Synthesis of galactosides locked in a 1,4B boat conformation and functionalized at the anomeric position

Article abstract of DOI:10.1016/j.tet.2006.12.028

A new methodology for the preparation of carbohydrates locked in a ^1,4B boat conformation is presented. The constrained molecules thus obtained are functionalized at the anomeric position by iodo-, fluoro-, hydroxyl- or/and phosphono-methylene

Full text of DOI:10.1016/j.tet.2006.12.028

Tetrahedron 63 (2007) 2070–2077
Synthesis of galactosides locked in a 1,4B boat conformation and
functionalized at the anomeric position
a
Audrey Caravano, Diane Baillieul, Christophe Ansiaux, Weidong Pan, Jose Kovensky,
c
c
c
b
ꢀ
a
a,c,
*
ꢀ
Pierre Sinay and Stephane P. Vincent
€
a
´
´
Ecole Normale Superieure, Departement de Chimie, CNRS UMR 8642, 24 rue Lhomond, 75231 Paris Cedex 05, France
Faculte des Sciences, Universite de Picardie Jules Verne, Laboratoire des Glucides 33, CNRS UMR 6219, rue saint Leu,
b
´
´
80039 Amiens Cedex, France
cUniversity of Namur, Laboratoire de Chimie-Bioorganique, Rue de Bruxelles 61 B-5000 Namur, Belgium
Received 14 November 2006; accepted 12 December 2006
Available online 16 January 2007
Abstract—A new methodology for the preparation of carbohydrates locked in a 1,4B boat conformation is presented. The constrained
molecules thus obtained are functionalized at the anomeric position by iodo-, fluoro-, hydroxyl- or/and phosphono-methylene moieties.
A remarkable diastereoselective opening of these quaternary acetals was also observed under non-acidic conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
half-chair or flattened chair conformations have been de-
signed to mimic high energy intermediates such as oxycar-
benium species.8 As a recent example, the biological
evaluation of a locked analogue of a biologically active hep-
arin fragment demonstrated that the conformation adopted
by a key L-iduronic acid residue when bound to antithrombin
AT-III was indeed a skew-boat conformation.9 Boat-locked
molecules may also be enzymatically relevant.10 In the
course of the mechanistic study of UDP-galactose mutase
(UGM),11–14 we synthesized the constrained sugar nucleo-
tide A in order to probe the conformational itinerary of the
galactose moiety during the enzymatic interconversion of
UDP-galactopyranose (UDP-Galp) and UDP-galactofura-
nose (UDP-Galf, Fig. 1).11
Constrained molecules are valuable tools for exploring and
probing enzyme’s binding and/or catalytic sites. By locking
a molecule in a chosen conformation and measuring its affin-
ity to a receptor or a biocatalyst, one may obtain interesting
insights into either the real ground state conformation adop-
ted by a molecule inside a protein cavity or even a transient
conformation through which a molecule is transformed
within an enzyme binding site.1 Due to the importance of
conformational and stereoelectronic effects in glycoscien-
ces,2,3 the obtention of locked glycosides is highly desirable
since they might be interesting mechanistic probes or selec-
tive inhibitors. Nucleoside analogues with conformationally
restricted ribosyl moieties have been extensively studied and
provided oligonucleotides with finely tuned binding proper-
ties.4,5 In addition, synthetic methods for constraining glyco-
sides to probe usual glycosyl processing enzymes (or lectins)
have also been explored. For the glycosidases6 and the
nucleotide-sugar binding proteins,7 glycosides adopting
Thus, we needed to develop a general synthetic strategy to
reach 1,4B boat-locked galactosides such as A (Fig. 1). The
few described methods that allow the construction of
1,4B-locked bicyclic glycosides are based either on a trans-
ketalization of galactosides15,16 or on cycloadditions followed
O
HO
HN
O
HO
OH
Mutase
O
OH
O
OH
O
O
UDP
O
OH
N
HO
O
HO
P
P
HO
O
O
HO
HO
HO
O
O
O
UDP
OH
Galp-UDP
Galf-UDP
A
HO
OH
Figure 1. Conformational probe (A) of the mutase catalyzed interconversion of UDP-Galactopyranose and UDP-galactofuranose.
Keywords: Boat conformation; C-glycosides; a-Fluoro-phosphonate; Glycals.
* Corresponding author. Tel.: +32 (0)81 72 45 21; fax: +32 (0)81 72 45 17; e-mail: Stephane.Vincent@fundp.ac.be
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.028

A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
2071
by asymmetric dihydroxylations,10,17,18 or epoxidation.19
Table 1. Cyclizations of exo-glycals
Entry Glycal Activator Product Solvent
Recently, Thomas et al. described the synthesis of a methyl-
ene analogue of 1,4-anhydrogalactose, which also presents
T
Yield (%)
1,4B boat conformation.19 However, none of these reactions
1
2
3
5
5
2
Silica gel
NIS
6
7
3
CH2Cl2
CH2Cl2
CH2Cl2
rt
57
(two steps)
62
(two steps)
58
(two steps)
a
described molecules functionalized at the anomeric position,
that is, with a quaternary anomeric carbon. The purpose of
the methodological study presented here was to explore
the chemistry allowing for the construction of galactosides
locked in a defined conformation with the simultaneous in-
stallation of diverse functional groups at the vicinity of the
anomeric center. Given the number of potential enzymatic
targets (galactosyl transferases, galactofuranosyl transfer-
ases, UGM.), we particularly explored the synthesis of
methylene-phosphonate derivatives. Here we report a
straightforward approach allowing the preparation of boat-
locked galactosides functionalized at the anomeric position
with phosphonyl-, iodo-, hydroxyl-, and fluoro-methylene
groups.
rt
rt
NIS
4
5
6
7
8
9
8
8
9
9
9
9
CSA
NIS
CSA
NIS
Selectfluor 14
m-CPBA, 15
CSA
10
11
12
13
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
reflux 70
rt 86
reflux 88
rt 79
CH3NO2 50 ꢀC 62
CH2Cl2
rt
75
10
9
DMDO
15
Acetone/ rt
CH2Cl2
64
parameters such as the activator, the substrate and the sol-
vent. In all cases, the 1,4B conformation was confirmed by
comparison with H NMR data of analogous compounds,
1
2. Results and discussion
with typically small coupling constants between H-2, H-3,
H-4, and H-5 (0.9<J<1.2 Hz).16–18
Our synthetic strategy relied on a key cyclization of methyl-
ene-exo-glycals 2 and 5 and phosphonylated exo-glycals 8
and9(Scheme1), unprotectedatthe5-position. Theseglycals
were prepared from a common precursor 1 easily obtained in
three steps from 1,4-galactonolactone.20 Methylene-exo-
glycals 2 and 5 could be synthesized from the corresponding
lactones through a methylenation using Tebbe’s reagent.
Due to their instability on silica gel, molecules 2 and 5
were directly subjected to cyclization experiments without
purification. The phosphonylated exo-glycals 8 and 9 were
prepared in a stepwise procedure recently developed by Lin
et al., which consists in the addition of the lithium anion of
dialkyl methyl phosphonate, yielding an intermediate lactol,
which is directly subjected to an efficient and diastereoselec-
tive elimination (Scheme 1).21,22
Different types of enol ether activation were also screened:
a catalytic acidic activation or stoichiometric electrophilic
ones. Not surprisingly, the glycals bearing the phosphonyl
group (molecules 8 and 9) were found less reactive under
acidic or electrophilic activation and more stable in acidic
conditions, such as silica gel chromatography, than their
non-phosphonylated analogues (molecules 2 and 5). This
is likely due to the electron-withdrawing character of the (di-
alkoxy)phosphoryl moiety. Thus, under acidic activation,
methylene-exo-glycals reacted at room temperature (entry
1) whereas phosphono-exo-glycals 8 and 9 needed to be
refluxed in CH2Cl2 to react (entries 4 and 6). These preli-
minary experiments constituted the base for the synthesis
of molecule A (Fig. 1).11 Several acids were tested and cam-
phorsulfonic acid (CSA, entries 4 and 6) appeared to give
the best results regarding the kinetics of the reaction and
the absence of side-reaction (nucleophilic acids may give ad-
dition products). PPh3$HBr, which is a valuable tool in glycal
Table 1 summarizes the experiments we performed to define
the scope of the cyclization reaction leading to 1,4-an-
hydrogalactopyranosyl derivatives. We varied different
TBSO
OH
TBSO
TBSO
O
O
TBS
TBSO
O
O
H+
O
O
b)
a)
O
O
97%
TBSO
TBSO
HO
OH
OTBS
OTBS
OH
OTBS
OTBS
5
4
1
6
NIS
O
O
TBS
TBSO
b)
I
O
O
TBSO
OH
OH
OTBS
O
NIS
I
7
O
TBSO
HO
OTBS
OTBS
3
2
O
P
X
O
10 : X = H ; R = Me
11 : X = I ; R = Me
12 : X = H ; R = Bn
13 : X = I ; R = Bn
14 : X = F ; R = Bn
TBS
TBSO
OR
TBSO
OH
OR
OR
O
O
OR
P
d)
c)
O
4
TBSO
O
OTBS
8 : R = Me (63%)
9 : R = Bn (77%)
OTBS
15 : X = OH ; R = Bn
Scheme 1. Synthesis of functionalized 1,4-boat locked galactosides. Reagents: (a) TBDMSCl, Im, DMF; (b) Tebbe’s reagent, then activator; (c) (RO)2POCH2Li,
THF, then Py/THF, (CF3CO)2O; (d) activator.

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A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
chemistry23 was also found amenable for this reaction,
although giving lower yields than CSA (data not shown).
This result was particularly interesting and surprising since
peracids are, usually, not suitable for epoxidizing exo- or
endo-glycals since their corresponding carboxylic acids,
once formed, react with the generated epoxide. In the case
of this specific reaction (entry 9), it is reasonable to assume
that the cyclization is quicker than the reaction of the
transient epoxide with m-chloroperbenzoic acid and/or
chlorobenzoic acid. Monitoring this reaction by 31P NMR
showed that a single diastereomer was formed under these
conditions. Unfortunately, we never obtained monocrystals
of molecules 13, 14, and 15 that would have allowed the
determination of the absolute configuration of the new
asymmetric center by X-ray diffraction analysis.
We found interesting to obtain constrained a-iodo-phospho-
nates such as 11 and 13 since the iodo group may allow a sub-
sequent derivatization via nucleophilic substitution or via
radical chemistry. When activated by NIS, the cyclization re-
actions were all complete within a few hours at room temper-
ature, regardless of the presence/absence of the phosphonyl
moiety (entries 2, 3, 5, and 7). Interestingly, the reaction with
the 5,6-diol 1 exclusively gave the expected 1,4-anhydroga-
lactopyranose structure (entry 3). The other possible product
(cyclization with the 6-OH group yielding a 1,6-anhydroga-
lactofuranose structure) could not be isolated. In this case the
formation of the [2.2.1]-bicyclic glycoside was specific over
the formation of the [3.2.1]-bicyclic structure. The cycliza-
tion reaction performed with NIS on phosphonylated glycals
8 and 9 was found diastereospecific (entries 5 and 7), the NIS
attack specifically occurring from one face of the enol ether.
When constrained acetal 12 was subjected to deprotection
using Bu4NF, a remarkable side-reaction was observed:
the expected triol 17 was contaminated by exo-glycal 16
(Scheme 2). This enol ether formation resulted from a b-
elimination or a retro-Michael addition. Surprisingly, none
of the three other possible isomers 18, 19, and 20 could be
observed at the end of the reaction. Indeed, this deprotection
could be monitored by 31P and 1H NMR, thus confirming the
presence in the crude reaction mixture of only two products,
molecules 17 and 16, once the desilylation was complete.
We also considered the fluoro-cyclization of particular im-
portance (entry 8). Indeed, the electron-withdrawing charac-
ter of the fluorine atom induces a decrease of the pKa valuesof
the deprotected phosphonic diacid, which might be a critical
element for the binding processes with enzymes. For this par-
ticular reaction we extrapolated the chemistry of Selectfluor
mediated 2-fluoro-glycosylations.24,25 After optimization,
we obtained the fluoro-phosphonate 14 in 62% yield as a
9/1 mixture of two separable diastereomers (entry 8). The
temperature of this cyclization was a very important para-
meter to optimize: performing the reaction at temperatures
higherthan 50 ꢀC led toside-reactionsandmuchloweryields.
The structure of exo-glycal 16 has been unambiguously
determined by its independent synthesis from 12. The (Z)-
1
configuration was assigned by H NMR and NOE experi-
ments.11,21,22 In order to optimize the preparation of 17,
we analyzed the ratio 17/16 as a function of the reaction con-
ditions (Table 2).
Table 2. Transformation of phosphonate 12 into 16 and/or 17
For the very same reasons (influence on the pKa of the phos-
phonate), the synthesis of the a-hydroxy-phosphonate 15
was developed either with m-CPBA (entry 9) or with
DMDO (entry 10), in 75% and 64% yields, respectively.
Given the literature data on the epoxidation of endo-gly-
cals,26 we first attempted the reaction with DMDO (entry
10). Exposing exo-glycal 9 to DMDO (or m-CPBA) yielded
an unstable epoxide that directly cyclized to give the ex-
pected constrained acetal 15. However, this product was
found difficult to purify under optimized conditions (entry
10). We then explored a more recent methodology developed
for epoxidizing exo-glycals based on the in situ generation of
trifluoro-DMDO.27 However, applied to molecule 9, this
methodology gave very poor yields of alcohol 15 (data not
shown). We finally obtained a reproducible procedure by
using dry m-CPBA and a catalytic amount of CSA (entry 9).
Entry Solvent
Bu4NF
T
Time Ratio
(h)
Yieldb
17/16a (%)
(equiv) (ꢀC)
1
2
3
4
5
6
7
8
THF
THF
THF
3
5
10
3
3
3
rt
rt
rt
rt
6
6
6
6
12
59/41 ndd
56/44 ndd
50/50 ndd
60/40 40c
85/15 70c
88/12 70c
THF/iPrOH 3/1
THF
THF
ꢁ50/rt
ꢁ50/10 12
ꢁ50/ꢁ5 36
THF
3
3
96/4
83c
THF/tBuOH 3/1
40
2
0/100 60e
Determined by 31P and 1H NMR.
a
b
After silica gel chromatography (AcOEt/EtOH 9/1, then acetone/DCM
8/2).
Isolated yield of acetal 17.
Not determined: the reaction was stopped when the deprotections were
complete but the products were not isolated.
Isolated yield of exo-glycal 16.
c
d
e
O
O
O
OBn
TBS
OBn
OBn
HO
P
OH
O
OBn
OBn
OBn
O
P
P
Bu4NF
Solvent, T
+
O
O
HO
TBSO
12
O
17
O
HO
OH
OH
HO
OH
16
OTBS
HO
O
HO
OH
OH
OBn
OBn
O
O
P
O
P
Not observed :
HO
HO
20
HO
OBn
OH
O
HO
OH
HO
BnO
OBn
19
18
P
O
BnO
Scheme 2. Fluoride induced deprotections and selective formation of exo-glycal 16.

A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
2073
O
P
H
S
O
+
RO
OR
2. selective (Z)-enol
ether formation
OBn 1. Selective C1-O5
OBn
O
OR
OBn
OBn
bond cleavage
P
16
O
H
RO
R
RO
O
OR
OR
Scheme 3. Hypothetical mechanism of the diastereoselective elimination.
When the reaction was performed at room temperature
(entries 1–3), the exo-glycal formation was slightly favored
by increasing the concentration of Bu4NF. The chromato-
graphic separation of 17 and 16 proved very demanding,
thus explaining that the isolated yields were always poorer
than the conversions observed by NMR. For instance, entry
4 describes an experiment for which a poor selectivity was
observed: the reaction was stopped when molecules 17 and
16 were the only final products. Under these conditions,
the obtention of pure acetal 17 required two silica gel puri-
fications. We finally discovered that the elimination leading
to exo-glycal 16 was highly temperature dependent (entries
5–8). The optimal conditions, at low temperature, to mini-
mize the formation of side-product 16, while maintaining
a reasonable desilylation rate, are described in entry 7 (Table
2). On the other hand, by heating the reaction mixture at
40 ꢀC, the elimination leading to 16 became predominant
(entry 8). This last reaction is significant since, to our knowl-
edge, methods describing the formation of an exo-glycal
stable for days in methanolic water at room temperature).
These observations are contrasting with the usual reactivity
of constrained quaternary acetals. Therefore, a concerted E2
type elimination, or even an E1cb, cannot be ruled out at this
stage. A cautious mechanistic investigation will be neces-
sary to unravel the fundamental origin of this surprising
diastereoselective transformation.
3. Conclusion
In conclusion, we developed an efficient methodology for
the synthesis of galactose derivatives locked in a 1,4B boat
conformation. Since these molecules are functionalized at
the anomeric position, they may be useful conformational
probes for glycosyl processing enzymes, such as galacto-
sidases, galactosyl transferases, and UDP-galactopyranose
mutase. The possibility of functionalizing the core structure
A at the vicinity of the anomeric center with electron-with-
drawing or charged groups should, in principle, enhance its
inhibition properties.
t
from an acetal are rare.28 iPrOH or BuOH (entries 4 and
8) was used as cosolvent to prevent the precipitation of
deprotected polyols.
The remarkable diastereoselectivity of this reaction might be
rationalized by decomposing this elimination into two dis-
tinct mechanistic steps. The first elemental step could be
the acetal opening giving rise to a single furanic oxycarb-
enium intermediate (Scheme 3). It is now well-established
that 1,4-anhydro-galactosides give only galactofuranosides
when exposed to nucleophiles under acidic conditions,16,29
thus showing that an intermediate pyranic oxycarbenium is
not formed. A stereoelectronic control has been invoked to
justify this specificity: given the positions of the lone pair
electrons of the oxygen O-4 and O-5 relative to the C1–O4
and C1–O5 s bonds, the C1–O5 bond may be considered
weakened due to its antiperiplanarity with one of the O-4
doublets. In this case, the acetal opening, under slightly basic
conditions, would not be justified by an acidic activation but
by a decrease of ring strain while the [2.2.1]-bicyclic glyco-
side collapses into a furanoside.
4. Experimental part
4.1. Materials and procedures
All chemicals were purchased from Sigma, Aldrich or Fluka
and were used without further purification. Tetrahydrofuran
and toluene were freshly distilled over sodium benzophe-
none, dichloromethane over P2O5, and nitromethane over
CaH2.1H, 13C, 31P, and 19F NMR spectra were recorded
with Bruker AC-250 and AMX-400 spectrometers. All new
1
compounds were characterized by H, 13C, 31P, 19F NMR
1
1
as well as by H–1H and H–13C correlation experiments.
Specific optical rotations were measured on a Perkin Elmer
241 Polarimeter in a 1 dm cell. Melting points were deter-
€
mined with a Buchi 535 apparatus. Column chromatogra-
phies were performed on silica gel Kieselgel Si 60
(40–63 mm). Molecules 1 and 4 were prepared following lit-
erature data.20 Compounds 6, 7, 8, 9, and 12 were previously
described.11
Then, the observed (Z)-specificity may be explained by a spe-
cific kinetic deprotonation of one of the two diastereotopic
hydrogen atoms of the phosphono-methylene moiety. This
possibility has already been invoked by Lin et al. for the
stereospecific formation of (Z)-exo-glycals.30 Thus, it would
signify that, in the transition state, the oxycarbenium adopts
a well-defined conformation placing the phosphonyl moiety
at the opposite of the C-2 position of the carbohydrate.
4.2. Atom and position numberings
We systematically numbered the phosphonate-methylene
group 10 and adopted the usual numbering for carbohydrates
from 1 to 6 with 1 for the anomeric position.
4.2.1. 1,4-Anhydro-2,3-di-O-tert-butyldimethylsilyl-1-de-
oxy-1-iodomethyl-D-galactopyranose (3). Tebbe’s reagent
(1.0 mL, 0.4 M in toluene, 0.4 mmol, 3.1 equiv) was added
dropwise at 0 ꢀC on a solution of 2,3-di-O-tert-butyldi-
methylsilyl-D-galactono-1,4-lactone 120 (55 mg, 0.13 mmol)
However, we have to outline that this reaction depends on the
presence of the basic fluoride anion (Table 1, entries 1–3).
The starting quaternary acetal 12 has been found stable
under slightly acidic conditions (Table 1, entry 6, CSA in
refluxing CH2Cl2), or in neutral conditions (molecule 17 is
dissolved in
a mixture of toluene/THF/Py 1/1/0.3

2074
A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
(2.3 mL). The dark red solution obtained was stirred for 1 h
at 0 ꢀC and 30 min at room temperature after which the re-
action was stopped by adding an aqueous solution of
NaOH (2.0 mL, 1 M) at 0 ꢀC. The resulting solution was fil-
tered through CeliteÒ and concentrated under vacuum. The
residue was dried by azeotropic evaporation with anhydrous
toluene (2ꢂ10 mL) and then dissolved in anhydrous CH2Cl2
(5 mL) under argon atmosphere. To this solution were suc-
(Si–C(CH3)3), 17.83 (Si–C(CH3)3), ꢁ4.21 (Si–Me), ꢁ4.51
(Si–Me), ꢁ4.70 (Si–Me), ꢁ4.82 (Si–Me), ꢁ5.44 (Si–Me),
ꢁ5.45 (Si–Me); 31P NMR (101 MHz, CDCl3) d 26.62; MS
(DCI-NH3): m/z 627 [M+H]+; elemental analysis for
C27H59O8PSi3: calcd (%) C 51.72, H 9.48; meas. C 51.73,
H 9.62.
4.2.3. 1,4-Anhydro-2,3,6-tri-O-tert-butyldimethylsilyl-1-
deoxy-1-(dimethoxyphosphoryl)iodomethyl-D-galacto-
pyranose (11). To a solution of 8 (58.4 mg, 0.09 mmol) and
˚
cessively added molecular sieves 4 A (200 mg) and NIS
(66 mg, 0.29 mmol, 2.2 equiv). The solution was stirred
for 45 min at 0 ꢀC, filtered through CeliteÒ, diluted with
CH2Cl2 (15 mL), and then washed twice with a saturated
solution of Na2S2O3 (10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated. The resi-
due was purified by chromatography on silica gel (eluent
cyclohexane/EtOAc: 20/1) to give compound 3 (31.7 mg,
58% yield) as a colorless oil.
˚
molecular sieves 4 A (150 mg) in dry dichloromethane
(5 mL) cooled to 0 ꢀC was added NIS (50.3 mg,
0.22 mmol, 2.5 equiv). The reaction mixture was stirred
for 1 h at 0 ꢀC after which it was allowed to warm to room
temperature and stirred overnight. The solution was then fil-
tered through a pad of CeliteÒ and the filtrate was washed
with an aqueous solution of Na2S2O3, brine, dried over
MgSO4, filtered, and concentrated. The final mixture was
chromatographed on silica gel with cyclohexane/EtOAc
(2/1) as eluent. Product 11 (60 mg, 86% yield) was obtained
as a pale yellow solid.
1
[a]2D1 +47.8 (c 1.4, CHCl3); H NMR (400 MHz, CDCl3)
d 4.37 (d, J3–4¼1.4 Hz, 1H, H-4), 4.01 (t, J2–3¼J3–4
¼
1.4 Hz, 1H, H-3), 3.93 (dd, J5–6a¼4.3 Hz, J5–6b¼5.1 Hz,
1H, H-5), 3.87 (d, J2–3¼1.4 Hz, 1H, H-2), 3.77 (ABX,
J5–6a¼4.3 Hz, J6a–6b¼11.6 Hz, 1H, H-6a), 3.70 (ABX,
J5–6b¼5.2 Hz, J6a–6b¼11.6 Hz, 1H, H-6b), 3.54 (AB,
JAB¼11.6 Hz, 2H, CH2–I), 0.94 (s, 9H, Si–tBu), 0.93 (s,
9H, Si–tBu), 0.14 (s, 9H, 3Si–Me), 0.10 (s, 3H, Si–Me);
13C NMR (100 MHz, CDCl3) d 105.44 (C-1), 84.60 (C-3),
83.78 (C-4), 81.97 (C-2), 77.09 (C-5), 63.50 (C-6), 25.70
(2Si–C(CH3)3), 18.05 (Si–C(CH3)3), 17.93 (Si–C(CH3)3),
1.31 (CH2–I), ꢁ4.71 (2Si–Me), ꢁ4.75 (2Si–Me); MS (DCI-
NH3): m/z 531 (100%) [M+H]+, 548 (5%) [M+NH4]+;
HRMS for C19H40O5Si2I: calcd 531.1459; meas. 531.1464.
[a]D20 +25.2 (c 0.9, CHCl3); mp 118–119 ꢀC; 1H NMR
(400 MHz, CDCl3) d 4.46 (d, J3–4¼1.5 Hz, 1H, H-4), 4.44
(s, 1H, H-3), 4.13 (d, J1 –P¼13.8 Hz, 1H, H-10), 3.87 (d,
0
JH–P¼11.2 Hz, 3H, OCH3), 3.86 (d, JH–P¼11.1 Hz, 3H,
OCH3), 3.85 (dd, J5–6a¼4.6 Hz, J5–6b¼9.8 Hz, 1H, H-5),
3.72 (s, 1H, H-2), 3.61 (ABX, J5–6a¼4.6 Hz, J6a–6b
¼
9.8 Hz, 1H, H-6a), 3.53 (t, J5–6b¼J6a–6b¼9.8 Hz, 1H, H-
6b), 0.94 (s, 9H, Si–tBu), 0.93 (s, 9H, Si–tBu), 0.90 (s, 9H,
Si–tBu), 0.21 (s, 3H, Si–Me), 0.17 (s, 3H, Si–Me), 0.12 (s,
6H, 2Si–Me), 0.07 (s, 6H, 2Si–Me); 13C NMR(100 MHz,
CDCl3) d 106.44 (d, J1–P¼5.1 Hz, C-1), 86.08 (d, J3–P
¼
4.2.2. 1,4-Anhydro-2,3,6-tri-O-tert-butyldimethylsilyl-1-
deoxy-1-(dimethoxyphosphoryl)methyl-D-galactopyra-
nose (10). To a solution of 8 (386 mg, 0.62 mmol) and
7.3 Hz, C-3), 83.84 (C-4), 80.08 (d, J2–P¼2.0 Hz, C-2),
78.24 (C-5), 61.57 (C-6), 54.12 (d, JC–P¼6.5 Hz, OCH3),
54.09 (d, JC–P¼6.6 Hz, OCH3), 25.81 (Si–C(CH3)3), 25.74
(Si–C(CH3)3), 25.70 (Si–C(CH3)3), 18.04 (Si–C(CH3)3),
0
˚
molecular sieves 4 A (600 mg) in dry dichloromethane
(7 mL) under argon atmosphere was added 10-d,l-camphor-
sulfonic acid CSA (214 mg, 0.92 mmol, 1.5 equiv). The
mixture was refluxed under argon for 15 h. The suspension
was then filtered through a pad of CeliteÒ and the filtrate
was washed with a saturated aqueous solution of NaHCO3,
dried over MgSO4, filtered, and concentrated. The final mix-
ture was chromatographed on a silica gel column with cyclo-
hexane/EtOAc (1.5/1) as eluent and product 10 (270 mg,
70% yield) was obtained as a colorless oil.
17.85 (Si–C(CH3)3), 17.82 (Si–C(CH3)3), 8.77 (d, J1 –P
¼
150.3 Hz, C-10), ꢁ4.01 (Si–Me), ꢁ4.29 (Si–Me), ꢁ4.42
(Si–Me), ꢁ4.78 (Si–Me), ꢁ5.42 (Si–Me), ꢁ5.45 (Si–Me);
31P NMR (101 MHz, CDCl3) d 20.65; MS (DCI-NH3): m/z
770 [M+NH4]+; elemental analysis for C27H58IO8PSi3:
calcd (%) C 43.07, H 7.76; meas. C 43.35, H 8.21.
4.2.4. 1,4-Anhydro-1-deoxy-1-(dibenzyloxyphosphoryl)-
iodomethyl-2,3,6-tri-O-tert-butyldimethylsilyl-D-galacto-
pyranose (13). Compound 9 (77.6 mg, 0.10 mmol) was
treated with NIS (112 mg, 0.50 mmol) according to the
same procedure described for 11. The reaction time was
12 h at room temperature and the crude was purified by silica
gel chromatography with cyclohexane/EtOAc (3/1) as eluent
to give 13 (71.2 mg, 79% yield) as a pale yellow solid.
1
[a]2D4 +36.4 (c 1.3, CHCl3); H NMR (400 MHz, CDCl3)
d 4.45 (d, J3–4¼1.3 Hz, 1H, H-4), 4.04 (t, J2–3¼J3–4
¼
1.3 Hz, 1H, H-3), 3.81 (d, JH–P¼11.0 Hz, 3H, OCH3), 3.79
(d, JH–P¼11.1 Hz, 3H, OCH3), 3.67 (br s, 1H, H-2), 3.66
(dd, J5–6a¼4.5 Hz, 1H, H-5), 3.57 (ABX, J5–6a¼4.5 Hz,
J6a–6b¼9.7 Hz, 1H, H-6a), 3.46 (t, J5–6b¼J6a–6b¼9.8 Hz, 1H,
1
0
0
0
H-6b), 2.43 (ABX, J1 a–1 b¼15.7 Hz, J1 a–P¼19.3 Hz, 1H, H-
[a]2D4 +24.4 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3)
10a), 2.38 (ABX, J1 a–1 b¼15.7 Hz, J1 b–P¼19.3 Hz, 1H,
H-10b), 0.93 (2s, 18H, Si–tBu), 0.91 (s, 9H, Si–tBu), 0.14
(2s, 6H, 2Si–Me), 0.12 (2s, 6H, 2Si–Me), 0.08 (s, 6H, 2Si–
d 7.38–7.30 (m, 10H, H arom.), 5.16 and 5.14 (2AX,
JH–P¼1.9 and 2.0 Hz, 4H, CH2Ph), 4.49 (br s, 1H, H-3),
0
0
0
0
4.47 (d, J3–4¼1.6 Hz, 1H, H-4), 4.22 (d, J1 –P¼13.9 Hz,
Me); 13C NMR (100 MHz, CDCl3) d 105.22 (d, J1–P
¼
1H, H-10), 3.85 (dd, J5–6a¼6.3 Hz, J5–6b¼8.2 Hz, 1H, H-
5), 3.74 (s, 1H, H-2), 3.55–3.50 (m, 2H, H-6a, H-6b), 0.95
(s, 9H, Si–tBu), 0.94 (s, 9H, Si–tBu), 0.88 (s, 9H, Si–tBu),
0.21 (s, 3H, Si–Me), 0.18 (s, 3H, Si–Me), 0.13 (2s, 6H,
2Si–Me), 0.02 (s, 6H, 2Si–Me); 13C NMR (100 MHz,
CDCl3) d 136.31 (d, JC–P¼6.6 Hz, Cq arom.), 136.15 (d,
4.9 Hz, C-1), 86.69 (d, J3–P¼6.7 Hz, C-3), 84.08 (C-4),
79.91 (d, J2–P¼1.4 Hz, C-2), 76.52 (C-5), 61.89 (C-6),
52.73 (d, JC–P¼6.1 Hz, OCH3), 52.45 (d, JC–P¼6.0 Hz,
OCH3), 26.53 (d, J1 –P¼142.1 Hz, C-10), 25.75 (2Si–
0
C(CH3)3), 25.70 (Si–C(CH3)3), 18.06 (Si–C(CH3)3), 17.90

A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
2075
JC–P¼7.1 Hz, Cq arom.), 128.40–127.85 (10 CH arom.),
106.63 (d, J1–P¼4.5 Hz, C-1), 86.06 (d, J3–P¼7.4 Hz, C-3),
83.75 (C-4), 80.14 (d, J2–P¼1.9 Hz, C-2), 78.27 (C-5),
68.76 (d, JC–P¼6.4 Hz, CH2Ph), 68.72 (d, JC–P¼6.5 Hz,
CH2Ph), 61.65 (C-6), 25.82 (Si–C(CH3)3), 25.72 (2Si–
C(CH3)3), 18.00 (Si–C(CH3)3), 17.85 (2Si–C(CH3)3), 9.67
3.73 (s, 1H, H-2), 3.55 (ABX, J5–6a¼4.8 Hz, J6a–6b¼9.9 Hz,
1H, H-6a), 3.51 (t, J5–6b¼J6a–6b¼9.9 Hz, 1H, H-6b), 0.95 (s,
9H, Si–tBu), 0.93 (s, 9H, Si–tBu), 0.85 (s, 9H, Si–tBu), 0.14
(s, 3H, Si–Me), 0.13 (s, 6H, 2Si–Me), 0.10 (s, 3H, Si–Me),
0.04 (s, 3H, Si–Me), 0.03 (s, 3H, Si–Me); 13C NMR
(100 MHz, CDCl3) d 136.08 (d, JC–P¼6.4 Hz, Cq arom.),
135.86 (d, JC–P¼6.5 Hz, Cq arom.), 128.50–127.86 (10 CH
arom.), 103.79 (dd, J1–P¼8.3 Hz, J1–F¼17.7 Hz, C-1),
84.94, 83.51 (dd, J3,4–P¼3.7 Hz, J3,4–F¼3.7 Hz, C-3, C-4),
(d, J1 –P ¼150.1 Hz, C-10), ꢁ4.00 (Si–Me), ꢁ4.27 (Si–
0
Me), ꢁ4.40 (Si–Me), ꢁ4.74 (Si–Me), ꢁ5.46 (2Si–Me);
31P NMR (101 MHz, CDCl3) d 18.83; MS (DCI-NH3): m/z
905 [M+H]+; elemental analysis for C39H66IO8PSi3: calcd
(%) C 51.75, H 7.35; meas. C 51.58, H 7.53.
83.53 (dd, J1 –P¼167.2 Hz, J1 –F¼185.1 Hz, C-10), 79.76 (C-
2), 76.46 (C-5), 68.86 (d, JC–P¼6.0 Hz, CH2Ph), 67.98 (d,
JC–P¼6.4 Hz, CH2Ph), 61.53 (C-6), 25.75 (Si–C(CH3)3),
25.72 (2Si–C(CH3)3), 18.06 (Si–C(CH3)3), 17.89 (2Si–
C(CH3)3), ꢁ4.20 (Si–Me), ꢁ4.64 (Si–Me), ꢁ4.72 (Si–Me),
ꢁ5.05 (Si–Me), ꢁ5.44 (Si–Me), ꢁ5.45 (Si–Me); 31P NMR
(101 MHz, CDCl3) d 13.87 (d, JP–F¼72.0 Hz); 19F NMR
0
0
0
4.2.5. 1,4-Anhydro-1-deoxy-1-(dibenzyloxyphosphoryl)-
fluoromethyl-2,3,6-tri-O-tert-butyldimethylsilyl-D-galac-
topyranose (14). Compound 9 (72 mg, 0.09 mmol) and
˚
molecular sieves 4 A (300 mg) were dissolved in freshly dis-
tilled nitromethane (5 mL) under argon. The suspension was
stirred for 1 h at room temperature and Selectfluor$BF4ꢁ
(79 mg, 0.22 mmol, 2.4 equiv) was added and the solution
was stirred at 50 ꢀC for 8 h. The reaction mixture was then
diluted with CH2Cl2 (30 mL), filtered through a pad of
CeliteÒ and concentrated. The residue was purified by chro-
matography on silica gel (eluent cyclohexane/EtOAc: 20/
1/15/1) to give compound 14 (37 mg), then its epimer
140 (8.2 mg) as colorless oils with a global yield of 62%.
(235 MHz, CDCl3) d ꢁ215.06 (dd, JP–F¼72.0 Hz, JF–H1 ¼
44.2 Hz); MS (DCI-NH3): m/z 797 (100%) [M+H]+, 814
(10%) [M+NH4]+.
4.2.6. 1,4-Anhydro-1-deoxy-1-(dibenzyloxyphosphoryl)-
hydroxymethyl-2,3,6-tri-O-tert-butyldimethylsilyl-D-gal-
actopyranose (15).
4.2.6.1. Procedure using m-CPBA. Crushed, acti-
˚
vated 3 A molecular sieves and a solution of 9 (70 mg,
0.090 mmol) in anhydrous CH2Cl2 (1 mL) were introduced
into a flame-dried flask filled with argon. 10-d,l-Camphor-
sulfonic acid (0.1 equiv, 2 mg, 0.064 mmol) and dry
m-chloroperbenzoic acid (1.2 equiv, 20 mg, 0.077 mmol)
were added at room temperature. The solution was then
stirred for 15 h at 20 ꢀC and filtered through a pad of CeliteÒ.
Saturated aqueous sodium bicarbonate solution (2 mL)
was added and the mixture was extracted with CH2Cl2
(3ꢂ5 mL), washed with a saturated aqueous Na2S2O3 solu-
tion (5 mL), a saturated aqueous NaHCO3 solution (5 mL),
and water (2 mL). The organic layers were dried (MgSO4),
filtered, and the solvents were removed under reduced pres-
sure. The crude material was purified by preparative thin
layer chromatography (cyclohexane/EtOAc: 70/30) afford-
ing 15 (54 mg, 75% yield) as a colorless oil.
4.2.5.1. Major compound 14. [a]2D2 +7.8 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) d 7.38–7.30 (m, 10H, H arom.),
5.27 (ABX, JH–P¼7.3 Hz, JH–H¼11.8 Hz, 1H, CHPh),
5.23 (ABX, JH–P¼8.6 Hz, JH–H¼11.8 Hz, 1H, CHPh), 5.14
(ABX, JH–P¼7.4 Hz, JH–H¼11.9 Hz, 1H, CHPh), 5.10
(ABX, JH–P¼8.6 Hz, JH–P¼11.9 Hz, 1H, CHPh), 5.07 (dd,
J1 –P¼8.6 Hz, J1 –F¼44.9 Hz, 1H, H-10), 4.55 (s, 1H, H-3),
4.50 (s, 1H, H-4), 3.76 (dd, J5–6a¼4.5 Hz, J5–6b¼9.8 Hz,
1H, H-5), 3.74 (s, 1H, H-2), 3.64 (ABX, J5–6b¼4.5 Hz,
J6a–6b¼9.8 Hz, 1H, H-6a), 3.47 (t, J5–6b¼J6a–6b¼9.8 Hz,
1H, H-6b), 0.93 (s, 9H, Si–tBu), 0.92 (s, 18H, 2Si–tBu),
0.21 (s, 3H, Si–Me), 0.16 (s, 3H, Si–Me), 0.14 (2s, 6H,
2Si–Me), 0.13 (s, 3H, Si–Me), 0.09 (s, 6H, 2Si–Me); 13C
NMR (100 MHz, CDCl3) d 136.19 (d, JC–P¼6.3 Hz, Cq
arom.), 135.68 (d, JC–P¼5.9 Hz, Cq arom.), 128.51–127.85
(10 CH arom.), 105.87 (dd, J1–P¼5.6 Hz, J1–F¼17.8 Hz,
0
0
4.2.6.2. Procedure using DMDO. Crushed, activated
˚
3 A molecular sieves and a solution of 9 (120 mg,
0
C-1), 85.05 (C-3), 84.29 (C-4), 84.06 (dd, J1 –P¼165.0 Hz,
J1 –F¼194.2 Hz, C-10), 80.22 (d, J2–P¼1.6 Hz, C-2), 76.04
0.154 mmol) in anhydrous CH2Cl2 (2 mL) were introduced
into a flame-dried flask filled with argon. The flask was
cooled to 0 ꢀC at each addition of a solution of dimethyl-
dioxirane (0.08 M in acetone, 10 equiv,w20 mL, 1.54 mmol)
portionwise (5ꢂ2 equiv/2 h) and dropwise. After each addi-
tion of DMDO at 0 ꢀC, the solution was allowed to warm to
15–20 ꢀC. The resulting mixture was stirred for 15 h and fil-
tered through a pad of CeliteÒ. The solvent of the filtrate was
removed under reduced pressure and the crude material was
diluted in CH2Cl2, dried (Na2SO4), filtered, and concen-
trated. The crude epoxide was diluted in anhydrous CH2Cl2
0
(C-5), 69.55 (d, JC–P¼5.8 Hz, CH2Ph), 68.16 (d, JC–P
¼
6.8 Hz, CH2Ph), 61.80 (C-6), 25.76 (Si–C(CH3)3), 25.73
(Si–C(CH3)3), 25.64 (Si–C(CH3)3), 18.06 (Si–C(CH3)3),
17.85 (Si–C(CH3)3), 17.79 (Si–C(CH3)3), ꢁ4.29 (Si–Me),
ꢁ4.69 (Si–Me), ꢁ4.79 (Si–Me), ꢁ4.83 (Si–Me), ꢁ5.44
(Si–Me), ꢁ5.46 (Si–Me); 31P NMR (101 MHz, CDCl3)
d 13.01 (d, JP–F¼66.8 Hz); 19F NMR (235 MHz, CDCl3)
0
d ꢁ220.16 (dd, JP–F¼66.8 Hz, JF–H1 ¼44.8 Hz); MS (DCI-
NH3): m/z 797 [M+H]+; HRMS for C39H67O8FSi3P: calcd
797.3865; meas. 797.3872.
˚
(3 mL) and stirred with 3 A molecular sieves (200 mg) at
4.2.5.2. Minor compound 140. [a]D21 +10.2 (c 0.7,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.38–7.30 (m, 10H,
H arom.), 5.23 (ABX, JH–P¼7.3 Hz, JH–H¼11.8 Hz, 1H,
CHPh), 5.20 (ABX, JH–P¼8.1 Hz, JH–H¼11.8 Hz, 1H,
0
room temperature under an atmosphere of argon. After 1 h,
10-d,l-camphorsulfonic acid (0.2 equiv, 10 mg, 0.043 mmol,
M.W. 232) was added. The resulting mixture was stirred for
5 h at room temperature, filtered through a pad of CeliteÒ,
and the solvents were removed under reduced pressure.
Two subsequent purifications by preparative thin layer
chromatography (cyclohexane/EtOAc: 90/10) afforded 15
(79 mg, 64% yield).
CHPh), 5.14(AX, JH–P¼8.7 Hz, 2H,CH2Ph), 4.99(dd, J1 –P
¼
7.6 Hz, J1 –F¼44.1 Hz, 1H, H-10), 4.56 (d, J3–4¼1.4 Hz, 1H,
H-4), 4.27 (dd, J2–3¼0.8 Hz, J3–4¼1.4 Hz, 1H, H-3), 3.75
(ddd, J4–5¼1.7 Hz, J5–6a¼4.8 Hz, J5–6b¼9.9 Hz, 1H, H-5),
0

2076
A. Caravano et al. / Tetrahedron 63 (2007) 2070–2077
[a]2D0 +8.000 (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.29–7.39 (m, 10H, H arom.), 5.08–5.22 (m, 4H,
CH2Ph), 4.52 (s, 1H, H-3), 4.48 (d, J3–4¼1.2 Hz, 1H, H-4),
H arom.), 5.22–5.18 (m, 4H, CH2Ph), 4.90 (dd, J1 –2
¼
0
1.6 Hz, J1 –P¼11.4 Hz, 1H, H-10), 4.65 (ddd, J1 –2¼1.6 Hz,
J2–3¼7.9 Hz, J2–P¼4.2 Hz, 1H, H-2), 4.38–4.33 (m,
J3–4¼5.6 Hz, J4–5¼1.9 Hz, 2H, H-3 and H-4), 3.94 (ddd,
J4–5¼1.9 Hz, J5–6a¼7.3 Hz, J5–6b¼5.8 Hz, 1H, H-5), 3.86
(m, 2H, J6a–6b¼6.3 Hz, H-6a, H-6b); 13C NMR (100 MHz,
0
0
4.31 (dd, J1 –OH¼4.6 Hz, J1 –P¼12.0 Hz, 1H, H-10), 3.74
(dd, J5–6a¼4.4 Hz, J5–6b¼9.2 Hz, 1H, H-5), 3.72 (s, 1H, H-
2), 3.61 (ABX, J5–6a¼4.4 Hz, J6a–6b¼9.6 Hz, 1H, H-6a),
0
0
0
3.44 (t, J5–6b¼J6a–6b¼9.4 Hz, 1H, H-6b), 2.67 (dd, JOH–1
¼
CD3OD) d 176.91 (d, J1–P¼1.9 Hz, C-1), 138.15 (d, JC–P¼
4.6 Hz, JOH–P¼16.6 Hz, 1H, OH), 0.89 (s, 18H, 2Si–tBu),
0.88 (s, 9H, Si–tBu), 0.11 (s, 3H, Si–Me), 0.10 (s, 3H, Si–
Me), 0.09 (s, 6H, 2Si–Me), 0.05 (s, 6H, 2Si–Me); 13C
NMR (100 MHz, CDCl3) d 136.68 (Cq arom.), 136.22 (Cq
7.2 Hz, C arom.), 138.08 (d, JC–P¼7.0 Hz, C arom.),
129.85–129.20 (10 CH arom.), 86.16 (C-4), 80.53 (d,
0
J1 –P¼195.7 Hz, C-10), 79.12 (d, J2–P¼12.9 Hz, C-2),
75.62 (C-3), 71.50 (C-5), 69.00 (d, JC–P¼5.2 Hz, CH2Ph),
68.74 (d, JC–P¼5.2 Hz, CH2Ph), 63.99 (C-6); 31P NMR
(101 MHz, CDCl3) d 21.35; MS (DCI-NH3): m/z 437
(100%) [M+H]+, 454 (55%) [M+NH4]+; HRMS for
C21H26O8P: calcd 437.1365; meas. 437.1372.
arom.), 127.71–128.64 (10 CH arom.), 107.08 (d, J1–P
5.9 Hz, C-1), 84.75 (C-3), 84.41 (C-4), 80.24 (C-2),
¼
75.93 (C-5), 68.95 (d, JC–P¼6.68 Hz, CH2Ph), 67.86 (d,
JC–P¼6.67 Hz, CH2Ph), 65.46 (d, J1 –P¼164 Hz, C-10),
0
61.89 (C-6), 25.75 (2Si–C(CH3)3), 25.68 (Si–C(CH3)3),
18.08 (Si–C(CH3)3), 17.83 (Si–C(CH3)3), ꢁ4.24 (Si–Me),
ꢁ4.61 (Si–Me), ꢁ4.75 (Si–Me), ꢁ5.44 (Si–Me); 31P NMR
(101 MHz, CDCl3) d 19.29; IR (KBr): 3345, 3067, 3035,
2956, 2931, 2889, 2858, 1949, 1758, 1499, 1470, 1388,
1363, 1305, 1256, 1217, 1101, 1020, 980, 940, 901,
838, 779, 758; MS (DCI-NH3): m/z 550 (100%)
[Mꢁ2TBDMSꢁOH]+, 795 (15%) [M+H]+, 812 (5%)
[M+NH4]+; HRMS for C39H68O9Si3P: calcd 795.3909;
meas. 795.3898.
Acknowledgements
We warmly thank Professor Krief and his team for sharing
their facilities and for their stimulating scientific discus-
sions. This work was supported by the Centre National de
´ ´
´
la Recherche Scientifique (CNRS), by the Ministeꢁre Delegue
aꢁla Recherche et aux Nouvelles Technologies (Ph.D. grant to
A.C.) as well as the University of Namur (post-doctoral
grants to D.B. and W.P. and a Ph.D. grant to C.A.).
4.2.7. (1(10)Z)-1-Deoxy-1-(dibenzyloxyphosphoryl)-
methylidene-D-galactofuranose (16) and 1,4-anhydro-1-
deoxy-1-(dibenzyloxyphosphoryl)methyl-D-galactopyr-
anose (17). To a solution of 12 (186 mg, 0.24 mmol) in
distilled THF (10 mL) cooled to ꢁ50 ꢀC was added tetra-
butylammonium fluoride trihydrate (226 mg, 0.72 mmol,
3 equiv). The reaction mixture was stirred for 16 h at
ꢁ5 ꢀC. The solvent was then removed from the solution un-
der reduced pressure and the crude was first purified by flash
chromatography on silica gel column with EtOAc/EtOH
(9/1) as eluent and secondly repurified by flash chromato-
graphy with acetone/CH2Cl2 (8/2) as eluent to separate 17
from exo-glycal 16. Compound 16 (86 mg) was obtained
in 83% yield as a colorless oil.
References and notes
1. Bruice, T. C. Acc. Chem. Res. 2002, 35, 139–148.
2. Sinnott, M. L. Chem. Rev. 1990, 90, 1171–1202.
3. Kirby, A. J. The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer: Berlin, Heidelberg, New York,
NY, 1983.
4. Sorensen, M. D.; Kvaerno, L.; Bryld, T.; Hakansson, A. E.;
Verbeure, B.; Gaubert, G.; Herdewijn, P.; Wengel, J. J. Am.
Chem. Soc. 2002, 124, 2164–2176.
5. Herdewijn, P. Biochim. Biophys. Acta 1999, 1489, 167–179.
€
6. Vasella, A.; Davies, G.; Bohm, M. Curr. Opin. Chem. Biol.
2002, 6, 619–629.
7. Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–
3092.
8. Heck, M.-P.; Vincent, S. P.; Murray, B.; Wong, C.-H.;
Mioskowski, C. J. Am. Chem. Soc. 2004, 126, 1171–1179.
9. Das, S. K.; Mallet, J.-M.; Esnault, J.; Driguez, P.-A.;
Duchaussoy, P.; Sizun, P.; Herbert, J.-M.; Petitou, M.; Sina€y,
P. Angew. Chem., Int. Ed. 2001, 40, 1670–1673.
10. Lorthiois, E.; Meyyappan, M.; Vasella, A. Chem. Commun.
2000, 1829–1830.
1
4.2.7.1. Compound 17. [a]2D4 +33.7 (c 1.0, CHCl3); H
NMR (400 MHz, CD3OD) d 7.56–7.52 (m, 10H, H arom.),
5.29–5.18 (2 ABX, 4H, 2CH2Ph), 4.64 (d, J3–4¼1.5 Hz,
1H, H-4), 4.00 (t, J2–3¼J3–4¼1.3 Hz, 1H, H-3), 3.97 (dd,
J5–6a¼6.0 Hz, J5–6b¼4.9 Hz, 1H, H-5), 3.88 (d, 1H, H-2),
3.72 (ABX, J5–6a¼6.0 Hz, J6a–6b¼11.6 Hz, 1H, H-6a),
3.67 (ABX, J5–6b¼4.9 Hz, J6a–6b¼11.6 Hz, 1H, H-6b),
2.84 (ABX, J1 a–1 b¼15.9 Hz, J1 a–P¼19.2 Hz, 1H, H-10a),
0
0
0
2.80 (ABX, J1 a–1 b¼15.9 Hz, J1 b–P¼19.0 Hz, 1H, H-10b);
13C NMR (100 MHz, CD3OD) d 137.90 (d, JC–P¼6.0 Hz,
Cq arom.), 137.87 (d, JC–P¼6.3 Hz, Cq arom.), 129.91–
129.45 (10 CH arom.), 107.08 (d, J1–P¼5.9 Hz, C-1),
0
0
0
11. Caravano, A.; Mengin-Lecreulx, D.; Brondello, J.-M.; Vincent,
€
S. P.; Sinay, P. Chem.—Eur. J. 2003, 23, 5888–5898.
€
12. Caravano, A.; Vincent, S. P.; Sinay, P. Chem. Commun. 2004,
86.98 (d, J3–P¼8.1 Hz, C-3), 85.84 (C-4), 79.86 (d, J2–P
¼
1216–1217.
13. Caravano, A.; Dohi, H.; Sinay, P.; Vincent, S. P. Chem.—Eur. J.
€
1.6 Hz, C-2), 78.86 (C-5), 69.36 (d, JC–P¼6.5 Hz, CH2Ph),
69.28 (d, JC–P¼6.5 Hz, CH2Ph), 63.79 (C-6), 28.36 (d,
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J1 –P¼141.8 Hz, C-10); 31P NMR (101 MHz, CDCl3)
0
d 26.94; MS (DCI-NH3): m/z 437 (100%) [M+H]+, 454
(20%) [M+NH4]+; elemental analysis for C21H25O8P: calcd
(%) C 57.80, H 5.77; meas. C 57.74, H 5.94.
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