol) and benzyl bromide
(3.14 mL, 26.4 mmol), followed by tetrabutylammonium
iodide (450 mg, 1.2 mmol). The solution was stirred for
2 h at rt under an argon atmosphere. The reaction was
quenched with methanol (0.5 mL), and extracted with
ether. The organic extract was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The crude product
was puri®ed by ¯ash chromatography to give 14 (9.3 g,
82%). Rfˆ0.20 (10% ethyl acetate/petroleum ether).
[a]2D3ˆ176.68 (cˆ2.74, CHCl3). 1H NMR: d 1.84 (m, 2H),
2.05 (m, 1H), 2.18 (m, 1H), 2.54 (s, 3H), 3.52 (dt, Jˆ4.6,
11.1 Hz, 1H), 3.85±4.00 (m, 3H), 4.33 (dd, Jˆ2.1, 10.6 Hz,
1H), 4.42 (dd, Jˆ4.7, 10.6 Hz, 1H), 4.58 (ABq,
Ddˆ63.5 Hz, Jˆ11.3 Hz, 2H), 4.92 (br s, 1H), 7.34±7.52
(m, 7H), 7.90 (d, Jˆ9.3 Hz, 1H). Anal. Calcd for
C22H25O6SF3: C, 55.69; H, 5.31. Found: C, 55.64; H, 5.46.
1 M NaOMe in MeOH (20 mL) was added to a mixture of
the crude material from the previous step in MeOH
(200 mL). The solution was stirred at rt for 2 h, then
adjusted to pH 8 by the dropwise addition of 10% HCl/
MeOH, and concentrated under reduced pressure. The
residue was diluted with brine and extracted with ether.
The organic phase was dried (Na2SO4), ®ltered and evapo-
rated in vacuo. Puri®cation of the residue by ¯ash chroma-
tography provided 16 (5.4 g, 73% from 13) as a light yellow
oil. Rfˆ0.85 (20% ethyl acetate/petroleum ether).
[a]2D3ˆ1398 (cˆ0.29, CH2Cl2). IR (neat) 3533,
1
1598 cm21. H NMR: d 1.19 (s, 9H), 1.38 (m, 1H), 1.68
(m, 1H), 1.98 (d, Jˆ8.0 Hz, D2O ex), 2.10 (m, 2H), 2.44
(s, 3H), 3.92 (dd, Jˆ6.8, 10.2 Hz, 1H), 4.11 (dd, Jˆ5.9,
10.2 Hz, 1H), 4.20 (t, Jˆ6.8 Hz, 1H), 5.08 (br s, 1H), 7.32
(d, Jˆ8.1 Hz, 2H), 7.77 (d, Jˆ8.1 Hz, 2H). 13C NMR: d
21.7, 25.2, 28.6, 28.8, 64.3, 67.9, 69.7, 74.6, 91.3, 128.1,
129.9, 132.9, 144.9. Anal. Calcd for C17H26O6S: C, 56.96;
H, 7.31. Found: C, 56.65; H, 7.42.
Tri¯uoroethyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-d-
gluco-non-8-enopyranoside (15). Allylmagnesium bro-
mide (90 mL of a 1 M solution in ether, 90 mmol) was
added to a mixture of 14 (7.80 g, 16.5 mmol), TMEDA
(0.85 mL) and dry ether (85 mL), at rt under an atmosphere
of argon. The reaction was stirred for 8 h, then quenched
with saturated aqueous NH4Cl and extracted with ether. The
organic extract was dried (Na2SO4), ®ltered and evaporated
under reduced pressure. Flash chromatography of the crude
residue afforded 15 (5.50 g, 98%). Rfˆ0.30 (10% ethyl
t-butyl 4-O-Benzyl-6-O-tosyl-2,3-dideoxy-a-d-galacto-
pyranoside (17). To a solution of 16 (5.39 g, 15.2 mmol)
in dry THF (50 mL) at 08C was added NaH (1.20 g, 60% in
mineral oil, 30.0 mmol), tetrabutylammonium iodide
(830 mg, 22.5 mmol), and benzyl bromide (2.8 mL,
26 mmol). The reaction mixture was warmed to rt, stirred
for an additional 2 h, then quenched by the addition of
methanol (1 mL), diluted with water and extracted with
ether. The organic phase was washed with brine, dried
(Na2SO4), ®ltered and concentrated in vacuo. The residue
was puri®ed by ¯ash chromatograpy to give 17 (4.83 g,
71%). Rfˆ0.75 (20% ethyl acetate/petroleum ether).
1
acetate/petroleum ether): IR (neat) 1641 cm21. H NMR:
d 1.65 (m, 1H), 1.90 (m, 2H), 2.05±2.50 (m, 5H), 3.30
(dt, Jˆ5.5, 11.0 Hz 1H), 3.78 (dt, Jˆ2.7, 9.0 Hz, 1H), 4.0
(m, 2H), 4.70 (ABq, Ddˆ0.20 ppm, Jˆ12.0 Hz, 2H), 4.97
(br s, 1H), 5.15 (m, 2H), 5.98 (m, 1H), 7.50 (m, 5H). 13C
1
[a]2D3ˆ1258 (cˆ0.32, CHCl3). H NMR: d 1.32 (s, 9H),
1.45 (m, 1H), 1.90±2.15 (m, 3H), 2.52 (s, 3H), 3.59 (br s,

9208
Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
1H), 4.21 (m, 2H), 4.29 (br t, Jˆ5.6 Hz, 1H), 4.54 (ABq,
Ddˆ0.27 ppm, Jˆ12.0 Hz, 2H), 5.22 (d, Jˆ2.6 Hz, 1H),
7.38 (m, 7H), 7.85 (d, Jˆ8.3 Hz, 2H). 13C NMR: d 20.4,
21.7, 25.7, 28.7, 68.1, 69.9, 70.7, 74.4, 91.3, 127.7, 127.8,
128.0, 128.4, 129.9, 133.0, 138.3, 144.8. Anal. Calcd for
C24H32O6S: C, 64.26; H, 7.19. Found: C, 64.32; H, 7.35.
of the residue afforded the iodide derivative (7.54 g, 85%).
Rfˆ0.60 (20% ethyl acetate/petroleum ether). [a]2D3ˆ1618
1
(cˆ0.68, CH2Cl2). H NMR: d 1.59±2.15 (m, 8H), 3.25
(m, 3H), 3.66 (m, 1H), 3.97 (m, 2H), 4.63 (m, 2H), 4.88
(br s, 1H), 7.30±7.50 (m, 5H). 13C NMR d 7.0, 23.5, 28.6,
29.6, 33.0, 63.9 (q, JCCFˆ35.0 Hz), 70.7, 71.7, 76.4, 96.80,
122.6 (q, JCFˆ278 Hz), 127.9, 128.5, 128.7, 138.3. HRMS
calcd for C17H22O3F3I 458.0589, found 458.0545.
t-Butyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-d-galacto-non-
8-enopyranoside (18). Tosylate 17 (4.47 g, 9.98 mmol) was
subjected to the allylation procedure used for the prepara-
tion of alkene 15. Flash chromatography of the crude
product provided alkene 18 (2.66 g, 84%). Rfˆ0.44 (10%
Diisopropylethylamine (0.7 mL, 3.8 mmol) was added to a
mixture of the iodide from the previous step (1.16 g,
2.53 mmol) and triphenylphosphine (1.33 g, 5.06 mmol) in
anhydrous toluene (40 mL) and acetonitrile (20 mL). The
reaction mixture was heated at re¯ux under an atmosphere
of argon for 24 h, at which time most of the solvent was
removed under reduced pressure. The resulting syrup
was triturated with hexane (2£25 mL) and the residual
gum was subjected to ¯ash chromatography to give the
phosphonium salt 7 (1.59 g, 87%) as a pale yellow gum.
1
ethyl acetate/petroleum ether). IR (neat) 1651 cm21. H
NMR: d 1.24 (s, 9H), 1.20±2.20 (m, 8H), 3.34 (br s, 1H),
3.91(m, 1H), 4.55 (ABq, Ddˆ0.28 ppm, Jˆ12.0 Hz, 2H),
4.94 (m, 2H), 5.16 (br s, 1H), 5.80 (m, 1H), 7.24±7.38
(m, 5H). 13C NMR: d 21.2, 26.1, 28.9, 30.0, 31.0, 69.8,
70.6, 72.7, 73.9, 91.2, 114.4, 127.5, 127.9, 128.4, 138.9,
139.0. Anal. Calcd for C20H30O3: C, 75.43; H, 9.50.
Found: C, 75.04; H, 9.62.
1
Rfˆ0.34 (10% MeOH/ethyl acetate). H NMR: d 1.40±
2.20 (m, 8H), 3.25 (m, 1H), 3.45 (m, 2H), 3.63 (m, 2H),
4.55 (ABq, Ddˆ46.9 Hz, Jˆ11.4 Hz, 2H), 4.79 (br s, 1H),
7.20±7.90 (m, 20H). 13C NMR d 19.2, 23.3, 23.4 (d, JCPˆ
Tri¯uoroethyl 4-O-Benzyl -2,3,6,7-tetradeoxy-a-d-gluco-
octopyranoside (19). A stream of O3 in O2 was bubbled
through a solution of alkene 15 (7.80 g, 22.7 mmol) in 4:1
CH2Cl2:MeOH (250 mL) at 2788C, until 15 was not detect-
able by tlc (10% ethyl acetate/petroleum ether). The mixture
was ¯ushed with N2 and then triphenylphosphine (6.60 g,
25.0 mmol) was added. The solution was warmed to rt,
stirred for 2 h, and concentrated in vacuo to give a slurry,
which was used directly in the next step. For characteriza-
tion purpose, a sample of the aldehyde product was puri®ed
by ¯ash chromatography: Rfˆ0.33 (20% ethyl acetate/
petroleum ether). [a]2D3ˆ11288 (cˆ0.38, CH2Cl2); IR
50.5 Hz), 28.2, 32.4 (d, JCCPˆ16.0 Hz), 64.2 (q, JCCF
ˆ
35.3 Hz), 70.7, 72.1, 76.3, 96.7, 118.1 (d, JCPˆ86.4 Hz),
122.6 (q, JCFˆ278 Hz, partially buried under aromatic
carbons), 127.6, 127.9, 128.4, 130.5 (d, JCCPˆ12.5 Hz),
133.6 (d, JCCCPˆ9.9 Hz), 135.0. MS (FAB), m/z 593
[(M2I)1, 100%].
t-Butyl pyranoside aldehyde (8). Alkene 18 (555 mg,
1.75 mmol) was subjected to the ozonolysis procedure
described in the preparation of 19. Flash chromatography
of the crude product provided aldehyde 8 (447 mg, 80%).
1
(neat) 2943, 1715 cm21. H NMR: d 1.85 (m, 3H), 2.12
1
(m, 2H), 2.40 (m, 1H), 2.60 (t, Jˆ6.1 Hz, 2H), 3.30
(m, 1H), 3.72 (dt, Jˆ2.6, 9.1 Hz, 1H), 3.95 (m, 2H), 4.67
(ABq, Ddˆ58.2 Hz, Jˆ11.7 Hz, 2H), 4.91 (s, 1H), 7.46
(m, 5H), 9.84 (s, 1H).
Rfˆ0.51 (20% ethyl acetate/petroleum ether). H NMR: d
1.22 (s, 9H), 1.27 (m, 1H), 1.75 (m, 1H), 2.05 (m, 4H), 2.48
(m, 2H), 3.38 (br s, 1H), 3.97 (dd, Jˆ5.2, 6.1 Hz, 1H), 4.55
(ABq, Ddˆ85.6 Hz, Jˆ12.0 Hz, 2H), 5.19 (br s, 1H), 7.31±
7.40 (m, 5H), 9.76 (s, 1H). 13C NMR d 21.5, 24.9, 26.5,
29.5, 40.9, 70.0, 71.3, 73.5, 74.5, 91.9, 128.3, 128.6, 129.0,
139.2, 203.2.
NaBH4 (5.63 mmol, 213 mg) was added at rt to a solution of
the crude mixture from the previous step in EtOH (100 mL).
The reaction mixture was stirred for 1 h, carefully treated
with 10% HCl in MeOH until the pH was 8, and evaporated
under reduced pressure. Flash chromatography of the
residue provided alcohol 19 (6.79 g, 87% from 15).
Rfˆ0.12 (20% ethyl acetate/petroleum ether). [a]2D3ˆ1978
(cˆ0.34, CH2Cl2). IR (neat) 3401 cm21. 1H NMR: d 1.53±
2.2 (m, 8H), 3.30 (dt, Jˆ4.4, 9.7 Hz, 1H), 3.75 (m, 3H), 4.06
(m, 2H), 4.67 (ABq, Ddˆ55.9 Hz, Jˆ11.4 Hz, 2H), 4.96
(s, 1H), 7.32±7.50 (m, 5H). 13C NMR: d 23.5, 28.3, 28.7,
63.0, 63.9 (q, JCCFˆ34.7 Hz), 70.8, 72.3, 76.6, 96.8, 122.7
(q, JCFˆ277 Hz), 127.8, 127.9, 128.5, 138.3. Anal. Calcd for
C17H23O4F3: C, 58.61; H, 6.65. Found: C, 58.41; H, 6.79.
t-Butyl-tri¯uoroethyl bispyranoside Z-alkene (20). Sodium
bis(trimethylsilyl) amide (1.38 mL of a 1 M solution in
toluene, 1.38 mmol) was added under an argon atmosphere,
at 08C, to solution of phosphonium salt 7 (1.18 g,
1.65 mmol) in dry toluene (25 mL). The yellow-orange
suspension was stirred for 1 h at rt then cooled to 2788C,
at which time a solution of aldehyde 8 (0.44 g, 1.38 mmol)
in dry toluene (20 mL) was added dropwise, over 30 min.
After an additional 15 min, the reaction mixture was
warmed to rt and diluted with ether (100 mL). The mixture
was ®ltered through Celite and the ®ltrate was concentrated
in vacuo. Flash chromatography of the residue afforded 20
(732 mg, 84%). Rfˆ0.55 (10% ethyl acetate/petroleum
Tri¯uoroethyl pyranoside-phosphonium salt (7). Iodine
(5.68 g, 22.4 mmol) was added to a mixture of alcohol
19 (6.75 g, 19.5 mmol), triphenylphosphine (7.65 g,
29.2 mmol) and imidazole (2.78 g, 40.8 mmol) in dry
benzene (200 mL). The reaction mixture was heated at
re¯ux for 1 h under an atmosphere of argon, then diluted
with ether and washed with 10% aqueous Na2S2O3, and
brine. The organic layer was dried (Na2SO4), ®ltered and
evaporated under reduced pressure. Flash chromatography
1
ether). H NMR: d 1.27 (s, 9H), 1.30±2.28 (m, 16H), 3.19
(dt, Jˆ3.8, 9.6 Hz, 1H), 3.37 (br s, 1H), 3.63 (dt, Jˆ1.3,
8.8 Hz, 1H), 3.75±4.00 (m, 3H), 4.58 (ABq, Ddˆ77.7 Hz,
Jˆ12.6 Hz, 2H), 4.60 (ABq, Ddˆ51.9 Hz, Jˆ11.7 Hz, 2H),
4.67 (br s, 1H), 5.19 (br s, 1H), 5.42 (m, 2H), 7.28±7.42
(m, 10H). 13C NMR: d 21.2, 23.2, 23.7, 26.1, 28.7, 28.9,
31.6, 31.9, 63.7 (q, JCCFˆ34.5 Hz), 69.9, 70.7, 70.8, 72.0,
72.9, 73.9, 76.8, 91.2, 96.6, 124.2 (q, JCFˆ278 Hz), 127.5,

Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
9209
127.8, 128.1, 128.3, 128.5, 129.5, 130.1, 138.4, 139.0. Anal.
Calcd for C36H49O6F3: C, 68.11; H, 7.78. Found: C, 67.85;
H, 7.84.
(q, JCCFˆ34.0 Hz), 69.9, 71.8, 71.9, 73.0, 73.6, 74.4, 77.8,
92.6, 99.5, 97.8, 97.9, 128.6±131.40 (multiple signals),
139.4, 139.7, 146.2.
t-Butyl-tri¯uoroethyl bispyranoside E-alkene (5). m-CPBA
(784 mg, 50% w/w, 2.5 mmol) was mixed with 4 M
NaH2PO4/Na2HPO4 buffer (40 mL) and CH2Cl2 (20 mL).
The suspension was added to a solution of 20 (635 mg,
0.998 mmol) in CH2Cl2 (20 mL). The reaction mixture
was stirred at rt for 1 h. The organic layer was separated,
washed successively with saturated, aqueous NaHCO3, 10%
aqueous Na2S2O3, and brine, dried (Na2SO4), and concen-
trated in vacuo. Flash chromatography of the residue
afforded the epoxide derivative (650 mg, 100%). Rfˆ0.45
(20% ethyl acetate/petroleum ether). 1H NMR: d 1.24
(s, 9H), 1.20±2.20 (m, 16H), 2.98 (m, 2H), 3.20 (m, 1H),
3.39 (br s, 1H), 3.60 (m, 1H), 3.79±4.07 (m, 3H), 4.40±4.75
(m, 4H), 4.86 (br s, 1H), 5.20 (br s, 1H), 7.28±7.42 (m, 10H).
A portion of the mixture obtained in the previous step
(137 mg, 0.236 mmol), trityl chloride (130 mg, 0.472
mmol), collidine (0.1 mL, 1 mmol), and freshly activated,
powdered 4A molecular sieves (100 mg), in anhydrous
CH2Cl2 (10 mL), was stirred at rt for 10 min. At that time
AgOCOCF3 (181 mg, 0.7 mmol) was added to the reaction
mixture and stirring was continued for an additional 4 h.
The reaction mixture was then poured into saturated
aqueous Na2S2O3, and extracted with ether. The organic
phase was dried (Na2SO4), ®ltered and evaporated in
vacuo. Flash chromatography of the residual gum afforded
6a/b (116 mg, 60%) as an inseparable mixture of anomers.
1
Rfˆ0.82 (20% ethyl acetate/petroleum ether). H NMR: d
1.00±2.40 (m, 16H,), 2.96 (m, ca 0.7H), 3.08 (br s, ca 0.7H),
3.22 (m, 1H), 3.42 (br s, ca 0.3H), 3.64 (m, 1H), 3.75±4.05
(m, ca 2.3H), 4.46 (m, ca 2.7H), 4.68 (m, 2H), 4.88 (br s,
1H) 5.24 (br s, ca 0.3H), 5.33 (br s, 2H), 7.20±7.67 (m, 25H);
a/b:ca 3:7 (based on the relative ratio of H4 singlets at 3.42
and 3.08). 13C NMR d 22.6, 24.2, 24.7, 26.4, 26.9, 27. 9,
29.8, 30.8, 31.9, 64.8 (q, JCCFˆ34.0 Hz), 71. 9, 72.1, 72.3,
73.1, 73.2, 77.9, 77.9, 78.3, 78.9, 88.3, 89.0, 94.0, 97.7,
99.3, 128.00±131.0 (multiple signals), 139.6, 139.9,
146.1. MS [CI(NH3)] m/z: 838 (M1NH4)1, 821 (M1H)1.
A stock solution (ca 0.5 M) of Ph2PLi was prepared by the
addition of a hexane solution of n-butyllithium (10.2 mmol,
6.6 mL of a 1.55 M) to a solution of Ph2PH (1.74 mL,
10.0 mmol) in dry THF (13.4 mL) at rt under an argon atmo-
sphere. The solution was stirred for 1 h at which time an
aliquot of the red solution of Ph2PLi (6.0 mL, 3.0 mmol)
was removed and added under an atmosphere of argon, to
a THF (10 mL) solution of the product from the previous
step (650 mg, 1.00 mmol). The reaction mixture was stirred
for an additional 2 h and then treated with freshly distilled
MeI (0.374 mL, 6.0 mmol). The mixture was stirred for
another 1 h, and n-butyllithium (,0.1 mL) was added
until a red color persisted. The reaction mixture was diluted
with ether (30 mL), ®ltered through Celite. The ®ltrate was
concentrated in vacuo and the residue was subjected to ¯ash
chromagraphy to give 5 (496 mg, 78%). Rfˆ0.54 (20%
THF-iodide (21). A mixture of trityl-E-tri¯uororethyl
alkenes 6a/b (600 mg, 0.75 mmol), CH2Cl2 (20 mL),
water (0.5 mL) and IDCP (540 mg, 1.15 mmol) was stirred
at rt for 20 min. The mixture was then poured into saturated,
aqueous Na2S2O3, and extracted with ether. The organic
phase was dried (Na2SO4), ®ltered and evaporated in
vacuo. Flash chromatography of the residue afforded cis-
THF-iodide 21 (406 mg, 79%). Rfˆ0.35 (2% ether/
1
ethyl acetate/petroleum ether). H NMR: d 1.27 (s, 9H),
1.20±2.23 (m, 16H), 3.19 (dt, Jˆ4.3, 9.9 Hz, 1H), 3.37
(br s, 1H), 3.63 (t, Jˆ8.2 Hz, 1H), 3.75±4.00 (m, 3H),
4.58 (ABq, Ddˆ77.7 Hz, Jˆ12.6 Hz, 2H), 4.60 (ABq,
Ddˆ51.9 Hz, Jˆ11.7 Hz, 2H), 4.67 (br s, 1H), 5.21 (br s,
1H), 5.39 (m, 2H), 7.28±7.42 (m, 10H). 13C NMR d 21.2,
23.6, 26.1, 28.6, 28.7, 28.9, 31.6, 32.0, 63.7
(q, JCCFˆ35.6 Hz), 69.9, 70.7, 70.8, 71.9, 72.9, 73.9, 76.8,
91.2, 96.6, 124.0 (q, JCFˆ278 Hz), 127.5, 127.8, 127.9,
128.3, 128.5, 130.0, 130.7, 138.4, 139.0. Anal. Calcd for
C36H49O6F3: C, 68.11; H, 7.78. Found: C, 68.00; H, 7.78.
1
CH2Cl2). IR (neat) 1723 cm21. H NMR (C6D6): d 1.04±
2.04 (m, 16H), 2.90 (m, 1H), 3.06 (m, 1H), 3.32 (m, 1H),
3.45±3.70 (m, 4H), 3.87 (m, 1H), 4.20±4.43 (m, 3H,), 4.38
(ABq, Ddˆ0.48 ppm, Jˆ11.8 Hz, 2H), 6.95±7.40 (m, 10H),
9.25 (s, 1H). 13C NMR (C6D6): d 23.4, 23.9, 27.3, 28.3, 31.6,
31.7, 32.2, 39.8, 42.5, 63.6 (q, JCCFˆ34.0 Hz), 70.2,
71.7, 72.8, 76.1, 80.2, 82.8, 83.6, 96.7, 127.0±129.0
(several signals buried under C6D6 triplet), 138.8, 139.2,
200.2. MS (FAB) m/z 703 [(M2H)1, 30%], 605
[(M2CF3CH2O)1, 45%], 577 [(M2I)1, 15%], 497 [(M2
CF3CH2O2C6H5CH2O)1, 100%). MS (ES) m/z 722
(M1NH14 ).
Trityl tri¯uoroethyl bispyranoside E-alkene (6a/b). A
solution of t-butyl tri¯uoroethyl bispyranoside E-alkene 5
(140 mg, 0.22 mmol) in a 3:1 mixture of THF-0.5M HCl
(12 mL) was stirred at rt for 4 h. The solution was then
poured into saturated, aqueous NaHCO3 and the mixture
was extracted with ether. The organic phase was dried
(Na2SO4), ®ltered and evaporated in vacuo. Flash chroma-
tography of the residue afforded the tri¯uoroethyl- pyranose
derivative (90 mg, 70%). Rfˆ0.15 (20% ethyl acetate/
Iodocyclization of t-butyl-E-alkene (5). t-butyl alkene 5
(496 mg, 0.782 mmol) was subjected to the iodoetheri®ca-
tion procedure that was described for the reaction of 6a/b,
using IDCP (549 mg, 1.17 mmol). Flash chromatography of
the crude product afforded an inseparable mixture (406 mg)
of cis-THF-iodide 21 and an unidenti®ed minor component.
The estimated ratio of products based on NMR signal ratio
was 6:1.
1
petroleum ether). H NMR: d 1.2±2.4 (m, 16H), 2.84 (br
s, 1H, D2O ex.), 3.24 (m, 1H), 3.37 (br s, ca 0.5H), 3.45 (br s,
ca 0.5H), 3.56 (m, ca 0.5H), 3.65 (m, 1H), 3.80±4.32
(m, 2H), 4.22 (m, ca 0.5H), 4.56 (m, 2H), 4.78 (m, ca
2.5H), 4.96 (br s, 1H), 5.40 (br s, H1 0.5H), 5.50 (br s,
2H), 7.08±7.52 (m, 10H). 13C NMR d 21.7, 24.0, 24.4,
24.6, 25.6, 26.5, 28.6, 29.7, 31.6, 32.3, 33.1, 33.4, 65.0
Iodo-alkene (22). A solution of methylenetriphenyl phos-
phorane was prepared by addition of n-BuLi (1.23 mL of
1.55 M solution in hexane, 1.91 mmol) to a suspension of
methyltriphenylphosphonium bromide (760 mg, 2.1 mmol)

9210
Z. Ruan et al. / Tetrahedron 56 (2000) 9203±9211
in dry THF (5 mL), at 08C, under an atmosphere of argon.
The mixture was stirred at this temperature for 1 h, then
cooled to 2788C, at which time a solution of 21 (270 mg,
0.383 mmol) in dry THF (5 mL) was slowly introduced. The
solution was allowed to warm to rt, stirred for an additional
10 min, and then diluted with ether. The resulting suspen-
sion was ®ltered through a short column of Celite, and the
®ltrate was concentrated in vacuo. Flash chromatography of
the residue gave 22 (205 mg, 76%). Rfˆ0.41 (10% ethyl
MeOH (4 mL) was stirred under hydrogen (balloon) for
16 h. The suspension was then ®ltered through Celite and
the ®ltrate was evaporated in vacuo. Flash chromatography
of the residue provided 25 (20 mg, 70%). Rfˆ0.25 (50%
ethyl acetate/petroleum ether). 1H NMR:
d
0.89
(t, Jˆ7.5 Hz, 6H), 1.20±1.60 (m, 12H), 1.72±1.98
(m, 8H), 2.94 (br s, 2H, D2O ex), 3.41 (m, 1H), 3.86 (m,
5H). 13C NMR: d 14.2, 22.9, 23.9, 28.1, 28.4, 28.6, 28.9,
32.7, 34.1, 72.0, 74.2, 81.2, 81.3, 83.1, 83.3. FABHRMS for
C18H34O4 314.2506, found 314.2435.
1
acetate/petroleum ether). H NMR (C6D6): d 1.00±2.35
(m, 16H), 2.89 (m, 1H), 3.18 (m, 1H), 3.34 (m, 1H),
3.45±3.86 (m, 4H), 3.95 (m, 1H), 4.23 (ABq,
Ddˆ0.22 ppm, Jˆ11.7 Hz, 2H), 4.35 (br s, 1H), 4.58
(ABq, Ddˆ0.30 ppm, Jˆ11.7 Hz, 2H), 4.94 (m, 2H), 5.70
(m, 1H), 6.80±7.70 (m, 10H). 13C NMR (C6D6): d 23.8,
27.7, 28.8, 30.3, 31.2, 32.1, 32.2, 32.7, 43.1, 63.9
(q, JCCFˆ33.5 Hz), 70.6, 72.2, 73.3, 76.5, 81.1, 83.2, 84.1,
97.1, 115.0, 128.6, 128.7, 128.90, 139.1, 139.3.
25-Diacetate. A mixture of diol 24 (5 mg), Ac2O (0.05 mL)
and DMAP (2 mg) in ethyl acetate (2 mL) was stirred at rt
for 20 min. Methanol (0.05 mL) was then added to the solu-
tion, and the mixture was concentrated under reduced
presure. Flash chromatography of the residue provided 25-
diacetate (20 mg, 70%). Rfˆ0.40 (20% ethyl acetate/petro-
1
leum ether). H NMR (500 MHz): 0.88 (t, Jˆ7.5 Hz, 6H),
1.20±1.40 (m, 12H), 1.55±1.90 (m, 8H), 2.05, 2.07 (both s,
3H ea), 3.83 (m, 1H), 3.86 (q, Jˆ6.5 Hz, 1H), 3.94
(q, Jˆ6.0 Hz, 1H), 3.98 (dt, Jˆ6.5 Hz, 1H), 4.89 (m, 1H),
4.92 (m, 1H).
c/th/c Bis-THF diene (24). To a solution of alkene 22
(160 mg, 0.228 mmol) in a 10:1 mixture of THF/H2O was
added BF3.Et2O (120 mL). The mixture was stirred at rt for
5 h, at which time an additional portion of BF3´Et2O
(120 mL) was introduced, and stirring continued for 2 d.
The solution was then poured into saturated, aqueous
NaHCO3 and the mixture extracted with ether. The organic
phase was dried (Na2SO4), ®ltered and evaporated in vacuo.
Flash chromatography of the residue afforded the lactol 23
(119 mg, 80%) as an a/b mixture of anomers: Rfˆ0.17
Acknowledgements
We thank the National Institutes of Health (NIH), General
Medical Sciences (GM 57865) for their support of this
research. `Research Centers in Minority Institutions'
award RR-03037 from the National Center for Research
Resources of the NIH, which supports the infrastructure
{and instrumentation} of the Chemistry Department at
Hunter, is also acknowledged. The contents are solely the
responsibility of the authors and do not necessarily represent
the of®cial views of the NCRR/NIH. We are also grateful to
Professors U. Koert and J. L. McLaughlin for their helpful
discussions.
1
(20% ethyl acetate/petroleum ether). H NMR (C6D6): d
1.0±2.3 (m, 16H), 2.38 (br s, 1H, D2O ex), 2.58 (br d,
Jˆ6.0 Hz, 1H, D2O ex), 2.93 (m, 1H), 3.20 (m, 2H), 3.75
(m, 2H), 4.04 (m, 1H), 4.01±5.05 (m, 7H), 5.70 (m, 1H),
6.90±7.50 (m, 10H).
A solution of methylenetriphenylphosphorane was prepared
by addition of n-BuLi (1.55 mL of 1.55 M solution in
hexane, 2.40 mmol) to a suspension of methyltriphenyl-
phosphonium bromide (942 mg, 2.64 mmol) in dry THF
(10 mL) at 08C, under an atmosphere of argon. The mixture
was stirred at this temperature for 1 h, then cooled to
2788C, at which time a solution of 23 (155 mg,
0.24 mmol) in dry THF (5 mL) was slowly introduced.
After 10 min, the solution was warmed to rt, stirred for an
additional 1 h, and then diluted with ether. The resulting
suspension was ®ltered through a short column of Celite,
and the ®ltrate concentrated in vacuo. Flash chroma-
tography of the residue gave 24 (83 mg, 68%). Rfˆ0.65
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1H NMR (C6D6): d 1.40±1.87 (m, 12H), 2.15±2.28 (m, 4H),
3.37 (q, Jˆ6.0 Hz, 1H), 3.57 (m, 1H), 3.72±3.92 (m, 4H),
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Á
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