A furan route to the asymmetric synthesis of trans-fused polyether building blocks

Article abstract of DOI:10.1016/j.tetlet.2003.09.076

A novel route towards chiral trans-fused polyether lactones 7 and 12 has been developed starting with commercially available furfural. Sharpless kinetic resolution and ring-closing metathesis reactions served as key steps in the strategy.

Full text of DOI:10.1016/j.tetlet.2003.09.076

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8227–8228
A furan route to the asymmetric synthesis of trans-fused
polyether building blocks
Urlam Murali Krishna, G. S. C. Srikanth and Girish K. Trivedi*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Received 6 August 2003; revised 3 September 2003; accepted 11 September 2003
Abstract—A novel route towards chiral trans-fused polyether lactones 7 and 12 has been developed starting with commercially
available furfural. Sharpless kinetic resolution and ring-closing metathesis reactions served as key steps in the strategy.
© 2003 Elsevier Ltd. All rights reserved.
Recently, synthesis of trans-fused polycyclic ethers has
received considerable attention due to their presence in
a variety of marine natural products with interesting
biological activities.1 After the first characterization of
brevetoxin B in 1981,2 many marine polycyclic ethers of
this type as exemplified by brevetoxins, ciguatoxins,
yessotoxin, gambierol, gambieric acids and maitotoxins,
have been reported. The imposing structural features
coupled with the impressive biological properties of
these natural products gave impetus for the develop-
ment of numerous synthetic methods for the construc-
tion of cyclic ethers. In this communication we report a
flexible and efficient approach to the synthesis of chiral
trans-fused polyether subunits from racemic 2-
furylcarbinols.
Our synthesis commenced with the preparation of
furylmethanol rac-2, by the Grignard reaction of the
commercially available furfural with vinylmagnesium
bromide (60% yield) (Scheme 1). The chiral furyl-
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide (1 M in THF), 60%; (b) Ti(O-i-Pr)4, L-(+)-DIPT, t-BuOOH,
CH2Cl2, −21°C, 30 h, 39%; (c) NBS, THF–H2O (4:1), 0°C, 0.5 h, 97%; (d) EVE, PPTS (cat.), CH2Cl2, 0.5 h, 82%; (e) NaBH4,
CeCl3·7H2O, MeOH, −60°C, 74%; (f) NaH, allyl bromide, n-Bu4NI, THF–DMF (4:1), 0°C–rt, 90%; (g) PPTS, Me2CO–H2O (4:1),
0.5 h; (h) MnO2, pyridine (cat.), CH2Cl2, 1 h, 80% (2 steps); (i) Grubbs’ catalyst (6 mol%), benzene, rt, 94%.
Keywords: furfural; kinetic resolution; ring-closing metathesis (RCM); polyether lactones.
* Corresponding author. E-mail: chgktia@chem.iitb.ac.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.076

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U. Murali Krishna et al. / Tetrahedron Letters 44 (2003) 8227–8228
methanol (R)-2 was obtained from rac-2, employing
the kinetic resolution of 2-furylcarbinols as developed
by Honda3 and Sato.4 Oxidative ring expansion of
(R)-2 using NBS in THF–H2O (4:1)5 afforded the
hydroxypyranone 3b in 97% yield. The anomeric
hydroxyl was protected as its ethoxyethyl (EE) ether
and the keto group was stereoselectively reduced under
Luche’s conditions (NaBH4–CeCl3, −60°C) to afford
the alcohol 4.6 The diastereomeric mixture of alcohols 4
was converted into the allyloxy derivative 5 (quantita-
tive), which was subsequently transformed to the
homochiral lactone 6 by deprotection of the anomeric
hydroxyl group (PPTS, Me2CO–H2O) followed by oxi-
dation with MnO2. The lactone 6 when treated with
Grubbs’ catalyst7 [benzylidene-bis(tricyclohexylphos-
phine)-dichlororuthenium] (6 mol%) in benzene at
room temperature, smoothly underwent ring-closing
metathesis to furnish the bicycle 7 in 94% yield.8
In conclusion, we have developed a facile route to the
asymmetric synthesis of polyether intermediates 7 and
12 from commercially available and inexpensive fur-
fural. A particular merit of this approach is that by
choosing an appropriate Grignard reagent it may be
possible to obtain oxacycles of various ring sizes. We
have demonstrated this for six- and seven-membered
rings; their enantiomers could be synthesized by using
the enantiomeric tartrate ester in the enantioselective
step.
Acknowledgements
We thank Department of Science and Technology, New
Delhi (India) for the financial support and fellowship to
UMK.
After preparing the chiral lactone 7, we attempted to
extend this simple protocol for the synthesis of
homologous chiral cyclic ether subunits as shown in
Scheme 2. Furylmethanol rac-8, obtained from furfural
by treatment with allylmagnesium bromide, was trans-
formed into the optically active furylmethanol (R)-8
([h]2D5 +36.2 (c 1.52, CHCl3), lit. [h]2D5 +39.9 (c 1.54,
CHCl3)) by employing kinetic resolution conditions.4
(R)-8 was oxidatively rearranged to the hemiacetals 9
using VO(acac)2/t-BuOOH. The (2R)-pyranone 9 was
then converted to intermediates 10 and 11 following the
reaction conditions given in Scheme 1 (conditions d–f,
and g, h). Dienes 10 and 11, on Grubbs’ ring-closure
olefin metathesis, gave compounds 12 and 13 in 88%
and 80% yields, respectively.8
References
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J.; Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem.
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1 1990, 639; (c) Honda, T.; Kametani, T.; Kanai, K.;
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1990, 1733.
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Kobayasho, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085.
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8. Selected data of compound 7: [h]2D5 +0.42 (c 0.48, CHCl3).
IR (neat) wmax 1731, 1645 cm−1 1H NMR (300 MHz,
.
CDCl3) l 6.96 (d, J=9.6 Hz, 1H), 6.02–5.98 (m, 2H),
5.87–5.83 (m, 1H), 4.71 (m, 1H), 4.4–4.2 (m, 3H). 13C
NMR (75 MHz, CDCl3) d 163.4, 148.0, 128.5, 124.4,
120.9, 74.9, 70.9, 67.1.
12: [h]2D5 −26.1 (c 1.57, CHCl3). IR (neat) wmax 1740, 1645
1
cm−1. H NMR (300 10 MHz, CDCl3) l 6.89 (dd, J=2.2,
Scheme 2. Reagents and conditions: (a) allyl bromide, Mg
4.4 Hz, 1H), 6.0–5.7 (m, 3H), 4.4–4.0 (m, 4H), 2.9–2.6 (m,
2H). 13C NMR (75 MHz, CDCl3) l 162.7,148.9, 131.4,
125.8, 119.8, 78.6, 78.4, 68.6, 34.0.
(excess), Et2O, 70%; (b) Ti(O-i-Pr)4, L-(+)-DIPT, t-BuOOH,
CH2Cl2, −21°C, 36 h, 42%; (c) t-BuOOH, VO(acac)2, CH2Cl2,
rt, 3 h, 91%; (d) EVE, PPTS (cat.), CH2Cl2, 0.5 h, 82%; (e)
NaBH4, CeCl3.7H2O, MeOH, −60°C, 76%; (f) NaH, allyl
bromide, n-Bu4NI, THF–DMF (4:1), 0°C–rt, 94%; (g) PPTS,
Me2CO–H2O (4:1), 0.5 h; (h) MnO2, pyridine (cat.), CH2Cl2,
1 h, 80% (2 steps); (i) Grubbs’ catalyst (5 mol%), benzene, rt,
88% for 12, 80% for 13.
13: [h]2D5 +5.55 (c 0.36, CHCl3). 1H NMR (300 MHz,
CDCl3) l 6.0–5.6 (m, 5H), 5.2–4.8 (m, 2H), 4.4–4.3 (m,
1H), 4.1–4.0 (m, 1H), 3.8–3.4 (m, 3H), 2.4–2.2 (m, 2H),
1.2–1.0 (m, 6H). HRMS calculated for C13H20O4:
240.1362, found 240.1403.