Stereoselective iodine-induced cyclisation of alkene acetals. Application to the synthesis of 3-deoxy-exo-glycals and substituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2004.03.091

2,5-Substituted tetrahydrofurans have been stereoselectively prepared by a iodine-induced cyclisation of alkene acetals, and the iodo derivatives obtained were transformed into 3-deoxy-exo-glycals and in polyhydroxy substituted tetrahydrofurans.

Full text of DOI:10.1016/j.tetlet.2004.03.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3721–3724
Stereoselective iodine-induced cyclisation of alkene acetals.
Application to the synthesis of 3-deoxy-exo-glycals and substituted
tetrahydrofurans
a
*
*
ꢀ
Pineda Molas, M Isabel Matheu and Sergio Castillon
ꢀ
ꢀ
ꢀ
ꢁ
Departament de Quımica Analıtica i Quımica Organica, Universitat Rovira i Virgili, Pl. Imperial Tarraco 1, 43005 Tarragona, Spain
Received 10 February 2004; revised 15 March 2004; accepted 16 March 2004
Abstract—2,5-Substituted tetrahydrofurans have been stereoselectively prepared by a iodine-induced cyclisation of alkene acetals,
and the iodo derivatives obtained were transformed into 3-deoxy-exo-glycals and in polyhydroxy substituted tetrahydrofurans.
Ó 2004 Elsevier Ltd. All rights reserved.
exo-Glycals1 have not been studied as much as the
corresponding endo-glycals, which are valuable inter-
mediates in synthesis.2;3 However, enol ether function of
exo-glycals1;4 also allows many interesting transforma-
tions, specially those directed to the synthesis of C-gly-
cosides and C-disaccharides.5 exo-Glycals have been
obtained by reacting a sugar lactone with the Tebbe
reagent6 (Scheme 1, path a), by Wittig type olefination
of glycosylphosphonium salts7 or sugar lactones8 (path
€
b), by a Ramberg–Backlund rearrangement of S-glyco-
sides9 (path c), by reacting 1-methyl endo-glycals with
bromine and elimination (path d),10 by reductive elimi-
nation of bromoketoses in Fisher–Zanch conditions11
(path e), by nucleophilic addition to sugar lactones12
or C-formylglycosides and elimination13 (path f) and
by halogens,14 sulfonate groups15 or selenoxide
O
O
Ph P=CHCOOMe
3
O
SO2CHRR'
R=H, R'=CO Me
2
path c
path b
Ramberg-Bäcklund
rearrangement
R=R'=H
Cp TiMe
(Tebbe reagent)
2
2
O
path a
R=R'=H
path d
O
R
Br , base
2
R=R'=H
R'
Elimination
R=R'=H
Zn/HOAc
Fischer-Zanch
R=R'=H
path g
O
path f
O
path e
Ar-M
R=Ar, R'=H
O
Br
X
X= I, Se(O)Ph, Ms
OBz
CHO
Scheme 1.
Keywords: Stereoselectivity; Cyclisation; exo-Glycals; Tetrahydrofurans.
* Corresponding authors. Tel.: +34-977559556; fax: +34-977559563; e-mail addresses: matheu@quimica.urv.es; castillon@quimica.urv.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.091

3722
P. Molas et al. / Tetrahedron Letters 45 (2004) 3721–3724
eliminations16 (path g). Recently, we reported the
preparation of 3,4-dideoxy-exo-glycals as intermediates
in the synthesis of C01-fluoromethyl-ddI.17
In order to obtain tetrahdyrofuran derivatives with a
defined stereochemistry, we focused in the Dabideen and
Mootoo work24 about the cyclisation of cyclic alkene-
acetals induced by (I(sym-coll)2ClO4).25 Thus, com-
pounds 3 and 7 were treated with (I(sym-coll)2ClO4) in a
mixture of CH3CN and H2O (Scheme 3) to give the
tetrahydrofuran derivatives 10 and 1326;27 in a complete
stereoselective way. Reaction of 10 and 13 with BzCl
afforded compounds 11 and 14, respectively, in quanti-
tative yields.
However, 3-deoxy-glycals have been studied consider-
ably less, and there are only a few reports, which
describe their synthesis based on the Wittig reaction
starting from the glycosylphosphonium salts of 2-deoxy-
carbohydrates.18
In this paper we report a short and stereoselective pro-
cedure for synthesising substituted tetrahydrofurans and
3-deoxy-furanoid glycals of erythro and threo configu-
ration, based on a stereoselective iodine-induced cycli-
sation of alkene acetals.
exo-Glycals were obtained by treating 11 and 14,
respectively, under basic conditions14 (Scheme 3). The
elimination was attempted with AgF and DBU, but the
results where best with t-BuOK. In this case the starting
material reacted to give the exo-cyclic glycals 12 and
15,28 of threo and erythro configuration, respectively, in
good yields. The exo-glycals proved to be stable enough
to be characterised by NMR techniques but slowly
isomerised to endo-glycals when they were left to stand,
particularly compound 12. This was proved by the
progressive appearance in the 1H NMR spectra of a
methyl group attached to position 1 of an endo-glycal.
As it was mentioned before exo-glycals can be synthes-
ised by an elimination reaction from iodomethyl-tetra-
hydrofuran derivatives, which in turn are commonly
synthesised from pentoses by a Wittig olefination and
subsequent iodine-induced cyclisation.19 The stereo-
selectivity of this cyclisation is controlled by the allylic
substituent,20 but mixtures of diasteromers are usually
obtained in their absence.
Stereoselective synthesis of alkenols 2 and 6 from gly-
ceraldehyde (1) by using appropriate chiral allylborane
reagents21 and titanium reagents22 has been reported
(Scheme 2). Free hydroxyl groups of compounds 2 and 6
were protected by reaction with BnBr to give the benzyl
ether derivatives 3 and 7, respectively, in good yields.
RO
RO
c
O
O
a
3
I
I
OBn
RO
10 R=H
11 R=Bz
12
b
Initially, we deprotected the acetal group in compounds
3 and 7, to give the alkenediols 4 and 8, which were
submitted to the iodine-induced cyclisation under
kinetic control (Scheme 2). Labelle et al.23 reported that
electronegative homoallylic groups can control the ste-
reoselectivity of the reaction. The resulting product has
this group and the iodomethyl chain in a trans relative
disposition. Cyclisation of 4 and 8 proceeded with good
yields to give the iododerivatives 5 and 9, respectively,
but diastereoselectivities were very low. The relative
stereochemistry of the resulting diastereomers was
determined after carrying out NOE experiments.
a
OBn
O
OR
RO
RO
c
7
O
13 R=H
14 R=Bz
15
b
Scheme 3. Reagents and conditions: (a) Ag(sym-coll)2ClO4, I2,
CH3CN, H2O, rt, 1 h (10: 63%, 13: 64%); (b) BzCl, Py, DMAP, rt, 2 h,
t
100%; (c) BuOK, CH2Cl2, 1–6 h (12: 43%, 15: 100%).
O
HO
OH
c
d
O
O
HO
HO
I
OR
a
a
OR
OBn
O
O
2 R=H
3 R=Bn
4
5
H
b
b
O
1
OH
O
OR
O
c
HO
d
O
I
OBn
OR
8
9
6 R=H
7 R=Bn
Scheme 2. Reagents and conditions: (a) Ref. 21. (b) NaH, BnBr, THF, 0 °C–rt, 16 h, 85%; (c) DOWEX/Hþ, MeOH, rt, 6 h, 100%; (d) I2, NaHCO3,
CH3CN, 0 °C, 15 min, (5: 86%, 9: 90%).

P. Molas et al. / Tetrahedron Letters 45 (2004) 3721–3724
3723
OR2
O
(d) Bandzouzi, M.; Lakhrissi, Y.; Chapleur, Y. J. Chem.
Soc., Perkin Trans. 1 1992, 1471; (e) Chapleur, Y. J. Chem.
Soc., Chem. Commun. 1984, 449.
R1O
OBn
O
BzO
a
b
14
OR3
OpNO2Bz
9. (a) Campbell, A. D.; Paterson, D. E.; Raynham, T. M.;
Taylor, R. K. J. Chem. Commun. 1999, 1599; (b) Griffin,
F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 8179.
16
17 R1=R3=H, R2=Bn
18 R1=Bz, R2=H, R3=pNO2Bz
Scheme 4. Reagents and conditions: (a) KOCOPhpNO2, 18-crown-6,
DMSO, 90 °C, 2 h, 64%; (b) EtOAc, NaBrO3, Na2S2O4, H2O, rt, 3 h,
62% (18).
ꢀ
ꢀ
10. Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, C.
Chem. Commun. 2002, 2022.
11. Lichtenthaler, F. W.; Hahn, S.; Flath, F.-J. Liebigs Ann.
1995, 2081.
12. Yang, W. B.; Chang, C. F.; Wang, C. F.; Teo, C. F.; Lin,
C. H. Tetrahedron Lett. 2001, 42, 4657.
13. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36,
195.
Tetrahydrofuran rings are present in a broad spectrum
of biological molecules.29 Then, we considered the
selective conversion of iodine derivative 14 in a differ-
ently protected polyhydroxylic derivative. For that, 14
was treated with KOCOPhpNO2 in dimethylsufoxide to
obtain compound 16 in 64% yield. Hydrolysis of com-
pound 16 to give 17 is a straightforward process.
However, when deprotection of benzyl group in 16
under hydrogenolytic conditions was tried, reduction of
nitro group was exclusively produced. Finally, 18 could
be obtained by using NaBrO3/Na2S2O4 (Scheme 4).30
€
14. (a) Tatibouet, A.; Rollin, P.; Martin, O. R. J. Carbohydr.
Chem. 2000, 19, 641; (b) Hirota, K.; Takasu, H.; Tsuji, Y.;
Sajiki, H. Chem. Commun. 1999, 1827.
15. Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky, S. J.;
Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996, 118,
2825.
16. Kobayashi, Y.; Fujimoto, T.; Fukuyama, T. J. Am. Chem.
Soc. 1999, 121, 6501.
ꢀ
17. Molas, P.; Dıaz, Y.; Matheu, M. I.; Castillon, S. Synlett
ꢀ
2003, 207.
In conclusion, we have developed a stereoselective pro-
tocol for the synthesis of 2,4,5-trisubstituted tetra-
hydrofurans, and of 3-deoxy-furanoid-exo-glycals,
based on a iodine-induced stereoselective cyclisation of
alkene acetals.
ꢀ
ꢀ
ꢁ
18. (a) Jaouen, V.; Jegou, A.; Lemee, L.; Veyrieres, A.
Tetrahedron 1999, 55, 9245; (b) Lieberknecht, A.; Griesser,
H.; Bravo, R. D.; Colinas, P. A.; Grigera, R. J. Tetra-
hedron 1998, 54, 3159.
€
19. Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc.,
Chem. Commun. 1981, 375.
ꢀ
20. (a) Bravo, F.; Castillon, S. Eur. J. Org. Chem. 2001, 507;
ꢀ
ꢀ
(b) Bravo, F.; Dıaz, Y.; Castillon, S. Tetrahedron: Asym-
metry 2001, 12, 1631, and references cited therein.
21. (a) Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60,
3806; (b) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.;
Straub, J. A.; Palkowitz, A. D. J. Org. Chem. 1990, 55,
4117.
22. Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org.
Chem. 2002, 67, 1982.
23. Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J. P.
J. Am. Chem. Soc. 1988, 110, 4533.
Acknowledgements
Financial support by DGESIC BQU2002-1155 (Minis-
ꢀ
terio de Educacion y Cultura, Spain) is acknowledged.
P.M. acknowledge Ministerio de Educacion y Cultura
for a grant. Technical assistance by the Servei de Re-
cursos Cientifics (URV) is acknowledged.
ꢀ
24. (a) Dabideen, D.; Mootoo, D. R. Tetrahedron Lett. 2003,
44, 8365; (b) Zhu, L.; Mootoo, D. R. Org. Lett. 2003, 5,
3475, and references cited therein.
References and notes
25. (a) Evans, R. D.; Magee, J. W.; Schauble, J. H. Synthesis
1988, 862; (b) Pauls, H. W.; Fraser-Reid, B. J. Am. Chem.
Soc. 1980, 102, 3956.
1. Taillefumier, C.; Chapleur, Y. Chem. Rev. 2004, 104, 263.
2. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380.
3. (a) Somsak, L. Chem. Rev. 2001, 101, 81; (b) Postema, M.
H. D. In C-Glycoside Synthesis; Rees, C. W., Ed.; CRC:
Boca de Raton, FL, 1995.
4. Taylor, R. J. K. Chem. Commun. 1999, 217.
5. (a) Alcaraz, M.-L.; Griffin, F. K.; Paterson, D. E.; Taylor,
R. J. K. Tetrahedron Lett. 1998, 39, 8183; (b) Gervay, J.;
Flaherty, T. M.; Holmes, D. Tetrahedron 1997, 53, 16355;
(c) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier: Exeter, 1995.
6. (a) Johnson, C. R.; Johns, B. A. Synlett 1997, 1406; (b)
RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51,
5458; (c) Wilcox, C. S.; Long, G. W.; Suh, H. Tetrahedron
Lett. 1984, 25, 395.
26. General method of cyclisation. A suspension formed with
Ag(sym-coll)2ClO4 (1.23 g, 2.61 mmol), CH3CN (7 mL)
and I2 (679 mg, 2.66 mmol) was stirred for 10 min at rt,
and was added a solution of alkeneacetal (3, 7) (500 mg,
1.91 mmol) in 6 mL of CH3CN/H2O (just two water
drops). After 1 h the reaction mixture was filtered, diluted
with 10%Na2S2O3, and extracted with CH2Cl2. The
organic layer was washed with 5% HCl, dried over MgSO4
and concentrated to dryness. Flash chromatography gave
compounds 10 and 13 (63% and 64% yield) as foams.
Compound 10: 1H NMR (300 MHz, CDCl3) d in ppm
(numbered as tetrahydrofuran derivatives): 7.38–7.22 (m,
5H, H–Ar), 4.52 (d, 1H, J ¼ 11:5 Hz, OCH2Ph), 4.45 (d,
1H, OCH2 Ph), 4.33–4.23 (m, 1H, H-5), 4.14 (dd, 1H,
J ¼ 8:7 Hz, H-2), 4.09–4.03 (m, 1H, H-3), 3.61 (dd, 1H,
J ¼ 11:7, 3.9 Hz, CH2OH), 3.50 (dd, 1H, J ¼ 11:7, 4.8 Hz,
CH2OH), 3.34–3.27 (m, 2H, CH2I), 2.95 (s, 1H, OH), 2.27
(ddd, 1H, J ¼ 13:2, 6.9, 6.9 Hz, H-4a), 2.03 (ddd, 1H,
J ¼ 13:2, 4.5, 4.5 Hz, H-4b). 13C NMR (75.4 MHz,
CDCl3) d in ppm: 137.4, 128.3, 127.6, 127.5, 84.2, 79.6,
78.7, 71.4, 62.4, 37.0, 10.1. Compound 13: 1H NMR
7. Ousset, J. B.; Mioskowski, C.; Yang, Y.-L.; Falck, J. R.
Tetrahedron Lett. 1984, 25, 5903.
8. (a) Lakhrissi, Y.; Taillefumier, C.; Chretien, F.; Chapleur,
ꢀ
Y. Tetrahedron Lett. 2001, 42, 7265; (b) Lakhrissi, Y.;
Chapleur, Y. Angew. Chem., Int. Ed. 1996, 35, 750; (c)
Lakhrissi, Y.; Chapleur, Y. J. Org. Chem. 1994, 59, 5752;

3724
P. Molas et al. / Tetrahedron Letters 45 (2004) 3721–3724
(300 MHz, CDCl3) d in ppm: 7.38–7.22 (m, 5H, H–Ar),
(300 MHz, CDCl3) d in ppm (numbered as 2,5-anhydro-
hex-1-enitol derivatives): 7.97 (d, 2H, J ¼ 8:1 Hz, H–Ar),
7.50–7.47 (m, 1H, H–Ar), 7.39–7.34 (m, 2H, H–Ar), 7.29–
7.20 (m, 5H, H–Ar), 4.64–4.52 (m, 3H, H-5, H-6), 4.40 (d,
1H, J ¼ 9:9 Hz, OCH2Ph), 4.36 (d, 1H, OCH2Ph), 4.30–
4.25 (m, 1H, H-4), 3.86–3.84 (m, 2H, H-1), 2.72–2.66 (m,
2H, H-3). 13C NMR (75.4 MHz, CDCl3) d in ppm: 166.5,
160.2, 137.5, 132.6, 129.6, 129.0, 128.5, 127.9, 127.6, 82.0,
80.4, 80.0, 71.5, 64.0, 37.0. Compound 15: 1H NMR
(300 MHz, CDCl3) d in ppm: 7.98 (d, 2H, J ¼ 7:9 Hz, H–
Ar), 7.50–7.48 (m, 1H, H–Ar), 7.41–7.38 (m, 2H, H–Ar),
7.28–7.19 (m, 5H, H–Ar), 4.63–4.49, 4.40–4.19 (2m, 7H, H-
1a, H-4, H-5, H-6, OCH2Ph), 3.85–3.84 (m, 1H, H-1b),
2.71–2.66 (m, 2H, H-3). 13C NMR (75.4 MHz, CDCl3) d in
ppm: 166.2, 160.0, 137.4, 132.8, 130.0, 129.5, 128.2, 128.0,
127.6, 81.5, 80.9, 80.8, 71.2, 63.5, 36.6.
4.56 (d, 1H, J ¼ 12:0 Hz, OCH2Ph), 4.35 (d, 1H,
OCH2Ph), 4.22–4.07 (m, 3H, H-2, H-3, H-5), 3.80 (dd,
1H, J ¼ 12:0, 5.2 Hz, CH2OH), 3.71 (dd, 1H, J ¼ 12:0,
4.6 Hz, CH2OH), 3.27–3.15 (m, 2H, CH2I), 2.59 (s, 1H,
OH), 2.29 (ddd, 1H, J ¼ 13:5, 6.0, 1.5 Hz, H-4a), 1.71
(ddd, 1H, J ¼ 13:5, 8.9, 5.0 Hz, H-4b). 13C NMR
(75.4 MHz, CDCl3) d in ppm: 137.5, 128.4, 127.9, 128.4,
82.3, 80.2, 76.6 71.3, 61.8, 38.2, 10.7.
27. For the use of a related product in the synthesis of
halichondrin see: Cooper, A. J.; Pan, W.; Salomon, R. G.
Tetrahedron Lett. 1993, 34, 8193.
28. General method of synthesis of exo-glycals 12, 15. To a
solution of 11, 14 (1 mmol) in CH2Cl2 (0.18 mL) was added
tBuOK (0.28 mmol) and let stir for 6 h. Afterwards the
reaction mixture was diluted with 10% Na2S2O3 and
extracted with CH2Cl2, the organic layer was dried over
MgSO4 and concentrated. Compounds 12 and 15 were
obtained in 43% and 100% yield, respectively. 12: 1H NMR
29. Faulkner, D. J. Nat. Prod. Rep. 1992, 9, 323.
30. Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 1999, 40, 8439.