De novo synthesis of racemic spirocyclopropane-annelated 2-deoxyhexose derivatives

Article abstract of DOI:10.1002/ejoc.200390081

High-pressure-induced inverse-electron-demand hetero-Diels-Alder reactions of ethyl trans-4-ethoxy-2-oxo-3-butenoate (2a) and methyl trans-4-benzyloxy-2-oxo-3-butenoate (2b) with benzyl (cyclopropylidenemethyl) ether (1) each yielded mixtures of two separable diastereomeric esters 7a (64%) and 7b (80%) which, in three subsequent steps, led to the 3-ethylated and 3-benzylated α- and β-anomeric benzyl spiro[2-deoxy-(D,L)-arabino-hexopyranoside-2,1′-cyclopropanes] α-10a,b and β-10a,b, respectively. The relative configuration of β-10a was proved by an X-ray crystal structure analysis. Deprotection of β-10b was achieved by Pd-catalyzed hydrogenation in dimethylacetamide leading to spiro[2-deoxy-α/β-2-(D,L)-arabino-hexopyranoside-2, 1′-cyclopropane] (4). ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390081

FULL PAPER
De Novo Synthesis of Racemic Spirocyclopropane-Annelated 2-Deoxyhexose
Derivatives[‡]
Armin de Meijere,*[a] Andrei Leonov,[a] Thomas Heiner,[a] Mathias Noltemeyer,[b] and
M. Teresa Bes[c]
Keywords: Carbohydrates / Cyclopropane derivatives / Cycloaddition / High-pressure chemistry
High-pressure-induced inverse-electron-demand hetero-
Diels−Alder reactions of ethyl trans-4-ethoxy-2-oxo-3-but-
panes] α-10a,b and β-10a,b, respectively. The relative config-
uration of β-10a was proved by an X-ray crystal structure
enoate (2a) and methyl trans-4-benzyloxy-2-oxo-3-butenoate analysis. Deprotection of β-10b was achieved by Pd-cata-
(2b) with benzyl (cyclopropylidenemethyl) ether (1) each lyzed hydrogenation in dimethylacetamide leading to
yielded mixtures of two separable diastereomeric esters 7a spiro[2-deoxy-α/β-2-( )-arabino-hexopyranoside-2,1Ј-cyclo-
D,L
(64%) and 7b (80%) which, in three subsequent steps, led to
the 3-ethylated and 3-benzylated α- and β-anomeric benzyl
propane] (4).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
spiro[2-deoxy-(
D
,
L
)-arabino-hexopyranoside-2,1Ј-cyclopro-
Introduction
consists of the stepwise assembly of the sugar moiety using
an aldol condensation of a sterically congested cyclopro-
panecarboxylic acid ester.[4f] An attractive synthetic proced-
ure for the preparation of carbohydrate derivatives — an
inverse-electron-demand hetero-DielsϪAlder reaction of
enol ethers with α,β-unsaturated carbonyl compounds —
has been known for more than 50 years[5] and has been
used many times for the synthesis of both racemic and en-
antiopure sugars and their derivatives.[6] DielsϪAlder reac-
tions of methylenecyclopropane derivatives under normal
or high pressure have previously been studied.[7aϪ7e] Here
we wish to report the de novo synthesis of some racemic 2-
spirocyclopropane-annelated 2-deoxy-arabino-hexopyrano-
side derivatives.
The chemical modification of natural compounds has
long since become a commonly used approach for the
formation of novel biologically active molecules with differ-
ent pharmacological characteristics. The desperate search
for effective anticancer and anti-HIV therapeutic agents has
greatly stimulated research on specifically altered sugars.[1]
Cyclopropanated[2,3] or spirocyclopropane-annelated sugar
derivatives, as well as their nucleosides, are of potential in-
terest with respect to their physiological activity because the
strain energy contained in the cyclopropane moiety is ex-
pected to induce an enhanced reactivity of such compounds
and/or of their metabolic intermediates and thus may pro-
voke them to act as enzyme inhibitors. To the best of our
knowledge, only a few syntheses of spirocyclopropane-an-
nelated sugars or sugar derivatives have been developed.[4]
One of these methodologies involves the transformation of
natural sugars or their derivatives.[4aϪ4e] Another approach
Results and Discussion
This approach to the 2-deoxy-arabino-hexopyranoside
skeleton utilizes an inverse-electron-demand hetero-
DielsϪAlder cycloaddition of an enol ether to an β,γ-unsat-
urated α-keto ester as the key step (Scheme 1).
[‡]
Cyclopropyl Building Blocks for Organic Synthesis, 83. Part 82:
T. Voigt, H. Winsel, A. de Meijere, Synlett 2002, 1362Ϫ1364.
Part 81: D. Frank, S. I. Kozhushkov, T. Labahn, A. de Meijere,
Tetrahedron 2002, 58, 7001Ϫ7007.
[a]
Institut für Organische Chemie der Georg-August Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/399-475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b]
Institut für Anorganische Chemie der Georg-August
Universität Göttingen,
Tammannstrasse 4, 37077 Göttingen, Germany
[c]
´
´
Departamento de Bioquımica y Biologıa Molecular y Celular,
Facultad de Ciencias, Universidad de Zaragoza,
Pza. San Francisco s/n, 50009 Zaragoza, Spain
Scheme 1
472
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0472 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 472Ϫ478

Spirocyclopropane-Annelated Sugar Derivatives
FULL PAPER
The starting material, benzyl (cyclopropylidenemethyl) NOESY experiment, since it showed a nuclear Overhauser
ether (1), was obtained in two steps from (1-bromocyclo- effect between 4-H and 8-H, whereas that for trans-7a did
propyl)methanol (5),[8] which was benzylated and then not.[14]
dehydrobrominated by treatment with potassium tert-
The ester cis-7a was reduced with LiAlH4 in diethyl ether
butoxide in good overall yield[9,10] (Scheme 2). Two appro- to give the alcohol cis-8a, which was transformed into the
priate heterodienes of type 2 — ethyl trans-4-ethoxy-2-oxo- acetate cis-9a by treatment with neat acetic anhydride in the
3-butenoate (2a) and methyl trans-4-benzyloxy-2-oxo-3- presence of DMAP (Scheme 4). Hydroboration of cis-9a
butenoate (2b) — were prepared according to published with BH3·SMe2 followed by oxidative workup (H2O2) led
procedures.[11,12]
to a completely diastereoselective[15aϪ15d] formation of 1,3-
diprotected spiro[2-deoxy-β-(,)-arabino-hexopyranoside-
2,1Ј-cyclopropane] (β-10a) in 66% yield along with some of
the acetate β-11a (5%) arising from incomplete hydrolysis
during the basic workup. An X-ray crystallographic analysis
of a single crystal of β-10a was performed in order to con-
firm that the relative configuration corresponds to that of 2-
deoxy-β-(,)-arabino-hexopyranose (Figure 1). In a similar
manner the cycloadduct trans-7a could be transformed into
the corresponding 1,3-diprotected spiro[2-deoxy-α-(,)-ar-
abino-hexopyranoside-2,1Ј-cyclopropane] (α-10a). However,
Scheme 2. Preparation of benzyl (cyclopropylidenemethyl) ether
(1): a) PhCH2Br, NaH, nBu4NI (cat.), THF, 0 Ǟ 25 °C, then 25
°C, 70 h; b) tBuOK, DMSO, 10 Ǟ 25 °C, then 25 °C, 2 h
To begin with, the stereochemical aspects of the cycload-
ditions of the enol ether 1 to heterodienes of type 2 were
studied with the ethoxy derivative 2a. In view of the thermal
instability of the α-ketocarboxylate 2a, as well as the steric
encumbrance of 1 with its trisubstituted double bond, ap-
plication of high pressure proved to be the method of choice
to accelerate the DielsϪAlder reaction between the two.[13]
When pressurized to 10 kbar in anhydrous dichlorome-
thane, 2a reacted smoothly with the enol ether 1 at 25 °C
and, after 20 h, gave the ester 7a as a 3:1 mixture of the cis-
and trans-diastereomers in 53% isolated yield (Scheme 3).
Higher reaction temperatures (32Ϫ50 °C) and longer reac-
tion times (30Ϫ70 h) increased the yield to 62%, but led to
slightly diminished diastereoselectivities (Table 1). Anhyd-
rous acetonitrile also turned out to be a good solvent: the
highest yield of 7a (64%) was achieved at 50 °C and 10 kbar
after 30 h. Even higher temperatures and longer reaction
times were of no advantage and resulted only in enhanced
oligomerisation of the heterodiene 2a. The two diastereo-
mers cis- and trans-7a were easily separated by column
chromatography on silica gel. The cis-configuration could
be assigned for the major diastereomer cis-7a by a simple
Scheme 4. Preparation of spiro[2-deoxy-α/β-(,)-arabino-hexopyr-
anoside-2,1Ј-cyclopropane]: a) LiAlH4, Et2O, 0 °C, 2.5 h; b) Ac2O,
DMAP, pyridine, 0 Ǟ 25 °C, then 25 °C, 3 h; c) BH3·SMe2, THF,
0 Ǟ 25 °C, then 25 °C, 5.5 h; d) EtOH, NaOH, H2O2, 0 °C, then
[
[
75 °C, 30 min. *] 8% of unchanged cis-9a was reisolated. **] 15%
of unchanged trans-9a was reisolated
Table 1. Conditions and yields of the hetero-DielsϪAlder reaction
of the diene 2a with enol ether 1 (1.2 equiv.) at 10 kbar
Solvent
T
[°C]
Time
[h]
Yield of 7a
(%)
Ratio
cis/trans
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
25
32
40
40
50
20
44
70
70
30
53
57
62
60
64
3.0
2.8
2.1
2.1
2.2
Figure 1. X-ray crystal structure of compound rac-β-10a[16]
Scheme 3. Inverse-electron-demand hetero-DielsϪAlder reaction of heterodiene 2a with the strained enol ether 1. For details see Table 1
Eur. J. Org. Chem. 2003, 472Ϫ478 473

A. de Meijere, A. Leonov, T. Heiner, M. Noltemeyer, M. Teresa Bes
FULL PAPER
hydroboration of trans-9a turned out to be more difficult; der neutral conditions because the adjacent cyclopropyl
for unknown reasons, it required prolonged reaction times group helps to stabilize a developing positive charge at the
as well as repeated additions of the borane complex and anomeric center.[17a,17b]
gave a significantly lower yield (27%) of α-10a.
The methyl hexopyranoside 12 was formed as a single
diastereomer, as the 13C NMR spectrum showed only a
single set of signals. This could be identified as the β-an-
omer by comparison of its spectrum with that of methyl β-
-glucoside. For 12, the chemical shift of carbon atom C-1
is δ ϭ 104.9 ppm and for methyl β--glucoside it has been
reported to be δ ϭ 104.5 ppm (δ ϭ 100.5 ppm for methyl α-
-glucoside).[18] 13C NMR spectra with and without proton
decoupling have been measured for 12. The direct coupling
Since it would obviously be advantageous to deprotect
both hydroxy groups in a key intermediate of type 10 in
one step, for example by hydrogenolysis, the benzyloxy-sub-
stituted heterodiene 2b[12] was employed in the [4ϩ2] cyclo-
addition with the enol ether 1 (Scheme 5). At 10 kbar in
anhydrous dichloromethane at 25 °C the reaction took
place to give, after 72 h, the glycal ester 7b as an easily sep-
arable mixture of the cis- and trans-diastereomers in 80%
yield (ratio 1.8:1). Like cis/trans-7a, the cycloadducts cis-7b
and trans-7b were transformed into the corresponding 1,3-
diprotected racemic spiro[2-deoxy-arabino-hexopyranoside-
2,1Ј-cyclopropane] derivatives β-10b and α-10b. Since alco-
hols of type 8 are unstable under these conditions
(Scheme 4), they were O-acetylated without purification.
H,H-COSY and H,C-HMQC-2D NMR spectra measure-
ments for β-10b confirmed the structure of this compound.
constant 1J13
between the anomeric carbon atom and
C,H
the proton was found to be 165 Hz. It is known that
changes in the substituent at C-2 position in the pyranose
1
ring do not affect the J13
value for the majority of 2-
C,H
deoxy--arabino-hexose derivatives, and the measured value
is typical for a β--glucoside.[18]
While an attempted deprotection of β-10b in water failed,
it was accomplished by hydrogenolysis in the presence of
10% Pd/C in dimethylacetamide (DMA). Unfortunately, it
proved difficult to remove the last trace of DMA by ly-
ophilisation and subsequent drying under reduced pressure.
The 2-deoxypyranoside 4 was obtained as a mixture of α-
and β-anomers in a 15:85 ratio. The relative configurations
of the anomers were assigned on the basis of their 13C
NMR spectroscopic data as in the case of the methyl hexo-
pyranoside β-12.
Compound 4 was tested as a 10Ϫ3  solution in H2O
against two α-fucosidases (bovine epididymis, human pla-
centa), five α-galactosidases (E. coli, bovine liver, Asper-
gillus niger, Aspergillus rizae, jack bean), five α-glucosidases
(maltase from yeast and from rice; isomaltase from baker’s
yeast; amyloglucosidase from Aspergillus niger and from
rhizopus mold), two β-glucosidases (from almond and from
Caldocelium saccharolyticum), two α-mannosidases (jack
bean, almond), one β-mannosidase (Helix pomatia), one β-
xylosidase (Aspergillus niger), one α-N-acetylgalactosamini-
dase (chicken liver), three β-N-acetylglucosaminidases (jack
bean, bovine epididymis A and B), at optimal values of pH.
Unfortunately, none of these enzymes were inhibited at
this concentration.[19]
Scheme 5. Hetero-DielsϪAlder reaction of diene 2b with the enol
ether 1 and further transformations: a) LiAlH4, Et2O, 0 °C, 2.5 h;
b) Ac2O, DMAP, pyridine, 0 Ǟ 25 °C, then 25 °C, 3 h; c)
BH3·SMe2, THF, 0 Ǟ 25 °C, then 25 °C, 18 h; d) EtOH, NaOH,
H2O2, 0 °C, then 75 °C, 1.5 h
In summary, a straightforward synthesis of the 3-OЈ-pro-
tected and totally deprotected 2-spirocyclopropane-annel-
ated deoxysugars has been achieved utilizing an inverse
electron-demand hetero-DielsϪAlder cycloaddition as the
key step. Further synthetic elaboration of the cyclopropane
Attempted debenzylation of β-10b by palladium-cata-
lyzed hydrogenation in methanol surprisingly gave the
methyl hexopyranoside β-12 in 91% yield (Scheme 6). The
formation of alkyl glycosides from aldoses and alcohols is
well-known, but usually occurs under acidic conditions
only. The spirocyclopropanated aldose β-10b apparently moiety may afford new routes to other 2-substituted 2-de-
undergoes this 1-OЈ-methylation particularly easily even un- oxysugars.
Scheme 6. Hydrogenation of β-10b: a) H2, 10% Pd/C, MeOH, 20 °C, 20 min; b) H2, 10% Pd/C, dimethylacetamide, 20 °C, 16 h
474
Eur. J. Org. Chem. 2003, 472Ϫ478

Spirocyclopropane-Annelated Sugar Derivatives
FULL PAPER
Fraction I: trans-7a (68 mg, 20%, Rf ϭ 0.31). IR (film): ν˜ ϭ 3065
cmϪ1, 2978, 1731, 1646. 1H NMR (250 MHz, CDCl3): δ ϭ 0.48
(m, 2 H), 0.70 (m, 1 H), 0.88 (m, 1 H), 1.15 (t, J ϭ 7.0 Hz, 3 H),
1.32 (t, J ϭ 7.0 Hz, 3 H), 3.23 (d, J ϭ 3.0 Hz, 1 H), 3.46 (dq, J ϭ
9.0, 7.0 Hz, 1 H), 3.66 (dq, J ϭ 9.0, 7.0 Hz, 1 H), 4.28 (q, J ϭ
7.0 Hz, 2 H), 4.62 (d, J ϭ 12.0 Hz, 1 H), 4.78 (s, 1 H), 4.89 (d, J ϭ
12.0 Hz, 1 H), 6.38 (d, J ϭ 3.0 Hz, 1 H), 7.32 (m, 5 H) ppm. 13C
NMR (62.9 MHz, CDCl3): δ ϭ 5.4, 5.5 (CH2), 14.1, 15.4 (CH3),
21.8 (C), 61.3, 64.9, 70.4 (CH2), 71.5, 102.2, 111.1 (CH), 127.7 (CH,
3 ϫ C), 128.3 (CH, 2 ϫ C), 137.2, 142.2 (C), 162.6 (CϭO) ppm.
MS (EI): m/z (%) ϭ 332 (Ͻ0.1) [Mϩ], 199 (4), 173 (8), 145 (100),
117 (49), 99 (27), 91 (26) [C7H7ϩ], 71 (78).
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
AM 250 at 250 (1H) and 62.9 [13C, additional DEPT (Distor-
tionless Enhancement by Polarisation Transfer)] MHz or a Varian
VXR 500 S instrument at 500 (1H) MHz in CDCl3, C6D6,
[D6]DMSO, D2O solution. 1H chemical shifts are relative to the
internal reference [δ ϭ 7.26 (for CHCl3), 7.16 (for [D5]benzene),
4.65 (for HDO), 2.49 (for [D5]DMSO)]; δ in ppm, J in Hz. 13C
chemical shifts are relative to the solvent resonance [δ ϭ 77.0 (for
CDCl3), 128.0 (for [D6]benzene), 39.7 (for [D6]DMSO)]. MS (EI):
Finnigan MAT 95 spectrometer (70 eV). HRMS: Varian MAT 311
A. IR: Bruker IFS 66 (FT-IR). M.p.: Büchi 510 capillary melting
point apparatus, values are uncorrected. TLC: MachereyϪNagel
precoated sheets, 0.25 mm G/UV254 silica. Starting materials: an-
hydrous diethyl ether and THF were obtained by distillation from
sodium benzophenone ketyl, DMSO from CaH2, and dichlorome-
thane from P4O10. All other chemicals were used as commercially
available (Merck, Acros, Bayer, Hoechst, Degussa AG, and Hüls
AG). All reactions were performed under argon. Attempted ele-
mental and HPLC analyses to prove bulk purities for compounds
1, cis-7b, trans-7b, trans-9b all failed. However, these compounds
were found to be at least Ն 95% pure according to their 1H and
13C NMR spectra as well as thin layer chromatography.
Fraction II: cis-7a (145 mg, 44%, Rf ϭ 0.15). IR (film): ν˜ ϭ 3064
1
cmϪ1, 2976, 2871, 1732, 1647. H NMR (250 MHz, CDCl3): δ ϭ
0.45 (m, 1 H), 0.63 (m, 1 H), 0.78 (m, 1 H), 1.05 (m, 1 H), 1.22 (t,
J ϭ 7.4 Hz, 3 H), 1.32 (t, J ϭ 7.5 Hz, 3 H), 3.29 (d, J ϭ 5.5 Hz, 1
H), 3.58 (dq, J ϭ 9.0, 7.4 Hz, 1 H), 3.66 (dq, J ϭ 9.0, 7.4 Hz, 1
H), 4.25 (q, J ϭ 7.5 Hz, 2 H), 4.40 (s, 1 H), 4.64 (d, J ϭ 13.2 Hz,
1 H), 4.83 (d, J ϭ 13.2 Hz, 1 H), 6.38 (d, J ϭ 5.5 Hz, 1 H), 7.30
(m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 6.5, 11.0 (CH2),
14.2, 15.5 (CH3), 22.7 (C), 61.3, 64.6, 69.8 (CH2), 73.4, 101.6,
110.2, 127.4 (CH), 127.7 (CH, 2 C), 128.2 (CH, 2 C), 137.4, 141.9
(C), 162.8 (CϭO) ppm. MS (EI): m/z (%) ϭ 332 (0.1) [Mϩ], 259
(9), 241 (13), 180 (4), 108 (9), 91 (100) [C7H7ϩ], 84 (27).
[cis-4-(Benzyloxy)-8-ethoxy-5-oxaspiro[2.5]oct-6-ene-6-yl]methanol
(cis-8a): A solution of cis-7a (543 mg, 1.63 mmol) in diethyl ether
(5 mL) was added dropwise at 0 °C to a suspension of lithium
aluminum hydride (34 mg, 0.90 mmol) in diethyl ether (5 mL). The
mixture was stirred for 2.5 h at this temperature, then water
(0.5 mL) and saturated sodium sulfate solution (5 mL) were added
carefully. The mixture was diluted with Et2O (50 mL), the aqueous
phase was extracted with diethyl ether (3 ϫ 20 mL), the combined
ether fractions were dried (MgSO4) and concentrated under re-
duced pressure to give cis-8a (468 mg, 99%) as a colorless oil. IR
(film): ν˜ ϭ 3416 cmϪ1, 3065, 2976, 1683, 1479. 1H NMR
(250 MHz, CDCl3): δ ϭ 0.40 (m, 1 H), 0.55 (m, 1 H), 0.70 (m, 1
H), 0.98 (m, 1 H), 1.18 (t, J ϭ 7.0 Hz, 3 H), 3.10 (br. s, 1 H), 3.19
(d, J ϭ 4.5 Hz, 1 H), 3.50 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 3.58 (dq, J ϭ
9.5, 7.0 Hz, 1 H), 3.92 (s, 2 H), 4.29 (s, 1 H), 4.59 (d, J ϭ 12.5 Hz,
1 H), 4.76 (d, J ϭ 12.5 Hz, 1 H), 5.18 (d, J ϭ 4.5 Hz, 1 H), 7.28
(m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 6.4, 10.4 (CH2),
15.3 (CH3), 22.4 (C), 62.0, 63.7, 69.4 (CH2), 73.5, 97.4, 101.2, 127.1
(CH), 127.3 (CH, 2 C), 127.9 (CH, 2 C), 137.6, 151.8 (C) ppm.
MS (EI): m/z (%) ϭ 290 (0.1) [Mϩ], 259 (2), 181 (56), 108 (100)
[PhCH2OHϩ], 107 (77) [PhCH2Oϩ], 91 (98) [C7H7ϩ], 79 (94)
[C6H7ϩ]. HRMS (EI) for C17H22O4: calcd. 290.1518; found
290.1518.
Benzyl (Cyclopropylidenemethyl) Ether (1): NaH (60% suspension
in mineral oil, 8.4 g, 211 mmol) was added in small portions to
an ice-cooled solution of (1-bromocyclopropyl)methanol (5; 30.2 g,
200 mmol), benzyl bromide (34.2 g, 200 mmol) and tetra-n-butyl-
ammonium iodide (1.0 g, 2.7 mmol) in THF (200 mL) with stirring
during 1 h. The reaction mixture was allowed to warm to ambient
temperature and stirred for 70 h, then water (50 mL) was added,
and THF was removed by evaporation under reduced pressure. The
residue was taken up in water (200 mL) and the aqueous solution
extracted with pentane (1 ϫ 200, 2 ϫ 100 mL). The pentane solu-
tion was washed with water (4 ϫ 100 mL) and brine (100 mL),
dried with MgSO4 and concentrated under reduced pressure at
room temperature to give the bromo ether 6 (50.3 g) as a colorless
oil. Without further purification, the crude bromoether 6 was ad-
ded to a solution of tBuOK (28.0 g, 250 mmol) in anhydrous
DMSO (160 mL) during 30 min with stirring and cooling with a
water bath. After stirring for 2 h at ambient temperature, the mix-
ture was diluted with pentane (250 mL) and ice-cold water
(600 mL). The water phase was extracted with pentane (3 ϫ
100 mL), the combined pentane solutions were washed with water
(5 ϫ 100 mL) and brine (300 mL), and dried over Na2SO4. Pentane
was removed under reduced pressure, and the residue was distilled
over a 20 cm Vigreux column to give enol ether 1 (28.6 g, 89%) as
a colorless liquid, b. p. 53Ϫ55 °C (0.2 Torr). IR (film): ν˜ ϭ 3032
cmϪ1, 2980, 1766, 1183. 1H NMR (250 MHz, CDCl3): δ ϭ
1.02Ϫ1.09 (m, 2 H), 1.22Ϫ1.29 (m, 2 H), 5.01 (s, 2 H), 6.74 (m, 1
H), 7.26Ϫ7.45 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ
0.8, 4.8, 70.7 (CH2), 94.4 (C), 127.4 (CH, 2C), 127.7 (CH), 128.4
(CH, 2C), 135.7 (CH), 138.0 (C) ppm. MS (EI): m/z (%) ϭ 160 (5)
[Mϩ], 145 (8), 131 (5), 116 (2), 91 (100) [C7H7ϩ], 65 (26).
[trans-4-(Benzyloxy)-8-ethoxy-5-oxaspiro[2.5]oct-6-ene-6-yl]meth-
anol (trans-8a): A solution of trans-7a (849 mg, 2.55 mmol) in di-
ethyl ether (10 mL) was added dropwise at 0 °C to a suspension
of lithium aluminum hydride (54 mg, 1.42 mmol) in diethyl ether
(10 mL). The mixture was stirred for 2.5 h at this temperature, then
water (0.5 mL) and saturated sodium sulfate solution (5 mL) were
added carefully. The mixture was diluted with diethyl ether
(30 mL), the water phase was extracted with Et2O (3 ϫ 20 mL),
the combined ether fractions were dried (MgSO4) and concentrated
Ethyl cis-4-(Benzyloxy)-8-ethoxy-5-oxaspiro[2.5]oct-6-ene-6-carb-
oxylate (trans-7a) and ethyl trans-4-(Benzyloxy)-8-ethoxy-5-oxaspi-
ro[2.5]oct-6-ene-6-carboxylate (cis-7a): A solution of 1 (192 mg,
under reduced pressure to give trans-8a (673 mg, 91%) as a color-
1
1.20 mmol) and 2a (172 mg, 1.00 mmol) in acetonitrile (1 mL) was less oil. H NMR (250 MHz, CDCl3): δ ϭ 0.40 (m, 1 H), 0.80 (m,
kept in a sealed Teflon tube for 30 h at 50 °C and 10 kbar pressure. 3 H), 1.19 (t, J ϭ 7.0 Hz, 3 H), 2.58 (br. s, 1 H), 3.49 (d, J ϭ
The mixture was concentrated under reduced pressure, and the res-
idue was subjected to chromatography (8 g of silica gel; 27 ϫ 1 cm
column) eluting with pentane/diethyl ether 5:1 to give two fractions.
4.0 Hz, 1 H), 3.48 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 3.58 (dq, J ϭ 9.5,
7.0 Hz, 1 H), 4.05 (s, 2 H), 4.61 (d, J ϭ 12.0 Hz, 1 H), 4.88 (d, J ϭ
12.0 Hz, 1 H), 5.03 (s, 1 H), 5.16 (d, J ϭ 4.0 Hz, 1 H), 7.32 (m, 5
Eur. J. Org. Chem. 2003, 472Ϫ478
475

A. de Meijere, A. Leonov, T. Heiner, M. Noltemeyer, M. Teresa Bes
H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 5.4, 6.3 (CH2), 15.4 (m, 1 H), 1.15 (t, J ϭ 7.0 Hz, 3 H), 2.14 (s, 3 H), 3.00 (br. s, 1 H),
FULL PAPER
(CH3), 22.9 (C), 62.3, 64.0, 70.6 (CH2), 73.9, 97.7, 100.2 (CH),
127.5 (CH, 2 C), 127.6 (CH), 128.2 (CH, 2 C), 137.4, 152.9 (C)
3.42 (d, J ϭ 8.0 Hz, 1 H), 3.53 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 3.57 (dq,
J ϭ 9.5, 7.0 Hz, 1 H), 3.62Ϫ3.75 (m, 1 H), 3.72 (dd, J ϭ 8.0,
ppm. MS (EI): m/z (%) ϭ [Mϩ] not observed, 259 (1), 147 (38), 7.0 Hz, 1 H), 4.38 (m, 1 H), 4.51 (m, 1 H), 4.56 (d, J ϭ 12.0 Hz, 1
133 (18), 108 (31) [PhCH2OHϩ], 107 (25) [PhCH2Oϩ], 91 (100)
[C7H7ϩ], 79 (39) [C6H7ϩ].
H), 4.70 (s, 1 H), 4.88 (d, J ϭ 12.0 Hz, 1 H), 7.32 (m, 5 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ ϭ 1.9, 3.8 (CH2), 15.4, 20.9
(CH3), 24.8 (C), 64.0, 69.3, 70.4 (CH2), 71.0, 74.1, 80.9, 99.7 (CH),
127.7 (CH, 3 C), 128.3 (CH, 2 C), 137.3 (C), 171.9 (CϭO) ppm.
MS (EI): m/z (%) ϭ [Mϩ] not observed, 333 (Ͻ0.1), 287 (1), 243
(10), 183 (5), 137 (10), 91 (100) [C7H7ϩ], 65 (14).
[cis-4-(Benzyloxy)-8-ethoxy-5-oxaspiro[2.5]oct-6-ene-6-yl]methyl
Acetate (cis-9a): Acetic anhydride (1.08 g, 10.6 mmol) and DMAP
(12 mg, 0.1 mmol) were added at 0 °C to a solution of cis-8a
(600 mg, 2.07 mmol) in pyridine (2 mL). The resulting clear solu-
tion was stirred at 25 °C for 3 h and concentrated under reduced
pressure as much as possible. The residue was additionally dried
for 1 h under reduced pressure (10Ϫ3 Torr), then taken up in diethyl
ether (40 mL), the ethereal solution was washed with saturated so-
dium bicarbonate solution (5 ϫ 10 mL) and brine (3 ϫ 10 mL),
dried (MgSO4) and concentrated under reduced pressure to give
Fraction III: β-10a (524 mg, 66%, Rf ϭ 0.26) as a colorless solid,
1
m.p. 95 °C. IR (KBr): ν˜ ϭ 3429 cmϪ1, 3068, 2969, 1456, 1097. H
NMR (500 MHz, CDCl3): δ ϭ 0.46 (m, 1 H), 0.60 (m, 2 H), 0.79
(m, 1 H), 1.14 (t, J ϭ 7.3 Hz, 3 H), 2.78 (br. s, 2 H), 3.44 (d, J ϭ
8.1 Hz, 1 H), 3.48 (dq, J ϭ 9.5, 7.3 Hz, 1 H), 3.52 (dq, J ϭ 9.5,
7.3 Hz, 1 H), 3.56Ϫ3.70 (m, 1 H), 3.62 (dd, J ϭ 8.1, 7.0 Hz, 1 H),
3.82 (m, 1 H), 3.95 (m, 1 H), 4.58 (d, J ϭ 12.4 Hz, 1 H), 4.79 (s, 1
H), 4.85 (d, J ϭ 12.4 Hz, 1 H), 7.30 (m, 5 H) ppm. 13C NMR
(62.9 MHz, CDCl3): δ ϭ 1.7, 3.6 (CH2), 15.4 (CH3), 24.9 (C), 62.8,
69.1, 70.7 (CH2), 71.6, 75.6, 81.0, 99.9 (CH), 127.6 (CH, 3 C), 128.3
(CH, 2 C), 137.3 (C) ppm. MS (EI): m/z (%) ϭ 308 (0.1) [Mϩ], 251
(14), 169 (10), 99 (16), 91 (100) [C7H7ϩ]. HRMS (EI) for C17H24O5:
calcd. 308.1623; found 308.1623.
cis-9a (674 mg, 98%) as a colorless oil. IR (film): ν˜ ϭ 3064 cmϪ1
,
1
3007, 2973, 1743 (CϭO), 1681. H NMR (250 MHz, CDCl3): δ ϭ
0.46 (m, 1 H), 0.59 (m, 1 H), 0.73 (m, 1 H), 1.02 (m, 1 H), 1.17 (t,
J ϭ 7.0 Hz, 3 H), 2.06 (s, 3 H), 3.19 (d, J ϭ 4.5 Hz, 1 H), 3.52 (dq,
J ϭ 9.5, 7.0 Hz, 1 H), 3.57 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 4.39 (s, 1
H), 4.39 (d, J ϭ 13.0 Hz, 1 H), 4.48 (d, J ϭ 13.0 Hz, 1 H), 4.58 (d,
J ϭ 12.5 Hz, 1 H), 4.79 (d, J ϭ 12.5 Hz, 1 H), 5.27 (d, J ϭ 4.5 Hz,
1 H), 7.28 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 6.4,
10.7 (CH2), 15.4, 20.6 (CH3), 22.5 (C), 63.6, 63.9, 69.3 (CH2), 73.4,
101.1, 101.2, 127.2 (CH), 127.4 (CH, 2 C), 128.0 (CH, 2 C), 137.5,
147.4 (C), 170.2 (CϭO) ppm. MS (EI): m/z (%) ϭ 332 (2) [Mϩ],
331 (2) [Mϩ Ϫ H], 259 (3), 225 (2), 166 (2), 135 (4), 91 (100)
[C7H7ϩ]. HRMS (EI) for C19H24O5: calcd. 332.1623; found
332.1623.
α-10a: BoraneϪdimethyl sulfide complex (2  in THF, 0.42 mL,
0.84 mmol) was added dropwise at 0 °C to a solution of trans-9a
(700 mg, 2.11 mmol) in THF (9 mL). The mixture was stirred at 25
°C, and two further portions of BH3·Me2S (0.40 mL, 0.80 mmol
and 0.42 mL, 0.84 mmol) were added after 21 h and an additional
2 h, respectively. The mixture was stirred for an additional 3 h, then
EtOH (3 mL) was added carefully at 0 °C followed by a solution
of H2O2 (30% in water, 0.22 mL, 2.1 mmol) and of NaOH (1  in
water, 2.1 mL, 2.1 mmol). The mixture was heated under reflux for
1 h, cooled and concentrated under reduced pressure, the residue
was shaken with diethyl ether (100 mL), the ether solution was
washed with brine (7 ϫ 10 mL), dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by column chro-
matography (20 g of silica gel, 21 ϫ 2 cm column) eluting with
diethyl ether to give two fractions.
[trans-4-(Benzyloxy)-8-ethoxy-5-oxaspiro[2.5]oct-6-ene-6-yl]methyl
Acetate (trans-9a): The trans-isomer of cis-9a was prepared analog-
ously starting from trans-8a (650 mg, 2.24 mmol) in 98% yield
(729 mg) as a colorless oil. IR (film): ν˜ ϭ 3066 cmϪ1, 3006, 2975,
1
1742 (CϭO), 1681. H NMR (250 MHz, CDCl3): δ ϭ 0.46 (m, 1
H), 0.72 (m, 2 H), 0.83 (m, 1 H), 1.17 (t, J ϭ 7.0 Hz, 3 H), 2.11 (s,
3 H), 3.49 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 3.53 (dq, J ϭ 9.5, 7.0 Hz, 1
H), 3.62 (d, J ϭ 4.0 Hz, 1 H), 4.51 (s, 2 H), 4.59 (d, J ϭ 12.0 Hz,
1 H), 4.87 (d, J ϭ 12.0 Hz, 1 H), 4.89 (s, 1 H), 5.18 (d, J ϭ 4.0 Hz,
1 H), 7.30 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 5.4,
6.0 (CH2), 15.4, 20.8 (CH3), 22.5 (C), 63.5, 64.3, 70.2 (CH2), 73.0,
100.6, 101.4 (CH), 127.6 (CH, 3 C), 128.2 (CH, 2 C), 137.3, 148.3
(C), 170.4 (CϭO) ppm. MS (CI): m/z (%) ϭ 350 (44) [M ϩ NH4ϩ],
Fraction I: trans-9a (103 mg, 15%, Rf ϭ 0.73) as a colorless oil.
Fraction II: α-10a (174 mg, 27%, Rf ϭ 0.32) as a colorless solid,
1
m.p. 77 °C. IR (KBr): ν˜ ϭ 3430 cmϪ1, 3088, 2974, 1458, 1023. H
NMR (250 MHz, CDCl3): δ ϭ 0.28 (m, 1 H), 0.38 (m, 1 H), 0.67
(m, 1 H), 0.76 (m, 1 H), 1.13 (t, J ϭ 7.0 Hz, 3 H), 2.70Ϫ3.30 (br.
s, 2 H), 3.59 (d, J ϭ 7.0 Hz, 1 H), 3.66 (dq, J ϭ 9.5, 7.0 Hz, 1 H),
3.70 (dq, J ϭ 9.5, 7.0 Hz, 1 H), 3.71 (m, 1 H), 3.82 (m, 1 H), 3.87
(d, J ϭ 3.0 Hz, 2 H), 4.00 (s, 1 H), 4.45 (d, J ϭ 12.0 Hz, 1 H), 4.68
(d, J ϭ 12.0 Hz, 1 H), 7.31 (m, 5 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ ϭ 4.3, 5.2 (CH2), 15.4 (CH3), 24.5 (C), 62.4, 68.6, 68.9
(CH2), 71.5, 72.8, 77.9, 103.8, 127.6 (CH), 127.8, 128.3 (CH, 2 C),
137.5 (C) ppm. MS (EI): m/z (%) ϭ [Mϩ] not observed, 307 (0.1)
[Mϩ Ϫ H], 262 (1), 217 (4), 201 (22), 127 (17), 91 (100) [C7H7ϩ].
304 (56) [M ϩ NH4 Ϫ EtOH], 287 (100) [Mϩ Ϫ EtO].
ϩ
β-11a: BoraneϪdimethyl sulfide complex (2  in THF, 0.60 mL,
1.20 mmol) was added dropwise at 0 °C to a solution of cis-9a
(858 mg, 2.58 mmol) in THF (9 mL). The mixture was stirred at 25
°C, and two further portions of BH3·Me2S (0.60 mL, 1.20 mmol
and 0.30 mL, 0.60 mmol) were added after 2 h and an additional
1.5 h, respectively. The mixture was stirred for another 2 h, then
EtOH (3 mL) was added carefully at 0 °C followed by a solution
of H2O2 (30% in water, 0.31 mL, 3.0 mmol) and NaOH solution (1
Methyl trans-4,8-Dibenzyloxy-5-oxaspiro[2.5]oct-6-ene-6-carboxy-
 in water, 3.0 mL, 3.0 mmol). The mixture was heated under reflux late (trans-7b) and Methyl cis-4,8-Dibenzyloxy-5-oxaspiro[2.5]-
for 30 min, cooled and concentrated under reduced pressure, the
residue was shaken with diethyl ether (100 mL), the ether solution
was washed with brine (7 ϫ 10 mL), dried (MgSO4) and concen-
trated under reduced pressure. The residue was purified by column
chromatography (20 g of silica gel, 21 ϫ 2 cm column) eluting with
diethyl ether to give three fractions.
Fraction I: cis-9a (68 mg, 8%, Rf ϭ 0.76) as a colorless oil.
Fraction II: β-11a (40 mg, 5%, Rf ϭ 0.54) as a colorless oil. 1H
NMR (250 MHz, CDCl3): δ ϭ 0.48 (m, 1 H), 0.59 (m, 2 H), 0.83
oct-6-ene-6-carboxylate (cis-7b): A solution of 1 (0.96 g, 6.0 mmol)
and 2b (1.10 g, 5.0 mmol) in dichloromethane (4 mL) was kept in
a sealed Teflon tube for 72 h at 25 °C and 10 kbar pressure. The
mixture was concentrated under reduced pressure, and the residue
was subjected to chromatography (100 g of silica gel, 24 ϫ 3.5 cm
column) eluting with pentane/diethyl ether 2:1 to give two fractions.
Fraction I: trans-7b (532 mg, 28%, Rf ϭ 0.46) as a colorless oil. IR
(film): ν˜ ϭ 3064 cmϪ1, 3030, 3007, 1734, 1645. 1H NMR
(250 MHz, CDCl3): δ ϭ 0.60 (m, 2 H), 0.75 (m, 1 H), 0.93 (m, 1
476
Eur. J. Org. Chem. 2003, 472Ϫ478

Spirocyclopropane-Annelated Sugar Derivatives
FULL PAPER
H), 3.83 (s, 3 H), 4.01 (d, J ϭ 3.3 Hz, 1 H), 4.50 (d, J ϭ 11.7 Hz, 128.3 (CH, 3 C), 137.3, 138.4, 149.0 (C), 170.5 (CϭO) ppm. MS
1 H), 4.64 (d, J ϭ 12.0 Hz, 1 H), 4.68 (d, J ϭ 11.7 Hz, 1 H), 4.87 (EI): m/z (%) ϭ [Mϩ] not observed, 287 (2), 244 (2), 181 (5), 91
(s, 1 H), 4.91 (d, J ϭ 12.0 Hz, 1 H), 6.31 (d, J ϭ 3.3 Hz, 1 H),
7.28Ϫ7.39 (m, 10 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 5.6,
5.8 (CH2), 22.0 (C), 52.3 (CH3), 70.6, 71.0 (CH2), 71.5, 102.1,
110.6, 127.5 (CH), 127.6, 127.7, 127.8, 128.3 (CH, 2 C), 128.4
(CH), 137.2, 138.0, 142.5 (C), 163.1 (CϭO) ppm. MS (EI): m/z
(%) ϭ [Mϩ] not observed, 194 (5), 166 (12), 107 (17), 91 (100)
[C7H7ϩ].
Fraction II: cis-7b (990 mg, 52%, Rf ϭ 0.34) as a colorless oil. IR
(film): ν˜ ϭ 3063 cmϪ1, 3029, 3007, 1734, 1648. 1H NMR
(250 MHz, CDCl3): δ ϭ 0.42 (m, 1 H), 0.69 (m, 1 H), 0.82 (m, 1
H), 1.05 (m, 1 H), 3.38 (dd, J ϭ 4.6, 0.5 Hz, 1 H), 3.80 (s, 3 H),
4.42 (d, J ϭ 0.5 Hz, 1 H), 4.60 (d, J ϭ 12.1 Hz, 1 H), 4.68 (d, J ϭ
12.5 Hz, 1 H), 4.73 (d, J ϭ 12.1 Hz, 1 H), 4.86 (d, J ϭ 12.5 Hz, 1
H), 6.39 (d, J ϭ 4.6 Hz, 1 H), 7.28Ϫ7.40 (m, 10 H) ppm. 13C NMR
(62.9 MHz, CDCl3): δ ϭ 6.8, 11.2 (CH2), 22.7 (C), 52.4 (CH3),
70.0, 70.4 (CH2), 72.2, 101.9, 109.9, 127.5 (CH), 127.6, 127.7, 127.8
(CH, 2 C), 128.2 (CH), 128.3 (CH, 2 C), 137.4, 138.44, 142.0 (C),
163.2 (CϭO) ppm. MS (EI): m/z (%) ϭ [Mϩ] not observed, 321
(1), 289 (3), 215 (4), 166 (8), 91 (100) [C7H7ϩ].
(100) [C7H7ϩ].
β-10b: BoraneϪdimethyl sulfide complex (2  in THF, 1.00 mL,
2.00 mmol) was added dropwise at 0 °C to a solution of cis-9b
(1.58 g, 4.01 mmol) in THF (10 mL). The mixture was stirred at 25
°C, and two further portions of BH3·Me2S (1.00 mL, 2.00 mmol
and 0.50 mL, 1.00 mmol) were added after 11 h and an additional
5 h, respectively. The mixture was stirred for an additional 3 h, then
EtOH (5 mL) was added carefully at 0 °C followed by a solution
of H2O2 (30% in water, 1.70 mL, 16.64 mmol) and of NaOH (3 
in water, 1.5 mL, 4.50 mmol). The mixture was heated under reflux
for 1 h, then a solution of NaOH (2.00 mL, 6.00 mmol) and water
(5.0 mL) were added, and the heating was continued for another
30 min. The cooled mixture was concentrated under reduced pres-
sure, the residue was shaken with diethyl ether (150 mL), the ether
solution was washed with brine (5 ϫ 15 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography (80 g of silica gel, 28 ϫ 3 cm column) elut-
ing with dichloromethane/acetone 5:1 to give β-10b (930 mg, 63%,
Rf ϭ 0.35) as a colorless solid. A small portion of this product was
recrystallized from benzene to give colorless crystals, m.p. 93Ϫ95
°C. IR (KBr): ν˜ ϭ 3301 cmϪ1, 3089, 3064, 3026, 3014, 2916, 2874,
(cis-4,8-Dibenzyloxy-5-oxaspiro[2.5]oct-6-ene-6-yl)methyl Acetate
(cis-9b): A solution of lithium aluminum hydride (1.37  in Et2O,
2.07 mL, 2.84 mmol) was added dropwise with stirring at 0 °C
within 5 min to a solution of cis-7b (1.80 g, 4.73 mmol) in diethyl
ether (20 mL). The mixture was stirred at this temperature for
2.5 h, then water (0.11 mL), a 3  NaOH solution (0.11 mL) and
water again (0.33 mL) were added. After stirring for 30 min, the
suspension was filtered with suction, the filter cake was washed
with diethyl ether (3 ϫ 20 mL), the filtrate was dried (MgSO4) and
concentrated under reduced pressure. The residue was dissolved in
pyridine (5 mL), and to this solution were added acetic anhydride
(2.48 g, 24.3 mmol) and DMAP (12 mg, 0.1 mmol). The resulting
clear solution was stirred for 3 h at 25 °C and concentrated under
reduced pressure as much as possible. The residue was dissolved in
diethyl ether (50 mL), washed with saturated NaHCO3 solution (4
ϫ 10 mL), brine (50 mL), dried (MgSO4) and concentrated under
reduced pressure to give cis-9b (1.64 g, 88%) as a colorless oil. IR
(film): ν˜ ϭ 3064 cmϪ1, 3030, 2934, 2864, 1743, 1681. 1H NMR
(250 MHz, CDCl3): δ ϭ 0.41 (m, 1 H), 0.59 (m, 1 H), 0.76 (m, 1
H), 1.02 (m, 1 H), 2.07 (s, 3 H), 3.29 (d, J ϭ 4.5 Hz, 1 H), 4.30 (s,
1 H), 4.42 (d, J ϭ 12.8 Hz, 1 H), 4.51 (d, J ϭ 12.8 Hz, 1 H), 4.59
(d, J ϭ 12.3 Hz, 1 H), 4.63 (d, J ϭ 12.5 Hz, 1 H), 4.68 (d, J ϭ
12.3 Hz, 1 H), 4.85 (d, J ϭ 12.5 Hz, 1 H), 5.28 (d, J ϭ 4.5 Hz, 1
H), 7.22Ϫ7.40 (m, 10 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ
6.8, 11.3 (CH2), 20.9 (CH3), 22.8 (C), 63.8, 69.6, 70.1 (CH2), 72.6,
100.9, 101.4, 127.4, 127.5 (CH), 127.7 (CH, 2 C), 127.8 (CH, 2 C),
128.2 (CH, 2 C), 128.3 (CH, 2 C), 137.7, 138.9, 148.0 (C), 170.5
(CϭO) ppm. MS (EI): m/z (%) ϭ [Mϩ] not observed, 303 (1), 287
(3), 215 (6), 197 (15), 91 (100) [C7H7ϩ]. C24H26O5 (394.47) calcd.
C 73.08, H 6.64; found C 73.94, H 6.25.
1
1497, 1364, 1082, 1016. H NMR (300 MHz, C6D6): δ ϭ 0.62 (m,
1 H), 0.77 (m, 1 H), 0.93 (m, 1 H), 1.15 (m, 1 H), 2.17 (t, J ϭ
3.7 Hz, 1 H), 2.45 (d, J ϭ 3.9 Hz, 1 H), 3.27 (ddd, J ϭ 8.8, 7.0,
4.5 Hz, 1 H), 3.39 (d, J ϭ 8.8 Hz, 1 H), 3.63 (dt, J ϭ 8.8, 3.9 Hz,
1 H), 3.86 (m, 2 H), 4.35 (d, J ϭ 12.0 Hz, 1 H), 4.42 (d, J ϭ
11.5 Hz, 1 H), 4.53 (s, 1 H), 4.60 (d, J ϭ 11.5 Hz, 1 H), 4.72 (d,
J ϭ 12.0 Hz, 1 H), 7.03Ϫ7.24 (m, 10 H) ppm. 13C NMR
(75.5 MHz, C6D6): δ ϭ 2.6, 4.1 (CH2), 25.5 (C), 63.2, 70.6 (CH2),
72.9 (CH), 75.4 (CH2), 76.0, 81.2, 100.1 (CH), 127.7 (CH, 3 C),
127.8, 127.9 (CH, 2 C), 128.6 (CH), 128.7 (CH, 2 C), 138.3, 139.2
(C) ppm. MS (EI): m/z (%) ϭ 370 (Ͻ0.1) [Mϩ], 369 (6) [M Ϫ Hϩ],
342 (12), 321 (8), 263 (7), 198 (8), 156 (11), 91 (100) [C7H7ϩ].
HRMS (EI) for C22H26O5: calcd. 370.1780; found 370.1780.
C22H26O5 (370.45) calcd. C 71.33, H 7.07; found C 71.09, H 6.98.
α-10b: The α-isomer of β-10b was prepared analogously starting
from trans-9b (1.31 g, 3.32 mmol). Chromatographic purification
(80 g of silica gel, 28 ϫ 3 cm column) eluting with dichlorome-
thane/acetone (10:1) gave α-10b (420 mg, 34%, Rf ϭ 0.20) as a col-
orless solid. A small portion of this product was recrystallized from
hexane/diethyl ether to give colorless crystals, m.p. 86Ϫ89 °C. IR
(KBr): ν˜ ϭ 3475 cmϪ1, 3085, 3066, 3031, 3005, 2927, 2877, 1497,
1454, 1402, 1367, 1129, 1013. 1H NMR (250 MHz, C6D6): δ ϭ 0.24
(m, 1 H), 0.39 (m, 1 H), 0.81 (m, 1 H), 1.02 (m, 1 H), 2.37 (br. s,
1 H), 2.70 (d, J ϭ 3.9 Hz, 1 H), 3.79 (dt, J ϭ 8.8, 3.9 Hz, 1 H),
3.87Ϫ4.06 (m, 3 H), 3.95 (s, 1 H), 4.15 (d, J ϭ 8.8 Hz, 1 H), 4.30
(d, J ϭ 12.1 Hz, 1 H), 4.37 (d, J ϭ 11.8 Hz, 1 H), 4.62 (d, J ϭ
11.8 Hz, 1 H), 4.63 (d, J ϭ 12.1 Hz, 1 H), 7.08Ϫ7.37 (m, 10 H)
ppm. 13C NMR (62.9 MHz, C6D6): δ ϭ 4.8, 5.8 (CH2), 25.1 (C),
63.2, 68.9 (CH2), 73.0, 73.5 (CH), 75.4 (CH2), 78.6, 104.3 (CH),
127.6, 127.8, 127.9 (CH, 2 C), 128.2 (CH), 128.5 (CH, 2 C), 128.6
(CH), 138.3, 139.3 (C) ppm. MS (EI): m/z (%) ϭ 370 (Ͻ 0.1) [Mϩ],
279 (6), 231 (8), 156 (10), 91 (100) [C7H7ϩ]. HRMS (EI) for
C22H26O5: calcd. 370.1780; found 370.1780. C22H26O5 (370.45)
calcd. C 71.33, H 7.07; found C 71.37, H 6.84.
(trans-4,8-Dibenzyloxy-5-oxaspiro[2.5]oct-6-ene-6-yl)methyl Acetate
(trans-9b): The trans-isomer of cis-9b was prepared analogously
starting from trans-7b (1.58 g, 4.15 mmol) in 83% yield (1.35 g) as
a colorless oil. IR (film): ν˜ ϭ 3064 cmϪ1, 3030, 2934, 2866, 1741,
1
1675. H NMR (250 MHz, CDCl3): δ ϭ 0.45 (m, 1 H), 0.81 (m, 3
H), 2.11 (s, 3 H), 3.67 (d, J ϭ 3.8 Hz, 1 H), 4.49 (d, J ϭ 11.8 Hz,
1 H), 4.53 (s, 2 H), 4.60 (d, J ϭ 12.0 Hz, 1 H), 4.62 (d, J ϭ 11.8 Hz, β-12: The protected sugar β-10b (278 mg, 0.75 mmol) in methanol
1 H), 4.88 (d, J ϭ 12.0 Hz, 1 H), 4.99 (s, 1 H), 5.20 (d, J ϭ 3.8 Hz, (50 mL) was hydrogenated in the presence of 10% Pd/C (50 mg) at
1 H), 7.27Ϫ7.39 (m, 10 H) ppm. 13C NMR (62.9 MHz, CDCl3): 20 °C and 1 bar for 20 min. The catalyst was filtered off, and the
δ ϭ 5.9, 6.4 (CH2), 20.9 (CH3), 22.7 (C), 63.6, 70.5, 70.6 (CH2), solution was concentrated under reduced pressure. The residue was
73.2, 100.4, 100.8 (CH), 127.6 (CH, 3 C), 127.7, 127.8 (CH, 2 C), then lyophilized twice to give β-12 (140 mg, 91%) as a colorless
Eur. J. Org. Chem. 2003, 472Ϫ478
477

A. de Meijere, A. Leonov, T. Heiner, M. Noltemeyer, M. Teresa Bes
FULL PAPER
glass. IR (KBr): ν˜ ϭ 3422 cmϪ1, 3006, 2902, 2835, 1102, 1030. 13
C
ated carbohydrates see: G. S. Cousins, J. O. Hoberg, Chem. Soc.
Rev. 2000, 29, 165Ϫ174.
NMR (62.9 MHz, [D6]DMSO): δ ϭ 3.6, 4.7 (CH2), 25.4 (C), 54.0
(CH3), 61.4 (CH2), 68.5, 71.0, 74.1, 105.0 (CH) ppm. MS (CI,
NH3): m/z (%) ϭ 426 (Ͻ0.1) [2M ϩ NH4ϩ], 222 (23) [M ϩ NH4ϩ],
[5]
R. I. Longley, Jr., W. S. Emerson, J. Am. Chem. Soc. 1950,
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For an excellent review in this field see: L. F. Tietze, G. Kett-
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190 (100) [M ϩ NH4 Ϫ CH3OH], 173 (36) [Mϩ Ϫ CH3O], 102
ϩ
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W. Adam, M. Dörr, K. Hill, E.-M. Peters, K.
α-4: A solution of β-10b (150 mg, 0.40 mmol) in N,N-dimethylacet-
amide (DMA) (15 mL) was hydrogenated in the presence of 10%
Pd/C (75 mg) at 20 °C and 1 bar for 16 h. The catalyst was filtered
off, and the solution was concentrated under reduced pressure. The
residue was lyophilized twice, then dried for one week under high
vacuum (10Ϫ3 Torr) to give α/β-4 (81 mg) as a colorless glass which
still contained 12 mol % of DMA, yield of α/β-4 93%. IR (KBr): ν˜
[α/β-4] ϭ 3474 cmϪ1, 3009, 2928, 1616, 1420, 1087, 1019. 13C NMR
(62.9 MHz, D2O): δ (β-4) ϭ 4.1, 5.5 (CH2), 26.1 (C), 62.0 (CH2),
69.7, 71.5, 74.1, 99.6 (CH); δ (α-4) ϭ 1.0, 3.4 (CH2), 26.1 (C), 62.0
(CH2), 71.2, 72.8, 77.6, 95.6 (CH) ppm. MS (CI, NH3) [α/β-4]:
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[8]
[9]
[10]
[11]
[12]
[13]
ϩ
m/z (%) ϭ 398 (0.5) [2M ϩ NH4ϩ], 380 (1) [2M ϩ NH4 Ϫ H2O],
ϩ
208 (31) [M ϩ NH4ϩ], 190 (100) [M ϩ NH4 Ϫ H2O], 173 (36)
[Mϩ Ϫ OH], 105 (29).
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Acknowledgments
This work was financially supported by the Deutsche Forschungs-
gemeinschaft (Graduiertenkolleg ‘‘Kinetics and Selectivity of
Chemical Processes in Compressed Fluid Phases’’), and the Fonds
der Chemischen Industrie as well as by BASF, Bayer, Degussa, and
Hüls AG through generous gifts of chemicals. T. H. is indebted
to the Hermann-Schlosser-Stiftung for a graduate fellowship. The
authors are grateful to Dr. Burkhard Knieriem for his careful
proof reading of the final manuscript. M. T. B. thanks the Euro-
pean Community for a postdoctoral grant (No. ERBCHBGCT
940731). The authors are indebted to Prof. Dr. P. Vogel, LGSA,
[16]
Crystal Structure Determination of rac-β-10a: Data were col-
lected on a Stoe AED2 four-circle diffractometer with graphite-
˚
monochromated Mo-Kα radiation (λ ϭ 0.71073 A). The struc-
ture was solved by direct methods (SHELXS-96, G. M. Sheld-
rick, Acta Crystallogr., Sect. A 1990, 46, 467) and refined ver-
sus F2 by the least-squares method with all data (SHELXS-96,
Program for Crystal Structure Refinement, University of
Göttingen, 1996). R values: R1 ϭ Σ||Fo| Ϫ |Fc||/ Σ|Fo|, wR2 ϭ
{Σ[w(Fo2 Ϫ Fc2)2]/Σ[w(Fo2)2]}1/2. Single crystal crystallized from
diethyl ether, colorless, monoclinic, space group P21/c; Z ϭ 4,
´
Institut de Chimie Moleculaire et Biologique, Ecole Polytechnique
´ ´
Federale de Lausanne (Switzerland), for the biological testing of
˚
˚
˚
a ϭ 12.844(3) A, b ϭ 13.791(3) A, c ϭ 9.871(2) A, β ϭ
compound 4.
3
112.46(3)°, V ϭ 1615.8(6) A ; ρcalcd. ϭ 1.268 Mg/m3. 4159
˚
Reflections, 2083 unique observed [I Ͼ 2σ(I)], were measured
at Ϫ80 °C. The non-hydrogen atoms were refined aniso-
tropically. All hydrogen atoms were refined on calculated posi-
tions by using a riding method. R1 ϭ 0.0602, wR2 ϭ 0.1760
(all data) for 201 parameters. Crystallographic data of β-10a
have been deposited as supplementary publication no. CCDC-
114680 with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained free of charge on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: (internat.) ϩ 44-1223/336-033; E-mail: deposit@ccdc.ca-
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