Stereoselective synthesis of C-glycosylphosphonates from their ketols. Reconsideration of an abandoned route

Article abstract of DOI:10.1016/S0957-4166(99)00477-2

Isosteric phosphonate analogues of glycosyl 1-phosphates have been obtained by addition of LiCH₂P(O)(OMe)₂ to glyconolactones followed by Et₃SiH-TMSOTf reductive dehydroxylation of the resultant ketols. The compounds prepared include four β-linked pyranose derivatives (D-galacto, 2-azido-2-deoxy-D-galacto, D-gluco, D-manno) and one β-linked furanose derivative (D-manno). In the latter case the ketol was activated as its 2-acetate. In agreement with an observation in another laboratory, the dehydroxylation of a model ketol phosphonate failed with the use of Et₃SiH-BF₃.Et₂O. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00477-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 305–317
Stereoselective synthesis of C-glycosylphosphonates from their
ketols. Reconsideration of an abandoned route
Alessandro Dondoni,∗ Alberto Marra ∗ and Claudia Pasti
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
Received 8 October 1999; accepted 26 October 1999
Abstract
Isosteric phosphonate analogues of glycosyl 1-phosphates have been obtained by addition of LiCH2P(O)(OMe)2
to glyconolactones followed by Et3SiH–TMSOTf reductive dehydroxylation of the resultant ketols. The com-
pounds prepared include four β-linked pyranose derivatives (D-galacto, 2-azido-2-deoxy-D-galacto, D-gluco, D-
manno) and one β-linked furanose derivative (D-manno). In the latter case the ketol was activated as its 2-acetate.
In agreement with an observation in another laboratory, the dehydroxylation of a model ketol phosphonate failed
with the use of Et3SiH–BF3·Et2O. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Carbohydrate processing in living organisms is mainly performed with nucleoside diphosphate sugars
as glycosyl donors and glycosyltransferases as active catalysts.1 The search for competitive inhibitors of
glycosyltransferases constitutes the basis for the development of potential drugs against carbohydrate-
based metabolic disorders.2 Consequently, considerable attention is currently focused on the synthesis
of enzymatically resistant analogues of glycosyl phosphates. Among them, isosteric phosphonates3 in
which the oxygen atom of the phosphoesteric linkage has been replaced by a CH2 or a CF2 group
are of primary importance.4 Various synthetic approaches to glycosylmethylphosphonates A have been
described over the years in which the phosphorylmethyl group was introduced by multi-step processes3
to ensure the control of the stereochemistry of the C-glycosidic bond. In particular, the synthesis
of 2-amino-2-deoxy derivatives, a class of compounds of special interest because of the widespread
biological activity of various glycosylamine phosphates, required an appropriate multi-step sequence for
the introduction of the amino and phosphorylmethyl groups with the correct relative stereochemistry.5
However, the direct installation of the phosphorylmethyl group at the anomeric carbon of aldoses by a
tandem Horner–Emmons–Michael-type reaction with different stabilized phosphorus ylides invariably
∗
Corresponding authors. E-mail: adn@dns.unife.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00477-2
tetasy 3113

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led to mixtures of anomeric C-glycosides in both the pyrano6 and furano7 series. An alternative, quite
straightforward entry to compounds A was envisaged by reaction of lithium dialkyl methylphosphonate
with glyconolactones B followed by reductive dehydroxylation of the resulting ketol.8 Unfortunately,
this route was reported not to be viable because the reduction step under the standard Kishi conditions9
employing triethylsilane–boron trifluoride proved unsuccessful. However, this method appeared quite
attractive to us because various sugar lactones were readily available in our laboratory in the context
of other C-glycoside syntheses.10 Hence, the challenge lay in finding new conditions that allow for the
reduction of ketol phosphonates and demonstrating to some extent the general applicability of the method
for the synthesis of compound A. The successful results of our efforts are reported below.
2. Results and discussion
We initially examined the reduction of the known11 ketol phosphonate12 2a that in turn was prepared in
very good yield (91%) by addition of lithium dimethyl methylphosphonate to 2,3,4,6-tetra-O-benzyl-D-
gluconolactone 1a (Scheme 1). It was first confirmed that treatment of 2a with excess triethylsilane and
boron trifluoride etherate (Et3SiH–BF3·Et2O) in dichloromethane at room temperature did not afford
any dehydroxylated product while a substantial amount of unaltered starting material was recovered.
This observation is in agreement with the unsuccessful reduction of the same compound 2a reported by
Nicotra under the above conditions.8 However, when BF3·Et2O was replaced with trimethylsilyl triflate
(TMSOTf), the reductive dehydroxylation of 2a occurred readily in a rather short time (45 min) to give a
mixture of two different C-glycosides, i.e. the β-C-glucosylphosphonate 3a and the phosphono exocyclic
enol ether13 4a in an 8:1 ratio and 52% overall yield. Interestingly, when the initial concentration of 2a
was reduced from 1 M to 0.1 M, the enol ether 4a was the main product (3a:4a 1:1.5, 47% total yield).
The catalytic hydrogenation of the mixture of 3a and 4a over Pd(OH)2 resulted in the formation of
the single β-C-glycoside 5a (97% yield) as a consequence of the removal of the O-benzyl groups and
reduction of the exocyclic carbon–carbon double bond. The glucosylmethylphosphonate 5a was fully
characterized through its tetra-O-acetyl derivative 6a.
Thus, it is noteworthy that the simple replacement of the boron by the silicon Lewis acid promoter
allows an entry to a sugar phosphonate by a method that was earlier not considered feasible.8 The use of
the Et3SiH–TMSOTf system was suggested by our earlier work on the synthesis of furyl14 and thiazolyl15
C-glycosides from the corresponding ketols. An explanation of the above successful deoxygenation is
1
tentatively advanced. The H NMR spectrum of compound 2a showed a long range (W) coupling of
HO-2 with H-3. This spectroscopic feature is consistent16 with the α-D configuration in which HO-2,
C-2, C-3, and H-3 are coplanar (Fig. 1), as favoured by the exo-anomeric effect. Moreover, this particular
orientation of the HO-2 group allows for a strong intramolecular hydrogen bonding with the phosphono
1
oxygen as shown by the downfield chemical shift of HO-2 (5.77 ppm) in its H NMR spectrum. It is
very likely that BF3·Et2O is unable to disrupt such a stable arrangement and promote the formation of
the sugar oxycarbenium ion 7a, the polar reaction intermediate that would lead to the product 5a via
stereoselective hydride addition from Et3SiH. On the other hand the efficiency of TMSOTf leading to 7a

A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
307
Scheme 1.
may be due to some stabilization of the latter by the presence of resulting trifluoromethanesulfonate
acting as a counterion.17 The hydride addition to the gluco oxycarbenium ion 7a occurs with high
facial selectivity as shown in Fig. 1, thus leading exclusively to the β-D-linked sugar phosphonate 5a
as shown by 1H NMR analysis (J2,3=10.0 Hz). This result merits special note, since a low α/β selectivity
was registered for the TMSOTf-promoted coupling at room temperature of another ketol of the gluco
series with various oxygen18 and phosphorus nucleophiles4 as well as the reduction15 in the presence
of triethylsilane. Finally, the formation of the exocyclic enol ether 4a may be explained by the loss of a
proton of the methylene group of 7a. Fortunately, the reduction of the exocyclic carbon–carbon double
bond of 4a was also highly stereoselective and converged on the formation of the same phosphonate 5a.
Fig. 1. Structure of ketol 2a showing the intramolecular hydrogen bonding and stereochemical models for the hydride addition
to the oxycarbenium ions 7a (gluco), 7b and 7c (galacto) (R=CH2P(O)(OMe)2)
The above Et3SiH–TMSOTf promoted reduction was successfully applied to the galactopyrano and
mannopyrano series. Quite rewardingly the ketol phosphonate12 2b, obtained from 2,3,4,6-tetra-O-
benzyl-D-galactonolactone15b 1b, afforded exclusively the β-linked galactosylmethylphosphonate 3b in
remarkably good yield (86%) (Scheme 2). Also the 3-azido derivative12 2c, prepared in the same way
from the 2-azido-2-deoxy-galactonolactone15b 1c, was readily reduced to the corresponding β-D-linked
methylphosphonate 3c although in lower yield (55%).

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A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
Scheme 2.
The high stereoselectivity of these reductions is in line with the stereochemical models 7b and 7c
(Fig. 1). This result was expected based on earlier observations regarding the reduction15b and other
reactions of a related galactopyrano compound.10 The O-benzyl ether groups of 3b were cleaved by
catalytic hydrogenation and the resultant C-galactosylmethylphosphonate 5b was characterized as the
acetyl derivative 6b. The transformation of 3c to the target acetamido-galactosylmethylphosphonate 5c
was conveniently carried out in two sequential steps, the first involving the reduction of the azido group
and its acetylation to give compound 8c, the second involving the removal of the O-benzyl groups. The
stepwise execution of these reactions gave better results than the one-pot reaction sequence. Finally, 5c
was characterized as the tri-O-acetyl derivative 6c. It is worth pointing out that the β-D-linkage in 5b
1
and 5c was easily assigned through their H NMR spectra, showing coupling constant values J2,3 of
4
9.6 and 10.0 Hz, respectively, typical of a trans-diaxial relationship in C-pyranosides adopting a C1
conformation.
The reduction of the ketol phosphonate12 2d derived from the 2,3,4,6-tetra-O-benzyl-D-
mannonolactone 1d afforded only the phosphono exocyclic enol ether13 4d as a reaction product
in modest yield (35%). Part of the unreacted ketose 2d (34%) was recovered from the reaction mixture
(Scheme 3). Following the same reaction scheme carried out for the gluco series, compound 4d was
subjected to the catalytic hydrogenation to give the β-D-linked mannosylmethylphosphonate 5d in very
high yield (95%) that in turn was characterized as the tetra-O-acetyl derivative 6d. Thus, also in this
case, the method proved to be successful for the synthesis of the target C-glycosylphosphonate. In this
series the assignment of the stereochemistry of the final product 5d was less straightforward than in the
above series. However, the well resolved 1H NMR spectrum of the acetate 6d showed a substantial NOE
between H-2 and both H-4 and H-6, thus indicating two trans-diaxial relationships for the anomeric
proton.
In contrast to the ketopyranoses 2a–d, the α-D-ketofuranose 10 derived from the mannonolactone 9

A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
309
Scheme 3.
turned out to be resistant to reduction by the Et3SiH–TMSOTf system as most of the compound 10 was
recovered unaltered under the above reaction conditions (Scheme 4). Guided by earlier research in our
laboratory regarding the successful reduction of thiazolylketoses through their acetates,15 we considered
the activation of the hydroxy group of 10 by conversion into the ketose acetate 11. This simple transfor-
mation was efficiently carried out (94% yield) by acetylation of 10 with Ac2O/pyridine in the presence
of 4-N,N-(dimethylamino)pyridine (DMAP). Deoxygenation of 11 occurred readily on treatment with
Et3SiH–TMSOTf in dichloromethane at 0°C to give the exocyclic enol ether13 12 in excellent isolated
yield (84%) as a 2:1 Z:E mixture. The stereoselective reduction of the carbon–carbon double bond of
12 by catalytic hydrogenation afforded the β-D-linked mannofuranosylmethylphosphonate 13 as a single
product. The anomeric carbon–carbon β-linkage in this compound was readily established by the strong
NOE between H-2 and H-5 proving their cis-relationship. On the other hand, the α-D-configuration of
1
the precursor, the acetate 11, was tentatively assigned by the close similarity of its H NMR spectrum
and that of the ketol12 10. In closing this section it is worth mentioning that the conversion of 11 to
12 can also be carried out under basic conditions via a 1,2-elimination process. Accordingly, we found
that treatment of 11 with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in refluxing acetonitrile afforded 12
in 80% isolated yield and 3:1 Z:E ratio. Unfortunately, the same procedure could not be extended to the
acetates derived from ketopyranoses 2a–d due to the unexpected difficult acetylation of these compounds
under various conditions.
Scheme 4.

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A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
In conclusion, the above results suggest that the dehydroxylation of ketol phosphonates as an entry
to C-glycosylmethylphosphonates should be recommended. The use of Et3SiH–TMSOTf as a reducing
system has been proven to operate efficiently in five model compounds, i.e. four pyranoses and one
furanose. Each compound appeared to have its own behaviour with respect to the formation of two
products, the target carbon-linked glycosylphosphonate and the exocyclic enol ether. Therefore, the
extension of this approach to other systems should be carefully considered in light of the above results.
3. Experimental
3.1. General methods
All moisture-sensitive reactions were performed under a nitrogen atmosphere using oven-dried glass-
ware. All solvents were dried over standard drying agents19 and freshly distilled prior to use. Com-
mercially available, activated 4-Å powdered molecular sieves (50 µm average particle size) were used
without further activation. Flash column chromatography20 was performed on silica gel 60 (230–400
mesh). Reactions were monitored by TLC on silica gel 60 F254 with detection by charring with sulfuric
acid. Melting points were determined with a capillary apparatus and are uncorrected. Optical rotations
were measured at 20±2°C in CHCl3. MALDI-TOF mass spectra were acquired using α-cyano-4-
1
hydroxycinnamic acid as the matrix. H (300 MHz) and 31P (121 MHz) NMR were recorded at rt
for CDCl3 solutions, unless otherwise specified. Assignments were aided by decoupling and/or two-
dimensional experiments. Lactones 1a–e were prepared in multigram scale as previously reported.15b
3.2. 3,4,5,7-Tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-α-D-gluco-2-heptulopyranose 2a
To a cooled (−70°C), stirred solution of freshly distilled dimethyl methylphosphonate (406 µL, 3.75
mmol) in anhydrous THF (7.5 mL) was added butyllithium (2.3 mL, 3.75 mmol, of a 1.6 M solution in
hexanes) and, after 20 min, a solution of lactone 1a (1.35 g, 2.50 mmol) in anhydrous THF (2.5 mL)
during 10 min. The mixture was allowed to reach −40°C over a 1 h period, then was diluted with 1 M
phosphate buffer at pH=7 (50 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic phases
were dried (Na2SO4) and concentrated. The residue was crystallized from cyclohexane to give pure 2a
(1.31 g, 79%). The mother liquor was concentrated and eluted from a column of silica gel with AcOEt
to afford 2a (0.20 g, 12%) as a solid. Mp 84–85°C (cyclohexane), lit.11 112–113°C (Et2O–petroleum
ether); [α]D=−18.6 (c 1.0, CHCl3), lit.11 [α]D=−15.6 (c 1, CHCl3). 1H NMR: δ 7.39–7.20 (m, 20H, 4
Ph), 5.77 (dd, 1H, J3,OH=1.7, JP,OH=1.1 Hz, OH), 5.00 and 4.67 (2 d, 2H, J=11.7 Hz, PhCH2), 4.94 (s,
2H, PhCH2), 4.88 and 4.60 (2 d, 2H, J=11.0 Hz, PhCH2), 4.50 (s, 2H, PhCH2), 4.14 (dd, 1H, J3,4=9.5,
J4,5=9.0 Hz, H-4), 4.10 (ddd, 1H, J5,6=10.1, J6,7a=2.0, J6,7b=3.6 Hz, H-6), 3.75 (dd, 1H, J7a,7b=10.7 Hz,
H-7a), 3.73 (dd, 1H, H-5), 3.69 and 3.64 (2 d, 6H, JH,P=11.1 Hz, 2 OMe), 3.61 (dd, 1H, H-7b), 3.28 (dd,
1H, H-3), 2.31 (dd, 1H, J1a,1b=15.2, J1a,P=17.6 Hz, H-1a), 1.68 (dd, 1H, J1b,P=18.6 Hz, H-1b). 31P NMR:
δ 32.2. Anal. calcd for C37H43O9P: C, 67.06; H, 6.54. Found: C, 67.28; H, 6.49.
3.3. 3,4,5,7-Tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-α-D-galacto-2-heptulopyranose 2b
The lactone 1b (1.35 g, 2.50 mmol) was treated with LiCH2P(O)(OMe)2 (1.5 equiv.) as described for
the preparation of 2a. Column chromatography of the residue (AcOEt) gave 2b (1.19 g, 72%) as a syrup;
[α]D=−18.4 (c 1.0). 1H NMR: δ 7.40–7.25 (m, 20H, 4 Ph), 5.84 (dd, 1H, J3,OH=1.6, JOH,P=1.1 Hz, OH),

A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
311
5.00 and 4.68 (2 d, 2H, J=11.6 Hz, PhCH2), 4.95 and 4.62 (2 d, 2H, J=11.5 Hz, PhCH2), 4.77 (s, 2H,
PhCH2), 4.44 and 4.40 (2 d, 2H, J=11.5 Hz, PhCH2), 4.25 (ddd, 1H, J5,6=1.2, J6,7a=6.8, J6,7b=6.2 Hz,
H-6), 4.10 (dd, 1H, J3,4=9.8, J4,5=2.8 Hz, H-4), 4.02 (dd, 1H, H-5), 3.74 (d, 1H, H-3), 3.67 and 3.62 (2
d, 6H, JH,P=11.2 Hz, 2 OMe), 3.56 (dd, 1H, J7a,7b=9.4 Hz, H-7a), 3.52 (dd, 1H, H-7b), 2.38 (dd, 1 H,
J1a,1b=15.3, J1a,P=17.7 Hz, H-1a), 1.74 (dd, 1H, J1b,P=18.6 Hz, H-1b). 31P NMR: δ 32.1. Anal. calcd for
C37H43O9P: C, 67.06; H, 6.54. Found: C, 67.19; H, 6.51.
3.4. 3-Azido-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-α-D-galacto-2-heptulopyranose
2c
The lactone 1c (1.18 g, 2.50 mmol) was treated with LiCH2P(O)(OMe)2 (1.5 equiv.) as described
for the preparation of 2a. Column chromatography of the residue (1:1 cyclohexane:AcOEt, then AcOEt)
gave 2c (0.52 g, 35%) as a solid; mp 99–100°C (cyclohexane); [α]D=+42.9 (c 1.0). 1H NMR: δ 7.45–7.26
(m, 15H, 3 Ph), 6.07 (dd, 1H, J3,OH=1.9, JP,OH=1.2 Hz, OH), 4.89 and 4.57 (2 d, 2H, J=11.2 Hz, PhCH2),
4.78 and 4.72 (2 d, 2H, J=11.0 Hz, PhCH2), 4.48 and 4.44 (2 d, 2H, J=11.5 Hz, PhCH2), 4.26 (ddd, 1H,
J5,6=1.0, J6,7a=7.2, J6,7b=6.2 Hz, H-6), 4.10–4.06 (m, 2H, H-4, H-5), 3.74 (d, 6H, JH,P=11.2 Hz, 2 OMe),
3.62 (dd, 1H, J7a,7b=9.1 Hz, H-7a), 3.59 (dd, 1H, J3,4=9.7 Hz, H-3), 3.56 (dd, 1H, H-7b), 2.64 (dd, 1H,
J1a,1b=15.2, J1a,P=18.0 Hz, H-1a), 2.15 (dd, 1H, J1b,P=18.7 Hz, H-1b). 31P NMR: δ 31.9. Anal. calcd for
C30H36N3O8P: C, 60.29; H, 6.07; N, 7.03. Found: C, 60.21; H, 6.03; N, 7.10.
3.5. 3,4,5,7-Tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-α-D-manno-2-heptulopyranose 2d
The lactone 1d (1.35 g, 2.50 mmol) was treated with LiCH2P(O)(OMe)2 (1.5 equiv.) as described
for the preparation of 2a. Column chromatography of the residue (AcOEt) gave first unreacted 1d (0.47
1
g, 35%). Eluted second was 2d (0.75 g, 45%) as a syrup; [α]D=+24.2 (c 1.0). H NMR: δ 7.41–7.18
(m, 20H, 4 Ph), 5.81 (bs, 1H, OH), 5.01 and 4.63 (2 d, 2H, J=11.6 Hz, PhCH2), 4.88 and 4.57 (2 d,
2H, J=11.0 Hz, PhCH2), 4.78 (s, 2H, PhCH2), 4.58 and 4.46 (2 d, 2H, J=11.9 Hz, PhCH2), 4.18 (dd,
1H, J3,4=2.6, J4,5=9.4 Hz, H-4), 4.06 (ddd, 1H, J5,6=9.7, J6,7a=4.8, J6,7b=1.7 Hz, H-6), 3.96 (dd, 1H,
H-5), 3.75 (dd, 1H, J7a,7b=11.0 Hz, H-7a), 3.73 (d, 1H, H-3), 3.72 and 3.64 (2 d, 6H, JH,P=11.1 Hz, 2
OMe), 2.61 (dd, 1H, J1a,1b=15.1, J1a,P=18.0 Hz, H-1a), 1.69 (dd, 1H, J1b,P=17.8 Hz, H-1b). 31P NMR:
δ 32.3. Anal. calcd for C37H43O9P: C, 67.06; H, 6.54. Found: C, 66.90; H, 6.57. The use of 3 equiv. of
LiCH2P(O)(OMe)2 did not improve the yield of 2d.
3.6. 2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-D-glycero-D-gulo-heptitol 3a
and 2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-D-gluco-hept-1-enitol 4a
Method a: To a cooled (0°C), stirred mixture of 2a (199 mg, 0.30 mmol), activated 4-Å powdered
molecular sieves (0.30 g), triethylsilane (476 µL, 3.00 mmol), and anhydrous CH2Cl2 (3.0 mL) was
added trimethylsilyl triflate (54 µL, 0.30 mmol). The mixture was stirred at 0°C for 10 min, then warmed
to room temperature, stirred for an additional 50 min, and treated with trimethylsilyl triflate (54 µL,
0.30 mmol). After 30 min the mixture was diluted with Et3N (ca. 0.2 mL) and CH2Cl2 (50 mL), filtered
through Celite, and concentrated. Column chromatography of the residue (2:1 AcOEt:cyclohexane, then
AcOEt) gave first a 10:1 mixture of an uncharacterized product and 2a (62 mg, ca. 30%). Eluted second
1
was a 1.5:1 mixture of 4a and 3a (91 mg, 47%). 4a: H NMR selected data: δ 5.07 (dd, 1H, J1,3=0.6,
J1,P=12.0 Hz, H-1), 4.12 (ddd, 1H, J5,6=9.8, J6,7a=2.0, J6,7b=3.1 Hz, H-6), 3.96 (ddd, 1H, J3,4=6.0,
J3,P=1.1 Hz, H-3), 3.88 (dd, 1H, J4,5=6.8 Hz, H-5), 3.84 (dd, 1H, J7a,7b=11.5 Hz, H-7a), 3.79 (dd, 1H, H-

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A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
4), 3.78 (dd, 1H, H-7b). 31P NMR: δ 20.6. 3a: 1H NMR selected data: δ 4.93 and 4.88 (2 d, 2H, J=11.8
Hz, PhCH2), 4.93 and 4.67 (2 d, 2H, J=11.3 Hz, PhCH2), 4.84 and 4.60 (2 d, 2H, J=11.4 Hz, PhCH2),
4.57 and 4.53 (2 d, 2H, J=12.0 Hz, PhCH2), 2.29 (ddd, 1H, J1a,1b=15.5, J1a,2=2.3, J1a,P=19.5 Hz, H-1a),
1.90 (ddd, 1H, J1b,2=9.4, J1b,P=16.4 Hz, H-1b). 31P NMR: δ 32.4.
Method b: To a stirred solution of 2a (331 mg, 0.50 mmol), triethylsilane (794 µL, 5.00 mmol), and
anhydrous CH2Cl2 (0.5 mL) was added dropwise trimethylsilyl triflate (90 µL, 0.50 mmol). The mixture
was stirred at room temperature for 45 min, then diluted with Et3N (ca. 0.2 mL), and concentrated.
Column chromatography of the residue (2:1 AcOEt:cyclohexane, then AcOEt) gave first a 15:1 mixture
of an uncharacterized product and 2a (86 mg, ca. 26%). Eluted second was a 8:1 mixture of 3a and 4a
(168 mg, 52%).
3.7. 2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol
3b
To a stirred solution of 2b (331 mg, 0.50 mmol), triethylsilane (794 µL, 5.00 mmol), and anhydrous
CH2Cl2 (0.5 mL) was added dropwise trimethylsilyl triflate (90 µL, 0.50 mmol). The mixture was
stirred at room temperature for 45 min, then diluted with Et3N (ca. 0.2 mL), and concentrated. Column
chromatography of the residue (AcOEt) gave 3b (278 mg, 86%) as a syrup; [α]D=−6.5 (c 1.2). 1H NMR:
δ 7.40–7.25 (m, 20H, 4 Ph), 5.00 and 4.67 (2 d, 2H, J=11.5 Hz, PhCH2), 4.96 and 4.63 (2 d, 2H, J=11.0
Hz, PhCH2), 4.77 and 4.68 (2 d, 2H, J=11.6 Hz, PhCH2), 4.47 and 4.42 (2 d, 2H, J=11.5 Hz, PhCH2),
4.02 (dd, 1H, J4,5=2.3, J5,6=0.6 Hz, H-5), 3.74–3.54 (m, 6H), 3.67 and 3.66 (2 d, 6H, JH,P=11.0 Hz, 2
OMe), 2.35 (ddd, 1H, J1a,1b=15.5, J1a,2=1.8, J1a,P=20.0 Hz, H-1a), 1.95 (ddd, 1H, J1b,2=9.8, J1b,P=16.0
Hz, H-1b). 31P NMR: δ 32.3. Anal. calcd for C37H43O8P: C, 68.72; H, 6.70. Found: C, 68.92; H, 6.72.
3.8. 2,6-Anhydro-3-azido-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-
heptitol 3c
To a stirred solution of 2c (299 mg, 0.50 mmol), triethylsilane (794 µL, 5.00 mmol), and anhydrous
CH2Cl2 (0.5 mL) was added dropwise trimethylsilyl triflate (90 µL, 0.50 mmol). The mixture was
stirred at room temperature for 45 min, then diluted with Et3N (ca. 0.2 mL), and concentrated. Column
chromatography of the residue (3:1 AcOEt:cyclohexane, then AcOEt) gave 3c (157 mg, 55%) as a syrup;
[α]D=−14.2 (c 1.0). 1H NMR: δ 7.42–7.24 (m, 15H, 3 Ph), 4.90 and 4.57 (2 d, 2H, J=11.4 Hz, PhCH2),
4.77 and 4.67 (2 d, 2H, J=11.5 Hz, PhCH2), 4.47 and 4.43 (2 d, 2H, J=11.6 Hz, PhCH2), 4.01 (dd,
1H, J4,5=2.8, J5,6=0.6 Hz, H-5), 3.73 (dd, 1H, J2,3=J3,4=9.8 Hz, H-3), 3.72–3.56 (m, 3H, H-6, 2 H-7),
3.72 and 3.70 (2 d, 6H, JH,P=11.0 Hz, 2 OMe), 3.52 (dd, 1H, H-4), 3.48 (dddd, 1H, J1a,2=2.3, J1b,2=9.5,
J2,P=13.2 Hz, H-2), 2.36 (ddd, 1H, J1a,1b=15.5, J1a,P=20.0 Hz, H-1a), 2.06 (ddd, 1H, J1b,P=16.8 Hz, H-
1b). 31P NMR: δ 31.8. Anal. calcd for C30H36N3O7P: C, 61.95; H, 6.24; N, 7.22. Found: C, 60.11; H,
6.28; N, 7.13.
3.9. 2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-D-manno-hept-1-enitol 4d
To a cooled (0°C), stirred mixture of 2d (199 mg, 0.30 mmol), activated 4-Å powdered molecular
sieves (0.30 g), triethylsilane (476 µL, 3.00 mmol), and anhydrous CH2Cl2 (3.0 mL) was added trime-
thylsilyl triflate (108 µL, 0.60 mmol). The mixture was stirred at 0°C for 10 min, then warmed to room
temperature, stirred for an additional 30 min, diluted with Et3N (ca. 0.2 mL) and CH2Cl2 (50 mL), filtered
through Celite, and concentrated. Column chromatography of the residue (2:1 AcOEt:cyclohexane,

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313
then AcOEt) gave first benzyl 3,4,5,7-tetra-O-benzyl-1-deoxy-1-dimethoxyphosphoryl-α-D-manno-2-
1
heptulopyranoside as a syrup (13 mg, 6%); [α]D=−6.1 (c 1.0). H NMR selected data: δ 4.54 (d, 1H,
J3,4=2.5 Hz, H-3), 4.19 (dd, 1H, J4,5=9.5 Hz, H-4), 4.02 (dd, 1H, J5,6=9.0 Hz, H-5), 3.74–3.67 (m, 3H,
H-6, 2 H-7), 3.66 and 3.63 (2 d, 6H, JH,P=10.8 Hz, 2 OMe), 2.85 (dd, 1H, J1a,1b=15.9, J1a,P=19.0 Hz,
H-1a), 2.50 (dd, 1H, J1b,P=18.4 Hz, H-1b). 31P NMR: δ 28.8. MALDI-TOF MS: 776.8 (M++Na), 792.2
(M++K). Anal. calcd for C44H49O9P: C, 70.20; H, 6.56. Found: C, 70.41; H, 6.48. Eluted second was
unreacted 2d slightly contaminated by the benzyl glycoside (68 mg, 34%). Eluted third was 4d (68 mg,
35%); [α]D=+2.8 (c 1.0). 1H NMR: δ 7.39–7.17 (m, 20H, 4 Ph), 5.04 (dd, 1H, J1,3=0.7, J1,P=12.0 Hz,
H-1), 4.73 and 4.51 (2 d, 2H, J=12.3 Hz, PhCH2), 4.68 and 4.58 (2 d, 2H, J=12.0 Hz, PhCH2), 4.63 and
4.47 (2 d, 2H, J=11.5 Hz, PhCH2), 4.62 and 4.55 (2 d, 2H, J=12.0 Hz, PhCH2), 4.20 (ddd, 1 H, J3,4=2.6,
J3,P=1.2 Hz, H-3), 4.06 (dd, 1H, J4,5=4.8, J5,6=8.0 Hz, H-5), 3.99 (ddd, 1H, J6,7a=3.0, J6,7b=4.3 Hz, H-6),
3.82 (ddd, 1H, J4,P=1.2 Hz, H-4), 3.78–3.75 (m, 2H, 2 H-7), 3.68 and 3.67 (2 d, 6H, JH,P=11.5 Hz, 2
OMe). 31P NMR: δ 20.5. Anal. calcd for C37H41O8P: C, 68.93; H, 6.41. Found: C, 69.08; H, 6.51.
When the reaction was carried out as described for the preparation of the C-galactoside 3b (1 M
solution of 2d in CH2Cl2, 1 equiv. of TMSOTf, rt, 1 h), a complex mixture of products was formed from
which the benzyl glycoside and the ketose 2d were isolated in ca. 25 and 10% yields, respectively.
3.10. 2,6-Anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-D-gulo-heptitol 5a
A vigorously stirred 1.5:1 mixture of 4a and 3a (194 mg, 0.3 mmol), 20% palladium hydroxide on
carbon (194 mg), AcOEt (3 mL), and MeOH (3 mL) was degassed under vacuum and saturated with
hydrogen (by a H2-filled balloon) three times. The suspension was stirred at room temperature for 3
h under a slightly positive pressure of hydrogen (balloon), then filtered through a plug of cotton and
concentrated to give 5a (83 mg, 97%) at least 95% pure by NMR analysis. 1H NMR (D2O): δ 3.82–3.62
(m, 2H), 3.71 and 3.70 (2 d, 6H, JH,P=11.0 Hz, 2 OMe), 3.54 (dddd, 1H, J1a,2=2.5, J1b,2=J2,3=10.0,
J2,P=12.0 Hz, H-2), 3.44–3.31 (m, 3H), 3.18–3.14 (m, 1H), 2.44 (ddd, 1H, J1a,1b=15.9, J1a,P=19.8 Hz,
H-1a), 2.07 (ddd, 1H, J1b,P=16.2 Hz, H-1b).
3.11. 2,6-Anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol 5b
The C-galactoside 3b (194 mg, 0.3 mmol) was hydrogenated as described for the preparation of 5a to
1
give 5b (84 mg, 98%) at least 95% pure by NMR analysis. H NMR (D2O): δ 3.85 (dd, 1H, J4,5=3.3,
J5,6=0.5 Hz, H-5), 3.66 (d, 6H, JH,P=11.0 Hz, 2 OMe), 3.63–3.51 (m, 3H, H-6, 2 H-7), 3.49 (dd, 1H,
J3,4=9.3 Hz, H-4), 3.43 (dddd, 1H, J1a,2=2.1, J1b,2=9.8, J2,3=9.6, J2,P=11.0 Hz, H-2), 3.32 (dd, 1H, H-3),
2.41 (ddd, 1H, J1a,1b=15.8, J1a,P=20.0 Hz, H-1a), 2.02 (ddd, 1H, J1b,P=16.3 Hz, H-1b).
3.12. 3-Acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-
manno-heptitol 8c
A vigorously stirred mixture of 3c (174 mg, 0.3 mmol), 20% palladium hydroxide on carbon (174 mg),
and AcOEt (6 mL) was degassed under vacuum and saturated with hydrogen (by a H2-filled balloon)
three times. The suspension was stirred at room temperature for 2 h under a slightly positive pressure
of hydrogen (balloon), then filtered through a plug of cotton and concentrated. A solution of the crude
amine in acetic anhydride (2.0 mL) was kept at room temperature for 1 h, then concentrated. Column
chromatography of the residue (4:1 acetone:AcOEt, then acetone) gave 8c (131 mg, 73%) as a solid; mp
1
115–116°C (Et2O–cyclohexane); [α]D=+28.8 (c 1.0). H NMR: δ 7.42–7.25 (m, 15H, 3 Ph), 5.17 (d,

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1H, J3,NH=8.9 Hz, NH), 4.95 and 4.62 (2 d, 2H, J=11.6 Hz, PhCH2), 4.72 and 4.40 (2 d, 2H, J=12.0
Hz, PhCH2), 4.48 and 4.46 (2 d, 2H, J=11.5 Hz, PhCH2), 4.18 (ddd, 1H, J2,3=10.0, J3,4=10.6 Hz, H-3),
4.02 (dd, 1H, J4,5=2.7, J5,6=0.6 Hz, H-5), 3.73–3.58 (m, 4H, H-2, H-6, 2 H-7), 3.67 and 3.66 (2 d, 6H,
JH,P=11.0 Hz, 2 OMe), 3.51 (dd, 1H, H-4), 2.16–2.07 (m, 2H, 2 H-1), 1.92 (s, 3H, Ac). 31P NMR: δ
33.0. Anal. calcd for C32H40NO8P: C, 64.31; H, 6.75; N, 2.34. Found: C, 64.24; H, 6.79; N, 2.30.
3.13. 3-Acetamido-2,6-anhydro-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol 5c
The C-galactoside 8c (119 mg, 0.2 mmol) was hydrogenated as described for the preparation of 5a to
give 5c (64 mg, 98%) at least 95% pure by NMR analysis. 1H NMR selected data (D2O): δ 3.86 (dd, 1H,
J4,5=3.0, J5,6=0.7 Hz, H-5), 3.74 (dd, 1H, J2,3=J3,4=10.0 Hz, H-3), 3.65 and 3.64 (2 d, 6H, JH,P=11.0 Hz,
2 OMe), 2.13 (ddd, 1H, J1a,1b=15.8, J1a,2=3.1, J1a,P=19.5 Hz, H-1a), 2.04 (ddd, 1H, J1b,2=9.6, J1b,P=16.6
Hz, H-1b), 1.92 (s, 3H, Ac).
3.14. 2,6-Anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-D-galacto-heptitol 5d
The exocyclic enol ether 4d (129 mg, 0.2 mmol) was hydrogenated as described for the preparation
of 5a to give 5d (54 mg, 95%) at least 95% pure by NMR analysis. 1H NMR (D2O): δ 3.76 (ddd, 1H,
J1a,2=J2,P=9.0, J2,3=0.8, J1b,2=4.6 Hz, H-2), 3.70 (dd, 1H, J6,7a=2.2, J7a,7b=12.5 Hz, H-7a), 3.68 (dd, 1H,
J3,4=3.3 Hz, H-3), 3.62 and 3.61 (2 d, 6H, JH,P=11.0 Hz, 2 OMe), 3.54 (dd, 1H, J6,7b=5.8 Hz, H-7b),
3.49 (dd, 1H, J4,5=9.8 Hz, H-4), 3.40 (dd, 1H, J5,6=9.5 Hz, H-5), 3.19 (ddd, 1H, H-6), 2.20 (ddd, 1H,
J1a,1b=15.9, J1a,P=17.0 Hz, H-1a), 2.06 (ddd, 1H, J1b,P=19.3 Hz, H-1b).
3.15. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-D-gulo-heptitol
6a
A solution of crude 5a (83 mg, ca. 0.29 mmol) in pyridine (1.5 mL) and acetic anhydride (1.5 mL) was
kept at room temperature overnight, then concentrated. The residue was eluted from a column of silica gel
with 1:1 acetone:AcOEt to give 6a (125 mg, 92% overall yield from the 3a/4a mixture) as a white solid;
mp 121–122°C (Et2O); [α]D=+3.5 (c 1.0). 1H NMR (C6D6): δ 5.29 (dd, 1H, J3,4=8.9, J4,5=9.4 Hz, H-4),
5.21 (dd, 1H, J5,6=9.6 Hz, H-5), 4.96 (dd, 1H, J2,3=9.5 Hz, H-3), 4.15 (dd, 1H, J6,7a=4.6, J7a,7b=12.3 Hz,
H-7a), 4.04 (dd, 1H, J6,7b=2.2 Hz, H-7b), 3.84 (dddd, 1H, J1a,2=2.8, J1b,2=9.2, J2,P=11.5 Hz, H-2), 3.48
and 3.34 (2 d, 6H, JH,P=10.8 Hz, 2 OMe), 3.23 (ddd, 1 H, H-6), 2.00 (ddd, 1H, J1a,1b=15.6, J1a,P=19.8
Hz, H-1a), 1.85 (ddd, 1H, J1b,P=15.5 Hz, H-1b), 1.71, 1.68, 1.64, and 1.60 (4 s, 12H, 4 Ac). 31P NMR: δ
30.3. Anal. calcd for C17H27O12P: C, 44.94; H, 5.99. Found: C, 45.17; H, 5.92.
3.16. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol
6b
Crude 5b (84 mg, ca. 0.29 mmol) was acetylated and purified as described for the preparation of 6a to
give 6b (128 mg, 94% overall yield from 3b) as a syrup; [α]D=+16.3 (c 1.1). 1H NMR (C6D6): δ 5.46
(dd, 1H, J4,5=3.5, J5,6=1.3 Hz, H-5), 5.37 (dd, 1H, J2,3=9.6, J3,4=10.2 Hz, H-3), 5.11 (dd, 1H, H-4), 4.06
(d, 2H, J6,7=6.5 Hz, 2 H-7), 3.90 (dddd, 1H, J1a,2=3.3, J1b,2=8.9, J2,P=10.8 Hz, H-2), 3.44 and 3.32 (2
d, 6H, JH,P=10.9 Hz, 2 OMe), 3.37 (dt, 1H, H-6), 2.11 (ddd, 1H, J1a,1b=15.5, J1a,P=19.5 Hz, H-1a), 2.02
(ddd, 1H, J1b,P=17.1 Hz, H-1b), 1.71, 1.64, 1.62, and 1.60 (4 s, 12H, 4 Ac). 31P NMR: δ 30.8. Anal.
calcd for C17H27O12P: C, 44.94; H, 5.99. Found: C, 45.19; H, 6.07.

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3.17. 3-Acetamido-4,5,7-tri-O-acetyl-2,6-anhydro-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-
manno-heptitol 6c
Crude 5c (64 mg, ca. 0.20 mmol) was acetylated as described for the preparation of 6a. Column
chromatography of the residue (acetone) gave 6c (84 mg, 93% overall yield from 8c) as a solid; mp
1
179–181°C (Et2O); [α]D=+3.4 (c 1.0). H NMR (C6D6): δ 7.07 (d, 1H, J3,NH=9.5 Hz, NH), 5.64 (dd,
1H, J4,5=3.3, J5,6=0.8 Hz, H-5), 5.33 (dd, 1H, J3,4=10.9 Hz, H-4), 4.70 (ddd, 1H, J2,3=10.0 Hz, H-3), 4.28
(dd, 1H, J6,7a=7.4, J7a,7b=11.3 Hz, H-7a), 4.20 (dd, 1H, J6,7b=5.4 Hz, H-7b), 4.12 (dddd, 1H, J1a,2=2.2,
J1b,2=9.8, J2,P=11.8 Hz, H-2), 3.98 (ddd, 1H, H-6), 3.54 and 3.14 (2 d, 6H, JH,P=11.0 Hz, 2 OMe), 2.36
(ddd, 1H, J1a,1b=15.9, J1a,P=19.3 Hz, H-1a), 2.18 (ddd, 1H, J1b,P=16.0 Hz, H-1b), 1.82, 1.74, 1.72, and
1.66 (4 s, 12H, 4 Ac). 31P NMR: δ 32.0. Anal. calcd for C17H28NO11P: C, 45.04; H, 6.23; N, 3.09.
Found: C, 45.16; H, 6.31; N, 3.00.
3.18. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-dimethoxyphosphoryl-D-glycero-D-galacto-
heptitol 6d
Crude 5d (54 mg, ca. 0.19 mmol) was acetylated and purified as described for the preparation of 6a to
give 6d (81 mg, 89% overall yield from 4d) as a syrup. The trituration with pentane of this syrup afforded
a low melting solid which could not be recrystallized; [α]D=−14.6 (c 0.5). 1H NMR (C6D6): δ 5.53 (dd,
1H, J4,5=J5,6=10.0 Hz, H-5), 5.44 (dd, 1H, J2,3=0.9, J3,4=3.4 Hz, H-3), 5.17 (dd, 1H, H-4), 4.27 (dd,
1H, J6,7a=5.0, J7a,7b=12.3 Hz, H-7a), 4.15 (dd, 1H, J6,7b=2.1 Hz, H-7b), 3.94 (dddd, 1H, J1a,2=J2,P=8.3,
J1b,2=5.3 Hz, H-2), 3.47 and 3.37 (2 d, 6H, JH,P=10.9 Hz, 2 OMe), 3.32 (ddd, 1H, H-6), 2.11 (ddd, 1H,
J1a,1b=15.4, J1a,P=17.8 Hz, H-1a), 1.80 (ddd, 1H, J1b,P=19.5 Hz, H-1b), 1.76, 1.72, 1.65, and 1.57 (4 s,
12H, 4 Ac). 31P NMR: δ 30.1. Anal. calcd for C17H27O12P: C, 44.94; H, 5.99. Found: C, 44.85; H, 6.05.
3.19. 1-Deoxy-1-dimethoxyphosphoryl-3,4:6,7-di-O-isopropylidene-α-D-manno-2-heptulofuranose 10
The lactone 9 (775 mg, 3.00 mmol) was treated with LiCH2P(O)(OMe)2 (1.5 equiv.) as described
for the preparation of 2a. Column chromatography of the residue (AcOEt) gave 10 (998 mg, 87%) as a
syrup; [α]D=+7.1 (c 1.0). 1H NMR: δ 5.48 (s, 1H, OH), 4.84 (ddd, 1H, J3,4=5.4, J4,5=3.7, J4,P=1.2 Hz,
H-4), 4.47 (dd, 1H, J3,P=0.8 Hz, H-3), 4.38 (ddd, 1H, J5,6=7.3, J6,7a=6.2, J6,7b=5.0 Hz, H-6), 4.17 (dd,
1H, H-5), 4.05 (dd, 1H, J7a,7b=8.4 Hz, H-7a), 3.99 (dd, 1H, H-7b), 3.80 and 3.74 (2 d, 6H, JH,P=11.1
Hz, 2 OMe), 2.40 (dd, 1H, J1a,1b=15.5, J1a,P=17.6 Hz, H-1a), 2.22 (dd, 1H, J1b,P=18.3 Hz, H-1b), 1.46,
1.42, 1.36, and 1.32 (4 s, 12H, 4 Me). 31P NMR: δ 32.3. Anal. calcd for C17H29O10P: C, 47.12; H, 7.12.
Found: C, 47.28; H, 7.07.
3.20. 2-O-Acetyl-1-deoxy-1-dimethoxyphosphoryl-3,4:6,7-di-O-isopropylidene-α-D-manno-2-
heptulofuranose 11
A solution of 10 (764 mg, 2.00 mmol) and 4-N,N-(dimethylamino)pyridine (24 mg, 0.20 mmol)
in pyridine (10 mL) and acetic anhydride (10 mL) was kept overnight at room temperature, then
concentrated. The residue was eluted from a short column (3×10 cm, d×h) of silica gel with 3:1
AcOEt:acetone to give 11 (798 mg, 94%) as a syrup; [α]D=+5.3 (c 1.0). 1H NMR: δ 4.89 (d, 1H, J3,4=5.4
Hz, H-3), 4.84 (ddd, 1H, J4,5=3.6, J4,P=0.7 Hz, H-4), 4.41 (ddd, 1H, J5,6=7.8, J6,7a=6.2, J6,7b=4.3 Hz, H-
6), 4.12 (dd, 1H, J7a,7b=8.8 Hz, H-7a), 4.06 (dd, 1H, H-5), 4.05 (dd, 1H, H-7b), 3.78 and 3.74 (2 d, 6H,
JH,P=11.0 Hz, 2 OMe), 2.98 (dd, 1H, J1a,1b=15.7, J1a,P=19.3 Hz, H-1a), 2.76 (dd, 1H, J1b,P=18.8 Hz,

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H-1b), 2.10 (s, 3H, Ac), 1.50, 1.48, 1.40, and 1.36 (4 s, 12 H, 4 Me). 31P NMR: δ 27.8. Anal. calcd for
C17H29O10P: C, 48.11; H, 6.89. Found: C, 48.30; H, 6.83.
3.21. (Z,E)-2,5-Anhydro-1-deoxy-1-dimethoxyphosphoryl-3,4:6,7-di-O-isopropylidene-D-manno-hept-
1-enitol 12
Method a: To a cooled (0°C), stirred solution of 11 (212 mg, 0.50 mmol) and triethylsilane (794
µL, 5.00 mmol) in anhydrous CH2Cl2 (0.5 mL) was added dropwise trimethylsilyl triflate (90 µL,
0.50 mmol). The mixture was stirred at 0°C for 20 min, then diluted with Et3N (ca. 0.2 mL) and
concentrated. Column chromatography of the residue (1:1 AcOEt:acetone) gave a 2:1 mixture of Z-12
and E-12 (153 mg, 84%). A pure sample of the major isomer Z-12 (having lower Rf value) was obtained
by crystallization of this mixture with Et2O. E-12: 1H NMR: δ 5.63 (ddd, 1H, J1,3=1.3, J3,4=5.9, J3,P=2.2
Hz, H-3), 4.91 (ddd, 1H, J1,4=0.5, J1,P=7.8 Hz, H-1), 4.83 (ddd, 1H, J4,5=3.8 Hz, H-4), 4.45 (ddd, 1H,
J5,6=7.3, J6,7a=6.3, J6,7b=4.6 Hz, H-6), 4.18 (dd, 1H, H-5), 4.13 (dd, 1H, J7a,7b=9.0 Hz, H-7a), 4.05 (dd,
1H, H-7b), 3.74 and 3.70 (2 d, 6H, JH,P=11.5 Hz, 2 OMe), 1.46, 1.41, 1.37 (3 s, 12H, 4 Me). 31P NMR:
δ 22.3. Z-12: mp 103–104°C (Et2O); [α]D=+118.0 (c 0.8). 1H NMR: δ 5.11 (ddd, 1H, J1,3=1.0, J3,4=5.5,
J3,P=3.8 Hz, H-3), 4.76 (ddd, 1H, J4,5=3.5, J4,P=2.0 Hz, H-4), 4.74 (dd, 1H, J1,P=9.7 Hz, H-1), 4.46 (ddd,
1H, J5,6=7.5, J6,7a=5.7, J6,7b=4.8 Hz, H-6), 4.38 (dd, 1H, H-5), 4.14 (dd, 1H, J7a,7b=9.0 Hz, H-7a), 4.11
(dd, 1H, H-7b), 3.71 and 3.70 (2 d, 6H, JH,P=11.5 Hz, 2 OMe), 1.47, 1.46, 1.39, and 1.38 (4 s, 12H, 4
Me). 31P NMR: δ 20.3. Anal. calcd for C15H25O8P: C, 49.45; H, 6.92. Found: C, 49.39; H, 6.98. The
deoxygenation did not take place when the ketose 10 was used as the starting material (0.1 M CH2Cl2
solution, 2 equiv. of TMSOTf, rt, 1 h).
Method b: A solution of 11 (212 mg, 0.50 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (150 µL,
1.00 mmol) in anhydrous CH3CN (2.5 mL) was refluxed for 1.5 h, then cooled to room temperature and
concentrated. The residue was eluted from a column of silica gel with 1:1 AcOEt:acetone to give a 3:1
mixture of Z-12 and E-12 (146 mg, 80%). The use of refluxing toluene or THF led to lower yields of 12.
3.22. 2,5-Anhydro-1-deoxy-1-dimethoxyphosphoryl-3,4:6,7-di-O-isopropylidene-D-glycero-D-galacto-
heptitol 13
A vigorously stirred mixture of 12 (109 mg, 0.3 mmol of a 2:1 Z:E mixture), 20% palladium hydroxide
on carbon (109 mg), and AcOEt (6 mL) was degassed under vacuum and saturated with hydrogen (by a
H2-filled balloon) three times. The suspension was stirred at room temperature for 3 h under a slightly
positive pressure of hydrogen (balloon), then filtered through a plug of cotton and concentrated to give
13 (107 mg, 98%) at least 95% pure by NMR analysis. An analytical sample was obtained by column
chromatography (1:1 acetone:AcOEt); mp 51–53°C (pentane); [α]D=−6.3 (c 1.0). 1H NMR: δ 4.78 (dd,
1H, J3,4=6.0, J4,5=3.6 Hz, H-4), 4.68 (ddd, 1H, J2,3=3.5, J3,P=0.7 Hz, H-3), 4.40 (ddd, 1H, J5,6=7.4,
J6,7a=6.0, J6,7b=4.9 Hz, H-6), 4.10 (dd, 1H, J7a,7b=8.7 Hz, H-7a), 4.04 (dd, 1H, H-7b), 3.88 (dddd, 1H,
J1a,2=6.8, J1b,2=6.6, J2,P=8.2 Hz, H-2), 3.78 and 3.77 (2 d, 6H, JH,P=10.9 Hz, 2 OMe), 3.54 (dd, 1H,
H-5), 2.32 (ddd, 1H, J1a,1b=15.3, J1a,P=18.4 Hz, H-1a), 2.21 (ddd, 1H, J1b,P=18.1 Hz, H-1b), 1.48, 1.46,
1.39, and 1.35 (4 s, 12H, 4 Me). 31P NMR: δ 31.2. Anal. calcd for C15H27O8P: C, 49.18; H, 7.43. Found:
C, 49.40; H, 7.37.

A. Dondoni et al. / Tetrahedron: Asymmetry 11 (2000) 305–317
317
Acknowledgements
We thank Mr. Paolo Formaglio (University of Ferrara) for NMR measurements. Financial support from
the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (Italy) is gratefully acknowledged.
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