Highly functionalized trans-2,5-disubstituted tetrahydrofurans from ribofuranoside templates: Precursors to linked polycyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2003.09.126

Iodoetherification of C5 allylated ribo-furanosides leads to trans-2,5-disubstituted tetrahydrofurans with high selectivity. The application of this reaction to the synthesis of complex polycyclic ethers is illustrated in the preparation of a truncated, tricyclic analog of monensin A.

Full text of DOI:10.1016/j.tetlet.2003.09.126

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8365–8368
Highly functionalized trans-2,5-disubstituted tetrahydrofurans
from ribofuranoside templates: precursors to linked
polycyclic ethersꢀ
Darrin Dabideen and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021 and The Graduate Center, CUNY,
365 5th Avenue, New York, NY 10016, USA
Received 29 July 2003; revised 12 September 2003; accepted 16 September 2003
Abstract—Iodoetherification of C5 allylated ribo-furanosides leads to trans-2,5-disubstituted tetrahydrofurans with high selectiv-
ity. The application of this reaction to the synthesis of complex polycyclic ethers is illustrated in the preparation of a truncated,
tricyclic analog of monensin A.
© 2003 Elsevier Ltd. All rights reserved.
The easy accessibility and chemical constitution of sim-
ple carbohydrate derivatives make them attractive start-
ing materials for the synthesis of highly oxygenated
structures.1 In this vein, we have shown that the
iodoetherification of C6 allylated pyranosides 1 lead to
cis-2,5-disubstituted tetrahydrofurans (THFs) 2, with
functionalized branches, in high yields and stereoselec-
tivity (Scheme 1).2,3
Screening of templates for the analogous trans-THF
frameworks revealed high stereoselectivity C5 allylated
2,3-O-isopropylidene-ribofuranosides.4 The iodoether-
ification reaction was also found to be compatible with
polyene monosaccharide substrates, a result of rele-
vance to more complex syntheses. These findings are
illustrated herein, in the synthesis of 5, an advanced
precursor to an analog (i.e. 4), of the polyether anti-
biotic monensin A, 3.5,6 Less substituted structures like
4 are relevant to a clear understanding of substituent
effects on the kinetics and thermodynamics of cation
binding and transport (Fig. 1).7
Scheme 1.
Preliminary experiments with methyl 2,3-O-ribofura-
noside 6 displayed high trans-THF selectivity, but also
indicated a significant amount of iodohydrin products
8. The formation of this side product could be reduced
by using more bulky aglycones. The isopropyl deriva-
tive 9 was found to be the most practical in terms of its
synthesis and the efficiency of the iodoetherification.
We envisaged that a triene derivative like 10 could lead
to the product 11 which is primed for elaboration to
linked polycyclic ether frameworks.8 However, major
concerns were the chemoselectivity of the key
iodoetherification reaction with respect to the triene
Figure 1.
Keywords:
polyethers.
iodoetherification;
tetrahydrofuran;
acetogenins;
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.126
* Corresponding author. Tel: +1-212-772-4356; fax: +1-212-772-5332;
e-mail: dmootoo@hunter.cuny.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.126

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D. Dabideen, D. R. Mootoo / Tetrahedron Letters 44 (2003) 8365–8368
water. This led to the desired product 11, but was
accompanied by an appreciable amount of products
that appeared to be arising from electrophilic attack on
the other alkenes. Optimal results were obtained by
pouring a premixed solution of 10 and IDCP into a
saturated solution of aqueous sodium thiosulfate. These
conditions afforded a 75% yield of 11 (based on 60%
conversion of 10, for reactions on up to 20 g scale),
with a trans:cis selectivity of greater than 20:1.12 The
stereochemistry of the THF isomers was assigned on
the basis of the results obtained in the cyclization of a
very closely related furanoside alkene substrate,13 and
the accepted mechanism of anti-addition in the
iodoetherification of alkenes (Scheme 4).14
The first step in transformation of 11 to 5 was the
olefination of aldehyde 11, under standard stabilized
ylide conditions. The E/Z (10/1) mixture of unsaturated
esters 18E/Z was next treated with AD-mix-b to
provide a mixture 19E/Z as a single vicinal diol
diastereomer in 55% yield, as determined by 13C and 1H
NMR analysis. The stereochemistry of the vicinal diol
was based on the high stereoselectivity that has been
observed for ‘AD-mixes’ and E-disubstituted alkenes
that are remote from resident stereogenic centers.15
That the reaction of 18E with AD-mix a gave a single,
diastereomeric diol product that was different from
19E, supports this argument. The moderate yield of
19E/Z was due to side products that arose from com-
peting dihydroxylation of the terminal alkene. Opti-
mization of the synthesis by utilization of these side
products is conceivable. Formation of the second THF
ring was effected by the reaction of dihydroxyiodide
19E/Z with dibutyltin oxide in benzene.16 These condi-
tions were found to be superior to base mediated
procedures, which led to side products resulting from
dehydroiodination. Dissolving metal reduction (Mg,
methanol) of bis-THF 20E/Z,17 followed by exposure
of the crude product to acidic conditions (CSA, molec-
ular sieves) provided lactone 21 in 60% overall yield
from 20E/Z.18 Thus the transformation of 11 to the
tricyclic skeleton of target compound 5 was accom-
plished in five simple operations. Protection of the
lactone 21 as the orthoester, followed by configura-
tional inversion of the homoallylic alcohol via the
Mitsonobu procedure,19 provided 5. The gross structure
of 5 was confirmed by NMR and HRMS analysis, and
the stereochemistry assigned on the basis of the well
documented stereoselectivity and specificity of the reac-
tions involved in the synthesis.20
Scheme 2.
Scheme 3. Reagents and conditions: (a) acetone, iPrOH,
CuSO4, H2SO4, 64%; (b) TsCl, Et3N, DMAP, CH2Cl2, (99%);
(c) AllylMgBr, TMEDA, Et2O, (80%); (d) O3, MeOH,
CH2Cl2, −78°C then Ph3P; (e) DIBALH, CH2Cl2, −78°C; (f)
Ph3P, I2, imidazole, CH2Cl2, 78% two steps; (g) Ph3P,
(iPr)2NEt, CH3CN, toluene, reflux, 87%; (h) 17,
NaN(SiMe3)2, toluene, −78°C, then 15, (75%).
residue, and the development of concise routes from 11
to the desired targets. These issues were examined
within the context of the truncated monensin A analog
5 (Scheme 2).
Furanoside triene 10 was obtained in a straightforward
fashion.9 Thus,
D
-ribose was transformed in a single
step to isopropyl 2,3-O-isopropylidene- -ribo-furano-
D
side 13 via a known procedure.10 Treatment of the
derived tosylate 14 with allylmagnesium bromide pro-
vided the C5 allylated furanoside 9. Ozonolysis of 9
gave aldehyde 15. Wittig reaction of 15 and the phos-
phorane obtained from phosphonium salt 17 led to the
desired triene in 75% yield with a Z/E selectivity of
greater than 95%, as determined from NMR analysis.
The phosphonium salt 17 was prepared from E-methyl
1,4-octadienoate via standard procedures (Scheme 3).11
In summary, the application of readily available isopro-
pyl 2,3-O-isopropylidene ribofuranoside as a precursor
to highly functionalized trans-2,5-disubstituted THFs
has been demonstrated. The observation that the key
iodocyclization reaction is compatible with polyene
substrates suggests that it should be possible to access
polyether systems of varying stereochemistry and
degrees of oxygenation, by altering the polyene residue.
As illustrated in the synthesis of 5, the methodology
appears to be especially well suited to linked polycyclic
ether frameworks found in the polyether antibiotics,21
and to the related motifs in the acetogenin group of
The iodocyclization of 10 was initially performed by
addition of iodonium dicollidine perchlorate (IDCP) to
a solution of 10 in a mixture of dichloromethane and

D. Dabideen, D. R. Mootoo / Tetrahedron Letters 44 (2003) 8365–8368
8367
Scheme 4. Reagents and conditions: (a) Ph3PꢀCHCO2Me, CH3CN, reflux (95%); (b) AD-mix b, MeSO2NH2, t-BuOH, H2O, −3°C
,
(55%); (c) Bu2SnO, PhH, Dean–Stark, reflux (86%); (d) (i) Mg, MeOH, reflux; (ii) CSA, CH2Cl2, 4 A MS, reflux, 60% two steps;
(e) ethylene glycol, CSA, Dowex 50WX8-400, PhH, MgSO4, reflux (89%); (f) (i) PPh3, DEAD, p-NO2-C6H4COOH, toluene; (ii)
3N aq. NaOH, EtOH, reflux 50% two steps.
natural products.22 Further investigations in these
directions are in progress.
Zhang, H.; Mootoo, D. R. J. Org. Chem. 1995, 60,
8134–8135; (b) Zhang, H.; Seepersaud, M.; Seepersaud,
S.; Mootoo, D. R. J. Org. Chem. 1998, 63, 2049–2052; (c)
Ruan, Z.; Mootoo, D. R. Tetrahedron Lett. 1999, 40,
49–52; (d) Dabideen, D.; Ruan, Z.; Mootoo, D. R.
Tetrahedron 2002, 58, 2077–2084.
Acknowledgements
5. Agtarap, A.; Chamberlin, J. W.; Pinkerton, M.; Stein-
rauf, L. J. Am. Chem. Soc. 1967, 84, 5737–5739.
6. Total syntheses of monensin A: (a) Fukayama, T.;
Akasaka, K.; Karanewsky, D. S.; Wang, C. L. J.;
Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101,
262–263; (b) Collum, D. B.; McDonald, J. H.; Still, W. C.
J. Am. Chem. Soc. 1980, 102, 2120–2121; (c) Ireland, R.
E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc.
1993, 113, 7166–7172.
Support was provided by NIGMS MBRS SCORE
grant 5 SO6 GM60654-02 to Hunter College. ‘Research
Centers in Minority Institutions’ award RR-03037 from
the National Center for Research Resources of the
NIH, which supports the infrastructure {and instru-
mentation} of the Chemistry Department at Hunter, is
also acknowledged.
7. (a) Peyrat, J.-F.; Figade`re, B.; Cave, A. Tetrahedron Lett.
1995, 36, 7653–7656; (b) Wang, X.; Erickson, S. D.;
Iimori, T.; Still, W. C. J. Am. Chem. Soc. 1992, 114,
4128–4137; (c) Li, G.; Still, W. C. Tetrahedron Lett. 1993,
34, 919–922.
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8368
D. Dabideen, D. R. Mootoo / Tetrahedron Letters 44 (2003) 8365–8368
(s, 3H), 1.68 (m, 1H), 1.77 (m, 2H), 1.89 (m, 1H),
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(m, 3H), 1.83 (m, 6H), 1.98 (m, 1H), 2.13 (m, 1H), 2.31
(m, 1H), 3.21 (br s, 1H, OH), 3.53 (m, 2H), 3.72 (m, 2H),
3.84 (m, 4H), 4.01 (m, 1H), 4.13 (m, 1H), 5.03 (dd,
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ether); IR (CHCl3 film) 3452, 1737, 1641 cm−1; H NMR
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1H), 1.50–1.80 (m, 8H), 1.93 (m, 1H), 2.02 (m, 1H), 2.34
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