1,2-O-Isopropylidene-5-alkene templates for the synthesis of oligo-tetrahydrofurans

Article abstract of DOI:10.1016/S0040-4020(02)00075-3

The highly functionalized THF 4 was prepared in eight steps from 2,5-cyclooctadiene. The key step in this synthesis was a novel desymmetrization reaction involving the iodoetherification of the C2 symmetric bis-isopropylidene alkene 6 to THF 4. The versatility of 4 was demonstrated by its conversion to bis-THF 3, a known precursor for trilobacin, and to the tris-THF-lactone 5, a potential relay compound for cyclic polyether analogues.

Full text of DOI:10.1016/S0040-4020(02)00075-3

TETRAHEDRON
Pergamon
Tetrahedron 58 02002) 2077±2084
1,2-O-Isopropylidene-5-alkene templates for the synthesis
of oligo-tetrahydrofurans
Darrin Dabideen, Zheming Ruan and David R. Mootoop
Department of Chemistry, Hunter College/CUNY, 695 Park Avenue, NewYork, NY 10021, USA
Received 21 September 2001; accepted 14 January 2002
AbstractÐThe highly functionalized THF 4 was prepared in eight steps from 2,5-cyclooctadiene. The key step in this synthesis was a novel
desymmetrization reaction involving the iodoetheri®cation of the C2 symmetric bis-isopropylidene alkene 6 to THF 4. The versatility of 4
was demonstrated by its conversion to bis-THF 3, a known precursor for trilobacin, and to the tris-THF-lactone 5, a potential relay compound
for cyclic polyether analogues. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Discussion
Bis-acetonide THF 4, by virtue of its alcohol substitution
pattern and different acetal protecting groups is primed
for transformation to oligo-THFs containing up to four
adjacently linked rings. Compound 4 could be obtained by
iodocyclization of bis-O-isopropylidene alkene 6 under
aqueous conditions, and acetonation of the product.
However, we were mindful of the possibility that iodo-
etheri®cation of 6 under anhydrous conditions could lead
directly to 4. The C2 symmetry of bis-isopropylidene alkene
6 suggested a two directional type synthesis starting from
0Z)-4-octenedial 7 0Scheme 1).
2,5-Disubstituted tetrahydrofurans 0THFs) are subunits of
several groups of bioactive natural products. Prominent
examples are the acetogenins and the polyether antibiotics
which are noted for their potent and wide ranging pharma-
cological properties.1,2 Both groups have attracted con-
siderable synthetic attention.3±6 We have been interested
in applying the halocyclization reaction of 5-alkoxyalkenes
towards the synthesis THFs, with a focus on templates
which allow for ef®cient access to adjacently linked bis-
THF motifs. The electrophilic cyclization of 5-alkoxy-
alkenes has been extensively used for stereoselective THF
synthesis but stereoselectivity is highly dependant on
substrate substitution.7 Based on the notion that the reaction
of conformationally rigid templates should be more stereo-
selective than more ¯exible systems, we have explored
C6-allylated pyranosides and 1,2-O-isopropylidene-5-
alkenes as precursors to complex cis-2,5- and trans-2,5-
disubstituted THFs, respectively.8,9 Herein we describe the
synthesis of the synthetically versatile, highly func-
tionalized THF 4, via our trans-THF methodology. The
utility of 4 as a precursor to adjacently, linked oligo-THFs
is illustrated by its conversion to the bis-THF 3 and the
tetracyclic lactone 5. Bis-THF 3 is a known precursor4e,f
to the acetogenin trilobacin 1.10 Trilobacin has been
shown to be over 1 billion times more cytotoxic against
human solid tumor lines than adriamycin. Compound 5 is
a potential relay intermediate for less substituted analogues
of kijimicin, a polyether which has shown promising anti-
HIV activity.11 Less substituted polyethers have attracted
interest as podands in computational and mechanistic
studies on ion transport.12
Selective oxidative cleavage of 2,5-cyclooctadiene via the
reported procedure13 provided crude 7, which was stabilized
by the addition of a crystal of 1,4-dihydroquinone, and
treated with vinylmagnesium bromide at 08C. The overall
yield of the bisallylic alcohol 8 from 2,5-cyclooctadiene was
40%. Claisen±Johnson rearrangement14 on 8 followed by
DIBALH reduction of the resulting diester provided
the E,Z,E-triene-diol 9 in 60% overall yield. Double
dihydroxylation of 9 using AD mix-b15 at 238C for 20 h
led primarily to the product resulting from double
dihydroxylation 055%) and a lesser amount of mono dihy-
droxylation product 034%). The composition of the product
from double dihydroxylation was determined after iso-
propylidination. NMR analysis indicated a 5:1 ratio of
bis-O-isopropylidene-Z-alkene 6 and another compound
presumed to be the E-isomer 10. The overall yield of the
desired product 6 was 43% over two steps. A longer reaction
time 0ca. 40 h) in the dihydroxylation reaction led to essen-
tially pure 6, but in lower yield 030% over two steps). The
correlation of longer reaction time with an increased propor-
tion of the desired Z-hexitol 0cf. 6) vs the E-regioisomer 0cf.
10) in the product of the double dihydroxylation, is likely a
result of the more rapid conversion of the latter to the
Keywords: iodoetheri®cation; tetrahydrofuran; acetogenins; polyethers.
Corresponding author. Tel.: 11-212-772-4356; fax: 11-212-772-5332;
e-mail: dmootoo@shiva.hunter.cuny.edu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020002)00075-3

2078
D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
Scheme 1.
completely hydroxylated product.15 Variations in the scale
of the reaction, catalyst concentration, and temperature led
to no signi®cant improvement. Operationally, best overall
yields of 6 0ca. 40±45% from 9) were obtained by using a
shorter reaction time for the dihydroxylation step, and
separating the material derived from 10 at a later stage
0i.e. compounds 15 or 18 vide infra). The optical purity of
6 was determined to be greater than 97% ee by conversion
of 5 to the known diol 11 0Scheme 2).16
due to the formation of a THF-oxonium ion intermediate
which has a cis fused [5.5.0] oxahydrindane type geometry.9a
The con®guration at the iodinated carbon was deduced from
the established anti addition in the electrophilic addition to
the alkene.17 The assignment was con®rmed by conversion
to the known compound 34e,f 0vide infra). The high yield of
the seven membered isopropylidene is consistent with the
intramolecular attack of the proximal alcohol on the oxo-
carbenium ion in the intermediate 13 0Scheme 3).
Treatment of an anhydrous solution of 6 with iodonium
dicollidine perchlorate 0IDCP) led to the iodo-THF 4 in
81% yield, with no evidence of the cis isomer. The stereo-
chemistry of the THF ring 4 was tentatively assigned on the
basis of the observed trans selectivity in the iodocyclization
of related isopropylidene alkenes.9 We have previously
suggested that the high stereoselectivity observed in the
reactions of these isopropylidene alkene systems may be
Compound 4 was next transformed through a straight-
forward series of reactions 0Swern oxidation, Wittig reac-
tion and acetal hydrolysis) to the tetrahydroxyiodide 15. T he
formation of the second THF ring was carried out by heating
15 in pyridine. The bis-THF product 16 was obtained
together with side products resulting from dehydroiodi-
nation. This reaction was somewhat capricious and resulted
in lower yields of the bis-THF product when the tempera-
Scheme 2. 0a) Vinylmagnesium bromide, THF; 0b) CH3C0OEt)3, CH3CH2COOH, 138±1408C; 0c) DIBALH, CH2Cl2, 2788C; 0d) AD mix-b, t-BuOh-H2O,
MeSONH2, 238C; 0e) Me2C0OMe)2, CSA, DMF; 0f) 0i) O3, CH2Cl2, MeOH then Ph3P; 0ii) NaBH4, EtOH.

D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
2079
Scheme 3.
Scheme 4. 0a) Swern's Ox; 0b) C6H13CHvPPh3, toluene; 0c) HCl, H2SO4; 0d) py, 1008C 067%); 0e) Bu2SnO, toluene, re¯ux 071%); 0h) H2/Pd/C, EtOAc 092%).
ture was not carefully controlled. The treatment of 15 with
dibutyltin oxide in toluene at re¯ux, was a more reliable
procedure,18 providing 16 in 71% yield, with no indication
of dehydroiodination products. Hydrogenation of 16 gave
the target compound 3, for which the 1H and 13C NMR data
were essentially identical to that recorded for the previously
prepared material.4e,f,19 The authencity of 3 con®rms the
initial stereochemical assignment of the iodocyclization
product 4 0Scheme 4).
alcohol in 4 was ®rst transformed in two straightforward
operations 0Swern oxidation and Wittig methylenation) to
a terminal alkene residue, which was to serve as a masked
carbonyl group 0Scheme 5). Selective acetal hydrolysis
of the resulting THF-alkene 17 furnished THF-diol 18.
Reaction of 18 under Mitsonobu type conditions led to a
single bis-THF product 19. Previous examples of this
etheri®cation reaction supports the product resulting from
activation of the primary alcohol and retention of con®gu-
ration at the secondary alcohol carbon.20 Treatment of 19
according to the identical two-step sequence 0acetonide
hydrolysis and dibutyltin oxide etheri®cation), that was
used on mono-THF 15, gave tris-THF 20 in 89% overall
yield from 19. Silylation of 20 followed by ozonolysis of the
product provided aldehyde 21. NaClO2 oxidation of 21, and
The conversion of 4 to precursors which could be used for
the preparation of analogues of the pentacyclic spiroketal-
polyether frameworks found in many polyether antibiotics,
was next undertaken. Speci®cally, aldehyde 21 and lactone
5 were viewed as attractive relay compounds. The primary
Scheme 5. 0a) Swern's Ox; 0b) CH2vPPh3, toluene; 0c) PPTS, EtOH; 0d) Ph3P, DEAD, CH2Cl2; 0e) BF3OEt2, THF-H2O; 0f) Bu2SnO, toluene, re¯ux;
0g) TBDPSCl, imidazole, DMF; 0h) O3, then Ph3P; 0i) NaClO2, CH3CN; 0j) 6N HCl-THF.

2080
D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
subsequent treatment of the resulting acid under acidic
conditions provided lactone 5. This three step sequence
from 20 to 5 has not been optimized. The gross structure
1 M aqueous HCl and extracted with ether. The ether extract
was washed with brine, dried 0Na2SO4) and then concen-
trated. FCC of the residue provided 8 021.5 g, 77%):
Rfˆ0.28 030% EtOAc/petroleum ether); IR 0neat) 3356,
1
of 5 was assigned on the basis HRMS, H and 13C NMR
1
analysis. The stereochemistry of 5 follows from the authen-
ticity of precursor 4, the stereospeci®city of the Mitsonobu
type etheri®cation 018!19),20 and the similarity of the
dibutyltin oxide mediated etheri®cation 019!20) to the
corresponding reaction in the synthesis of 3 0i.e. 15!16).
1644 cm21; H NMR d 1.58 0m, 4H), 2.16 0m, 4H), 2.58
0s, 2H, D2O ex.), 4.12 0m, 2H), 5.15 0m, 4H), 5.40 0m, 2H),
5.87 0m, 2H). 13C NMR d 23.2, 37.0, 72.3, 114.6, 129.9,
141.3. FABHRMS calcd for C12H21O2 0M1H) 197.1542,
found 197.1539.
In summary, the elaboration of 6 to 3 and 5, illustrates the
use of bis-1,2-O-isopropylidene-alkenes as precursors to
complex oligo-THFs. Key aspects of the methodology are
the easy accessibility of the isopropylidene alkene pre-
cursors, the ef®ciency of the pivotal iodoetheri®cation reac-
tion, and the versatility of the iodo-THF product of this
reaction. The preparation of the trilobacin precursor 3 011
steps from 2,5-cyclooctadiene, ca. 5% overall yield) indi-
cates that the methodology is of comparable ef®ciency to
other strategies for the adjacently linked bis-THF segments
of the acetogenins. It is anticipated that application of
similar chemistry to stereoisomers of 6 would lead to a
variety of analogues of 3 and 5.
3.1.2. )4E,8Z,12E)-Hexadecatriene-1,16-diol 9. A 100 mL,
one-necked round-bottomed ¯ask containing a magnetic
stirring bar was ®tted with a Claisen adaptor, two ther-
mometers and a receiving ¯ask. The ¯ask was charged
with ethyl orthoacetate 0160 mL), 8 017.8 g, 90 mmol) and
propionic acid 00.8 mL). Ethanol was distilled from the
reaction mixture, and heating was continued between 138
and 1428C, for additional 2 h. The reaction mixture was then
cooled to rt and excess ethyl orthoacetate and propionic acid
were removed by distillation under reduced pressure, to give
the crude triene ester. IR 0neat) 1727 cm21; 1H NMR d 1.24
0t, Jˆ6.6 Hz, 6H), 2.03 0m, 8H), 2.33 0m, 8H), 4.16 0q,
Jˆ6.6 Hz, 4H), 5.34 0m, 2H), 5.46 0m, 4H). 13C NMR d
14.5, 27.4, 28.1, 32.7, 34.6, 60.4, 128.6, 129.5, 131.2, 173.4.
FABHRMS calcd for C20H33O4 0M1H) 337.2379, found
337.2380.
3. Experimental
3.1. General
A solution of DIBAL 0347 mL, 347 mmol, 1 M in heptane)
was added, dropwise, under argon, to a stirred solution of
above diester 030.3 g, 90 mmol) in dry CH2Cl2 0300 mL) at
2788C. The mixture was stirred for 1 h at this temperature,
then warmed to rt, and poured into an ice cold solution of
saturated aqueous KNaC4H4O6 0500 mL). The mixture was
warmed to rt, and stirred until all the solid was dissolved.
The organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined organic phase was
washed with brine, dried 0Na2SO4) and concentrated in
vacuo. FCC of the residue afforded 9 016.15 g, 71% from
7): Rfˆ0.55 0EtOAc); IR 0neat) 3329, 1657 cm21; 1H NMR
d 1.59 0m, 4H), 2.03 0m, 12H), 2.43 0s, 2H, D2O ex.), 3.59 0t,
Jˆ4.5 Hz, 4H), 5.33 0m, 2H), 5.41 0m, 4H). 13C NMR d
27.4, 29.0, 32.46, 36.8, 62.4, 129.6, 130.0, 130.5.
FABHRMS calcd for C16H29O2 0M1H) 253.2167, found
253.2167.
TLC was performed on aluminum sheets precoated with
silica gel 60 0HF-254, E. Merck) to a thickness of
0.25 mm. Flash column chromatography was performed
using Kieselgel 60 0230±400 mesh, E. Merck) and
employed a stepwise solvent polarity gradient, correlated
1
with TLC mobility. Unless otherwise stated, H and 13C
NMR spectra were recorded at 300 and 75 MHz, respec-
tively, in CDCl3 solutions, with CHCl3 as internal standard.
Elemental analysis was performed in Schwarzkopf Micro-
analysis Laboratory. High resolution mass spectroscopy
was carried out at the Mass Spectrometry Facility at the
University of Illinois at Urbana-Champaign.
3.1.1. )Z)-1,6,11-Dodecatriene-3,10-diol 8. CH3COOOH
039 mL, 0.2 mol) was slowly added, at rt, to a rapidly stirred
suspension of 1,5-cyclooctadiene 024.5 g, 0.2 mol) and
NaOAc 016.4 g, 0.2 mol) in CHCl3 0750 mL). After stirring
for 1 h, the reaction mixture was ®ltered, and the ®ltrate was
washed with aqueous NaHCO3 and brine. The organic phase
was dried 0Na2SO4), ®ltered and evaporated in vacuo. To the
crude residue was added a solution of periodic acid 045.6 g,
0.2 mol) in H2O 0700 mL). The mixture was stirred for 1 h
at 408C, then cooled to 08C, neutralized with aqueous
NaHCO3, diluted with brine and extracted with CH2Cl2.
The organic phase was dried 0Na2SO4) and ®ltered. The
®ltrate was stabilized by addition of hydroquinone
010 mg) and concentrated to give crude 7 019.9 g, ca.
3.1.3. )8Z,4R,5R,12R,13R)-Hexadecaene-4,5:12,13-diiso-
propylidenedioxy-1,16-diol 6.
A mixture of t-butyl
alcohol 060 mL), H2O 060 mL), AD-mix-b 015.9 g), and
MeSO2NH2 01.08 g, 11.3 mmol) was stirred at rt until
both phases were clear, and then cooled to 238C, where-
upon the inorganic salts partially precipitated. At this point,
triene diol 9 01.60 g, 12.6 mmol) was added, and the hetero-
geneous slurry was stirred vigorously at 238C for 20 h. The
reaction was then quenched by addition of sodium sul®te
017 g), warmed to rt and stirred for an additional 1 h. The
organic layer was separated and the aqueous layer was
extracted with t-butyl alcohol 01£) and EtOAc 04£). The
combined organic phase was washed with 2N KOH, dried
0Na2SO4) and concentrated in vacuo. FCC of the residue
gave two fractions: 00.60 g, 34%, Rfˆ0.55, 20% MeOH/
EtOAc) and 01.13 g, 55%, Rfˆ0.30, 20% MeOH/EtOAc).
1
71%). H NMR d 2.30 0m, 4H), 2.44 0m, 4H), 5.28 0m,
2H), 9.68 0s, 2H). 13C NMR d 20.0, 43.5, 128.9, 201.8.
A solution of 7 019.9 g, 142 mmol) in dry THF 0150 mL)
was added, dropwise, to a solution of vinylmagnesium
bromide 0300 mL, 1 M) in dry THF 0440 mL) at 08C. The
reaction was stirred at this temperature for 1 h, diluted with
1
For major component in the more polar fraction: H NMR
0CD3OD) d 1.58 0m, 12H), 2.20 0m, 4H), 3.40 0m, 4H), 3.58

D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
2081
0m, 4H), 5.40 0bt, Jˆ4.4 Hz, 2H). 13C NMR 0CD3OD) d
24.8, 30.3, 30.6, 34.2, 63.2, 74.9, 75.3, 131.0. FABHRMS
calcd for C16H33O6 0M1H) 321.2277, found 321.2276.
iodide 4 0795 mg, 1.51 mmol) in CH2Cl2was slowly intro-
duced. The reaction mixture was stirred for 25 min at
2788C, at which time Et3N 01.47 mL, 10.57 mmol) was
added. After warming to rt, the mixture was stirred for
additional 10 min, diluted with ether, washed with saturated
NaHCO3, dried 0Na2SO4) and concentrated in vacuo. FCC
of the residue gave the aldehyde derivative of 4 0710 mg,
90%): Rfˆ0.60 060% EtOAc/petroleum ether); IR 0neat)
2,2-Dimethoxypropane 00.86 mL, 7.0 mmol) and camphor-
sulfonic acid 0487 mg, 4.35 mmol) were added to a solution
of the more polar material 01.13 g, 3.5 mmol) in anhydrous
DMF 040 mL) at 08C. The reaction mixture was warmed to
rt, stirred for 30 min at this temperature, poured into satu-
rated aqueous NaHCO3 and extracted with ether 03£) and
EtOAc 01£). The organic phase was dried 0Na2SO4) and
concentrated in vacuo. FCC of the crude material provided
an inseperable mixture of 6 and another compound
presumed to be 10 03.28 g, 94%). For 6: Rfˆ0.50
1
1723 cm21; H NMR d 1.26, 1.30 0both s, 6H), 1.33 0s,
6H), 1.20±2.22 0m, 14H), 2.64 0m, 2H), 3.62 0m, 5H),
3.90 0m, 1H), 4.05 0m, 2H), 9.78 0s, 1H). 13C NMR d
25.1, 25.4, 25.4, 27.4, 28.5, 29.3, 30.6, 31.2, 32.1, 33.0,
40.5, 41.9, 62.1, 74.2, 79.7, 79.8, 82.6, 82.7, 100.7, 108.6,
201.7. FABHRMS calcd for C22H38O6I 0M1H) 525.1713,
found 525.1716.
1
0EtOAc); IR 0neat) 3419, 1448 cm21; H NMR d 1.32 0s,
12H), 1.58 0m, 12H), 2.14 0m, 4H), 3.58 0m, 8H), 3.82 0bs,
2H, D2O ex.), 5.35 0m, 2H). 13C NMR d 24.1, 27.6, 27.7,
29.9 02 carbons), 33.2, 62.9, 80.7, 81.1, 108.3, 129.8.
FABHRMS calcd for C22H40O6 0M1H) 401.2903, found
To a solution of heptyl triphenylphosphonium iodide
0988 mg, 2.02 mmol) in dry toluene 050 mL) was added a
1 M solution of sodium bis0trimethylsilyl) amide 01.89 mL,
1.89 mmol) in toluene, under an argon atmosphere. The
yellow±orange suspension was stirred for 1 h at rt then
cooled to 2788C. A solution of the aldehyde prepared in
previous step 0710 mg, 1.35 mmol) in dry toluene 030 mL),
was added dropwise over 30 min. After an additional
15 min, the reaction mixture was warmed to rt, then diluted
with ether 0100 mL). The mixture was ®ltered through a pad
of Celite and the ®ltrate was evaporated under reduced
pressure. The residue was puri®ed by FCC to afford 14
0708 mg, 77%): Rfˆ0.35 020% EtOAc/petroleum ether);
1
401.2903. Selected data for 10: H NMR d 5.42 0m). 13C
NMR d 62.8, 78.5, 81.4, 81.5, 108.4, 130.4. The approxi-
mate ratio of 6/10 based on the integration of the signals at d
5.35 and 5.42, respectively, was 5:1.
3.1.4. )4R,5R)-4,5-)Isopropylidenedioxy)-1,8-octanediol
11. A solution of 6 040 mg, 0.1 mmol) in 4:1 CH2Cl2/
MeOH 02 mL) was cooled to 2788C. A stream of O3 in
O2 was bubbled through the solution until 5 was not detect-
able by TLC 010% EtOAc/PE). The mixture was ¯ushed
with N2 and then triphenylphosphine 040 mg, 0.15 mmol)
was added. The solution was warmed to rt, stirred for 2 h,
and concentrated in vacuo to give a slurry, which was
dissolved in EtOH 05 mL) and treated with NaBH4 05 mg,
0.13 mmol) at rt. The reaction mixture was stirred for 1 h,
and then diluted with 10% HCl in MeOH until the pH was 8.
The ethanol was removed under reduced pressure. FCC of
the residue afforded 11 025 mg, 57%): Rf:0.38 010% MeOH/
1
IR 0neat) 1651 cm21; H NMR d 0.84 0t, Jˆ6.6 Hz, 3H),
1.28, 1.30 0both s, 6H), 1.35 0s, 6H), 1.20±2.22 0m, 26H),
3.63 0m, 5H), 3.90 0m, 1H), 4.06 0m, 2H), 5.35 0m, 2H). 13C
NMR d 14.3, 22.8, 23.9, 25.4, 25.4, 27.4, 27.5, 28.5, 29.1,
29.4, 29.8, 30.5, 31.2, 31.9, 32.2, 33.1, 33.2, 42.0, 62.1,
74.2, 79.9, 80.4, 82.6, 82.7, 100.7, 108.2, 128.8, 131.1.
MS 0ES, m/z) 624.3 0M1NH4).
26
26
EtOAc); [a]D ˆ29.88 0c 0.52, CHCl3); Lit: [a]D ˆ29.28 0c
0.51, CHCl3); 1H NMR d 1.39 0s, 6H), 1.50±1.90 0m, 8H),
2.42 0s, 2H, D2O ex.), 3.67 0m, 6H). 13C NMR d 27.5, 29.6,
29.7, 62.8, 81.1, 108.4. FABHRMS calcd for C11H23O4
0M1H) 219.1596, found 219.1583.
3.1.7. THF-tetraol 15. To a stirred solution of 14 0400 mg,
0.66 mmol) in MeOH 020 mL) at rt, was added H2SO4
0100 mL). After 14 h, the reaction mixture was neutralized
with 1 M NaOMe in MeOH and the solvent was removed in
vacuo. The residue was diluted with brine and extracted
with ether. The organic phase was dried 0Na2SO4), and
evaporated under reduced pressure. FCC of the residue
afforded 15 0307 mg, 88%): Rfˆ0.60 0EtOAc); IR 0neat)
3.1.5. THF iodide 4. To a solution of 6 0563 mg, 1.4 mmol)
in dry CH3CN 050 mL) was added IDCP 0985 mg, 2.1
mmol). The mixture was stirred at rt for 10 min, then poured
into saturated, aqueous Na2S2O3, and extracted with ether.
The combined organic phase was dried 0Na2SO4), ®ltered
and evaporated in vacuo. FCC of the crude residue gave 4
0616 mg, 83%): Rfˆ0.50 0EtOAc); IR 0neat) 3455 cm21; 1H
NMR d 1.31, 1.32 0both s, 6H), 1.36 0s, 6H), 1.65 0m, 12H),
1.95, 2.05 0both m, 4H), 2.40 0bs, 1H, D2O ex.), 3.60 0m,
7H), 3.85 0m, 1H), 4.01 0m, 2H). 13C NMR d 25.4, 27.5,
28.5, 29.4, 29.7, 30.6, 31.2, 32.1, 33.0, 41.9, 62.1, 62.8,
74.3, 80.0, 80.9, 82.6, 82.8, 100.8, 108.5. FABHRMS
calcd for C22H40O6I 0M1H) 527.1870, found 527.1869.
1
3395 cm21; H NMR d 0.87 0t, Jˆ6.6 Hz, 3H), 1.00±2.31
0m, 26H), 2.57 0s, 1H, D2O ex.), 3.05 0s, 1H, D2O ex.), 3.25±
3.80 0m, 7H, partial D2O ex.), 3.92 0m, 2H), 4.37 0m, 1H),
5.37 0m, 2H). 13C NMR d 14.3, 22.8, 23.6, 27.5, 28.9, 29.2,
29.9, 30.5, 31.5, 31.8, 32.0, 33.4, 33.6, 41.24, 62.9, 73.2,
74.3, 82.6, 83.9, 129.0, 131.1. FABHRMS calcd for
C23H44O5I 0M1H) 527.2234, found 527.2234.
3.1.8. Bis-THF alkene 16. A mixture of 15 061 mg,
0.116 mmol) and pyridine 04 mL) was heated at 1008C for
1 h. After cooling to rt, the excess pyridine was removed in
vacuo. FCC of the residue afforded the bis-THF alkene 16
031 mg, 67%): Rfˆ0.35 0EtOAc); IR 0neat) 3411, 1638
3.1.6. THF alkene 14. A 50 mL, round-bottomed ¯ask,
equipped with a magnetic stirring bar, was charged with
oxalyl chloride 00.336 mL, 3.78 mmol) and CH2Cl2
010 mL). The set up was purged with argon and cooled to
2788C. DMSO 00.54 mL, 7.55 mmol) was added, dropwise,
and stirring continued for 20 min. Then a solution of THF
1
cm21; H NMR d 0.86 0t, Jˆ6.6 Hz, 3H), 1.28 0m, 8H),
1.55 0m, 4H), 1.70 0m, 5H), 1.90 0m, 1H), 1.98 0m, 6H),
2.15 0m, 2H), 3.01 0bs, 3H, D2O ex.), 3.41 0m, 2H), 3.64 0t,
Jˆ5.7 Hz, 2H), 3.83 0m, 2H), 3.97 0m, 1H), 4.06 0m, 1H),
5.34 0m, 2H). 13C NMR d 14.3, 22.8, 23.7, 26.9, 27.4, 28.3,

2082
D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
28.4, 29.0, 29.2, 29.4, 29.9, 30.8, 32.0, 34.5, 62.9, 74.0,
74.1, 81.1, 81.8, 82.7, 83.3, 129.3, 130.8. FABHRMS
calcd for C23H43O5 0M1H) 399.3111, found 399.3114.
3.1.12. Bis-THF 19. Diol 18 01.34 g, 2.77 mmol) and
triphenylphosphine 01.45 g, 5.54 mmol) were dissolved in
dry CH2Cl2 050 mL). DEAD 00.9 mL, 5.54 mmol) was then
added and the reaction mixture was stirred for 2 h. Removal
of the solvent under reduced pressure and FCC of the
residue gave bis-THF 19 01.09 g, 85%): Rfˆ0.80 010%
In an alternative procedure, a mixture of 15 085 mg,
0.16 mmol) and Bu2SnO 046 mg, 0.18 mmol) in benzene
020 mL) was heated at re¯ux for 17 h, with the azeotropic
removal of water. The solution was concentrated in vacuo,
and the residue was processed by FCC to afford 16 046 mg,
71%).
1
EtOAc/petroleum ether); IR 0neat) 1640 cm21; H NMR d
1.35 0s, 6H), 1.60 0m, 3H), 1.70±2.30 0m, 13H), 3.650m,
2H), 3.75 0m, 2H), 3.85 0m, 1H), 4.00 0m, 2H), 4.10 0m,
1H), 4.95 0m, 2H), 5.80 0m, 1H). 13C NMR d 26.7, 28.1,
28.1, 28.9, 29.6, 30.9, 31.4, 32.4, 32.8, 34.0, 41.9, 69.3,
80.9, 82.5, 83.5, 108.8, 115.6, 138.1. FABHRMS calcd for
C22H34O4I 0M1H) 465.1502, found 465.1507.
3.1.9. Bis-THF 3. A suspension of 16 024 mg, 0.065 mmol)
and 10% w Pd/C in EtOAc 04 mL) was stirred for 16 h under
hydrogen 0balloon). The suspension was ®ltered through a
short plug of Celite and concentrated in vacuo to give 3
3.1.13. Tris-THF-alkene 20. BF3 EtO2 03.5 mL) was added
to a solution of 19 01.42 g, 3.06 mmol) in THF 040 mL) and
H2O 06 mL) at room temperature. The reaction mixture was
stirred for 2 d. The solution was neutralized to pH 7 by the
addition of saturated aqueous sodium bicarbonate. The
mixture was then concentrated under reduced pressure,
diluted with water 050 mL) and extracted with CH2Cl2
03£50 mL). The organic extract was washed with brine,
dried 0Na2SO4) and concentrated in vacuo. The residue
was puri®ed by FCC to afford recovered 19 0112 mg) and
the dihydroxy-iodide derivative 01.11 g, 93% based on
recovered 19): Rfˆ0.30 010% acetone/CHCl3, double
23
022 mg, 92%): Rfˆ0.35 0EtOAc); [a]D ˆ11.48 0c 0.38,
1
CHCl3), H NMR 0400 MHz) d 0.86 0t, Jˆ6.7 Hz, 3H),
1.26 0m, 15H), 1.42±2.05 0m, 13H), 2.90 0bd, 3H, D2O
ex.), 3.39 0m, 2H), 3.43 0m, 2H), 3.65 0apparent t, Jˆ
5.6 Hz, 2H), 3.83 0m, 2H), 3.97 0m, 1H), 4.06 0m, 1H).
13C NMR 0100 MHz) d 14.3, 22.9, 26.0, 26.9, 28.4, 29.0,
29.4, 29.5, 29.8, 29.9, 30.8, 32.1, 34.5, 62.9, 74.0, 74.7,
81.1, 81.8, 82.7, 83.2. FABHRMS calcd for C23H45O5
0M1H) 401.3267, found 401.3266.
3.1.10. THF-alkene 17. To a solution of methyl triphenyl-
phosphonium iodide 04.73 g, 11.8 mmol) in dry toluene
0200 mL) was added a 0.6 M solution of sodium bis0tri-
methylsilyl) amide 019.5 mL, 11.8 mmol) in toluene,
under an argon atmosphere. The yellow orange suspension
was stirred for 1 h at rt then cooled to 2788C. A solution of
the aldehyde derivative of 4 04.08 g, 7.79 mmol, see syn-
thesis of 14) in dry toluene 050 mL), was added dropwise
over 30 min. After an additional 15 min, the reaction
mixture was warmed to rt, then diluted with ether 0200
mL). The mixture was ®ltered through a pad of Celite and
the ®ltrate was evaporated under reduced pressure. The
residue was puri®ed by FCC to afford THF-alkene 17
03.49 g, 86%): Rfˆ0.7 020% EtOAc/petroleum ether); IR
1
elution); H NMR d 1.50±2.35 0m, 16H), 2.75 0s, 2H),
3.40 0m, 2H), 3.80 0m, 3H), 4.00 0m, 2H), 4.15 0m, 2H),
4.95 0m, 2H), 5.80 0m, 1H). 13C NMR d 26.2, 28.3, 29.1,
30.2, 30.8, 31.4, 32.9, 33.8, 41.1, 68.7, 73.4, 74.1, 82.0,
83.1, 83.2, 115.1, 138.5. FABHRMS calcd for C17H30O4I
0M1H) 425.1189, found 425.1188.
A mixture of dihydroxy-iodide from the previous step
0839 mg, 1.98 mmol) and Bu2SnO 0493 mg, 1.98 mmol) in
benzene 030 mL) was heated at re¯ux for 17 h using a
Dean±Stark set-up for the azeotropic removal of water.
Removal of the solvent in vacuo, and FCC of the residue
provided tris-THF-alkene 20: 0563 mg, 96%): Rfˆ0.70 010%
1
1
0neat) 1641 cm21; H NMR d 1.20, 1.25 0both s, 6H),
acetone/CHCl3, double elution); H NMR d 1.30±2.30 0m,
1.30 0s, 6H), 1.35±2.25 0m, 16H), 3.60 0m, 5H), 3.85 0m,
1H), 4.00 0m, 2H), 4.95 0m, 2H), 5.75 0m, 1H). 13C NMR d
25.3, 25.4, 27.4, 27.5, 28.4, 29.3, 30.2, 30.5, 31.2, 32.2,
33.1, 41.9, 62.0, 74.1, 79.7, 80.1, 82.4, 82.6, 100.5, 108.1,
114.9, 137.9. FABHRMS calcd for C23H40O5I 0M1H)
523.1921, found 523.1926.
16H), 2.90 0d, Jˆ6.0 Hz, 1H), 3.30 0m, 1H), 3.65±3.95 0m,
6H), 4.00 0m, 1H), 4.95 0m, 2H), 5.80 0m, 1H). 13C NMR d
26.1, 27.4, 28.3, 28.5, 28.8, 30.1, 33.6, 68.7, 74.1, 81.3, 81.4,
81.9, 82.2, 82.6, 114.6, 138.6. FABHRMS calcd for C17H29O4
0M1H) 297.2066, found 297.2064.
3.1.14. Tris-THF-aldehyde 21. A solution of 20 090 mg,
0.30 mmol), TBDPSCl 00.25 mL, 0.9 mmol) and imidazole
061.3 mg, 0.9 mmol) in anhydrous DMF 02 mL) was stirred
at 508C for 3 h. The reaction mixture was then diluted with
water and extracted with ether. The combined organic phase
was washed with brine, dried 0Na2SO4), ®ltered and evapo-
rated under reduced pressure. The residue was puri®ed by
FCC to give the silyl ether derivative 0105 mg, 66%) as a
colorless oil; Rfˆ0.8 020% EtOAc/petroleum ether); 1H
NMR d 1.05 0s, 9H), 1.30±2.05 0m, 16H), 3.60±3.95 0m,
8H), 4.80 0m, 2H), 5.50 0m, 1H), 7.35 0m, 6H), 7.70 0m, 4H);
13C NMR d 19.8, 26.1, 26.7, 27.4, 28.41, 28.7, 28.9,
29.3, 29.8,32.5, 68.7, 75.0, 81.6, 81.8, 81.9, 114.2, 127.4,
129.4, 134.2, 134.6, 136.0, 138.7. FABHRMS calcd for
C33H45O4Si 0M2H) 533.3087, found 533.3087.
3.1.11. THF-diol 18. The bis-O-isopropylidene derivative
17 02.02 g, 3.87 mmol) was dissolved in EtOH 025 mL).
PPTS 0586 mg, 2.33 mmol) was then added and stirred for
3 h. The reaction was quenched with saturated aqueous
sodium bicarbonate and extracted with ether 03£50 mL).
The ethereal extract was washed with brine, dried
0Na2SO4), ®ltered and concentrated in vacuo. The residue
was puri®ed by FCC to yield THF-diol 18 01.31 g, 70%):
Rfˆ0.10 010% EtOAc/petroleum ether); IR 0neat) 3420,
1
1640 cm21; H NMR d 1.35 0s, 6H), 1.40±2.30 0m, 16H),
3.05 0br s, 2H), 3.40 0m, 1H), 3.60 0m, 4H), 3.90 0m, 2H),
4.05 0m, 1H), 4.95 0m, 2H), 5.80 0m, 1H). 13C NMR d 27.4,
27.5, 28.8, 29.3, 30.2, 30.4, 31.6, 32.2, 32.4, 33.1, 41.6,
62.7, 74.1, 79.7, 80.2, 82.5, 83.6, 108.2, 114.9, 137.9.
FABHRMS calcd for C20H36O5I 0M1H) 483.1607, found
483.1612.
A solution of the material from the previous step 0105 mg,

D. Dabideen et al. / Tetrahedron 58 /2002) 2077±2084
2083
0.20 mmol) in 4:1 CH2Cl2/MeOH 05 mL) was cooled
References
to 2788C. A stream of O3 in O2 was bubbled through
the solution until the starting material was not detectable
by TLC. The mixture was ¯ushed with N2 and then
triphenylphosphine 055 mg, 0.21 mmol) was added. The
solution was warmed to rt, stirred for 1 h and concentrated
in vacuo. The resulting slurry was puri®ed by FCC to afford
21 089 mg, 85%) as a colorless oil; Rfˆ0.55 020% EtOAc/
1. 0a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat.
Prod. 1990, 53, 237±278. 0b) Fang, X.; Rieser, M. J.; Gu,
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1
petroleum ether); H NMR d 1.05 0s, 9H), 1.50±2.00 0m,
14H), 2.30 0m, 2H), 3.65±3.90 0m, 8H), 7.30 0m, 6H), 7.75
0m, 4H), 9.55 0s, 1H); 13C NMR d 19.7, 25.4, 26.0, 26.5,
27.2, 28.3, 28.6, 28.8, 28.9, 40.1, 68.5, 74.2, 81.5, 81.6,
81.7, 81.7, 81.9, 127.4, 127.5, 129.6, 133.8, 134.2, 135.9,
135.9, 201.9. FABHRMS calcd for C32H43O5Si 0M2H)
535.2880, found 535.2882.
2. Westley, J. W., Ed.; Polyether Antibiotics: Naturally
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Á
3. Recent reviews on synthesis of THF acetogenins: 0a) Figadere,
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3.1.15. Tris-THF-lactone 21. To a mixture of 21 089 mg,
0.17 mmol) and NaH2PO4´H2O 0234.6 mg, 1.7 mmol) in
CH3CN±H2O 05:1 mL) were successively added 30%
aqueous H2O2 06 mL, 0.2 mmol) aqueous NaClO2 018.5
mg, 0.2 mmol) in water 01.5 mL) at 0±58C. The reaction
mixture was warmed to rt, stirred for an additional 1 h,
then quenched by addition of Na2SO3 0100 mg). The
mixture was extracted with EtOAc 03£10 mL). The organic
extract was washed with water and brine, dried 0Na2SO4)
and concentrated in vacuo. The residue was puri®ed by FCC
to yield the acid derivative 082 mg, 89%) as a colorless oil;
Rfˆ0.90 060% EtOAc/petroleum ether); 1H NMR d 1.05 0s,
9H), 1.45±2.00 0m, 14H), 2.30 0m, 2H), 3.55±3.90 0m, 8H),
7.35 0m, 6H), 7.75 0m, 4H); 13C NMR d 19.8, 26.1, 26.49,
27.3, 28.1, 28.3, 28.6, 28.9, 28.9, 30.2, 68.6, 74.1, 81.5,
81.7, 81.8, 81.9, 127.4, 127.5, 129.5, 129.61, 134.0, 134.1,
136.0, 178.8. FABHRMS calcd for C32H43O6Si 0M2H)
551.2829, found 551.2831.
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To a solution of the acid obtained in the previous step
024.7 mg, 0.045 mmol) in THF 02 mL) was added an
aqueous solution of 6N HCl 02 mL) and stirred for 2 d.
The solution was then extracted with EtOAc 03£5 mL),
and the organic phase was washed with brine, dried
0Na2SO4) and concentrated in vacuo. The residue was puri-
®ed by FCC to afford 5 08.1 mg, 61%) as a colorless oil;
Rfˆ0.3 060% EtOAc/petroleum ether); IR 0CHCl3 ®lm)
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1
1772 cm21; H NMR 0500 MHz, C6D6) d 1.34 0m, 2H),
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0m, 1H), 3.96 0m, 1H); 13C NMR 0C6D6) d 25.0, 26.9, 27.6,
28.6, 28.7, 29.0, 29.3, 29.9, 68.9, 81.1, 81.8, 81.9, 82.3,
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297.1702, found 297.1703.
Á
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Acknowledgements
Support was provided by the National Institute of General
Medical Sciences 0MBRS SCOREÐ5 SO6 GM60654 and
GM 57865). `Research Centers in Minority Institutions'
award RR-03037 from the National Center for Research
Resources of the NIH, which supports the infrastructure
0and instrumentation) of the Chemistry Department at
Hunter, is also acknowledged. We are also grateful to Dr
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Á
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