Benzyl ethers as nucleophiles: From hydroxy cyclooctanes toward bridged C-furanosides

Article abstract of DOI:10.1080/07328300902999329

Attempted Lewis acid-mediated opening of a benzyloxy-functionalized eight-membered ring epoxide resulted in an intramolecular nucleophilic attack by a favorably disposed benzyloxy group to give a bridged furanose. A corresponding intramolecular nucleophil

Full text of DOI:10.1080/07328300902999329

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Benzyl Ethers as Nucleophiles: From
Hydroxy Cyclooctanes Toward Bridged C-
Furanosides
Stefan Jürs a b & Joachim Thiem a
a Faculty of Science, Department of Chemistry , University of
Hamburg , Hamburg, Germany
b Department of Chemistry and Biochemistry , University of British
Columbia , Vancouver, B.C., Canada
Published online: 06 Jul 2009.
To cite this article: Stefan Jürs & Joachim Thiem (2009) Benzyl Ethers as Nucleophiles: From Hydroxy
Cyclooctanes Toward Bridged C-Furanosides, Journal of Carbohydrate Chemistry, 28:5, 293-297, DOI:
10.1080/07328300902999329
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Journal of Carbohydrate Chemistry, 28:293–297, 2009
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300902999329
Benzyl Ethers as Nucleophiles:
From Hydroxy Cyclooctanes
Toward Bridged C-Furanosides
Stefan Ju¨rs1 and Joachim Thiem2
1Faculty of Science, Department of Chemistry, University of Hamburg, Hamburg, Ger-
many; and Department of Chemistry and Biochemistry, University of British Columbia,
Vancouver, B.C., Canada
2Faculty of Science, Department of Chemistry, University of Hamburg, Hamburg,
Germany
Attempted Lewis acid-mediated opening of a benzyloxy-functionalized eight-membered
ring epoxide resulted in an intramolecular nucleophilic attack by a favorably disposed
benzyloxy group to give a bridged furanose. A corresponding intramolecular nucle-
ophilic attack of a benzyloxy group in a triflated cyclooctenol again gave a bridged
furanose derivative.
Keywords Hydroxy cyclooctanes; Bridged C-furanosides
The protection of hydroxyl functionalities as benzyl ethers by means of
deprotonation followed by reaction with a benzyl halide represents a
widespread method particularly in carbohydrate chemistry and oligosaccha-
ride synthesis.[1] The resulting benzyl ethers exhibit high stability under
acidic, basic, and oxidative conditions and are readily removed employing cat-
alytic hydrogenation. Since anionic benzyloxy groups have bad leaving group
properties, they may undergo 1,2-eliminations only under strongly basic condi-
tions if favorable steric and electronic prerequisites are met. The latter aspect
relates particularly to acidic vicinal protons that enhance the elimination ten-
dency of a benzyl ether substituent ultimately as benzyl alcohol.
Reactions in which the benzyl ether oxygen itself can act as a nucleophile
leading to ring closures are rarely described. The nucleophilic opening of an
iodonium ion intermediate 1 by the benzyl ether oxygen with concomitant
Received March 06, 2009; accepted April 27, 2009.
Address correspondence to Joachim Thiem, Faculty of Science, Department of Chem-
istry, University of Hamburg, Martin-Luther-King-Platz 6, D- 20146 Hamburg, Ger-
many. E-mail: thiem@chemie.uni-hamburg.de
This paper is dedicated to Professor Robert V. Stick on the occasion of his 65th birthday.
293

S. Ju¨rs and J. Thiem
294
C6H5
C6H5
I
O
I
Me
O
O
Me
Me
-(C7H7)
I
1
2
3
Scheme 1. Nucleophilic opening of an iodonium intermediate by the benzyl ether oxygen.
cleavage of the benzyl residue was observed and elaborated by Bartlett et al.
as a ring closing reaction for the construction of cis-2,5 disubstituted tetrahy-
drofuran derivatives such as 3 (Sch. 1).[2]
A corresponding transbenzylation of the 2,6-dideoxy glycopyranosyl chlo-
ride 5, obtained from 4 and oxalyl chloride, in an attempted glycosylation re-
action with the benzylated acceptor saccharide 7 was observed. This resulted
in 63% of an anomeric mixture of benzyl glycosides 8 (α : 27%, ß: 39%) appar-
ently via attack of the benzyloxy group at the intermediate oxocarbenium ion
structure 6 (Sch. 2).[3]
Along studies toward functionalized cyclooctanoid natural product
analogues,[4–6] several interesting and corresponding examples of intramolec-
ular tetrahydrofuran formations could be observed. Eight-membered ring sys-
tems feature a considerably more flexible carbocyclic framework compared to
their five- and six-membered counterparts.[7,8] Thus, a benzylether oxygen can
interact much more easily with electrophilic centers provided sufficient spa-
tial proximity is given and a thermodynamically stable ring system can be
formed.
Upon treatment of epoxide 9[5] with boron trifluoride in methanol/
tetrahydrofuran, none of the expected regioisomeric methyl ethers 10 and 11
could be isolated. Instead, a bicyclic ether system resulted via epoxide open-
ing by the 2-benzyloxy group of 9 to give exclusively one product in a good
yield of 79%. It is assumed that the cleavage of the benzyl substituent occurred
simultaneously and presumably released the mesomerically stabilized cation
(C7H7)+. Alternatively, intramolecular attack at C-6 would give the bridged
six-membered ring system 12, whereas opening at C-5 would result in forma-
tion of the bridged five-membered compound 13. Since the 1H NMR data (shifts
and couplings) are ambiguous, there is evidence by the 13C NMR data. In
C6H5
OBn
OpMBz
O
OpMBz
O
Me
MeO
O
O
Me
MeO
Me
MeO
X
Me
HO
OBn
O
OpMBz
- Cl
6
7
8
4 X = OH
5 X = Cl
Scheme 2. Transbenzylation instead of glycosylation of 2,6-dideoxy-ribohexopyranosides.

Benzyl ethers as nucleophiles
295
O
OH
O
OMe
OH
O
6
5
O
+
2
BnO
BnO
OMe
BnO
BnO
OBn
BnO
OBn
BnO
OBn
10
11
9
.
BF3 Et2O
MeOH/THF
O
O
O
O
6
5
OH
6
O
O
O
2
- (C7H7)+
79%
5
2
2
C6H5
BnO
OBn
BnO
OBn
BnO
OBn
12
13
Scheme 3. Regioselective intramolecular opening of an epoxide by a benzyl ether oxygen.
keeping with findings in structurally related eight-membered derivatives,[4–6]
the resonances of the ether carbons as well as the high field shift of the ter-
tiary alcohol carbon C-6 (δ 71.44) give evidence for formation of the bridged
furan structure 13.
In another experiment alcohol 14[4,5] was treated with triflic anhydride
in pyridine/dichloromethane at –25◦C to give the corresponding triflate. This
highly reactive intermediate 15 could not be isolated. Again, intramolecular
attack of the 3-O-benzyl group at C-6 from the bottom of the ring plane substi-
tuted the triflate. Under release of the benzyl cation (C7H7)+, the bicyclic ether
16 was obtained in 94% yield (Sch. 4).
In summary, we have shown two examples of intramolecular ring closures
based on the nucleophilicity of benzyloxy groups in conformationally flexible
medium-sized ring systems. The novel bridged tetrahydrofuran compounds
were obtained in good to excellent yields without detection of any byprod-
ucts. Apart from the interesting synthetic access to the isolated compounds
and the potential applicability of this approach in natural product synthesis,
they represent at the same time bridged C-furanoside derivatives due to their
Tf2O, Py
CH2Cl2, -25°C
O
6
3
HO
BnO
- OTf-
C6H5
TfO
OBn
OBn
O
- (C7H7)+
BnO
OBn
BnO
OBn
14
15
16
94%
Scheme 4. Intramolecular triflate substitution by a benzyl ether oxygen.

S. Ju¨rs and J. Thiem
296
oxygenated substitution pattern and might therefore be useful building blocks
for the construction of unnatural nucleotides.
For general methods cf. references 4–6.
(2S, 3R, 4S, 5S, 6R)-2,5-Anhydro-3,4-dibenzyloxy-
cyclooctan-2,5,6-triol-1-one (13)
A solution of (2S, 3R, 4S, 5R, 6R)-2,3,4-tribenzyloxy-5,6-epoxy-cyclooctane
9[5] (7.9 mg, 17 µmol) in tetrahydrofuran (0.8 mL) was treated with BF3· Et2O
(3.3 µL, 3.7 mg, 26 µmol) and methanol (0.1 mL) for 3 h at 70◦C. Addition
of some drops of triethylamine and dilution with dichloromethane (1 mL) re-
sulted in the raw material. This was purified by column chromatography on
silica gel with EtOAc/pet. ether 1:2 to give 13 (5 mg, 14 µmol, 79%) as a color-
20
546
less syrup. [α]
82.7 (c 0.36 in CHCl3). δH (400 MHz; CDCl3) 1.87–1.92 (2H,
m H7a,b), 2.34–2.40 (1H, m, H8b), 4.24 (1H, broad s, H4), 4.42, 4.43 (2 × 1H, 2
× d, OCH2), 4.46 (1H, dd, J4,5 = 0.5, J5,6 = 5.1, H5), 4.50 (1H, ddd, J2,3 = 8.9,
J3,4 = 2.0, H3), 4.54, 4.62 (2 × 1H, 2 × d, OCH2), 4.69 (1H, d, J2,3 = 8.9, H2),
7.27–7.38 (10H, m, Ar). δC (100 MHz; CDCl3) 27.41 (1C, C7), 37.72 (1C, C8),
71.44 (1C, C6), 71.67, 73.12 (2C, OCH2), 84.13 (1C, C4), 85.97 (1C, C2), 87.23
(1C, C5), 87.28 (1C, C3), 127.97, 128.04, 128.59 (10C, Ar), 137.32, 137.67 (2C,
Ar), 211.79 (1C, C1). Maldi-Tof calc. for C22H24O5 368.46, found [M+Na]+ 391
[M+K]+ 407.νmax(thin-film)/cm−1 1716 (C=O).
cis-(3S, 4R, 5R, 6R)-3,6-Anhydro-4,5-dibenzyloxy-cycloocten (16)
A solution of cis-(1S, 2R, 3R, 4S)-2,3,4-tribenzyloxy-cyclooct-5-en-1-ol 14[4,5]
(55 mg, 124 µmol) in dichloromethane (2 mL), and pyridine (40 µL, 40 mg,
495 µmol) was cooled to –25◦C. After addition of triflic anhydride (25 µL, 42
mg, 148 µmol) and stirring at –20◦C for 1 h, the mixture was slowly warmed
to rt and the solvents evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel with EtOAc/pet. ether 1:10
20
546
to give 16 (39 mg, 116 µmol, 94%) as a colorless syrup. [α]
–129.6 (c 1 in
CHCl3). δH (500 MHz, C6D6) 1.55–1.61 (1H, m, H7b), 1.85–1.99 (2H, m, H8b,
7a), 2.28–2.34 (1H, m, H8a), 4.01 (1H, dd, J4,5 = 4.3, J5,6 = 2.5, H5), 4.23, 4.26
(2 × 1H, 2 × d, OCH2), 4.33 (1H, dd, J3,4 = 6.8, J4,5 4.3 H4), 4.37, 4.41 (2 × 1H,
2 × d, OCH2), 4.45 (1H, dd, J5,6 = 2.5, H6), 4.69 (1H, dd ∼ t, J2,3 = 5.7, J3,4
6.8, H3), 5.63–5.66 (1H, dd, J1,2 = 11.7, J2,3 = 5.7, H2), 5.75 (1H, ddd, J1,2
=
=
11.7, H1), 7.07–7.32 (1OH, m, Ar). δC (100 MHz; C6D6) 25.35 (1C, C8), 33.32
(1C, C7), 71.93, 72.64 (2C, OCH2), 78.26 (1C, C3), 81.91(1C, C6), 88.36 (1C,
C5), 89.00 (1C, C4), 127.95, 127.99, 128.55, 128.58 (10C, Ar), 130.32 (1C, C2),
132.01 (1C, C1), 138.81, 138.92 (2C, Ar). Maldi-Tof calc. for C22H24O3 336.46,
found [M+Na]+ 359, [M+K]+ 375.

Benzyl ethers as nucleophiles
297
ACKNOWLEDGMENTS
Support of this study by the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (SFB 470) is acknowledged.
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