Stereospecific debenzylative cycloetherification of carbohydrate-derived allylic alcohols, ethers and esters to form vinyl C-furanosides

Article abstract of DOI:10.1039/b718060h

Benzyl ether protected polyhydroxylated alkene compounds containing allylic alcohol, ether or ester functionality undergo a stereospecific cyclisation reaction upon treatment with TFA-acetonitrile-toluene with inversion of configuration at the allylic position and loss of a benzyl ether to give tetrahydrofurans. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718060h

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Stereospecific debenzylative cycloetherification of carbohydrate-derived
allylic alcohols, ethers and esters to form vinyl C-furanosidesw
Riccardo Cribiu and Ian Cumpstey*
Received (in Cambridge, UK) 22nd November 2007, Accepted 28th January 2008
First published as an Advance Article on the web 7th February 2008
DOI: 10.1039/b718060h
Benzyl ether protected polyhydroxylated alkene compounds
containing allylic alcohol, ether or ester functionality undergo
a stereospecific cyclisation reaction upon treatment with TFA–
acetonitrile–toluene with inversion of configuration at the allylic
position and loss of a benzyl ether to give tetrahydrofurans.
compounds identical to 6 (94%) and 7 (87%), respectively. A
mixture of inseparable compounds was also isolated. The
NMR spectra of this mixture were inconclusive, but MS
showed a peak at m/z 573, i.e. MNa+ for M = 550, indicating
the presence of an extra benzyl group, presumably arising
from random substitution by the benzylic cation (generated on
ring-closure) on the aromatic rings of the benzyl ethers. We
concluded that to optimise this cyclisation reaction, we should
try adding scavengers to remove this benzyl cation. However,
while the addition of various scavengers did result in a
decrease in the amount of benzylated by-products, it also led
to excessive debenzylation (Table 1, entries 3–5). Using less
acid (e.g. 70% TFA in water) gave less debenzylation but also
a slower reaction.
The occurrence of tetrahydrofuran (THF) motifs in a wide
variety of natural products ensures a continuing interest in
their synthesis.1 Carbohydrates have been used as cheap and
convenient starting materials2 for the synthesis of highly
substituted THFs, either as substructures of natural products3
or as non-natural compounds with interesting properties.4
C-furanosides, hydrolytically stable analogues of furanosides
in which the exocyclic glycosidic oxygen is formally replaced
by a methylene group resulting in a THF structure, are
relevant in glycobiology. For example, galactofuranosides5
or, very unusually, glucofuranosides6 are components of
bacterial polysaccharides, and structural analogues of these
compounds could be used to investigate biochemical processes
in bacteria, or possibly lead to new antibiotics.7
After some experimentation, we discovered that treatment
of 1 with 70% TFA in acetonitrile with 20 equiv. toluene gave
the cyclised product 4 in good yield, with excellent purity after
flash chromatography and with only traces of benzylated and
debenzylated by-products seen on TLC (Table 1, entry 6). A
mixture of 2- and 4-benzyltoluenes could be isolated, indicat-
ing that toluene was indeed acting as a scavenger. The epimeric
diol 2 also underwent cyclisation under these conditions to
give the diastereomeric THF 5 (Table 1, entry 7). The cyclisa-
tion reaction of 1 could be carried out on a 1 g scale under
these conditions (Table 1, entry 8).
Our own interest in THF synthesis began with the observa-
tion that treatment of the partially protected unsaturated
polyol 1 (easily obtained along with its C-1 epimer 2 by
treatment of tetrabenzyl glucose 3 with vinylmagnesium bro-
mide, Scheme 18) with 90% aqueous TFA resulted in the
formation of a major product, which was assigned the cyclic
structure 4 (Table 1, entry 1; HMBC showed that the benzyl
ether had been lost from O-4; for stereochemical assignment,
see below). Similar debenzylative cyclisations have been re-
ported before in iodoetherification reactions9,10 or for cyclisa-
tion reactions onto good SN2 leaving groups, e.g. sulfonates or
epoxides.11 Treatment of the epimer 2 under the same reaction
conditions gave a major product, a different compound, that
was also assigned a THF structure 5 (Table 1, entry 2). In both
cases, a number of by-products were seen, but only a single
stereoisomer of the respective THFs could be detected. The
most significant by-products in both reactions, easily separable
from the major products by column chromatography, were the
THFs 6 and 7 (Fig. 1), differing in structure from the major
products 4 and 5 by benzylation at O-5. This was proved by
benzylation (NaH, BnBr, DMF) of THFs 4 and 5 to give
We then prepared the respective bis-acetate (8 and 9) and
bis-para-bromobenzyl ether (10 and 11) derivatives of the two
diols 1 and 2 (Scheme 1), and subjected these compounds to
the same reaction conditions. In every case, a single cyclised
product was formed, all in very good isolated yields (Table 1,
entries 10–13). The stereochemical outcome of these reactions
followed that of the parent diols, i.e. acetylation or p-bromo-
benzylation of
4 gave 12 (Ac2O, py, 98%) or 14
(BrCH2C6H4Br, NaH, DMF, 92%), while 5 gave 13 (Ac2O,
py, 94%) or 15 (BrCH2C6H4Br, NaH, DMF, 88%).
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Stockholm, Sweden. E-mail: cumpstey@organ.su.se; Fax:
+46 (0)8 154908; Tel: +46 (0)8 674 7263
w Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/b718060h
Scheme 1 Reagents and conditions: (i) vinylmagnesium bromide,
THF, 0 1C - RT; 1, 65%; 2, 29%; (ii) Ac2O, py, DMAP; 8, 96%;
9, 95%; (iii) BrCH2C6H4Br, NaH, DMF; 10, 94%; 11, 94%.
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Table 1 Cyclisation of glucose-derived compounds
Scheme 2 Reagents and conditions: (i) vinylmagnesium bromide,
THF, 0 1C - RT; 17, 32%; 18, 53%; (ii) Ac2O, py, DMAP; 20,
92%; 21, 88%.
lated and debenzylated products were detected on TLC. The
galactose diacetates 20 and 21 underwent smooth and high
yielding ring-closure to give THFs 24 and 25 (Table 2, entries
3, 4). That the stereochemical outcome of the cyclisation
reaction was the same for diols and diacetates was proved
by acetylation of 22 and 23 (Ac2O, py) to obtain 24 (93%) and
25 (86%), respectively.
We assessed the stereochemistry of the C-glycosides by
comparison with literature NMR data. Compounds 4, 5, 24,
25 were converted to their respective saturated tetraacetates
26–29 by catalytic hydrogenation followed by peracetylation
(Scheme 3). Each of the tetraacetates 26–29 showed good
agreement in 13C chemical shift data with one of a known
series of a- or b- gluco or galacto configured C-furanoside
tetraacetates for C-2–C-6.13 Differences at C-1 would be due
to the significantly different aglycon in the literature com-
pounds. A second comparison between 4, 5, 22 and 23 and a
series of perbenzylated vinyl C-xylo- or arabinofuranopento-
sides14 (i.e. with the a- or b- gluco or galacto configurations at
C-1–C-4) corroborated this assignment: a good correlation for
C-1b, C-1a, C-1–C-4 was seen between each of 4, 5, 22 and 23
and one of the literature compounds. Chemical shifts for C-1
and C-2 were lower for a-configured compounds 5 and 23 than
for the b-compounds 4 and 22, while the shifts for C-4 were
lower for gluco 4 and 5 than for galacto 21 and 22 com-
pounds.13,14 Finally, 2D NOESY experiments on the perace-
tylated compounds with well separated signals (i.e. 26, 28 and
29) gave results consistent with our assignment (see ESIw).
This means that for all the cyclisation reactions reported
here, we see a stereospecific reaction with retention of config-
uration at C-4 and inversion of configuration at C-1. It is
expected that the allylic group should be more susceptible to
substitution reactions, either by an SN1 mechanism with an
intermediate stabilised allylic carbocation, or by an SN2
mechanism where the transition state can be stabilised by
the CQC p orbitals. Particularly interesting, then, is that we
see stereospecific substitution reaction of alcohols with inver-
sion of configuration under Brønsted acidic conditions. For all
four cases, no other diastereomeric products can be detected.
The same stereospecific reaction is seen with other leaving
groups, i.e. acetates or para-bromobenzyl ethers. Brønsted and
Lewis acid catalysed cyclisations of activated (i.e. allylic15 or
benzylic16,17) alcohols to give THF derivatives have been
reported before, but as far as we are aware, this is the first
time a cyclisation of this kind must be described as stereo-
specific.
Starting
Entry material
Scavenger
Solventa (equiv.)
Product
t/h (yield %)b
R
1
1
H
H
H
H
H
H
H
H
A
A
A
B
A
C
C
C
C
C
C
C
C
—
—
3
3
4
3
0.5
4 (65)c
5 (69)c
4 (37)
4 (34)
2
2
3
1
EtSH (10)
PhMe (16)
PhSMe (5)
PhMe (20)
PhMe (20)
PhMe (20)
—
PhMe (10)
PhMe (10)
PhMe (10) 10
PhMe (10) 10
4
1
d
5
1
—
6
1
7.5 4 (75)
7
2
8
8
9
5
5
5 (76)
4 (68)e
4 (55)
12 (80)
13 (86)
14 (82)
15 (81)
8
1
9
1
H
10
11
12
13
a
8
9
10
11
Ac
Ac
PBBf
PBBf
Solvent A: TFA–H2O, 90 : 10; B: TFA–H2O, 85 : 15; C:
b
TFA–MeCN, 70 : 30. Isolated yields. Product inseparable from
c
d
minor amounts of benzylated impurities. No product Reaction
e
f
carried out using 1 g of starting material. PBB = para-bromo-
benzyl.
We went on to investigate the reaction of galactose deriva-
tives. Addition of vinylmagnesium bromide to galactose hemi-
acetal 16 gave the open-chain diols 17 and 18 (Scheme 2). The
stereochemistry was proved by deprotection of 18 (Na in NH3 (l)
and THF, 71%) to give the known compound 19
(Fig. 1).12 Treatment of diols 17 and 18 with acetic anhydride
and pyridine gave the respective diacetates, 20 and 21.
Cyclisation of the galactose diols 17 and 18 under the
optimised reaction conditions gave THFs 22 and 23, respec-
tively, in lower yields than for glucose (Table 2, entries 1, 2).
The reactions were somewhat less clean than the cyclisation
reactions of the glucose derivatives 1 and 2, and some benzy-
The reaction products are vinyl C-furanosides. These are
potentially useful compounds as the vinyl group may be
Fig. 1
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Table 2 Cyclisation of galactose-derived compounds
Scheme 4 Reagents and conditions: (i) oct-1-ene (6 equiv.), Grubbs’
2nd generation catalyst (0.025 equiv.), CH2Cl2, reflux, 8 h, 89%.
Financial support from the Swedish Research Council
(Vetenskapsradet) and the Carl Trygger Stiftelse for Vetens-
kaplig Forskning is gratefully acknowledged.
Notes and references
1 For recent references see: S. Hanessian and G. J. Reddy, Synlett,
2007, 475–479; H. Kim, C. M. Wooten, Y. Park and J. Hong, Org.
Lett., 2007, 9, 3965–3968; D. C. Braddock, R. Bhuva, D. S. Millan,
Y. Perez-Fuertes, C. A. Roberts, R. N. Sheppard, S. Solanski, E. S.
E. Stokes and A. J. P. White, Org. Lett., 2007, 9, 445–448; T.
Nakato and S. Yamauchi, J. Nat. Prod., 2007, 70, 1588–1592.
2 F. W. Lichtenthaler and S. Mondel, Pure Appl. Chem., 1997, 69,
1853–1866.
3 For recent references, see: D. K. Mohapatra, S. Mohapatra and M.
K. Gurjar, Tetrahedron Lett., 2006, 47, 5943–5947; A. Cordero-
Vargas, B. Quiclet-Sire and S. Z. Zard, Org. Biomol. Chem., 2005,
3, 4432–4443.
Entry
Starting material
R
t/h
Product (yield %)a
1
2
3
4
a
17
18
20
21
H
H
Ac
Ac
10
10
5
22 (51)b
23 (60)b
24 (81)c
25 (84)c
5
Isolated yields. Reactions carried out in TFA–MeCN, 70 : 30
b
c
with 20 equiv. toluene or 10 equiv. toluene.
4 M. D. Smith, D. D. Long, D. G. Marquess, T. D. W. Claridge and
G. W. J. Fleet, Chem. Commun., 1998, 2039–2040.
5 D. C. Crick, S. Mahapatra and P. J. Brennan, Glycobiology, 2001,
11, 107R–118R.
6 T. C. Ray, A. R. W. Smith, R. Wait and R. C. Hignett, Eur. J.
Biochem., 1987, 170, 357–361.
7 D. J. Owen, R. J. Thomson and M. von Itzstein, Carbohydr. Res.,
2002, 337, 2017–2022; J. Kovensky, A. F. Cirelli and P. Sinay,
Carbohydr. Lett., 1999, 3, 271–276; J. Kovensky, M. McNeil and
P. Sinay, J. Org. Chem., 1999, 64, 6202–6205; A. Caravano, D.
Mengin-Lecreulx, J.-M. Brondello, S. P. Vincent and P. Sinay,
Chem.–Eur. J., 2003, 9, 5888–5898.
8 I. Cumpstey, Tetrahedron Lett., 2005, 46, 6257–6259.
9 S. D. Rychnovsky and P. A. Bartlett, J. Am. Chem. Soc., 1981, 103,
3963–3964.
10 F. Nicotra, L. Panza, F. Ronchetti, G. Russo and L. Toma,
Carbohydr. Res., 1987, 171, 49–57.
11 O. R. Martin, F. Yang and F. Xie, Tetrahedron Lett., 1995, 36,
47–50; B.-H. Yang, J.-Q. Jiang, K. Ma and H.-M. Wu, Tetrahe-
dron Lett., 1995, 36, 2831–2834; H. Dehmlow, J. Mulzer, C. Seilz,
A. R. Strecker and A. Kohlmann, Tetrahedron Lett., 1992, 33,
3607–3610; G. R. Gray, F. C. Hartman and R. Barker, J. Org.
Chem., 1964, 30, 2020–2025; L. V. R. Reddy, A. D. Roy, R. Roy
and A. K. Shaw, Chem. Commun., 2006, 3444–3446.
12 A. Palmelund and R. Madsen, J. Org. Chem., 2005, 70, 8248–8251.
13 B. Wright, L. R. Hughes, S. S. Qureshi and A. H. Davidson, Magn.
Reson. Chem., 1988, 26, 1062–1067.
14 R. Persky and A. Albeck, J. Org. Chem., 2000, 65, 5632–5638.
15 S. H. Kang and C. Y. Hong, Tetrahedron Lett., 1987, 28, 675–678;
M. A. Tabrizi, P.G. Baraldi, M. Guarneri, S. Manfredini, G. P.
Pollini and D. Simoni, Tetrahedron Lett., 1991, 32, 683–686.
16 W. Frick and R. R. Schmidt, Liebigs Ann. Chem., 1989, 565–570.
17 F. F. Huerta, C. Gomez, A. Guijarro and M. Yus, Tetrahedron,
1995, 51, 3375–3388; G. V. M. Sharma, K. R. Kumar, P. Sreenivas,
P. R. Krishna and M. S. Chorghade, Tetrahedron: Asymmetry,
2002, 13, 687–690; S. Yamauchi and Y. Kinoshita, Biosci. Bio-
technol. Biochem., 2001, 65, 1559–1567.
Scheme 3 Reagents and conditions: (i) H2, Pd(C), EtOAc–MeOH–H2O
(2 : 4 : 1); (ii) Ac2O, py, DMAP; 26, 66%; 27, 94%; 28, 95%; 29, 88%.
modified so that the molecules may be used as general
C-furanoside building blocks. It has been shown that fatty
chain derivatives of galactofuranose have antimycobacterial
properties.18 In order to demonstrate the potential utility of
these C-furanosides, we carried out
a cross-metathesis
reaction19 between glucose-derived THF 4 and oct-1-ene to
give the long-chain C-glucofuranoside 30 (Scheme 4).
In conclusion, we describe a straightforward procedure
whereby carbohydrate-derived allylic alcohols, ethers or acet-
ates undergo a stereospecific debenzylative cyclisation with
inversion of configuration at the allylic carbon. The reaction is
carried out at room temperature without the need for anhy-
drous conditions or an inert atmosphere. This gives vinyl C-
furanohexosides which may be derivatised at the aglycon
CQC double bond, for example by cross-metathesis.
18 C. B. Davis, R. D. Hartnell, P. D. Madge, D. J. Owen, R. J.
Thomson, A. K. J. Chong, R. L. Coppel and M. von Itzstein,
Carbohydr. Res., 2007, 342, 1773–1780.
19 O. Plettenburg, C. Mui, V. Bodmer-Narkevitch and C.-H. Wong,
Adv. Synth. Catal., 2002, 344, 622–626.
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1248 | Chem. Commun., 2008, 1246–1248