Synthesis of C-furanosides from a d-glucal-derived cyclopropane through a ring-expansion/ring-contraction sequence

Article abstract of DOI:10.1039/c0cc02244f

gem-Dibromocyclopropane 1, prepared from tri-O-benzyl-d-glucal, undergoes thermal and silver-promoted ring expansion in the presence of alcohols to give substituted oxepines. With further heating, ring contraction to highly substituted tetrahydrofurans fo

Full text of DOI:10.1039/c0cc02244f

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Synthesis of C-furanosides from a D-glucal-derived cyclopropane through
a ring-expansion/ring-contraction sequencewz
Russell J. Hewitt and Joanne E. Harvey*
Received 30th June 2010, Accepted 31st August 2010
DOI: 10.1039/c0cc02244f
gem-Dibromocyclopropane 1, prepared from tri-O-benzyl-D-glucal,
undergoes thermal and silver-promoted ring expansion in the
presence of alcohols to give substituted oxepines. With further
heating, ring contraction to highly substituted tetrahydrofurans
follows. These represent C-furanosides, potentially useful as
precursors to C-nucleosides and other carbohydrate mimics.
cyclopropane 1 with allyl alcohol and methanol. As with the
formation of acetate 5,4 a temperature of approximately
100 1C was necessary for efficient cyclopropane ring opening.
This is in striking contrast to ring expansions of the lower
homologues, bicyclo[3.1.0] systems, which typically proceed at
ambient temperature in the presence of silver salts.10 Synthesis
of the allyloxy compound 6 was carried out in refluxing allyl
alcohol (bp 98 1C), with silver acetate added to promote
bromide abstraction and ring opening (Scheme 2). As shown
in Table 1, the desired oxepine 6 was isolated as a mixture of
C1-epimers,y along with a small amount of the acetate product
5 (entry 1). To circumvent the formation of 5, use of a non-
nucleophilic counterion seemed prudent. However, the yield of
the expected product 6 obtained with silver nitrate (entry 2)
was no better than with silver acetate, despite the lack of a
competing nucleophilic silver counter-ion. It was postulated
that the nitric acid by-product is detrimental to the
acetal functionality within 6, and this was borne out by the
subsequent experiment in which the reaction was refluxed for
an extended time (entry 3). After 3 days, none of the expected
oxepine 6 was isolated; instead, three compounds bearing
highly functionalised tetrahydrofuran rings were obtained in
a combined yield of 51%. One was assigned the structure 7,
which contains a brominated enol ether side-chain. The
remaining two compounds appeared to be diastereomers
represented by structure 8. These assignments were made on
the basis of the obtained 1D and 2D NMR data,z8 and were
supported by mass spectrometry.
Carbohydrates are valuable chiral pool reagents1 due to their
degree of functionalisation and defined stereochemistries.
Cyclopropanation of carbohydrate scaffolds2 enables the
preparation of a diverse range of modified sugars, such as
C-branched glycosides3,4 and septanoside precursors.4–7
Carbohydrate mimics such as these are sought after for,
inter alia, their inhibition of carbohydrate-processing
enzymes.8 Halogenated cyclopropanes are widely used in
synthesis on account of their controllable chemistry.9 Jayaraman
and co-workers have demonstrated the utility of 2-oxyglycal-
derived gem-dihalocyclopropanes in generating a range of
septanosides, including di- and tri-saccharides.6 We have
recently shown that gem-dibromocyclopropane 1, derived
from D-glucal, provides 2-branched pyranosides 2–4 upon
treatment with basic oxygen nucleophiles (Scheme 1).4
Alternatively, silver-promoted ring expansion in the presence
of nucleophilic acetate efficiently delivers oxepine 5 in a
reasonable yield and as a 3.5 : 1 mixture of C1-stereoisomers.4
The pursuit of a range of seven-membered cyclic products
related to 5 led us to explore the silver-promoted reactions of
Use of silver trifluoroacetate as the promoter gave a mixture
of oxepine 6, tetrahydrofurans 7 and 8 after 3 days reaction in
allyl alcohol (entry 4). Finally, an attempt to ring expand
cyclopropane 1 in the absence of silver salts produced, after 2
days of refluxing in allyl alcohol, the tetrahydrofuran products
7 and 8 in a combined yield of 57% (entry 5).
In contrast to the reactivity with allyl alcohol, silver-
mediated reactions in methanol were sluggish and low yielding.
For instance, the silver acetate reaction resulted in 15% yield
of oxepines 9 alongside 61% recovered starting material 1
after 5 days (entry 6).4 This is because the requirement for high
temperature (ca. 100 1C) to promote the cyclopropane ring
expansion in this system is not met by methanol (bp 65 1C).
Thereafter, subjection of cyclopropane 1 to thermal ring
expansion in methanol was performed in a sealed tube under
microwave conditions14 (130 1C, ca. 8 bar) for 1 hour. The
enol ether 10 and acetal 11 (the latter as a mixture of two
stereoisomers) were isolated in a combined yield of 74%, and
no oxepine was observed (entry 7). When the microwave
reactions in methanol were halted prematurely (e.g. after only
10 minutes), the crude reaction mixtures contained oxepines 9
as well as traces of C-furanosides 10 and 11 (entry 8).
Scheme 1 Divergent reactions of D-glucal-derived cyclopropane 1.4
School of Chemical and Physical Sciences, Victoria University of
Wellington, PO Box 600, Wellington, New Zealand.
E-mail: joanne.harvey@vuw.ac.nz; Fax: +64 4 4635237;
Tel: +64 4 4635956
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for all new compounds. See
DOI: 10.1039/c0cc02244f
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 421–423 421

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Scheme 2 Formation of oxepines and/or substituted tetrahydrofurans from cyclopropane 1.
Table 1 Silver-mediated and thermal reactions of cyclopropane 1 in allyl alcohol or methanol
Yielda
6 or 9b
7 or 10
8 or 11b
5
1
Entry
ROH
Additive
Temperature
Time
1
2
3
4
5
6
7
8
CH2QCHCH2OH
CH2QCHCH2OH
CH2QCHCH2OH
CH2QCHCH2OH
CH2QCHCH2OH
CH3OH
AgOAc
AgNO3
AgNO3
AgOCOCF3
None
AgOAc
None
AgOAc
98 1C
98 1C
98 1C
98 1C
98 1C
65 1C
130 1C (MW)
100 1C (MW)
27 h
29 h
3 d
3 d
2 d
5 d
1 h
10 min
51%, 1.1 : 1
50%, 1 : 1.8
0%
22%, 1 : 1.8
0%
15%, 1 : 2.8
0%
4%, 3 : 1
0%
0%
15%
22%
12%
0%
0%
0%
4%
0%
0%
0%
0%
0%
0%
0%
13%
16%
0%
5%
0%
61%
4%
ca. 70%
36%, 1 : 2.5
8%, ca. 1 : 10c
45%, 1 : 1.6
0%
61%, 1 : 3
Trace
CH3OH
CH3OH
13%
Trace
a
Yields quoted are isolated yields, with the exception of compounds 1, 10 and 11 in entry 8, in which the quantity of compound 1 was estimated
b
from the 1H NMR spectrum of the crude reaction mixture, and 10 and 11 were detected by TLC. Ratios quoted are calculated from the yields of
the separated stereoisomers, and are shown as the isomer with higher TLC mobility followed by the more polar isomer. For 6 and 9, the isomers
c
have been assigned such that the ratios give b-anomer : a-anomer. This ratio is of the isolated but unseparated isomers of 8.
It appears that the C-furanosyl products are formed via the
oxepines upon heating of the cyclopropane ring expansion
reaction for prolonged times. In confirmation, heating a
solution of the major isomer of oxepine 6 in allyl alcohol at
reflux in the presence of silver nitrate gave, after one day, the
tetrahydrofurans 7 and 8, with only a trace of the oxepine 6
remaining in the crude reaction mixture (according to
1H NMR spectroscopy). Similarly, reaction of oxepine 6
(as a mixture of epimers) with allyl alcohol in the absence of
silver salts led to formation of the acetal isomers 8.
A likely mechanism for the formation of the C-furanoside
products from cyclopropane 1 is shown in Scheme 3. Cyclopropyl
ring opening is thermally allowed and is promoted by silver(I)
salts; attack on the intermediate 12 by an alcohol provides, after
deprotonation, the oxepine isomers 13. Acid-promoted ring
opening of the oxepine acetal and attack by the ring oxygen at
C3 of the highly activated, conjugated alkene in intermediate 14
would lead to the bromoenol ether 15. The observation of only a
single isomer of the isolated enol ethers 7 and 10 is consistent with
electron delocalisation in oxonium intermediate 14 and preferred
Scheme 3 Proposed mechanism of formation of tetrahydrofuran
attack of the hydroxyl group from one face of the alkene. The
products from cyclopropane 1.
bromoenol ether of 15 is highly reactive towards electrophilic
addition, and is converted into the acetal 16. The mechanistic
processes encompassing transformation of oxepine 13 into 15 and
16 are catalysed by acid and are related to those proposed by
Skattebøl in a less substituted system.15 It is noteworthy that the
reactions in which these tetrahydrofuran products dominate are
those in which a stoichoimetric amount of hydrogen bromide or
nitric acid is released upon cyclopropane opening and formation
of the oxepines (viz. Table 1, entries 3, 5, 7).
In conclusion, D-glucal-derived cyclopropane 1 undergoes
silver-mediated or thermal ring expansion in alcohol solvents
to provide complex oxepines. Further reaction leads to ring
contraction and the formation of a series of highly substituted
tetrahydrofuran derivatives (7 and 8, 10 and 11); these
represent new C-glycosides with potential for elaboration to
C-nucleosides and glycosidase inhibitors.
The products obtained are highly functionalised,
enantiomerically pure tetrahydrofurans.16 They are closely
related to intermediates used previously in the formation of
ulosonic acids17 and C-nucleosides.18,19
The authors gratefully acknowledge the Cancer Society of
New Zealand for a PhD scholarship (RJH). We extend our
thanks to Dr Brendan Burkett for advice and assistance with
the microwave experiments.
c
422 Chem. Commun., 2011, 47, 421–423
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Notes and references
y In the crude mixtures obtained from all the silver-mediated reactions of
1 in allyl alcohol, the ratio of allyloxy-substituted oxepines 6 was ca.
1 : 1.4, as judged by 1H NMR integration. The major allyloxy-
substituted oxepine epimer has been assigned as the 1S-isomer (the
a-anomer, using carbohydrate nomenclature) on the basis of a nOe
enhancement of the H-7 signal upon irradiation of H-1. Similar ratios
were observed in reactions with methanol, and the 1H and 13C NMR
shifts of the methoxy compounds correlated very closely with the allyloxy
derivatives, leading to assignment of the major component of 9 as the
a-anomer. However, the isolated ratios varied between experiments. For
instance, in Table 1, entry 1, the isomer that was isolated in a greater
quantity was actually the minor isomer. This indicates that erosion of the
true yield of the major isomer occurred during column chromatography
in our efforts to obtain pure material.
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z The enol ether moiety of 7 was evident in the NMR spectra by virtue of
the alkene proton signal at d 6.69, which was directly connected (HSQC)
to a carbon at d 146. This position demonstrated a long-range coupling
(HMBC) with an allyloxy group, indicating the two groups might
comprise an enol ether moiety. It also showed HMBC correlations with
an unprotonated carbon resonating at d 101.6, which was assigned as the
adjacent olefinic carbon at C-2, and an oxymethine at d 82.4 (C-3). No
HMBC correlation was observed between positions 3 and 6; however, the
signals were fully consistent with the tetrahydrofuran ring structure of 7.
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bromoenol ether 7 with n-butyllithium, to effect bromine-for-lithium
exchange, and a subsequent water quench. While the product was not
isolated, the singlet corresponding to H-1 in the 1H NMR spectrum was
now observed at d 6.53 as a doublet with a coupling constant of 12.5 Hz,
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8 The two partially separable isomers of 8 were obtained in a 1 : 2.5
ratio. Both contained an acetal signal in their 13C NMR spectra, at d
101.9 and d 100.2, respectively, which were directly connected (HSQC) to
protons at d 4.80 and d 4.44, respectively. The acetal position in the
major isomer showed HMBC cross-peaks to two allyl groups and a
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pattern indicated that this latter centre could be a bromomethine
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interchange in the formation of the acetal isomers from enol ether 7. The
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This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 421–423 423