Ring-rearrangement metathesis of substituted dihydropyrans and dihydrofurans

Article abstract of DOI:10.1016/j.tet.2010.11.036

The rearrangement of dihydropyrans and dihydrofurans featuring appending olefins has been studied. The rearranged products bear resemblance with polyunsaturated di- and trisaccharides. Examples of functionalization prior to, or following, rearrangement are provided suggesting that the method should be useful for the synthesis of nonclassical saccharides. This work also illustrates the power of cascade methatetic processes for increasing molecular complexity starting from relatively simple heterocycles. Copyright

Full text of DOI:10.1016/j.tet.2010.11.036

Tetrahedron 67 (2011) 339e357
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-rearrangement metathesis of substituted dihydropyrans and dihydrofurans
*
*
ꢀ
€
Morgan Donnard , Theophile Tschamber , Didier Le Nouen, Sandy Desrat, Karen Hinsinger,
Jacques Eustache
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Organique et Bioorganique associe au CNRS, Universite de Haute-Alsace, Ecole Nationale Superieure de Chimie de Mulhouse, 3, rue Alfred Werner,
F-68093 Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The rearrangement of dihydropyrans and dihydrofurans featuring appending olefins has been studied.
The rearranged products bear resemblance with polyunsaturated di- and trisaccharides. Examples of
functionalization prior to, or following, rearrangement are provided suggesting that the method should
be useful for the synthesis of nonclassical saccharides. This work also illustrates the power of cascade
methatetic processes for increasing molecular complexity starting from relatively simple heterocycles.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 September 2010
Received in revised form 5 November 2010
Accepted 8 November 2010
Available online 13 November 2010
Keywords:
Ring-rearrangement
Metathesis
Dihydropyrans
Dihydrofurans
1. Introduction
dihydropyran derivatives 1 (see Fig. 1, B) and the conversion of 2 to
a simple polydeoxydisaccharide.3 The method was subsequently
For some time, we have been interested in the Ring-Rearrange-
ment Metathesis (RRM)1 of oxygen heterocycles as a method for
accessing complex, polycyclic, oxygenated molecules. The principle
of our approach, which is summarized in Fig. 1, A, consists in sub-
jecting a substrate A, containing one or two unsaturated oxygen
heterocycles bearing olefinic appendages to metathesis conditions
using Grubbs second generation catalyst ([Ru]-2, Fig. 1). During the
reaction, there is extensive reorganization of bonds and rings and
the product B bears little resemblance to the substrate. Therefore,
the method is expected to be useful for synthesizing otherwise
difficult to prepare molecules from relativelysimple precursors. One
may conceive many possible variations of this general principle: in
particular the method should be applicable to the preparation of di-
or trisaccharides. Although several efficient methods exist for the
preparation of classical oligosaccharides, they are almost invariably
based on the coupling of activated monosaccharide units. While this
is convenient when using readily available sugars, problems may
arisewhendealing withuncommon natural orsyntheticsaccharides
and in this case, nontraditional methods may compete.2
extended to the preparation of polyunsaturated trisaccharides, e.g.,
4 from the bis-dihydropyran derivative 3, using an extended Ring-
Closing MetathesiseRing-Opening Metathesis (RCMeROM) se-
quence (Fig. 1, C).3b
During these studies we observed that the success of the re-
action depended on a number of steric/electronic factors and that
the dihydropyrans we used as RRM substrates behaved differently
from their carbocyclic (cyclohexenes) counterpart.4 Our initial
studies and the conclusions that could be drawn regarding di-
saccharide synthesis are summarized in Fig. 1, B.3a,5 (Experimental
and analytical data corresponding to the synthesis of compounds in
Fig. 1B are described in the Supplementary data). Briefly:
1. Initiation at the anomeric olefin does not appear to be pro-
ductive with respect to the expected RRM. The success of the
rearrangement requires the initiation step to take place on the
4-O-allyl or homoallyl side chain. As a consequence, electron-
poor acrylates, 3-butenoyl esters (likely chelate formation)6
and more surprisingly acrolein ketals, being unsuitable for
initiation, no reaction is observed).
2. Results and discussion
2. A cis relationship between the C-4 and C-5 substituents is re-
quired see (Fig. 2B).
In recent, exploratory work, we reported the metathesis-based
3. The configuration at the anomeric carbon (a or b) is not im-
preparation of simple unsaturated disaccharides e.g., 2 from the
portant with regard to RRM (see Fig. 2B).
* Corresponding authors. Tel.: þ33 3 89 33 6838; fax: þ33 3 89 33 6860; e-mail
addresses: morgan.donnard@uha.fr (M. Donnard), theophile.tschamber@uha.fr
(T. Tschamber).
We have attempted to understand the reasons behind the above
limitations. It is well established that in some RCM substrates,
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.036

340
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
A
( )m
O
O
O
O
O
N
N
Mes
Mes
( )l
O
RRM
( )m
( )l
( )n
Cl
Cl
o
( )n
Ru
PCy3
[Ru]-2 =
R's
R's
B (shown for o = 1)
A
B
Cis relationship required
C
Stereochemistry
6
O
O
not important
O
O
5 O
O
O
O
O
4
R2
R1
O
O
O
[Ru]-2
O
O
1
O
[Ru]-2
AcO
3
2
( )m
86%
AcO
O
68%
OAc
1
2
3
4
R1 = OAc, R2= H, m = 1
R1 = OMe, R2= H, m = 0
R1, R2= O, m = 0 or 1
No reaction
}
Fig. 1. Examples of RRMs leading to unsaturated saccharides.
O
OR
O
OR
O
OR
or
O
O
O
[Ru]
[Ru]
[Ru]
C
D
Fig. 2. Transition states for the RRM of trans and cis substrates.
stable 5, 6, or to a lesser extent 7, membered chelates may be
formed by complexation of the initial ruthenium carbene by
neighboring oxygen-containing functions and that this complexa-
tion may inhibit metathesis.7 In our case it is conceivable that the
carbene formed by putative initiation at the anomeric olefin site is
2.1. Dihydropyran-based substrates
Following these initial results, the next step of our program
focused on broadening the scope of the method by: (a) increasing
the complexity of the RRM substrate and/or chemical modification
of the RRM products and (b) using alternative heterocyclic relays.
We first checked that the anomeric olefin could be modified.
According to our earlier observations the anomeric olefin intervenes
only at the last step of the metathesis cascade therefore we were
confident that extensive structural variation should be possible. For
the sake of simplicity, we selected for this study the 4-O-allyl group
as initiation site since it led to good results in our previous explor-
atory work. Two RRM substrates (10a and 10b) were then prepared
by a short sequence starting with Ferrier rearrangement of glycal 5
(commercially available), using hex-3-en-1-ol and 3-methylbut-3-
en-1-ol, respectively, as alcohols. As expected, when submitted to
RCM conditions a good yield of rearranged products 11a and 11b was
obtained, suggesting (11b) that branched disaccharides could be
prepared by this method (Scheme 1).
WethenexaminedanotherfamilyofRRMsubstratesderivedfrom
2-allyloxy-6-(hydroxymethyl)-3,6-dihydro-2H-pyran 17 (Scheme 2).
Inthesesubstrates, theendocyclic double bondhasbeenshifted from
the 3,4 (as used previously) to the 4,5 position (pyran numbering)
andtheappendingolefinsaresimpleallyloxygroups. Rearrangement
should give rise to a new type of disaccharide-like molecules. These
substrates were prepared as shown in Scheme 3.
sequestered in a way that prevents the ROM to proceed. That a,b-
ethylene ketals seem not to be suitable as initiation sites for the
RRM is surprising but it is worth noting that although there are
numerous literature examples of ethylene ketals participating in
RCM, cases in which their involvement at the initiation step has
been demonstrated are very rare.7
Finally, that a cis relationship between the C-4 and C-5 sub-
stituents is required for the RRM to succeed is not unexpected as
many examples of RCM successes or failures have been linked to the
relative configurations of substituents proximal to the olefinic
double bonds of the substrates. It is well established that following
initiation, success requires adequate prepositioning of the carbe-
noid and olefinic double bond so that the strained fused ruth-
enacyclobutane intermediate can be formed. Generally, failure can
be explained by considering steric factors that would hinder access
to such fairly rigid bicyclic systems. In our case, the tricyclic in-
termediates C and D arise from trans and cis substrates, re-
spectively (Fig. 2).4 In such completely locked systems, steric/
electronic factors are expected to play a crucial role. At the present
time however, inspection of molecular models of the possible
transition states C and D do not reveal obvious strain differences
that could account for the observed large reactivity difference be-
tween trans and cis substrates.
Treatment of tri-O-acetyl-
D
-galactal 12 with allylic alcohol and
polymer-supported triphenylphosphine. HBr complex afforded

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
341
O
N
OiPr
R'OH
BF3.Et2O
iPrO
N
O
O
O
OR'
O
OR'
pNBzOH, PPh3
AcO
CH2Cl2, 20°C, 1 h
RO
THF, 20°C, 6 h
RO
OAc
6a,b
MeONa/MeOH
20°C, 6 h
: R = Ac, 90% and 82%
8a,b
5
MeONa/MeOH
20°C, 6 h
: R =pNBz, 93% and 93%
7a,b: R = H, 92% and 87%
9a,b: R = H, 81% and 72%
O
OR'
O
O
R
[Ru]-2
toluene,
6a, 7a, 8a, 9a, 10a: R' =
6b, 7b, 8b, 9b, 10b: R' =
, NaH
Br
O
O
DMF, 20°C, 6 h
60°C, 3 h
11a: R = H, 78%
10a,b: 76% and 73%
11b
: R = CH3, 73%
Scheme 1. RRM of 2,5-disubstituted dihydropyrans.
allyl 2-deoxy-3,4-di-O-acetyl-
D
-galactopyranoside 13 as
a
4:1
For the preparation of substrates 22 and 23, we needed to convert
17 to the carboxylic acid 21. After failing to effect a classical two-step
oxidation using several methods (1. TPAP10/NMO or IBX11 or TEMPO,
PhI(OAc)212 and 2. NaClO2) we found out that direct oxidation using
TEMPO, PhI(OAc)213 proceeded well to afford the sensitive acid 21 in
good yield, which was converted to the corresponding allyl ester 22.
a/b
mixture.8 Standard deacetylation and selective primary alcohol
silylation provided diol 14, which was converted to diene 17 by
CoreyeWinter olefination.9 Compound 17 was converted to the
RCM substrates 18, 19, and 20 by O-alkylation (18) and O-acylation
(19 and 20).
OH
α:β=4:1
OAc
OAc
1. MeONa/MeOH
OTBDMS
O
O
O
PPh2.HBr
20°C, 6 h
O
O
AcO
CH2Cl2, 20°C, 16 h
2. TBDMSCl, imidazole
DMF, 20°C, 18 h
AcO
HO
OAc
12
OAc
13: 87%
OH
14: 72%
OTBDMS
O
N
N
N
N
OR
O
P(OMe)3
O
O
S
O
O
CH2Cl2, 20°C, 18 h
120°C, 18 h
TBAF, THF
20°C, 20 min.
16: R = TBDMS, 77%
17: R = H, 85%
S
15: 75%
O
O
O
HO
TEMPO
PhI(OAc)2
CH3CN / H2O 1:1
20°C, 5h
21: 70%
O
O
OH
0
20°C
16 h
DCC, DMAP
CH2Cl2
O
OH
Cl
Br
iPr2EtN
CH2Cl2
NaH
DCC, DMAP
CH2Cl2
DMF
20°C
6 h
O
O
O
0
20°C
16 h
0
20°C
1 h
22
: 75%
1. DIBAH, CH2Cl2, -78°C, 45 min.
2. Ac2O, pyridine,
DMAP
-78°C, 12h
0°C, 1h
OAc
O
O
O
O
O
O
O
O
O
O
O
O
O
O
18
: 92%
19
: 77%
20
: 92%
23
: 70%
Scheme 2. RRM of 2,6-disubstituted dihydropyran: preparation of the substrates.

342
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
Scheme 3. RRM of 2,6-disubstituted dihydropyrans.
Low temperature reduction/acetylation according to Rychnovsky
et al.14 afforded the unsaturated ketal 23.
OH
OH
O
O
O
O
The RRM results are reported in Scheme 3. Using standard
metathesis conditions (substrate concentration 0.002 M in toluene,
[Ru]-2, 5 mol %, 70 ꢀC, 3 h), precursors 18 and 19 reacted smoothly
to afford the corresponding ring-rearranged products 24 and 25 in
good yield. In contrast the acrylic ester 20 remained unchanged. As
17
17'
Fig. 3. Expected products during rearrangement of 17.
expected, allyl ester 22 did not cyclize (there is probably formation
The method also works with more functionalized substrates as
shown in Scheme 4. The triene 34 was prepared in a few steps from
6
€
of a stable ruthenium complex as proposed by Furstner) but the
mixed ketal 23 afforded in good yield the simple unsaturated di-
saccharide 27.
tri-O-acetyl-2-acetoxy- -glucal 28. Ferrier reaction of the latter
D
with allyl alcohol15a,b afforded the 2-acetoxy-2,3-unsaturated gly-
coside 29, which upon treatment with LiAlH4 collapsed to the
rearranged glycoside 30 in good yield. A short protection/depro-
tection sequence of the primary hydroxyl group allowed the se-
quential methylation of 2-OH (carbohydrate numbering) and
allylation of 6-OH providing the RRM substrate 34, which smoothly
rearranged to 35 upon exposure to [Ru]-2.
These results are very similar to those obtained in our earlier
studies:3 for the RRM to proceed, initiation of the metathetic pro-
cess should take place at the olefin distal from the anomeric posi-
tion. Should this not be possible either for electronic reasons (20) or
because a stable complex may be formed following initiation (22),
no reaction is observed. That initial formation of a metalcarbene at
the anomeric position does not lead to RRM is further confirmed
when using alcohol 17 as substrate. One would expect a mixture of
two pyran derivatives to be observed: 17 and the rearranged
product 170 (Fig. 3). In fact, at low substrate concentration (0.003 M)
no reaction takes place and in more concentrated solutions (0.1 M)
only formation of dimer 26 (Scheme 3) is observed.
2.2. Dihydrofuran-based substrates
Another way of increasing the versatility of the method would be
to switch to other types of RRM substrates leading to different olefin
patterns in the rearranged product. An obvious development of this
OH
α / β, 6:1)
AcO
O
O
O
O
O
BF3.Et2O
LiAlH4
AcO
AcO
HO
OAc
AcO
OAc
OH
CH2Cl2, 0 20°C, 1 h
THF, 0°C, 1 h
OAc
28
29: 67%
30: 77%
[Ru]-2, 5 mol%
TBDMSCl, imidazole
DMF, 20°C, 18 h
O
O
O
O
O
RO
toluene, 60°C, 3h
OR'
MeO
35: 81%
31: R = TBDMS, R' = H, 73%
32: R = TBDMS, R' = Me, 81%
33: R = H, R'= Me, 89%
NaH, MeI, DMF, 20°C, 6 h
TBAF, THF, 20°C, 110 min.
0
Br
, NaH, DMF, 20°C, 6 h
34: R =
, R'= Me, 89%
Scheme 4. RRM of 2,6-disubstituted dihydropyrans.

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
343
work is the use of dihydrofurans instead of dihydropyrans as relay
moieties (Fig. 4).
Thus we could show that provided certain structural re-
quirements in the substrates are respected, RRM is a valid approach
to simple disaccharides. We could also show that utilization of
functionalized RRM substrates (e.g., 23 and 34) and dihydrofurans
(e.g., 42) as relays is possible, thereby further broadening the scope
of the method. The RRM products feature two olefinic double bonds,
whose position is determined by the choice of the RRM substrate
and which should be easily functionalized byconventional methods,
giving rise to various 1-deoxy disaccharide-analogues.
O
O
O
O
O
O
Fig. 4. Example of RRM with dihydrofuran relays.
The remaining problem is linked to the unexpected lack of re-
activity of acrolein ketals (e.g., 20), which restricts the variety of
substrates that can be used. Indeed, although 1-deoxy-2,3-un-
saturated disaccharides such as 11, 24 or 35 are readily obtained by
rearrangement of allyl ether-containing substrates, direct access to
‘real’ disaccharides would require using the corresponding non-
reactive acrolein ketals.
An appealing solution to this problem would be to perform the
functionalization after the RRM has taken place and the key ques-
tion is whether one can perform a selective oxidation at C-1 in
1-deoxy-2,3-unsaturated disaccharides, such as 11, 24, 35 or 48. For
these studies 48 was chosen as model compound (Scheme 6). We
initially attempted to selectively shift the 2,3-olefinic double bond
in 48 to the 1,2 position using [Ru]-2, as described by Schmidt,17
with the aim of converting the resulting glycal 50 to the corre-
sponding 2-deoxy disaccharide. Unfortunately 50 could never
be obtained in useful yield without simultaneous formation of the
undesired isomer 49 in which both the 2,3 and the 20,30 double
bonds have migrated. Furthermore, despite numerous attempts, we
The synthesis of the required substituted dihydrofuran sub-
strates is shown in Scheme 5: tetra-O-acetyl- -ribofuranose
(commercially available) was first converted to the -homo-
D
b
allylribofuranoside 36. Removal of the acetates, selective protection
of 2-OH and 3-OH by acetonide formation and allylation of 5-OH
afforded intermediate 39. After cleavage of the acetonide, treat-
ment by 1,10-(thiocarbonyl)diimidazole (TCDI) afforded the thio-
carbonate 41, which, upon heating in trimethylphosphite, furnished
the sensitive crude triene 41.16a Alternatively, selective removal of
the 2- and 3-acetates in 3616b and treatment by TCDI led to thio-
carbonate 44, which was converted in a few steps (acetate removal,
acrylate formation, CoreyeWinter olefin formation), to the crude
RRM substrate 47. The RRM results are reported in Scheme 5: the
triene 42 afforded cleanly the rearranged product 48. In contrast,
the acrylate 47 did not react. As observed earlier, using dihy-
dropyrans as relays (see Scheme 1), successful RRM apparently
requires the initiation step to take place on the olefin distal to the
anomeric position. This is possible in 42 but not in 47.
OH
O
O
tBuOK
O
O
SnCl4
CH3CN, 0°C
OAc
OAc
O
AcO
AcO
R'O
MeOH, 0 20°C, 6 h
OAc
AcO
O
AcO
OR
RO
acetone
2-methoxypropene
PTSA, 0 20°C, 0.5 h
37: R = R' = H, 97%
36: 63%
38: R,R =
R' = H, 86 %
O
O
Br
O
O
O
P(OMe)3
O
O
NaH
Im2C=S
O
O
O
115°C
4 h
CH2Cl2
20°C
MeOH, 0 20°C, 40 min
O
O
RO OR
O
O
S
, 84%
39: R,R =
TFA/H2O
-5°C, 3h
41: 87%
42
40: R ,R = H, 52%
MeOH,
tBuOK
MeOH,
Na2CO3
O
O
O
O
P(OMe)3
O
O
O
AcO
RO
RO
36
122°C
2 h
0°C, 1 h
OR
0°C, 45 min
O
O
O
43: R = H, 61 %
Im2C=S
CH2Cl2
20°C, 5 h
S
O
47
45: R = H, 60 %
Cl
iPrNEt2
20°C, 1 h
O
, 88%
O
44: R,R =
O
, 59%
S
46: R =
RRM product
/ yield
RRM product
/ yield
RRM
RRM
Conditions
a
Conditions
substrate
substrate
O
O
O
47
NR
42*
a
48: 58%
* Crude Corey-Winter product was used
a) Substrate 0.002 M in toluene, [Ru]-2, 5 mol%, 60°C, 30 min.
Scheme 5. RRM of 2,5-disubstituted dihydrofurans.

344
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
5
1'
O
O
O
O
O
O
O
O
[Ru]-2, NaOH
MeOH,
X
O
O
O
O
5'
4'
4
3
+
2'
iPrOH
toluene
110°C
1
PPTS
MeO
2
3'
48
49: 16%
50: 34%
51
N
CrO3
N
H
O
O
O
O
O
O
H2, Pd/C
AcOEt
20°C, 16h
DIBAL
O
O
O
O
CH2Cl2
-20°C, 2h
toluene
-78°C, 2 h
O
HO
52: 62%
53: 58%
54: 69%
Scheme 6. Functionalization of RRM products.
were unable to cleanly convert the vinyl ether moiety in 50 to
the desired corresponding O-methyl O-methyl polydeoxyglycoside
a readily available starting material and involved the construction of
a tetraene applying the methodology developed previously.
51. It is likely that the sensitive
a
,b
-unsaturated ketal also present in
Tetra-O-acetyl-D-ribofuranose was condensed with ribofurano-
the molecule does not stand the acidic conditions of the reaction.
We were more successful when performing a direct, regiose-
lective, CrO3 oxidation at the C-1 allylic position which led cleanly
to lactone 52.18 Catalytic hydrogenation of both olefinic double
bonds in 52 and DIBAL reduction of the lactone 53 afforded the
simple polydeoxydisaccharide 54.
It is worth mentioning that in lactone 52 the two olefinic double
bonds have different chemical reactivities and should be easily
functionalized independently.
Having explored the scope of the method with regard to di-
saccharide synthesis, we turned our attention to more elaborated
targets involving more complex metathetic rearrangements. We had
already shown that trisaccharide analogues could be synthesized by
RRM, using dihydropyran relays (see Fig. 1, C) and we deemed it
worthwhile to examine whether dihydrofuran relays could be used
for the same purpose. Our initial attempts (Scheme 7) used ribose as
side 38 to afford the protected disaccharide 55. Deacetylation and
isopropylidene formation produced 57 in which only the un-
protected primary hydroxyl group OH-50 is available for allylation.
The intermediate 58 thus obtained is converted in a few steps to the
crude RRM substrate 61. The RRM results were unexpected and dis-
appointing: in contrast to the facile conversion 42/48 (Scheme 5),
only dimer 62 was formed. The structure of this dimer was
determined by NMR of 62 and of the decomposition products 63 and
64, which are cleanly and rapidly formed upon standing of 62 in
CDCl3 solution. Although we cannot offer a clear explanation to this
(in our view) surprising behavior, it is well established that in olefin
metathesis apparently minor structural differences may result in
important changes in reactivity and we suspected that the cis re-
lationship between the C1, C4 andC10, C40 substituents in 61 might be
responsible for the RRM failure. To check this possibility we decided
to prepare an ‘all trans’ substrate with respect to C1, C4 and C10, C40
andtoexaminetheeffectsofthismodificationonthereactioncourse.
O
O
O
O
O
O
OAc
O
HO
AcO
AcO
SnCl4, CH3CN
0°C, 20min
+
O
O
O
OAc
AcO
AcO
OAc
O
O
38
55: 46%
O
MeO
OMe
5
4
1
O
O
5'
O
1'
O
O
4'
3'
O
tBuOK, MeOH
O
O
HO
2
RO
3
2'
rt, 6h
TsOH, rt, 3h
O
O
O
HO
OH
O
O
56, 99%
AllylBr, NaH
DMF, 0°C to rt
57: R = H, 33% over 2 steps
58: R = allyl, 66%
5
O
4
1
O
5'
O
O
O
1'
O
4'
3'
TFA/H2O
O
P(OMe)3,
O
O
O
2
3
2'
115 °C
ca 3.5h
-5°C, ca 3h
R'O OR'
61
R'O OR'
59: R' = H
60: R',R' =
45%
80%
Im2C=S
O
O
CH2Cl2,
4h
S
O
O
O
O
O
O
O
OH
CDCl3
[Ru]-2
+
O
Benzene, 70 °C
45min
O
O
O
OH
O
O
63
64
62
Scheme 7. Failed trisaccharide synthesis by RRM of 2,5-disubstituted dihydrofurans.

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
345
HO
RO
H3C
RO
Ra/Ni
NEt3
O
O
O
OAc
OAc
OAc
Steps
TsCl
HO
HO
D-Mannose
DMAP,
Pyridine,
EtOH
20°C, 20h
O
O
O
O
O
O
5°C to rt, 4h
Ac2O
65
NaI
66: R = OTs
67: R = I: 40%
68: R = H
C5H5N
DMAP
rt, 20h
2-Butanone
69: R = Ac: 90%
reflux, 3h
(5 steps)
(2 steps)
H3C
RO
H3C
RO
O
O
Buten-3-ol
SnCl4
69
O
Br
O
O
O
SnCl4
NaH
O
O
CH3CN
-4° to 0°C
CH3CN, -3°C, 3h
DMF
0°C to rt, 2h
O
O
O
O
70: R = Ac: 30%*
71: R =H: 89%
tBuOK,
72: R = Ac: 78%
73: R =H: 94%
tBuOK, MeOH
MeOH,
rt, 3h
rt, 3h
H O
O
H
* + 50% recovery of 76
H3C
O
H3C
O
O
O
O
O
O
O
P(OMe)3
[Ru]-2
O
O
O
H
OR OR
117 °C
5h
Benzene
70 °C
O
H
RO
OR
15 min
O
77
78: 42%
(2 steps)
O
O
O
, 85%
74: R, R =
75: R = H
TFA/H2O, 0 °C, ca 3h
Im2C=S, CH2Cl2,
rt, 20h
O
76: R, R =
, 32% (2 steps)
S
Scheme 8. Trisaccharide synthesis by RRM of 2,5-disubstituted dihydrofurans.
This studyissummarized inScheme8. Thesynthesisstartedfromthe
known intermediate 65, easily prepared in a few steps from man-
nose.19 Selective tosylation of the primary hydroxyl in 65 and dis-
placement of the tosyl group by iodine was followed by reduction
using Raney nickel to afford the 6-deoxy mannose derivative 68. The
latterwasconverted toglycoside71, whichwascondensed with69to
difficult to prepare related analogues such as 1-deoxy saccharides
are indeed reachable using our approach.
From the methodological viewpoint, the method illustrates
again the power of ring-rearrangement metathesis regarding
access to complex molecules from readily available starting mate-
rials. Except in simple cases (formation of medium-size rings), the
difficulty of predicting the course of a particular metathesis is
a known problem and our work is no exception: why certain con-
versions (e.g., 77/78) work well whereas others (e.g., RRM of 61)
fail despite apparent close similarities is unclear and this lack of
predictability constitutes an obvious limitation of the method.
Despite this drawback, we are confident that the RRM approach can
be used for the preparation of natural, uncommon, saccharides.
This work is underway in our laboratory.
furnish the protected a-disaccharide 72. Finally, deacetylation, ally-
lation and CoreyeWinter olefin formation provided the crude tet-
raene 77. We were pleased to observe that in sharp contrast with the
‘all cis’ substrate 61, the ‘all trans’ 77 smoothly rearranged to the
expected 1-deoxy unsaturated trisaccharide 78. The behavior of 61
and77 withrespect to metathesisis puzzlingas noobviousstructural
difference can be identified explaining the considerable
reactivity difference betweenthese twosubstrates (cross-metathesis
followed by macrocycle formation for 61 and RRM for 77). While one
can assume that initiation shouldbe similarin 61 and 77, subtle steric
factors must operate during the propagation step, which change
dramatically the course of the reaction.
4. Experimental section
4.1. (2S,3R)-6-((Z)-Hex-3-enyloxy)-2-methyl-3,6-dihydro-2H-
pyran-3-yl acetate (6a)
3. Conclusion
Under argon, to a solution of 3,4-di-O-acetyl
3.25 mmol, 1 equiv) in dichloromethane (5 mL) was added cis-3-
hexen-1-ol (587
L, 4.87 mmol, 1.5 equiv). At 0 ꢀC, 4 drops of
BF3$Et2O were added and the resulting solution was allowed to
warm up slowly to room temperature. After 1 h, the reaction was
quenched with NaHCO3(aq) (15 mL) and extracted with ethyl acetate
(3ꢁ15 mL). The organic layers were combined, washed with brine,
dried over anhydrous MgSO4, and concentrated in vacuo. Purifica-
tion by flash column chromatography with silica gel (10% EtOAc in
cyclohexane) provided 744 mg (2.92 mmol, 90%) of the title
L-rhamnal (870 mg,
In summary, several trienes and tetraenes were synthesized
containing built-in dihydropyran or dihydrofuran moieties. They
were designed to serve as relays in domino metathesis processes in
a new approach to di- or trisaccharides. The method was success-
fully applied to the preparation of a series of advanced, versatile,
intermediates structurally close to di- or trisaccharides. We could
show that regioselective functionalization of these intermediates is
possible either prior to, or following, the rearrangement, thereby
suggesting that unusual di- or trisaccharides as well as otherwise
m

346
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
compound as a clear, pale yellow oil. The compound was obtained
4.5. (2S,3S)-6-((Z)-Hex-3-enyloxy)-2-methyl-3,6-dihydro-2H-
pyran-3-yl 4-nitrobenzoate (8a)
as an anomeric mixture (
a
/b
¼6:1). 1H NMR (CDCl3, 300 MHz) major
isomer:
d
5.83 (m, 2H), 5.47 (m, 1H), 5.35 (m, 1H), 5.05 (m, 1H), 4.97
(s, 1H), 3.98 (m, 1H), 3.76 (m, 1H), 3.51 (m, 1H), 2.36 (q, J¼7.0 Hz,
Under argon, to a solution of DIAD (1.42 mL, 7.07 mmol,
1.2 equiv) in THF (15 mL) were added sequentially triphenylphos-
phine (1.85 g, 7.07 mmol, 1.2 equiv), p-nitro-benzoic acid (1.07 g,
7.07 mmol, 1.2 equiv), and finally a solution of alcohol 7a (1.25 g,
5.88 mmol, 1 equiv) in THF (3 mL). The resulting mixture was
stirred for 6 h at room temperature, then concentrated in vacuo,
and purified by flash column chromatography with silica gel (20%
EtOAc in cyclohexane) to provide p-nitro-benzoate 16a (1.98 g,
2H), 2.07 (s, 3H), 2.03 (m, 2H), 1.22 (d, J¼6.3 Hz, 3H), 0.97
(t, J¼7.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d 170.5,
133.8, 129.5, 127.8, 124.6, 94.2, 70.8, 68.2, 64.7, 27.9, 21.1, 20.6, 17.9,
14.2. LRMS calcd for C14H22NaO4 [MþNa] 277.14, found 277.
4.2. (2S,3R)-2-Methyl-6-(3-methylbut-3-enyloxy)-3,6-
dihydro-2H-pyran-3-yl acetate (6b)
5.47 mmol, 93%) as a yellow solid. 1H NMR (CDCl3, 300 MHz)
d 8.26
Under argon, to a solution of 3,4-di-O-acetyl
L
-rhamnal (2 g,
(m, 4H), 6.19 (dd, J¼5.2, 10.0 Hz, 1H), 6.09 (dd, J¼3.0, 10.0 Hz, 1H),
5.49 (m, 1H), 5.35 (m, 1H), 5.16 (dd, J¼2.4, 5.3 Hz, 1H), 5.09 (d,
J¼2.9 Hz,1H), 4.37 (dq, J¼2.3, 6.6 Hz, 1H), 3.78 (m, 1H), 3.56 (m, 1H),
9.34 mmol, 1 equiv) in dichloromethane (15 mL) was added
3-methyl-3-buten-1-ol (1.42 mL,14 mmol,1.5 equiv). At 0 ꢀC, 8 drops
of BF3$Et2O were added and the resulting solution was allowed to
warm up slowly to room temperature. After 1 h, the reaction was
quenched with NaHCO3(aq) (45 mL) and extracted with ethyl acetate
(3ꢁ45 mL). The organic layers were combined, washed with brine,
dried overanhydrous MgSO4, andconcentrated invacuo. Purification
by flash column chromatography (silica gel, 10% EtOAc in cyclohex-
ane) provided 6b (1.86 g, 7.72 mmol, 82%) as a clear, pale yellow oil.
2.40 (q, J¼7.1 Hz, 2H), 2.07 (p, J¼7.2 Hz, 2H), 1.42
b, 1.29 a (d,
J¼6.6 Hz, 3H), 0.97 (t, J¼7.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major
isomer:
d 164.25, 150.55, 133.90, 131.24, 130.84, 130.60, 125.12,
124.49, 123.44, 94.09, 68.13, 66.64, 64.52, 27.82, 20.61, 16.21, 14.22.
LRMS calcd for C19H23NNaO6 [MþNa] 384.14, found 384.
4.6. (2S,3S)-2-Methyl-6-(3-methylbut-3-enyloxy)-3,6-
dihydro-2H-pyran-3-yl 4-nitrobenzoate (8b)
The compound was obtained as an anomeric mixture (
a/b
¼6:1). 1H
NMR (CDCl3, 300 MHz)
d
5.83 (m, 2H), 5.03 (dd, J¼1.3, 9.1 Hz, 1H),
4.96 (s, 1H), 4.78 (s, 1H), 4.73 (s, 1H), 3.91 (m, 2H), 3.60 (dt, J¼6.8,
Under argon, to a solution of DIAD (1.43 mL, 7.21 mmol,
1.2 equiv) in THF (15 mL) were added sequentially triphenylphos-
phine (1.85 g, 7.07 mmol, 1.2 equiv), p-nitro-benzoic acid (1.09 g,
7.21 mmol, 1.2 equiv), and finally a solution of alcohol 7b (1.19 g,
6.02 mmol, 1 equiv) in THF (3 mL). The resulting mixture was
stirred for 6 h at room temperature, then concentrated in vacuo,
and purified by flash column chromatography (silica gel, 20% EtOAc
in cyclohexane) to provide 2.07 g (5.91 mmol, 93%) of the title
compound as a yellow solid. 1H NMR (CDCl3, 300 MHz) major iso-
9.7 Hz,1H), 2.32 (t, J¼6.9 Hz, 2H), 2.07 (s, 3H),1.75 (s, 3H),1.30
b,1.21
a
(d, J¼6.3 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d 170.5,
142.6, 129.5, 127.7, 111.6, 94.3, 70.8, 66.9, 64.8, 37.8, 22.7, 21.0, 17.9.
LRMS calcd for C13H20NaO4 [MþNa] 263.13, found 263.
4.3. (2S,3R)-6-((Z)-Hex-3-enyloxy)-2-methyl-3,6-dihydro-2H-
pyran-3-ol (7a)
Under argon, to a solution of 6a (677 mg, 2.66 mmol, 1 equiv) in
methanol (35 mL), sodium (183 mg, 7.98 mmol) was added por-
tionwise. The resulting mixture was stirred for 6 h at room tem-
perature, quenched with NH4Cl(aq) (15 mL) and extracted with ethyl
acetate (3ꢁ35 mL). Organic layers were combined, washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash column chromatography (silica gel, 40% EtOAc
in cyclohexane) provided alcohol 7a (517 mg, 2.44 mmol, 92%) as
mer:
d
8.26 (m, 4H), 6.19 (dd, J¼5.2, 10.0 Hz, 1H), 6.09 (dd, J¼3.0,
10.0 Hz, 1H), 5.16 (dd, J¼2.4, 5.3 Hz, 1H), 5.10 (d, J¼2.9 Hz, 1H), 4.80
(s, 1H), 4.76 (s, 1H), 4.37 (dq, J¼2.4, 6.5 Hz, 1H), 3.93 (m, 1H), 3.68
(m, 1H), 2.35 (t, J¼6.9 Hz, 2H), 1.78 (s, 3H), 1.31 (d, J¼6.6 Hz, 3H). 13C
NMR (CDCl3, 75 MHz) major isomer:
d 164.2, 150.6, 142.5, 135.2,
131.2, 130.8, 125.2, 123.5, 111.5, 94.2, 66.8, 66.6, 64.6, 37.7, 22.7, 22.0,
21.9, 16.2. LRMS calcd for C18H21NNaO6 [MþNa] 370.13, found 370.
a clear, colorless oil. 1H NMR (CDCl3, 300 MHz)
1H), 5.73 (m, 1H), 5.46 (m, 1H), 5.33 (m, 1H), 5.10
d
5.91 (d, J¼10.0 Hz,
4.7. (2S,3S)-6-((Z)-Hex-3-enyloxy)-2-methyl-3,6-dihydro-2H-
pyran-3-ol (9a)
b
, 4.93 (s, 1H),
a
3.77 (m, 3H), 3.49 (m, 1H), 2.34 (q, J¼7.0 Hz, 2H), 2.05 (p, J¼7.4 Hz,
2H), 1.35
b
, 1.31
a
(d, J¼6.1 Hz, 3H), 0.95 (t, J¼7.5 Hz, 3H). 13C NMR
Under argon, to a solution of 8a (1.91 g, 5.47 mg, 1 equiv) in
methanol (50 mL), sodium (377 mg, 16.41 mmol) was added por-
tionwise. The resulting mixture was stirred for 6 h at room tem-
perature, quenched with NH4Cl(aq) (40 mL) and extracted with ethyl
acetate (3ꢁ50 mL). Organic layers were combined, washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash column chromatography (silica gel, 40% EtOAc
in cyclohexane) provided alcohol 9a (945 mg, 4.45 mmol, 81%) as
(CDCl3, 75 MHz) major isomer:
d 133.8, 133.4, 126.6, 124.6, 94.2,
69.6, 68.1, 67.9, 27.9, 20.6, 17.9, 14.2. HRMS calcd for C12H20NaO3
[MþNa] 235.1310, found 235.1314.
4.4. (2S,3R)-2-Methyl-6-(3-methylbut-3-enyloxy)-3,6-
dihydro-2H-pyran-3-ol (7b)
Under argon, to a solution of 6b (1.75 g, 7.30 mmol, 1 equiv) in
methanol (60 mL), sodium (503 mg, 21.90 mmol) was added por-
tionwise. The resulting mixture was stirred for 6 h at room tem-
perature, quenched with NH4Cl(aq) (30 mL) and extracted with ethyl
acetate (3ꢁ60 mL). The organic layers were combined, washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash column chromatography (silica gel, 40% EtOAc
in cyclohexane) provided 1.26 g (6.34 mmol, 87%) of 7b as a clear,
a clear, yellow oil. 1H NMR (CDCl3, 300 MHz) major isomer:
d 6.15
(dd, J¼5.5, 9.9 Hz, 1H), 5.86 (dd, J¼3, 9.9 Hz, 1H), 5.46 (m, 1H), 5.32
(m, 1H), 4.94 (d, J¼3.0 Hz, 1H), 4.13 (dq, J¼2.1, 6.6 Hz, 1H), 3.72 (m,
1H), 3.56 (m, 1H), 3.48 (m, 1H), 2.33 (q, J¼7.0 Hz, 2H), 2.04 (p,
J¼7.3 Hz, 2H), 1.84 (br s, 1H), 1.28 (d, J¼6.6 Hz, 3H), 0.95 (t, J¼7.5 Hz,
3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d 133.8, 130.3, 128.1,
124.6, 94.3, 67.9, 66.3, 63.9, 27.8, 20.6, 16.1, 14.2. HRMS calcd for
C12H20NaO3 [MþNa] 235.1310, found 235.1312.
colorless oil. 1H NMR (CDCl3, 300 MHz)
5.73 (m, 1H), 5.11 , 4.93 (s, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 3.86 (m,
d
5.90 (d, J¼10.0 Hz, 1H),
b
a
4.8. (2S,3S)-2-Methyl-6-(3-methylbut-3-enyloxy)-3,6-
dihydro-2H-pyran-3-ol (9b)
2H), 3.65 (m, 2H), 2.31 (t, J¼7.0 Hz, 2H), 1.74 (s, 3H), 1.35
b
, 1.31
a
(d, J¼6.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d 142.5,
133.4, 126.6, 111.4, 94.3, 69.6, 68.0, 66.8, 37.8, 22.8, 18.0. HRMS calcd
Under argon, to a solution of 8b (2.0 g, 5.72 mg,1 equiv) in methanol
for C11H18NaO3 [MþNa] 221.1154, found 221.1158.
(60 mL), sodium (394 mg, 17.2 mmol) was added portionwise. The

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
347
resulting mixture was stirred for 6 h at room temperature, quenched
with NH4Cl(aq) (50 mL) and extracted with ethyl acetate (3ꢁ60 mL).
Organic layers were combined, washed with brine, dried over anhy-
drous MgSO4, and concentrated in vacuo. Purification by flash column
chromatography (silica gel, 40% EtOAc in cyclohexane) provided al-
cohol 9b (823 mg, 4.17 mmol, 72%) as a clear, yellowoil.1HNMR(CDCl3,
at this temperature for 2 h, concentrated in vacuo, and purified by
flash column chromatography (silica gel, 10% EtOAc in cyclohexane)
to provide the ring-rearranged product 11a (160 mg, 0.81 mmol,
83%) of the title compound as a clear oil. 1H NMR (CDCl3, 300 MHz)
major isomer:
d
6.02 (m, 2H), 5.86 (dq, J¼2.3, 8.6 Hz, 1H), 5.72 (dtd,
J¼1.3, 2.8, 10.1 Hz, 1H), 5.03 (t, J¼1 Hz, 1H), 4.96 (m, 1H), 4.67 (m,
2H), 3.98 (m, 2H), 3.71 (ddt, J¼1, 6.2, 11.1 Hz, 1H), 2.31 (m, 1H), 1.90
(dddt, J¼1, 4.1, 5.1, 17.8 Hz, 1H), 1.11 (d, J¼6.4 Hz, 3H). 13C NMR
300 MHz) major isomer:
d
6.15 (dd, J¼5.5, 9.9 Hz, 1H), 5.86 (dd, J¼3.1,
9.9 Hz, 1H), 4.95 (d, J¼3.1 Hz, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 4.12 (dq,
J¼2.1, 6.6 Hz,1H), 3.87 (dt, J¼7.1, 9.8 Hz,1H), 3.59 (dt, J¼6.9, 9.7 Hz,1H),
3.54 (m, 1H), 2.30 (t, J¼6.9 Hz, 2H), 1.83 (br s, 1H), 1.74 (s, 3H), 1.28 (d,
(CDCl3, 75 MHz) major isomer: d 129.1, 128.1, 126.7, 126.1, 92.0, 88.5,
75.6, 74.1, 57.2, 24.7, 14.7. HRMS calcd for C11H16NaO3 [MþNa]
J¼6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d
142.5, 130.3,
219.0992, found 219.0976.
128.0, 111.4, 94.4, 66.6, 66.4, 63.9, 37.7, 22.7, 16.1. HRMS calcd for
C11H18NaO3 [MþNa] 221.1154, found 221.1156.
4.12. 6-((S)-1-((S)-2,5-Dihydrofuran-2-yl)ethoxy)-4-methyl-
3,6-dihydro-2H-pyran (11b)
4.9. (2S,3S)-3-(Allyloxy)-6-((Z)-hex-3-enyloxy)-2-methyl-3,6-
dihydro-2H-pyran (10a)
Under argon, at 40 ꢀC, to a solution of 10b (40 mg, 0.17 mmol,
1 equiv) in degassed toluene (90 mL, c¼2.10ꢂ3 M), was added [Ru]-
Under argon, at 0 ꢀC, to a solution of alcohol 9a (80 mg,
2 (7 mg, 8 m
mol, 5 mol %). The resulting mixture was stirred at 40 ꢀC
0.38 mmol, 1 equiv) in DMF (1 mL) were added sequentially NaH
(14 mg, 0.53 mmol, 1.5 equiv) and allyl bromide (52 mL, 0.61 mmol,
for 2 h, concentrated in vacuo, and purified by flash column chro-
matography (silica gel, 10% EtOAc in cyclohexane) to provide 26 mg
(0.12 mmol, 73%) of ring-rearranged product 11b as a clear oil. 1H
1.3 equiv). The resulting mixture was stirred for 6 h at room tem-
perature, quenched with NH4Cl(aq) (3 mL) and extracted with ethyl
acetate (3ꢁ3 mL). The organic layers were combined, washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash column chromatography with silica gel (10%
EtOAc in cyclohexane) provided 74 mg (0.29 mmol, 76%) of the title
compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) major
NMR (CDCl3, 300 MHz) major isomer:
d
5.97 (dq, J¼1.7, 6.3 Hz, 1H),
5.82 (m, 1H), 5.42 (s, 1H), 5.01 (s, 1H), 4.94 (m, 1H), 4.64 (m, 2H),
3.94 (m, 2H), 3.69 (dd, J¼6.2, 11.4 Hz, 1H), 2.24 (m, 1H), 1.73 (m, 4H),
1.08 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major isomer:
d
137.5, 128.0, 126.6, 120.1, 92.7, 88.5, 75.5, 74.2, 57.3, 29.5, 23.0, 14.7.
HRMS calcd for C12H18NaO3 [MþNa] 233.1154, found 233.1165.
isomer:
d
6.13 (dd, J¼5.0, 10.2 Hz, 1H), 5.91 (m, 2H), 5.45 (m, 1H),
5.34 (m, 1H), 5.26 (dq, J¼1.6, 17.2 Hz, 1H), 5.16 (dq, J¼1.3, 10.4 Hz,
1H), 5.00 (d, J¼2.9 Hz, 1H), 4.12 (m, 2H), 4.02 (ddt, J¼1.3, 5.7,
12.8 Hz, 1H), 3.72 (dt, J¼7.2, 9.6 Hz, 1H), 3.49 (dt, J¼7.1, 9.6 Hz, 1H),
3.44 (dd, J¼2.6, 5.3 Hz, 1H), 2.33 (q, J¼7.0 Hz, 2H), 2.04 (p, J¼7.4 Hz,
2H), 1.30 (d, J¼6.7 Hz, 3H), 0.95 (t, J¼7.5 Hz, 3H). 13C NMR (CDCl3,
4.13. Allyl 2-deoxy-3,4,6-tri-O-acetyl- -galactopyranoside (13)
D
Under argon, to a solution of 3,4,6-tri-O-acetyl
D-galactal (1.0 g,
3.7 mmol, 1 equiv) 12 and allyl alcohol (816 L, 12 mmol, 3.2 equiv)
m
in anhydrous dichloromethane (20 mL) was added polymer-sup-
ported TPHB (PPh3$HBr)20 (240 mg, 0.74 mmol, 0.2 equiv). The
mixture was stirred overnight, filtered, and concentrated in vacuo
75 MHz) major isomer: d 135.1, 133.7, 129.3, 127.5, 124.6, 116.8, 94.2,
70.0, 69.3, 67.8, 66.2, 27.9, 20.6, 16.2, 14.2. HRMS calcd for
C15H24NaO3 [MþNa] 275.1623, found 275.1631.
to provide the title compound (1.06g, 87%, pale yellow oil) as an
b
a/
(4:1) mixture of anomers, in agreement with the litterature.21
4.10. (2S,3S)-3-(Allyloxy)-2-methyl-6-(3-methylbut-3-
enyloxy)-3,6-dihydro-2H-pyran (10b)
It is also possible to perform the reaction using nonsupported
TPHB following the procedure described by Falk, Mioskowski et al.8
followed by purification by flash column chromatography (silica
gel, 20% EtOAc in cyclohexane). 1H NMR (CDCl3, 300 MHz) (major
Under argon, at 0 ꢀC, to a solution of alcohol 9b (80 mg,
0.40 mmol, 1 equiv) in DMF (1 mL) were added sequentially NaH
isomer a) d 5.97e5.84 (m, 1H), 5.37e5.17 (m, 4H), 5.06 (br d,
(14 mg, 0.53 mmol, 1.5 equiv) and allyl bromide (52
m
L, 0.61 mmol,
J¼2.9 Hz, 1H), 4.19e4.08 (m, 4H), 3.99 (ddt, J¼12.9, 6.0, 1.3 Hz, 1H),
1.3 equiv). The resulting mixture was stirred for 6 h at room tem-
perature, quenched with NH4Cl(aq) (3 mL) and extracted with ethyl
acetate (3ꢁ3 mL). The organic layers were combined, washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash column chromatography with silica gel (10%
EtOAc in cyclohexane) provided 70 mg (0.30 mmol, 73%) of the title
compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) major
2.14 (s, 3H), 2.11 (m, 1H), 2.06 (s, 3H), 1.98 (s, 3H), 1.91 (m, 1H). 13C
NMR (major isomer a) (CDCl3, 75 MHz) d 170.5, 170.3, 170.0, 133.7,
117.5, 96.6, 68.2, 66.7, 66.6, 66.2, 62.4, 30.1, 20.8, 20.8 (2C). LRMS
calcd for C15H22NaO8 [MþNa] 353.12, found 353.0.
4.14. Allyl 6-O-tert-butyl-dimethylsilyl-2-deoxy-3,4,6-tri-O-
acetyl-D-galactopyranoside (14)
isomer:
d
6.13 (dd, J¼5.2 et 10.1, 1H), 5.96 (dd, J¼3.4, 9.9 Hz, 1H),
5.88 (m, 1H), 5.26 (dq, J¼1.6, 17.2 Hz, 1H), 5.15 (dq, J¼1.2, 10.3 Hz,
1H), 5.00 (d, J¼2.9 Hz, 1H), 4.76 (s, 1H), 4.72 (s, 1H), 4.13 (m, 2H),
4.02 (ddt, J¼1.3, 5.7,12.8 Hz,1H), 3.87 (dt, J¼7.1, 9.8 Hz,1H), 3.60 (dt,
J¼6.8, 9.8 Hz, 1H), 3.44 (dd, J¼2.7, 5.2 Hz, 1H), 2.31 (t, J¼6.9 Hz, 2H),
1.74 (s, 3H), 1.31 (d, J¼6.7 Hz, 3H). 13C NMR (CDCl3, 75 MHz) major
A cold (0 ꢀC) solution of 13 (8.27 g, 25 mmol, 1 equiv) in
methanol (20 mL) was placed under Ar atmosphere. Sodium
methanolate (135 mg, 2.5 mmol) was added and the mixture was
allowed to warm to room temperature and stirred for 2 h. The
methanol was removed in vacuo and the residue was co-evapo-
rated with toluene and dried under vacuum for 3 h. The diol was
dissolved in DMF (30 mL), the solution was placed under argon
atmosphere and imidazole (2.50 g, 36.7 mmol, 1.5 equiv) and tert-
butyldimethylsilyl chloride (4.11 g, 27.5 mmol, 1.1 equiv) were
added. The mixture was allowed to warm to room temperature and
stirred for 18 h, then it was diluted with ether (100 mL). The mix-
ture was washed with brine (2ꢁ80 mL). The aqueous layers were
extracted with ether (3ꢁ100 mL), the combined organic layers were
washed with brine (200 mL), dried over anhydrous MgSO4, fil-
trated, and concentrated in vacuo. Purification by flash column
isomer: d 142.6, 135.1, 129.3, 127.5, 116.8, 111.4, 94.3, 70.0, 69.3, 66.4,
66.3, 37.8, 22.7, 16.2. HRMS calcd for C14H22NaO3 [MþNa]261.1467,
found 261.1470.
4.11. 6-((S)-1-((S)-2,5-Dihydrofuran-2-yl)ethoxy)-3,6-dihydro-
2H-pyran (11a)
Under argon, at 40 ꢀC, to a solution of 10a (220 mg, 0.98 mmol,
1 equiv) in degassed toluene (200 mL, c¼2.10ꢂ3 M), was added
[Ru]-2 (42 mg, 49 mmol, 5 mol %). The resulting mixture was stirred

348
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
chromatography (silica gel, 40% EtOAc in cyclohexane) provided the
title compound (5.73 g, 72%, colorless oil) as an (4:1) mixture of
anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
5.97e5.84
(ddt, J¼10.3, 2.8, 1.3 Hz, 1H), 5.08 (br d, J¼4.7 Hz, 1H), 4.35e4.22 (m,
2H), 4.08 (ddt, J¼12.9, 6.1, 1.3 Hz, 1H), 3.74 (ddd, J¼11.4, 7.0, 3.3 Hz,
1H), 3.63 (ddd, J¼11.4, 5.8, 5.8 Hz,1H), 2.54e2.40 (m,1H), 2.16e2.07
a/b
a) d
(m, 1H), 5.28 (ddt, J¼17.2, 3.4, 1.7 Hz, 1H), 5.18 (ddt, J¼10.5, 3.1,
1.5 Hz, 1H), 4.99e4.97 (m, 1H), 4.17e4.09 (m, 1H), 4.13 (ddt, J¼13.1,
5.2, 1.6 Hz, 1H), 4.02e3.87 (m, 4H), 3.79e3.72 (m, 1H), 1.89 (m, 2H),
(m, 1H), 1.90 (br s,1H). 13C NMR (CDCl3, 75 MHz) (major isomer
a)
d
134.3, 125.0, 123.8, 117.3, 95.0, 68.4, 68.2, 65.1, 29.9. HRMS calcd
for C9H14NaO3 [MþNa] 193.0841, found 193.0838.
0.89 (s, 9H), 0.08 (s, 6H). 13C NMR (major isomer
a) d 134.1, 116.9,
96.9, 69.5, 69.0, 67.7, 65.8, 64.0, 33.0, 25.8 (3C), 18.2, ꢂ5.4 (2C).
4.18. (S)-2-(Allyloxy)-6-(allyloxymethyl)-3,6-dihydro-2H-
pyran (18)
LRMS calcd for C15H30NaO5Si [MþNa] 341.18, found 341.1.
4.15. Allyl 6-O-tert-butyl-dimethylsilyl-2-deoxy-
D
-
Under argon at 0 ꢀC, to a solution of alcohol 17 (80 mg,
galactopyranoside 3,4-thionocarbonate (15)
0.47 mmol, 1 equiv) in DMF (1 mL) were added, respectively, dry
NaH (19 mg, 0.70 mmol, 1.5 equiv) and allyl bromide (52
mL,
Under argon, at room temperature, to a solution of diol 14
(5.40 g, 17 mmol, 1 equiv) in anhydrous dichloromethane (25 mL)
was added 1,10-(thiocarbonyl)diimidazole (4.50 g, 25 mmol,
1.5 equiv). The mixture was stirred for 18 h, diluted with ether
(50 mL), and quenched with water (30 mL). The aqueous layer was
extracted with ether (3ꢁ50 mL), the combined organic layers were
washed with brine (80 mL), dried over anhydrous MgSO4, filtrated,
and concentrated in vacuo. Purification by flash column chroma-
tography (silica gel, 15% EtOAc in cyclohexane) provided the title
0.61 mmol, 1.3 equiv). Then the reaction was stirred at room tem-
perature for 6 h, quenched with NH4Cl(aq) (3 mL) and extracted with
ethyl acetate (3ꢁ3 mL). The organic layers were combined, dried
over anhydrous MgSO4, and concentrated in vacuo. Purification by
flash column chromatography (silica gel, 10% EtOAc in cyclohexane)
provided the title compound (91 mg, 92%, colorless oil) as an
(4:1) mixture of anomers. 1H NMR (CDCl3, 300 MHz) (major
isomer
a/
b
a
)
d
6.02e5.88 (m, 2H), 5.81 (ddt, J¼2.2, 4.0, 9.6 Hz, 2H),
5.73e5.69 (m, 1H), 5.30 (ddq, J¼1.6, 3.3, 17.0 Hz, 2H), 5.20 (ddq,
J¼1.6, 2.9, 10.4 Hz, 2H), 5.09 (br d, J¼4.8 Hz, 1H), 4.42e4.36 (m, 1H),
4.29 (ddt, J¼1.4, 5.2, 12.9 Hz, 1H), 4.12e4.05 (m, 3H), 3.59e3.50 (m,
2H), 2.53e2.43 (m, 1H), 2.15e2.06 (m, 1H). 13C NMR (CDCl3,
compound (4.60 g, 75%, yellow oil) as an
a
/b
(4:1) mixture of
5.99e5.76
anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
a) d
(m, 1H), 5.27 (ddt, J¼17.2, 3.2, 1.5 Hz, 1H), 5.22e5.17 (m, 2H),
5.08e4.92 (m, 2H), 4.22 (ddt, J¼12.9, 5.2, 1.4 Hz, 1H), 4.02 (dt, J¼6.2,
1.1 Hz, 2H), 3.96 (td, J¼6.8,1.4 Hz,1H), 3.85e3.73 (m, 1H), 2.48 (ddd,
J¼15.8, 5.6, 4.2 Hz, 1H), 1.91 (ddd, J¼15.8, 6.4, 3.6 Hz, 1H), 0.89 (s,
75 MHz) (major isomer a) d 134.6, 134.4, 125.7, 122.9, 117.2, 117.1,
95.0, 72.4, 72.3, 68.1, 67.1, 29.8. HRMS calcd for C12H18NaO3 [MþNa]
233.1148, found 233.1149.
9H), 0.09 (2s, 6H). 13C NMR (CDCl3, 75 MHz) (major isomer
a)
d
191.8, 133.7, 117.6, 94.3, 78.3, 76.9, 68.4, 67.7, 60.7, 29.0, 25.8 (3C),
4.19. (S)-(6-(Allyloxy)-5,6-dihydro-2H-pyran-2-yl)methyl
18.17, 0.99 (2C). HRMS calcd for C16H28NaO5SSi [MþNa] 383.1324,
pent-4-enoate (19)
found 383.1311.
Under argon, to
a solution of pent-4-enoic acid (42 mL,
4.16. (((2S)-6-(Allyloxy)-5,6-dihydro-2H-pyran-2-yl)methoxy)
(tert-butyl)dimethylsilane (16)
0.46 mmol, 1.05 equiv) in DCM (3 mL) were added alcohol 17
(75 mg, 0.44 mmol, 1 equiv) and DMAP (2 mg, 0.02 mmol, 4 mol %).
Then the reaction mixture was cooled down to 0 ꢀC and DCC
(96 mg, 0.46 mmol, 1.05 equiv) was added. Finally the mixture was
let to stir at room temperature for a night. The white precipitate
was then removed by filtration over Celite. The filtrate was then
washed twice with a cold saturated solution of citric acid (2ꢁ5 mL),
three times with NaHCO3satd, and finally once with brine. The or-
ganic layers were combined, dried over anhydrous MgSO4, and
concentrated in vacuo. Purification by flash column chromatogra-
phy (silica gel, 10% EtOAc in cyclohexane) provided the title com-
Under argon, a solution of thiocarbonate 15 (2.60g, 7.2 mmol,
1 equiv) in trimethylphosphite (25 mL) was refluxed overnight
before the mixture was concentrated in vacuo. Purification by flash
column chromatography (silica gel, 10% EtOAc in cyclohexane)
provided the title compound (1.58 g, 77%, clear, colorless oil) as an
a/b
(4:1) mixture of anomers. 1H NMR (CDCl3, 300 MHz) (major
isomer
a
)
d
6.01e5.89 (m, 1H), 5.77 (br s, 2H), 5.29 (dq, J¼17.1,
1.5 Hz, 1H), 5.20e5.16 (m, 1H), 5.04 (d, J¼4.8 Hz, 1H), 4.31e4.18 (m,
2H), 4.06 (ddt, J¼12.9, 6.3, 1.2 Hz, 1H), 3.75 (dd, J¼10.2, 6.0 Hz, 1H),
3.63 (dd, J¼10.2, 6.0 Hz, 1H), 2.47e2.39 (m, 1H), 2.13e2.05 (m, 1H),
pound (86 mg, 0.34 mmol, 77%, colorless oil) as an
a/b
(4:1) mixture
6.21e6.12
of anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
a) d
0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (CDCl3, 75 MHz) (major isomer
a
)
(m, 1H), 6.03e5.94 (m, 2H), 5.32e5.19 (m, 2H), 5.10 (bd. J¼4.2 Hz
1H), 5.02e4.91 (m, 2H), 4.45e4.32 (m. 2H), 4.15 (ddt, J¼13.0, 6.1,
1.5 Hz, 1H), 3.73 (ddd. J¼11.4, 7.3, 3.0 Hz, 1H), 3.54 (m, 1H),
2.85e2.65 (m, 4H), 2.50e2.38 (m, 1H), 2.20e2.05 (m, 1H). 13C NMR
d
134.3, 126.0, 122.1, 117.0, 94.7, 68.5, 67.8, 65.5, 29.8, 25.7 (3C), 18.1,
ꢂ5.7 (2C). LRMS calcd for C15H28NaO3Si [MþNa] 307.17, found
307.2.
(CDCl3, 75 MHz) (major isomer a) d 175.2, 136.2, 135.1, 125.4, 124.2,
4.17. ((2S)-6-(Allyloxy)-5,6-dihydro-2H-pyran-2-yl)-methanol
117.5, 116.4, 96.1, 67.1, 66.9, 65.0, 34.7, 30.1, 28.7.
(17)
4.20. (S)-(6-(Allyloxy)-5,6-dihydro-2H-pyran-2-yl)methyl
A solution of 16 (1.68 g, 5.9 mmol, 1 equiv) in anhydrous THF
(30 mL), under argon, at 0 ꢀC, was treated dropwise with 1 M TBAF
in THF (5.9 mL, 5.9 mmol, 1 equiv). The mixture was stirred for
20 min at 0 ꢀC and then was allowed to warm to room temperature
within 90 min. The reaction was quenched by addition of water
(20 mL) and extracted with ether (2ꢁ50 mL). The organic layers
were washed with brine (40 mL), dried over anhydrous MgSO4, and
concentrated in vacuo. Purification by flash column chromatogra-
phy (silica gel, 30% EtOAc in cyclohexane) provided the title com-
prop-2-enoate (20)
Under argon, to a solution of alcohol 17 (100 mg, 0.59 mmol,
1 equiv) in dichloromethane (5 mL) was added diisopropylethyl-
amine (623
m
L, 3.54 mmol, 6 equiv). Then, the resulting mixture
was cooled to 0 ꢀC, acryloyl chloride (142
mL, 1.77 mmol, 3 equiv)
was added and the solution was stirred for 1 h at room tempera-
ture. The reaction was quenched with NH4Cl(aq) (5 mL) and
extracted with ethyl acetate (3ꢁ5 mL). The organic layers were
combined, washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. Purification of the brown crude residue by
flash column chromatography (silica gel, 10% EtOAc in cyclohexane)
pound (851 mg, 85%, pale yellow oil) as an
anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
(m, 2H), 5.67e5.63 (m, 1H), 5.30 (ddt, J¼17.2, 3.9, 1.5 Hz, 1H), 5.20
a
/b
(4:1) mixture of
a) d
6.00e5.81

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
349
provided acrylate 20 120 mg (0.54 mmol, 92%) as a clear, colorless
oil. 1H NMR (CDCl3, 300 MHz) (major isomer
6.27e6.23 (m, 1H),
ꢂ78 ꢀC for 12 h, and then the mixturewas warmed to 0 ꢀC and stirred
for additional 30 min. The reaction was quenched by the sequential
addition of NH4Cl(aq) (3 mL) and saturated aqueous sodium potas-
sium tartrate (3 mL). The resulting emulsion was removed from the
ice water bath and stirred vigorously for one night. The obtained
biphasic mixture was extracted with dichloromethane (3ꢁ4 mL).
The organic layers were combined, washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. Purification by flash
column chromatography (triethylamine-deactivated silica gel, 10%
EtOAc in cyclohexane with 3% Et3N) provided 66 mg (0.25 mmol,
70%) of the title compound 23 as clear, colorless oil. 1H NMR (CDCl3,
a) d
6.00e5.81 (m, 2H), 5.72e5.63 (m, 1H), 5.51e5.43 (m, 2H), 5.35 (ddt,
J¼17.2, 3.9, 1.7 Hz, 1H), 5.22 (ddt, J¼10.3, 2.8, 1.5 Hz, 1H), 5.08 (br d,
J¼4.7 Hz, 1H), 4.50e4.32 (m, 2H), 4.08 (ddt, J¼12.9, 6.1, 1.3 Hz, 1H),
3.74 (ddd, J¼11.4, 7.0, 3.3 Hz, 1H), 3.63 (ddd, J¼11.4, 5.8, 5.8 Hz, 1H),
2.52e2.40 (m, 1H), 2.20e2.05 (m, 1H). LRMS calcd for C12H17O4
[MþH] 225.11, found 225.2.
4.21. (2S)-6-(Allyloxy)-5,6-dihydro-2H-pyran-2-carboxylic
acid (21)
300 MHz) (major isomers
a
)
d
6.02e5.83 (m, 3H), 5.35 (ddt, J¼16.7,
Under argon, PhIOAc2 (827 mg, 2.57 mmol, 2.2 equiv), TEMPO
(36 mg, 0.23 mmol, 0.2 equiv) and the alcohol 17 (200 mg,
1.17 mmol, 1 equiv) were dissolved in a 1:1 aqueous acetonitrile
(2 mL, 0.5 M). The reaction mixture was stirred for 5 h, then filtered,
and concentrated in vacuo. Purification by flash column chroma-
tography (silica gel, 60% EtOAc in cyclohexane) provided the title
7.4,1.5 Hz,1H), 5.30e5.29 (m,1H), 5.24 (ddt, J¼22.3,10.4,1.5 Hz,1H),
5.14 (dd, J¼3.8, 3.8 Hz,1H), 4.93e4.91 (m,1H), 4.69 (dt, J¼5.8,1.3 Hz,
2H), 4.38 (ddt, J¼12.9, 5.2, 1.4 Hz, 1H), 4.29e4.13 (m, 2H), 2.48e2.38
(m, 1H), 2.24e2.14 (m, 1H), 2.12 and 2.14 (2s, 3H). 13C NMR (CDCl3,
75 MHz) (major isomers a) d 170.2, 170.1, 134.1, 131.6, 124.5, 123.5,
123.0, 118.9, 117.4, 117.3, 95.4, 95.1, 95.0, 70.3, 68.9, 65.8, 29.9, 29.8,
compound (151 mg, 70%, pale yellow oil) as an
a/
b
(4:1) mixture of
9.66 (s, 1H),
21.2. LRMS calcd for C14H21O5 [MþH] 269.14, found 269.0.
anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
a) d
6.01e5.83 (m, 3H), 5.32 (ddt, J¼18.9, 3.3, 1.5 Hz, 1H), 5.22 (ddt,
J¼10.2, 2.7, 1.5 Hz, 1H), 5.16 (dd. J¼2.1, 1.5 Hz, 1H), 4.89e4.86 (m,
1H), 4.33 (ddd, J¼12.9, 1.5, 1.5 Hz), 4.14 (ddd, J¼12.9, 1.5, 1.5 Hz, 1H),
2.53e2.43 (m, 1H), 2.23e2.13 (m, 1H). 13C NMR (CDCl3, 75 MHz)
(major isomer a) d 171.9, 133.7, 124.1, 122.2, 117.8, 95.4, 78.2, 68.9,
29.4. HRMS calcd for C9H12NaO4 [MþNa] 207.0628, found 207.0625.
4.24. (S)-5,60-Oxybis(5,6-dihydro-2H-pyran) (24)
Under argon, at 70 ꢀC, to a solution of 18 (50 mg, 0.24 mmol,
1 equiv) in degassed toluene (110 mL, c¼2.10ꢂ3 M), was added [Ru]-
2 (11 mg, 12 mmol, 5 mol %). The resulting mixture was stirred at
70 ꢀC for 3 h, concentrated in vacuo, and purified by flash column
chromatography (silica gel, 10% EtOAc in cyclohexane) to provide
36 mg (0.20 mmol, 84%) of ring-rearranged product 24 as a clear oil.
4.22. (2S)-Allyl 6-(allyloxy)-5,6-dihydro-2H-pyran-2-
carboxylate (22)
1H NMR (CDCl3, 300 MHz) (major isomer
a) d 5.97 (br s, 2H), 5.72
(br s, 2H), 4.97 (t, J¼4.0 Hz, 1H), 4.33e4.25 (m, 1H), 4.24e4.15 (m,
3H), 4.11e4.03 (m, 1H), 3.88 (dd, J¼3.8, 11.8 Hz, 1H), 3.79 (dd, J¼3.5,
11.8 Hz, 1H), 2.43e2.35 (m, 1H), 2.23e2.15 (m, 1H). 13C NMR (CDCl3,
Under argon, to a solution of acid 21 (150 mg, O.81 mmol,
1 equiv) in CH2Cl2 (6 mL) were added allylic alcohol (61
mL,
0.89 mmol, 1 equiv) and DMAP (2 mg, 0.02 mmol, 3 mol %). The
mixture was cooled to 0 ꢀC and DCC (177 mg, 0.85 mmol,1.05 equiv)
was added. Then, the reaction was allowed to warm to room tem-
perature and was stirred over the night. After elimination of the
white precipitate by filtration on Celite, the mixture was washed
twice with a saturated aqueous solution of citric acid, once with
NaHCO3(aq), and once with water. The organic layer was dried over
anhydrous MgSO4 and concentrated in vacuo. Purification by flash
column chromatography (silica gel, 20% EtOAc in cyclohexane)
75 MHz) (major isomer a) d 130.0, 125.5, 125.1, 121.7, 95.5, 67.5, 67.1,
65.1, 61.3, 30.5. LRMS calcd for C10H14NaO3 [MþNa] 205.08, found
205.1.
4.25. (S,5Z)-7-(3,6-Dihydro-2H-pyran-2-yloxy)-3,4,7,8-
tetrahydrooxocin-2-one (25)
Under argon, at 70 ꢀC, to a solution of 19 (20 mg, 0.08 mmol,
1 equiv) in degassed toluene (35 mL, c¼2.10ꢂ3 M), was added [Ru]-
provided the title compound (137 mg, 75%, pale yellow oil) as an
(4:1) mixture of anomers. 1H NMR (CDCl3, 300 MHz) (major
isomer
a/
2 (4 mg, 4 m
mol, 5 mol %). The resulting mixture was stirred at 70 ꢀC
b
for 3 h, concentrated in vacuo, and purified by flash column chro-
matography (silica gel, 10% EtOAc in cyclohexane) to provide 11 mg
(0.05 mmol, 66%) of ring-rearranged product 25 as a clear oil. 1H
a
)
d
6.02e5.86 (m, 3H), 5.34 (ddt, J¼17.2, 7.5, 1.5 Hz, 1H),
5.30e5.29 (m, 1H), 5.24 (ddt, J¼22.3, 10.4, 1.5 Hz, 1H), 5.12 (dd, J¼4,
4 Hz, 1H), 4.93e4.92 (m, 1H), 4.69 (dt, J¼5.8, 1.3 Hz, 2H), 4.39 (ddt,
J¼12.9, 5.2, 1.4 Hz, 1H), 4.18 (ddt, J¼12.9; 6.2, 1.3 Hz, 1H), 2.48e2.38
(m, 1H), 2.24e2.14 (m, 1H). 13C NMR (CDCl3, 75 MHz) (major isomer
NMR (CDCl3, 300 MHz) (major isomer a) d 5.80e5.71 (m, 3H), 5.61
(ddt, J¼10.5, 3.7, 1.8 Hz, 1H), 5.15 (d, J¼5.5 Hz, 1H), 4.70 (dd, 11.3,
2.13 HZ, 1H), 4.50e4.41 (m, 2H), 3.94e3.86 (m,1H), 3.74 (dd, J¼10.9,
10.9 Hz, 1H), 2.56e2.46 (m, 2H), 2.41e2.43 (m, 2H), 2.10e2.01 (m,
a) d 170.1, 134.1, 131.7, 124.5, 122.9, 118.9, 117.4, 95.4, 70.2, 68.8, 65.8,
27.7. HRMS calcd for C12H16NaO4 [MþNa] 247.0941, found 247.0941.
2H). 13C NMR (CDCl3, 75 MHz) (major isomer
a) d 173.7, 130.7, 130.6,
124.3, 123.6, 99.4, 72.6, 66.5, 64.8, 33.7, 30.4, 30.2. LRMS calcd for
C12H17O4 [MþH] 225.11, found 225.2.
4.23. (S)-Allyloxy(6-(allyloxy)-5,6-dihydro-2H-pyran-2-yl)
methyl ethanoate (23)
Under argon, at ꢂ78 ꢀC, to a solution of ester 22 (80 mg,
4.26. (S)-3-(3,6-Dihydro-2H-pyran-2-yloxy)-3,6-dihydro-2H-
pyran-2-yl ethanoate (27)
0.35 mmol, 1 equiv) in dichloromethane (3 mL), DIBAH (1.5 M in
toluene, 468 mL, 0.70 mmol, 2 equiv) was added slowly over a period
of 15 min (Caution! The internal solution temperature must be kept
Under argon, at 70 ꢀC, to a solution of 23 (20 mg, 0.07 mmol,
1 equiv) in degassed toluene (35 mL, c¼2.10ꢂ3 M), was added [Ru]-
below ꢂ72 ꢀC). The solution was stirred for an additional 45 min at
ꢂ78ꢀC and pyridine (85
m
L,1.05 mmol, 3 equiv)wasadded dropwise,
2 (4 mg, 4 m
mol, 5 mol %). The resulting mixture was stirred at 70 ꢀC
while maintaining the temperature below ꢂ76 ꢀC. Then a solution of
DMAP (86 mg, 0.70 mmol, 2 equiv) in dichloromethane (1 mL) was
immediately added at a rate such as to maintain the temperature
for 3 h, concentrated in vacuo, and purified by flash column chro-
matography (silica gel, 10% EtOAc in cyclohexane) to provide 12 mg
(0.05 mmol, 74%) of ring-rearranged product 27 as a clear oil. 1H
below ꢂ72 ꢀC. Finally, acetic anhydride (198
mL, 2.10 mmol, 6 equiv)
NMR (CDCl3, 300 MHz) (major isomers
5.00e4.87 (m, 1H), 4.96e4.91 (m, 1H), 4.43e3.59 (m, 4H),
2.64e2.37 (m, 1H), 2.21e2.07 (m, including 2s at
¼2.12 and 2.10,
a) d 6.53e5.46 (m, 5H),
was added and, again, the internal temperature was not allowed to
rise above ꢂ72 ꢀC. The resulting light yellow solution was stirred at
d

350
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
4H). 13C NMR (CDCl3, 75 MHz) (major isomers
125.0, 122.5, 121.6, 96.2, 92.5, 67.7, 61.3, 30.3, 29.7, 21.0.
a)
d
169.7, 129.0,
J¼4.4 Hz, 1H), 4.31 (ddt, J¼12.8, 5.2, 1.6 Hz, 1H), 4.21e4.20 (m, 1H),
4.17e4.10 (m, 2H), 3.70 (dd, J¼10.2, 5.7 Hz, 1H), 3.59 (dd, J¼10.2,
6.0 Hz, 1H), 1.60 (br s, 1H), 0.90 (s. 9H), 0.07 (s, 6H). 13C NMR (CDCl3,
4.27. (2R,3S)-6-(Allyloxy)-2-(ethanoyloxymethyl)-3,6-
dihydro-2H-pyran-3,5-diyl diethanoate (29)
75 MHz) (major isomer a) d 133.8,127.6,127.3,117.8, 95.9, 69.2, 68.9,
65.5, 64.3, 25.9 (3C), ꢂ5.2, ꢂ5.3. LRMS calcd for C15H28NaO8Si
[MþNa] 323.17, found 323.2.
Under argon, to a solution of 2,3,4,6-tetra-O-acetyl
D-glucal
(500 mg, 1.51 mmol, 1 equiv) 28 in dichloromethane (2 mL) was
added allylic alcohol (154 L, 2.26 mmol, 1.5 equiv). The mixture
4.30. (((2S,5R)-6-(Allyloxy)-5-methoxy-5,6-dihydro-2H-
pyran-2-yl)methoxy)(tert-butyl)dimethylsilane (32)
m
was cooled to 0 ꢀC, 3 drops of BF3$Et2O were added and the
resulting solution was allowed to warm up slowly to room tem-
perature. After 1 h, the reaction was quenched with NaHCO3(aq)
(10 mL) and extracted with ethyl acetate (3ꢁ10 mL). The organic
layers were combined, washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. Purification by flash column
chromatography (silica gel, 10% EtOAc in cyclohexane) provided the
title compound (332 mg, 1.01 mmol, 67%) as a clear, pale yellow oil.
Under argon at 0 ꢀC, to a solution of alcohol 31 (70 mg,
0.23 mmol, 1 equiv) in DMF (1 mL), NaH (9 mg, 0.35 mmol,
1.5 equiv) and MeI (19 mL, 0.30 mmol, 1.3 equiv) were added. Then
the reaction was let to stir at room temperature for 6 h, quenched
with NH4Cl(aq) (2 mL), and extracted thrice with EtOAc (3ꢁ2 mL).
Organic layers were combined, washed with brine, dried over
MgSO4, and finally concentrated in vacuo. Purification by flash
column chromatography (silica gel, 5% EtOAc in cyclohexane) pro-
vided the title compound (60 mg, 0.19 mmol, 81%) as a clear, col-
orless oil. The compound was obtained as an anomeric mixture
The compound was obtained as an anomeric mixture with a 6:1 (
a/
b
) ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
a) d
5.96e5.82 (m,
1H), 5.73 (d, J¼2.15 Hz, 1H), 5.47e5.43 (m, 1H), 5.35e5.17 (m, 3H),
5.08 (br s, 1H), 4.38e4.05 (m, 5H), 2.15 (s, 3H), 2.08 (s, 3H), 2.06 (s,
with a 6:1 (a/b a)
) ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
3H). 13C NMR (CDCl3, 75 MHz) (major isomer
a
)
d
170.6, 170.0, 168.1,
d
6.05e5.91 (m,1H), 5.87e5.76 (m, 2H), 5.33 (ddt, J¼17.2, 3.0,1.4 Hz,
148.1, 133.6, 117.7, 115.3, 92.9, 69.3, 67.1, 65.2, 62.4, 20.9 (3C). HRMS
calcd for C15H20NaO8 [MþNa] 351.1050, found 351.1053.
1H), 5.24e5.19 (m, 1H), 5.15 (br d, J¼4 Hz, 1H), 3.29 (ddt, J¼12.9, 5.2,
1.3 Hz, 1H), 4.21e4.12 (m, 2H), 3.97e3.93 (m, 1H), 3.70 (dd, J¼10.3,
5.8 Hz, 1H), 3.61 (dd, J¼10.3, 5.9 Hz, 1H), 3.44 (br s, 3H), 0.91 (s, 9H),
4.28. (3R,6S)-2-(Allyloxy)-6-(hydroxymethyl)-3,6-dihydro-2H-
0.08 (s, 6H). 13C NMR (CDCl3, 75 MHz) (major isomer
a) d 134.1,
pyran-3-ol (30)
127.8, 124.2, 118.0, 73.2, 69.7, 68.5, 65.5, 56.6, 25.9, ꢂ5.2, ꢂ5.3.
LRMS: [calcd 314.19]; found 314 [337.2¼MþNa]. LRMS calcd for
C16H30NaO4Si [MþNa] 337.18, found 337.2.
Under argon at 0 ꢀC, to a solution of LAH (70 mg, 1.82 mmol,
3 equiv) in THF (4 mL), a THF (1 mL) solution of compound 29
(200 mg, 0.61 mmol, 1 equiv) was added dropwise over 30 min.
After 1 h at the same temperature were added successively EtOAc
(0.1 mL), water (0.1 mL), heptane (6 mL), and finally a 15% NaOH
aqueous solution (0.1 mL). Then, the mixture is warmed up to room
temperature and stirred overnight. After filtration over Celite, the
reaction mixture is concentrated in vacuo. Purification by flash
column chromatography (silica gel, 40% EtOAc in cyclohexane)
provided the title compound (87 mg, 0.47 mmol, 77%) as a clear,
pale yellow oil. The compound was obtained as an anomeric mix-
4.31. ((2S,5R)-6-(Allyloxy)-5-methoxy-5,6-dihydro-2H-pyran-
2-yl)methanol (33)
To a solution of 32 (60 mg, 0.19 mmol,1 equiv) in anhydrous THF
(1 mL), underargonat 0 ꢀC, TBAF(1 M inTHF, 0.19 mmol,1 equiv)was
added dropwise. After 20 min at 0 ꢀC, the reaction mixture was
allowed to warm up to room temperature. After 90 min the reaction
was quenched with water (2 mL) and extracted with ether (2ꢁ2 mL).
Organic layers were combined, washed with brine, dried over
MgSO4, filtrated, and concentrated in vacuo. Purification by flash
column chromatography (silica gel, 20% EtOAc in cyclohexane)
provided the title compound (34 mg, 0.17 mmol, 89%) as a clear,
colorless oil. The compound was obtained as an anomeric mixture
ture with a 6:1 (a/b
) ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
a
)
d
6.03e5.87 (m, 1H), 5.82 (d, J¼10.6 Hz, 1H), 5.70 (d, J¼10.6 Hz,
1H), 5.32 (ddt, J¼17.2, 3.1, 1.5 Hz, 1H), 5.23 (ddt, J¼10.6, 2.5, 1.5 Hz,
1H), 5.08e5.07 (m, 1H), 4.30 (ddt, J¼12.8, 5.3, 1.3 Hz, 1H), 4.26e4.21
(m. 2H), 4.12 (ddt, J¼12.8, 6.2, 1.2 Hz, 1H), 3.73 (dd, J¼10.6, 3.1 Hz,
1H), 3.60 (dd, J¼11.5, 5.9 Hz, 1H), 2.09 (br s, 2H). 13C NMR (CDCl3,
with a 6:1 (a/b a)
) ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
d
6.04e5.91 (m, 1H), 5.86 (ddd, J¼10.7, 3.6, 1.6 Hz, 1H), 5.73 (dt, 10.7,
75 MHz) (major isomer
a
)
d
133.6, 128.8, 126.3, 117.9, 95.9, 69.1,
1.8 Hz,1H), 5.34 (ddt, J¼17.2, 3.0, 1.5 Hz,1H), 5.25e5.21 (m, 1H), 5.18
(br d, J¼3.9 Hz, 1H), 4.33e4.27 (m, 2H), 4.17 (ddt, J¼10.8, 6.6, 1.1 Hz,
1H), 3.99e3.96 (m,1H), 3.75 (dd, J¼11.5, 3.3 Hz,1H), 3.61 (dd, J¼11.5,
5.9 Hz, 1H), 3.44 (s, 3H), 1.89 (br s, 1H). 13C NMR (CDCl3, 75 MHz)
69.0, 64.8, 64.1. LRMS calcd for C9H15O4 [MþH] 187.10, found 187.1.
4.29. (3R,6S)-2-(Allyloxy)-6-((tert-butyldimethylsilyloxy)
methyl)-3,6-dihydro-2H-pyran-3-ol (31)
(major isomer a) d 133.9,126.5,125.7,118.1, 94.2, 73.1, 69.6, 68.7, 64.8,
56.6. HRMS calcd for C10H16NaO4 [MþNa] 223.0941, found 223.0940.
To alcohol 30 (80 mg, 0.43 mmol, 1 equiv) in solution in DMF
(1 mL) under argon at 0 ꢀC, imidazole (44 mg, 0.65 mmol, 1.5 equiv)
and TBDMSCl (72 mg, 0.48 mmol, 1.1 equiv) were added. Then the
reaction is allowed to warm up to room temperature and let like
this for 18 h. Then the mixture was diluted with ether (2 mL) and
washed with brine (2ꢁ1 mL). The aqueous phase was then
extracted thrice with ether (3ꢁ2 mL). The combined organic layers
were then washed with brine, dried over MgSO4, filtrated, and
concentrated in vacuo. Purification by flash column chromatogra-
phy (silica gel, 10% EtOAc in cyclohexane) provided the title com-
pound (93 mg, 0.31 mmol, 73%) as a clear, pale yellow oil. The
4.32. (3R,6S)-2-(Allyloxy)-6-(allyloxymethyl)-3-methoxy-3,6-
dihydro-2H-pyran (34)
Underargon at 0 ꢀC, toa solution of alcohol 33(50 mg, 0.25 mmol,
1 equiv) in DMF (1 mL) were added, respectively, dry NaH (10 mg,
0.41 mmol,1.5 equiv) and allyl bromide (29 mL, 0.33 mmol,1.3 equiv).
Then the reactionwas stirred at room temperature for 6 h, quenched
with NH4Cl(aq) (2 mL), and extracted with ethyl acetate (3ꢁ2 mL).
The organic layers were combined, dried over anhydrous MgSO4,
and concentrated in vacuo. Purification by flash column chroma-
tography (silica gel, 10% EtOAc in cyclohexane) provided the title
compound was obtained as an anomeric mixture with a 6:1 (
a/b)
ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
a
)
d
6.01e5.88 (m,
compound (53 mg, 0.22 mmol, 89%, colorless oil) as an
mixture of anomers. 1H NMR (CDCl3, 300 MHz) (major isomer
6.04e5.85 (m, 2H), 5.80e5.79 (m, 2H), 5.37e5.32 (m, 2H),
a/b (6:1)
1H), 5.83 (d, J¼10.5 Hz, 1H), 5.75 (d, J¼10.5 Hz, 1H), 5.31 (ddt,
a)
J¼17.2, 3.1, 1.6 Hz, 1H), 5.23 (ddt, J¼10.5, 2.6, 1.2 Hz, 1H), 5.04 (br d,
d

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
351
5.26e5.17 (m, 3H), 4.36e4.28 (m, 2H), 4.17 (dd, J¼12.9, 6.6 Hz, 1H),
4.06 (br d, 5.6 Hz, 2H), 4.00e3.98 (m, 2H), 3.51 (br d, J¼5.4 Hz, 1H),
added. The two reaction mixtures were combined, filtered, and
evaporated to dryness. The residue was chromatographed (AcOEt/
cyclohexane 8:2 then 9:1 then pure AcOEt) to yield the crude triol
3.43 (s, 3H).13C NMR (CDCl3, 75 MHz) (major isomer
a
)
d
134.5,134.0,
20
127.2, 124.8, 118.0, 117.4, 94.2, 73.1, 72.5, 72.0, 68.6, 68.2, 56.6. LRMS
calcd for C13H21O4 [MþH] 241.14, found 241.3.
37 (3.61 g, 97%). [
a
]
ꢂ66 (c 1.0, CHCl3) (compound not clean in
D
NMR). 1H NMR(400 MHz, CDCl3):
d
¼5.79 (ddd, J¼17.1, 10.3, 6.8 Hz,
1H), 5.11 (dq, J¼17.1, 1.5 Hz, 1H), 5.07 (dm, J¼10.1 Hz, 1H), 4.97 (br s,
1H), 4.38 (t, J¼5.3 Hz, 1H), 4.08 (dt, J¼5.5, 3.5 Hz, 1H), 4.07 (d,
J¼5.5 Hz, 1H), 3.81 (dd, J¼12.1, 3.3 Hz, 1H), 3.78 (dt, J¼9.6, 6.8 Hz,
1H), 3.67 (dd, J¼12.1, 3.8 Hz, 1H), 3.54 (dt, J¼9.6, 6.6 Hz, 1H), 2.34
4.33. (R)-2-((S)-3,6-Dihydro-2H-pyran-3-yloxy)-3-methoxy-
3,6-dihydro-2H-pyran (35)
Under argon, at 60 ꢀC, to a solution of 34 (50 mg, 0.21 mmol,
1 equiv) in degassed toluene (105 mL, c¼2.10ꢂ3 M), was added
(qt, J¼6.8, 1.1 Hz, 2H). 13C NMR (100.6 MHz, CDCl3)
¼134.7, 116.9,
d
107.3, 83.6, 75.3, 71.9, 67.6, 63.9, 33.9. HRMS calcd for C9H16NaO5
[Ru]-2 (10 mg, 11
m
mol, 5 mol %). The resulting mixture was stirred
[MþNa] 227.0890, found 227.0886.
at 60 ꢀC for 3 h, concentrated in vacuo, and purified by flash column
chromatography (silica gel, 5/10% EtOAc in cyclohexane) to pro-
vide 36 mg (0.17 mmol, 81%) of ring-rearranged product 35 as
a clear oil. The compound was obtained as an anomeric mixture
4.36. 3-Butenyl 2,3-O-isopropylidene-b-D-ribofuranoside (38)
To a stirred solution of crude triol 37 (2.848 g, 13.94 mmol) in
acetone (50 mL) and 2-methoxypropene (15 mL) at 0 ꢀC was added
a solution of PTSA (26 mg) in acetone (2 mL). After 10 min the re-
action was warmed to 20 ꢀC and stirred for 30 min (TLC, silica gel,
AcOEt/cyclohexane 3:7). When the starting material had dis-
appeared the reaction was quenched with MeOH (5 mL) and H2O
(2 mL), stirred 2 h at 20 ꢀC and neutralized with solid NaHCO3 (ca.
100 mg). The solvent was evaporated and the residue chromato-
with a 6:1 (a/b a)
) ratio. 1H NMR (CDCl3, 300 MHz) (major isomer
d
6.01e5.85 (m, 4H), 4.92 (d, J¼2.4 Hz, 1H), 4.24 (ddt, J¼16.8, 4.25,
2.1 Hz, 1H), 4.18e4.17 (m, 2H), 4.13e4.04 (m, 2H), 3.91 (dd, J¼11.8,
3.6 Hz, 1H), 3.81 (dd, J¼11.8, 3.5 Hz, 1H), 3.63e3.60 (m, 1H), 3.46 (s,
3H). 13C NMR (CDCl3, 75 MHz) (major isomer
a) d 130.5, 129.4,
125.0, 122.2, 97.8, 73.2, 67.8, 67.6, 65.1, 60.6, 56.9. HRMS calcd for
C11H16NaO4 [MþNa] 235.0941, found 235.0931.
graphed (AcOEt/cyclohexane 1:9) to yield acetonide 38 (2.912 g,
4.34. 3-Butenyl 2,4,6-tri-O-acetyl-
(36 anomer and anomer)
D-ribofuranoside
86%). [
a]
ꢂ67 (c 1.2, CHCl3). 1H NMR(400 MHz, CDCl3):
¼5.78
d
20
D
a
b
(ddt, J¼17.1, 10.1, 6.8 Hz, 1H), 5.12 (dq, J¼17.1, 1.7 Hz, 1H), 5.09 (dm,
J¼10.3 Hz, 1H), 5.07 (s, 1H), 4.85 (d, J¼5.8 Hz, 1H), 4.61 (d, J¼6.0 Hz,
1H), 4.42 (t, J¼2.6 Hz, 1H), 3.81 (dt, J¼9.6, 6.7 Hz, 1H), 3.70 (dd,
J¼12.6, 2.0 Hz, 1H), 3.61 (ddb, J¼12.8, 2.8 Hz, 1H), 3.57 (dt, J¼9.6,
6.6 Hz, 1H), 3.25 (br s, 1H, OH), 2.36 (qt, J¼6.6, 1.3 Hz, 2H), 1.49 (, s,
To a solution of 1,2,3,5-tetra-O-acetyl-D-ribofuranose (2.500 g,
7.85 mmol) (commercially available) in acetonitrile (40 mL) was
added 3-buten-1-ol (1.00 mL, 1.5 equiv). The reaction mixture was
cooled at 0 ꢀC and SnCl4 (1.8 mL, 15.4 mmol, 2.0 equiv) was added
slowly. After 20 min (TLC, silica gel, AcOEt/cyclohexane 4:6, for-
mation of two less polar compounds), the reaction was quenched
with aqueous NaHCO3 (5 mL).
3H), 1.32 (s, 3H). 13C NMR (100.6 MHz, CDCl3)
d¼134.3, 117.3, 112.0,
109.0, 88.0, 86.0, 81.5, 67.8, 64.0, 33.8, 26.3, 24.6. HRMS calcd for
C12H20NaO5 [MþNa] 267.1203, found 267.1209.
The same reaction was repeated four times and all the mixtures
were combined and extracted with CH2Cl2. The organic layer was
dried over MgSO4, filtered, and evaporated to dryness. The residue
4.37. 3-Butenyl 5-O-allyl-2,3-O-isopropylidene-b-D-
ribofuranoside (39)
was chromatographed (AcOEt/cyclohexane 2:8) to afford 36
b
(
b
A solution of acetonide 38 (3.005 g, 12.30 mmol) in DMF (30 mL)
was divided in three parts. To each one was added at 0 ꢀC NaH/oil
(55%) (400 mg, ca. 2 equiv). After 5 min the reaction was warmed to
anomer), (oil, 6.31 g, 63%) and the corresponding
oil, 1.24 g, 12%).
a anomer (36a,
36b: [
a
]
D
20 ꢂ27 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d¼5.79
20 ꢀC, allyl bromide (710
mL, 2 equiv) was added slowly and the
(ddt, J¼17.0, 10.2, 6.7 Hz, 1H), 5.33 (dd, J¼6.8, 4.8 Hz, 1H), 5.24 (db,
J¼4.5 Hz, 1H), 5.09 (dq, J¼17.1, 1.5 Hz, 1H), 5.05 (dm, J¼10.3 Hz, 1H),
5.01 (1H, s), 4.35e4.27 (m, 2H), 4.12 (dd, J¼13.3, 5.3 Hz, 1H), 3.77
(dt, J¼9.3, 6.8 Hz, 1H), 3.46 (dt, J¼9.3, 6.8 Hz, 1H), 2.32 (qt, J¼6.8,
1.3 Hz, 2H), 2.11 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H). 13C NMR
reaction was stirred for 40 min (TLC, silica gel, AcOEt/cyclohexane
3:7). The reaction was cooled to 0 ꢀC and hydrolysed with MeOH.
The three reaction mixtures were combined and poured in water,
extracted with CH2Cl2, dried over MgSO4, filtered, and evaporated
to dryness. The residue was chromatographed (AcOEt/cyclohexane
20
(100.6 MHz, CDCl3)
d
¼170.6, 169.6, 169.6, 134.6, 116.8, 105.1, 78.4,
0.5:9.5) to yield the allyl ether 39 (2.949 g, 84%). [
a]
ꢂ69 (c 1.0,
D
74.7, 71.6, 67.4, 64.7, 33.8, 20.8, 20.6, 20.5. HRMS calcd for
C15H22NaO8 [MþNa]: 353.1207, found 353.1207. Anal. Calcd for
C15H22O8: C 54.54; H 6.71, found C 54.67; H 6.74.
CHCl3). 1H NMR(400 MHz, CDCl3):
d
¼5.90 (ddt, J¼17.1, 10.3, 5.5 Hz,
1H), 5.80 (ddt, J¼17.1, 10.3, 6.8 Hz, 1H), 5.28 (dq, J¼17.1, 1.6 Hz, 1H),
5.19 (dq, J¼10.6, 1.3 Hz, 1H), 5.08 (dq, J¼17.1, 1.5 Hz, 1H), 5.06 (s, 1H),
5.04 (dm, J¼10.3 Hz, 1H), 4.68 (d, J¼5.8 Hz, 1H), 4.60 (d, J¼6.0 Hz,
1H), 4.32 (dd, J¼8.3, 6.8 Hz, 1H), 4.06e3.96 (m, 2H), 3.70 (dt, J¼9.6,
7.1 Hz, 1H), 3.50e3.40 (m, 3H), 2.30 (qd, J¼6.8, 1.3 Hz, 2H), 1.48 (s,
36a
: [
a]
20 þ141 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3):
d¼5.80
D
(ddt, J¼17.1, 10.3, 6.8 Hz, 1H), 5.26 (d, J¼4.5 Hz, 1H), 5.15 (dd, J¼7.3,
4.3 Hz,1H), 5.09 (dq, J¼17.1,1.6 Hz,1H), 5.04 (dm, J¼10.3 Hz,1H), 4.96
(dd, J¼7.3, 4.5 Hz,1H), 4.36 (dd, J¼11.8, 3.0 Hz,1H), 4.28 (q, J¼4.0 Hz,
1H), 4.20 (dd, J¼11.8, 4.3 Hz,1H), 3.78 (dt, J¼10.1, 6.8 Hz,1H), 3.57 (dt,
J¼10.1, 6.8 Hz,1H), 2.36 (qt, J¼6.8,1.1 Hz, 2H), 2.13 (s, 3H), 2.11 (s, 3H),
3H), 1.32 (s, 3H). 13C NMR (100.6 MHz, CDCl3):
d
¼135.0, 134.5, 117.2,
116.6, 112.3, 108.0, 85.2, 85.0, 82.2, 72.2, 71.0, 66.8, 33.8, 26.4, 24.9.
2.10 (s, 3H).13C NMR (100.6 MHz, CDCl3)
d
¼170.6,170.4,169.9,134.9,
4.38. 3-Butenyl 5-O-allyl- -ribofuranoside (40)
b-D
116.5, 100.4, 78.8, 70.7, 69.8, 67.7, 63.4, 34.0, 20.8, 20.7, 20.5. Anal.
Calcd for C15H22O8: C 54.54; H 6.71, found C 54.32; H 6.88.
To acetonide 39 (1.049 g, 3.69 mmol) cooled at ꢂ5 ꢀC was added
a cold (ꢂ5 ꢀC) mixture of TFA/H2O (7:3) (5 mL). The reaction was
stirred at ꢂ5/ꢂ3 ꢀC for ca. 3 h. The reaction was monitored by TLC
(silica gel, AcOEt/cyclohexane 6:4) and stopped by addition of cold
ethyl acetate when the spot at Rf¼0.25 corresponding to the desired
diol 40 became the majorone. Other products present in the reaction
4.35. 3-Butenyl b-D-ribofuranoside (37)
A solution of triacetate 36 (6.04 g, 18.3 mmol) in MeOH (120 mL)
was divided in two parts. To each one t-BuOK (42 mg) was added at
0
ꢀC and stirred under Ar. The reaction was gradually warmed to
mixture were 4-O-allyl-
material 39 (Rf¼0.70). The volatile components were evaporated at
D
-ribofuranose (Rf¼0.05) and the starting
20 ꢀC and stirred for 6 h. Ion exchange resin Dowex 50ꢁ8 (Hþ) was

352
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
0 ꢀC under reduced pressure at 0 ꢀC. The residue was diluted again
with AcOEt and the mixture was concentrated almost to dryness at
cyclohexane 2:8) to afford the thiocarbonyl derivate 44 (208 mg,
88%). 1H NMR(300 MHz, CDCl3):
d
¼5.75 (ddt, J¼10.6, 6.8 Hz, H), 5.37
0
ꢀC. Finally, the residue was diluted with toluene and the solvent
(d, J¼6.8 Hz, 1H), 5.32 (s, 1H), 5.24 (d, J¼6.8 Hz, 1H), 5.10 (dq, J¼17.2,
1.7 Hz,1H), 5.07 (dm, J¼10.4 Hz,1H), 4.63 (dd, J¼8.0, 6.4 Hz,1H), 4.19
(dd, J¼11.5, 8.0 Hz, H), 4.14 (dd, J¼11.6, 6.5 Hz, 1H), 3.75 (dt, J¼9.5,
6.8 Hz,1H), 3.52 (dt, J¼9.5, 6.2 Hz,1H), 2.32 (qt, J¼6.7,1.4 Hz, 2H), 2.11
(s, 3H). HRMS calcd for C12H16NaO6S [MþNa] 311.0560, found
311.0564.
was removed under reduced pressure at 20 ꢀC. Chromatography
(AcOEt/cyclohexane 6:4) gave the starting acetonide 39 (591 mg,
20%), the desired diol 40 (469 mg, 52%) and 4-O-allyl-
D
-ribofuranose
(156 mg, 22%). 40: 1H NMR(400 MHz, CDCl3):
d
¼5.91 (ddt, J¼17.1,
10.3, 5.8 Hz, 1H), 5.79 (ddt, J¼17.0, 10.3, 6.7 Hz, 1H), 5.29 (dq, J¼17.1,
1.5 Hz, 1H), 5.20 (dq, J¼10.3, 1.5 Hz, 1H), 5.08 (dq, J¼17.1, 1.8 Hz, 1H),
5.04 (dm, J¼10.3 Hz, 1H), 4.96 (s, 1H), 4.24 (dd, J¼6.4, 4.9 Hz, 1H),
4.09e4.04 (m, 4H), 3.75 (dt, J¼9.6, 6.9 Hz,1H), 3.62 (dd, J¼9.8, 5.9 Hz,
1H), 3.56 (dd, J¼9.8, 5.8 Hz, 1H), 3.45 (dt, J¼9.6, 6.7 Hz, 1H), 2.31 (qt,
4.42. 3-Butenyl 2,3-O-thiocarbonyl-b-D-ribofuranoside (45)
To a solution of 44 (315 mg, 1.09 mmol) in MeOH was added
solid Na2CO3 (25 mg) and the heterogeneous mixture was stirred at
20 ꢀC for 1 h (monitoring by TLC, silica gel, AcOEt/cyclohexane 2:8).
The reaction was poured in a concentrated solution of NH4Cl in
water and extracted with CH2Cl2. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The residue
was chromatographed (AcOEt/cyclohexane 2:8) to yield 45
J¼6.8,1.3 Hz, 2H). 13C NMR(100.6 MHz, CDCl3):
¼134.9,134.4,117.5,
d
116.5, 107.1, 81.6, 75.0, 72.8, 72.4, 72.1, 67.1, 33.9. HRMS calcd for
C12H20NaO5 [MþNa] 267.1203, found 267.1203.
4.39. 3-Butenyl 5-O-allyl-2,3-O-thiocarbonyl-b-D-
ribofuranoside (41)
(181 mg, 60%). 1H NMR (300 MHz, CDCl3):
d
¼5.77 (ddt, J¼17.2, 10.3,
To a solution of diol 40 (1.318 g, 5.39 mmol) in CH2Cl2 (40 mL)
was added 1,10-thiocarbonyldiimidazole (1.442 g, 8.09 mmol,
1.5 equiv). After stirring at 20 ꢀC for 24 h, the solvent was removed
under vacuum and the residue was chromatographed (AcOEt/cy-
6.9 Hz,1H), 5.50 (d, J¼6.7 Hz,1H), 5.32 (s,1H), 5.22 (d, J¼6.7 Hz,1H),
5.15 (dq, J¼17.2, 1.7 Hz, 1H), 5.13 (dm, J¼10.3 Hz, 1H), 4.70 (t,
J¼2.9 Hz, 1H), 3.87 (dt, J¼9.5, 6.7 Hz, 1H), 3.80e3.71 (m, 2H), 3.67
(dt, J¼9.5, 6.2 Hz, 1H), 3.08 (dd, J¼10.0, 4.1 Hz, 1H), 2.39 (qt, J¼6.4,
clohexane 2:8) to yield the thiocarbonyl derivative 41 (1.342 g,
1.2 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
89.0, 87.1, 86.5, 68.6, 63.0, 33.6.
d¼189.7, 133.7, 117.9, 106.8,
20
87%). [
a
]
ꢂ82 (c 1.1, CHCl3). IR (neat, cmꢂ1
) n 2945, 2866, 1363,
D
1348, 1304, 1277, 1252, 1158, 1102, 1063. 1H NMR(400 MHz, CDCl3):
d
¼5.88 (ddt, J¼17.2, 10.4, 5.6 Hz, 1H), 5.75 (ddt, J¼17.0, 10.2, 6.8 Hz,
4.43. 3-Butenyl 5-O-acryloyl-2,3-O-thiocarbonyl-b-D-
ribofuranoside (46)
1H), 5.38 (d, J¼6.8 Hz, 1H), 5.29 (s, 1H), 5.28 (dq, J¼17.1, 1.5 Hz, 1H),
5.22 (dq, J¼10.3, 1.3 Hz, 1H), 5.21 (d, J¼6.8 Hz, 1H), 5.10 (dq, J¼17.1,
1.5 Hz, 1H), 5.07 (dm, J¼10.3 Hz, 1H), 4.59 (dd, J¼9.3, 5.8 Hz, 1H),
4.03 (ddt, J¼12.8, 5.8, 1.5 Hz, 1H), 3.99 (ddt, J¼12.8, 5.8, 1.5 Hz, 1H),
3.72 (dt, J¼9.6, 6.8 Hz, 1H), 3.54 (dd, J¼10.1, 5.8 Hz, 1H), 3.50 (dt,
J¼9.6, 6.6 Hz, 1H), 3.46 (t, J¼9.7 Hz, 1H), 2.31 (qt, J¼6.7, 1.4 Hz, 2H).
To a solution of alcohol 45 (140 mg, 0.57 mmol) in CH2Cl2 (5 mL)
was added acryloyl chloride (55 L, 1.2 equiv) and N,N-diisopro-
pylethylamine (300
L) and the reaction was stirred at 20 ꢀC for 1 h
m
m
under Ar (TLC, silica gel, AcOEt/cyclohexane 2:8). The mixture was
poured in a diluted aqueous solution of NH4Cl, extracted with
CH2Cl2, the organic layer was dried over MgSO4, filtered and the
solvent was removed. The residue was chromatographed (AcOEt/
cyclohexane 2:8) to yield 46 (100 mg, 59%). 1H NMR (300 MHz,
13C NMR (100.6 MHz, CDCl3):
d
¼189.9, 134.3, 133.9, 117.7, 117.1,
106.3, 88.4, 86.5, 83.8, 72.2, 69.2, 67.6, 33.6. HRMS calcd for
C13H19O5S [MþH] 287.0948, found 287.0964.
4.40. 3-Butenyl 5-O-acetyl-
b
-
D
-ribofuranoside (43)
anomer, 454 mg, 1.37 mmol) in
CDCl3):
d
¼6.47 (dd, J¼17.2, 1.2 Hz, H), 6.14 (dd, J¼17.2, 10.5 Hz, 1H),
5.93 (dd, J¼10.5, 1.2 Hz, 1H), 5.75 (ddt, J¼17.2, 10.5, 6.9 Hz, 1H), 5.39
(d, J¼6.7 Hz,1H), 5.33 (s, 1H), 5.25 (d, J¼6.7 Hz,1H), 5.09 (dq, J¼17.2,
1.7 Hz, 1H), 5.08 (dm, J¼10.3 Hz, 1H), 4.68 (t, J¼7.2 Hz, 1H), 4.28 (dd,
J¼11.7, 8.1 Hz, 1H), 4.23 (dd, J¼11.7, 6.7 Hz, 1H), 3.76 (dt, J¼9.5,
6.9 Hz, 1H), 3.52 (dt, J¼9.5, 6.7 Hz, 1H), 2.32 (qt, J¼6.7, 1.2 Hz, 2H).
To a solution of triacetate 36 (
b
MeOH (17 mL) at 0 ꢀC was added potassium tert-butoxide (10 mg).
The reaction was stirred under Ar for ca. 45 min and carefully
monitored by TLC (silica gel, AcOEt/cyclohexane 6:4). Four spots
gradually appeared. By order of increasing polarity: the starting
material, a monodeacylated compound, the desired diol 43 and the
fully deacylated sugar 37. When the spot corresponding to the diol
became the major one, the reaction was stopped by addition of
Dowex Hþ. The resin was filtered-off and the solvent was evapo-
rated. The residue was chromatographed (AcOEt/cyclohexane 6:4)
to afford successively 36 (14 mg, 3%), a diacetate (5 mg, 1%), 43
(208 mg, 61%), and the triol 37 (72 mg, 26%).
4.44. (5-But-3-enoxy-2,5-dihydrofuran-2-yl)methyl prop-2-
enoate (47)
A solution of thiocarbonate 46 (100 mg, 0.33 mmol) in P(OMe)3
was stirred in an oil bath at 122 ꢀC for 2 h. Progress of the reaction
was controlled by 1H NMR of aliquots. The solvent was thoroughly
removed under vacuum at 60 ꢀC to afford crude 47. 1H NMR
Compound 43: 1H NMR (300 MHz, CDCl3):
d
¼5.79, (ddt, J¼17.0,
(300 MHz, CDCl3):
d
¼6.46 (dd, J¼17.4, 1.5 Hz, 1H), 6.16 (dd,
10.3, 6.7 Hz, 1H), 5.09 (dq, J¼17.2, 1.7 Hz, 1H), 5.05 (dm, J¼10.3 Hz,
1H), 4.96 (s, 1H), 4.35e4.05 (m, 5H), 3.76 (dt, J¼9.5, 6.7 Hz, 1H), 3.45
(dt, J¼9.5, 6.9 Hz, 1H), 2.58 (dd, J¼3.8, 1.7 Hz, 1H), 2.52 (dd, J¼7.2,
1.9 Hz, 1H), 2.31 (qt, J¼6.7, 1.2 Hz, 2H), 2.11 (s, 3H).
J¼17.2 Hz, 1H), 6.15 (dt, J¼6.0, 1.2 Hz, 1H), 5.93 (ddd, J¼6.0, 2.2,
1.0 Hz, 1H), 5.86 (dd, J¼10.3, 1.4 Hz, 1H), 5.81 (ddt, J¼17.2, 10.3,
6.7 Hz, 1H), 5.31 (s, 1H), 5.10 (dq, J¼17.2, 1.4 Hz, 1H), 5.03 (dm,
J¼10.3 Hz, 1H), 4.93 (m, 1H), 4.32 (dd, J¼11.4, 3.8 Hz, H), 4.17 (dd,
J¼11.7, 6.2 Hz,1H), 3.79 (dt, J¼9.5, 6.9 Hz,1H), 3.58 (dt, J¼9.3, 6.7 Hz,
1H), 2.35 (qt, J¼5.5, 1.2 Hz, 2H).
4.41. 3-Butenyl 5-O-acetyl-2,3-O-thiocarbonyl-b-D-
ribofuranoside (44)
4.45. (S)-3-[[(6R)-3,6-Dihydro-2H-pyran-6-yl]oxy]-3,6-
dihydro-2H-pyran (48)
Toa solutionof diol 43(201 mg, 0.82 mmol)in CH2Cl2 (15 mL)was
added thiocarbonyldiimidazole (150 mg, 0.84 mmol) and the re-
action was stirred under Ar at 20 ꢀC and monitored by TLC (silica gel,
AcOEt/cyclohexane 5:5). After 3 h, more thiocarbonyldiimidazole
(150 mg) was added and stirring was continued for 2 h. The solvent
was evaporated and the residue chromatographed (AcOEt/
A solution of thiocarbonyl derivative 41 (715 mg, 2.50 mmol) in
trimethylphosphite was heated under Ar at 115 ꢀC for ca. 4 h. Prog-
ress of the reaction was controlled by 1H NMR of aliquots after
evaporation of the solvent. The reaction mixture was concentrated

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
353
under vacuum and the crude 42 (470 mg) was diluted in benzene
(200 mL) and divided in two parts. To each part, [Ru]-2 catalyst
(45 mg) was added and the solution was heated to 60 ꢀC and stirred
for 30 min at which time formation of a more polar compound was
observed (TLC, silica gel, AcOEt/cyclohexane 2:8). After evaporation
of the solvents, the two residues were combined and chromato-
graphed to yield the bis-dihydropyran 48 (266 mg, 58% over two
steps).
(795 mg, 8.27 mmol) was added rapidly under stirring. After 15 min
a solution of bis-dihydropyran 48 (124 mg, 0.68 mmol) in CH2Cl2
(2 mL) was added. After stirring at ꢂ20 ꢀC for 2 h, the reaction
mixture was quickly filtered over silica gel (eluent: AcOEt). The
filtrate was evaporated and the residue immediately chromato-
graphed (AcOEt/cyclohexane 4:6) to yield lactone 52 (83 mg, 62%).
1H NMR (400 MHz, C6D6):
d¼6.05 (dd, J¼10.1, 3.8 Hz, 1H), 5.69 (dd,
J¼10.1, 1.1 Hz, 1H), 5.63 (ddm, J¼10.2, 5.8 Hz, 1H), 5.46 (dtd, J¼10.1,
2.8, 1.3 Hz, 1H), 4.69 (s, 1H), 4.06 (ddd, J¼11.6, 6.0, 0.5 Hz, 1H), 3.97
(ddd, J¼11.6, 4.5, 0.5 Hz, 1H), 3.63 (m, 1H), 3.53 (td, J¼11.6, 3.6 Hz,
1H), 3.28 (dd, J¼11.1, 6.1 Hz, 1H), 1.88 (m, 1H), 1.27 (dm, J¼17.9 Hz,
Compound 42: 1H NMR(300 MHz, C6D6):
d¼5.88e5.73 (m, 3H),
5.70 (q, J¼1.1 Hz, 1H), 5.58 (ddd, J¼6.0, 2.3, 1.1 Hz, 1H), 5.20 (dq,
J¼17.3,1.7 Hz,1H), 5.05 (dm, J¼12.2 Hz,1H), 5.02e4.97 (m, 2H), 4.84
(tm, J¼6.2 Hz, 1H), 3.84e3.77 (m, 3H), 3.53 (dd, J¼9.6, 6.2 Hz, 1H),
3.48e3.31 (m, 2H), 2.30 (qt, J¼6.6, 1.5 Hz, 2H). HRMS calcd for
1H). 13C NMR (100.6 MHz, C6D6):
94.2, 70.5, 66.6, 57.3, 24.6.
d¼162.1, 144.3, 129.4, 125.7, 122.4,
C12H18NaO3 [MþNa] 233.1148, found 233.1147.
20
Compound 48: [
a
]
þ75 (c 1.0, CHCl3). 1H NMR(400 MHz,
4.48. (5S)-5-[(2R)-Tetrahydropyran-2-yl]oxytetrahydropyran-
2-one (53)
D
C6D6):
d
¼5.85 (dq, J¼10.3, 2.5 Hz, 1H), 5.68 (d, AB, J¼10.1 Hz, 1H),
5.65 (d, AB, J¼10.1 Hz,1H), 5.47 (dtd, J¼10.6, 2.6,1.5 Hz,1H), 5.02 (br
s, 1H), 4.15 (m, 1H), 4.07 (dd, J¼11.3, 4.5 Hz, 1H), 3.88 (dq, J¼16.6,
2.3 Hz, 1H), 3.87e3.78 (m, 2H), 3.79 (dq, J¼16.9, 2.5 Hz, 1H), 3.43
(dd, J¼10.8, 6.1 Hz, 1H), 1.96 (ddd, J¼17.6, 11.6, 5.8 Hz, 1H), 1.34 (dt,
A solution of lactone 52 (233 mg, 1.19 mmol) in AcOEt (14 mL)
was hydrogenated for 16 h at atmospheric pressure (1 atm) in
presence of Pd/C 10% (80 mg). The reaction mixture was filtered
over Celite and the solvent was evaporated. Chromatography (silica
gel, AcOEt/cyclohexane 4:6) afforded 53 (138 mg, 58%). IR (neat,
J¼17.9, 3.3 Hz, 1H). 13C NMR (100.6 MHz, C6D6):
¼129.6, 128.6,
d
126.9, 126.1, 93.9, 69.5, 69.2, 65.1, 57.2, 24.9. HRMS calcd for
C10H14NaO3 [MþNa] 205.035, found 205.0832.
cmꢂ1
) n
3407, 2942, 2868, 1710, 1134, 1072, 1021, 988. 1H NMR
(400 MHz, C6D6):
d
¼4.33 (t, J¼3.5 Hz, 1H), 4.09 (ddd, J¼11.8, 4.0,
4.46. (3S)-3-[[(2R)-3,4-Dihydro-2H-pyran-2-yl]oxy]-3,4-
dihydro-2H-pyran (49) and (3S)-3-[[(6R)-3,6-dihydro-2H-
pyran-6-yl]oxy]-3,4-dihydro-2H-pyran (50)
1.8 Hz, 1H), 3.75 (dd, J¼11.8, 3.5 Hz, 1H), 3.59 (ddd, J¼11.3, 9.1,
2.8 Hz, 1H), 3.37 (quint., J¼4.3 Hz, 1H), 3.24 (dtd, J¼11.1, 4.4, 1.3 Hz,
1H), 2.29 (ddd, J¼17.1, 9.6, 7.0 Hz, 1H), 1.96 (ddd, J¼17.1, 6.8, 5.5 Hz,
1H), 1.62e1.53 and 1.43e1.10 (m, 8H). 13C NMR (100.6 MHz, C6D6)
To a solution of bis-dihydropyran 48 (64 mg, 0.35 mmol) in
toluene (2 mL) was added isopropanol (0.25 mL), solid NaOH
(∼9 mg), and [Ru]-2 catalyst (∼1.5 mg). The reaction was heated at
110 ꢀC for 0.5e1 h. The progress of the reaction was monitored by
TLC (silica gel, AcOEt/cyclohexane 2:8, 50: Rf ∼0.50, 48: Rf ∼0.62):
when the spot corresponding to 50 became the major one the re-
action was cooled to 20 ꢀC and ethyl acetate was added. Prolonged
reaction times lead to increased formation of the apparently ther-
modynamically favored 49 at the expense of 50 while 48 is still
present in the mixture. After washing with water, the organic layer
was dried over MgSO4, filtered, and evaporated. The residue was
chromatographed (AcOEt/cyclohexane 0.5:9.5 then 1:9) to yield 49
(10 mg, 16%), a mixture of 49 and 50 (8 mg, 12%), pure 50 (21.5 mg,
34%), and remaining 48 (6.5 mg, 10%).
d
¼169.3, 97.3, 72.0, 67.7, 62.0, 31.0, 26.7, 25.6, 24.5, 19.4. HRMS calcd
for C10H16NaO4 [MþNa] 223.0941, found 223.0938.
4.49. (5S)-5-[(2R)-Tetrahydropyran-2-yl]oxytetrahydropyran-
2-ol (54)
To a cold (ꢂ78 ꢀC) solution of lactone 53 (99 mg, 0.494 mmol) in
dry toluene (9 mL), DIBAL-H (1 M in toluene, 0.66 mL) was added
under stirring. Stirring at ꢂ78 ꢀC was continued for 45 min after
which time more DIBAL-H (0.33 mL) was added. After an additional
1.5 h the reaction was quenched with Rochelle salt (3 mL), allowed to
warm to 20 ꢀC, neutralized with saturated NaHCO3 (6 mL), and
extracted with Et2O (three times). The organic layer was dried over
MgSO4, filtered, and evaporated. The residue was chromatographed
(silicagel, AcOEt/cyclohexane4:6)toyieldthepolydeoxydisaccharide
54 (69 mg, 69%, as a mixture of two anomers (Mþm) in the ratio of
0.55: 0.45) (M¼Major product, m¼minor product). 1H NMR
Compound 49: 1H NMR(400 MHz, C6D6):
d¼6.33 (dt, J¼6.0,
2.0 Hz, 1H), 6.14 (ddd, J¼6.0, 1.8, 1.3 Hz, 1H), 4.86 (t, J¼3.0 Hz, 1H),
4.60 (m,1H), 4.43 (ddd, J¼6.0, 4.8, 3.0 Hz,1H), 4.21 (ddd, J¼10.3, 3.5,
2.0 Hz, 1H), 3.97 (m, 1H0), 3.72 (dd, J¼10.0, 9.0 Hz, 1H), 2.10e2.00
(m, 2H), 1.94 (ddt, J¼16.6, 7.7, 2.5 Hz, 1H), 1.67e1.49 (m, 3H). 13C
(400 MHz, C6D6):
d¼4.80 (t, J¼3.1 Hz, 1H,), 4.71 (m,1H), 4.63 (t,
J¼3.6 Hz, 1H), 4.56 (t, J¼3.5 Hz, 1H), 4.20 (m,1H), 4.05 (dd, J¼11.1,
8.5 Hz, 1H), 3.85 (ddd, J¼10.8, 4.1, 1.6 Hz, 1H), 3.78 (dt, J¼8.8, 3.1 Hz,
1H), 3.76 (dt, J¼8.8, 3.1 Hz,1H), 3.67e3.56 (m, 3H), 3.35e3.28 (m, 2H),
NMR (100.6 MHz, C6D6):
d
¼144.2, 140.7, 101.7, 97.3, 95.8, 69.4, 68.5,
27.2, 26.9, 16.3. HRMS calcd for C10H14NaO3 [MþNa] 205.0835,
found 205.0831.
1.9e1.2 (m). 13C NMR (100.6 MHz, C6D6):
d¼97.4 (m), 97.1 (M), 94.2
Compound 50: 1H NMR(400 MHz, C6D6):
d
¼6.36 (dt, J¼6.0,
(m), 92.2 (M), 70.6 (M), 70.5 (M), 66.6 (m), 65.1 (M), 62.01 (m), 61.98
(M), 31.3 (m), 31.2 (M), 29.5 (M), 29.0 (m), 25.8 (2C) (Mþm), 25.3 (m),
24.9 (M), 19.7 (m), 19.6 (M). HRMS calcd for C10H17O3 [(MþH)ꢂH2O]
185.1172, found 185.1163.
2.0 Hz, 1H), 5.67 (dd, J¼10.0, 5.3 Hz, 1H), 5.61 (dt, J¼10.5, 2.5 Hz,
1H), 4.97 (s, 1H), 4.45 (ddd, J¼6.0, 4.5, 3.0 Hz, 1H), 4.23 (ddd, J¼10.3,
3.3, 1.8 Hz, 1H), 3.97e3.90 (m, 1H), 3.81 (t, J¼9.5 Hz, 1H), 3.77 (td,
J¼11.3, 3.5 Hz, 1H), 3.42 (dd, J¼10.9, 6.2 Hz, 1H), 2.12e2.04 (m, 1H),
2.01e1.90 (m, 2H), 1.34 (ddd, J¼17.6, 4.8, 4.0 Hz, 1H). 13C NMR
4.50. 3-Butenyl 2,3-O-isopropylidene-5-O-(2,3,5-tri-O-acetyl-
b-D-ribofuranosyl)-b-D-ribofuranoside (55)
(100.6 MHz, C6D6):
d
¼144.2, 128.6, 126.8, 97.6, 93.5, 69.6, 68.8, 57.2,
27.2, 24.9. HRMS calcd for C10H14NaO3 [MþNa] 205.0835, found
205.0830.
A solution of acetonide 38 (0.963 g, 3.94 mmol) and commercial
1,2,3,5-tetra-O-acetyl- -ribofuranose (1.50 g, 4.73 mmol,
1.20 equiv) in acetonitrile (25 mL) was stirred at 0 ꢀC, under Ar.
SnCl4 (276 L) was slowly dripped along the wall of the flask during
b-D
4.47. (3S)-3-[[(6R)-3,6-Dihydro-2H-pyran-6-yl]oxy]-2,3-
dihydropyran-6-one (52)
m
which formation of a white solid was observed. The reaction was
monitored by TLC (silica gel, AcOEt/cyclohexane 4:6, the spot cor-
responding to 55 appears between those of the starting materials)
and was complete after 15e20 min. The reaction was quenched
Powdered CrO3 (824 mg, 8.24 mmol) previously dried under
vacuum over P2O5 was suspended in dry CH2Cl2 (7 mL) under Ar.
The mixture was cooled at ꢂ20 ꢀC and 3,5-dimethylpyrazole

354
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
with aqueous NaHCO3 and extracted with CH2Cl2. The organic layer
was washed with water, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Chromatography of the residue
(AcOEt/cyclohexane 2:8) afforded the protected disaccharide 55
1.5 Hz, 1H), 5.09 (dq, J¼17.1, 1.5 Hz, 1H), 5.05 (dm, J¼10.3 Hz, 1H),
4.68 (dd, J¼6.0, 0.8 Hz, 1H), 4.65 (d, J¼6.0 Hz, 1H), 4.59 (s, 2H), 4.35
(ddd, J¼7.8, 6.8, 0.8 Hz, 1H), 4.26 (t, J¼7.3 Hz, 1H), 4.01 (dq, J¼5.5,
1.3 Hz, 2H), 3.70 (dt, J¼9.6, 6.8 Hz, 1H), 3.65 (dd, J¼10.1, 7.8 Hz, 1H),
3.48 (dd, J¼9.6, 6.6 Hz, 1H), 3.46e3.39 (m, 3H), 2.29 (qt, J¼6.6,
1.3 Hz, 2H), 1.48 (s, 3H), 1.32 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
(0.963 g, 46%). [
a]
20 ꢂ63 (CHCl3, c 1.0). IR (neat, cmꢂ1
)
n
2982, 2939,
¼5.77
D
1745, 1371, 1214, 1085, 1043. 1H NMR (400 MHz, CDCl3):
d
(ddt, J¼17.1, 10.3, 6.7 Hz, 1H), 5.34 (dd, J¼6.7, 4.8 Hz, 1H), 5.26 (dd,
J¼4.8,1.0 Hz,1H), 5.07 (dq, J¼17.4,1.7 Hz,1H), 5.06 (s,1H), 5.04 (br s,
1H), 5.04 (dm, J¼10.3 Hz, 1H), 4.64 (br d, J¼6.0 Hz, 1H), 4.60 (d,
J¼6.0 Hz,1H), 4.34e4.27 (m, 3H), 4.17e4.11 (m,1H), 3.70 (dd, J¼10.1,
8.1 Hz, 1H), 3.69 (dt, J¼9.6, 6.8 Hz, 1H), 3.50 (dd, J¼10.1, 6.6 Hz, 1H),
3.42 (dt, J¼9.6, 6.6 Hz, 1H), 2.29 (qt, J¼6.8, 1.3 Hz, 2H), 2.11 (s, 3H),
2.10 (s, 3H), 2.06 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H). 13C NMR
d
¼134.9, 134.5, 117.4, 116.7, 112.4 (2C), 108.5, 108.0, 85.2, 85.2 (2C),
85.1, 82.1, 82.0, 72.2, 70.9, 68.8, 66.9, 33.8, 26.4 (2C), 25.0, 24.9.
HRMS calcd for C23H36NaO9 [MþNa] 479.2252, found 479.2258.
4.54. 3-Butenyl 5-O-(5-O-allyl-b-D-ribofuranosyl)-b-D-
ribofuranoside (59)
(100.6 MHz, CDCl3):
d
¼170.6, 169.6, 169.5, 134.9, 116.6, 112.4, 108.1,
The protected disaccharide 58 (466 mg, 0.102 mmol) was placed
in a round-bottomed flask and cooled to ꢂ5 ꢀC. A cold (ꢂ5 ꢀC)
mixture of TFA/H2O (7:3, 6 mL) was added and the reaction mixture
was stirred. Monitoring of the reaction (TLC, silica gel, AcOEt/cy-
clohexane 6:4) revealed transient formation of a compound
(Rf¼0.28; AcOEt, Rf¼0.54), presumably a diol, then of the more
polar 59 (AcOEt, Rf¼0.15). When 59 became the main product
according to TLC, cold AcOEt (6 mL) was added and the solvent was
evaporated at 0 ꢀC (high vacuum necessary). This operation was
repeated twice and the residue was dissolved in toluene and
evaporated at 20 ꢀC. Chromatography (AcOEt) afforded crude 59
105.3, 85.1, 84.8, 81.9, 78.6, 74.7, 71.3, 69.2, 66.9, 64.4, 33.8, 26.3,
24.9, 20.7, 20.5, 20.5. HRMS calcd for C23H34NaO12 [MþNa]
525.1943, found 525.1949.
4.51. 3-Butenyl 2,3-O-isopropylidene-5-O-(-
b-D-
ribofuranosyl)- -ribofuranoside (56)
b-D
A solution of 55 (1.271 g, 2.53 mmol) in MeOH (35 mL) was
placed under argon atmosphere and maintained at 20 ꢀC. t-BuOK
(12 mg) was added and the reaction was stirred for 6 h (monitoring:
TLC, silica gel, AcOEt/cyclohexane 5:5). Quenching (Dowex Hþ)
followed by evaporation of the solvent afforded the crude 56
(172 mg, 45%). 1H NMR (300 MHz, CDCl3):
d¼5.91 (ddt, J¼17.2, 10.6,
5.8 Hz, 1H), 5.78 (ddt, J¼17.1, 10.2, 6.8 Hz, 1H), 5.30 (dq, J¼17.2,
1.1 Hz, 1H), 5.22 (dq, J¼10.3, 1.1 Hz, 1H), 5.09 (dq, J¼17.1, 1.4 Hz, 1H),
5.04 (dm, J¼10.3 Hz, 1H), 5.02 (1H, s), 4.93 (s, 1H), 4.22 (t, J¼5.4 Hz,
1H), 4.16e4.01 (m), 3.81e3.39 (m), 2.30 (br q, J¼6.7 Hz, 2H).
(0.947 g, 99%). 1H NMR (300 MHz, CDCl3)
d¼5.77 (ddt, J¼17.2, 10.3,
6.7 Hz, 1H), 5.09 (s, 1H), 5.09 (dq, J¼17.2, 1.8 Hz, 1H), 5.04 (dm,
J¼10.0 Hz, 1H), 4.98 (s, 1H), 4.63e4.59 (m, 2H), 4.47e4.39 (m, 2H),
4.08e4.02 (m, 2H), 3.87 (dd, J¼12.4, 2.9 Hz, 1H), 3.73 (dt, J¼9.5,
6.7 Hz, 1H), 3.70e3.59 (m, 3H), 3.43 (dt, J¼9.5, 6.7 Hz, 1H), 2.30 (qt,
J¼6.7, 1.2 Hz, 2H), 1.48 (s, 3H), 1.32 (s, 3H).
4.55. 3-Butenyl 5-O-(5-O-allyl-2,3-O-thiocarbonyl-
b-D-
ribofuranosyl)-2,3-O-thiocarbonyl -ribofuranoside (60)
b-D
4.52. 3-Butenyl 2,3-O-isopropylidene-5-O-(2,3-O-
isopropylidene-b-D-ribofuranosyl)-b-D-ribofuranoside (57)
Under argon atmosphere, a solution of 59 (172 mg, 0.457 mmol)
and thiocarbonyldiimidazole (300 mg, 3.7 equiv) in dry (dist. over
CaH2) CH2Cl2 (5 mL) was stirred for 4 h. The solvent was removed
A solution of crude 56 (1.895 g, 5.034 mmol) and p-toluene-
sulfonic acid (50 mg) in acetone (26 mL) and 2-methoxypropene
(13 mL) was stirred for 3 h at 20 ꢀC (monitoring: TLC, silica gel,
AcOEt/cyclohexane 8:2 and 3:7). Methanol (5 mL) and water (1 mL)
were added and the reaction was stirred for 2 h. Solid NaHCO3 (ca.
100 mg), was added. After filtration, the solvent was evaporated
and the residue was chromatographed (silica gel: AcOEt/cyclo-
hexane 2:8) to yield 57 (702 mg, 33% over two steps). 1H NMR
and the residue chromatographed (AcOEt/cyclohexane 2:8) to give
D20
pure 60 (169 mg, 0.367 mmol, 80%). Mp: 119e124 ꢀC. [
a]
ꢂ90
(CHCl3, c 1.0). IR (neat, cmꢂ1
)
n
2950, 2879, 1357, 1320, 1300, 1279,
¼5.88
1244, 1158, 1101, 1051, 1002. 1H NMR (400 MHz, CDCl3):
d
(ddt, J¼17.1, 10.3, 5.5 Hz, 1H), 5.75 (ddt, J¼17.1, 10.3, 6.8 Hz, 1H), 5.39
(d, J¼6.8 Hz, 1H), 5.33e5.23 (m, 4H), 5.32 (s, 1H), 5.30 (s, 1H), 5.18
(d, J¼6.8 Hz, 1H), 5.11 (dq, J¼17.1, 1.5 Hz, 1H), 5.10 (dm, J¼10.3 Hz,
1H), 4.67 (t, J¼6.6 Hz, 1H), 4.53 (dd, J¼8.3, 6.8 Hz, 1H), 4.03 (dt,
J¼5.5, 1.1 Hz, 1H), 3.76e3.69 (m, 2H), 3.63 (dd, J¼10.3, 6.6 Hz, 1H),
3.57 (dd, J¼10.3, 6.0 Hz, 1H), 3.53 (dt, J¼9.6, 6.3 Hz, 1H), 3.48 (dd,
J¼10.3, 7.5 Hz, 1H), 2.32 (qt, J¼6.6, 1.2 Hz, 2H). 13C NMR (100.6 MHz,
(300 MHz, CDCl3):
d
¼5.78 (ddt, J¼17.2, 10.3, 6.7 Hz, 1H), 5.12 (s, 1H),
5.10 (s, 1H), 5.09 (dm, J¼17.2 Hz, 1H), 5.04 (dm, J¼10.1 Hz, 1H), 4.79
(d, J¼6.0 Hz, 1H), 4.65 (d, J¼7.2 Hz, 1H), 4.61 (d, J¼6.0 Hz, 1H), 4.56
(dl, J¼6.2 Hz, 1H), 4.45e4.39 (m, 2H), 3.77e3.60 (m, 5H), 3.45 (dt,
J¼9.5, 6.4 Hz, 1H), 1.49 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
CDCl3):
d
¼189.5, 189.5, 134.1, 133.7, 118.1, 117.5, 107.1, 106.3, 88.4,
88.2, 86.2, 85.9, 84.4, 83.7, 72.3, 69.2, 68.2, 67.9, 33.6. HRMS calcd
for C19H24NaO9S2 [MþNa] 483.0754, found 483.0758.
4.53. 3-Butenyl 2,3-O-isopropylidene-5-O-(5-O-allyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-b-D-ribofuranoside (58)
4.56. Attempted RRM of 60
To a stirred solution of 57 (700 mg, 1.68 mmol) in DMF (8 mL) at
0 ꢀC was added NaH (55% in oil) (200 mg). After 5 min the reaction
A solution of 60 (53 mg, 0.11 mmol) in P(OMe)3 (3 mL) was
placed under Ar atmosphere and heated at 115 ꢀC for 3.25 h. The
solvent was evaporated under vacuum and the resulting crude
tetraene 61 was dissolved in dry benzene (12 mL). [Ru]-2 (6 mg)
was added and the temperature of the mixture was raised from
20 ꢀC to 70 ꢀC. After 45 min at 70 ꢀC, the solvent was evaporated
and the residue was chromatographed (silica gel, AcOEt/cyclohex-
ane 1:9 then 2:8) to provide the unstable pseudo dimer 62 (14 mg)
and recovered crude 61 (3 mg).
mixture was allowed to warm to 20 ꢀC. Allyl bromide (350
mL,
>2 equiv) was added and the reaction was stirred for 1h (TLC, silica
gel, AcOEt/cyclohexane 3:7). MeOH was added slowly at 0 ꢀC, the
solvents were evaporated and the residue dissolved in CH2Cl2 and
water. After extraction with water, the organic layer was dried over
MgSO4. The solvent was removed under reduced pressure and the
residue was chromatographed (AcOEt/cyclohexane 1:9) to afford
20
58 (509 mg, 66%). [
a
]
D
ꢂ88 (CHCl3, c 1.1). IR (neat, cmꢂ1
) n 2984,
2932, 2911, 1370, 1272, 1245, 1207, 1161, 1111, 1082, 1045. 1H NMR
Compound 61 (crude): 1H NMR (300 MHz, C6D6):
d¼5.88e5.75
(300 MHz, CDCl3):
J¼17.1,10.3, 6.8 Hz,1H), 5.29 (dq, J¼17.1,1.5 Hz,1H), 5.20 (dq, J¼10.3,
d
¼5.90 (ddt, J¼17.1, 10.3, 5.5 Hz, 1H), 5.77 (ddt,
(m), 5.71 (q, J¼1.1 Hz, 1H), 5.59 (ddd, J¼6.1, 2.2, 1.1 Hz, 2H), 5.21 (dq,
J¼17.3, 1.8 Hz, 1H), 5.07e4.97 (m, 3H), 4.93 (tm, J¼5.8 Hz, 1H), 4.81

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
355
(tm, J¼5.9 Hz, 1H), 3.84e3.76 (m, 4H?), 3.51 (dd, J¼9.7, 6.2 Hz, 1H),
3.47e3.31 (m, 4H), 2.29 (qt, J¼6.7, 1.4 Hz, 2H).
TLC, silica gel, AcOEt/cyclohexane 3:7). The solvent was co-evapo-
rated with toluene under reduced pressure and the residue was
purified by chromatography (silica gel, AcOEt/cyclohexane 2:8 then
3:7) to yield 69 (3.107 g, 90%).
Compound 62: 1H NMR (400 MHz, C6D6):
d¼6.11 (br s, 1H), 6.05
(, dt, J¼6.0, 1.3 Hz, 1H), 5.94 (dtt, J¼15.6, 6.8, 1.6 Hz, 1H), 5.72 (dt,
J¼6.0, 1.3 Hz, 1H), 5.62 (dt, J¼5.8, 1.5 Hz, 1H), 5.59 (s, 1H), 5.44 (dtt,
J¼15.6, 4.8, 1.3 Hz, 1H), 5.34 (ddd, J¼5.8, 2.0, 0.7 Hz, 1H), 4.93
(m,1H), 4.63 (m, 1H), 3.93 (dd, J¼9.6, 4.8 Hz, 1H), 3.81e3.69 (m, 3H),
3.57 (dd, J¼9.6, 7.6 Hz, 1H), 3.49 (dd, J¼10.3, 3.3 Hz, 1H), 3.44 (dt,
J¼8.8, 3.8 Hz, 1H), 3.30 (dd, J¼10.3, 4.3 Hz, 1H), 2.31e2.21 (m, 1H),
Compound 68: 1H NMR (300 MHz, CDCl3):
d
¼6.17 (s, 1H), 4.91
(dd, J¼5.8, 3.8 Hz, 1H), 4.70 (d, J¼6.0 Hz, 1H), 4.08 (dq, J¼7.4, 6.3 Hz,
1H), 3.96 (ddd, J¼7.7, 4.0, 0.5 Hz, 1H), 2.08 (s, 3H), 1.50 (s, 3H), 1.35
(s, 3H), 1.34 (d, J¼6.2 Hz, 3H).
20
Compound 69: mp 54e55 ꢀC (AcOEt/pentane). [
a]
þ53 (c 1.1,
D
2.03e1.95 (m, 1H). 13C NMR (100.6 MHz, C6D6):
131.0, 127.4, 127.4, 127.0, 108.1, 108.0, 85.1, 84.3, 71.3, 70.5, 67.8.
d
¼134.3, 133.9,
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼6.16 (s, 1H), 5.15 (dq, J¼7.3,
6.4 Hz, 1H), 4.79 (dd, J¼5.8, 3.6 Hz, 1H), 4.66 (d, J¼6.0 Hz, 1H), 4.03
(dd, J¼7.5, 3.8 Hz, 1H), 2.08 (3H, s, Ac), 2.06 (3H, s, Ac), 1.45 (3H, s,
CH3), 1.35 (3H, d, J¼6.2 Hz, CH3), 1.30 (3H, s, CH3). 13C NMR
4.57. 1-O-Acetyl-2,3-O-isopropylidene-6-O-tosyl-a-D-
mannofuranose (66)
(75.5 MHz, CDCl3):
d
¼169.8, 169.4, 113.2, 100.6, 84.8, 83.7, 79.2,
68.2, 26.0, 24.9, 21.2, 21.1, 17.2. HRMS calcd for C13H20NaO7 [MþNa]
311.1101, found 311.1105. Anal. Calcd for C13H20O7: C 54.16, H 6.99, O
38.85. Found: C 54.25, H 7.05.
The monoacetonide 65 (16.39 g, 62.5 mmol) was dissolved at
0 ꢀC in pyridine (320 mL) and DMAP (7.60 g, 62.2 mmol) was added
in four portions. The mixture was stirred until clear and tosyl
chloride (23.8 g, 124.8 mmol) was added portionwise. Stirring was
continued at 5e6 ꢀC for 45 min and for 4 h at 20 ꢀC. Then the re-
action was cooled in an ice bath and water (10 mL) was added. The
solvents were co-evaporated with toluene and the residue was
partitioned between ethyl acetate and water. The organic layer was
extracted with ethyl acetate, the combined organic layers were
dried (MgSO4) and the solvent was removed under reduced pres-
sure to afford 66 (20.50 g), which was used directly for the next
4.60. 3-Butenyl 5-O-acetyl-2,3-O-isopropylidene-a-D-
rhamnofuranoside (70)
To a cold (ꢂ3 ꢀC) solution of 69 (0.483 g, 1.67 mmol) in aceto-
nitrile (15 mL) and under argon atmosphere were sequentially
added 3-buten-1-ol (90 mL) and SnCl4 (24 mL). After stirring for 3 h
the reaction was quenched with aqueous NaHCO3. The mixture was
extracted with CH2Cl2, the organic layer was washed with water,
dried over MgSO4 and, after filtration, the solvent was removed
under reduced pressure. The residue was chromatographed (silica
gel, AcOEt/cyclohexane 2:8) to yield 70 (151 mg 30%) and along
step. For analytical purposes, a pure sample was prepared by
20
chromatography (silica gel, AcOEt/cyclohexane 4:6). [
a
]
þ38 (c
D
1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼7.80 (d, J¼8.3 Hz, 2H),
7.36 (d, J¼8.1 Hz, 2H), 6.12 (s, 1H), 4.90 (dd, J¼5.8, 3.8 Hz, 1H), 4.69
(d, J¼5.8 Hz, 1H), 4.28 (m, 1H), 4.19e4.09 (m, 2H), 4.05 (dd, J¼8.1,
3.8 Hz, 1H), 2.72 (d, J¼5.1 Hz, 1H, OH), 2.46 (s, 3H), 2.07 (s, 3H), 1.45
with recovered 69 (0.236 g, 50%). [
(300 MHz, CDCl3):
a
]
20 þ57 (c 1.0, CHCl3). 1H NMR
D
d
¼5.79 (ddt, J¼17.0, 10.2, 6.6 Hz, 1H), 5.13 (dq,
J¼7.7, 6.2 Hz, 1H), 5.09 (dm, J¼17.0 Hz, 1H), 5.05 (ddt, J¼10.2, 1.9,
1.2 Hz, 1H), 5.00 (s, 1H), 4.70 (dd, J¼5.8, 3.6 Hz, 1H), 4.56 (d,
J¼5.8 Hz, 1H), 3.89 (ddd, J¼7.9, 3.6, 0.4 Hz, 1H), 3.68 (dt, J¼9.8,
6.6 Hz, 1H), 3.48 (dt, J¼9.8, 6.6 Hz, 1H), 2.32 (qt, J¼6.6, 1.3 Hz, 2H),
2.05 (s, 3H), 1.43 (s, 3H), 1.36 (d, J¼6.4 Hz, 3H), 1.28 (s, 3H). 13C NMR
(s, 3H), 1.33 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d
¼169.3, 145.1,
132.5, 129.9 (2C), 128.0 (2C), 113.4, 100.3, 84.6, 80.3, 79.4, 71.6, 67.8,
25.9, 24.6, 21.6, 21.0. HRMS calcd for C18H24NaO9S [MþNa]
439.1033, found 439.1034.
(75.5 MHz, CDCl3):
79.4, 68.4, 66.6, 33.9, 26.0, 24.9, 21.3, 17.5. HRMS calcd for
d
¼169.9, 135.0, 116.6, 112.5, 106.0, 84.8, 81.5,
4.58. 1-O-Acetyl-6-iodo-2,3-O-isopropylidene-
a
-
D-
mannofuranose (67)
C15H24NaO6 [MþNa] 323.1465, found 323.1466.
A solution of 66 (20.50 g) in butanone (400 mL) was refluxed
with NaI, 2H2O (21.2 g, 113.98 mmol) for 3 h (monitoring: TLC, silica
gel, AcOEt/cyclohexane 5:5). The solvent was evaporated and the
residue partitioned between diethyl ether and aqueous sodium
hydrogenosulfite. The organic layer was extracted with H2O, dried
over MgSO4, and the solvents were evaporated. Chromatography of
the residue (silica gel, AcOEt/cyclohexane 4:6) yielded 67 (10.02 g,
yield from mannose over five steps: 40%). 1H NMR (300 MHz,
4.61. 3-Butenyl 2,3-O-isopropylidene-a-D-rhamnofuranoside
(71)
To a solution of 70 (599 mg,1.99 mmol) in methanol (25 mL) was
added t-BuOK (300 mg) and the reaction was stirred under Ar at-
mosphere at 20 ꢀC for 3 h. Dowex Hþ was added and after stirring
for 5 min the resin was filtered-off and the solvent was evaporated.
Pure 71 (458 mg, 1.77 mmol, 89%).was obtained by column chro-
20
CDCl3):
d
¼6.15 (s, 1H), 4.92 (dd, J¼5.8, 4.0 Hz, 1H), 4.71 (d, J¼5.8 Hz,
matography (silica gel, AcOEt/cyclohexane 2:8). [
a
]
D
þ59 (c 1.1,
1H), 4.01 (dd, J¼8.2, 3.8 Hz, 1H), 3.79 (m, 1H), 3.57 (dd, J¼10.4,
3.3 Hz, 1H), 3.38 (dd, J¼10.5, 6.8 Hz, 1H), 2.60 (d, J¼5.8 Hz, 1H, OH),
2.08 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼5.79 (ddt, J¼17.1, 10.3, 6.7 Hz,
1H), 5.09 (dq, J¼17.3, 1.5 Hz, 1H), 5.04 (s, 1H), 5.04 (ddt, J¼10.2, 2.1,
1.3 Hz, 1H), 4.85 (dd, J¼6.0, 3.8 Hz, 1H), 4.59 (d, J¼6.0 Hz, 1H), 4.08
(dt, J¼7.0, 6.4 Hz, 1H), 3.75 (ddd, J¼7.2, 3.8, 0.5 Hz, 1H), 3.69 (dt,
J¼9.8, 6.8 Hz, 1H), 3.47 (dt, J¼9.8, 6.6 Hz, 1H), 2.31 (qt, J¼6.8, 1.3 Hz,
2H), 1.49 (s, 3H), 1.35 (d, J¼6.4 Hz, 3H), 1.32 (s, 3H). 13C NMR
d
¼169.4, 113.4, 100.4, 84.8, 83.5, 79.4, 68.8, 26.0, 24.7, 21.1, 12.4.
HRMS calcd for C11H17INaO6 [MþNa] 394.9962, found 394.9960.
4.59. 1-O-Acetyl-2,3-O-isopropylidene- -rhamnofuranose
a
-D
(75.5 MHz, CDCl3):
d
¼135.0, 116.5, 112.6, 105.8, 84.9, 83.0, 80.0, 66.5
(68) and 1,5-Di-O-acetyl-2,3-O-isopropylidene-
a
-D-
(2C), 33.8, 25.9, 24.5, 20.4. HRMS calcd for C13H22NaO5 [MþNa]
rhamnofuranose (69)
281.1359, found 281.1359.
To a solution of 67 (4.47 g, 12 mmol) in ethanol (100 mL) were
added 2.5 g of a Ra/Ni slurry and triethylamine (2.5 mL). The re-
action was stirred under H2 atmosphere at 20 ꢀC for 20 h. The
mixture was filtered over Celite, the Celite was carefully washed
with EtOH and the filtrate was concentrated to afford the crude 75,
which was directly treated with pyridine (25 mL), Ac2O (15 mL),
and DMAP (one crystal) and stirred at 20 ꢀC overnight (monitoring:
4.62. 3-Butenyl 2,3-O-isopropylidene-5-O-(5-O-acetyl-2,3-O-
isopropylidene-a-D-rhamnofuranosyl)-a-D-rhamnofuranoside
(72)
A solution of 71 (222 mg, 0.86 mmol) in acetonitrile (10 mL) and
68 (186 mg, 0.64 mmol, 1.5 equiv) was cooled at ꢂ4 ꢀC and placed
under argon atmosphere. SnCl4 (60 mL) was added and the reaction

356
M. Donnard et al. / Tetrahedron 67 (2011) 339e357
mixture was stirred for 1.5 h at 0 ꢀC. Aqueous NaHCO3 was added
and the mixture was extracted with CH2Cl2. The organic layer was
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. Chromatography (AcOEt/cyclohexane 2:8) yielded 72
(327 mg, 78%), which was used directly for the next step, along with
recovered 68 (107 mg).
(100.6 MHz, CDCl3):
d
¼135.5, 135.0, 116.5 (2C), 112.3, 111.8, 106.7,
106.0, 85.0, 84.9, 82.6, 82.5, 79.5, 79.4, 72.2, 71.8, 70.3, 66.4, 33.9,
26.11, 26.07, 25.0, 24.9, 19.5, 17.7. HRMS calcd for C25H40NaO9
[MþNa] 507.2565, found 507.2560.
4.65. 3-Butenyl 5-O-(5-O-allyl-a-D-rhamnofuranosyl)-a-D-
rhamnofuranoside (75)
Compound 72: 1H NMR (300 MHz, CDCl3):
d¼5.79 (ddt, J¼17.0,
10.2, 6.6 Hz, 1H), 5.26 (s, 1H), 5.14 (dq, J¼7.9, 6.2 Hz, 1H), 5.08 (dm,
J¼17.1 Hz, 1H), 5.04 (dm, J¼9.8 Hz, 1H), 4.96 (s, 1H), 4.70 (d,
J¼6.0 Hz, 1H), 4.69 (d, J¼5.8 Hz, 1H), 4.55 (d, J¼5.8 Hz, 1H), 4.54 (d,
J¼6.0 Hz, 1H), 4.01 (dq, J¼9.0, 6.2 Hz, 1H), 3.97 (dd, J¼8.1, 3.7 Hz,
1H), 3.69 (dd, J¼8.6, 3.4 Hz, 1H), 3.65 (dt, J¼9.8, 6.8 Hz, 1H), 3.45 (dt,
J¼9.8, 6.6 Hz, 1H), 2.30 (qt, J¼6.6, 1.4 Hz, 2H), 2.05 (s, 3H), 1.44 (s,
6H), 1.37 (d, J¼6.2 Hz, 3H), 1.31 (s, 3H), 1.29 (d, J¼6.2 Hz, 3H), 1.29 (s,
3H).
Compound 74 (105 mg, 0.22 mmol) was cooled to ꢂ8 ꢀC and
a cold (ꢂ5 ꢀC) mixture of TFA/H2O (7:3, 4 mL) was slowly added.
The reaction mixture was stirred and allowed to warm up to 0 ꢀC.
The reaction was monitored by TLC (silica gel, AcOEt, Rf ca. 0.35 for
75). After 3 h, the starting material was almost completely con-
sumed and a polar impurity (possibly resulting from cleavage of the
homoallylic side chain) begins to appear. At that time, cold AcOEt
was added and the solvents were evaporated under reduced
pressure while maintaining the temperature at 0 ꢀC. The residue
was dissolved in AcOEt and the solvent evaporated again at 0 ꢀC.
The residue was then taken up in toluene and evaporated at
20e30 ꢀC. Column chromatography (silica gel, AcOEt/cyclohexane
4:6 then 8:2) afforded 75 (56 mg), which was used directly for the
4.63. 3-Butenyl 2,3-O-isopropylidene-5-O-(2,3-O-
isopropylidene-a-D-rhamnofuranosyl)-a-D-rhamnofuranoside
(73)
To a solution of 72 (654 mg,1.34 mmol) in methanol (27 mL) was
added t-BuOK (300 mg) and the reaction was stirred under Ar at-
mosphere at 20 ꢀC for 3 h. Dowex Hþ was added and after stirring
for 5 min the resin was filtered-off and the solvent was evaporated.
Compound 73 was purified by column chromatography (silica gel,
next step. 1H NMR (300 MHz, CDCl3):
d
¼5.99e5.86 (m, 1H), 5.80
(ddt, J¼17.0, 10.2, 6.6 Hz, 1H), 4.44 (m, 1H), 5.30 (dq, J¼17.1, 1.5 Hz,
1H), 5.22 (dq, J¼10.2, 1.5 Hz, 1H), 5.22 (d, J¼3.0 Hz, 1H), 5.09 (dm,
J¼17.1 Hz, 1H), 5.04 (dm, J¼10.2 Hz, 1H), 4.97 (dd, J¼10.4, 1.5 Hz,
1H), 4.24e4.04 (m), 4.01e3.85 (m), 3.71 (dtd, J¼9.4, 6.8, 4.3 Hz, 1H),
3.50 (dtd, J¼9.6, 6.8, 0.9 Hz, 1H), 2.33 (br q, J¼6.8 Hz, 2H), 1.36 (d,
J¼6.6 Hz, 3H), 1.33 (d, J¼6.6 Hz, 3H).
AcOEt/cyclohexane 2:8) (562 mg, 94%). [
NMR (400 MHz, CDCl3):
a
]
20 þ72 (c 1.0, CHCl3). 1H
D
d
¼5.78 (ddt, J¼17.1, 10.3, 6.6 Hz, 1H), 5.30
(s, 1H), 5.08 (dq, J¼17.3, 1.5 Hz, 1H), 5.03 (dm, J¼10.1 Hz,1H), 4.95 (s,
1H), 4.84 (dd, J¼5.8, 3.8 Hz, 1H), 4.70 (dd, J¼5.8, 3.3 Hz, 1H), 4.57 (d,
J¼5.8 Hz, 1H), 4.54 (d, J¼5.8 Hz, 1H), 4.07 (quint., J¼6.9 Hz, 1H), 4.01
(dq, J¼9.1, 6.3 Hz, 1H), 3.81 (dd, J¼7.6, 3.8 Hz, 1H), 3.69 (dd, J¼9.1,
3.5 Hz, 1H), 3.64 (dt, J¼9.8, 6.8 Hz, 1H), 3.45 (dt, J¼9.8, 6.6 Hz, 1H),
2.30 (qt, J¼6.6, 1.3 Hz, 2H), 1.49 (s, 3H), 1.44 (s, 3H), 1.36 (d, J¼6.6 Hz,
3H), 1.33 (s, 3H), 1.30 (s, 3H), 1.28 (d, J¼6.3 Hz, 1H). 13C NMR
4.66. 3-Butenyl 5-O-(5-O-allyl-2,3-O-thiocarbonyl-a-D-
rhamnofuranosyl)-2,3-O-thiocarbonyl-a-D-rhamnofuranoside
(76)
To a solution of 75 (169 mg) in CH2Cl2 (12 mL) was added 1,10-
thiocarbonyldiimidazole (250 mg) and the reaction was stirred
under argon for 3 h (monitoring: TLC, AcOEt/cyclohexane 8:2 then
3:7) at which time more 1,10-thiocarbonyldiimidazole (136 mg) was
added. After stirring overnight, the solvent was evaporated and the
residue chromatographed (silica gel, AcOEt/cyclohexane 3:7, Rf ca.
(100.6 MHz, CDCl3):
d
¼135.0, 116., 112., 112., 106.6, 106.1, 85.0 (2C),
83.1, 82.6, 80.0, 79.5, 71.9, 66.6, 66.5, 33.9, 26.1, 25.9, 25.0, 24.5, 20.4,
19.0. HRMS calcd for C22H36NaO9 [MþNa] 467.2252, found
467.2251.
4.64. 3-Butenyl 2,3-O-isopropylidene-5-O-(5-O-allyl-2,3-O-
0.37) to give pure 76 (101 mg, 32% over two steps). [
a
]
20 ꢂ4 (c 1.0,
D
isopropylidene-
a
-D
-rhamnofuranosyl)-
a
-D
-rhamnofuranoside
CHCl3). 1H NMR (400 MHz, CDCl3):
d¼5.94 (ddt, J¼17.1, 10.3, 5.5 Hz,
(74)
1H), 5.76 (ddt, J¼17.1, 10.3, 6.6 Hz, 1H), 5.49 (s, 1H), 5.45 (dd, J¼6.6,
3.3 Hz, 1H), 5.38 (dd, J¼6.8, 3.8 Hz, 1H), 5.30 (dq, J¼17.1, 1.5 Hz, 1H),
5.26 (s, 1H), 5.20 (dq, J¼10.3, 1.5 Hz, 1H), 5.16 (d, J¼6.6 Hz, 1H), 5.14
(d, J¼6.6 Hz, 1H), 5.10 (dq, J¼17.1, 1.8 Hz, 1H), 5.08 (br dq, J¼10.3,
1.2 Hz, 1H), 4.16 (ddt, J¼12.1, 5.8, 1.3 Hz, 1H), 4.09 (dd, J¼7.3, 6.6 Hz,
1H), 4.06 (ddt, J¼12.1, 5.5, 1.5 Hz, 1H), 4.02 (dd, J¼9.3, 3.5 Hz, 1H),
3.93 (dd, J¼7.6, 3.8 Hz, 1H),3.77 (dq, J¼8.8, 6.0 Hz, 1H), 3.71 (dt,
J¼9.6, 6.6 Hz, 1H), 3.56 (dt, J¼9.8, 6.6 Hz, 1H), 2.32 (qt, J¼6.6, 1.3 Hz,
2H), 1.37 (d, J¼6.3 Hz, 3H), 1.32 (d, J¼6.0 Hz, 3H). 13C NMR
To a cool (0 ꢀC) solution of 73 (502 mg, 1.13 mmol) in DMF
(10 mL) was added NaH/oil (55%) (180 mg). After stirring for
10 min under an argon atmosphere at 0 ꢀC, the bath was re-
moved, the reaction was allowed to reach 20 ꢀC and allyl bro-
mide (250
mL) was added. Stirring was continued for 2 h
(monitoring: TLC, silica gel, AcOEt/cyclohexane 2:8), the reaction
was cooled again to 0 ꢀC and quenched with methanol and H2O.
The reaction mixture was extracted with CH2Cl2, the organic
layer was dried over MgSO4 and the solvent was evaporated. The
residue was chromatographed (column chromatography, silica
(100.6 MHz, CDCl3):
d
¼190.2, 189.8, 134.6, 134.3, 117.23, 117.17,
105.4, 104.0, 87.5, 87.4, 84.7, 84.1, 82.8, 81.9, 72.6, 71.6, 70.3, 67.3,
33.6, 18.7, 17.2. HRMS calcd for C21H28NaO9S2 [MþNa] 511.1067,
found 511.1063.
gel, AcOEt/cyclohexane 0.5:9.5) to furnish 74 as an oil (466 mg,
20
85%). [
a
]
þ70 (c 1.0, CHCl3). IR (neat, cmꢂ1
)
n
2979, 2945, 2890,
¼5.96
D
1383, 1373, 1206, 1080, 1017. 1H NMR (400 MHz, CDCl3):
d
4.67. (2S,5S)-2-[(1R)-1-Allyloxyethyl]-5-[(1R)-1-[(2S,5S)-5-but-
3-enoxy-2,5-dihydrofuran-2-yl]ethoxy]-2,5-dihydrofuran (77)
and (2R,3S,6S)-3-[[(6S)-3,6-dihydro-2H-pyran-6-yl]oxy]-2-
methyl-6-[[(2R,3S)-2-methyl-3,6-dihydro-2H-pyran-3-yl]oxy]-
3,6-dihydro-2H-pyran (78)
(ddt, J¼17.1, 10.3, 5.5 Hz, 1H), 5.78 (ddt, J¼17.1, 10.9, 6.8 Hz, 1H),
5.28 (dq, J¼17.4, 1.5 Hz, 1H), 5.21 (s, 1H), 5.15 (dm, J¼10.3 Hz,
1H), 5.08 (dq, J¼17.1, 1.5 Hz, 1H), 5.04 (dm, J¼10.3 Hz, 1H), 4.95
(s, 1H), 4.77 (dd, J¼5.8, 3.0 Hz, 1H), 4.70 (dd, J¼6.0, 3.5 Hz, 1H),
4.54 (2ꢁd, J¼6.0 Hz, 2H), 4.54 (2ꢁd, 2ꢁ J¼6.0 Hz, 2H), 4.12 (ddt,
J¼12.6, 5.8, 1.5 Hz, 1H), 4.06 (ddt, J¼12.6, 5.8, 1.5 Hz, 1H), 4.00
(dq, J¼9.1, 6.0 Hz, 1H), 3.85e3.77 (m, 2H), 3.69 (dd, J¼9.1, 3.3 Hz,
1H), 3.64 (dt, J¼9.6, 6.6 Hz, 1H), 3.45 (dt, J¼9.8, 6.6 Hz, 1H), 2.30
(qt, J¼6.8, 1.3 Hz, 2H), 1.46 (s, 3H), 1.44 (s, 3H), 1.32 (s, 3H), 1.30
(s, 3H), 1.29 (d, J¼5.5 Hz, 3H), 1.28 (d, J¼6.5 Hz, 3H). 13C NMR
Compound 76 (30 mg, 0.06 mmol) was dissolved in trimethyl-
phosphite (1 mL) and heated under argon at 117 ꢀC for 5 h. The
reaction was monitored by 1H NMR in of aliquots (C6D6), after
evaporation of most of the trimethylphosphite. P(OMe)3 was re-
moved under reduced pressure to furnish crude 77, which was

M. Donnard et al. / Tetrahedron 67 (2011) 339e357
357
taken up in benzene (4 mL). [Ru]-2 (3 mg) was added and the re-
References and notes
action mixture was heated at 70 ꢀC for 15 min. The solvent was
evaporated and chromatography afforded pure 78 (AcOEt/cyclo-
hexane 1:9) (8 mg, 42%, two steps from 76).
1. For a recent review on RRM, see: Holub, N.; Blechert, S. Chem.dAsian J. 2007, 2,
1064e1082.
2. (a) McDonald, F. E.; Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120, 4246e4247; (b)
Trost, B.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 6634e6640; (c) Babu, R. S.;
Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126, 3428e3429; (d) Morton,
G. E.; Barrett, A. G. M. Org. Lett. 2006, 8, 2859e2861; (e) Di Bussolo, V.; Chec-
chia, L.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2008, 10, 2493e2496.
3. (a) Donnard, M.; Tschamber, T.; Desrat, S.; Hinsinger, K.; Eustache, J. Tetrahedron
Lett. 2008, 49, 1192e1195; (b) Donnard, M.; Tschamber, T.; Eustache, J. Tetra-
hedron Lett. 2008, 49, 7325e7327.
Compound 77: 1H NMR (300 MHz, C6D6):
d
¼6.01e5.96 (m),
5.90e5.73 (m), 5.70e5.57, 5.21 (dq, J¼17.1, 1.7 Hz, 1H), 5.09e4.97
(m), 4.84e4.75 (m), 3.92e3.70 (m), 3.49e3.38 (m), 3.25 (quint.,
J¼6.0 Hz, 1H), 2.32 (q, J¼6.8 Hz, 2H), 1.32 (d, J¼6.4 Hz, 3H), 1.09 (d,
J¼6.2 Hz, 3H).
20
Compound 78: [
a
]
þ187 (c 1.1, C6H6). IR (neat, cmꢂ1
) n 3450,
D
4. Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118,
6634e6640.
2974, 2933, 2880, 2827, 1448, 1400, 1377, 1295, 1186, 1151, 1098,
1033. 1H NMR (400 MHz, C6D6):
d
¼6.22 (dq, J¼10.3, 2.0 Hz, 1H),
5. Full experimental details are provided in the Supplementary data. Experi-
mental data for trisaccharides have been described in Ref. 3b.
6.13 (dt, J¼10.3, 2.0 Hz, 1H), 5.72 (dt, J¼10.3, 1.8 Hz, 1H), 5.68
(ddm, J¼10.3, 5.8 Hz, 1H), 5.60 (dtd, J¼10.1, 2.5, 1.0 Hz, 1H), 5.45
(dq, J¼10.3, 2.5 Hz, 1H), 5.10 (q, J¼1.6 Hz, 1H), 4.92 (s, 1H), 4.01
(dm, J¼8.3 Hz, 1H), 3.91 (dq, J¼8.3, 2.3 Hz, 1H), 3.90e3.86 (m,
2H,), 3.83 (dd, J¼11.3, 3.5 Hz, 1H), 3.72 (dq, J¼8.0, 6.3 Hz, 1H),
3.60 (dq, J¼8.1, 6.2 Hz, 1H), 3.46 (ddt, J¼10.8, 6.0, 1.0 Hz, 1H),
1.97 (m, 1H), 1.37 (m, 1H), 1.37 (d, J¼6.3 Hz, 3H), 1.27 (d,
€
6. Furstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002, 21, 331e335.
7. For an example of homodimerization of an acrolein ketal (thus requiring ini-
tiation at an ethylene ketal-type olefin) and for possible deactivation of ru-
thenium by electron-donating homoallylic see: Blackwell, H. E.; O’Leary, D. J.;
Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58e71 and references therein.
8. Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem. 1990, 55,
5812e5813.
9. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677e2678.
10. Ley, S.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639e666.
11. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019e8022.
12. Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888e890.
13. (a) de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153e1174; (b)
Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293e295.
J¼6.0 Hz, 3H). 13C NMR (100.6 MHz, C6D6):
¼132.9, 129.3, 129.1,
d
128.8, 127.6, 126.5, 99.1, 95.9, 77.5, 76.8, 73.6, 72.9, 65.3, 57.3,
24.9, 18.9, 18.6. HRMS calcd for C17H24NaO5 [MþNa] 331.1516,
found 331.1507.
14. Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191e198.
15. (a) Hanessian, S.; Tyler, P. C.; Chapleur, Y. Tetrahedron Lett. 2006, 46,
4583e4586; (b) Ichikawa, Y.; Hirata, Y.; Ohbayashi, M.; Isobe, M. Chem.dEur. J.
2004, 10, 3241e3251.
Acknowledgements
16. (a) Although 49 is cleanly formed during the CoreyeWinter reaction, it is very
sensitive to acidic conditions and difficult to isolate and store. Therefore for the
subsequent RRM step, we normally used the crude 49 obtained by evaporation
under vacuum of the CoreyeWinter reaction mixture. Interestingly, remaining
trimethyl phosphate and sulfur-containing contaminants do not interfere with
the metathesis step. (b) We found that the two secondary acetates in 43 could be
(although not totally) selectively cleaved by careful transesterification at 0 ꢀC.
17. (a) Schmidt, B.; Biernat, A. Org. Lett. 2008, 10, 105e108; (b) Schmidt, B. Chem.
Commun. 2004, 742e743; (c) Schmidt, B. J. Org. Chem. 2004, 69, 7672e7687.
18. (a) Marco, J. A.; Carda, M.; Rodriguez, S.; Castillo, E.; Kneteman, M. N. Tetra-
hedron 2003, 59, 4085e4101; (b) Salmond, G. S.; Barta, M. A.; Havens, J. L. J. Org.
Chem. 1978, 43, 2057e2059.
ꢁ
ꢀ
We thank the Ministere franc¸ ais de l’enseignement superieur et
de la recherche for a fellowship to M.D.
Supplementary data
1H and 13C NMR spectra for all described compounds. Experi-
mental and analytical data corresponding to the synthesis of
compounds in Fig. 1B are also described. Supplementary data as-
sociated with this article can be found in online version at
doi:10.1016/j.tet.2010.11.036. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
19. Garcia-Moreno, M. I.; Ortiz Mellet, C.; Garcia Fernandez, J. M. Eur. J. Org. Chem.
2004, 1803e1819.
€
20. Jaunzems, J.; Kashin, D.; Schonberger, A.; Kirschning, A. Eur. J. Org. Chem. 2004,
3435e3446.
21. Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5468e5472.