Highly functionalized, enantiomerically pure furo[x,y-c]pyrans via alkylidenecarbenes derived from sugar templates: synthesis and mechanism study via computational chemistry

Article abstract of DOI:10.1016/j.tet.2009.08.080

The new method for the generation of alkylidenecarbenes based on the reaction of trimethylsilylazide/Bu₂SnO with α-cyanomesylates has been applied to readily available sugar derivatives for the synthesis of highly functionalized, enantiomerical

Full text of DOI:10.1016/j.tet.2009.08.080

Tetrahedron 65 (2009) 9378–9394
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly functionalized, enantiomerically pure furo[x,y-c]pyrans via
alkylidenecarbenes derived from sugar templates: synthesis and mechanism
study via computational chemistry
,
a
a
a
Albert Nguyen Van Nhien a , Romaric Cordonnier , Marie-Delphine Le Bas , Sebastien Delacroix ,
*
´
b
b
a,
*
´
Elena Soriano , Jose Marco-Contelles , Denis Postel
a
´
´
Laboratoire des Glucides, Universite de Picardie Jules Verne, Faculte des Sciences, 33, rue Saint Leu, 80039 Amiens, France
b Laboratorio de Radicales Libres y Qu´ımica Computacional (IQOG, CSIC), C/ Juan de la Cierva, 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2009
Received in revised form 24 August 2009
Accepted 29 August 2009
Available online 3 September 2009
The new method for the generation of alkylidenecarbenes based on the reaction of trimethylsilylazide/
Bu2SnO with a-cyanomesylates has been applied to readily available sugar derivatives for the synthesis of
highly functionalized, enantiomerically pure furo[x,y-c]pyrans. The furo[x,y-c]pyran heterocyclic ring
system is present in a number of natural or non-natural products of biological interest such as the mi-
haramycins, and deserve particular attention. The scope and extent of the present new methodology has
been investigated by systematic modification of the starting sugar precursor (
D-glucose, D-galactose, etc.)
in the hexo- )- -pyranoside forms, bearing also different O-protecting groups, the effect of the ab-
a(b D
solute configuration of the substituent at the anomeric position, the location (C-2, -3 and -4) of the
alkylidenecarbene species on the pyran nucleus, as well as the substitution (H or Ph) at the ‘carbon
donor’ in the 1,5 C–H bond insertion process. In overall, using these key 1,5 C–H bond insertion reactions
a simple protocol results for the synthesis of the furo[x,y-c]pyrans, difficult to be prepared by other
methodologies, from moderate to good yields. To examine the reactivity of the alkylidenecarbene, we
have undertaken a systematic investigation of the insertion reactions of various alkylidenecarbene de-
rivatives into C–H bonds using density functional theory.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
temperature, in the presence of tetrabutylammonium hydro-
genosulfate, with
a-cyanomesylates derived from conveniently
Over the last few years, the synthesis and subsequent trans-
formation of reactive species such as alkylidenecarbenes has been
the object of a continuous interest.1 Accordingly, a number of
methods have been documented for the generation of these highly
functionalized uloses, produced alkylidenecarbenes as very re-
active intermediates that were trapped in situ in intermolecular
processes with an azide anion, the solvent, or alkenes to give
branched sugars and nucleosides.4 The obvious interest of this
methodology was hampered by the well known explosive combi-
nation of sodium azide and halogenated solvents4; in fact, and
unfortunately, this protocol has been neglected and these papers
scarcely cited in the current carbene chemistry. However, Czer-
necki’s discovery3 paved the way for further improvements on this
subject.5 In this context, in a recent communication6 we have
reported a new and more friendly protocol for the preparation of
alkylidenecarbenes in sugar templates and some intramolecular
transformations of these species, such as the rare 1,6 C–H bond
insertion reactions.7 Taking into account the presumed mechanism
reactive species, such as fluoride-induced
chlorovinylsilanes or silylvinyl triflates,2a,b thermal decomposition
of tosylazoalkenes,2c or diazoalkenes,2d weak base-induced
elimination of alkenyliodonium salts,2e samarium diiodide reaction
with 1,1-dihalogenoalkenes,2f or from
-epoxy-N-aziridinyl imi-
nes.2g Particularly, in carbohydrate chemistry Czernecki was the
first to use -cyanomesylates, upon treatment with sodium azide/
a-elimination of a-
a
-
a,b
a
DMF, to form a presumed alkylidenecarbene species that after 1,2-H
shift gave acetylenic derivatives.3 Some years later it was reported
that the reaction of sodium azide in methylene chloride, at room
for the generation of alkylidenecarbenes from
based on the tetrazolyl anion formation after the reaction of the
a
-cyanomesylates,4
azide anion with the cyano moiety followed by a-elimination of
* Corresponding authors. Tel.: þ33 3 22827570; fax: þ33 3 22827568.
E-mail addresses: albert.nguyen-van-nhien@u-picardie.fr (A. Nguyen Van
Nhien), denis.postel@u-picardie.fr (D. Postel).
the mesylate group, we reasoned that Wittenberger’s method8 for
the synthesis of 5-substituted tetrazoles, using trimethylsilylazide,
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.080

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9379
OP
OP
dibutyltin oxide, in toluene, when applied to selected precursors
would presumably yield these -mesyltetrazolyl intermediates that
smoothly and in mild reaction conditions would lead to the desired
alkylidenecarbenes species.
O
CO2H
O
a
H2N
HN
O
OR
OP
N
HO
HO
R
N
O
N
In our preliminary experiments6 we made a comparative study
with the reported4 intermolecular reaction of the alkylidene-
carbene derived from the benzoate 1a with cyclohexene to give
the exo-methylenecyclopropyl derivative 2. Using our conditions,
the reaction of 1a with cyclohexene (40 equiv) in the presence of
TMSN3 (1.2 equiv) and Bu2SnO (1 equiv), at 98 ꢀC for 6 h, afforded
2 in a higher yield, 42% (vs 35%)4 in the isomeric ratio 1/1.2
(Scheme 1). Under similar experimental conditions, precursor 1b
HO
I
H2N
O
N
N
HO
O
NH
OR
H2N
miharamycins (R= H, OH)
OP
O
II
OP
OP
OP
O
O
OP
O
OR
OMe
OR
OR
OP
HO
NC
OP
afforded an isomeric mixture of 3
a/
b
in 45% yield, in a 4/1 ratio
OMs
OMe
OMe
(Scheme 2).
IV
III
A
Chart 1.
O
O
BzO
O
O
O
2. Results and discussion
TMSN3, OSnBu2
BzO
O
H
H
2.1. Synthesis and reactivity
NC OMs
1a
2.1.1.
D-Glucose derivatives. Starting with a mixture of the 2-O- and
3-O-methyl ethers 4 and 5 that we were unable to separate,11 the
one-pot-two-step oxidation plus cyanomesylate formation pro-
tocol provided pure methyl glucosides 6 and 7, as a mixture of di-
astereomers at C-3 and C-2, respectively. The C2–OMe substituted
derivatives (6) were separated from their C3–OMe isomers (7), and
independently, submitted to further reaction (Scheme 3). Under the
standard conditions (see Experimental part) diastereomers 6 gave
the expected alkylidenecarbene intermediate that afforded the 1,5
C–H insertion product 8 in 24% yield (Scheme 3). The structure of
this compound was unequivocally assigned by detailed spectro-
scopic analysis as well as by comparison with the data reported for
the same compound by Amelia P. Rauter and colleagues.12 Com-
pound 8 has been synthesized from 2-O-benzoyl-4,6-O-benzyli-
2 (42%, 1:1.2)
Scheme 1.
O
O
O
TMSN3
O
N
O
BnO
BnO
OSnBu2
TBAF
O
- FSiMe3
F- Bu4N+
N
OMs
SiMe3
NC OMs
N
(45-50%)
N
O
1b
O
O
N
O
N
dene-a-D-hexopyranoside, in four steps comprising Wittig–Horner
- N2
- OMs
BnO
BnO
reaction, iodine-double bond isomerization, LAH-promoted re-
duction and heterocyclization, in 79% overall yield, as a model study
for the synthesis of miharamycins.12 A related derivative has been
also recently synthesized in good yield, an intramolecular ring-
closing-metathesis reaction being the key step for the installation
of the fused dihydrofuran ring moiety.10
O
O
N
OMs
N
OMs
N
N
N
N
O
O
O
H
O
O
O
O
O
O
O
O
O
O
Ph
O
Ph
O
BnO
Ph
O
O
O
OMe
OMe
O
b
OMe
MsO
O
H
24%[27%]
Ph
3
OMe
O
NC
HO
OMe
Ph
6
[32% (78/22)]
+
8
(1:4)
4
A
a
+
Scheme 2.
O
O
O
Ph
O
Ph
O
Ph
b
O
O
OMe
OMs
CN
O
OMe
O
OMe
With this promising results in mind, next we planned a simple
approach for the synthesis of chiral, advanced intermediates9 in
66%
MeO
MeO
OH
O
5
route to miharamycins10 (Chart 1) starting from
a-D-glucose. In the
7
[14% (73/27)]
9
structure of these natural products, a perhydrofuro[2,3-c]pyran
motif is present that could be possibly implemented in a synthetic
sequence using intermediates I–III prepared from sugar IV, via
a key 1,5 C–H bond insertion on the alkylidenecarbene A (Chart 1).
The successful accomplishment of this objective (see below) led us
to investigate in depth the scope and limitations of the present
methodology for the synthesis of a series of differently function-
alized furo[x,y-c]pyrans. In this work we will describe the synthesis
of all these key precursors, the generation of the alkylidene-
carbenes, and the 1,5 C–H insertion results, accompanied by a DFT
computational analysis in order to explain the regioselectivity or
regiochemistry of some of these processes.
Scheme 3. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
TMSN3, OSnBu2, toluene, reflux.
Certainly the chemical yield of our 1,5 C–H bond insertion re-
action leading to product 8 was low, but very interestingly, this
result proved to be substrate-dependent, as the isomers 7, under
the same experimental conditions, gave compound 9 in higher and
more synthetically useful yield (66%) (see Experimental part)
(Scheme 3). These observations coupled to the obvious synthetic
interest of the resultant chiral furo[2,3-c]pyran type of compounds
prompted us to undertake an extensive study in order to un-
derstand more deeply the stereo- and regiochemical outcome of

9380
A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
O
O
O
O
the 1,5 C–H bond insertion reaction on these alkylidenecarbene
reactive intermediates. In this study, we have taken into account
the different structural and functional parameters at hand for
modification, such as the location of the alkylidenecarbene at C2,
C3 and C4, the anomeric configuration and the substitution at the
‘carbon donor’ in the 1,5 C–H insertion reaction.
O
O
Ph
O
Ph
O
Ph
O
OMe
OMe
OMs
OMe
a
b
70%
BnO
NC
51%
O
BnO
OH
(75/25)
(75/25)
19
Ph
21
20
Thus, for the next experiment we considered the same
D-glucose
Scheme 6. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
derivatives as intermediates, but as their -anomers (12 and 13). These
b
TMSN3, OSnBu2, toluene, reflux.
precursors were prepared following similar synthetic protocols from
known glycosides 10 and 11 (Scheme 4).11 As shown before (Scheme
3), now diastereomers 12, where the alkylidenecarbene functional
moiety is located at C-3 (sugar numbering) provided the expected
product 14, albeit in very poor yield. Conversely, intermediates 13
leading to an alkylidenecarbene, located at C-2, gave only one product
(15), in good yield, as the result of a total regiochemical 1,5 C–H bond
insertion reaction favouring exclusively the transfer of the proton
linked to C–O–(C-3) instead of the proton linked to C–O–(C-1).
The possible competitive 1,5 C–H bond insertion reactions be-
tween protons located in the methylene moiety of the O-benzyl
groups, at C-3 or C-1, in the a-anomer 23, a precursor prepared
from sugar 22,14 has also been investigated. In the usual conditions,
only one compound (24), as a mixture of diastereomers, was iso-
lated in good yield, and characterized (Scheme 7). This reactivity is
similar to the one observed in the di-O-methyl precursor 7
(Scheme 2), and strongly points out to a systematic preferred
regiochemical migration of the proton located at the ether located
at C-3, regardless of the spatial orientation of O-methyl ether at C-
1, in the 1,5 C–H process with alkylidenecarbenes located at C-2.
O
O
O
O
O
Ph
O
Ph
O
Ph
O
O
OMe
OMe
b
4%
OMe
MsO
OMe
NC
O
HO
OMe
12
[13% (73/27)]
10
O
O
14
O
O
O
O
a
+
Ph
O
2
Ph
O
+
Ph
O
OBn
OBn
OMs
OBn
O
O
a
b
O
Ph
O
Ph
O
Ph
O
20%
BnO
NC
52%
O
BnO
OH
O
OMe
OMs
b
O
OMe
O
OMe
(100/0)
(75/25)
22
Ph
24
23
73%
MeO
13
MeO
OH
CN
O
11
[34% (90/10)]
15
Scheme 7. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
TMSN3, OSnBu2, toluene, reflux.
Scheme 4. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
TMSN3, OSnBu2, toluene, reflux.
Note also that in the previous investigated precursors the hy-
droxyl groups at positions C-4 and C-6 were part of a benzylidene
nucleus that conferred to the corresponding substrates an obvious
rigidity, preventing free conformational mobility, hence possibly
favouring the 1,5 C–H bond insertion reactions. This was the reason
In the examples described above we have used O-methyl ethers as
the ‘donor’ partner in the insertion process. In order to investigate the
effect of a substituent such a phenyl group, we considered as starting
material the known D
-gluco derivative 1611 bearing a O-benzyl group at
C-2 (Scheme 5). Following the usual synthetic sequence we isolated
compound 17 as a diastereomeric mixture of epimers at C-3, in
a complex reaction, where we could detect also the corresponding
unreacted intermediate ulose (see Experimental part). Very in-
terestingly, under the standard reaction conditions, the diastereomeric
mixture of cyamomesylates 17 provided compounds 18 in low yield, in
an uncomplete reaction, and as a mixture of isomers (65/35) at the
newly formed stereocenter (C-8) that we did not try to separate, and
configurationally identify. Consequently, the most important fact from
this reaction is that the 1,5 C–H bond insertion process is still possible,
that the presence of a phenyl group linked to the carbon forming the
new C–C bond do not preclude the reaction by steric hindrance, and
that the partial failure of the process from the synthetic point of view
must be ascribed to a general reactivity pattern for the alkylidiene-
carbene species when located at C-3 in these substrates [compare with
the results obtained from precursors 6 (Scheme 3) and 13 (Scheme 4)].
This was nicely confirmed whenwe repeated the process starting from
why a per-O-benzylated
to test the influence of this structural feature. Consequently, methyl
3,4,6-tri-O-benzyl- -glucofuranoside (25) was synthesized as
D-gluco derivative was of interest in order
a-D
described,15 and submitted to oxidation and cyanomesylation re-
actions to afford the key intermediate 26. The subsequent reaction
with trimethylsilylazide and dibutyltin oxide provided the alkyli-
denecarbene species that smoothly cyclized to the mixture of di-
astereomers 27 (Scheme 8) in a similar yield to the one obtained for
precursor 20 leading to compound 21 (Scheme 6). This result
means that a restricted conformation induced by benzylidene
protecting group for the hydroxyl groups at C-4 and C-6 is not
a condition for the 1,5 C–H insertion takes place, and that simple O-
benzyl protecting groups are enough to afford the same result.
BnO
BnO
BnO
BnO
BnO
O
O
2
O
BnO
OMe
OMe
OMs
(78/22)
OMe
known D
-gluco derivative 19,13 via intermediates 20, leading to the
furo[3,2-c]pyran derivatives 21 (Scheme 6), isolated in a convenient
chemical yield (51%) as a mixture of diastereomers (75/25) at C-8.
a
b
52%
BnO
44%
O
BnO
OH
NC
26
(72/28)
Ph
27
25
Scheme 8. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
TMSN3, OSnBu2, toluene, reflux.
O
O
O
O
O
Ph
O
Ph
O
Ph
O
O
OMe
OMe
b
OMe
a
MsO
22% (26%)
OBn
O
NC
HO
OBn
Finally, we have synthesized additional useful intermediates in
order to prepare alkylidenecarbene species located at C-4 in the
sugar skeleton, and tested their reactivity. In these cases opportu-
nities to evaluate the competition between the 1,5 versus 1,6 C–H
bond insertion reactions are possible, and will be discussed.
(65/35)
17
16
[14% (73/27)]
Ph
18
Scheme 5. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl; (b)
TMSN3, OSnBu2, toluene, reflux.

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9381
-gluco derivatives 2816
-cyano-
BnO
HO
BnO
BnO
BnO
MsO
Starting from known per-O-alkylated
D
O
O
O
O
(OMe) and 29 (OBn),17 the diastereomeric mixtures of
a
HO
MsO
OMe
OMe
OMe
OMe
a
b
+
mesylates 30 and 31, were obtained, respectively. Next, the
generation of the alkylidenecarbene as usual provided com-
pound 32 and 33 (Scheme 9) in moderate yield (49%) as the only
insertion products, and in the case of furopyran 33, as a di-
astereomeric mixture at the newly formed stereocenter in 81/19
ratio. This result rules out the formation of 1,6 C–H bond in-
sertion products, the 1,5 C–H mode of cyclization being the only
observed.
R2
38
OR1
R = Me, R2= H
MeO
39
OMe
(13%)
O
1
RO
34
OR
RO
36
OR
R= Me
R= Bn
R= Me
R= Bn
35
37
40 R1= Bn, R2= Ph
Scheme 10. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl [34–36
(80/20): 83%; 35–37 (60/40): 50%]; (b) TMSN3, OSnBu2, toluene, reflux [36–38: 81%;
37–40 (74/26: 47%)].
until now on these studies. Product 39 was the decyano derivative
of 36 with the b-D-gluco configuration as we could easily assign in
view of the high vicinal (9.5 Hz) constant for H-4/H-5, showing that
these protons are in a trans-arrangement, in a chair like confor-
mation. A detailed analysis of the reaction leading to intermediate
36 clearly showed that compound 39 was also formed in traces in
this step due to an incomplete oxidation reaction, followed by
mesylation of unreacted alcohol 34. On the other hand the trans-
formation of diastereomers 37 afforded the expected compounds
40 in moderate yield.
BnO
BnO
BnO
HO
O
O
O
NC
MsO
OMe
OMe
OMe
a
b
R2
OR1
O
RO
OR
RO
28
29
OR
32 R1= Me, R2= H
30 R= Me
31 R= Bn
R= Me
R= Bn
1
2
33
R = Bn, R = Ph
Scheme 9. Reagents and conditions: (a) i. PCC; ii. NaCN, NaHCO3, then MsCl [28–30
(56/44): 62%; 29–31 (70/30): 89%]; (b) TMSN3, OSnBu2, toluene, reflux [30–32: 49%;
31–33 (81/19): 49%].
In Charts 2 and 3 we have shown the most relevant facts as-
sociated with the observed insertion reactions on
D-gluco de-
rivatives for the synthesis of chiral, densely functionalized
furo[2,3-c]([3,2-c])pyrans. The synthetic methodology is simple
and flexible as it works on a number of different types of sub-
strates, affording the expected molecules from moderate to good
yield. Of particular interest is the high regiochemical control re-
garding the ‘C–H donor’ moiety, as well as the prevalent 1,5
versus 1,6 C–H insertion process, when competition is possible.
All these experimental facts need to be evaluated and considered
in a more rational basis using computational chemistry. Accord-
ingly, in the last section we present a theoretical study aimed at
explaining these results.
In the b-anomeric series we were very pleased to see similar
and good overall results. Starting with the known methyl gly-
cosides 3418 and 35,17 the synthesis of the corresponding pre-
cursors 36 and 37 was easily achieved as usual (see Experimental
part). For the diastereomeric mixture of sugar 36 we obtained
a mixture of compounds 38 and 39, that we could separate and
characterize (Scheme 10).
Major compound (38) is the expected and exclusive 1,5 C–H
bond insertion product, and was isolated in the highest yield (81%)
Low-yielding 1,5 C-H bond insertion reactions
High-yielding 1,5 C-H bond insertion reactions
O
O
O
O
O
O
Ph
O
Ph
24%
O
Ph
66%
O
Ph
O
2
OMe
OMe
O
OMe
O
O
3
O
O
O
H
X
O
H
H
8
9
O
O
O
O
O
Ph
O
Ph
73%
O
Ph
4%
O
Ph
O
O
OMe
O
OMe
OMe
3
O
O
2
O
O
O
H
X
O
H
H
14
15
O
O
O
O
O
O
O
Ph
O
Ph
22%
O
Ph
O
Ph
O
2
OMe
O
OMe
OR
O
3
R
O
O
O
H
X
O
H
H
Ph
Ph
Ph
Ph
21 R= Me (51%)
24 R= Bn (52%)
R= H
18
R= Ph
Chart 2.

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A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
O
O
Ph
H
O
O
BnO
O
Ph
O
Ph
O
O
O
OMe
O
OMe
OMe
4
49%
O
H
49%
H
O
O
OMe
O
OMe
Ph
52
H
Ph
32
Chart 3.
2.1.2.
D
-Galactose derivatives. With the reactivity on the
D
-gluco
have prepared precursors 48 (Scheme 12) and 51 (Scheme 13),
similar to the -gluco derivatives 17 (Scheme 5) and 20 (Scheme 6).
derivatives in mind, next we investigated the synthesis and cycli-
zation of series of -galacto intermediates, as their epimers at C-4.
In fact, to start with this analysis we used also similar precursors
(44 and 45) (see Scheme 3). These compounds have been synthe-
sized from commercial methyl 4,6-O-benzylidene-a-D-galactopyr-
anoside (41), after unselective methylation to give an unseparable
mixture of O-methyl ethers 42 and 43, followed by standard oxi-
dation, cyanohydrin formation and mesylation. Very interestingly,
under the usual conditions, the unseparable mixture of
regioisomers 44þ45 (61/39 ratio) gave only one compound (46) in
60% yield (Scheme 11). The structure of this compound was clearly
established by 1H NMR analysis as protons H6 and H6a are vicinal
showing 4.0 Hz as coupling constant. Neither the presumed de-
rivative from precursor 45 nor the same intermediate was detected
in the crude reaction; we have no explanation for this unexpected
result. This result was very surprising, and in sharp contrast with
the sluggish reactivity observed on the same alkylidenecarbene
D
D
The synthesis of compounds 49 and 52 proceeded as expected
starting from alcohols 4719 and 50,19 respectively, via cyanomesy-
lates 48 and 51. Compounds 49 and 52 were isolated as mixtures of
diastereomers at the newly formed stereocenter, that we did not try
to separate, and whose structures were in good agreement with
their spectroscopic data. Although the yield of furopyran 52 (49%)
arising from an alkylidenecarbene located at C-2 was significantly
higher than the yield of compound 49 (33%), obtained from an
alkylidenecarbene at C-3, the difference was not so high as we have
previously found in related substrates in D-gluco series (see above).
In addition, the cyclization leading to compound 52 from in-
termediate 51 is apparently contradictory with the unsuccessful
cyclization on related compound 45 (Scheme 11), although the
presence of a phenyl group in the carbon donor partner in in-
termediate 51 must have some positive influence. It is also impor-
tant to highlight that in the formation of furopyran 52, only the
proton in the O-benzyl side is transferred to the carbene in pref-
erence to the proton in the O–Me vicinal group (see Chart 3).
species at C-3 in the D-gluco series, as described above. In order to
test the extent of this particular and different type of reactivity we
2.1.3.
-galacto series we decided to prepare precursors 54 (Scheme 14)
and compare results with the ones obtained with the -methyl
glycosides and epimers at C-2 (compounds 17; Scheme 5), and
epimers at C-4 (compound 48, Scheme 12). In addition, with
compounds 54 we will deal with an alkylidenecarbene at C-3, the
most favourable situation until now that we have observed in our
studies from the synthetic point of view.
D-Mannose derivatives. In view of the results obtained in the
D
O
Ph
O
a
O
O
O
OMe
Ph
Ph
O
a
b
OMe
R1O
OR2
41%
37%
42 R1= Me, R2= H
43 R1= H, R2= Me
HO
OH
41
O
O
O
O
O
O
Ph
O
Ph
O
O
O
Ph
O
OMe
OMe
OMs
CN
Ph
O
O
OMe
+
c
O
MsO
OMe
O
OMe
a
b
MsO
60%
O
MeO
OMe
NC
49%
OBn
CN
54
HO
OBn
44
45
46
(75/25)
53
Scheme 11. Reagents and conditions: (a) i. Bu2SnO, MeOH, then IMe; (b) i. PCC; ii.
NaCN, NaHCO3, then MsCl; (b) TMSN3, OSnBu2, toluene, reflux.
O
O
O
Ph
O
Ph
O
OMe
O
OMe
+
O
O
O
O
NC
OBn
O
O
Ph
O
Ph
O
Ph
O
Ph
55
56 (6%)
O
OMe
OMe
b
33%
OMe
a
(11%)
MsO
OBn
28%
O
NC
HO
OBn
Scheme 14. Reagents and conditions: (a) i. Dess–Martin; ii. NaCN, NaHCO3, then MsCl;
(b) TMSN3, OSnBu2, toluene, reflux.
48
(1/2)
47
Ph
49
Scheme 12. Reagents and conditions: (a) i. Dess–Martin; ii. NaCN, NaHCO3, then MsCl;
(b) TMSN3, OSnBu2, toluene, reflux.
Starting from alcohol 5320 and following the usual steps we
were able to prepare and isolate a mixture of diastereomers 54 in
75/25 ratio, that were submitted to the standard cyclization pro-
tocol, giving compound 55 as a pure diastereomer at C-8, and the
deoxygenated derivatived 56, in 11 and 6%, respectively.
O
O
O
O
O
O
Ph
O
Ph
O
Ph
O
OMe
OMs
OMe
OMe
a
b
17%
49%
BnO
BnO
OH
O
NC
51
3. Reactivity and mechanism based on a DFT approach
(8/2)
50
Ph
52
The results summarized above describe regioselective 1,5 C–H
insertions of key transient intermediates alkylidenecarbenes as
a means to construct functionalized furo[x,y-c]pyrans. The insertion
Scheme 13. Reagents and conditions: (a) i. Dess–Martin; ii. NaCN, NaHCO3, then MsCl;
(b) TMSN3, OSnBu2, toluene, reflux.

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9383
of simple carbenes (such as halogenated dimethyl carbenes) into C–
H21 bonds and alkylidenecarbenes into O–H22 bonds has already
been treated by theory. However, to our knowledge, there is still no
computational report on the insertion reaction of alkylidene-
carbenes into C–H bonds.
To examine the reactivity of the alkylidenecarbene, we have
undertaken a systematic investigation of the insertion reactions of
various alkylidenecarbenes derivatives into C–H bonds using den-
sity functional theory. The relative reactivity of various types of
carbon–hydrogen bonds for the process has been assessed, and the
results have been compared to those observed experimentally.
Alkylidenecarbenes can exist in singlet state (S0) in singlet state
(S1) and the triplet state (T1). In S0 there is an empty pp orbital on
the carbene carbon, and the nonbonding unshared spin-paired
electrons occupy an sp orbital in the plane of the molecule. Singlet
state (S1) refers to two singly occupied orbitals. In the triplet state
(T1) two nonbonding electrons have parallel spins and occupy an sp
orbital as well as an orbital with substantial p character.1a
Singlet carbenes are expected to show electrophilic and nucleo-
philic behaviour because of the lone pair and the vacant orbital,
whereas triplet carbenes are expected to exhibit diradical re-
activity. The relative stability, reactivity, singlet–triplet gap (
DEST),
lifetime and philicity of carbenes are dependent on -electron
p
delocalization and the substituents bonded to the electron-de-
ficient carbene carbon atom (spectator substituents), neighbouring
substituents (by-stander substituents) and remote substituents.
Because the reactivity of a carbene is dependent on whether it is
in the singlet or triplet state, the magnitude of the singlet–triplet
gap is of great importance. According to Hund’s rule, the triplet state
of a carbene should be more stable than the singlet state. However,
the singlet–triplet gap (DEST) is dependent on the energy separation
Figure 2. Enthalpy profile (in kcal molꢁ1) for the 1,5 C–H insertion process of the al-
kylidenecarbene into the substituents at C-1 and C-3. (Free energy differences are
shown in parenthesis.)
between the two nonbonding orbitals. If that gap is small, Hund’s
rule is operative, and the triplet state is favoured. As the separation
between the two orbitals increases, it eventually outweighs the
greater Coulombic repulsion between the two electrons in the
singlet state, and the singlet form becomes the ground state.
(Fig. 2). In this conformation, the non-reactive methoxy group
forms a weak hydrogen bond with the endocyclic oxygen (C–H/
O¼2.608 Å),23,24 whereas the electrostatic repulsion between both
heteroatoms (endo- and exocyclic oxygens) is minimized. These
effects could block, at least partially, the formation of the regioi-
someric adduct. Rotamers B2–B3 involve both heteroatoms par-
tially aligned, and therefore repelling each other. Hence, these
results suggest that the formation of a five-membered CH/O hy-
drogen bond plays an important role in making conformation B1 as
the most favourable for both the states.
3.1. The reactivity of alkylidenecarbene at C-2/C-3
Firstly, we have focussed on an alkylidenecarbene at C-2, and
accordingly, we have analyzed the alkylidenecarbene B as theo-
retical model of the carbene derived from 13 (Scheme 4). Con-
formers B1–B3 (Fig. 1) in the single state show a suitable
conformation of the methyl ether moiety in relation to the carbene
to undergo the insertion process. Noteworthy, B1 showing the
lowest energy should give rise to the observed cyclopentene C
As depicted in Figure 1, our calculations indicate that carbene B
should have a singlet ground state. Experimental evidence for
Figure 1. Relative energy (in kcal molꢁ1) of the singlet and triplet state for conformers B1–B4.

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A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
a singlet state may be found in earlier work by Gilbert and Ohira
who have confirmed that C–H insertion into a stereochemically
defined methine proceeded with retention of absolute config-
uration.5c,25 Moreover, it should be noted that the excitation en-
ergies from the singlet ground state to the first triplet excited state
are quite large (45.5–48.3 kcal molꢁ1). This means that production
of the first excited triplet state under experimental conditions is
practically impossible. Thus, only the singlet potential surface was
considered throughout this work.26
A close inspection by IRC calculations of the electronic nature of
the involved moieties around the transition state (Fig. 3) indicates
a notable development of negative charge at the carbene atom, on
going from the open to the cyclized form. As can be seen in Figure 3,
the insertion of the alkylidenecarbene into the C–H bond occurs
initially through an electrophilic phase followed by a nucleophilic
phase resulting in a net charge flow from the alkane to the inserting
carbene during the first part of the reaction.
The experimental observations indicated that glycoside 13 (and
The conformers B1–B3 show short H/CCARB distance and long
C–H bond so they can be viewed as precursor complexes25 or even
ylide-like complexes, since they all possess a similar ylide structure.
They are true minima on the potential energy surface, with energy
values in the range ꢁ2.4–(þ1.4) kcal molꢁ1 in relation to the cor-
responding uncoordinated carbene structure B4.
The optimized six-membered transition structure to form TSB1
resembles a half chair, showing the hydrogen atom of interest in
a plane defined by the carbon atom to which it originally is attached
and the doubly bound carbon atoms of the carbene (deviation of
10.4ꢀ). In this arrangement, methyl C–H bond molecular orbital is
periplanar with and therefore can overlap with the empty orbital of
the alkylidenecarbene.27 This is a late transition structure, since the
C–H length is long (1.517 Å) and the CCARB–H bond is nearly formed
(1.156 Å).
However, the C–CCARB distance is still rather large, suggesting
a strong asynchronicity in the formation of both the C–C and C–H
bonds. These results might put forward a stepwise insertion
mechanism, a reaction path that indeed we have found for the
triplet state (see Supplementary data). However, IRC calculations
have verified that this transition structure connects precursor
complex B1 to the insertion product C1. The 1,5-insertion reaction
with C–H by alkylidenecarbenes is strongly exothermic
(ꢁ78.0 kcal molꢁ1, Fig. 2), and hence irreversible.
its a-anomer 7) gives rise to 15 (and 9), suggesting a total regio-
chemical 1,5 C–H bond insertion of the alkylidenecarbene in-
termediate into the methyl ether at C-3. The calculations on the
alternative path (i.e., insertion into the substituent at C-1) for the
theoretical model reveal that the likely carbene intermediate B2 is
isoenergetic with the transition structure TSB1 in the reaction path
driving to C1. Going from B2 toTSB2 the C–H bond is lengthened from
1.109 to 1.515 Å, whereas the distance from the carbene carbon to the
alkene carbon and moving hydrogen decrease dramatically from
2.235 and 1.154 Å. The alkene insertion leads to the formation of C2,
which lies 78.8 kcal/mol below carbene B2 (Fig. 2). The free energy
required to reach TSB2 from B2 is 3.2 kcal/mol, being 3.1 kcal molꢁ1
less stable than the regioisomeric transition structure TSB1
.
These results account for the experimental evidences (regiose-
lective formation of cyclopentenes 9 and 15), which indicated a se-
lective 1,5 C–H bond insertion reaction favouring exclusively the
transfer of the proton linked to the substituent at C-3 instead of the
proton linked to that at C-1, and suggest that the regioselectivity may
be related to the anomeric effect. Thus, the conformation of the
anomeric methoxy moiety in B1 and the ensuing TSB1 and product
C1, involving a weak hydrogen bond with the endocyclic oxygen and
minimization of electrostatic repulsion between heteroatoms,
would promote the regioselective C–H insertion of the carbene into
the substituent at C-3. To verify this hypothesis, we have estimated
the activation barrier for this step from conformer B2 devoid of these
stabilizing interactions. As expected, the transition structure TS0B1 is
2.4 kcal molꢁ1 higher than TSB1 so the conformation of the sub-
stituent at the anomeric position has a critical effect in the reactivity
and regioselectivity in the insertion step in an apolar medium.
While 13 bearing the ‘donor carbon’ at C-3 afforded regiose-
lectively 15 in high yield, its isomer 12 bearing the ‘donor carbon’ at
C-2 provided the cyclized product 14 in very poor yield. Further-
more, this outcome appears independent of the anomeric config-
uration, since the alkylidenecarbene epimers from 6 and 7 provided
the cyclized adduct in low and high yield, respectively (Scheme 3).
These striking results were also analyzed by DFT methodology. The
Alkylidenecarbenes are expected to be electrophilic because of
their electron deficiency. This is confirmed by the computed NPA
atomic charge on the carbene carbon on B1 (þ0.148). The NPA
computation also reveals a charge of ꢁ0.295 for the alkane carbon
(þ0.151 for the CH2 fragment). These results contrast with those of
the cyclized product, that shows values of ꢁ0.217 and ꢁ0.123
(þ0.319), respectively. The charge for the moving hydrogen varies
from þ0.242 in B1 to þ0.256 in C1.
Figure 3. Evolution of the charge on the reactive moieties around the transition state.
Figure 4. Transition structure for alkylidenecarbene intermediates D and E.

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9385
Bn
The results summarized above rationalize some of the experi-
mental evidences regarding the position of the alkylidenecarbene
on the pyran and anomeric configuration.
Our next target was the analysis of the substitution (H or Ph) at
the ‘carbon donor’ in the 1,5 C–H bond insertion process and the
competition with a 1,6 C–H bond insertion (Scheme 9).
O
O
OMe
OBn
BnO
F
Figure 5.
3.2. The analysis of the substitution (H or Ph) at the ‘carbon
donor’ in the 1,5 C–H bond insertion process
computed data reveal that the insertion of the alkylidenecarbene
models D ( -anomer) and E ( -anomer) (Fig. 4) proceeds by over-
a
b
coming an enthalpy barrier of 4.0 and 3.3 kcal/mol, respectively
(free energy barriers of 5.1 and 4.6 kcal molꢁ1, respectively). In
every case, the interatomic distances of the endocyclic and
methoxy oxygen in the transition state (2.671 and 2.814, re-
spectively; see Fig. 4) are shorter than the sum of the van der Waals
radii of the oxygen atoms. This effect could account for the de-
stabilization of the transition structure, even if the substituent at
the anomeric site adopts the most favourable conformation.
On other hand, the electronic properties indicate that the effect
of two ether groups at the anomeric carbon C-1, enhances the
We have selected structure F as theoretical model. In this case, it
is remarkable that the structure of the alkylidenecarbene, which
shows a strong interaction of the vacant orbital on the carbene with
an oxygen lone pair of the O-benzyl oxygen (Fig. 5). This interaction
produces the transient oxonium ylide, which would block the in-
sertion with that branch, hence driving the insertion with the
substituent at C-3.
The 1,5 C–H insertion is initiated by interaction of the LUMO of
the carbene with the alkane, i.e., the hydrogen moves towards the
carbenic carbon by following a trajectory in the plane of C4–CCARB
–
charge separation in the alkylidenecarbene group C-2–CCARB
,
C plane. At the transition state TSF5 (Fig. 5), the attacked C–H bond
is almost broken (1.513 Å), whereas with 1.159 Å the distance be-
tween the carbene carbon and the hydrogen corresponds almost to
a C–H bond. The forming C–C bond presents a large value (2.317 Å).
The insertion proceeds with an enthalpy barrier of 1.1 kcal molꢁ1
making a more electrophilic CCARB, whereas this effect is negligible
and the charge separation lower when carbene is located at C-3
(ꢁ0.393 and þ0.148 in B1, ꢁ0.371 and þ0.134 in D). However, the
computed barriers seem low and cannot wholly justify the low
yield for this process, so likely other factors must come into play.
(D
G#¼2.5 kcal molꢁ1).
Figure 6. Enthalpy profile (in kcal molꢁ1) for the 1,5 and 1,6 C–H insertion processes of the alkylidenecarbene G into the substituents at C-3 and C-5. (Free energy differences are
shown in parenthesis.)

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A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
On the other hand, the transition structure for the 1,5 C–H
substitution (H or Ph) at the ‘carbon donor’ in the 1,5 C–H bond
insertion process. In overall, using these key 1,5 C–H bond insertion
reactions a simple protocol results for the synthesis of the furo
[x,y-c]pyrans, difficult to be prepared by other methodologies, from
moderate to good yields. Finally, the DFT study of different struc-
tural parameters such as the location of the alkylidenecarbene (C2,
C3 and C4), the anomeric configuration and the substitution at the
‘carbon donor’ in the 1,5 C–H insertion reaction has allowed us to
rationalize the experimental findings and get insights into the acute
regioselectivity observed when a 1,6 C–H insertion is also possible.
insertion of the methyl ether analogue, G, shows similar lengths
for the forming (1.151 Å) and breaking (1.526 Å) C–H bonds. In
contrast, it displays a shorter distance for the forming C–C bond
than the O-benzyl analogue, which suggests a later transition
state with larger synchronicity. The enthalpy barrier to achieve
the transition state is 3.8 kcal molꢁ1
(D
G#¼4.2 kcal molꢁ1), and
expectedly the reaction is strongly exothermic
(D
H¼ꢁ74.5,
D
G¼ꢁ73.5 kcal molꢁ1).
The computed results for F and G agree with previous findings,
which suggest that the intramolecular 1,5 C–H bond insertion re-
action of alkylidenecarbenes is dependent on, among other things,
the dissociation energy of the C–H bond undergoing insertion. That
is to say, the efficiency of the 1,5 mode in aliphatic systems is in-
versely related to the dissociation energy of the C–H bond un-
dergoing insertion2d,28 (i.e., primary>benzylic).
5. Experimental
5.1. General
Materials and methods. Melting points were determined on
a digital melting-point apparatus (Electrothermal) and are un-
corrected. Optical rotations were recorded in CH2Cl2, CHCl3, MeOH,
with a digital polarimeter using a 1 dm cell. 1H NMR and 13C NMR
spectra were recorded in CDCl3, acetone-d6, Me2SO-d6, or MeOD-d3
(internal SiMe4), respectively, at 300.13 MHz and at 75.47 MHz. TLC
was performed on Silica F254 and detection by UV light at 254 nm
or by charring with phosphomolybdic acid–H2SO4 reagent. Column
chromatography was effected on Silica Gel 60 (230 mesh). Acetone,
hexane, cyclohexane, ethyl acetate and diethyl ether were distilled
before use. Bases and solvents were used as supplied. 13C NMR
resonances have been assigned by using standard NMR (DEPT,
COSY, HSQC) experiments. FTIR spectra were obtained neat using
3.3. The site selectivity with regard to insertion at C-5
versus C-6
The site selectivity with regard to insertion at C-5 versus C-6
of the alkylidenecarbene was qualitatively assessed by exami-
nation of the cyclation for both alkylidenecarbenes F and G.
Gilbert et. al have suggested a stepwise pathway for this less
frequent insertion process where a intermolecular H exchange
takes place with the medium.7b In contrast, Feldman et al. have
found evidences that rule out any mechanism that requires H
exchange.7a
The 1,6 C–H insertion takes place through a seven-membered
transition structure, that is very similar for both alkylidene-
carbenes from structural and energetic standpoints. As example,
we describe here the results for G, whose transition structure
TSG6 shows the moving H bonded to the carbene carbon (1.122 Å)
at a distance of 1.601 Å of the donor carbon. The distance C–C is
large at this stage (2.443 Å) pointing to a highly asynchronic
transition structure. The enthalpy barrier for this step is higher
than that for the 1,5 C–H insertion process, 5.8 kcal molꢁ1
ATR and are reported in cmꢁ1
.
5.2. General method for Swern oxidation (A)
DMSO (3.0 equiv) was added dropwise to oxalyl chloride
(2.0 equiv) in CH2Cl2 at ꢁ55 ꢀC and the solution stirred (0.5 h). The
alcohol (1.0 equiv) in CH2Cl2 was then added dropwise to the so-
lution and the resulting solution stirred at ꢁ55 ꢀC (1.5 h). The so-
lution was then warmed to ꢁ30 ꢀC followed by dropwise addition
of Et3N (3.0 equiv). The solution was then warmed to rt and stan-
dard workup (CH2Cl2) yielded the ketone that was used in the next
step without any further purification.
(D
G#¼7.4 kcal molꢁ1, Fig. 6).
These results are in agreement with experimental findings and
justify the total regioselectivity. This preference has its origin in the
enthalpic and additionally entropic factors that favour six- versus
seven-membered cyclic transition states. Thus, the 1,5 C–H in-
sertion step is accompanied by an entropic change,
D
S#, of
ꢁ1.7 cal molꢁ1 Kꢁ1, whereas for the 1,6 process it increases to
5.3. General method for oxidation with PCC (B)
ꢁ5.2 cal molꢁ1 Kꢁ1
.
These data also help to understand the present and precedent
results6,7 showing that only when the 1,5 C–H insertion is blocked,
the reaction pathway redirects the carbene to a less common, ki-
netically less favoured, 1,6-C–H insertion.
To a solution of PCC (2.5 equiv) and powder molecular sieves 3 Å
(2.5 equiv w/w) in CH2Cl2 was slowly added a solution of starting
material in CH2Cl2. The mixture was stirred at rt under argon. After
evaporation of the solvent, the reaction mixture was dissolved with
EtOAc, and filtered through a silica pad. The filtrate was concen-
trated under vacuum and the crude ulose was used in the next step
without further purification.
4. Conclusion
To sum up, our new method for the generation of alkylidene-
carbenes based on the reaction of trimethylsilylazide/Bu2SnO with
a
-cyanomesylates has been applied to readily available sugar de-
5.4. General method for Dess–Martin periodinane oxidation (C)
rivatives for the synthesis of highly functionalized, enantiomeri-
cally pure furo[x,y-c]pyrans. The furo[x,y-c]pyran heterocyclic ring
system is present in a number of natural or non-natural products of
biological interest such as the miharamycins, and deserve partic-
ular attention. The scope and extent of the present new method-
ology has been investigated by systematic modification of the
To a solution of Dess–Martin reagent (3 or 4 equiv) in anhydrous
CH2Cl2 was slowly added a solution of starting material in anhy-
drous CH2Cl2. The mixture was stirred at rt under argon overnight.
Diethyl ether (100 mL), a saturated solution of NaHCO3 (100 mL)
and Na2S2O3 (10 g) were added and stirred for 5 min. After ex-
traction, the organic layer was successively washed with a satu-
rated solution of NaHCO3 (100 mL) and water (100 mL). The organic
phase was separated, dried (Na2SO4), filtered and evaporated to
dryness. The crude ulose was used in the next step without further
purification.
starting sugar precursor (D-glucose, D-galactose, D-mannose) in the
hexo- )- -pyranoside forms, bearing also different O-protecting
a(b D
groups, the effect of the absolute configuration of the substituent at
the anomeric position, the location (C-2, -3 and -4) of the alkyli-
denecarbene species on the pyran nucleus, as well as the

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9387
5.5. General method for cyanomesylation (D)
3H, 2ꢂOSO2CH3); 13C NMR (CDCl3, 75 MHz)
d
136.5–126.3
(2ꢂC6H5), 114.3 (2ꢂCN), 102.2 (2ꢂC-7), 99.5 (2ꢂC-1), 80.6 (2ꢂC-2),
79.3/79.1 (C-3), 78.4 (2ꢂC-4), 68.8/68.7 (C-6), 63.9 (2ꢂC-5), 62.9/
62.8 (OMe), 57.0/56.9 (OMe), 40.4/40.3 (OSO2CH3); HRMS
C17H21NO8NaS: calcd 422.0886, found 422.0893.
To a solution of crude ulose in CH2Cl2 was added a solution of
NaHCO3 (2 equiv) in water and KCN (2.1 equiv). The resulting
mixture was stirred vigorously at rt then extracted with CH2Cl2
(ꢂ2) or the crude ulose was added to a solution of diethyl ether/
H2O (2/1), NaCN (1 equiv) and NaHCO3 (2 equiv) and vigorously
stirred at rt. The organic phase was separated, dried (Na2SO4), fil-
tered and evaporated to dryness. The crude cyanohydrins were
dissolved in CH2Cl2 followed by addition of Et3N (8 equiv) and MsCl
(5.5 equiv) at 0 ꢀC. After stirring at rt, the mixture was extracted by
slow addition of water and CH2Cl2. The residue was purified by
flash chromatography. Alternatively, to a solution of crude ulose in
MeOH was added Ti(OiPr)4 (2 equiv) and the solution was stirred at
rt for 5 h or overnight; then, TMSCN (2 equiv) was added. After
24 h, a few drops of water were added, and EtOAc to dilute the
solution. After evaporation of the solvent, the reaction mixture was
dissolved in EtOAc and filtered through a silica pad. The filtrate was
concentrated under vacuum and the crude cyanohydrins were used
in the next step without further purification.
5.6.2. (2R,4aR,6S,6aR,9bS)-4,4a,6,6a,8,9b-Hexahydro-6-methoxy-2-
phenyl-furo[30,20:4,5]pyrano[3,2-d]1,3-dioxin (8). Following the
general method E, compound 6 (165 mg, 0.41 mmol), Bu2SnO
(102 mg, 0.41 mmol) and TMSN3 (0.09 mL, 0.68 mmol) in toluene
(6.5 mL) reacted for 18 h 30 min, at 100 ꢀC, to give after flash
chromatography (EtOAc/cyclohexane, 1/1), compound 8 (28 mg,
24%) and unreacted starting material (6) (24 mg (14%)). Compound
20
8: white solid; mp 171–173 ꢀC; [
n
a]
þ148 (c 0.22, MeOH); IR (ATR)
D
1382, 1147, 1094, 1042, 962 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.56–7.40 (m, 5H, C6H5), 5.79 (br s, 1H, H-9), 5.67 (s, 1H, H-2), 4.90
(d, J6,6a¼3.5 Hz, 1H, H-6), 4.86 (br s, 1H, H-6a), 4.84–4.81 (m, 2H, H-
8), 4.31 (dd, J4a,4A¼4.2 Hz, J4A,4B¼9.9 Hz, 1H, H-4A), 4.28–4.24 (m,
1H, H-9b), 3.87 (t, J4a,4B¼9.9 Hz, 1H, H-4B), 3.79 (dt, J4a,9b¼9.9 Hz,
1H, H-4a), 3.47 (s, 3H, OMe); 13C NMR (CDCl3, 75 MHz)
d 137.6–
126.7 (C6H5), 133.4 (C-9a), 117.0 (C-9), 102.3 (C-2), 100.7 (C-6), 84.4
(C-6a), 78.4 (C-8), 78.2 (C-9b), 69.9 (C-4), 65.1 (C-4a), 55.7 (OMe).
HRMS C16H18O5Na: calcd 313.1052, found 313.1066.
5.6. General method for alkylidenecarbene generation (E)
To a solution of cyanomesylate in dry toluene under argon,
dibutyltin oxide (1 equiv) and TMSN3 (2 equiv) were added. The
reaction was heated to 100–108 ꢀC and stirred for 1 h 30 min to 19 h
and then the solvent was removed under vacuum. The crude product
was submitted to flash chromatography (EtOAc/cyclohexane).
4
O
4a
Ph
2
O
6
O
OCH3
9b
9a
6a
7
O
8
5.6.1. Methyl 4,6-O-benzylidene-3-C-cyano-3-O-mesyl-2-O-methyl-
a
-
D
-gluco(allo)pyranoside (6) and methyl 4,6-O-benzylidene-2-C-
5.6.3. (2R,4aR,6S,9aR,9bS)-4,4a,6,8,9a,9b-Hexahydro-6-methoxy-2-
phenyl-furo[20,30:4,5]pyrano[3,2-d]1,3-dioxin (9). Following the
general method E, compound 7 (100 mg, 0.25 mmol), Bu2SnO
(62.5 mg, 0.25 mmol) and TMSN3 (0.05 mL, 0.37 mmol), in toluene
(4 mL) reacted for 17 h at 100–103 ꢀC, to give after flash chroma-
cyano-2-O-mesyl-3-O-methyl- -gluco(manno)pyranoside
a-D
(7). Following the general method B, a mixture of 4 and 511 (5.0 g,
16.9 mmol), PCC (8.3 g, 38.7 mmol), powdered molecular sieves 3 Å
(15 g) and CH2Cl2 (2ꢂ50 mL), reacted for 18 h 30 min to give the
corresponding crude ulose (2.8 g) that was used in the next step
without further purification. Following the general method D, to
a solution of this crude ulose in ethyl ether (195 mL) and water
(95 mL) was added NaHCO3 (1.6 g, 19.04 mmol) and NaCN (466 mg,
9.52 mmol). After stirring for 22 h 30 min, the crude cyanohydrins
were dissolved in pyridine (38 mL) followed by slow addition of
MsCl (2.2 mL, 28.56 mmol). After 19 h and extraction (CHCl3/H2O),
the residue was purified by flash chromatography (EtOAc/cyclo-
hexane, 5/5–7/3) to give successively mixtures of diastereoisomers
6 [2.15 g (32%), 78/22 ratio], and 7 [949 mg, (14%), 73/27 ratio].
tography (EtOAc/cyclohexane, 3/7), compound 9 (48 mg, 66%), as
20
a white solid: mp 146–148 ꢀC; [
a]
þ75 (c 0.14, MeOH); IR (ATR)
n
D
2107, 1453, 1378, 1180, 1084, 1053, 1058, 961 cmꢁ1; 1H NMR (CDCl3,
300 MHz) 7.53–7.35 (m, 5H, C6H5), 5.92 (br s, 1H, H-7), 5.60 (s, 1H,
d
H-2), 5.33 (s, 1H, H-6), 5.08–5.10 (m,1H, H-9a), 4.76–4.78 (m, 2H, H-
8), 4.34 (dd, J4a,4A¼4.9 Hz, J4A,4B¼10.0 Hz, 1H, H-4A), 3.93 (dt,
J4a,4B¼J4a,9b¼9.5 Hz, 1H, H-4a), 3.79 (t, J4a,4B¼10.0 Hz, 1H, H-4B),
3.66 (t, J9a,9b¼9.5 Hz, 1H, H-9b), 3.45 (s, 3H, OMe); 13C NMR (CDCl3,
75 MHz) d 137.5–126.7 (C6H5), 135.2 (C-6a), 123.8 (C-7), 101.8 (C-2),
97.7 (C-6), 84.4 (C-9b), 83.5 (C-9a), 76.0 (C-8), 69.3 (C-4), 62.2 (C-
4a), 55.3 (OMe); HRMS C16H18NO5Na: calcd 313.1052, found
313.1053.
Compound 6: solid; IR (ATR)
NMR (CDCl3, 300 MHz)
n
1368, 1184, 1091, 1047, 959 cmꢁ1; 1H
d
7.53–7.36 (m, 5H, 2ꢂC6H5), 5.61 (m, 1H,
2ꢂH-7), 5.00 (m, 1H, 2ꢂH-1), 4.41–4.37 (m, 1H, 2ꢂH-6A), 4.19–4.09
(m, 2H, 2ꢂH-4, 2ꢂH-5), 3.84 (m, 1H, 2ꢂH-2), 3.81–3.77 (m, 1H,
2ꢂH-6B), 3.67 (s, 3H, 2ꢂOMe), 3.52 (s, 3H, 2ꢂOMe), 3.19 (s, 3H,
5.6.4. Methyl 4,6-O-benzylidene-3-C-cyano-3-O-mesyl-2-O-methyl-
b-
D-gluco(allo)pyranoside (12) and methyl 4,6-O-benzylidene-2-C-
2ꢂOSO2CH3); 13C NMR (CDCl3, 75 MHz)
d
129.9–126.7 (2ꢂC6H5),
cyano-2-O-mesyl-3-O-methyl- -gluco(manno)pyranoside
b-D
112.4 (2ꢂCN), 102.7/102.3 (C-7), 97.9 (2ꢂC-1), 82.5 (2ꢂC-3), 81.8/
81.3 (C-2), 79.1 (2ꢂC-4), 69.0/68.8 (C-6), 61.4 (2ꢂC-5), 61.0/60.7
(OMe), 56.5 (2ꢂOMe), 40.4 (2ꢂOSO2CH3); HRMS C17H21NO8NaS:
(13). Following the general method B, a mixture of 10 and 1111
(3.27 g (10.92 mmol)), PCC (5.4 g, 25.11 mmol), molecular sieves 3 Å
(5.4 g) and CH2Cl2 (2ꢂ50 mL) reacted for 18 h to give a crude ulose
(2.35 g), which was used in the next step without further purifi-
cation. Following the general method D, to a solution of this crude
ulose in ethyl ether (160 mL) and water (80 mL) were added
NaHCO3 (1.34 g, 15.98 mmol) and NaCN (392 mg, 15.98 mmol). Af-
ter stirring for 23 h, the crude cyanohydrins were dissolved in
CH2Cl2 (40 mL) followed by addition of Et3N (2.0 mL, 14.35 mmol)
and MsCl (3.4 mL, 43.94 mmol). After 4 h 45 min and extraction,
the residue was purified by flash chromatography (EtOAc/cyclo-
hexane, 5/5) to give a mixture of diastereoisomers 12 [584 mg
(13%), 73/27] and a mixture of diastereoisomers 13 [1.52 g (34%),
calcd 422.0886, found 422.0873. Compound 7: solid; IR (ATR)
n
1374, 1184, 1091, 1002, 964 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 7.50–
7.38 (m, 5H, 2ꢂC6H5), 5.61 (m, 1H, 2ꢂH-7), 5.41/5.27 (s, 1H, 2ꢂH-1),
4.33–4.30 (m, 1H, 2ꢂH-6A), 4.01–3.88 (m, 4H, 2ꢂH-3, 2ꢂH-4,
2ꢂH5, 2ꢂH-6B), 3.76 (s, 3H, 2ꢂOMe), 3.56 (s, 3H, 2ꢂOMe), 3.32 (s,
4
O
2
4a
Ph
O
6
O
OCH3
9b
9a
6a
O
9
8
90/10]. Compound 12: colourless oil; IR (ATR)
n 2358, 1451, 1363,

9388
A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
1183, 1083, 1012, 961, 828 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.55–
6), 85.0 (C-9a), 83.8 (C-9b), 76.5 (C-8), 69.2 (C-4), 66.2 (C-4a), 57.6
(OMe). HRMS C16H18O5Na: calcd 313.1052, found 313.1057.
7.28 (m, 5H, 2ꢂC6H5), 5.64, 5.60 (s, 1H, 2ꢂH-7), 4.58, 4.57 (d,
J1,2¼7.6 Hz, 1H, 2ꢂH-1), 4.46 (m, 1H, 2ꢂH-6A), 4.13 (m, 1H, 2ꢂH-4),
3.87–3.78 (m, 2H, 2ꢂH-6B, 2ꢂH-5), 3.76, 3.72 (s, 3H, 2ꢂOMe), 3.62,
3.58 (s, 3H, 2ꢂOMe), 3.56 (m, 1H, 2ꢂH-2), 3.18 (s, 3H, 2ꢂOSO2CH3);
5.6.7. Methyl 4,6-O-benzylidene-3-C-cyano-3-O-mesyl-2-O-benzyl-
a-D-gluco(allo)pyranoside (17). Following the general method B,
13C NMR (CDCl3, 75 MHz)
d
136.7–126.6 (2ꢂC6H5), 112.3 (2ꢂCN),
1611 (4.35 g, 11.69 mmol), PCC (5.56 g, 26.81 mmol), molecular
sieves 3 Å (10 g) and CH2Cl2 (2ꢂ50 mL) reacted for 18 h to give
crude ulose (3.73 g), which was used in the next step without
further purification. Following the general method D, to a solution
of this crude ulose in CH2Cl2 (190 mL) were added NaHCO3 (1.69 g,
20.07 mmol) in water (95 mL) and KCN (654 mg,10.03 mmol). After
stirring for 2 days and 12 h, the crude cyanohydrins were dissolved
in CH2Cl2 (190 mL) followed by addition of Et3N (14.3 mL,
102.6 mmol) and MsCl (4.3 mL, 55.20 mmol). After 2 days and 4 h
and extraction, the residue was purified by flash chromatography
104.0 (2ꢂC-1), 102.3 (2ꢂC-7), 82.2/83.3 (C-2), 83.2 (2ꢂC-3), 80.0/
79.0 (C-4), 69.0/68.7 (C-6), 65.4/63.3 (C-5), 62.5/62.2 (OMe), 58.3/
58.0 (OMe), 40.5 (2ꢂOSO2CH3). HRMS C17H21NO8NaS: calcd
422.0886, found 422.0886. Compound 13 (major isomer): white
solid; mp 151–153 ꢀC; IR (ATR)
n
2249, 1456, 1372, 1186, 1097, 965,
7.51–7.38 (m, 5H, C6H5), 5.61
751 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
(s, 1H, H-7), 4.79 (s, 1H, H-1), 4.41 (dd, J5,6A¼4.9 Hz, J6A,6B¼10.5 Hz,
1H, H-6A), 3.98–3.85 (m, 3H, H-3, H-4, H-6B), 3.74 (s, 3H, OMe),
3.67 (s, 3H, OMe), 3.55 (m, 1H, H-5), 3.27 (s, 3H, OSO2CH3); 13C NMR
(CDCl3, 75 MHz)
d
137.0–126.3 (C6H5), 112.4 (CN), 101.0, 101.8 (C-7,
(EtOAc/cyclohexane, 1/1) to give a mixture of the two di-
C-1), 83.4 (C-2), 81.9, 80.8 (C-3, C-4), 68.4 (C-6), 67.2 (C-5), 62.3
(OMe), 58.5 (OMe), 40.7 (OSO2CH3). HRMS C17H21NO8NaS: calcd
422.0886, found 422.0886.
astereoisomers 17 [693 mg (14%) 73/27 ratio], and a mixture of
unreacted ulose, cyanohydrins and cyanomesylate (1.65 g). Com-
pound 17: solid; IR (ATR)
n
2253, 1962, 1360, 1184, 1078, 970,
7.54–7.37 (m, 10H, 2ꢂC6H5),
947 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
4
O
2
5.62, 5.60 (s, 1H, 2ꢂH-7), 5.03/4.88 (d, JA,B¼11.9 Hz, 1H, OCH2C6H5),
4.94/4.75 (d, 1H, OCH2Ph), 4.65/4.59 (d, J1,2¼3.6 Hz, 1H, H-1), 4.34
(m, 1H, 2ꢂH-6A), 4.19–4.11 (m, 1H, 2ꢂH-5), 3.95/3.89 (d, 1H, H-2),
3.83 (d, J4,5¼9.5 Hz, 1H, 2ꢂH-4), 3.71 (t, J6A,6B¼J5,6B¼10.4 Hz, 1H,
2ꢂH-6B), 3.43/3.41 (s, 3H, 2ꢂOMe), 3.23/3.14 (s, 3H, 2ꢂOSO2CH3);
4a
Ph
O
6
O
OCH3
9b
9a
6a
O
9
8
13C NMR (CDCl3, 75 MHz)
d
137.0–126.7 (2ꢂC6H5), 115.5/112.6 (CN),
102.4/102.3 (C-7), 98.8/98.5 (2ꢂC-1), 79.7/79.2 (C-4), 78.8/77.1 (C-
2), 76.5 (2ꢂC-3), 74.8/74.2 (OCH2C6H5), 68.9 (2ꢂC-6), 61.4/58.4 (C-
5), 56.8/56.5 (OMe), 40.7, 40.5 (OSO2CH3). HRMS C23H25NO8NaS:
calcd 498.1199, found 498.1195.
5.6.5. (2R,4aR,6R,6aR,9bS)-4,4a,6,6a,8,9b-Hexahydro-6-methoxy-2-
phenyl-furo[30,20:4,5]pyrano[3,2-d]1,3-dioxin (14). Following the
general method E, compound 12 (169 mg, 0.42 mmol), Bu2SnO
(105 mg, 0.42 mmol) and TMSN3 (0.10 mL, 0.75 mmol) in toluene
(6.7 mL) reacted for 17 h at 103 ꢀC to give after flash chromatog-
4
O
2
raphy (EtOAc/cyclohexane, 2/8), compound 14 (5 mg, 4%) as a white
4a
20
Ph
O
solid: mp 177–179 ꢀC; [
a
]
ꢁ28 (c 0.06, CHCl3); IR (ATR)
n 2109,
6
D
O
OCH3
1452, 1369, 1210, 1092, 1022, 969 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
7.55–7.35 (m, 5H, C6H5), 5.81–5.80 (m, 1H, H-9), 5.67 (s, 1H, H-2),
9b
9a
6a
d
8 O
Ph
9
4.82–4.79 (m, 2H, H-8), 4.60–4.55 (m, 1H, H-6a), 4.39 (dd,
J4a,4A¼4.7 Hz, J4A,4B¼10.5 Hz, 1H, H-4A), 4.32 (d, J6,6a¼7.1 Hz, 1H, H-
6), 4.27–4.23 (m, 1H, H-9b), 3.90 (t, J4a,4B¼10.5 Hz, 1H, H-4B), 3.60
(s, 3H, OMe), 3.37 (dt, J9b,4a¼9.3 Hz, 1H, H-5); 13C NMR (CDCl3,
5.6.8. (2R,4aR,6S,6aR,8R,9bS)- and (2R,4aR,6S,6aR,8S,9bS)-6-Methoxy-
4,4a,6,6a,9b-pentahydro-2,8-di-phenyl-furo[30,20:4,5]pyrano[3,2-d]1,3-
dioxin (18). Following the general method E, products 17 (200 mg,
0.42 mmol), Bu2SnO (105 mg, 0.42 mmol) and TMSN3 (0.09 mL,
0.68 mmol), in toluene (8.5 mL) reacted for 18 h at 108 ꢀC to give
after flash chromatography (EtOAc/cyclohexane, 2/8), compounds 18
[34 mg (22%), 65/35 ratio], and unreacted starting material (17)
75 MHz)
d 137.5 (C-9a), 136.2–126.6 (C6H5), 117.8 (C-9), 107.4 (C-6),
102.2 (C-2), 86.3 (C-6a), 78.1 (C-9b), 77.7 (C-8), 71.3 (C-4a), 69.6 (C-
4), 57.6 (OMe) HRMS C16H18O5Na: calcd 313.1052, found 313.1059.
4
O
2
4a
Ph
O
6
O
OCH3
9b
9a
6a
7
(35 mg, 17%). Compound 18: solid; IR (ATR)
n
1647, 1454, 1370, 1091,
7.57–7.30 (m, 10H,
O
1043, 977 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
8
4ꢂC6H5), 6.01, 5.94 (m,1H, 2ꢂH-8), 5.88, 5.74 (m,1H, 2ꢂH-9), 5.69 (s,
1H, 2ꢂH-2), 5.06–4.98 (m, 2H, 2ꢂH-6, 2ꢂH-6a), 4.39–4.31 (m, 2H,
2ꢂH-9b, 2ꢂH-4A), 3.98–3.82 (m, 2H, 2ꢂH-4a, 2ꢂH-4B), 3.53/3.50 (s,
5.6.6. (2R,4aR,6R,9aR,9bS)-4,4a,6,8,9a,9b-Hexahydro-6-methoxy-2-
phenyl-furo[20,30:4,5]pyrano[3,2-d]1,3-dioxin (15). Following the
general method E, compound 13 (400 mg, 1.0 mmol), Bu2SnO
(249 mg, 1.0 mmol) and TMSN3 (0.23 mL, 1.73 mmol) in toluene
(16 mL) reacted for 16 h 30 min at 98–103 ꢀC to give after flash
3H, 2ꢂOMe); 13C NMR (CDCl3, 75 MHz)
d 141.6/141.2 (C-9a), 137.6–
126.7 (4ꢂC6H5), 120.8/120.6 (C-9), 102.3 (2ꢂC-2), 100.1 (2ꢂC-6),
90.9/90.6 (2ꢂC-8), 84.2 (2ꢂC-6a), 78.0/77.9 (C-9b), 66.9 (2ꢂC-4)
65.4/64.6 (2ꢂC-4a), 55.8/55.6 (OMe). HRMS C22H22O5Na: calcd
389.1365, found 389.1362.
chromatography (EtOAc/cyclohexane, 3/7), compound 15 (214 mg,
20
73%) as a white solid: mp 176–8 ꢀC; [
a
]
D
ꢁ75 (c 0.22, CHCl3); IR
5.6.9. Methyl 4,6-O-benzylidene-2-C-cyano-2-O-mesyl-3-O-benzyl-
a-D-manno(gluco)pyranoside (20). Following the general method C,
(ATR)
n
1454, 1382, 1207, 1076, 1049, 1010, 946 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz)
d
7.54–7.35 (m, 5H, C6H5), 6.00 (br s, 1H, H-7),
product 1913 (1.0 g, 2.68 mmol) in anhydrous CH2Cl2 (20 mL) was
treated with Dess–Martin reagent (3.42 g, 8.06 mmol, 3 equiv) in
anhydrous CH2Cl2 (20 mL) for 24 h to give the crude ulose (430 mg).
Following the general method D, to a solution of the crude ulose
(300 mg, 0.81 mmol) in MeOH (20 mL), reacted with Ti(OiPr)4
(0.48 mL,1.62 mmol) and TMSCN (0.22 mL,1.62 mmol) to provide the
5.59 (s, 1H, H-2), 5.06 (s, 1H, H-6), 4.92–4.90 (m, 1H, H-9a), 4.79–
4.77 (m, 2H, H-8), 4.39 (dd, J4a,4A¼5.0 Hz, J4A,4B¼10.5 Hz, 1H, H-4A),
3.85 (t, J4a,4B¼10.2 Hz, 1H, H-4B), 3.64 (t, J9a,9b¼J9b,4a¼9.5 Hz, 1H, H-
9b), 3.64 (s, 3H, OMe), 3.52 (dt, 1H, H-4a); 13C NMR (CDCl3, 75 MHz)
d
137.5–126.6 (C6H5), 135.7 (C-6a), 122.8 (C-7), 101.7 (C-2), 99.7 (C-

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9389
crude cyanohydrins, which were dissolved in CH2Cl2 (20 mL). After
addition of Et3N (0.91 mL, 6.48 mmol) and CH3SO2Cl (0.34 mL,
4.46 mmol), the reaction mixture was stirred overnight; then,
extracted and the residue purified by flash chromatography (EtOAc/
cyclohexane, 25/75) to give a mixture of diastereoisomers 20 [270 mg
(70%), (75/25 ratio)] as a slight yellow syrup; 1H NMR (CDCl3,
(OCH2C6H5), 68.7 (C-6), 63.4 (C-5), 40.2 (OSO2CH3). HRMS
C29H29NO8NaS: calcd 574.1512, found 574.1500.
5.6.12. (2R,4aR,6S,8R,9aR,9bS)- and (2R,4aR,6S,8S,9aR,9bS)-6-Benzyl
oxy-4,4a,6,9a,9b-pentahydro-2,8-di-phenyl-furo[20,30:4,5]pyr-
ano[3,2-d]1,3-dioxin (24). Following the general method E, com-
pound 23 (100 mg, 0.18 mmol), Bu2SnO (45 mg, 0.18 mmol) and
TMSN3 (0.04 mL, 0.31 mmol) in toluene (3 mL) reacted for 18 h at
93–96 ꢀC to give after flash chromatography (EtOAc/cyclohexane, 2/
8), compound 24 [41 mg (52%), 25/75 ratio] as a white solid; IR
300 MHz)
d
7.52–7.36 (m, 5H, 2ꢂC6H5), 5.64/5.63 (s, 2H, H-7), 5.44/
5.28 (s, 2H, H-1), 4.97–4.81 (m, 3H, OCH2C6H5), 4.78 (d, J¼11.8 Hz, 1H,
OCH2C6H5), 4.37–4.29 (m, 3H, 2ꢂH-6A, H-4), 4.20 (d, J3,4¼9.6 Hz, 1H,
H-4), 4.05 (d, 1H, H-3), 4.01–3.97 (m, 2H, 2ꢂH-3, H-5), 3.93–3.89 (m,
3H, H-5, 2ꢂH-6B), 3.55 (s, 3H, 2ꢂOCH3), 3.25/3.12 (s, 3H,
(ATR)
300 MHz)
n ;
2922, 2108, 1454, 1373, 1093, 1025 cmꢁ1 1H NMR (CDCl3,
2ꢂOSO2CH3); 13C NMR (CDCl3, 75 MHz)
d
137.9–137.2, 129.6–126.4
d
7.58–7.36 (m, 15H, 6ꢂC6H5), 5.95–5.91 (m, 1H, 2ꢂH-7),
(2ꢂC6H5), 114.6/114.5 (CN), 102.2/102.1 (C-7), 99.6/99.5 (C-1), 80.9/
79.5(C-2), 80.4/78.4,78.0/77.2(2ꢂC-3,2ꢂC-4), 76.5/76.4(OCH2C6H5),
68.8/68.7 (C-6), 63.9/63.1 (C-5), 57.0/56.9 (OCH3), 40.2 (2ꢂOSO2CH3).
HRMS C23H25NO8NaS: calcd 498.1199, found 498.1187.
5.88–5.87 (m, 1H, 2ꢂH-8), 5.68/5.65 (s,1H, 2ꢂH-2), 5.60/5.57 (s, 1H,
2ꢂH-6), 5.38–5.28 (m, 1H, 2ꢂH-9a), 4.84–4.80 (m, 1H,
2ꢂOCH2C6H5), 4.68–4.64 (m, 1H, 2ꢂOCH2C6H5), 4.35–4.30 (m, 1H,
2ꢂH-4A), 4.14–4.10 (m, 1H, 2ꢂH-4a), 3.89–3.78 (m, 2H, 2ꢂH-9b,
2ꢂH-4B); 13C NMR (CDCl3, 75 MHz)
d
140.9 (2ꢂC-6a), 137.5–127.4
(6ꢂC6H5), 126.8/126.5 (2ꢂC-7), 101.8 (2ꢂC-2), 96.0 (2ꢂC-6), 88.8/
88.4 (C-8), 85.3/85.0 (C-9b), 83.7 (2ꢂC-9a), 69.9/69.6 (OCH2C6H5),
69.3 (2ꢂC-4), 62.5 (2ꢂC-4a). HRMS C28H26O5Na: calcd 465.1678,
found 465.1688.
4
O
2
4a
Ph
O
6
O
OCH3
9b
9a
6a
7
8
O
5.6.13. Methyl
3,4,6-tri-O-benzyl-2-C-cyano-3-O-mesyl-a-D-gluco
(manno)pyranoside (26). Following the general method B, com-
pound 2515 (1.0 g, 2.15 mmol), PCC (1.16 g, 5.38 mmol), molecular
sieves 3 Å (2.5 g) and CH2Cl2 (2ꢂ30 mL) reacted for 24 h to give the
crude ulose (950 mg), which was used in the next step without
further purification. Following the general method D, to a solution
of this crude ulose in CH2Cl2 (30 mL) were added NaHCO3 (361 mg,
4.3 mmol) in water (4.98 mL) and KCN (299 mg, 4.60 mmol). After
stirring for 27 h, the crude cyanohydrins were dissolved in CH2Cl2
(30 mL) followed by addition of Et3N (2.41 mL,17.2 mmol) and MsCl
(0.91 mL, 11.82 mmol). After 5 h and extraction, the residue was
purified by flash chromatography (EtOAc/cyclohexane, 20/80) to
give an unseparable mixture of diastereoisomers 26 [637 mg (52%),
Ph
5.6.10. (2R,4aR,6S,8R,9aR,9bS)- and (2R,4aR,6S,8S,9aR,9bS)-6-Me-
thoxy-4,4a,6,9a,9b-pentahydro-2,8-di-phenyl-furo[20,30:4,5]pyr-
ano[3,2-d]1,3-dioxin (21). Following the general method E,
compound 20 (500 mg, 1.05 mmol), Bu2SnO (260 mg, 1.05 mmol)
and TMSN3 (0.28 mL, 2.10 mmol) in toluene (10.5 mL) reacted for
18 h at 100 ꢀC to give after flash chromatography (EtOAc/cyclo-
hexane, 1/9), products 21 (196 mg, 51%, 25/75 ratio) as a white
solid; 1H NMR (CDCl3, 300 MHz)
d
7.57–7.42 (m, 10H, 4ꢂC6H5),
5.96–5.89 (m, 2H, 2ꢂH-7, 2ꢂH-8), 5.66 (s, 1H, 2ꢂH-2), 5.40/5.38 (s,
1H, 2ꢂH-6), 5.28–5.23 (m, 1H, 2ꢂH-9b), 4.40 (dd, J4a,4A¼4.8 Hz,
J4A,4B¼10.5 Hz, 1H, 2ꢂH-4A), 4.09, 3.98 (m, 1H, 2ꢂH-4a), 3.91–3.79
(m, 2H, 2ꢂH-4B, 2ꢂH-9a), 3.49 (s, 3H, 2ꢂOCH3); 13C NMR (CDCl3,
78/22 ratio] as a slight yellow syrup; IR (ATR)
n
2929–2864, 1454,
7.43–7.21
1372, 1185, 1061, 1026 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
(m, 15H, 6ꢂC6H5), 5.49/5.40 (s, 1H, 2ꢂH-1), 5.09–4.54 (m, 6H,
6ꢂOCH2C6H5), 4.32/4.23 (d, J3,4¼8.8 Hz, 1H, 2ꢂH-3), 4.02–3.93 (m,
2H, 2ꢂH-4, 2ꢂH-5), 3.83 (dd, J5,6A¼4.0 Hz, J6A,6B¼11.0 Hz, 1H, 2ꢂH-
6A), 3.75 (dd, J5,6B¼1.5 Hz, 1H, 2ꢂH-6B), 3.57/3.55 (s, 3H, 2ꢂOCH3),
75 MHz)
d
140.9 (2ꢂC-6a), 137.6–135.6, 129.4–126.8 (4ꢂC6H5, 2ꢂC-
7), 101.8 (2ꢂC-2), 97.8/97.6 (C-6), 88.8/88.4 (C-8), 85.3/85.0 (C-9a),
83.7/83.6 (C-9b), 69.3 (C-4), 62.3/62.2 (C-4a), 55.3 (2ꢂOCH3). HRMS
C22H22O5Na: calcd 389.1365, found 389.1356.
3.21/3.06 (s, 3H, 2ꢂOSO2CH3); 13C NMR (CDCl3, 75 MHz)
d 138.4–
137.4 (6ꢂCq C6H5), 129.0–128.0 (C6H5), 115.2/114.5 (CN), 98.3 (2ꢂC-
1), 81.5/78.8 (C-2), 77.0/74.7 (C-4), 77.0/76.9/76.0/75.9/74.0/73.9
(OCH2C6H5), 72.2/71.3 (C-5), 68.5/68.4 (C-6), 56.8/56.7 (OCH3),
40.5/40.1 (OSO2CH3). HRMS C27H32N3O10S: calcd 590.1808, found
590.1812.
5.6.11. Benzyl 4,6-O-benzylidene-2-C-cyano-2-O-mesyl-3-O-benzyl-
a-D-gluco(manno)pyranoside (23). Following the general method B,
product 2214 (1.4 g, 3.12 mmol), PCC (1.5 g, 7.19 mmol), molecular
sieves 3 Å (2.8 g) and CH2Cl2 (2ꢂ14 mL) reacted for 17 h to give
a crude ulose (937 mg), which was used in the next step without
further purification. Following the general method D, to a solution
of this crude ulose in ethyl ether (40 mL) and water (15 mL) were
added NaHCO3 (353 g, 4.2 mmol) and NaCN (103 mg, 2.1 mmol).
After stirring for 2 days and 12 h, the crude cyanohydrins were
dissolved in CH2Cl2 (14 mL) followed by addition of Et3N (2.9 mL,
20.80 mmol) and MsCl (0.89 mL, 11.5 mmol). After 19 h 30 min and
extraction, the residue was purified by flash chromatography
(EtOAc/cyclohexane, 3/7) to give compound diastereomerically
pure 23 (230 mg, 20%) and a complex mixture of cyanomesylate
BnO
8
7
6
O
BnO
OMe
3a
4
3
7a
O
2
Ph
5.6.14. (2R,4S,6R,7S,7aR)- and (2S,4S,6R,7S,7aR)-7-(Benzyloxy)-6-(ben-
zyloxymethyl)-4-methoxy-2-phenyl-4,6,7,7a-tetrahydro-2H-furo[3,2-
c]pyran (27). Following the general method E, compounds 26
(325 mg, 0.57 mmol), Bu2SnO (142 mg, 0.57 mmol) and TMSN3
(0.15 mL, 1.14 mmol) in toluene (5.7 mL) reacted for 19 h at 100 ꢀC to
give after flash chromatography (EtOAc/cyclohexane, 15/85), com-
pound 27 [117 mg (44%), 72/28 ratio] and unreacted starting material
and unreacted alcohol (632 mg). Compound 23: oil; IR (ATR)
n 2351,
1455, 1374, 1185, 1076, 1017, 962 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.48–7.33 (m, 15H, 3ꢂC6H5), 5.66 (s, 1H, H-7), 5.64 (s, 1H, H-1),
4.98, 4.88 (d, J¼11.6 Hz, 2H, OCH2C6H5), 4.78, 4.74 (d, 2H,
OCH2C6H5), 4.27–4.22 (m, 2H, H-6A, H-3), 4.04–3.95 (m, 2H, H-5, H-
(26) (48 mg (6.7%)). Compound 27: yellow syrup; IR (ATR)
2856, 1495, 1454, 1357, 1099, 1064, 1026, 970 cmꢁ1; 1H NMR (CDCl3,
300 MHz)
n 2917–
4), 3.85 (t, J6A,6B¼J5,6B¼9.9 Hz, 1H, H-6B), 3.09 (s, 3H, OSO2CH3); 13
C
d
7.39–7.25 (m, 15H, 6ꢂC6H5), 5.94/5.91 (d, J7,7a¼4.4 Hz,1H,
NMR (CDCl3, 75 MHz)
d
137.1–126.4 (3ꢂC6H5), 114.4 (CN), 102.4 (C-
2ꢂH-7), 5.87/5.80 (m, 1H, 2ꢂH-3), 5.41/5.38 (s,1H, 2ꢂH-4), 5.31/5.23
(m, 1H, 2ꢂH-2), 5.07–4.96/4.72–4.58 (m, 4H, 4ꢂOCH2C6H5), 4.02–
7), 98.4 (C-1), 80.9 (C-2), 80.5, 78.2 (C-3, C-4), 76.5 (OCH2C6H5), 72.4

9390
A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
3.90 (m, 1H, 2ꢂH-6), 3.85–3.81 (m, 2H, 2ꢂH-8a, 2ꢂH-8b), 3.79–3.72
(m, 1H, 2ꢂH-7a), 3.49–3.48 (s, 3H, 2ꢂOCH3); 13C NMR (CDCl3,
the reaction mixture was stirred overnight; then, extracted and the
residue purified by flash chromatography (EtOAc/cyclohexane, 20/
80) to give a mixture of diastereoisomers 31 [960 mg (89%), 70/30
75 MHz)
d
141.4 (2ꢂC-3a), 138.6–135.8 (6ꢂCq C6H5), 129.0–126.9
(6ꢂC6H5), 125.8/125.3 (C-3), 97.0/96.7 (C-4), 88.6/88.5 (C-7), 88.3
(2ꢂC-2), 80.5/80.4 (C-7a), 73.9 (2ꢂOCH2C6H5), 73.3/73.1
(2ꢂOCH2C6H5), 69.8 (2ꢂC-6), 69.3/69.1 (2ꢂC-8), 55.1 (2ꢂOCH3).
HRMS C29H30O5Na: calcd 481.2000, found 481.1991.
ratio] as slight yellow syrup; IR (ATR):
n
1454, 1371, 1186, 1112, 1028,
7.46–7.36 (m, 15H, 6ꢂC6H5),
961 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
5.04 (m, 1H, OCH2C6H5), 4.89–4.57 (m, 6H, 2ꢂH-1, 5ꢂOCH2C6H5),
4.33–4.23 (m, 2H, 2ꢂH-3, 2ꢂH-5), 4.08–4.01 (m, 1H, 2ꢂH-6A),
3.92–3.75 (m, 2H, 2ꢂH-2, 2ꢂH-6B), 3.47/3.45 (s, 3H, 2ꢂOSO2CH3),
5.6.15. Methyl 2,3-di-O-methyl-6-O-benzyl-4-C-cyano-4-O-mesyl-
a-
3.03/2.92 (s, 3H, 2ꢂOCH3); 13C NMR (CDCl3, 75 MHz)
d 138.1–137.2,
D-gluco(galacto)pyranoside (30). Following the general method C,
129.2–128.0 (6ꢂC6H5), 114.4/113.0 (CN), 98.2/97.8 (C-1), 80.5/79.1
(C-4), 80.1/79.8/76.0 (2ꢂC-2, 2ꢂC-3), 77.6/76.6/74.3/74.2/74.1
(6ꢂOCH2C6H5), 71.4/70.3 (C-5), 68.8/68.4 (C-6), 56.3/56.2 (OCH3),
40.4/40.1 (OSO2CH3). HRMS C30H33O8NSNa: calcd 590.1848, found
590.1825.
product 2816 (1.88 g, 6.02 mmol) in anhydrous CH2Cl2 (20 mL) was
treated with Dess–Martin reagent (7.67 g, 18.1 mmol, 3 equiv) in
anhydrous CH2Cl2 (20 mL) for 24 h to give the crude ulose (1.87 g,
6.02 mmol). Following the general method D, this ulose reacted
with Ti(OiPr)4 (3.61 mL, 12.05 mmol) and TMSCN (1.61 mL,
12.05 mmol) in MeOH (20 mL) to give the crude cyanohydrins,
which were dissolved in CH2Cl2 (20 mL). After addition of Et3N
(6.78 mL, 48.2 mmol) and CH3SO2Cl (2.57 mL, 33.1 mmol), the re-
action mixture was stirred overnight then, extracted and the resi-
due purified by flash chromatography (EtOAc/cyclohexane, 35/65)
to provide a mixture of diastereomers 30 [1.56 g (62%), 56/44 ratio]
H
4B
BnO
H
4
4A
O
6
3a
O
OMe
3
7a
7
Ph
OBn
as a slight yellow syrup. A fraction of pure isomer has been isolated
20
for analysis: oil; [
a
]
D þ91 (c 0.26, CH2Cl2); IR (ATR)
n 2970–2849,
1456, 1364, 1187, 1155, 1108, 1057, 1025 cmꢁ1
300 MHz)
;
1H NMR (CDCl3,
d
7.33–7.26 (m, 5H, C6H5), 4.91 (d, J1,2¼3.5 Hz, 1H, H-1),
5.6.18. (2S,4S,6S,7R,7aS)- and (2R,4S,6S,7R,7aS)-7-Benzyloxy-4-(ben-
zyloxymethyl)-6,7-dimethoxy-2-phenyl-4,6,7,7a-tetrahydro-2H-
furo[3,2-c]pyran (33). Following the general method E, product 31
(984 mg, 1.73 mmol), Bu2SnO (431 mg, 1.73 mmol) and TMSN3
(0.46 mL, 3.46 mmol) in toluene (17.3 mL), in 17 h at 100 ꢀC, gave
after flash chromatography (EtOAc/cyclohexane, 30/70), compound
4.61 (d, J¼11.9 Hz, 1H, OCH2C6H5), 4.55 (d, 1H, OCH2C6H5), 4.12 (dd,
1H, H-5), 3.98 (dd, J5,6A¼2.5 Hz, J6A,6B¼10.9 Hz, 1H, H-6A), 3.85 (d,
J2,3¼9.6 Hz, 1H, H-3), 3.78 (dd, J5,6B¼6.8 Hz, 1H, H-6B), 3.66 (s, 3H,
OCH3), 3.52 (m, 4H, H-2, OCH3), 3.45 (s, 3H, OCH3), 3.14 (s, 3H,
OSO2CH3); 13C NMR (CDCl3, 75 MHz)
d 138.0–128.1 (C6H5), 112.9
(CN), 97.2 (C-1), 81.6, 81.4 (C-2, C-3), 80.5 (C-4), 74.0 (OCH2C6H5),
70.2 (C-5), 68.3 (C-6), 62.3, 59.6, 56.1 (3ꢂOCH3), 40.2 (OSO2CH3).
HRMS C18H25O8NSNa: calcd 438.1196, found 438.1199.
33 [393 mg (49%) 19/81 ratio] as a slight yellow syrup; IR (ATR)
n
2929–2835,1454,1089, 1044,1028 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.32 (m, 15H, 3ꢂC6H5), 5.88 (m, 1H, H-2), 5.58 (m, 1H, H-3), 5.22
(m,1H, H-7a), 4.93 (d, J¼12.5 Hz,1H, OCH2C6H5), 4.87 (d, J6,7¼3.4 Hz,
1H, H-6), 4.81 (d, 1H, OCH2C6H5), 4.62 (m, 2H, OCH2C6H5), 4.55 (m,
1H, H-4), 3.83 [dd, J4,4A¼4.7 Hz, J4A,4B¼10.2 Hz, 1H, C6H5CH2O-
CH(A)2], 3.75 [dd, J4,4B¼5.9 Hz, 1H, C6H5CH2OCH(B)2], 3.60 (dd,
J7,7a¼8.7 Hz, 1H, H-7), 3.52 (s, 3H, OCH3); 13C NMR (CDCl3, 75 MHz)
BnO
4
O
6
3a
OMe
3
2
7a
7
O
OMe
d
141.6 (C-3a), 138.6–127.3 (2ꢂC6H5), 123.6 (C-3), 99.7 (C-6), 88.3 (C-
5.6.16. (4S,6S,7R,7aS)-4-(Benzyloxymethyl)-6,7-dimethoxy-4,6,7,7a-
tetrahydro-2H-furo[3,2-c]pyran (32). Following the general method
E, compound 30 (583 mg, 1.40 mmol), Bu2SnO (350 mg, 1.40 mmol)
and TMSN3 (0.37 mL, 2.80 mmol), in toluene (14 mL) reacted for
2), 85.8 (C-7a), 81.3 (C-7), 73.9/72.4 (OCH2C6H5), 70.5
[C6H5CH2OCH2], 65.8 (C-4), 56.1 (OCH3). HRMS C29H30O5Na: calcd
481.2000, found 481.1991.
19 h at 100 ꢀC to give after flash chromatography (EtOAc/cyclo-
5.6.19. Methyl 2,3-di-O-methyl-6-O-benzyl-4-C-cyano-4-O-mesyl-
b-
20
hexane, 30/70), compound 32 (188 mg, 49%): syrup; [
0.32, CH2Cl2); IR (ATR)
1025 cmꢁ1 1H NMR (CDCl3, 300 MHz)
a
]
þ85.6 (c
D-gluco(galacto)pyranoside (36). Following the general method A,
D
n
2932–2822, 1454, 1201, 1127, 1094, 1045,
7.36–7.28 (m, 5H, C6H5),
product 3418 (850 mg, 2.72 mmol), DMSO (0.58 mL, 8.17 mmol),
oxalyl chloride (0.46 mL, 5.44 mmol) and Et3N (1.14 mL, 8.17 mmol)
in CH2Cl2 (20 mL) gave the crude ulose (840 mg), which was used in
the next step without further purification. Following the general
method D, to a solution of the crude ulose in CH2Cl2 (20 mL) were
added NaHCO3 (457 mg, 5.44 mmol) in water (6.3 mL) and KCN
(378 mg, 5.82 mmol). After stirring for 20 h, the crude cyanohy-
drins were dissolved in CH2Cl2 (20 mL) followed by addition of Et3N
(3.06 mL, 21.76 mmol) and MsCl (1.15 mL, 14.96 mmol). After 4 h
30 min and extraction, the residue was purified by flash chroma-
tography (EtOAc/cyclohexane, 25/75) to give an unseparable mix-
;
d
5.60 (m, 1H, H-3), 4.94–4.88 (m, 2H, H-6, H-7a), 4.70–4.56 (m, 4H,
2ꢂH-2, OCH2C6H5), 4.43 (m, 1H, H-4), 3.80 [dd, J¼4.7 Hz, J¼10.1 Hz,
1H, C6H5CH2OCH(A)2], 3.74 [dd, J¼5.9 Hz, 1H, C6H5CH2OCH(B)2],
3.54 (s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.24 (dd, J6,7¼3.3 Hz,
J7,7a¼8.6 Hz, 1H, H-7); 13C NMR (CDCl3, 75 MHz)
d 138.2–128.1
(C6H5), 135.8 (C-3a), 119.6 (C-3), 98.9 (C-6), 85.1 (C-7a), 83.9 (C-7),
75.6/73.9 (C-2, OCH2C6H5), 70.4 (C6H5CH2OCH2), 65.7 (C-4), 58.8/
56.0 (2ꢂOCH3). HRMS C17H22O5Na: calcd 329.1373, found 329.1365.
5.6.17. Methyl
2,3,6-tri-O-benzyl-4-C-cyano-4-O-mesyl-
a
-
D
-gluco
ture of the two diastereomers 36 [943 mg (83%), 80/20 ratio].
20
(galacto)pyranoside (31). Following the general method C, com-
pound 2917 (941 mg, 2.02 mmol) in anhydrous CH2Cl2 (20 mL) was
treated with Dess–Martin reagent (2.58 g, 6.06 mmol, 3 equiv) in
anhydrous CH2Cl2 (20 mL) for 24 h to give the corresponding ulose
(974 mg, 93%). Following the general method D, this crude ulose
was reacted with Ti(OiPr)4 (3.78 mL, 3.78 mmol) and TMSCN
(0.50 mL, 3.78 mmol) in MeOH (20 mL) to give the crude cyano-
hydrins, which were dissolved in CH2Cl2 (20 mL). After addition of
Et3N (2.16 mL, 15.37 mmol) and CH3SO2Cl (0.81 mL, 10.57 mmol),
Compound 36: slight yellow syrup; [
(ATR)
(CDCl3, 300 MHz)
a
]
ꢁ21.0 (c 0.23, CH2Cl2); IR
D
n
2966–2853, 1453, 1353, 1174, 1080, 1058 cmꢁ1 1H NMR
;
d
7.37–7.28 (m, C6H5), 5.29 (s, 1H, 2ꢂH-1), 4.61
(m, 2H, 2ꢂOCH2C6H5), 4.27 (m, 1H, 2ꢂH-5), 4.05 (m, 1H, 2ꢂH-6A),
3.86–3.79 (m, 2H, 2ꢂH-3, 2ꢂH-6B), 3.70 (s, 3H, 2ꢂOCH3), 3.64–3.54
(m, 7H, 4ꢂOCH3, 1ꢂH-2), 3.25/3.17 (s, 3H, OSO2CH3); 13C NMR
(CDCl3, 75 MHz)
d
138.0–128.0 (2ꢂC6H5), 114.4/112.9 (CN), 104.7/
104.6 (C-1), 85.3/84.2/83.7/80.6 (C-2, C-3), 83.6/80.7 (C-4), 76.0/
74.9 (C-5), 74.2/74.0 (OCH2C6H5), 68.8/68.7 (C-6), 62.8/62.3/61.4/

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9391
61.0/57.7/57.6 (OCH3), 40.4/40.3 (OSO2CH3). HRMS C18H25O8NSNa:
calcd 438.1183, found 438.1199.
(CDCl3, 300 MHz)
d
7.37–7.21 (m, 15H, 6ꢂC6H5), 5.89 (s, 1H, 2ꢂH-2),
5.73, 5.64 (m, 1H, 2ꢂH-3), 4.97–4.84 (m, 3H, 2ꢂH-7a,
2ꢂOCH2C6H5), 4.70–4.57/4.52–4.47 (m, 1H, 2ꢂH-6), 4.35 (m, 1H,
2ꢂH-4), 3.89–3.77 (m, 2H, 4ꢂBnOCH2), 3.63 (m, 3H, 2ꢂOCH3),
5.6.20. (4S,6R,7R,7aS)-4-(Benzyloxymethyl)-6,7-dimethoxy-4,6,7,7a-
tetrahydro-2H-furo[3,2-c]pyran (38) and methyl 6-O-benzyl-4-O-
3.57–3.50 (m, 1H, 2ꢂH-7); 13C NMR (CDCl3, 75 MHz)
d 141.8/141.3
methanosulfonyl-2,3-di-O-methyl-
b
-
D
-glucopyranoside
(C-3a), 138.7–126.6 (6ꢂC6H5), 123.9/123.3 (C-3a), 104.2/104.1 (C-6),
89.1/89.0 (C-2), 88.7/88.4 (C-7a), 84.1/83.7 (C-7), 74.1/74.0/73.7/
73.5 (OCH2C6H5), 70.7/70.6 (BnOCH2), 69.9/69.8 (C-4), 57.6
(2ꢂOCH3). HRMS C29H30O5Na: calcd 481.1991, found 481.1999.
(39). Following the general method E, compound 36 (720 mg,
1.73 mmol), Bu2SnO (431 mg, 1.73 mmol) and TMSN3 (0.46 mL,
3.46 mmol) in toluene (17.3 mL), in 16 h at 100 ꢀC, gave after flash
chromatography (EtOAc/cyclohexane, 25/75) products 38 (368 mg,
20
81%) and 39 (106 mg, 13%). Compound 38: yellow syrup; [
(c 0.05, MeOH); IR (ATR):
1H NMR (CDCl3, 300 MHz)
a
]
D
þ71
5.6.23. Methyl 4,6-O-benzylidene-2-O-methyl-
(42) and methyl 4,6-O-benzylidene-3-O-methyl-
(43). To a solution of commercial methyl 4,6-O-benzylidene-a-D-
a
-
D
D
-galactopyranose
-galactopyranose
n
2966–2837, 1755, 1453, 1103, 1073 cmꢁ1
7.36–7.28 (m, 5H, C6H5), 5.66 (m,1H, H-
;
a-
d
3), 4.69–4.57 (m, 5H, H-7a, 2ꢂH-2, OCH2C6H5), 4.31 (d, J6,7¼7.6 Hz,
1H, H-6), 4.22 (m, 1H, H-4), 3.83 [dd, J4,4A¼5.1 Hz, J4A,4B¼10.0 Hz,
1H, C6H5CH2OCH(A)2], 3.79 [dd, J4,4B¼6.1 Hz, 1H, C6H5CH2OCH(B)2],
3.59 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.06 (dd, J7,7a¼7.6 Hz, 1H, H-
galactopyranoside (41) (4 g, 14.2 mmol) in toluene (100 mL) and
MeOH (10 mL) was added Bu2SnO (3.53 g, 14.2 mmol). The reaction
mixture was stirred at reflux for 25 min until the solution became
clear. After stirring overnight at 50 ꢀC, the solvent was removed
under vacuum. The residue was dissolved in dry toluene (150 mL)
and tetrabutylammonium iodide (5.24 g, 14.2 mmol), iodomethane
(3.89 mL, 62.5 mmol) and molecular sieves 4 Å (12.15 g) were
added. After stirring overnight at 100 ꢀC and removal of the solvent
under vacuum, EtOAc was added to the mixture, which was filtered
through a gel silica pad. The filtrate was concentrated and the crude
purified by flash chromatography (EtOAc/cyclohexane, 2/8) to afford
compounds 42þ43 (1.72 g, 41%) as a mixture of diastereoisomers in
a 55/45 ratio. HRMS C15H20O6Na: calcd 319.1158, found 319.1163.
7); 13C NMR (CDCl3, 75 MHz)
d 138.2, 128.8–128.1 (C6H5), 136.0 (C-
3a), 119.8 (C-3), 103.8 (C-6), 88.3 (C-7a), 85.4 (C-7), 76.4/74.0 (C-2,
OCH2C6H5), 70.6 (C6H5CH2OCH2), 69.7 (C-4), 59.957.4 (2ꢂOCH3).
HRMS C17H22O5Na: calcd 329.1373, found 329.1365. Compound 39:
20
yellow syrup; [
a
]
þ49 (c 0.22, MeOH); IR (ATR)
n
2966–2853,
1H NMR (CDCl3, 300 MHz)
7.35–7.26 (5H, m, C6H5), 4.59 (m, 2H, OCH2C6H5), 4.46 (t,
D
1453, 1353, 1174, 1080, 1058 cmꢁ1
;
d
J3,4¼J4,5¼9.5 Hz, 1H, H-4), 4.21 (d, J1,2¼7.7 Hz, 1H, H-1), 3.84 (dd,
J4,4A¼2.2 Hz, J4A,4B¼10.9 Hz, 1H, H-4A), 3.65 (m, 1H, H-4B), 3.60 (s,
3H, OCH3), 3.58 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.51 (m, 1H, H-5),
3.32 (t, 1H, H-3) 3.13 (dd, 1H, H-2), 3.07 (s, 3H, OSO2CH3); 13C NMR
5.6.24. Methyl 4,6-O-benzylidene-2-C-cyano-2-O-mesyl-3-O-methyl-
(CDCl3, 75 MHz)
d
138.4–128.0 (C6H5), 104.5 (C-1), 84.2 (C-2), 83.6
a-D-galacto(talo)pyranoside (44) and methyl 4,6-O-benzylidene-3-C-
(C-3), 78.5 (C-4), 74.0 (OCH2C6H5), 73.5 (C-5), 69.1 (C-6), 60.9
(OCH3), 57.5 (OCH3), 57.5 (OCH3), 39.0 (OSO2CH3). HRMS
C17H26O8NaS: calcd 413.1246, found 413.1245.
cyano-3-O-mesyl-2-O-methyl- -galacto(ido)pyranoside
a-D
(45). Following the general method A, compounds 42þ43 (1.06 g,
3.58 mmol), Dess–Martin periodinane (6.08 g, 14.3 mmol) in CH2Cl2
(30 mL) in 12 h led to the corresponding mixture of crude uloses
(0.76 g, 72%). HRMS C15H18O6Na: calcd 317.1001, found 317.0988.
Following the general method B, these uloses (0.76 g, 2.59 mmol),
Ti(OiPr)4 (0.93 mL, 3.11 mmol), TMSCN (0.69 mL, 5.17 mmol) in
MeOH (5 mL) led after flash chromatography (EtOAc/cyclohexane,
2/8) to a mixture of cyanohydrins (0.64 g, 76%) in a 49/51 ratio.
HRMS C16H19NO6Na: calcd 344.1110, found 344.1108. Following the
general method C, these cyanohydrins (0.64 g, 1.98 mmol), MsCl
(0.84 mL, 11 mmol), Et3N (0.97 mL, 6.93 mmol) in CH2Cl2 (10 mL) in
12 h led after flash chromatography (EtOAc/cyclohexane, 4/6) to
compounds 44þ45 (0.47 g, 59%) as a mixture of diastereoisomers in
5.6.21. Methyl
2,3,6-tri-O-benzyl-4-C-cyano-4-O-mesyl-b-D-gluco
(galacto)pyranoside (37). Following the general method A, product
3517 (411 mg, 0.88 mmol), DMSO (0.19 mL, 2.65 mmol), oxalyl
chloride (0.15 mL, 1.77 mmol) and Et3N (0.37 mL, 2.65 mmol) in
CH2Cl2 (20 mL) gave the crude ulose (400 mg), which was used in
the next step without further purification. Following the general
method D, to a solution of this crude ulose in CH2Cl2 (20 mL) were
added NaHCO3 (148 mg, 1.77 mmol) in water (2.1 mL) and KCN
(123 mg, 1.89 mmol). After stirring for 20 h, the crude cyanohydrins
were dissolved in CH2Cl2 (20 mL) followed by addition of Et3N
(0.99 mL, 7.08 mmol) and MsCl (0.37 mL, 4.86 mmol). After 4 h
30 min, and extraction, the residue was purified by flash chroma-
tography (EtOAc/cyclohexane, 60/40) to give an unseparable mix-
ture of the two diastereoisomers 37 [251 mg (50%) 80/20 ratio] as
a 61/39 ratio: syrup; IR (ATR):
n
1361, 1192, 1155, 1086, 1055,
7.55–7.34 (m, 15H, 2ꢂC6H5),
1014 cmꢁ1; 1H NMR (CDCl3 300 MHz)
d
5.75 (s, 1H, 2ꢂCHC6H5), 5.01 (d, J1,2¼3.9 Hz) and 4.69 (s) (1H, H-1),
4.93 (d, J3,4¼3.9 Hz, 1H, H-3), 4.31 (dd, J6A,6B¼12.7 Hz, 2H, H-6A),
4.13 (m, 1H, H-4), 3.98 (m, 1H, H-6B), 3.96 (d, 1H, H-2), 3.70 (m, 1H,
H-5), 3.63/3.45 (s, 6H, 4ꢂOCH3), 3.08 (s, 3H, 2ꢂO2SCH3); 13C NMR
a syrup; IR (ATR)
NMR (CDCl3, 300 MHz)
n
2936–2837,1454,1371,1185,1100,1028 cmꢁ1; 1H
d
7.42–7.35 (m, 15H, 6ꢂC6H5), 5.12–4.94 (m,
2H, 2ꢂOCH2C6H5), 4.85–4.65 (m, 4H, 4ꢂOCH2C6H5), 4.47–4.41 (m,
1H, 2ꢂH-1), 4.17–4.05 (m, 1H, 2ꢂH-6A), 3.97–3.76 (m, 3H, 2ꢂH-6B,
2ꢂH-5, 2ꢂH-3), 3.66–3.59 (m, 4H, 2ꢂH-2, 2ꢂOCH3), 3.01/2.92 (s,
(CDCl3 75 MHz)
d
137.0–126.4 (2ꢂC6H5), 115.0/114.2 (CN), 101.3/
101.8 (2ꢂCHC6H5), 98.9/96.6 (C-1), 77.6/75.9 (C-2), 76.7/75.2 (C-3),
77.0 (2ꢂC-4), 70.0/68.8 (C-6), 62.4/58.4 (C-5), 60.0/58.7/56.6/56.4
(OCH3), 40.2/40.0 (O2SCH3). HRMS C17H21NO8NaS: calcd 422.0886,
found 422.0892.
3H, 2ꢂOSO2CH3); 13C NMR (CDCl3, 75 MHz)
d 135.0–127.9
(6ꢂC6H5), 114.6/112.9 (CN), 105.0 (2ꢂC-1), 83.1/82.6/82.0/78.5 (C-2,
C-3), 80.8/77.9 (C-4), 76.5/75.1 (C-5), 77.5/76.5/75.6/74.3
(6ꢂOCH2C6H5), 68.9/68.8 (C-6), 57.9/57.8 (OCH3), 40.3/40.2
(OSO2CH3). HRMS C30H33NO8NaS: calcd 590.1825, found 590.1830.
4
O
2
4a
Ph
O
6
O
OCH3
9b
9a
6a
O
5.6.22. (2S,4S,6R,7R,7aS)- and (2R,4S,6R,7R,7aS)-7-(Benzyloxy)-4-
(benzyloxymethyl)-6-methoxy-2-phenyl-4,6,7,7a-tetrahydro-2H-
furo[3,2-c]pyran (40). Following the general method E, product 37
(163 mg, 0.287 mmol), Bu2SnO (71 mg, 0.287 mmol) and TMSN3
9
8
5.6.25. (2R,4aR,6S,6aR,9bR)-4,4a,6,6a,8,9b-Hexahydro-6-methoxy-
2-phenyl-furo[30,20:4,5]pyrano[3,2-d]1,3-dioxin (46). Following the
general method D, a mixture of compounds 44þ45 (0.38 g,
0.96 mmol), TMSN3 (0.26 mL, 1.92 mmol) and Bu2SnO (0.24 g,
9.59 mmol) reacted for 12 h to give after flash chromatography
(77
after flash chromatography (EtOAc/cyclohexane, 17/83), compound
40 [63 mg (47%) 74/26 ratio] as a slight yellow syrup; IR (ATR)
3087–3007, 2936–2834,1453,1098,1071,1043,1028 cmꢁ1; 1H NMR
m
L, 0.574 mmol) in toluene (2.87 mL), in 15 h at 100 ꢀC, gave
n

9392
A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
(EtOAc/cyclohexane, 28/72) compound 46 (86 mg, 60%) as a yellow
diastereomers (1/2): syrup; IR (ATR)
n
2961, 1356, 1260, 1084, 1049,
7.56–7.35 (m, 10H,
20
syrup: [
a
]
þ85 (c 0.1; MeOH); IR (ATR):
n
2924, 1454, 1338, 1145,
1023, 797 cmꢁ1 1H NMR (CDCl3 300 MHz)
;
d
1051 cmꢁ1D
;
1H NMR (CDCl3 300 MHz)
d
7.54–7.28 (m, 5H, C6H5),
2ꢂC6H5), 7.09 (d, J8,9¼6.0 Hz, 1H, H-8), 6.19 (s, 1H, H-2), 5.96 (d, 2H,
H-9), 5.85 (m,1H, H-6a), 5.68 (s,1H, H-6), 5.24/5.12 (d, J9b,4a¼3.2 Hz;
d, J9b,4a¼3.8 Hz,1H, H-9b), 4.34 (s, 3H, OCH3), 4.13 (d, J4A,4B¼12.4 Hz,
1H, H-4A), 4.11 (d, 1H, H-4B), 3.93(m, 2H, H-4a); 13C NMR (CDCl3
6.01 (d, 1H, H-9), 5.62 (s, 1H, H-2), 5.12 (m, 1H, H-6a), 5.01 (d,
J6,6a¼4.0 Hz, 1H, H-6), 4.81 (s, 1H, H-9b), 4.74 (m, 2H, H-8), 4.36 (dd,
J4A,4a¼1.3 Hz, J4A,4B¼12.7 Hz, 1H, H-4A), 4.17 (dd, J4A,4a¼2.0 Hz, 1H,
H-4B), 3.59 (m, 1H, H-4a), 3.47 (s, 3H, OCH3); 13C NMR (CDCl3
75 MHz)
d
140.8/140.3 (C-9a), 138.4–137.5, 131.2–128.3 (2ꢂC6H5),
75 MHz)
d
138.1 (C-9a), 133.0–126.7 (C6H5), 124.3 (C-9), 101.2 (C2),
127.0, 126.6 (C-9), 101.6/100.9 (C-2 and C-6), 89.8/88.8 (C-6a), 86.4/
86.2 (C-9b), 81.3/81.2 (C-8), 76.5/75.2 (C-4a), 70.0/69.9 (C-4), 64.6/
64.5 (OCH3); HRMS C22H22O5Na: calcd 389.1365, found 389.1373.
100.9 (C-6), 81.0 (C-6a), 76.6 (C-8), 73.4 (C-9b), 69.9 (C-4), 63.0 (C-
4a), 56.0 (OCH3) HRMS C16H18NO5Na: calcd 313.1052, found
313.1063.
5.6.28. Methyl 3-O-benzyl-4,6-O-benzylidene-2-C-cyano-2-O-mesyl-
5.6.26. Methyl 4,6-O-benzylidene-2-O-benzyl-3-C-cyano-3-O-mesyl-
a-D-galacto(talo)pyranoside (51). Following the general method A,
a
-
D
-galacto(ido)pyranoside (48). Following the general method A,
compound 5019 (710 mg, 1.91 mmol), Dess–Martin periodinane
compound 4719 (900 mg, 2.43 mmol), Dess–Martin periodinane
(3.24 g, 7.63 mmol) in CH2Cl2 (20 mL) for 15 h led to the corre-
20
(4.11 g, 9.68 mmol) in CH2Cl2 (50 mL) for 14 h led to a crude ulose
sponding crude ulose (650 mg, 92%) {syrup, [
a
]
D
þ49 (c 0.22,
20
(750 mg, 84%): syrup, [
a]
þ49 (c 0.22, CHCl3); IR (ATR)
n
1750,
CHCl3)}; IR (ATR):
(CDCl3 300 MHz)
n
2928, 1716, 1267, 1049, 1016 cmꢁ1
7.51–7.35 (m, 10H, 2ꢂC6H5), 5.58 (s, 1H,
;
1H NMR
D
1453, 1372, 1163, 1090, 1050, 1034 cmꢁ1; 1H NMR (CDCl3 300 MHz)
d
d
7.51–7.35 (m, 10H, 2ꢂC6H5), 5.56 (s, 1H, CHC6H5), 4.97 (d,
CHC6H5), 5.11 (d, J1,2¼3.9 Hz, 1H, H-1), 4.90 (d, J¼11.6 Hz, 1H,
CH2C6H5), 4.80 (d, 1H, H-4), 4.52 (d, 1H, CH2C6H5), 4.47 (d,
J4,3¼1.4 Hz, 1H, H-3), 4.34 (dd, J6A,5¼1.4 Hz, J6A,6B¼12.8 Hz, 1H, H-
6A), 4.13 (d, J6B,5¼1.6 Hz, 1H, H-6B), 3.85 (m, 1H, H-5); 13C NMR
J¼12.6 Hz, 1H, CH2C6H5), 4.84 (s, 1H, H-1), 4.63 (m, 2H, CH2C6H5, H-
4), 4.58 (d, J1,2¼4.0 Hz, 1H, H-2), 4.29 (d, J6A,6B¼12.4 Hz, 1H, H-6A),
4.09 (d, 1H, H-6B), 4.02 (s, 1H, H-5), 3.48 (s, 3H, OCH3); 13C NMR
(CDCl3 75 MHz)
d
199.1 (C-3), 137.5–126.6 (C6H5), 102.6 (CHC6H5),
(CDCl3 75 MHz) d 199.1 (C-3), 137.5–126.6 (C6H5), 102.6 (CHC6H5),
100.9 (C-1), 82.1 (C-4), 79.6 (C-3), 73.1 (CH2C6H5), 69.1 (C-6), 64.7
(C-5), 56.2 (OCH3); HRMS C21H22O6Na: calcd 393.1314, found
393.1305. Following the general method B, the crude ulose (0.11 g,
0.29 mmol), Ti(OiPr)4 (0.11 mL, 0.35 mmol), TMSCN (0.08 mL,
0.59 mmol) in MeOH (5 mL) led after flash chromatography (EtOAc/
100.9 (C-1), 82.1 (C-4), 79.6 (C-2), 73.1 (CH2C6H5), 69.1 (C-6), 64.7
(C-5), 56.2 (OCH3). HRMS C21H22O6Na: calcd 393.1314, found
393.1306. Following the general method B, the crude ulose (0.64 g,
1.73 mmol), Ti(OiPr)4 (0.40 mL, 2.08 mmol), TMSCN (0.48 mL,
3.46 mmol) in MeOH (6 mL) led after flash chromatography (EtOAc/
cyclohexane, 3/7) to an intermediate cyanohydrin (one di-
cyclohexane, 3/7) to the expected cyanohydrin (0.32 g, 47%) (one
20
20
astereomer) (0.10 g, 85%) as a yellow syrup {[
CHCl3)}; IR (ATR)
1064 cmꢁ1 1H NMR (CDCl3 300 MHz)
a
]
þ90 (c 0.28,
diastereoisomer) {syrup; [
a]
þ60 (c 0.23, MeOH)}; IR (ATR):
n
D
D
n
2914, 1450, 1371, 1250, 1147, 1109, 1082,
7.50–7.28 (m, 10H,
3373, 1450, 1147, 1134, 1082, 1064, 1041 cmꢁ1
;
1H NMR (CDCl3
;
d
300 MHz) 7.50–7.28 (m, 10H, C6H5), 5.65 (s, 1H, CHC6H5), 4.91(d,
d
2ꢂC6H5), 5.40 (s, 1H, CHC6H5), 5.00 (m, 1H, H-1), 4.86 (m, 2H,
CH2C6H5), 4.24 (m, 3H, CH2C6H5, H-4), 4.12 (d, J6A,6B¼12.7 Hz,1H, H-
6A), 4.11 (d, 1H, H-6B), 4.01 (m, 1H, H-2), 3.64 (s, 1H, H-5), 3.48 (s,
J¼11.8 Hz, 1H, CH2C6H5), 4.78 (d, J3,4¼3.6 Hz, 1H, H-4), 4.73 (d, 1H,
CH2C6H5), 4.54 (s, 1H, H-1), 4.32 (dd, J6A,5¼1.5 Hz, J6A,6B¼12.6 Hz,
1H, H-6A), 4.23 (s, 1H, OH), 4.08 (dd, J6B,5¼1.4 Hz, 1H, H-6B), 4.07 (d,
J3,4¼3.6 Hz, 1H, H-3), 3.91(m, 1H, H-5), 3.41 (s, 3H, OCH3); 13C NMR
3H, OCH3); 13C NMR (CDCl3 75 MHz)
d 137.4–126.1 (C6H5), 118.5
(CN), 102.2 (CHC6H5), 101.8 (C-1), 73.8 (C-2), 73.4 (C-4), 72.4
(CH2C6H5), 71.6 (C-3), 69.4 (C-6), 62.9 (C-3), 56.8 (OCH3) HRMS
C22H23NO6Na: calcd 420.1423, found 420.1426. Following the gen-
eral method C, this cyanohydrin (0.65 g, 1.64 mmol), MsCl (0.70 mL,
9.01 mmol), Et3N (0.81 mL, 5.74 mmol) in CH2Cl2 (7 mL) for 8 h led
(CDCl3 75 MHz) d 137.3–126.4 (C6H5), 118.7 (CN), 101.2 (CHC6H5),
99.0 (C-1), 78.0 (C-3), 73.8 (CH2C6H5), 73.4 (C-4), 72.0 (C-2), 69.5 (C-
6), 59.0 (C-5), 56.8 (OCH3). HRMS C23H25NO8SNa: calcd 498.1199,
found 498.1194. Following the general method C, the cyanohydrin
(0.32 g, 0.80 mmol), MsCl (0.34 mL, 4.43 mmol), Et3N (0.40 mL,
2.82 mmol) in CH2Cl2 (5 mL) for 18 h led after flash chromatogra-
after flash chromatography (EtOAc/cyclohexane, 3/7) to compound
20
48 (0.31 g, 40%) (one diastereoisomer): mp 106–108 ꢀC; [
a
]
D
þ52
phy (EtOAc/cyclohexane, 3/7) to compound 51 (0.15 g, 39%) (one
20
(c 0.19, CHCl3); IR (ATR)
n
2937, 1454, 1367, 1172, 1109, 1078 cmꢁ1
;
diastereoisomer): syrup, [
a
]
þ18 (c 0.17, MeOH); IR (ATR):
n
1367,
D
1H NMR (CDCl3 300 MHz)
d
7.58–7.36 (m, 10H, 2ꢂC6H5), 5.45 (m,
1172, 1109, 1076, 1045 cmꢁ1; 1H NMR (CDCl3 300 MHz)
d 7.58–7.36
2H, CHC6H5, H-1), 4.90 (m, 2H, CH2C6H5), 4.30 (d, J6A,6B¼12.8 Hz,
1H, H-6A), 4.21 (d, J1,2¼2.5 Hz, 1H, H-2), 4.10 (m, 2H, H-4, H-6B),
3.06 (m, 1H, H-5), 3.51 (s, 3H, OCH3), 3.05 (s, 3H, O2SCH3); 13C NMR
(m, 10H, 2ꢂC6H5), 5.69 (s, 1H, CHPh), 4.94 (d, J¼11.68 Hz, 1H,
CH2Pha), 4.77 (d, 1H, CH2Phb), 4.73 (d, J4,3¼3.94 Hz, 1H, H-4), 4.69
(s,1H, H-1), 4.30 (dd, J6a,6b¼12.75 Hz,1H, H-6a), 4.14 (m, 2H, H-3, H-
(CDCl3 75 MHz)
d
136.1–126.9 (2ꢂC6H5), 115.6 (CN), 101.5 (CHC6H5),
5), 4.01 (m, 1H, H-6b), 3.40 (s, 3H, OCH3), 3.33 (s, 3H, O2SCH3); 13
C
99.4 (C-1), 76.3 (C-2), 75.0 (C-3), 72.9 (CH2C6H5), 71.2 (C-4), 69.2 (C-
6), 62.7 (C-5), 57.2 (OCH3), 40.7 (O2SCH3); HRMS C23H25NO8NaS:
calcd 498.1199, found 498.1188.
NMR (CDCl3 75 MHz)
d
137.0–126.4 (2ꢂC6H5), 114.7 (CN), 101.5
(CHPh), 98.0 (C-1), 77.7 (C-2), 75.8 (C-4), 74.9 (CH2Ph), 74.2 (C-3),
69.2 (C-6), 58.7 (C-5), 56.8 (OCH3), 40.4 (O2SCH3); HRMS
C23H25NO8SNa: calcd 498.1199, found 498.1212.
4
O
2
4a
4
Ph
O
6
O
2
O
OCH3
4a
9b
Ph
O
9a
6
6a
O
OCH3
9b
8 O
Ph
9a
9
6a
7
8
O
Ph
5.6.27. (2R,4aR,6S,6aR,8R,9bR)- and (2R,4aR,6S,6aR,8S,9bR)-6-Me-
thoxy-4,4a,6,6a,9b-pentahydro-2,8-di-phenyl-furo[30,20:4,5]pyr-
ano[3,2-d]1,3-dioxin (49). Following the general method D,
compound 48 (0.30 g, 0.63 mmol), TMSN3 (0.17 mL,1.26 mmol) and
Bu2SnO (0.16 g, 0.63 mmol) for 12 h led after flash chromatography
(EtOAc/cyclohexane, 3/7) to product 49 (8 mg, 33%) as a mixture of
5.6.29. (2R,4aR,6S,8R,9aR,9bR)- and (2R,4aR,6S,8S,9aR,9bR)-6-Me-
thoxy-4,4a,6,9a,9b-pentahydro-2,8-di-phenyl-furo[20,30:4,5]pyr-
ano[3,2-d]1,3-dioxin (52). Following the general method D,
compound 51 (0.10 g, 0.21 mmol), TMSN3 (0.06 mL, 0.42 mmol) and
Bu2SnO (0.05 g, 0.21 mmol) for 12 h led after flash chromatography

A. Nguyen Van Nhien et al. / Tetrahedron 65 (2009) 9378–9394
9393
O
O
(EtOAc/cyclohexane, 3/7) to product 52 (15 mg, 49%) as a mixture of
20
Ph
O
diastereomer (8/2): isolated diastereomer: syrup; [
MeOH); IR (ATR):
2849, 1454, 1362, 1100, 1052, 1006 cmꢁ1
NMR (CDCl3 300 MHz)
J7,8¼1.8 Hz,1H, H-7), 5.92 (m,1H, H-8), 5.65 (s,1H, H-2), 5.32 (m,1H,
H-9a), 5.24 (m, J6,6a¼3.9 Hz, 1H, H-6), 4.94 (m, 1H, H-9b), 4.41 (dd,
J4A,4a¼1.1 Hz, J4A,4B¼12.65 Hz, 1H, H-4A), 4.20 (dd, J4B,4a¼1.9 Hz, 1H,
H-4B), 3.63 (m, 1H, H-4a), 3.52 (s, 3H, OCH3); 13C NMR (CDCl3
a
]
þ22 (c 0.1,
D
OCH3
n
;
1H
7.46–7.22 (m, 10H, 2ꢂC6H5), 6.01 (d,
d
NC
OBn
20
Compound 56: [
a
]
þ61 (c 0.1, MeOH); IR (ATR):
n
2914, 1455,
D
1378, 1133, 1102, 1093, 1046, 993 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
75 MHz) d 141.1 (C-6a), 138.1–126.7 (C6H5), 126.5 (C-7), 101.3 (2C, C-
2, C-6), 89.3 (C-8), 81.0 (C-9a), 73.7 (C-9b), 69.9 (C-4), 63.3 (C-4a),
56.1 (OCH3) HRMS C22H22O5Na: calcd 389.1365, found 389.1358.
d
7.53–7.33 (m, 10H, 2ꢂC6H5), 5.61 (s, 1H, CHC6H5), 4.74 (d,
J1,2¼1.1 Hz, 1H, H-1), 4.64 (m, 2H, OCH2C6H5), 4.34 (dd, J5,6A¼4.9 Hz,
J6A,6B¼10.3 Hz, 1H, H-6A), 4.22 (ddd, J4,5¼9.7 Hz, 1H, H-5), 4.11 (d,
J3,4¼5.0 Hz, 1H, H-4), 3.84 (t, J5,6B¼10.3 Hz, 1H, H-6B), 3.95 (dd,
J2,3¼2.2 Hz,1H, H-2), 3.46 (s, 3H, OCH3), 3.39 (dd,1H, H-3); 13C NMR
5.6.30. Methyl 4,6-O-benzylidene-3-C-cyano-3-O-mesyl-2-O-benzyl-
a-D-altro(manno)pyranoside (54). Following the general method C,
alcohol 5320 (1.07 g, 2.87 mmol) dissolved in anhydrous CH2Cl2
(30 mL) was treated with Dess–Martin reagent (4.88 g, 11.5 mmol,
4 equiv) in anhydrous CH2Cl2 (20 mL) for 24 h to give the crude
ulose (0.96 g, 91%). Following the general method D, Ti(OiPr)4
(1.72 mL, 5.75 mmol) and TMSCN (0.77 mL, 5.75 mmol) in MeOH
(20 mL) gave crude cyanohydrins (0.91 g), which were dissolved
in CH2Cl2 (20 mL). After addition of Et3N (2.58 mL, 18.3 mmol)
and CH3SO2Cl (0.97 mL, 12.6 mmol), the reaction mixture was
stirred overnight then, extracted and the residue purified by flash
chromatography (EtOAc/cyclohexane, 25/75) to give a mixture of
diastereoisomers 54 [667 mg (49%) 75/25 ratio] as a slight yellow
(CDCl3, 75 MHz)
d
137.2, 136.8, 129.8–126.8 (2ꢂC6H5), 116.3 (CN),
102.7 (C-7), 98.8 (C-1), 75.6 (C-2), 73.1 (OCH2Ph), 72.5 (C-4), 69.2
(C-6), 61.4 (C-5), 55.5 (OCH3), 32.8 (C-3). HRMS C22H23NO5Na: calcd
404.1474, found 404.1463.
5.7. Theoretical methods
All calculations were carried out with the Gaussian 03 pro-
gram.29 No constraints were imposed on the structures in the
equilibrium-geometry calculations or in the transition-state op-
timizations. Molecular geometries were optimized at the re-
stricted level (closed-shell) for singlets and the unrestricted level
(open-shell) for triplets. The optimizations were carried out using
hybrid density functional B3LYP30 with the 6-31G(d,p) basis set.
Single-point energy calculations with 6-311þG(d,p) were later
performed on the optimized geometries. Basis sets with diffuse
functions are recommended for molecules with lone pairs, for
anions, and for systems with significant negative charge. Vibra-
tional frequency analyses were carried out in order to assess the
nature of the stationary points and obtain the zeropoint vibra-
tional energies (ZPVEs) and thermodynamic parameters. IRC cal-
culations were used to connect the transition state to its
respective precedent and ensuing minima. Natural bond orbital
(NBO) analyses31 have been performed by the module NBO v.3.1
implemented in Gaussian 03 to evaluate the NPA charges at the
optimization level.
syrup; IR (ATR):
n
2938, 1372, 1184, 1105, 1075, 1001, 960 cmꢁ1
7.55–7.41 (m, 10H, 2ꢂC6H5), 5.64 (s,
;
1H NMR (CDCl3, 300 MHz)
d
1H, CHC6H5), 4.96 (d, J¼11.0 Hz, 1H, OCH2C6H5), 4.76 (d, 1H,
OCH2C6H5), 4.70 (s, 1H, H-1), 4.58 (s, 1H, H-2), 4.35 (dd,
J5,6A¼5.3 Hz, J6A,6B¼10.1 Hz, 1H, H-6A), 4.31 (d, J4,5¼9.5 Hz, 1H, H-
4), 4.22 (dt, J5,6B¼J4,5¼9.5 Hz, 1H, H-5), 3.79 (dd, 1H, H-6B), 3.39
(s, 3H, OCH3), 3.22 (s, 3H, OSO2CH3); 13C NMR (CDCl3, 75 MHz)
d
137.0, 136.4, 129.7–126.6 (2ꢂC6H5), 114.8 (CN), 102.6 (C-7), 99.2
(C-1), 76.8 (C-4), 76.2 (C-3), 76.1 (C-2), 75.7 (OCH2C6H5), 58.9 (C-
5), 56.1 (OCH3), 40.3 (OSO2CH3). HRMS C23H25NO8NaS: calcd
498.1199, found 498.1178.
5.6.31. Cyclization of methyl 4,6-O-benzylidene-3-C-cyano-3-O-me-
syl-2-O-benzyl-a-D-altro(manno)pyranoside (54). Following the
general method E, 350 mg (0.73 mmol) of 10a,a0, 183 mg
(0.73 mmol) of Bu2SnO and 0.19 mL (1.47 mmol) of TMSN3 in tolu-
ene (7.3 mL) for 20 h at 100 ꢀC gave successively after flash chro-
matography (EtOAc/cyclohexane,15/85), (2R,4aR,6R,6aR,8R,9bS)-and
(2R,4aR,6R,6aR,8S,9bS)-6-methoxy-4,4a,6,6a,9b-pentahydro-2,8-
di-phenyl-furo[30,20:4,5]pyrano[3,2-d]1,3-dioxin (55) (30 mg, 11%)
(one diastereomer) and methyl 2-O-benzyl-4,6-O-benzylidene-3-
Acknowledgements
`
R.C. thanks the Ministere Français de la Recherche for a fellow-
ship. D.P. and A.N.V.N. thank the Conseil Regional de Picardie and
the Ministere Français de la Recherche for financial support.
´
`
deoxy-3-C-cyano-
a
-D
-tallopyranoside (56) (18 mg, 6%).
Supplementary data
4
O
2
4a
Ph
O
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.080.
6
O
OCH3
9b
9a
6a
8 O
Ph
9
References and notes
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20
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a
]
þ73 (c 0.06, MeOH); IR (ATR):
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D
d
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´
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´
¨
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