Bis-tetrahydrofurans from carbohydrates via iodoetherification and iodine substitution

Article abstract of DOI:10.1055/s-1999-3392

Iodocyclization followed by nucleophilic displacement of iodine affords mainly trans-2,5-substituted THF related to annonaceous acetogenins.

Full text of DOI:10.1055/s-1999-3392

330
PAPER
Bis-Tetrahydrofurans from Carbohydrates via Iodoetherification and Iodine
Substitution
Philippe Bertrand, Hanadi El Sukkari, Jean-Pierre Gesson,* Brigitte Renoux
Laboratoire de Chimie 12, UniversitŽ de Poitiers et CNRS, 40 avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
Fax +33(5)49453501; E-mail: jean-pierre.gesson@cri.univ-poitiers.fr
Received 29 April 1998; revised 19 June 1998
Unsaturated alcohols 2 (5S) and 3 (5R) were prepared
Abstract: Iodocyclization followed by nucleophilic displacement
from the known aldehyde 113 and the Grignard reagent of
of iodine affords mainly trans-2,5-substituted THF related to an-
3-bromobut-1-ene in a 4:1 ratio in THF and in a 2:1 ratio
nonaceous acetogenins.
in diethyl ether (Scheme 2).14Ð17 These compounds were
Key words: carbohydrates, bis-tetrahydrofurans, iodoetherifica-
tion, nucleophilic displacement of iodine, trans-2,5-disubstituted
tetrahydrofurans
easily separated by flash chromatography and character-
ized by 1H NMR in agreement with literature data for sim-
ilar alcohols derived from 1.10,14Ð16 Iodocyclization was
first studied with the major isomer 2 since the threo con-
The synthesis of 2,5-disubstituted tetrahydrofurans (THF)
was initially studied in connection with the chemistry of
ionophore antibiotics.1 This interest has now been re-
newed because of the potent cytotoxic, pesticidal and im-
munosuppressive activities demonstrated by most
members of the large family (over 280) of recently isolat-
ed annonaceous acetogenins.2 Among the available
metho-dologies reviewed by Figad•re3 and Boivin,4 the
iodocyclization of g,d-unsaturated alcohols and ethers pi-
oneered by Bartlett5 is particularly worthy of note for the
selective preparation of trans- and cis-2,5-disubstituted
THF lacking other ring substituents (Scheme 1).
figuration between C-4 and C-5 is similar to the one pre-
vailing for most adjacent acetogenins (Scheme 3).
Scheme 2
Table 1 Iodocyclization of Alkene 2
Conditionsa
Yield (%)b trans/cis ratio
A, CH3CN, 0°C
A, Et2O/H2O (5:2), 0°C
A, DMF, 20°C
A, CH2Cl2, 20°C
A, THF, 20°C
86
80
72
69
54
71
76:24
81:19
77:23
54:46
73:27
69:31
Scheme 1
This methodology has been applied by Mootoo for both
the cyclization of carbohydrate derivatives6,7 and g,d-un-
saturated acetonides8 and by Brimble9 for the preparation
of bis-THF compounds from mono-THF ones. These re-
cent reports prompt us to describe, as part of an ongoing
project on the synthesis of tetrahydrofuran acetogenins
and analogues from carbohydrates,10Ð13 the iodocycliza-
tion of g,d-unsaturated alcohols derived from D-glucose
and the attempted nucleophilic displacement of the inter-
mediate iodo derivatives. The latter reaction has not been
reported in detail in the literature since most compounds
obtained by iodocyclization have been reduced.4,5 This
strategy could be an alternative to the preparation of bis-
THF through epoxidationÐcyclization which has been de-
scribed previously for similar g,d-unsaturated alcohols
and shown to generate a 1:1 mixture of cis- and trans-
THF.10,12 It was thus expected that this sequence of reac-
tion would give the trans-THF (this isomer being more
common among bioactive acetogenins than the cis one)
with higher selectivity.
B, CH2Cl2/THF (4:1), 20°C
a
A: I2-NaHCO3 (3.2 equiv), 1 h B: NIS (2 equiv), 30 min.
Overall isolated yield for the mixture of iodides 4/5 after flash chro-
matography.
b
The ratio of trans- and cis-iodides was determined by
HPLC and the results are reported in Table 1. In each case,
except in CH2Cl2 as solvent, a major isomer was obtained
with an optimal ratio of 4:1 observed in the biphasic wa-
1
ter/diethyl ether mixture. At this point, H NMR data of
the 4/5 mixture did not allow us to confirm the predomi-
nant formation of the trans isomer. Such a determination
has been done by Brimble9 by comparison of the H-2 and
H-5 chemical shifts, according to the Cassady model,18 for
compounds 6 and 7. In our case these protons are hidden
by those of the carbohydrate moiety. Indeed, the CH2I
protons appear in our case at similar figures (d = 3.15 and
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PAPER
Bis-Tetrahydrofurans from Carbohydrates
331
Scheme 3
Table 2 Nucleophilic Displacement of a 4:1 Mixture of trans and cis
Iodo Derivatives 4 and 5
3.36) for both compounds in agreement with the reported
values for 6 (d = 3.18 and 3.28) and 7 (d = 3.18 and 3.25).
Similarly, 13C NMR data did not provide conclusive evi-
dence for iodide configuration: two CH2I signals at d =
10.1 and 10.5 were observed in a 5:1 ratio (as compared
to 4:1 in HPLC), while Brimble9 has reported d = 10.2 and
10.7 respectively for 7 and 6. However, as it will be dem-
onstrated later, this similarity would have lead to a wrong
attribution of a cis configuration to the major isomer.
Conditions
Product
Ratioc
Distribution
(Yield, %)b
EtCO2H, Cs2CO3 (10 equiv), DMFa
EtCO2H, Cs2CO3 (1.5 equiv), DMF
EtCO2Cs (1 equiv), DMF
EtCO2Cs (10 equiv), DMF
EtCO2Cs (10 equiv), THF
8a, 9a (56) 10 (41.5) 57:43
8a, 9a (24) 10 (17) 58:42
8a, 9a (45) 10 (45) 50:50
8a, 9a (65) 10 (28) 69:31
8a, 9a (26) 10 (31) 46:54
8b, 9b (49) 10 (36) 58:42
PhCO2H, CsF, DMF, 60°C
KO2 (3 equiv), 18-crown-6, DMSO, rt 8c, 9c (61) 10 (31)
66:34
TBAN (1.5 equiv), toluene, 80°C
8d, 9d (55) 10 (26) 68:32
a
Reactions with EtCO2Cs carried out at 60°C.
Isolated yield after flash chromatography.
Ratio between compounds arising from nucleophilic substitution (8
and 9) and elimination (10).
b
c
The mixture of iodo derivatives 4 and 5 was then treated
with various oxygen nucleophiles (Table 2) since their (∆d +0.18 ppm for 13) with respect to the cis one. This
separation could be efficiently carried out only on an ana- was also in agreement with the Cassady model (∆d
lytical scale. The use of either cesium propionate (either +0.12 ppm reported between threo-trans-threo and threo-
pure or generated in situ19) or cesium benzoate,20 or potas- cis-threo model compounds).20 Interestingly, similar
sium superoxide,21 or TBAN22 (tetrabutylammonium ni- chemical shifts were observed for H-6 and H-1' for the
trate), respectively led to the formation of inseparable trans compounds 11 and 13 and for the cis ones 12 and 14
mixtures of esters, alcohols and nitrates, together with ke- (see Table 3), although no attribution is possible between
tone 10. The structure of the latter was easily character- these protons (even by comparison with the model com-
ized by IR; n = 1719 cmÐ1, 1H NMR: d = 2.14 (3H, s) and pounds of Fujimoto23).
13C NMR: d = 209.3. However at this stage the 8/9 ratio
could not be determined by 1H NMR since no significant
difference was observed between the CH2O protons for all
isomeric pairs.
As we have shown before,10,12 Pd/C catalyzed hydro-
genolysis of the benzyl group of compounds 8a, 9a
(80:20) gave an easily separable (flash chromatography)
mixture of alcohols 11 and 12 (75:25 ratio, 95% overall
yield). At this stage H-5 and H-2' chemical shifts (unam-
1
biguously determined using HÐ1H COSY) were com- This result confirmed the favored formation of the trans-
pared to those previously observed for compounds 13 and isomer in the iodocyclizations reported herein and led us
14 whose structures have been earlier confirmed by chem- to study the behavior of the isomeric alcohol 3. Upon
ical correlation (Table 3).10 As expected, H-2' was slightly treatment with I2, 3 afforded a mixture of iodo derivatives
more deshielded (∆d +0.11 ppm) for the trans-isomer 11 15 and 16 in good yield (acetonitrile: 90%; diethyl ether/
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332
P. Bertrand et al.
PAPER
Table 3 Selected 1H NMR Data of Alcohols 11, 12, 13 and 14
Table 4 Selected 1H NMR Data of Alcohols 20, 21, 22 and 23
Protona
11
12
13
14
Protona
20
21
22
23
H-5
H-8
H-6, H-1'
4.47
4.36
3H, 2.15
1H, 1.63
4.48
4.25
2H, 2.12
2H, 1.92
4.52
4.32
3H, 2.14
1H, 1.70
4.44
4.14
2H, 2.13
2H, 1.91
H-5
H-8
H-6, H-1'
4.28
4.28
1H, 2.22
1H, 2.15
1H, 1.85
1H, 1.75
4.18
4.33
1H, 2.16
1H, 2.08
1H, 1.95
1H, 1.82
4.28
4.14
1H, 2.22
1H, 2.15
2Hb
4.10
4.10
2H, 2.10
2Hb
1.8–2.0
a All signals appear as multiplets.
1.7–1.9
a All signals appear as multiplets.
b Partly hindered with H-4'.
water: 85%). However no separation was observed in
HPLC and, as in the case of 4 and 5, 1H and 13C NMR data
did not allow us to determine their relative configurations.
Indeed, two signals at d = 10.5 and 10.2 in a 2.5:1 ratio
were observed, thereby indicating a lower selectivity
compared to 4 and 5. Upon treatment with in situ generat-
ed EtCO2Cs in DMF, a 58:42 mixture of esters 17, 18 and
ketone 19 was obtained. Hydrogenolysis of the ester mix-
ture afforded alcohols 20 and 21 in a 70:30 ratio (after
flash chromatography). Identification of 20 as the trans-
isomer was carried out as described above by comparison
of selected 1H NMR data with those of the previously re-
ported 22 and 23.12 Furthermore in the case of erythro-
trans-threo (or erythro) and erythro-cis-threo (or erythro)
configurations, a deshielding of ca. 0.10 ppm (trans vs.
cis) has also been reported by Cassady. Such a deshielding
(∆d +0.10 ppm) was observed for H-5 but not for H-2'
(∆d Ð0.05 ppm) for 20 and 21 (the latter may result from
different side chain conformations in both isomers). Al-
though H-6 and H-1' were partly hindered in the case of
22 and 23, their chemical shifts were similar respectively
to those of 20 and 21.
In conclusion, iodocyclization followed by nucleophilic
displacement of iodine allows the preparation of a 2,5-di-
substituted THF from alcohols 2 and 3, with a trans/cis se-
lectivity of about 3:1 (instead of a 1:1 ratio obtained using
epoxidationÐcyclization). This is in agreement with all re-
ported examples of iodocyclization of g,d-unsaturated al-
cohols. Furthermore, a selective access toward cis
compounds may also be considered by the method of
Marek and Normant24 through cyclization of the corre-
sponding tert-butyl esters. However, this study shows that
the nucleophilic substitution of iodine is always accompa-
nied by the formation of a g-hydroxy ketone. This has
been previously observed in the silver carbonate treatment
of 6 and 7 by Brimble,9 who has suggested the intermedi-
acy of a primary carbenium ion, after solvolysis of iodide,
followed by hydride migration and hydrolysis. However
the intermediate formation of the unstable enol ether 24
resulting from elimination should be considered since
treatment of the 4/5 mixture with DBU (1.5 equiv) in
DMF gives only ketone 10 (72%) (Scheme 4).
Scheme 4
Overall, this methodology appears to be less diastereose-
lective than the Kennedy cyclization of homoallylic alco-
hols induced by rhenium derivatives.25 Nevertheless, it
offers a simple alternative which is however limited by
the elimination process leading to ketone 10. Finally, it
should be pointed out that the intermediate (iodometh-
yl)tetrahydrofurans, which are very prone toward elimina-
tion, may be considered as good substrates to test new
nucleophilic substitution conditions in the future.
Mps were recorded on a Buchi Tottoli 510 and are uncorrected. 1H
and 13C NMR spectra were recorded on a Bruker Advance DPX 300
operating at 300 MHz for 1H and 75 MHz for 13C. Chemical shifts
are expressed in ppm positive values downfield from internal TMS.
Elemental and MS analyses were measured by the Service Central
dÕAnalyse du CNRS (Vernaison). Optical rotations were measured
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PAPER
Bis-Tetrahydrofurans from Carbohydrates
333
on a Schmidt Polartronic HN8 polarimeter. IR spectra were record-
ed on a Nicolet Magna 750 FTIR spectrophotometer. All solvents
were dried using standard methods. Separations were done under
flash chromatography conditions on silica gel (Matrex, 25Ð40 mm)
and TLC were performed on silica gel plates (Merck, 60GF254).
Analysis of iodide mixtures was carried by HPLC using a PhaseSep
Spherisorb S5CN column (15 cm × 4.6 mm) with EtOAc/hexane
(20:80) as eluent (Waters 486 absorbance detector, 254 nm). Carbo-
hydrate numbering has been used for all compounds.
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2'-hydroxy-3'-
iodopropyl]-1,2-O-isopropylidene-a-D-glucofuranose 15/16
1H NMR (CDCl3): d = 1.3 and 1.4 (2 s, 6H, 2 CH3), 1.76 and 2.2 (2
m, 4H, 2 H-6, 2 H-1'), 3.18 (dd, 1H, H-3', J = 10 Hz), 3.25 (dd, 1H,
H-3', J = 4 Hz), 3.9 (d, 1H, H-3, J = 3 Hz), 4.01 (m, 1H, H-5), 4.1
(t, 1H, H-4, J = 2.3 Hz), 4.35 (dd, 1H, H-2'), 4.56 (d, 1H, H-2, J =
3.8 Hz), 4.68 (d, 2H, OCH2Ph, J = 11.8 Hz), 5.9 (d, 1H, H-1, J =
4.1 Hz), 7.34 (m, 5H, 5 H arom).
Nucleophilic Displacement of Iodo Derivatives 4/5 and 15/16:
Cesium Carbonate
Allylation of Aldehyde 1
To a suspension of magnesium (0.44 g, 18 mmol) in anhyd Et2O
(5 mL) was added 3-bromobut-1-ene (1.85 mL, 13 mmol). The re-
sulting solution was refluxed for 1 h and then cooled with an ice
bath prior to the addition of the aldehyde 1 (1 g, 3.6 mmol) in Et2O
(2 mL). After further stirring for 1 h, the mixture was poured into
sat. aq NH4Cl and extracted with Et2O. The organic layer was dried
(Na2SO4) and evaporated in vacuo. Flash column chromatography
of the residue (silica gel, 10Ð15% EtOAc/petroleum ether) afforded
2 (S) as a white powder (0.78 g) and 3 (R) as an oil (0.18 g) in a 4:1
ratio. The overall yield was 80%.
To a solution of propionic acid (0.074 mL, 1 mmol) in DMF
(0.15 mL) was added Cs2CO3 (0.33 g, 1 mmol). The mixture was
stirred for 30 min before addition of 4/5 (52 mg, 0.11 mmol). The
resulting solution was then heated at 60¡C overnight. Quenching
with H2O and extraction with Et2O afforded a crude residue which
was then separated by preparative layer chromatography (Merck
silica gel 60 PF254). An inseparable mixture of cis-trans esters 8a/
9a was obtained (25 mg, 56%) together with ketone 10 (15 mg,
41.5%).
The same procedure applied on the isomers 15/16 afforded an 58:42
ratio of esters 17/18 and ketone 19, yield 90%.
6-C-Allyl-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-b-L-ido-
furanose (2)
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2'-hydroxy-3'-
(propionyloxy)propyl]-1,2-O-isopropylidene-b-L-idofuranose
8a/9a
Mp 90¡C, [ ]D20 Ð54.5 (c = 1.1, CH2Cl2).
a
1H NMR (CDCl3): d = 1.33 and 1.49 (2 s, 6H, 2 CH3), 1.56 (m, 2H,
2 H-6), 2.19 (m, 2H, 2 H-1'), 2.79 (s, 1H, OH), 3.96 (m, 3H, H-3,
H-4, H-5), 4.48 (d, 1H, OCHPh, J = 11.8 Hz), 4.67 (d, 1H, H-2, J =
3.8 Hz), 4.75 (d, 1H, OCHPh, J = 11.8 Hz), 4.97 (m, 2H, 2 H-3'),
5.77 (m, 1H, H-2'), 5.97 (d, 1H, H-1, J = 3.8 Hz), 7.33 (m, 5H, 5 H
arom).
Oil; Rf 0.45 (EtOAc/petroleum ether 30:70).
IR (CH2Cl2): n = 1026 and 1078 (CÐOÐC); 1462,2856, and 2928
(CÐH); 1748 cmÐ1 (C=O).
1H NMR (CDCl3): d = 1.12 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.32
and 1.5 (2 s, 6H, 2 CH3), 1.68 and 1.97 (2 m, 4H, 2 H-6, 2 H-1'),
2.33 (q, 2H, OCOCH2, J = 6 Hz), 3.89 (d, 1H, H-3, J = 2.8 Hz), 4.1
(m, 4H, H-4, H-5, 2 H-3'), 4.3 (m, 1H, H-2'), 4.45 (d, 1H, OCHPh,
J = 12 Hz), 4.65 (d, 1H, H-2, J = 4 Hz), 4.72 (d, 1H, OCHPh, J =
12 Hz), 5.98 (d, 1H, H-1, J = 3.8 Hz), 7.33 (m, 5H, 5 H arom).
13C NMR (CDCl3): d = 26.5, 26.9, 29.7, 32.3, 69.4, 72.1, 82.6, 83.0,
105.0, 111.9, 114.8, 128.0, 128.3, 128.7, 138.4.
Anal (C19H26O5): calcd C, 68.24; H, 7.84. Found C, 67.94; H, 7.61.
13C NMR (CDCl3): d = 9.26 (C-12); 26.61 and 27.13 (2 CH3);
27.50, 27.71, 28.19, 28.31, 28.56 (C-6, C-1', C-11); 66.42, 66.52,
71.97, 78.06, 78.14, 78.71, 82.28, 83.01, 83.16, 83.33, and 83.75
(C-2, C-3, C-4, C-5, C-2', C-3', OCH2Ph); 105.81 (C-1); 111.88
(CMe2); 127.92, 128.17, 128.68, and 137.62 (6 C arom); 174.43 (C-
10).
a
6-C-Allyl-3-O-benzyl-6-deoxy-1,2-O-isopropylidene- -D-gluco-
furanose (3)
Oil,[a]D20 Ð74 (c = 0.16, CHCl3).
1H NMR (CDCl3): d = 1.33 and 1.48 (2 s, 6H, 2 CH3), 1.7 (m, 2H,
2 H-6), 2.17 (m, 2H, 2 H-1'), 3.93 (m, 1H, H-5), 3.97 (d, 1H, H-3, J
= 2.8 Hz), 4.06 (t, 1H, H-4, J = 2.5 Hz), 4.45 (d, 1H, OCHPh, J =
11.8 Hz), 4.65 (d, 1H, H-2, J = 3.8 Hz), 4.75 (d, 1H, OCHPh, J =
11.8 Hz), 4.98 (m, 2H, 2 H-3'), 5.8 (m, 1H, H-2'), 5.97 (d, 1H, H-1,
J = 3.8 Hz), 7.33 (m, 5H, 5 H arom).
HRMS (EI): m/z 406.1990 (C22H30O7), calcd 406.1991.
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2'-hydroxy-3'-
(propionyloxy)propyl]-1,2-O-isopropylidene-a-D-glucofura-
nose 17/18
Iodocyclization of Alcohols 2 and 3
A solution of the alcohol 2 or 3 (0.1 g, 0.23 mmol) in DMF (6 mL)
was treated successively with NaHCO3 (63 mg, 0.75 mmol) and I2
(0.19 g, 0.75 mmol). After stirring at r.t. for 1 h, the mixture was
quenched with H2O and extracted with Et2O. The organic layers
were washed successively with sat. aq Na2S2O3 and H2O, dried
(Na2SO4) and evaporated in vacuo. The residue was chromato-
graphed (silica gel, 10Ð15% EtOAc/petroleum ether) to yield an in-
separable mixture of cis-trans isomers 4/5 (72%) from alcohol 2
and cis-trans isomers 15/16 (58%) from alcohol 3.
Oil; Rf 0.4 (EtOAc/petroleum ether 15:85).
IR (CH2Cl2): n = 1027, 1079, and 1215 (CÐO); 1462, 2884, and
2941 (CÐH); 1743 cmÐ1 (C=O).
1H NMR (CDCl3): d = 1.12 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.3 and
1.48 (2 s, 6H, 2 CH3), 1.73 and 2.02 (2 m, 4H, 2 H-6, 2 H-1'), 2.34
(q, 2H, OCOCH2, J = 6 Hz), 4.01 (m, 5H, H-3, H-4, H-5, 2 H-3'),
4.28 (m, 1H, H-2'), 4.57 (d, 1H, H-2, J = 3.7 Hz), 4.66 (d, 2H,
OCH2Ph, J = 11.8 Hz), 5.99 (d, 1H, H-1, J = 3.8 Hz), 7.33 (m, 5H,
5 H arom).
13C NMR (CDCl3): d = 8.96 (C-12); 26.17 and 26.76 (2 CH3); 27.37
and 27.57 (C-11); 28.18, 28.87, and 29.39 (C-6, C-1'); 66.01, 66.25,
72.88, 75.73, 76.10, 77.79, 81.00, 82.62, 82.69, and 83.04 (C-2, C-
3, C-4, C-5, C-2', C-3', OCH2Ph); 105.13 (C-1); 111.43 and 111.48
(CMe2); 127.50, 127.58, 128.24, 137.91, and 138.01 (6 C arom);
173.97 and 174.00 (C-10).
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2'-hydroxy-3'-
iodopropyl]-1,2-O-isopropylidene-b-L-idofuranose 4/5
1H NMR (CDCl3): d = 1.32 and 1.49 (2 s, 6H, 2 CH3), 1.99 and 2.19
(2 m, 4H, 2 H-6, 2 H-1'), 3.17 (dd, 1H, H-3', J = 10 Hz), 3.33 (dd,
1H, H-3', J = 4 Hz), 3.88 (d, 1H, H-3, J = 3 Hz), 4.07 (t, 1H, H-4, J
= 2.5 Hz), 4.13 (m, 1H, H-5), 4.37 (dd, 1H, H-2'), 4.45 (d, 1H,
OCHPh, J = 12 Hz), 4.65 (d, 1H, H-2, J = 3.7 Hz), 4.71 (d, 1H,
OCHPh, J = 12 Hz), 5.99 (d, 1H, H-1, J = 3.8 Hz), 7.33 (m, 5H, 5
H arom).
HRMS (EI): m/z 406.1990 (C22H30O7), calcd 406.1991.
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334
P. Bertrand et al.
PAPER
6-C-Acetonyl-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-b-L-
1H NMR (CDCl3): d = 1.32 and 1.49 (2 s, 6H, 2 CH3), 1.94 and 2.04
(2 m, 4H, 2 H-6, 2 H-1'), 2.41 (s, 1H, OH), 3.52 (dd, 1H, H-3', J =
11.8 and 5.9 Hz), 3.66 (dd, 1H, H-3', J = 11.8 and 3 Hz), 3.89 (d,
1H, H-3, J = 2.8 Hz), 4.09 (m, 2H, H-4, H-5), 4.27 (m, 1H, H-2'),
4.45 (d, 1H, OCHPh, J = 12 Hz), 4.64 (d, 1H, H-2, J = 3.8 Hz), 4.71
(d, 1H, OCHPh, J = 12 Hz), 5.98 (d, 1H, H-1, J = 3.7 Hz), 7.33 (m,
5H, 5 H arom).
13C NMR (CDCl3): d = 14.04 (C-3'); 26.26 and 26.76 (2 CH3);
27.30, 27.83, and 28.28 (C-6, C-1'); 60.13, 64.52, 71.66, 77.92,
79.59, 80.06, 81.9, 82.54, 83.33, and 83.48 (C-2, C-3, C-4, C-5, C-
2', OCH2Ph); 105.41 (C-1); 111.59 (CMe2); 127.62, 127.85, 128.34,
and 137.22 (6 C arom).
idofuranose (10)
20
a
Mp 98ûC; [ ]D Ð72 (c = 0.07, CHCl3); Rf 0.5 (EtOAc/petroleum
ether 40:60).
IR (CH2Cl2): n = 1025, 1077, and 1215 (CÐOÐC); 1455, 2871, and
2934 (CÐH); 1719 (C=O); 3605 cmÐ1 (OÐH).
1H NMR (CDCl3): d = 1.33 and 1.48 (2 s, 6H, 2 CH3), 1.72 (m, 2H,
2 H-6), 2.14 (s, 3H, 3 H-2'), 2.58 (m, 2H, 2 H-1'), 3.04 (s, 1H, OH),
3.98 (m, 3H, H-3, H-4, H-5), 4.45 (d, 1H, OCHPh, J = 12 Hz), 4.65
(d, 1H, H-2, J = 3.8 Hz), 4.72 (d, 1H, OCHPh, J = 12 Hz), 5.99 (d,
1H, H-1, J = 3.8 Hz), 7.33 (m, 5H, 5 H arom).
13C NMR (CDCl3): d = 26.17 and 26.68 (2 CH3); 26.90, 29.64, and
39.29 (C-6, C-1', C-3'); 68.71, 71.85, 72.97, 82.20, and 82.71 (C-2,
C-3, C-4, C-5, OCH2Ph); 104.74 (C-1); 111.63 (CMe2); 127.73,
127.99, 128.42, and 136.78 (6 C arom); 208.37 (C-2').
HRMS (EI): m/z 350.1732 (C19H26O6), calcd 350.1729.
Tetrabutylammonium Nitrate
A mixture of 4/5 (46 mg, 0.1 mmol) and Bu4NNO3 (45.6 mg,
0.15 mmol) in benzene (1 mL) was heated and stirring for 7 d. The
mixture was then poured into H2O, extracted with Et2O, dried
(Na2SO4) and concentrated. The residue was purified by preparative
layer chromatography (Merck silica gel 60 PF254) to give 8d/9d
(22 mg, 56%) and 10 (10 mg, 29%).
HRMS (EI): m/z 350.1721 (C19H2606), calcd 350.1729.
Cesium Benzoate
Iodo compounds 4/5 (0.23g, 0.5 mmol) were dissolved in DMF
(0.5 mL). Benzoic acid (20 mg, 0.17 mmol) and CsF (40 mg,
0.26 mmol) were successively added and the resulting solution was
stirred at 60¡C overnight. The mixture was quenched with H2O and
extracted with Et2O. The combined organic layers were dried
(Na2SO4) and evaporated in vacuo. Chromatography (silica gel, 20Ð
30% EtOAc/petroleum ether) afforded the benzoic esters 8b/9b
(72 mg, 32%) together with ketone 10 (54 mg, 30%).
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2'-hydroxy-3'-
nitroxypropyl]-1,2-O-isopropylidene-b-L-idofuranose 8d/9d
Mp 72Ð74¡C; Rf 0.25 (EtOAc/petroleum ether 20:80).
IR (CH2Cl2): n = 1027 and 1076 (CÐOÐC); 1452 and 2931 (CÐH);
1641 cmÐ1 (OÐNO2).
2',5-Anhydro-3-O-benzyl-5-C-[(2'R,S)-3'-benzoyloxy-2'-
hydroxypropyl]-6-deoxy-1,2-O-isopropylidene-b-L-idofura-
nose 8b/9b
1H NMR (CDCl3): d = 1.32 and 1.49 (2 s, 6H, 2 CH3), 1.74Ð2.04 (2
m, 4H, 2 H-6, 2 H-1'), 3.89 (d, 1H, H-3, J = 2.7 Hz), 4.08 (t, 1H, H-
4, J = 2.5 Hz), 4.3 (m, 1H, H-2'), 4.45 (d, 1H, OCHPh, J = 12 Hz),
4.47 (m, 3H, H-5, 2 H-3'), 4.66 (d, 1H, H-2, J = 3.8 Hz), 4.72 (d, 1H,
OCHPh, J = 12 Hz), 5.98 (d, 1H, H-1, J = 3.8 Hz), 7.34 (m, 5H, 5
H arom).
13C NMR (CDCl3): d = 26.43 and 26.95 (2 CH3); 27.30, 28.06,
28.58, 29.71 (C-6, C-1'); 71.84, 74.33, 74.42, 75.18, 75.51, 78.31,
78.85, 82.03, 82.12, 82.72, 82.94, and 83.28 (C-2, C-3, C-4, C-5, C-
2', C-3', OCH2Ph); 105.63 (C-1); 111.87 (CMe2); 127.82, 128.09,
128.58, 137.32 (6 C arom).
Oil; Rf 0.30 (EtOAc/petroleum ether 20:80).
IR (CH2Cl2): n = 1025 and 1083 (CÐOÐC); 1452, 2873, and 2935
(CÐH); 1725 cmÐ1 (C=O).
1H NMR (CDCl3): d = 1.33 and 1.5 (2 s, 6H, 2 CH3), 1.83 and 2.05
(2 m, 4H, 2 H-6, 2 H-1'), 3.91 (d, 1H, H-3, J = 2.7Hz), 4.11 (t, 1H,
H-4, J = 2.5 Hz), 4.38 (m, 4H, H-5, H-2', 2 H-3'), 4.46 (d, 1H,
OCHPh, J = 12 Hz), 4.65 (d, 1H, H-2, J = 3.7 Hz), 4.72 (d, 1H,
OCHPh, J = 12 Hz), 6 (d, 1H, H-1, J = 3.8 Hz), 7.31 (m, 10H, 10 H
arom).
HRMS (EI): m/z 395.1589 (C19H25NO8), calcd 395.1580.
13C NMR (CDCl3): d = 26.41 and 26.93 (2 CH3); 27.39, 28.23,
28.48, and 29.69 (C-6, C-1'); 66.87, 71.79, 77.32, 78.04, 78.59,
82.1, 82.77, 82.98, 83.19, and 83.65 (C-2, C-3, C-4, C-5, C-2', C-3',
OCH2Ph); 105.63 (C-1); 111.76 (CMe2); 127.73, 128.00, 128.32,
128.53, 129.74, 130.31, 132.89, and 137.39 (12 C arom); 166.55
(C=O).
Debenzylation: General Procedure
To a solution of esters 8a/9a (0.16 g, 0.39 mmol) in MeOH (0.8 mL)
was added 10% Pd/C (32 mg). The resulting suspension was stirred
for 1.5 h at r.t. under H2. After filtration over Celite, MeOH was re-
moved in vacuo. The residue was chromatographed (silica gel, 10Ð
20% EtOAc/petroleum ether) to afford 11 and 12 in overall yield of
97% (120 mg).
HRMS (EI): m/z 454.1983 (C26H30O7), calcd 454.1991.
The same procedure applied to 17/18 furnished 20 and 21 in a 70:30
ratio (95%).
Potassium Superoxide
To a solution of KO2 (0.1 g, 1.5 mmol) and 18-crown-6 (40 mg,
0.15 mmol) in DMSO (3 mL) were added iodo compounds 4/5
(0.23 g, 0.5 mmol). After stirring for 30 min at r.t., the mixture was
diluted with sat. aq brine and extracted with CH2Cl2. The combined
organic layers were washed successively with sat. aq Na2S2O3 and
H2O, dried (Na2SO4) and evaporated in vacuo. The crude product
was chromatographed (silica gel, 10Ð30% EtOAc/petroleum ether)
to yield 8c/9c (0.1 g, 57%) and 10 (60 mg, 34%).
2',5-Anhydro-6-deoxy-5-C-[(2'S)-2'-hydroxy-3'-(propionyl-
oxy)propyl]-1,2-O-isopropylidene-b-L-idofuranose (11)
Mp 84Ð86¡C; [a]D20 +8.5 (c = 0.12, CHCl3); Rf 0.4 (EtOAc/petro-
leum ether 40:60).
IR (CH2Cl2): n = 1017, 1076, and 1215 (CÐOÐC); 1463, 2882, and
2984 (CÐH); 1744 (C=O); 3456 cmÐ1 (OÐH).
1H NMR (CDCl3): d = 1.13 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.31
and 1.47 (2 s, 6H, 2 CH3), 1.63 and 2.15 (2 m, 4H, 2 H-6, 2 H-1'),
2.36 (q, 2H, OCOCH2, J = 6 Hz), 4.08 (m, 3H, H-4, 2 H-3'), 4.23 (d,
1H, H-3, J = 2.8 Hz), 4.36 (m, 1H, H-2'), 4.47 (m, 1H, H-5), 4.49
(d, 1H, H-2, J = 3.7 Hz), 4.6 (d, 1H, OH, J = 3.7 Hz), 5.95 (d, 1H,
H-1, J = 3.8 Hz).
2',5-Anhydro-3-O-benzyl-6-deoxy-5-C-[(2'R,S)-2',3'-dihydroxy-
propyl]-1,2-O-isopropylidene-b-L-idofuranose 8c/9c
Oil; Rf 0.25 (EtOAc/petroleum ether 50:50).
IR (CH2Cl2): n = 1028, 1078, and 1214 (CÐOÐC); 1454, 2873, and
2934 (CÐH); 3495 cmÐ1 (OÐH).
Synthesis 1999, No. 2, 330–335 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Bis-Tetrahydrofurans from Carbohydrates
335
13C NMR (CDCl3): d = 9.01 (C-12); 26.14 and 26.83 (2 CH3); 27.44
(C-11); 27.59 and 28.90 (C-6, C-1'); 65.89 (C-3'); 76.84 (C-3);
78.46, 78.48, and 85.54 (C-2, C-5, C-2'); 80.26 (C-4); 104.79 (C-1);
111.46 (CMe2); 174.09 (C-10).
Acknowledgement
We thank the Minist•re des Affraires Etrang•res for a fellowship
(HES), the CNRS and the ÒLigue Nationale contre le Cancer,
ComitŽ de Charente-Maritime Ó for Þnancial support.
HRMS (EI): m/z 317.1607 (C15H24O7), calcd for MH+ 317.160028.
2',5-Anhydro-6-deoxy-5-C-[(2'R)-2'-hydroxy-3'-(propionyl-
oxy)propyl]-1,2-O-isopropylidene-b-L-idofuranose (12)
Mp 44Ð46¡C; [a]D20 Ð14 (c = 0.04, CHCl3); Rf 0.3 (EtOAc/petro-
leum ether 40:60).
References
(1) Westley, J. W. In Polyether Antibiotics: Naturally Occurring
Acid Ionophores; Marcel Dekker: New York, 1983; Vols. 1
and 2.
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Natural Products; Herz, W., Kirby, G. W., Moore, R. E., Steg-
lich, W., Tamm, Ch. Eds.; Springer: Wien, New York, 1997;
Vol. 70; pp 81Ð288.
IR (CH2Cl2): n = 1016, 1077, and 1215 (CÐOÐC); 1463, 2856, and
2929 (CÐH); 1743 (C=O); 3460 cmÐ1 (OÐH).
1H NMR (CDCl3): d = 1.13 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.32
and 1.48 (2 s, 6H, 2 CH3), 1.91 and 2.12 (2 m, 4H, 2 H-6, 2 H-1'),
2.33 (q, 2H, OCOCH2, J = 6 Hz), 4.05 (d, 2H, H-3'), 4.13 (d, 1H, H-
3, J = 2.7 Hz), 4.25 (m, 2H, H-4, H-5), 4.48 (m, 2H, H-2, H-2'), 4.59
(d, 1H, OH, J = 3.7 Hz), 5.94 (d, 1H, H-1, J = 3.8 Hz).
13C NMR (CDCl3): d = 9.11 (C-12); 26.24 and 26.95 (2 CH3); 27.41
(C-11); 27.55 and 29.07 (C-6, C-1'); 66.1 (C-3'); 76.4 and 78.66 (C-
4, C-5); 79.17 and 85.67 (C-2, C-2'); 79.84 (C-3); 104.92 (C-1);
111.59 (CMe2); 174.19 (C-10).
Gu, Z. M.; Zhao, G. X.; Oberlies, N. H.; Zeng, L.; McLaugh-
lin, J. L. Recent Advances in Phytochemistry; Arnason, J. T.,
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(3) Harmange, J.-C.; Figad•re, B. Tetrahedron: Asymmetry 1993,
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(4) Boivin, T. L. J. Tetrahedron 1987, 43, 3309.
(5) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981,
103, 3963.
HRMS (EI): m/z 317.1600 (C15H24O7), calcd for MH+ 317.160028.
(6) Zhang, H.; Mootoo, D. R. J. Org. Chem. 1995, 60, 8134.
(7) Zhang, H.; Wilson, P.; Shan, W.; Ruan, Z.; Mootoo, D. R.
Tetrahedron Lett. 1995, 36, 649.
2',5-Anhydro-6-deoxy-5-C-[(2'R)-2'-hydroxy-3'-(propionyl-
oxy)propyl]-1,2-O-isopropylidene-a-D-glucofuranose (20)
Oil; [a]D20 Ð14 (c = 0.58, CHCl3); Rf 0.25 (EtOAc/petroleum ether
30:70).
(8) Wilson, P.; Zhang, H.; Mootoo, D. R. J. Carbohydr. Chem.
1994, 13, 133.
IR (CH2Cl2): n = 1019 and 1076 (CÐOÐC); 1463, 2885, and 2983
See also Zang, H.; Seepersaud, M.; Seepersaud, S.; Mootoo,
D. R. J. Org. Chem. 1998, 63, 2049.
(CÐH); 1742 (C=O); 3516 cmÐ1 (OÐH).
1H NMR (CDCl3): d = 1.14 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.31
and 1.48 (2 s, 6H, 2 CH3), 1.75, 1.95, 2.08, 2.16 (4 m, 4H, 2 H-6, 2
H-1'), 2.34 (q, 2H, OCOCH2, J = 6 Hz), 3.48 (s, 1H, OH), 4.07 (m,
3H, H-4, 2 H-3'), 4.28 (m, 3H, H-3, H-5, H-2'), 4.54 (d, 1H, H-2, J
= 3.8 Hz), 5.96 (d, 1H, H-1, J = 3.8 Hz).
(9) Brimble, M. A.; Edmonds, M. K. Tetrahedron 1995, 51, 9995.
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(12) Autissier, L.; Bertrand, P.; Gesson, J.-P.; Renoux, B. Tetrahe-
dron Lett. 1994, 35, 3919.
13C NMR (CDCl3): d = 9.04 (C-12); 26.17 and 26.83 (2 CH3);
27.54, 27.79, 29.81 (C-6, C-1', C-11); 65.81 and 82.20 (C-4, C-3');
75.33, 77.28, and 77.46 (C-3, C-5, C-2'); 85.25 (C-2); 105.23 (C-1);
111.51 (CMe2); 174.51 (C-10).
(13) Bertrand, P.; Gesson, J.-P.; Renoux, B.; Tranoy, I. Tetrahe-
dron Lett. 1995, 36, 4073.
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(17) Tamaru, Y.; Hojo, M.; Kawamura, S.-i.; Sawada, S.; Yoshida,
S.-i. J. Org. Chem. 1987, 52, 4062.
HRMS (EI): m/z 316.1536 (C15H24O7), calcd 316.1531.
2',5-Anhydro-6-deoxy-5-C-[(2'S)-2'-hydroxy-3'-(propionyl-
oxy)propyl]-1,2-O-isopropylidene-a-D-glucofuranose (21)
Oil; [a]D20 +16 (c = 0.09, CHCl3); Rf 0.30 (EtOAc/petroleum ether
40:60).
(18) Gale, J. B.; Yu, J.-G.; Khare, A.; Hu, X. E.; Hu, D. K.; Cassa-
dy, J. M. Tetrahedron Lett. 1993, 34, 5851.
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Singh, S.; Singh, M.; Gupta, Y. K., Sahai, M. Chem. Pharm.
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IR (CH2Cl2): n = 1018 and 1075 (CÐOÐC); 1463, 2884, and 2983
(CÐH); 1744 (C=O); 3468 cmÐ1 (OÐH).
1H NMR (CDCl3): d = 1.14 (t, 3H, OCOCH2CH3, J = 6 Hz), 1.32
and 1.49 (2 s, 6H, 2 CH3), 1.82, 1.95, 2.08, 2.16 (4 m, 4H, 2 H-6,
2 H-1'), 2.35 (q, 2H, OCOCH2, J = 6 Hz), 3.41 (s, 1H, OH), 4.05 (m,
3H, H-3, 2 H-3'), 4.18 (m, 1H, H-5), 4.33 (m, 2H, H-4, H-2'), 4.54
(d, 1H, H-2, J = 3.7 Hz), 5.96 (d, 1H, H-1, J = 3.8 Hz).
13C NMR (CDCl3): d = 9.07 (C-12); 26.17 and 26.86 (2 CH3); 27.28
and 29.10 (C-6, C-1'); 27.50 (C-11); 65.51 (C-5); 75.46 and 78.19
(C-4, C-2'); 77.52 and 81.93 (C-3, C-3'); 85.28 (C-2); 105.24 (C-1);
111.56 (CMe2); 174.23 (C-10).
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6022.
HRMS (EI): m/z 316.1530 (C15H24O7), calcd 316.1531.
Synthesis 1999, No. 2, 330–335 ISSN 0039-7881 © Thieme Stuttgart · New York