Synthesis of a carbohydrate-derived 1-oxaspiro[4.4]nonane skeleton and its conversion into spironucleosides

Article abstract of DOI:10.1055/s-0029-1218828

An easy entry to the 1-oxaspiro[4.4]nonane skeleton has been developed starting from a d-glucose-derived substrate. The key steps involve (a) installation of olefin moieties at the appropriate places through simple transformations and (b) construction of spiro rings by utilizing ring-closing metathesis reactions between these olefin functionalities. Subsequent deprotection of the acetonide functionality, peracetylation, nucleosidaton under Vorbrggen reaction conditions, and final deprotections result in the formation of the spironucleosides. The involvement of an interesting intra/intermolecular acetyl migration has been used to rationalize the product distribution during desilylation. Various 1D and 2D NMR techniques and X-ray analyses of some important intermediates were used for assigning the structures and stereochemistry of the products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218828

PAPER
2533
Synthesis of a Carbohydrate-Derived 1-Oxaspiro[4.4]nonane Skeleton and Its
Conversion into Spironucleosides
C
arbohydr
o
ate-Derived
y
1-Oxaspiro[4.4]non
K
a
ne Skeleton rishna Maity,a Basudeb Achari,a Michael G. B. Drew,b Sukhendu B. Mandal*a
a
Chemistry Division, Indian Institute of Chemical Biology (a unit of CSIR), Jadavpur, Kolkata 700032, India
Fax +91(33)24735197; E-mail: sbmandal@iicb.res.in
b
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
Received 29 March 2010
tural modifications of nucleosides,9–12 and syntheses of a
number of spiro derivatives including C-1¢-spiro,13 C-2¢-
spiro,14 C-3¢-spiro,15 and C-4¢-spironucleosides,8,16,17 as
conformationally restricted/biased analogues, have ap-
Abstract: An easy entry to the 1-oxaspiro[4.4]nonane skeleton has
been developed starting from a D-glucose-derived substrate. The
key steps involve (a) installation of olefin moieties at the appropri-
ate places through simple transformations and (b) construction of
spiro rings by utilizing ring-closing metathesis reactions between peared in the literature. The structures of some of these
nucleosides (1,13 2,14 3,15 4,8 5,16c and 69) are shown in
Figure 1.
these olefin functionalities. Subsequent deprotection of the
acetonide functionality, peracetylation, nucleosidaton under
Vorbrüggen reaction conditions, and final deprotections result in
the formation of the spironucleosides. The involvement of an inter-
esting intra/intermolecular acetyl migration has been used to ratio-
nalize the product distribution during desilylation. Various 1D and
2D NMR techniques and X-ray analyses of some important inter-
mediates were used for assigning the structures and stereochemistry
of the products.
O
N
O
N
O
HN
NH
NH
O
O
O
O
O
O
HO
HO
HO
O
Key words: alkenes, spiro compounds, ring-closing metathesis,
nucleosides, carbohydrates
HO
OH
O
OTBDMS
HO
O
O
1
2
3
NMe2
O
N
The observations that the first natural herbicidal spironu-
cleoside (+)-hydantocidin1 shows potent plant-growth-
regulatory activities and low toxicity to microorganisms
and mammals and that the synthetic spironucleoside
TSAO-T2 exhibits anti-HIV activity inspired Miyasaka3
and others4 to synthesize C-1¢-spironucleosides as confor-
mationally restricted molecules. Although conformations
of the ribose ring in natural nucleosides equilibrate in so-
lution between C-3¢-endo (N-type) and C-2¢-endo (S-
type) due to low energy barriers,5,6 restriction of this con-
formational flipping could provide nucleoside analogues
with greater selectivity and less toxicity7 for the treatment
NH
N
N
OH
X
NH
OH
NH2
N
O
N
N
O
OH
O
X
HO
HO
O
OH
6
4 X = O, S
HO
5 X = S, NEt
OH
Figure 1 Some structurally unique spironucleosides
Several years ago Paquette’s group18 reported pinacolic
ring expansion initiated by oxonium ions to generate a
of viral diseases. Paquette8 subsequently introduced the spiroketone that could serve as a sugar mimic after a series
concept of spirocyclic restriction in nucleosides through of transformations including chiral resolution at an appro-
insertion of a carbocyclic ring at C-4¢ of furanose/thio- priate stage (Scheme 1). But the synthesis of such nucleo-
furanose rings. The free-radical-induced degradation of sides or similar analogues starting from carbohydrates has
the ribose ring of nucleosides by C-4¢ hydrogen abstrac- received scant attention. We decided to utilize easily de-
tion can thus be precluded, resulting in enhanced metabol- rived intermediates from natural carbohydrates to synthe-
ic stability as well as conformational rigidity in the size spirocyclic nucleosides in enantiomerically pure
furanose ring. These nucleosides carrying a ring residue form. The present article deals with the results on the gen-
between C-4¢ and C-5¢ could occupy more space, affecting eration of spiro[5.5] rings at C-4 of the furanose moiety
the conformation of the furanose ring, and the product
would be expected to play a different role in the biochem-
ical reactions, improving the binding properties and the
O
NH
base pairing preference when inserted in oligonucleotides.
Considerable attention has thereafter been paid to struc-
O
OH
O
N
O
O
SYNTHESIS 2010, No. 15, pp 2533–2542
Advanced online publication: 17.06.2010
x
x.
x
x
.
2
0
1
0
HO
DOI: 10.1055/s-0029-1218828; Art ID: P04710SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Spiro sugar mimic

2534
J. K. Maity et al.
PAPER
followed by insertion of a nucleoside base at the anomeric
center from D-glucose-derived substrates.
O
O
O
a, b
O
HO
R
Our intended synthetic scheme was based on the utiliza-
tion of the known starting material 716c (Scheme 2) con-
taining a 4,4-disubstituted furanose ring. The free CH2OH
group was to be elaborated through oxidation followed by
methylenation (path I) or Barbier allylation (path II). The
silyl-protected primary alcohol group could then be
deprotected and subjected to oxidation followed by allyla-
tion (path I) or methylenation (path II). Subsequent ring-
closing metathesis (RCM) reaction of the two olefin-bear-
ing substituents at C-4 of the furanose ring was expected
to provide spiro rings for further elaboration, culminating
in the introduction of the nucleoside base. The results of
these studies are discussed below.
O
O
BnO
BnO
12
13 R = β-OH (62%)
14 R = α-OH (8%)
Scheme 3 Reagents and conditions: (a) DMP, CH2Cl2, 0 °C, 1 h; (b)
aq NH4Cl–THF (5:1), AllBr, 0 °C, 5 min, Zn dust, 0 °C to r.t., 12 h.
The diene 13 was then treated with the Grubbs catalyst in
dichloromethane–benzene, but without success. Howev-
er, benzylation of its hydroxy group afforded the hydroxy-
protected diene 15 (Scheme 4), which upon RCM reaction
in benzene in the presence of the first-generation Grubbs
catalyst under prolonged reflux furnished 16 (70%). Sim-
ilarly, RCM reaction of 17 (where the hydroxy group was
protected by an acetyl group) generated 18 (79%). The
structure of 18 was confirmed by X-ray diffraction analy-
sis (Figure 2). Deacetylation of 18 afforded 19 (94%),
which could be converted into 16 through benzylation of
the hydroxy group, thus completing the correlation.
path I
path II
(i) oxidation
and olefination
(i) oxidation
and allylation
HO
TBDMSO
HO
TBDMSO
O
O
O
O
O
O
BnO
BnO
(ii) deprotection,
oxidation and
olefination
(ii) deprotection,
oxidation and
allylation
7
7
O
O
O
O
O
O
a
BnO
HO
AcO
AcO
94%
O
O
OH
BnO
BnO
BnO
BnO
13
15
O
O
c
96%
b 70%
O
O
HO
O
O
BnO
BnO
O
O
8
10
O
O
(iii) RCM
reaction
(iii) RCM
reaction
BnO
O
O
BnO
BnO
17
16
OH
5
d
79%
f
84%
O
O
1
1
O
O
8
O
O
HO
e
O
O
BnO
BnO
11
9
94%
HO
O
O
18
19
Scheme 2 Pathways to generate spiro rings
Scheme 4 Reagents and conditions: (a) 1. NaH, THF, 0 °C, 5 min;
2. BnBr, TBAI, r.t., 2 h; (b) Grubbs I cat., benzene, reflux, 45 h; (c)
Ac2O, py, r.t., 12 h; (d) Grubbs I cat., CH2Cl2, r.t., 5 h; (e) K2CO3,
MeOH, r.t., 30 min; (f) 1. NaH, THF, r.t., 10 min; 2. BnBr, TBAI,
reflux, 10 h.
The dienes 13 and/or 14, the key intermediates required
for the preparation of the spiro[5.5] rings, with a hydroxy
group at C-8 (via path I) could be synthesized from easily
accessible 4-vinylfuranose derivative 1219 (Scheme 3).
Oxidation of 12 with Dess–Martin periodinane and subse-
quent Barbier allylation of the resulting aldehyde by using
allyl bromide and zinc dust provided diene 13 (62%) as
the major product in addition to 14 (8%) as the minor
product, via the preferential attack of the allyl anion on the
aldehyde group (in forming 13) from the less hindered
side, opposite to the vinyl group. The presence of two vi-
nyl groups in each of these products was inferred from
NMR spectral analyses. The orientation of the hydroxy
group in 13 as indicated was confirmed by subsequent X-
ray diffraction analysis of 18, derived from the RCM re-
action of the acetate derivative of 13. This automatically
settled the structure of 14 as well.
The diene 14 was also elaborated to the spirocycle 21 via
benzylation of the hydroxy group and RCM reaction using
the first-generation Grubbs catalyst (Scheme 5). The suc-
cess of the RCM reaction of 20 in obtaining 21 was evi-
dent from the absence of two olefinic carbon signals and
O
O
a
b
O
O
14
67%
90%
BnO
BnO
BnO
O
O
BnO
20
21
Scheme 5 Reagents and conditions: (a) 1. NaH, THF, 0 °C, 5 min;
2. BnBr, TBAI, r.t., 2 h; (b) Grubbs I cat., benzene, reflux, 45 h.
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

PAPER
Carbohydrate-Derived 1-Oxaspiro[4.4]nonane Skeleton
2535
Next, with the objective to generate a [5.5]-spirocycle
with a C-8 hydroxy group (via path II), the carbohydrate
derivative 7 was subjected to Dess–Martin periodinane
oxidation (Scheme 7) followed by allylation of the result-
ing aldehyde with allyl bromide and zinc to produce an
epimeric mixture of inseparable alcohols 26, which on
acetylation afforded an acetate mixture 27 (inseparable as
well). Treatment of 27 with tetrabutylammonium fluoride
for removal of the tert-butyldimethylsilyl group led to a
mixture of four products, which could be formed in the re-
action by intra- and intermolecular acyl migration. These
were separated and identified as 28 (13%), 29 (20%), 30
(41%), and 31 (15%).
OAc
OH
Figure 2 ORTEP diagram of 18 with ellipsoids at 30% probability
O
O
a
b
O
O
O
7
the presence of only two olefinic proton signals in the 13C
and 1H NMR spectra of the product.
94%
63%
TBDMSO
TBDMSO
O
O
O
BnO
BnO
26
27
To realize our goals to synthesize spiro[5.5] nucleosides
with a C-8¢ hydroxy group we set about as follows. Re-
moval of 1,2-acetonide protection from 18 by acid treat-
ment and subsequent peracetylation generated an
anomeric mixture of diacetates, which, without purifica-
tion, was subjected to nucleosidation under Vorbrüggen
reaction conditions20 (Scheme 6) by use of 2,4-bis(tri-
methylsiloxy)pyrimidine in the presence of a Lewis acid,
to provide the b-nucleoside 22 (58%) as the sole product.
Removal of the acetyl groups of 22 generated 23 (95%),
which produced the keto product 24 (25%) along with the
normal trihydroxy product 25 (54%) upon transfer hydro-
genolysis. The unexpected formation of the keto function-
ality in the nucleosides could be explained by invoking
migration of the double bond under catalytic conditions to
give the enol form and subsequent tautomerization.
OAc
OH
O
O
c
O
+
AcO
AcO
O
BnO
BnO
28 (13%)
29 (20%)
OH
O
OAc
O
O
O
+
+
HO
HO
O
O
BnO
31 (15%)
BnO
30 (41%)
Scheme 7 Reagents and conditions: (a) 1. DMP, CH2Cl2, 0 °C, 1 h;
2. aq NH4Cl–THF (5:1), AllBr, 0 °C, 5 min, Zn dust, 0 °C to r.t, 12 h;
(b) Ac2O, py, r.t., 12 h; (c) TBAF, THF, r.t., 3 h.
On the other hand, due to the poor yield of 14, the spiro-
cycle 21 (derived from 14) was not subjected to the nu-
cleosidation reaction.
Deacetylation of 28–30 (Scheme 8) furnished in each case
the dihydroxy product 32 (89–95% yield). This was dis-
tinct from 31. As the stereochemistry of the hydroxy
group of the solid product 29 was deduced by X-ray dif-
fraction analysis (Figure 3), the stereochemistry of the hy-
droxy/acetoxy groups in 28, 30, and 31 was also settled.
O
O
NH
NH
O
N
O
N
a
b
OH
O
O
18
28
O
a
58%
95%
O
29
HO
AcO
89–95%
HO
OAc
O
OH
O
BnO
BnO
30
O
22
23
BnO
32
Scheme 8 Reagents and conditions: (a) K2CO3, r.t., 30 min.
NH
NH
O
N
O
N
c
O
O
+
Oxidation of the hydroxy group of 30 by Dess–Martin
periodinane and subsequent Wittig reaction with methyl-
enetriphenylphosphorane furnished 33 (65%) (Scheme 9).
This diene, upon RCM reaction in the presence of the
first-generation Grubbs catalyst in dichloromethane, af-
forded 34 in 81% yield. The structure of 34 was confirmed
by the presence of two olefinic proton signals at d = 5.77
O
HO
OH
OH
HO
HO
24 (25%)
25 (54%)
Scheme 6 Reagents and conditions: (a) 1. H2SO4 (4%), MeCN–
H2O (3:1), r.t., 12 h; 2. Ac2O, py, r.t., 12 h; 3. 2,4-bis(trimethylsil-
oxy)pyrimidine, MeCN, TMSOTf, reflux, 6 h; (b) K2CO3, MeOH,
r.t., 30 min; (c) Pd/C (10%), cyclohexene, EtOH, reflux, 6 h.
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

2536
J. K. Maity et al.
PAPER
cyclohexene and palladium on carbon (10%) yielded the
keto nucleoside 37 (29%) along with the normal nucleo-
side 38 (51%).
In conclusion, the judicious manipulation of inserting a
carbocyclic ring into the carbohydrate framework by
RCM reactions on D-glucose-derived substrates has per-
mitted entry to spironucleosides with the 1-oxa-
spiro[4.4]nonane skeleton. The precursor assembly for
RCM reactions appears simple, making the strategy an at-
tractive one. The scope of the strategy to synthesize other
ring systems could be investigated.
Melting points were determined in open capillaries and are uncor-
1
rected. H and 13C NMR spectra of samples in CDCl3, C5D5N, or
D2O as solvent and with TMS as internal standard were recorded on
a Bruker AM-300 L model spectrometer. Mass spectra were record-
ed in ESI mode on a Micromass Q-Tof micro TM spectrometer.
Specific rotations were measured at 589 nm. Precoated plates (0.25
mm, silica gel 60 F254) were used for TLC. The PE fraction boiling
at 60–80 °C was used.
Figure 3 ORTEP diagram of 29 with ellipsoids at 30% probability
OAc
O
OAc
O
b
a
O
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-vinyl-5-[(1S)-1-
hydroxybut-3-enyl]tetrahydrofuro[2,3-d][1,3]dioxole (13) and
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-vinyl-5-[(1R)-1-
hydroxybut-3-enyl]tetrahydrofuro[2,3-d][1,3]dioxole (14)
A soln of alcohol 12 (3.00 g, 9.80 mmol) in CH2Cl2 (40 mL) was
added to a soln of DMP (6.27 g, 14.7 mmol) in CH2Cl2 (40 mL) at
r.t. under N2. After 1 h, more CH2Cl2 (20 mL) was added to the mix-
ture. The soln was then washed with a 10% aq Na2S2O3–sat. aq
NaHCO3 mixture (1:1, 40 mL) and subsequently with brine (2 × 40
mL). The organic solvent was dried (Na2SO4) and evaporated in
vacuo to give the corresponding aldehyde, which was dried (P2O5)
and used without further purification. To a soln of the above alde-
hyde (2.68 g) in a sat. aq NH4Cl–THF mixture (5:1, 48 mL) at 0 °C
was added allyl bromide (2.30 mL, 26.46 mmol), and the mixture
was stirred for 5 min. Zn dust (3.46 g, 52.92 mmol) was added por-
tionwise at 0 °C and the reaction mixture was stirred at r.t. for 12 h.
The reaction was quenched with sat. aq NaHCO3 soln (20 mL) and
the solvent was removed by distillation to furnish a residue, which
was extracted with CHCl3 (3 × 30 mL). The combined extract was
washed with brine (2 × 30 mL), dried (Na2SO4), and evaporated in
vacuo. The crude product was purified by flash column chromatog-
raphy (silica gel, 230–400 mesh, EtOAc–PE, 2:23); this gave 13 as
thick liquid. The same solvents used in the ratio 9:91 subsequently
eluted 14 as a viscous liquid.
O
30
81%
65%
O
O
BnO
BnO
33
34
Scheme 9 Reagents and conditions: (a) 1. DMP, CH2Cl2, 0 °C, 1 h;
2. Ph3PMeBr, t-BuOK, THF, 0 °C to r.t., 4 h; (b) Grubbs I cat.,
CH2Cl2, r.t., 5 h.
(d, J = 1.8 Hz, 1 H) and 5.94–5.96 (m, 1 H), and carbon
1
signals at d = 133.1 and 137.3 in the H and 13C NMR
spectra, respectively.
Towards the synthesis of the targeted spironucleoside, we
applied the known nucleosidation procedure on 34 as
well. Opening of the 1,2-acetonide followed by peracety-
lation and nucleosidation under Vorbrüggen reaction con-
ditions produced the b-spironucleoside 35 (55%) as the
sole product (Scheme 10). Deacetylation of this com-
pound (furnishing 36) and transfer hydrogenolysis with
O
O
NH
NH
OAc
O
OH
N
O
N
O
Compound 13
b
a
O
Yield: 2.10 g (62%); [a]D25 +3.4 (c 0.76, CHCl3).
34
91%
55%
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H), 1.58 (s, 3 H), 2.00–
2.05 (m, 1 H), 2.32–2.42 (m, 2 H), 3.64 (d, J = 10.1 Hz, 1 H), 4.32
(d, J = 1.5 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), partially merged
with 4.63 (m, 1 H), 4.75 (d, J = 11.7 Hz, 1 H), 5.05–5.09 (m, 2 H),
5.29 (d, J = 10.9 Hz, 1 H), 5.49 (d, J = 17.3 Hz, 1 H), 5.75–5.89 (m,
1 H), partially merged with 5.85 (d, J = 4.5 Hz, 1 H), 6.14 (dd,
J = 10.9, 17.3 Hz, 1 H), 7.30–7.36 (m, 5 H).
OAc
O
OH
BnO
BnO
35
36
O
NH
NH
O
O
OH
c
N
O
N
+
O
O
13C NMR (75 MHz, CDCl3): d = 27.4 (CH3), 27.9 (CH3), 35.2
(CH2), 72.1 (CH2), 74.7 (CH), 83.7 (CH), 86.7 (CH), 90.0 (C),
103.3 (CH), 113.9 (C), 116.1 (CH2), 117.2 (CH2), 127.7–127.8
(3 × CH), 128.3 (2 × CH), 134.2 (CH), 135.4 (CH), 137.4 (C).
OH
37 (29%)
OH
38 (51%)
HO
HO
ESI-MS: m/z = 369 [M + Na]+.
Scheme 10 Reagents and conditions: (a) 1. H2SO4 (4%), MeCN–
H2O (3:1), r.t., 12 h; 2. Ac2O, py, r.t., 12 h; 3. 2,4-bis(trimethylsil-
oxy)pyrimidine, MeCN, TMSOTf, reflux, 6 h; (b) K2CO3, MeOH, 30
min; (c) Pd/C (10%), cyclohexene, EtOH, reflux, 5 h.
Anal. Calcd for C20H26O5: C, 69.34; H, 7.56. Found: C, 69.08; H,
7.39.
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

PAPER
Carbohydrate-Derived 1-Oxaspiro[4.4]nonane Skeleton
2537
Compound 14
Yield: 140 mg (84%); [a]D25 –10.8 (c 0.11, CHCl3).
Yield: 275 mg (8%); [a]D25 +7.5 (c 0.80, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.34 (s, 3 H), 1.52 (s, 3 H), 2.42
(d, J = 16.8 Hz, 1 H), 2.78 (br d, 1 H), 4.22 (d, J = 3.2 Hz, 1 H),
4.57–4.67 (m, 5 H), 4.76 (d, J = 3.9 Hz, 1 H), 5.88 (d-like, J = 3.9
Hz, 2 H), 6.05 (d, J = 5.7 Hz, 1 H), 7.29 (br s, 10 H).
13C NMR (75 MHz, CDCl3): d = 26.2 (CH3), 26.8 (CH3), 37.6
(CH2), 71.7 (CH2), 72.3 (CH2), 81.5 (CH), 83.2 (CH), 85.9 (CH),
100.3 (C), 104.1 (CH), 112.2 (C), 127.4–128.3 (10 × CH), 129.8
(CH), 134.3 (CH), 137.8 (C). 138.3 (C).
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 3 H), 1.48 (s, 1 H), 1.57
(s, 3 H), 2.04–2.14 (m, 1 H), 2.25 (m, 1 H), 3.65 (d, J = 7.2 Hz, 1
H), 4.25 (d, J = 2.8 Hz, 1 H), 4.56 (d, J = 11.8 Hz, 1 H), 4.64 (ap-
parent t, J = 3.5 Hz, 1 H), 4.77 (d, J = 11.8 Hz, 1 H), 5.04–5.08 (m,
2 H), 5.31 (d, J = 11.0 Hz, 1 H with finer splitting), 5.43 (d, J = 17.3
Hz, 1 H with finer splitting), 5.79–5.96 (m, 3 H), 7.35 (br s, 5 H).
13C NMR (75 MHz, CDCl3): d = 27.4 (CH3), 27.7 (CH3), 36.0
(CH2), 72.1 (CH2), 73.1 (CH), 85.4 (CH), 86.2 (CH), 90.4 (C),
103.4 (CH), 113.8 (C), 116.1 (CH2), 117.1 (CH2), 127.6–128.4
(5 × CH), 133.8 (CH), 135.2 (CH), 137.3 (C).
ESI-MS: m/z = 431 [M + Na]+.
Anal. Calcd for C25H28O5: C, 73.51; H, 6.91. Found: C, 73.28; H,
6.69.
ESI-MS: m/z = 369 [M + Na]+.
Anal. Calcd for C20H26O5: C, 69.34; H, 7.56. Found: C, 69.31; H,
7.53.
(3aR,5S,6R,6aR)-5-[(1S)-1-Acetoxybut-3-enyl]-6-(benzyloxy)-
2,2-dimethyl-5-vinyltetrahydrofuro[2,3-d][1,3]dioxole (17)
A soln of 13 (1.35 g, 3.90 mmol) in py (20 mL) was treated with
Ac2O (0.44 mL, 4.68 mmol) and the mixture was stirred at r.t. for
12 h. The solvent was evaporated and the crude product was puri-
fied by column chromatography (silica gel, 60–120 mesh, EtOAc–
PE, 1:9); this gave 17 as a viscous liquid.
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-vinyl-5-[(1S)-1-
(benzyloxy)but-3-enyl]tetrahydrofuro[2,3-d][1,3]dioxole (15)
Oil-free NaH (157 mg, 6.54 mmol) was added portionwise to a soln
of 13 (567 mg, 1.64 mmol) in anhyd THF (30 mL) at 0 °C and the
mixture was stirred for 5 min. BnBr (0.23 mL, 1.97 mmol), and
TBAI (61 mg, 0.164 mmol) were added to the reaction mixture,
which was stirred at r.t. for 2 h. Excess NaH was destroyed by the
addition of aq NH4Cl (6 mL). The solvent was evaporated in vacuo
and the residue was extracted with CHCl3 (3 × 25 mL). The CHCl3
soln was washed with H2O (2 × 30 mL), dried (Na2SO4), and con-
centrated to afford a liquid, which was purified by column chroma-
tography (silica gel, 60–120 mesh, EtOAc–PE, 7:93); this gave 15
as a colorless liquid.
Yield: 1.45 g (96%); [a]D25 –21.3 (c 0.18, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.37 (s, 3 H), 1.62 (s, 3 H), 1.86
(s, 3 H), 2.07–2.19 (m, 1 H), 2.45–2.51 (m, 1 H), 4.05 (d, J = 1.9 Hz,
1 H), 4.49 (1 H, J = 12.0 Hz), 4.62 (dd, J = 2.0, 4.4 Hz, 1 H), 4.73
(d, J = 12.0 Hz, 1 H), 4.95–5.02 (m, 2 H), 5.23 (dd, J = 2.6, 10.6 Hz,
1 H), 5.34 (dd, J = 1.8, 10.9 Hz, 1 H), 5.49 (dd, J = 1.8, 17.4 Hz, 1
H), 5.58–5.73 (m, 1 H), 5.91 (d, J = 4.4 Hz, 1 H), 6.00 (dd, J = 10.9,
17.4 Hz, 1 H), 7.28–7.45 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3), 26.9 (CH3), 27.2
(CH3), 34.0 (CH2), 71.9 (CH2), 74.6 (CH), 85.3 (CH), 85.7 (CH),
88.6 (C), 103.9 (CH), 113.4 (C), 116.4 (CH2), 117.3 (CH2), 127.7
(2 × CH), 127.8 (CH), 128.3 (2 × CH), 133.2 (CH), 134.1 (CH),
137.3 (C), 170.1 (C).
Yield: 672 mg (94%); [a]D25 – 6.3 (c 0.16, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 3 H), 1.52 (s, 3 H), 2.21–
2.28 (m, 1 H), 2.42–2.49 (m, 1 H), 3.65 (dd, J = 2.9, 9.3 Hz, 1 H),
4.27 (d, J = 1.7 Hz, 1 H), 4.54 (d, J = 11.9 Hz, 1 H), 4.61–4.67 (m,
4 H), 4.99 (br d, J = 10.0 Hz, 1 H), 5.08 (br d, J = 17.1 Hz, 1 H),
5.27 (dd, J = 2.0, 10.9 Hz, 1 H), 5.49 (dd, J = 2.0, 17.4 Hz, 1 H),
5.79–5.94 (m, 2 H), 6.13 (dd, J = 10.9, 17.4 Hz, 1 H), 7.26–7.29 (m,
10 H).
ESI-MS: m/z = 411 [M + Na]+.
Anal. Calcd for C22H28O6: C, 68.02; H, 7.27. Found: C, 67.91; H,
7.00.
13C NMR (75 MHz, CDCl3): d = 27.2 (CH3), 27.6 (CH3), 35.9
(CH2), 72.5 (CH2), 74.7 (CH2), 83.1 (CH), 84.9 (CH), 86.6 (CH),
91.7 (C), 104.4 (CH), 113.5 (C), 116.1 (CH2), 116.9 (CH2), 127.2–
128.8 (10 × CH), 134.9 (CH), 136.8 (CH), 138.0 (C), 138.9 (C).
(2R,3R,4R,5S,9S)-9-Acetoxy-4-(benzyloxy)-2,3-O-isopropy-
lidene-1-oxaspiro[4.4]non-6-ene (18)
Grubbs I cat. (117 mg, 0.142 mmol) was added to a soln of 17 (1.10
g, 2.84 mmol) in CH2Cl2 (473 mL) and the soln was stirred at r.t. for
5 h under N2. The solvent was evaporated in vacuo and the residue
was purified by column chromatography (silica gel, 100–200 mesh,
EtOAc–PE, 4:21); this gave 18 as a colorless crystalline solid.
ESI-MS: m/z = 459 [M + Na]+.
Anal. Calcd for C27H32O5: C, 74.29; H, 7.39. Found: C, 74.09; H,
7.23.
Yield: 806 mg (79%); mp 50–52 °C (EtOAc–PE, 1:8); [a]D25 –36.6
(c 0.71, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.31 (s, 3 H), 1.50 (s, 3 H), 1.97
(s, 3 H), 2.22–2.28 (m, 1 H), 3.02–3.10 (m, 1 H), 4.39 (s, 1 H), 4.61
(d, J = 11.8 Hz, 1 H), 4.71 (d, J = 11.8 Hz, 1 H), 4.73 (partially
merged d, J = 3.7 Hz, 1 H), 5.28 (d, J = 5.1 Hz, 1 H), 5.92 (d, J = 4.1
Hz, 1 H), 5.95 (m, 1 H), 6.00 (m, 1 H), 7.28–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3), 25.5 (CH3), 25.7
(CH3), 39.8 (CH2), 72.1 (CH2), 77.1 (CH), 81.2 (CH), 84.4 (CH),
99.5 (C), 104.5 (CH), 111.6 (C), 127.4 (2 × CH), 127.6 (CH), 128.2
(2 × CH), 128.9 (CH), 135.0 (CH), 137.3 (C), 169.4 (C).
(2R,3R,4R,5S,9S)-4,9-Bis(benzyloxy)-2,3-O-isopropylidene-1-
oxaspiro[4.4]non-6-ene (16)
From 15: The Grubbs I cat. (123 mg, 0.149 mmol) was added to a
soln of 15 (650 mg, 1.49 mmol) in benzene (248 mL), and the soln
was heated at reflux for 45 h under N2. The solvent was evaporated
under vacuum and the residue was purified by column chromatog-
raphy (silica gel, 60–120 mesh, EtOAc–PE, 1:19); this gave 16 as a
thick liquid.
Yield: 426 mg (70%).
From 19: NaH (45 mg, 1.88 mmol) was added to a soln of 19 (130
mg, 0.41 mmol) in THF (15 mL), and the mixture was stirred at r.t.
for 10 min. BnBr (0.67 mL, 0.56 mmol) and TBAI (15 mg, 0.04
mmol) were added to the mixture, which was then heated at reflux
for 10 h under N2. After the mixture had been cooled and the excess
of NaH had been destroyed by the addition of aq NH4Cl (2 mL), the
solvent was evaporated under vacuum to provide a crude residue,
which was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–PE, 1:19); this gave 16 as a viscous liquid.
ESI-MS: m/z = 383 [M + Na]+.
Anal. Calcd for C20H24O6: C, 66.65; H, 6.71. Found: C, 66.41; H,
6.59.
Crystallographic Data of 1821
C20H24O6, M = 360.39, monoclinic, space group P21, Z = 2,
a = 8.2378(11), b = 11.1137(11), c = 9.9902(11) Å, b = 92.128(11)°,
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

2538
J. K. Maity et al.
PAPER
U = 1860.6(4)°, dcalc = 1.310 g·cm–3. 3224 independent data were
collected with Mo Ka radiation at 100 K using the Oxford Diffrac-
tion X-Calibur CCD System. The crystal was positioned at 50 mm
from the CCD. 321 frames were measured with a counting time of
10 s. Data analysis was carried out with the CrysAlis program.22a
The structure was solved using direct methods with the Shelxs97
program.22b The non-hydrogen atoms were refined with anisotropy
thermal parameters. The hydrogen atoms bonded to carbon were in-
cluded in geometric positions and given thermal parameters equiv-
alent to 1.2 times those of the atom to which they were attached. The
structure was refined on F2 using Shelxl97 to R1 0.0550; wR2
0.1240 for 2726 reflections with I > 2s(I).
residue was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–PE, 7:93); this gave 21 as a colorless gum.
Yield: 126 mg (67%); [a]D25 –81.7 (c 0.17, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 3 H), 1.58 (s, 3 H), 2.41–
2.54 (m, 2 H), 3.90 (d, J = 1.6 Hz, 1 H), 3.98 (t, J = 5.3 Hz, 1 H),
4.42–4.49 (m, 2 H), 4.60 (d, J = 11.9 Hz, 1 H), 4.67 (d, J = 11.9 Hz,
1 H), 4.71 (dd, J = 2.0, 4.3 Hz, 1 H), 5.86–5.97 (m, 3 H), 7.29–7.31
(m, 10 H).
13C NMR (75 MHz, CDCl3): d = 27.5 (CH3), 27.8 (CH3), 36.1
(CH2), 71.9 (CH2), 72.6 (CH2), 80.4 (CH), 85.0 (CH), 85.9 (CH),
94.9 (C), 104.8 (CH), 113.8 (C), 127.9–128.8 (10 × CH), 131.5
(CH), 133.1 (CH), 137.8 (C), 138.9 (C).
(2R,3R,4R,5S,9S)-4-(Benzyloxy)-9-hydroxy-2,3-O-isopropy-
lidene-1-oxaspiro[4.4]non-6-ene (19)
ESI-MS: m/z = 431 [M + Na]+.
Anal. Calcd for C25H28O5: C, 73.51; H, 6.91. Found: C, 73.39; H,
6.68.
K2CO3 (126 mg, 0.91 mmol) was added to a soln of 18 (300 mg, 0.
83 mmol) in MeOH (15 mL) and the mixture was stirred at r.t. for
30 min. The solvent was evaporated under reduced pressure and the
crude product was purified by column chromatography (silica gel,
60–120 mesh, EtOAc–PE, 3:17); this gave 19 as a colorless liquid.
(2R,3R,4R,5S,9R)-3,9-Diacetoxy-4-(benzyloxy)-2-(2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)-1-oxaspiro[4.4]non-6-ene (22)
Compound 18 (450 mg, 1.25 mmol) was treated with 4% H2SO4 (10
mL) in aq MeCN (75%) and stirred at r.t. for 12 h. The mixture was
neutralized by portionwise addition of solid CaCO3. The precipitate
was collected by filtration and the filtrate was evaporated in vacuo
to give a gummy mass (330 mg). It was then acetylated with py (10
mL) and Ac2O (0.40 mL) to an anomeric mixture of diacetates (456
mg). A soln of uracil (356 mg, 3.18 mmol) in HMDS (12 mL) and
TMSCl (2 drops) was heated at 135–140 °C under N2 for 12 h. The
solvent was removed by distillation under vacuum, and the soln of
the residue thus obtained in MeCN (8 mL) was added to a stirred
soln of the above diacetate mixture in MeCN (15 mL) containing
TMSOTf (0.25 mL, 1.36 mmol). The mixture was heated at reflux
for 6 h under N2. The reaction mixture was neutralized with solid
CaCO3; H2O (2–3 drops) was added to it, and the solvent was evap-
orated to leave a residue, which was extracted with CHCl3–MeOH
(98:2, 3 × 25 mL). The combined extract was washed with brine
(2 × 25 mL), dried (Na2SO4), and concentrated to a gummy residue.
The crude product was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–PE, 3:7); this gave 22 as white foamy
solid.
Yield: 248 mg (94%); [a]D25 –58.5 (c 0.16, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 3 H), 1.60 (s, 3 H), 2.27–
2.35 (m, 1 H), 2.91–3.01 (m, 2 H), 4.43 (s, 1 H), 4.50 (dd, J = 3.5,
7.4 Hz, 1 H), 4.59 (d, J = 11.9 Hz, 1 H), 4.65 (d, J = 11.9 Hz, 1 H),
4.70 (d, J = 3.7 Hz, 1 H), 5.72–5.76 (m, 1 H), 5.94 (d, J = 3.7 Hz, 1
H), 5.99–6.03 (m, 1 H), 7.29–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 25.9 (CH3), 26.3 (CH3), 41.3
(CH2), 73.3 (CH2), 78.8 (CH), 81.9 (CH), 84.3 (CH), 102.4 (C),
105.4 (CH), 112.5 (C), 127.9 (2 × CH), 128.3 (CH), 128.9
(2 × CH), 129.5 (CH), 135.4 (CH), 137.9 (C).
ESI-MS: m/z = 341 [M + Na]+.
Anal. Calcd for C18H22O5: C, 67.91; H, 6.97. Found: C, 67.75; H,
6.71.
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-vinyl-5-[(1R)-1-
hydroxybut-3-enyl]tetrahydrofuro[2,3-d][1,3]dioxole (20)
Compound 14 (208 mg, 0.60 mmol) was benzylated by employing
the procedure used for the preparation of 15 from 13: NaH (58 mg,
2.42 mmol), BnBr (0.09 mL, 0.72 mmol), TBAI (22 mg, 0.06
mmol), and THF (20 mL). The crude product was purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc–PE, 7:93);
this gave 20 as a viscous liquid.
Yield: 333 mg (58%); mp 80–83 °C; [a]D25 +18.3 (c 0.24, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.08 (s, 3 H), 2.28
(d, J = 18.1 Hz, 1 H), 3.06 (br d, J = 18.1 Hz, 1 H), 4.32 (s, 1 H),
4.65 (d, J = 11.6 Hz, 1 H), 4.74 (d, J = 11.6 Hz, 1 H), 5.20 (d,
J = 4.7 Hz, 1 H), 5.24 (s, 1 H), 5.62 (d, J = 7.5 Hz, 1 H), 6.04 (br s,
1 H), 6.07 (s, 1 H), 6.20 (br s, 1 H), 7.26–7.34 (m, 5 H), 7.56 (d,
J = 8.1 Hz, 1 H), 8.68 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.9 (CH3), 21.3 (CH3), 40.1
(CH2), 72.9 (CH2), 77.3 (CH), 79.8 (CH), 81.2 (CH), 88.4 (CH),
100.7 (C), 102.7 (CH), 127.9 (CH), 128.4 (2 × CH), 128.7 (CH),
128.9 (2 × CH), 137.1 (C), 137.6 (CH), 140.5 (CH), 150.4 (C),
163.2 (C), 169.7 (C), 170.0 (C).
Yield: 235 mg (90%); [a]D25 +3.8 (c 0.15, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H), 1.53 (s, 3 H), 2.28–
2.35 (m, 2 H), 3.43 (dd, J = 3.3, 8.8 Hz, 1 H), 4.17 (d, J = 3.1 Hz, 1
H), 4.47 (d, J = 11.8 Hz, 1 H), 4.49 (d, J = 11.0 Hz, 1 H), 4.57 (d,
J = 11.0 Hz, 1 H), 4.60 (partially merged dd, J = 3.0, 4.5 Hz, 1 H),
4.74 (d, J = 11.8 Hz, 1 H), 4.97–5.04 (m, 2 H), 5.32 (dd, J = 1.8,
10.8 Hz, 1 H), 5.49 (dd, J = 1.8, 17.4 Hz, 1 H), 5.78–5.91 (m, 2 H),
6.00 (dd, J = 10.8, 17.4 Hz, 1 H), 7.27–7.35 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 27.8 (CH3), 27.9 (CH3), 34.7
(CH2), 71.9 (CH2), 73.8 (CH2), 81.8 (CH), 85.7 (CH), 86.6 (CH),
89.8 (C), 103.1 (CH), 114.1 (C), 116.3 (CH2), 116.5 (CH2), 127.3–
128.3 (10 × CH), 134.5 (CH), 136.1 (CH), 137.3 (C), 138.3 (C).
ESI-MS: m/z = 479 [M + Na]+.
Anal. Calcd for C23H24N2O8: C, 60.52; H, 5.30; N, 6.14. Found: C,
60.33; H, 5.07; N, 5.86.
ESI-MS: m/z = 459 [M + Na]+.
(2R,3R,4R,5S,9R)-4-(Benzyloxy)-2-(2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)-3,9-dihydroxy-1-oxaspiro[4.4]non-6-ene (23)
To a soln of 22 (100 mg, 0.22 mmol) in anhyd MeOH (10 mL) was
added K2CO3 (33 mg, 0.24 mmol) and the mixture was stirred at r.t.
for 30 min. The solvent was evaporated and the crude product was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc–PE, 3:2) to furnish 23 as a foamy solid.
Anal. Calcd for C27H32O5: C, 74.29; H, 7.39. Found: C, 74.19; H,
7.32.
(2R,3R,4R,5S,9R)-4,9-Bis(benzyloxy)-2,3-O-isopropylidene-1-
oxaspiro[4.4]non-6-ene (21)
Grubbs I cat. (39 mg, 0.046 mmol) was added to a soln of 20 (200
mg, 0.46 mmol) in benzene (77 mL) and the soln was heated at re-
flux for 45 h under N2. The solvent was evaporated in vacuo and the
Yield: 78 mg (95%); mp 89–91 °C; [a]D25 +14.6 (c 0.18, MeOH).
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

PAPER
Carbohydrate-Derived 1-Oxaspiro[4.4]nonane Skeleton
2539
1H NMR (300 MHz, C5D5N): d = 2.53 (dd, J = 1.7, 16.6 Hz, 1 H),
2.89 (dd, J = 6.8, 16.6 Hz, 1 H), 4.71–4.83 (m, 4 H), 5.84 (d, J = 8.1
Hz, 1 H), 6.05–6.07 (m, 1 H), 6.24 (apparent d, J = 5.8 Hz, 1 H),
6.63 (s, 1 H), 7.12 (br s, 1 H), 7.17–7.41 (m, 6 H), 7.99 (d, J = 8.1
Hz, 1 H), 8.21 (br s, 1 H), 13.27 (br s, 1 H).
ESI-MS: m/z = 487 [M + Na]+.
(2R,3R,4R,5R)-5-[(1R/1S)-1-Acetoxybut-3-enyl]-4-(benzyloxy)-
5-(tert-butyldimethylsiloxymethyl)-2,3-O-isopropylidenetetra-
hydrofuran (27)
The isomeric mixture of 26 (3.5 g, 7.54 mmol) was acetylated ac-
cording to the procedure described for the preparation of 17. Usual
workup followed by purification by column chromatography (silica
gel, 60–120 mesh, EtOAc–PE, 1:24) afforded 27 as an isomeric
mixture.
13C NMR (75 MHz, C5D5N): d = 40.8 (CH2), 72.5 (CH2), 78.4 (CH),
79.7 (CH), 83.0 (CH), 90.5 (CH), 100.9 (C), 102.1 (CH), 127.9
(3 × CH), 128.6 (2 × CH), 130.8 (CH), 134.6 (CH), 138.8 (C),
140.8 (CH), 152.1 (C), 164.3 (C).
ESI-MS: m/z = 395 [M + Na]+.
Yield: 3.59 g (94%).
ESI-MS: m/z = 529 [M + Na]+.
Anal. Calcd for C19H20N2O6: C, 61.28; H, 5.41; N, 7.52. Found: C,
61.00; H, 5.18; N, 7.27.
(2R,3R,4R,5R)-5-[(1S)-1-Acetoxybut-3-enyl]-5-(acetoxymeth-
yl)-4-(benzyloxy)-2,3-O-isopropylidenetetrahydrofuran (28),
(2R,3R,4R,5R)-5-(Acetoxymethyl)-4-(benzyloxy)-5-[(1S)-1-hy-
droxybut-3-enyl]-2,3-O-isopropylidenetetrahydrofuran (29),
(2R,3R,4R,5R)-5-[(1S)-1-Acetoxybut-3-enyl]-4-(benzyloxy)-2,3-
O-isopropylidene-5-(hydroxymethyl)tetrahydrofuran (30), and
(2R,3R,4R,5R)-4-(Benzyloxy)-5-[(1R)-1-hydroxybut-3-enyl]-5-
(hydroxymethyl)-2,3-O-isopropylidenetetrahydrofuran (31)
TBAF (1.83 g, 6.98 mmol) was added portionwise to a soln of 27
(3.21 g, 6.34 mmol) in THF (70 mL) and the mixture was stirred at
r.t. for 3 h. The solvent was evaporated in vacuo and the residue was
extracted with CHCl3 (3 × 40 mL). The CHCl3 soln was washed
with brine (2 × 30 mL), dried (Na2SO4), and concentrated to afford
a gummy mass, which was then purified by column chromatogra-
phy (silica gel, 100–200 mesh, EtOAc–PE, 3:22); this gave 28 as a
colorless liquid, 29 as a white crystalline solid, and 30 and 31 as vis-
cous liquids.
(2R,3R,4R,5R)-1-(3,4-Dihydroxy-6-oxo-1-oxaspiro[4.4]nonan-
2-yl)-1H-pyrimidine-2,4-dione (24) and (2R,3R,4R,5S,6S)-1-
(3,4,6-Trihydroxy-1-oxaspiro[4.4]nonan-2-yl)-1H-pyrimidine-
2,4-dione (25)
To a soln of 23 (50 mg, 0.13 mmol) in EtOH (10 mL) were added
Pd/C (10%, 15 mg) and cyclohexene (0.20 mL), and the mixture
was heated at reflux for 6 h. The catalyst was collected by filtration,
the solvent was evaporated, and the crude residue was purified by
column chromatography (silica gel, 100–200 mesh, EtOAc–PE,
39:11); this gave 24 and 25 as white foamy materials.
Compound 24
25
Yield: 9 mg (25%); mp 95–98 °C (dec); [a]D –19.0 (c 0.36,
MeOH).
1H NMR (300 MHz, C5D5N + D2O): d = 1.95–2.09 (m, 3 H), 2.21–
2.31 (m, 2 H), 2.89–2.96 (m, 1 H), 4.99 (s, 1 H), 5.01 (s, 1 H), 5.97
(d, J = 8.1 Hz, 1 H), 6.93 (d, J = 8.1 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1
H).
13C NMR (75 MHz, C5D5N): d = 19.5 (CH2), 33.0 (CH2), 37.0
(CH2), 77.9 (CH), 81.8 (CH), 89.9 (CH), 90.1 (C), 104.6 (CH),
142.1 (CH), 153.4 (C), 165.4 (C), 218.5 (C).
Compound 28
Yield: 350 mg (13%); [a]D25 +26.1 (c 0.36, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H), 1.56 (s, 3 H), 1.94
(s, 3 H), 1.99 (s, 3 H), 2.34–2.45 (m, 2 H), 4.02 (d, J = 11.8 Hz, 1
H), 4.16–4.21 (m, 2 H), 4.52 (d, J = 11.9 Hz, 1 H), 4.69–4.78 (m, 2
H), 4.99–5.07 (m, 2 H), 5.22 (dd, J = 4.4, 8.4 Hz, 1 H), 5.68–5.82
(m, 1 H), 6.01 (d, J = 4.4 Hz, 1 H), 7.31–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 20.6 (CH3), 21.4 (CH3), 27.8
(2 × CH3), 34.4 (CH2), 63.7 (CH2), 72.1 (CH), 72.6 (CH2), 85.1
(CH), 87.0 (C), 87.4 (CH), 104.8 (CH), 114.3 (C), 117.7 (CH2),
127.8–128.3 (5 × CH), 133.8 (CH), 137.1 (C), 169.2 (C), 170.1 (C).
ESI-MS: m/z = 305 [M + Na]+.
Anal. Calcd for C12H14N2O6: C, 51.06; H, 5.00; N, 9.93. Found: C,
50.82; H, 4.77; N, 9.66.
Compound 25
Yield: 20 mg (54%); mp 118–120 °C; [a]D25 +4.9 (c 0.52, MeOH).
1H NMR (300 MHz, C5D5N + D2O): d = 1.86 (m, 1 H), 2.06–2.09
(m, 2 H), 2.28 (m, 2 H), 2.86 (m, 1 H), 4.68 (s, 1 H), 4.91 (s, 1 H),
5.28 (s, 1 H), 6.00 (d, J = 8.0 Hz, 1 H), 6.59 (s, 1 H), 8.26 (d, J = 8.0
Hz, 1 H).
ESI-MS: m/z = 457 [M + Na]+.
Anal. Calcd for C23H30O8: C, 63.58; H, 6.96. Found: C, 63.77; H,
6.71.
13C NMR (75 MHz, C5D5N): d = 22.0 (CH2), 33.1 (CH2), 35.2
(CH2), 78.1 (CH), 78.8 (CH), 85.2 (CH), 93.2 (CH), 101.1 (C),
103.9 (CH), 143.5 (CH), 153.9 (C), 166.1 (C).
Compound 29
Yield: 500 mg (20%); mp 61–63 °C (EtOAc–PE, 1:4); [a]D25 –19.4
(c 0.45, CHCl3).
ESI-MS: m/z = 307 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H), 1.57 (s, 3 H), 1.95
(s, 3 H), 2.19–2.25 (m, 1 H), 2.32–2.42 (m, 2 H), 3.85 (dd, J = 3.0,
10.0 Hz, 1 H), 4.03 (d, J = 11.8 Hz, 1 H), 4.13 (d, J = 11.8 Hz, 1 H),
4.22 (d, J = 1.4 Hz, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.79–4.87 (m,
2 H), 5.07–5.15 (m, 2 H), 5.82–5.96 (m, 1 H), 6.08 (d, J = 4.4 Hz, 1
H), 7.32–7.39 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 20.6 (CH3), 27.7 (CH3), 27.8
(CH3), 34.6 (CH2), 63.8 (CH2), 71.8 (CH), 72.8 (CH2), 85.6 (CH),
87.4 (CH), 88.3 (C), 104.9 (CH), 114.3 (C), 117.1 (CH2), 128.2
(2 × CH), 128.3 (CH), 128.5 (2 × CH), 135.3 (CH), 136.6 (C),
170.1 (C).
Anal. Calcd for C12H16N2O6: C, 50.70; H, 5.67; N, 9.85. Found: C,
50.46; H, 5.43; N, 9.58.
(2R,3R,4R,5R)-4-(Benzyloxy)-5-(tert-butyldimethylsiloxymeth-
yl)-5-[(1R/1S)-1-hydroxybut-3-enyl]-2,3-O-isopropylidenetet-
rahydrofuran (26)
According to the procedure described above (for the preparation of
13 and 14 from 12), compound 7 (5.50 g, 12.97 mmol) in CH2Cl2
(120 mL) was treated with DMP (8.28 g, 19.46 mmol) and then al-
lylated by using allyl bromide (1.96 mL, 22.56 mmol), Zn dust
(2.95 g, 45.12 mmol), and an aq NH4Cl–THF mixture (5:1, 96 mL).
Usual workup followed by purification of the crude products by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc–PE, 3:47)
furnished 32 as an epimeric mixture.
ESI-MS: m/z = 415 [M + Na]+.
Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C, 64.06; H,
7.43.
Yield: 3.77 g (63%).
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

2540
J. K. Maity et al.
PAPER
Crystallographic Data of 2921
C21H28O7, M = 392.43, orthorhombic, space group P212121, Z = 4,
J = 11.8 Hz, 1 H), 3.80 (dd, J = 3.0, 9.7 Hz, 1 H), 4.31 (d, J = 2.5
Hz, 1 H), 4.58 (d, J = 11.5 Hz, 1 H), 4.78 (d, J = 11.5 Hz, 1 H), 4.81
(partially merged dd, J = 2.7, 4.2 Hz, 1 H), 5.05–5.12 (m, 2 H),
5.81–5.95 (m, 1 H), 6.04 (d, J = 4.5 Hz, 1 H), 7.31–7.36 (m, 5 H).
a = 11.1647(15),
b = 11.6164(15),
c = 15.9757(11)
Å,
U = 2071.9(4)°, dcalc = 1.258 g·cm–3. 5731 independent data were
collected with Mo Ka radiation at 100 K using the Oxford Diffrac-
tion X-Calibur CCD System. The crystal was positioned at 50 mm
from the CCD. 321 frames were measured with a counting time of
10 s. Data analysis was carried out with the CrysAlis program.22a
The structure was solved using direct methods with the Shelxs97
program.22b The non-hydrogen atoms were refined with anisotropic
thermal parameters. The hydrogen atoms bonded to carbon were in-
cluded in geometric positions and given thermal parameters equiv-
alent to 1.2 times those of the atom to which they were attached. The
structure was refined on F2 using Shelxl97 to R1 0.0593; wR2
0.1206 for 3604 reflections with I > 2s(I).
13C NMR (75 MHz, CDCl3): d = 27.2 (CH3), 27.6 (CH3), 35.3
(CH2), 62.6 (CH2), 72.2 (CH), 72.8 (CH2), 85.4 (CH), 86.7 (CH),
91.1 (C), 104.8 (CH), 113.7 (C), 116.8 (CH2), 127.7 (2 × CH),
128.1 (CH), 128.5 (2 × CH), 135.5 (CH), 136.7 (C).
ESI-MS: m/z = 373 [M + Na]+.
Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 65.01; H,
7.33.
(3aR,5R,6R,6aR)-5-[(1S)-1-Acetoxybut-3-enyl]-6-(benzyloxy)-
2,2-dimethyl-5-vinyltetrahydrofuro[2,3-d][1,3]dioxole (33)
A soln of 30 (640 mg, 1.63 mmol) dissolved in CH2Cl2 (25 mL) was
oxidized to the aldehyde by using DMP (1.04 g, 2.44 mmol) accord-
ing to the procedure adopted for the preparation of 13 and 14 from
12. The crude aldehyde (610 mg) was dried (P2O5) and subsequent-
ly used without further purification. A soln of this aldehyde in THF
(10 mL) was added dropwise for 45 min to a soln of Ph3PMeBr
(1.39 g, 3.89 mmol) and t-BuOK (381 mg, 3.12 mmol) in anhyd
THF (15 mL) at 0 °C under N2. The mixture was stirred at 0 °C for
2 h and subsequently at r.t. for 2 h. The reaction was quenched by
the addition of sat. aq NH4Cl soln (15 mL). The solvent was evapo-
rated in vacuo and the residue was extracted with CHCl3 (3 × 30
mL). The CHCl3 soln was washed with H2O (2 × 30 mL) and dried
(Na2SO4), and the solvent was evaporated to leave a crude product,
which was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–PE, 1:19); this gave 33 as a viscous liquid.
Compound 30
Yield: 1.02 g (41%); [a]D25 +24.0 (c 0.34, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 3 H), 1.56 (s, 3 H), 1.91
(br s, 1 H), 1.99 (s, 3 H), 2.29–2.40 (m, 2 H), 3.51 (d-like, J = 11.8
Hz, 1 H), 3.69 (d-like, J = 11.8 Hz, 1 H), 4.26 (d, J = 9.0 Hz, 1 H),
4.55 (d, J = 11.8 Hz, 1 H), 4.72 (partially merged d, J = 11.7 Hz, 1
H), 4.74 (t-like, J = 3.3, 4.2 Hz, 1 H), 4.98–5.05 (m, 2 H), 5.19 (dd,
J = 4.0, 8.8 Hz, 1 H), 5.67–5.80 (m, 1 H), 5.98 (d, J = 4.6 Hz, 1 H),
7.27–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 21.3 (CH3), 27.6 (CH3), 27.9
(CH3), 34.5 (CH2), 62.2 (CH2), 72.2 (CH), 72.8 (CH2), 84.8 (CH),
87.1 (CH), 89.6 (C), 104.6 (CH), 114.0 (C), 117.4 (CH2), 127.6–
128.7 (5 × CH), 134.0 (CH), 137.3 (C), 169.4 (C).
ESI-MS: m/z = 415 [M + Na]+.
Yield: 410 mg (65%); [a]D25 +35.5 (c 0.13, CHCl3).
Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C, 64.11; H,
7.01.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 3 H), 1.47 (s, 3 H), 1.97
(s, 3 H), 2.29–2.35 (m, 2 H), 3.98 (d, J = 2.9 Hz, 1 H), 4.54 (d,
J = 11.9 Hz, 1 H), 4.68 (dd, J = 3.0, 4.6 Hz, 1 H), 4.73 (d, J = 11.9
Hz, 1 H), 4.95–5.02 (m, 2 H), 5.14–5.23 (m, 2 H), 5.42 (d, J = 17.2
Hz, 1 H), 5.68–5.81 (m, 1 H), 5.88 (dd, J = 10.9, 17.3 Hz, 1 H), 6.07
(d, J = 4.6 Hz, 1 H), 7.28–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 21.4 (CH3), 27.4 (CH3), 27.9
(CH3), 34.1 (CH2), 72.6 (CH2), 73.9 (CH), 87.3 (CH), 88.7 (C), 89.9
(CH), 104.7 (CH), 114.0 (C), 115.3 (CH2), 117.2 (CH2), 127.6
(2 × CH), 127.8 (CH), 128.3 (2 × CH), 134.4 (CH), 137.1 (CH),
137.1 (C), 169.2 (C);
Compound 31
Yield: 327 mg (15%); [a]D25 –8.1 (c 0.15, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.34 (s, 3 H), 1.55 (s, 3 H), 2.21–
2.47 (m, 4 H), 3.77 (d, J = 11.8 Hz, 1 H), 3.86 (d, J = 11.8 Hz, 1 H),
3.96 (dd, J = 2.4, 10.6 Hz, 1 H), 4.29 (d, J = 1.1 Hz, 1 H), 4.57 (d,
J = 11.4 Hz, 1 H), 4.78 (d, J = 11.4 Hz, 1 H), overlapping with
4.75–4.76 (m, 1 H), 5.07–5.14 (m, 2 H), 5.78–5.94 (m, 2 H), 7.31–
7.39 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 26.9 (CH3), 27.4 (CH3), 36.1
(CH2), 62.8 (CH2), 73.1 (CH2), 73.3 (CH), 85.6 (CH), 85.7 (CH),
89.8 (C), 105.3 (CH), 113.3 (C), 117.5 (CH2), 128.2–129.2
(5 × CH), 136.2 (CH), 137.1 (C).
ESI-MS: m/z = 411 [M + Na]+.
Anal. Calcd for C22H28O6: C, 68.02; H, 7.27. Found: C, 67.85; H,
7.09.
ESI-MS: m/z = 373 [M + Na]+.
(2R,3R,4R,5R,9S)-9-Acetoxy-4-(benzyloxy)-2,3-O-isopropy-
lidene-1-oxaspiro[4.4]non-6-ene (34)
Grubbs I cat. (43 mg, 0.052 mmol) was added to a soln of 33 (400
mg, 1.03 mmol) in CH2Cl2 (172 mL) and the soln was stirred at r.t.
for 5 h under N2. The solvent was evaporated in vacuo and the res-
idue was purified by column chromatography (silica gel, 100–200
mesh, EtOAc–PE, 1:19); this gave 34 as a thick liquid.
Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 65.05; H,
7.31.
(2R,3R,4R,5R)-4-(Benzyloxy)-5-[(1S)-1-hydroxybut-3-enyl]-5-
(hydroxymethyl)-2,3-O-isopropylidenetetrahydrofuran (32)
Compounds 28 (70 mg, 0.16 mmol), 29 (35 mg, 0.09 mmol), and 30
(40 mg, 0.10 mmol) were separately deacetylated with K2CO3 (2.2
equiv for 28 and 1.1 equiv for 29 and 30 respectively) in anhyd
MeOH (20 mL for 28 and 10 mL for 29 and 30 respectively) follow-
ing the procedure adopted for the deacetylation of 18. Usual workup
and purification of the crude product from each of the reactions by
column chromatography (silica gel, 60–120 mesh, EtOAc–PE,
3:22) furnished the same product 32 as a thick liquid.
Yield: 300 mg (81%); [a]D25 +32.9 (c 0.15, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H), 1.53 (s, 3 H), 2.05
(s, 3 H), 2.34–2.41 (m, 1 H), 2.73 (dd, J = 6.4, 16.8 Hz, 1 H), 3.96
(d, J = 1.9 Hz, 1 H), 4.52 (d, J = 11.8 Hz, 1 H), 4.71 (a merged sig-
nal, 1 H), 4.73 (d, J = 11.8 Hz, 1 H), 5.53 (dd, J = 4.1, 6.4 Hz, 1 H),
5.77 (br d, J = 5.9 Hz, 1 H), 5.87 (d, J = 4.2 Hz, 1 H), 5.94–5.96 (m,
1 H), 7.26–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 21.1 (CH3), 26.9 (CH3), 27.5
(CH3), 37.0 (CH2), 72.2 (CH2), 72.3 (CH), 84.8 (CH), 87.1 (CH),
93.9 (C), 104.6 (CH), 113.0 (C), 127.5 (2 × CH), 127.7 (CH), 128.3
(2 × CH), 132.2 (CH), 133.1 (CH), 137.2 (C), 170.7 (C).
Yield: 53 mg (95% from 28); 29 mg (92% from 29); 31 mg (89%
from 30); [a]D25 –15.3 (c 0.28, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.37 (s, 3 H), 1.56 (s, 3 H), 2.21–
2.39 (m, 2 H), 2.55 (br s, 2 H), 3.56 (d, J = 11.8 Hz, 1 H), 3.67 (d,
Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

PAPER
Carbohydrate-Derived 1-Oxaspiro[4.4]nonane Skeleton
2541
ESI-MS: m/z = 383 [M + Na]+.
Compound 37
Yield: 13 mg (29%); mp 101–102 °C; [a]D25 –12.5 (c 0.60, MeOH).
Anal. Calcd for C20H24O6: C, 66.65; H, 6.71. Found: C, 66.49; H,
6.45.
1H NMR (300 MHz, C5D5N + D2O): d = 1.91–1.95 (br s, 1 H), 2.11–
2.30 (m, 3 H), 2.47–2.58 (m, 2 H), 4.89 (d, J = 6.5 Hz, 1 H), 5.03 (t,
J = 6.2 Hz, 1 H), 5.89 (d, J = 8.1 Hz, 1 H), 6.76 (d, J = 6.0 Hz, 1 H),
8.95 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, C5D5N): d = 18.7 (CH2), 37.0 (CH2), 37.8
(CH2), 80.4 (CH), 83.1 (CH), 88.9 (CH), 90.5 (C), 104.3 (CH),
142.7 (CH), 153.8 (C), 165.4 (C) 219.7 (C).
(2R,3R,4R,5R,9S)-3,9-Diacetoxy-4-(benzyloxy)-2-(2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)-1-oxaspiro[4.4]non-6-ene (35)
Compound 34 (328 mg, 0.91 mmol) was subjected to a procedure
similar to that described for the conversion of 18 to 22, by using
H2SO4–MeCN–H2O (1:18:6, 10 mL) for acetonide deprotection, py
(10 mL) and Ac2O (0.30 mL) for acetylation, and uracil (261 mg,
2.33 mmol), HMDS (10 mL), TMSCl (2 drops), TMSOTf (0.33
mL, 1.82 mmol), and MeCN (15 mL) for nucleosidation. The reac-
tion yielded 35 as white foamy solid after purification by column
chromatography (silica gel, 60–120 mesh, EtOAc–PE, 7:13).
ESI-MS: m/z = 305 [M + Na]+.
Anal. Calcd for C12H14N2O6: C, 51.06; H, 5.00; N, 9.93. Found: C,
50.85; H, 5.01; N, 9.68.
Yield: 228 mg (55%); mp 79–80 °C; [a]D25 +12.9 (c 0.26, CHCl3).
Compound 38
Yield: 23 mg (51%); mp 120–122 °C; [a]D25 +8.2 (c 0.17, MeOH).
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H), 2.15 (s, 3 H), 2.36–
2.44 (m, 1 H), 2.71–2.73 (m, 1 H), 3.85 (d, J = 1.6 Hz, 1 H), 4.55
(d, J = 11.4 Hz, 1 H), 4.69 (d, J = 11.4 Hz, 1 H), 5.28 (br d, J = 1.8
Hz, 1 H), 5.56 (d, J = 8.2 Hz, 1 H), 5.62 (t-like, J = 5.7, 6.9 Hz, 1
H), 5.79–5.82 (m, 1 H), 6.01–6.05 (m, 1 H), 6.16 (d, J = 1.9 Hz, 1
H), 7.25–7.38 (m, 5 H), 7.99 (d, J = 8.2 Hz, 1 H), 9.32 (br s, 1 H).
1H NMR (300 MHz, C5D5N): d = 1.43–1.57 (m, 1 H), 1.76–1.89 (m,
1 H), 1.97–2.18 (m, 4 H), 4.72 (d, J = 6.9 Hz, 1 H), 4.85 (t-like,
J = 8.4, 9.3 Hz, 1 H), 5.15 (t, J = 6.6 Hz, 1 H), 5.73 (d, J = 8.1 Hz,
1 H), 6.78 (d, J = 6.3 Hz, 1 H), 9.10 (d, J = 8.1 Hz, 1 H), 13.13 (br
s, 1 H); the peaks for 3 H groups (3 × OH) are not discernible.
13C NMR (75 MHz, C5D5N): d = 19.3 (CH2), 31.5 (CH2), 34.8
(CH2), 73.3 (CH), 78.7 (CH), 79.7 (CH), 87.3 (CH), 92.4 (C), 102.5
(CH), 142.9 (CH), 152.7 (C), 165.1 (C).
13C NMR (75 MHz, CDCl3): d = 20.8 (2 × CH3), 36.3 (CH2), 71.9
(CH), 72.2 (CH2), 79.4 (CH), 83.3 (CH), 87.7 (CH), 95.4 (C), 101.7
(CH), 128.3–128.5 (5 × CH), 130.4 (CH), 134.4 (CH), 136.3 (C),
140.6 (CH), 150.4 (C), 163.3 (C), 169.5 (C), 169.9 (C).
ESI-MS: m/z = 307 [M + Na]+.
ESI-MS: m/z = 479 [M + Na]+.
Anal. Calcd for C12H16N2O6: C, 50.70; H, 5.67; N, 9.85. Found: C,
50.43; H, 5.41; N, 9.67.
Anal. Calcd for C23H24N2O8: C, 60.52; H, 5.30; N, 6.14. Found: C,
60.27; H, 5.09; N, 5.89.
Acknowledgment
(2R,3R,4R,5R,9S)-4-(Benzyloxy)-3,9-dihydroxy-2-(2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)-1-oxaspiro[4.4]non-6-ene (36)
Compound 35 (105 mg, 0.23 mmol) was deacetylated according to
the procedure described for the preparation of 23 from 22. Usual
workup and purification by column chromatography (silica gel, 60–
120 mesh, EtOAc–PE, 63:37) afforded 36 as foamy solid.
The Council of Scientific and Industrial Research (CSIR) Network
Project No. NWP00036 supported the work. The authors gratefully
acknowledge the CSIR for providing Senior Research Fellowships
(J.K.M.) and an Emeritus Scientist scheme (to B.A.). We also thank
the EPSRC and the University of Reading for funds for the CCD
diffractometer.
Yield: 78 mg (91%); mp 93–95 °C; [a]D25 +33.8 (c 0.13, MeOH).
1H NMR (300 MHz, C5D5N + D2O): d = 2.76 (d, J = 6.4 Hz, 2 H),
4.53 (d, J = 5.9 Hz, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.98 (d,
J = 12.0 Hz, 1 H), 5.04 (t-like, J = 6.7 Hz, 1 H), 5.12 (t, J = 5.6 Hz,
1 H), 5.85 (d, J = 8.1 Hz, 1 H), 6.07 (d, J = 6.0 Hz, 1 H), 6.10 (d,
J = 6.0 Hz, 1 H), 6.66 (d, J = 5.4 Hz, 1 H), 7.38–7.55 (m, 5 H), 8.99
(d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, C5D5N): d = 39.7 (CH2), 71.0 (CH), 72.7 (CH2),
77.5 (CH), 86.1 (CH), 87.9 (CH), 92.9 (C), 102.1 (CH), 127.9–
128.7 (5 × CH), 133.9 (CH), 134.9 (CH), 138.8 (C), 142.3 (CH),
152.5 (C), 164.2 (C).
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Synthesis 2010, No. 15, 2533–2542 © Thieme Stuttgart · New York

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