Conversion of an arabinose-derived allyl vinyl ether system into the functionalized 4-cycloheptenone via Claisen rearrangement

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Conversion of an Arabinose-Derived Allyl
Vinyl Ether System into the Functionalized 4-
Cycloheptenone via Claisen Rearrangement
Stefan Jürs a & Joachim Thiem a
a Institut für Organische Chemie, University of Hamburg ,
Martin‐Luther‐King‐Platz 6, Hamburg, Germany
Published online: 02 Feb 2007.
To cite this article: Stefan Jürs & Joachim Thiem (2005) Conversion of an Arabinose-Derived Allyl Vinyl
Ether System into the Functionalized 4-Cycloheptenone via Claisen Rearrangement, Journal of Carbohydrate
Chemistry, 24:8-9, 843-847, DOI: 10.1080/07328300500434224
To link to this article: http://dx.doi.org/10.1080/07328300500434224
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Journal of Carbohydrate Chemistry, 24:843–847, 2005
Copyright # Taylor & Francis LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500434224
Conversion of an Arabinose-
Derived Allyl Vinyl Ether
System into the
Functionalized
4-Cycloheptenone via
Claisen Rearrangement
Stefan Ju¨rs and Joachim Thiem
Institut fu¨r Organische Chemie, University of Hamburg, Martin-Luther-King-Platz 6,
Hamburg, Germany
Keywords Claisen rearrangement, Carbocycles, Allyl vinyl ethers
A large number of natural products display seven-membered rings as a distinc-
tive structural feature.[1] Since they frequently contain both oxygenated func-
tions and stereogenic centers, their synthesis is quite demanding, particularly
starting from achiral compounds. The employment of carbohydrate derivatives
proved to be a useful alternative for a number of synthetic purposes in natural
product chemistry.[2] Previous reports have shown the successful application of
the Claisen rearrangement on pyranoses for ring enlargement purposes to give
eight-membered ring structures.[3–5] In contrast to these findings, furanoses
have attained relatively little attention with regard to corresponding synthetic
approaches. Recently, Zhang et al. reported on the synthesis of a seven-
Dedicated to the memory of Prof. Jacques van Boom.
Address correspondence to Joachim Thiem, Institute of Organic Chemistry, University
of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany. Fax: þ49 40
42838 4325; E-mail: thiem@chemie.uni-hamburg.de
843

S. Ju¨rs and J. Thiem
844
membered carbocycle starting from D-glucose. The whole reaction sequence
involved 11 steps, which seems to be a rather extended route for a relatively
simple but useful chiral building block.[6] Krohn et al. observed the formation
of a seven-membered carbocycle by intramolecular carbocyclization of an open-
chain sugar derivative in a 14-step sequence.[7] The present communication
outlines a considerably shorter approach toward a chiral cycloheptenone
derivative involving Claisen rearrangement of a properly functionalized
furanose.
Considering the progress in C-glycoside synthesis in recent years, the
introduction of a vinyl group at the anomeric center of a furanose was con-
sidered to be feasible using an a-halide. To make use of the Claisen rearrange-
ment in the sense of a ring enlargement, the generation of a second double bond
would be required to furnish the allyl vinyl ether substructure. Thus, D-(2)-
arabinose was chosen as starting material and the highly reactive a-furanosyl-
bromide 2 synthesized according to Fletcher’s procedure[8] (Sch. 1).
The subsequent Grignard reaction using vinylmagnesiumbromide[9] gave 3
in 66% yield. It should be emphasized that this is unexpectedly successful
because yields in this type of C-glycosylations with peracylated carbohydrates
are usually between 25% and 45% due to competing elimination reactions.
Apparently, in this case, the elimination is much less favored due to the cis
orientation of both the 2-benzoate and the a-bromide in relation to the
hydrogen atom on the adjacent carbon. The obtained anomeric mixture was
peracetylated to facilitate the separation from large amounts of inorganic
[10]
´
salts. After deacetylation under Zemplen conditions,
the primary OH-
group could be selectively tosylated to give 4 and directly transformed by ben-
zoylation to give 5. The tosylation was accompanied by the formation of the
bicyclic anhydro side product 9 in moderate amounts. For the same reason
the introduction of benzyl groups (NaH, BnBr, DMF) was not successful
since 10 was formed in major amounts under these stronger basic conditions.
The tosylate 5 was transformed into the bromide 6 by Finkelstein reaction.
By subsequent elimination using silver fluoride in pyridine,[11] the synthesis of
the exocyclic enol ether 7 was accomplished and the product obtained as an
inseparable mixture of anomers. In contrast to previous reports of correspond-
ing yet unsubstituted 2-vinyl-5-methylene-tetrahydrofuranes,[12] compounds
7a and 7b proved to be surprisingly stable even during column chromato-
graphy and could be stored for an extended time at –188C without decompo-
sition. No isomerization to the internal enol ether with dihydrofurane
structure (furanoide glycal) could be observed.
In an initial attempt to effect rearrangement, the mixture of compounds
7a and 7b was heated to 1008C in DMSO with bis[1,2-bis(diphenylphos-
phino)ethane]palladium as catalyst. Whereas Trost et al.[13] were able to
rearrange several furanose derivatives to the corresponding cycloheptenones
using this methodology, it did not effect any conversion in this case. Hence,

Allyl Vinyl Ether System
845
Scheme 1: Claisen rearrangement of a D-(2)-arabinose derived furanose precursor a) AcCl,
MeOH, then BzCl, py, 79%; b) HBr/HOAc, in situ; c) CH255CHMgBr, THF, then Ac2O, py; 66%; d)
NaOMe, MeOH, 100%; e) TsCl, py; f) BzCl, DMAP, py, 61% (two steps); g) NaBr, DMF, 708 C, 100%;
h) AgF, py, 52%; i) decane/toluene 6:1, microwave, 1808 C, 20 min, 54%; j) “basic conditions”
(TsCl, py; NaH, BnBr, DMF, respectively).
the thermal method was employed using nonoxygenated solvents to avoid
decomposition and formation of side products. Furthermore, a preferably
high heat capacity of the solvent should effect an improved energy trans-
fer onto the substrate. These considerations prompted the use of decane
as solvent with an addition of toluene to improve solubility.a Under
aConcentration of 7 in decane/toluene 6:1 approx. 0.013 M.

S. Ju¨rs and J. Thiem
846
these conditions, the enantiopure product 8b could be isolated in 54% yield
1
together with 46% of a recovered 7a and 7b mixture. Its H NMR spectrum
confirmed the presence of an anomeric mixture, however, with the opposite
a/b-ratio (A:B ꢀ 1:2) compared to the precursor 7a and 7b mixture
(A:B ꢀ 2:1). This suggests that one anomer A undergoes the Claisen
rearrangement exclusively or at least much faster than the other anomer B.
To verify this assumption, the amount of recovered 7a and 7b mixture was
heated again under the same conditions as before, which resulted in the
complete consumption of A. Since the exact determination of the anomeric con-
figuration by means of coupling constants is usually unreliable for furanoses,
NOE spectra were recorded. In spite of the minor signal intensity (H-
2A:H-2B ¼ 0.5:1.0), a stronger NOE between H-2A and H-4A than between
H-2B and H-4B was observed, indicating a greater spacial proximity of the
former. Hence, the faster rearranging anomer A presumably corresponds to
the a-anomer.
The 4-cycloheptenone derivative 8 contains a (Z)-configurated double
bond, which is energetically favorable during the Claisen process since it
is positioned within a ring. For the 4-cycloheptenone system itself, there
are only the two conformations boat—(B) and chair (C).[14] Generally, the
chair conformation is preferred due to minimized van der Waals repulsions
of the p-electrons. Since the NMR spectra of 8 showed sharp signals of
only one single conformer in benzene solution, this compound is assumed
to feature the chair conformation (4,5C1) with a trans-diaxial arrangement
of H-2 and H-3, supported by
a
large vicinal coupling constant
(J2,3 ¼ 9.7 Hz). The exact determination of the actual conformation of 8
in the solid state depends on X-ray analysis, and current attempts are
being made to obtain suitable crystals of compound
derivatives.
8
or other
ACKNOWLEDGEMENT
The support of this work by the Deutsche Forschungsgemeinschaft (GRK 464)
and the Fonds der Chemischen Industrie is gratefully acknowledged.
20
546
bCompound 8: mp: 102–1048C; [a]
-84 (c 0.5, CHCl3), 1H NMR (400 MHz, C6D6):
( ¼ 1.45–1.54 (m, 1 H, H-6b), 1.95–2.05 (m, 1 H, H-6a), 2.14–2.22 (m, 1 H, H-7b),
2.27 (ddd, 1 H, H-7a), 5.41–5.48 (m, 1 H, H-5), 5.56 (ddd, 1 H, H-4, J3,4 ¼ 3.8,
J4,5 ¼ 11.8 Hz), 6.11 (d, 1 H, H-2, J2,3 ¼ 9.7 Hz), 6.23–6.27 (m, 1 H, H-3, J2,3 ¼ 9.7,
J3,4 ¼ 3.8 Hz), 6.85–7.11, 8.10–8.17 (2 ꢁ m, 10 H, Ar) ppm. 13C NMR (100 MHz,
C6D6): ( ¼ 22.1 (1 C, C-6), 40.4 (1 C, C-7), 70.2 (1 C, C-3), 78.9 (1 C, C-2), 127.7–128.6,
130.0, 130.2, 132.7, 133.3 (14 C, C-4, C-5, Ar), 165.7, 165.9 (2 C, PhCO2), 201.1 (1 C,
CO) ppm. Anal. Calcd for C21H18O5 (350.39): MALDI-TOF: m/z 373.2 (M þ Na), 389.1
(M þ K).

Allyl Vinyl Ether System
847
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