New stereoselective synthesis of phosphono analogues of glycosyl phosphates

Article abstract of DOI:10.1016/S0957-4166(02)00329-4

A new and stereoselective synthesis of isosteric phosphono analogues of glycosyl phosphates is reported. Appropriately protected glyconolactones, easily available from the parent sugars are reacted with ethyl-α-iodomethylphosphonate in THF in the presence of a soluble low-valent cobalt-phosphine complex, either in stoichiometric or sub-stoichiometric amounts, in the latter case in the presence of magnesium metal. The use of magnesium metal alone works, but in a less efficient and predictable way. The intermediate addition product can be subsequently deoxygenated with triethylsilane in the presence of boron trifluoride.

Full text of DOI:10.1016/S0957-4166(02)00329-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1307–1313
New stereoselective synthesis of phosphono analogues of glycosyl
phosphates
F. Orsini* and E. Di Teodoro
Dipartimento di Chimica Organica e Industriale, Via Venezian 21, 20133 Milan, Italy
Received 29 May 2002; accepted 24 June 2002
Abstract—A new and stereoselective synthesis of isosteric phosphono analogues of glycosyl phosphates is reported. Appropriately
protected glyconolactones, easily available from the parent sugars are reacted with ethyl-a-iodomethylphosphonate in THF in the
presence of a soluble low-valent cobalt–phosphine complex, either in stoichiometric or sub-stoichiometric amounts, in the latter
case in the presence of magnesium metal. The use of magnesium metal alone works, but in a less efficient and predictable way.
The intermediate addition product can be subsequently deoxygenated with triethylsilane in the presence of boron trifluoride.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
potential biological activities.4 Therefore, the C-glyco-
sidic analogues of glycosyl phosphates have been the
object of significant efforts in synthetic chemistry5 and
the development of new synthetic methodologies is still
an appealing target.
The replacement of the oxygen atom of the phosphoes-
teric linkage in a phosphate with a carbon atom pro-
duces a modified molecule, which may still fit the active
sites or receptors of the parent phosphate, but impor-
tantly has enhanced physiological stability1 (due to the
stability of the carbonꢀphosphorus bond to enzymatic
degradation by phosphatase enzymes) and better cell
permeability2 (due to its lower polarity). These features
explain the considerable interest in phosphonates as
biologically active surrogates of naturally occurring
phosphates. Among them, glycosyl phosphates are of
great interest as they behave as glycosyl donors in the
biosynthesis of oligo- and polysaccharides, and glyco-
conjugates;3 C-glycosides are also of interest for their
2. Results and discussion
We have found that appropriately protected glycono-
lactones (of general formula 1), react with a-halophos-
phonates in THF in the presence of
a soluble
low-valent cobalt complex with trimethyl- or
triphenylphosphine to give addition products 2, as
shown in Scheme 1.
Scheme 1.
* Corresponding author. Tel.: +02-50314111; fax: +02-50314106; e-mail: fulvia.orsini@unimi.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00329-4

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F. Orsini, E. Di Teodoro / Tetrahedron: Asymmetry 13 (2002) 1307–1313
The lactose 2 are useful intermediates for the presence
of the ‘anomeric’ hydroxyl which can be further elabo-
rated to give a variety of compounds, among them the
C-glycosidic analogues of glycosyl phosphates, obtain-
able from lactols 2 by dehydroxylation with triethyl-
silane in acidic conditions.
Compared to procedure A, procedure B has the advan-
tage of using a lower quantity of cobalt and phosphine,
offsetting the disadvantage of their use, and making
purification of the product easier. A further advantage
is the colour of the solution, which continuously
changes from yellow-brown (Co(0) complex) to dark
blue-violet (Co(II) complex) during the addition of the
organic reagent to the Co complex. This colour change
allows easy monitoring of the course of the reaction.
The cobalt complexes mentioned above have already
been reported as efficient mediators for Reformatsky-
and aldol-type reactions to produce b-hydroxy esters,6
b-hydroxy ketones7 and b-hydroxy phosphonates.8
To investigate whether an organomagnesium com-
pound might be involved in the sub-stoichiometric pro-
cedure, we designed a third series of experiments
(procedure C) and we performed parallel experiments,
adding the halophosphonate and the glyconolactone to
magnesium alone in THF.
To find the best experimental conditions for the synthe-
sis of the title compounds, different experiments were
designed. The obtained results are summarised in Table
1.
In a first series of experiments (procedure A, stoichio-
metric method), a variety of glyconolactones, obtained
from different or differently protected parent sugars,
was reacted with diethyl-a-iodomethylphosphonate
(selected as a model for an a-halophosphonate) in the
presence of (Me3P)4Co(0).9 The stoichiometry of the
reaction was investigated using different molar ratios of
the halophosphonate, the electrophile and the Co(0)
complex, and different orders of addition of the organic
reagents to the Co(0) complex were also examined. The
best results were obtained with a ‘one pot’ procedure in
which the two organic reagents were added simulta-
neously to the Co(0) complex, using a 2.0:2.0:1.0 mol
ratio of halophosphonate:cobalt(0) complex:lactone,
and a 0.2–0.3 M solution with respect to the sugar
lactone.10 Diethyl-a-chloromethylphosphonate was also
tested but afforded lower yields of the expected lactols.
Conveniently, as ancillary ligand to cobalt, the volatile
trimethylphosphine can be replaced by the non-volatile
triphenylphospine without affecting the yields and the
course of the reactions.
We observed that the reaction proceeded equally well
(comparable yields and stereochemical outcome) with
magnesium alone11 as far as the reaction was frequently
monitored by thin-layer chromatography and worked-
up as soon as the starting lactone disappeared. How-
ever, in the absence of cobalt, the reactions, depending
on magnesium activation, were slower, less repro-
ducible and required variable time of induction, there-
fore, affording side products and lowering the yields.
These observations point to a key role of cobalt under
sub-stoichiometric conditions. One more piece of evi-
dence that might prove the actual involvement of cobalt
is the colour of the solution that continuously changes
from yellow-brown (Co(0) complex) to deep blue-violet
(Co(II) complex) during the addition of the organic
reagents and allows a facile visualisation of the end
point of the reaction and thus minimises the formation
of by-products.
Once the experimental conditions to obtain lactols 2
were optimised, compound 2f, chosen as a model for
the dehydroxylation reaction, was treated with triethyl-
silane in the presence of a Lewis acid. The reaction
afforded the glycosyl phosphonate 3f in good yields
(Scheme 2).
In a second series of experiments (procedure B, sub-sto-
ichiometric method) we observed that the addition
product was also formed very cleanly when the reaction
was carried out with a 10:10:1 mol ratio of the organic
reagents to the cobalt(0) complex, provided that mag-
nesium metal was present to carry out the reduction of
Co(II) to Co(0). The yields and the stereochemical
outcome of the reactions are comparable with those
obtained in the first series of experiments.
3. Conclusions
The most direct way to prepare isosteric phosphono
analogues of glycosyl phosphates is the reaction of an
appropriately protected aldose with the ylide,
(diphenylphosphoranylidine)methanephosphonate, or
with the anion of a tetraalkyl methylenediphosphonate,
a reaction which affords the desired C-glycosyl methyl-
ene phosphonate in two steps (via an a,b-unsaturated
phosphonate intermediate), but unfortunately, is not
stereoselective and is not generally applicable. A more
general procedure requires the preparation of a C-gly-
cosyl halide, followed by its reaction with a trialkyl
phosphite.
In all cases, the only isolated product was the addition
compound to the carbonyl. Yields ranged from 50 to
82% and depended on the experimental conditions and,
chiefly, on the starting lactone which was recovered
unchanged in 10–40%, easily separated by chromatog-
raphy and recycled.
Only one stereoisomer was generally obtained, with the
exception of the lactone from 2,3,5-tri-O-benzyl-ara-
binofuranose, which afforded the two diastereomers in
a 3:1 ratio. The anomeric configuration of compounds
2a–g was determined by NOE experiments, which evi-
More recently a three step synthesis of C-glycosyl
denced
a
correlation between one or both the
analogues of b-fucopyranosyl phosphate and b-L-
rhamnopyranosyl phosphate was reported, based on
the reaction of the corresponding glycono lactones with
methylenic hydrogens adjacent to the carbonyl carbon
and the hydrogen at C-2.

F. Orsini, E. Di Teodoro / Tetrahedron: Asymmetry 13 (2002) 1307–1313
1309
Table 1. Co(0)- and/or Mg-mediated reactions of glyconolactones 1a–g with diethyl-a-iodomethylphosphonate
a
Procedure A: glyconolactone, ethyl-a-iodomethylphosphonate and [Co(PMe3)]4 has been used in a 1:2.5:2.5 ratio. Procedure B: the reaction has
been performed using a sub-stoichiometric quantity of Co(PMe3)4 (10%). Procedure C: the reaction has been performed using metallic
magnesium only.
The brackets refer to recovered starting ester.
Yields determined by H NMR.
b
c

1310
F. Orsini, E. Di Teodoro / Tetrahedron: Asymmetry 13 (2002) 1307–1313
Scheme 2.
lithium dimethyl methyl phosphonate at low
temperature.12
silica gel Merck Kieselgel 60 (230–400 mesh ASTM).
Thin-layer chromatography was performed on silica gel
plates (60 F254, Merck): zones were detected visually by
ultraviolet irradiation (254 nm) and/or using Pancaldi
reagent, followed by heating at 100°C. All reactions were
performed under a dry nitrogen atmosphere, using glass-
ware dried by flaming in a stream of dry nitrogen.
With respect to known procedures, the reported cobalt-
or magnesium-mediated syntheses of the phosphonate
analogues of glycosyl phosphates, via addition of a-
halophosponates to glyconolactones, represent valid
alternatives, with some advantages: mild experimental
conditions; user-friendly and easily stored reagents; high
stereoselection; no requirement of strictly anhydrous
conditions; and, with respect to procedures using glycosyl
halides, more readily available substrates.
Dry THF (99.9% from Aldrich) was generally used for
the cobalt-mediated reactions.
4.1. Typical procedure for the synthesis of
glyconolactones
When magnesium alone is used, the purification of the
product is easier, but the reaction has the disadvantage
of heterogeneous conditions and it is less reproducible.
A good compromise can be the use of the Co(0) complex
under sub-stoichiometric conditions: a protocol that
overcomes the problems with separation of cobalt salts;
offsets the disadvantage of using phosphines; appears to
be less sensitive to the activation of magnesium; allows
very easy monitoring of the course and the end point of
the reaction by the alternation of the Co(0) and Co(II)
colours in the solution.
A solution of the protected sugar (1 mmol) in dry
methylene chloride (5 mL) was added under nitrogen to
a suspension of pyridinium chlorochromate (0.75 g, 3.5
mmol) and molecular sieves (0.3 mm from Merck, 0.5 g)
in methylene chloride (2 mL). The reaction mixture was
stirred under nitrogen in the dark and was monitored by
thin layer chromatography (silica gel, eluting with ethyl
acetate:petroleum ether 6:4). At the end of the reaction,
the reaction mixture was filtered over silica gel eluting
with ethyl acetate:petroleum ether 4:6. Removal of the
solvent under reduced pressure afforded the glyconolac-
tone (80–85% yields), which was used directly.
4. Experimental
Reagent grade THF was heated under reflux over LiAlH4
and distilled. Reagent grade dichloromethane was heated
under reflux over CaH2 and distilled. Reagent grade
acetonitrile was heated under reflux over CaH2 and
4.2. Typical procedure for the stoichiometric reaction
mediated by (Me3P)4Co (procedure A)
A 1 M solution of trimethylphosphine in THF (10 mL)
was added to a mixture of activated magnesium
turnings18,19 (ca. 0.3 g) and anhydrous CoCl2 (0.32 g, 2.5
mmol). The reaction mixture was stirred at room temper-
ature until a dark brown colour developed.20 The excess
of magnesium was filtered off, and to the resulting
solution were added diethyl-a-iodomethylphosphonate
(0.41 mL, 2.5 mmol) and the lactone (0.54 g, 1 mmol)
in THF, dropwise over a period of 1 h. The reaction was
monitored by thin layer chromatography (silica gel,
eluting with ethyl acetate–petroleum ether 7:3). At the
end of the reaction, the mixture was stirred under air until
a green blue colour developed. Two different work-up
procedures were then used depending on the water-solu-
bility of the lactone and of the product.
distilled.
2,3,4,6-tetra-O-benzyl-
-mannofuranose were purchased
2,3,5-Tri-O-benzyl-b-
D-arabinofuranose,
-glucopyranose and 2,3:5,6-di-
D
O-isopropylidene-a-
D
from Sigma and converted to the corresponding lactones
1a13 and 1d14 and 1b15 according to the procedure
reported below. 2,3,4-Tri-O-benzyl-L-fucopyranose,
2,3,4,6-tetra-O-benzyl-galattopyranose and 2,3,4-tri-O-
benzyl- -rhamnopyranose were purchased from Toronto
L
Research Chemicals (Canada) and converted to the
corresponding lactones 1f,16 1e17 and 1g12 according to
the procedure reported below. 2,3-O-Isopropylidene-D-
erythronolactone 1c was purchased from Aldrich. Proton
and carbon nuclear magnetic resonance (1H and 13C
NMR) spectra were recorded at 200 and 300 MHz on
Bruker spectrometers. MS spectra were recorded with a
VG7070 E9 spectrometer. Melting points were obtained
by using a Buchi 535 apparatus. Optical rotation mea-
surements were obtained with a Perkin–Elmer 241 Polar-
imeter and elemental analyses for the new compounds
were determined on a Perkin–Elmer 240 Analyser. Flash-
column chromatography purification was performed on
For water-insoluble compounds the reaction mixture was
diluted with ethyl acetate and poured into aqueous HCl
(5%, 2–3 mL). The aqueous phase was extracted with
ethyl acetate (3×15 mL). The organic layers were col-
lected, dried (Na2SO4), and evaporated to dryness. Occa-
sionally a light blue or green colour still persistent

F. Orsini, E. Di Teodoro / Tetrahedron: Asymmetry 13 (2002) 1307–1313
1311
in the crude material was eliminated by dissolving in
ethyl acetate and by washing with a saturated EDTA
(bis-sodium salt) solution.
1H, J=10.5, 3.3 Hz), 4.10 (2H, dq, J=7.5, 7.5, 7.5,
7.5), 4.18 (2H, dq, J=7.5, 7.5, 7.5, 7.5 Hz), 4.40 (1H, d,
J=4.8 Hz), 4.83 (1H, dd, J=4.8, 3.3 Hz); 13C NMR
(CDCl3): l 2×16.31 (q), 24.92 (q), 26.30 (q), 31.09 (t,
JCP=140.6 Hz), 2×62.27 (t, JCP=105.4 Hz), 71.24 (t),
For partially water soluble-compounds, the reaction
mixture was filtered through silica gel eluting with ethyl
acetate:petroleum ether to remove cobalt salts.
80.62 (d), 85.55 (d), 104.09 (s), 112.52 (s); 31P NMR
(CDCl3): l 29.42; MS, m/z: 292 (M+−H2O), 247 (292−
CH3CH2O), 151 (CH2P(O)(OEt)2). Anal. calcd for
C12H23O7P: C, 46.45; H, 7.42. Found: C, 46.25; H,
7.40%.
The crude material was purified by chromatography
over silica gel, eluting with ethyl acetate:petroleum
ether 7:3 and ethyl acetate:methanol 9:1, to separate the
Compound 2d: colourless viscous oil; [h]D=−8.67 (c
product
from
unreacted
starting
lactone.
1
13.3 mg/mL, CHCl3); H NMR (CDCl3): l 1.20 (3H, t,
Trimethylphosphine can be conveniently substituted
with triphenylphosphine without affecting the course of
the reaction.
J=7.7 Hz), 1.26 (3H, t, J=7.7 Hz), 1.70 (1H, dd,
J=19.3, 15.4 Hz), 2.28 (1H, d, J=17.4, 15.4 Hz), 3.25
(1H, d, J=9.7 Hz), 3.59 (dd, 1H, J=11.6, 3.1 Hz), 3.66
(1H, dd, J=8.5, 8.5 Hz), 3.74 (1H, dd, J=11.6, 3.9
Hz), 3.99 (2H, dq, J=7.7 Hz), 4.08 (2H, m), 4.10 (1H,
m), 4.11 (1H, m), 4.45 and 4.5 (AB system, 2H, J=11.6
Hz), 4.57 (1H, d, J=11.6 Hz), 4.63 (1H, d, J=11.6 Hz),
4.84 (1H, d, J=11.6 Hz), 4.9 (2H, s), 4.96 (1H, d,
J=11.6 Hz), 7.25–7.4 (20H); 13C NMR (CDCl3): l
Compound 2a (mixture of diastereoisomers): colourless
1
viscous oil; H NMR (CDCl3): l (major), 1.26 (3H, t,
J=6.5 Hz), 1.30 (3H, t, J=6.5 Hz), 2.28 (1H, dd,
J=17.5, 15.0 Hz), 2.46 (1H, dd, J=17.5, 15.0 Hz), 3.53
(1H, dd, J=10.0, 4.8 Hz), 3.58 (1H, dd, J=10.0, 4.6
Hz), 3.91 (1H, dd, J=4.9, 4.8 Hz), 4.02 (1H, d, J=4.9
Hz), 4.05 (2H, dq, J=6.3 Hz), 4.18 (1H, dq, J=6.9
Hz), 4.36 (1H, ddd, J=4.8, 4.8, 4.6 Hz), 7.25–7.45
(15H, m); 13C NMR (CDCl3): l (major), 2×16.34 (q),
32.20 (dt, JCP=134.4), 2×62.05 (dt, JCP=106.1), 70.20
(t), 72.01 (t), 73.30 (t), 73.42 (t), 80.93 (d), 82.89 (d),
88.08 (dd, JCP=35.4), 104.4 (s), 6×127.67 (d), 6×127.82
(d), 3×128.41 (d), 137.66 (s), 137.79 (s), 138.48 (s); 31P
NMR (CDCl3): l 29.29. MS, m/z: 552 (M+−H2O), 507
(M+−H2O−CH3CH2O), 444 (M+−H2O−PhCH2OH),
151 [CH2P(O)(OEt)2].
2×16.2 (q), 33.14 (t, JCP=140.6 Hz), 2×62.0 (t, JCP
=
58.6 Hz), 69.79 (t), 71.00 (d), 73.37 (t), 74.70 (t), 75.10
(t), 75.55 (t), 79.44 (d), 92.96 (d), 93.15 (d), 96.83 (s,
JCP=11.72 Hz), 4×127.65 (d), 4×127.84 (d), 4×129.30
(d), 8×129.57 (d), 2×137.98 (s), 139.33 (s), 139.82 (s);
31P NMR (CDCl3): l 29.20; MS, m/z: 672 (M+−H2O),
539 (M+−CH2P(O)(OEt)2), 152 [CH3P(O)(OEt)2], 91
(PhCH2). Anal. calcd for C39H47O9P: C, 67.83; H, 6.81.
Found: C, 67.53; H, 6.78%.
Compound 2e: colourless viscous oil; [h]D=+9.7 (c 10.5
mg/mL, CHCl3); 1H NMR (CDCl3): l 1.19 (3H, t,
J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.77 (1H, dd,
J=17.2, 15.1 Hz), 2.37 (1H, dd, J=17.2, 15.1 Hz), 3.51
(1H, dd, J=9.9, 6.5 Hz), 3.59 (1H, dd, J=9.9, 8.6 Hz),
3.74 (1H, d, J=8.6 Hz), 4.24 (1H, dd, J=6.5, 6.5 Hz),
4.44 (2H, s), 4.61 (1H, d, J=11.6 Hz), 4.68 (1H, d,
J=11.6 Hz), 4.75 (2H, s), 4.95 (1H, d, J=11.6 Hz), 5.0
(1H, d, J=11.6 Hz), 7.25–7.40 (20H); 13C NMR
(CDCl3): l 2×16.27 (q), 34.19 (t, JCP=131.95 Hz),
61.93 (t, JCP=88.0 Hz), 61.99 (t, JCP=88.0 Hz), 68.91
(t), 72.78 (t), 73.30 (t), 74.75 (t), 76.00 (t), 75.38 (d),
79.27 (d), 79.48 (d), 80.36 (d), 97.41 (s), 4×127.51 (d),
2×127.72 (d), 2×128.11 (d), 4×128.31 (d), 8×128.65 (d),
138.06 (s), 138.35 (s), 138.58 (s), 138.99 (s); 31P NMR
(CDCl3): l 29.68; MS, m/z: 672 (M+−18), 581 (M+−18−
19), 91 (PhCH2). Anal. calcd for C39H47O9P: C, 67.83;
H, 6.81. Found: C, 67.50; H, 6.70%.
The minor diastereoisomer was identified by the follow-
ing signals in the NMR spectra. H NMR (CDCl3): l
1
2.17 (1H, dd, J=18.3, 15.0 Hz), 2.34 (1H, dd, J=18.3,
15.0 Hz); 13C NMR (CDCl3): l 2×16.34 (q), 34.76 (dt,
J
CP=134.4), 72.79 (t), 80.52 (d), 84.34 (d), 86.43 (d),
101.35 (s); 31P NMR: 27.19.
Compound 2b: colourless crystals; mp=88–89°C
(petroleum ether–ethyl acetate); [h]D=+9.5 (c 11 mg/
1
mL, CHCl3); H NMR (CDCl3): l 1.30 (3H, s), 1.30
(3H, t, J=7.0 Hz), 1.31 (3H, t, J=7.0 Hz), 1.34 (3H, s),
1.41 (3H, s), 1.44 (3H, s), 2.14 (1H, dd, J=18.4, 15.6
Hz), 2.33 (1H, dd, J=17.0, 15.6 Hz), 3.9–4.1 (6H, m),
4.08 (1H, dd, J=7.1, 4.3 Hz), 4.31 (1H, dd, J=12.7, 5.7
Hz), 4.41 (1H, d, J=5.6 Hz), 4.78 (1H, dd, J=5.6, 4.3
Hz); 13C NMR (CDCl3): 2×16.13 (q), 24.33 (q), 24.93
(q), 25.76 (q), 26.59 (q), 30.88 (t, JCP=144.9 Hz), 61.83
(t, JCP=58.0 Hz), 61.98 (t, JCP=58.0 Hz), 66.54 (t),
72.88 (d), 79.32 (d), 80.06 (d), 85.89 (d, JCP=8.7 Hz),
103.48 (s, JCP=8.7 Hz), 103.83 (s), 112.53 (s); 31P NMR
(CDCl3): l 29.18; MS, m/z: 410 (M+), 392 (M+−H2O),
Compound 2f: colourless viscous oil; [h]D=+5.5 (c 4.8
mg/mL, CHCl3); 1H NMR (CDCl3): l 1.1 (3H, d,
J=6.8 Hz), 1.27 (3H, dt, J=6.8, 6.8, 3.8 Hz), 1.76 (1H,
dd, J=18.8, 15.0 Hz), 2.34 (1H, dd, J=18.0, 15.0 Hz),
3.68 (1H, dd, J=3.0, 1.5 Hz), 3.72 (1H, d, J=9.75 Hz),
3.97 (2H, dq, J=6.8, 6.8, 6.8, 6.8 Hz), 4.13 (2H, dq,
J=6.8 Hz), 4.08–4.18 (2H), 4.68 (1H, d, J=10 Hz),
4.70 (1H, d, J=10 Hz), 4.75 and 4.79 (2H, AB system,
J=10.5 Hz), 4.96 (1H, d, J=6.7), 5.1 (1H, d, J=6.7),
7.25–7.45 (15H); 13C NMR (CDCl3): l 2×16.46 (q,
316
(392−H2O−CH3COCH3),
259
(M+−
CH2P(O)(OEt)2). Anal. calcd for C17H31O9P: C, 49.75;
H, 7.56. Found: C, 49.35; H, 7.53%.
Compound 2c: colourless viscous oil; [h]D=−38.05 (c
1
10.8 mg/mL, CHCl3); H NMR (CDCl3): l 1.29 (3H,
s), 1.30 (3H, d, J=7.5 Hz), 1.31 (3H, t, J=7.5 Hz), 1.43
(3H, s), 2.22 (1H, dd, J=18.0, 15.0 Hz), 2.43 (1H, dd,
J=18.0, 15.0 Hz), 3.9 (1H, d, J=10.5 Hz), 4.35 (dd,
J
CP=27.8 Hz), 33.40 (t, JCP=138.76 Hz), 63.4 (t, JCP=
61.1 Hz), 72.85 (t), 74.69 (t), 75.84 (t), 77.92 (d), 79.02
(d), 79.29 (d), 80.60 (d), 97.05 (s, JCP=13.88 Hz),

1312
F. Orsini, E. Di Teodoro / Tetrahedron: Asymmetry 13 (2002) 1307–1313
2×127.49 (d), 127.64 (d), 4×129.12 (d), 4×129.28 (d),
4×128.61 (d), 138.29 (s), 138.59 (s), 138.76 (s); 31P
NMR (CDCl3): l 29.95; MS, m/z: 566 (M+−H2O), 475
(M+−H2O−CH2Ph), 152 [CH2P(O)(OEt)2]. Anal. calcd
for C32H41O8P: C, 65.75; H, 7.02. Found: C, 65.45; H,
6.98%.
4.4. Typical procedure for the reaction mediated by
magnesium (procedure C)
To a suspension of activated magnesium turnings (0.3
g), in freshly distilled dry THF (2 mL), was added
dropwise a THF solution (10 mL) of lactone (1 mmol)
and diethyl-a-iodomethylphosphonate (1.2 mmol, 0.2
mL). The reaction was monitored by thin layer chro-
matography (silica gel, eluting with ethyl acet-
ate:petroleum ether 7:3). The magnesium was removed
by filtration and the filtrate was treated according to
one of the two procedures described in Section 4.3,
depending on the water-solubility of the product.
Compound 2g: colourless viscous oil; [h]D=−15.2 (c 6.8
mg/mL, CHCl3); 1H NMR (CDCl3): l 1.26 (3H, d,
J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2
Hz), 1.65 (1H, dd, J=17.2, 14.3 Hz), 2.55 (1H, dd,
J=17.2, 14.3 Hz), 3.60 (1H, t, J=8.6 Hz), 3.71 (1H, d,
J=2.9 Hz), 4.04 (1H, dq, J=7.2 Hz), 4.04 (2H, m),
4.13 (1H, dd, J=8.6, 2.9 Hz), 4.16 (2H, m), 4.63 (1H, d,
J=11.4 Hz), 4.65 (1H, d, J=11.4 Hz), 4.92 (1H, d,
J=11.4 Hz), 4.98 (1H, d, J=11.4 Hz), 7.25–7.45 (15H);
13C NMR (CDCl3): l 16.14 (q), 16.26 (q), 17.81 (q),
33.72 (dt, JCP=132.3 Hz), 62.0 (dt, JCP=79.4 Hz), 62.0
(dt, JCP=79.4 Hz), 68.67 (d), 72.91 (t), 74.84 (t), 75.83
(t), 78.78 (d), 80.23 (d), 81.32 (d), 96.98 (s, JCP=5.29
Hz), 2×127.50 (d), 127.68 (d), 2×127.93 (d), 2×128.23
(d), 4×128.33 (d), 4×128.45 (d), 138.33 (s), 2×138.88 (s);
31P NMR (CDCl3): l 30.14; MS, m/z: 566 (M+−H2O),
475 (M+−H2O−CH2Ph), 152 [CH2P(O)(OEt)2]. Anal.
calcd for C32H41O8P: C, 65.75; H, 7.02. Found: C,
65.40; H, 6.96%.
4.5. Reduction of 2f with triethylsilane
Triethylsilane (0.08 mL, 0.5 mmol) was added at 0°C to
a solution of 2e (0.06 g, 0.1 mmol) in dry acetonitrile,
followed by freshly distilled BF3·Et2O (0.05 mL, 0.5
mmol). The reaction was kept at 0°C and monitored by
thin-layer chromatography (silica gel, eluting with ethyl
acetate:petroleum ether 3:7). A saturated solution of
NaHCO3 was added until pH 8 and the aqueous phase
was extracted with methylene chloride (3×15 mL). The
combined organic extracts were dried (Na2SO4) and the
solvent removed under reduced pressure. The crude
material was chromatographed on silica gel (ethyl ace-
tate:n-hexane 3:7) and afforded phosphonate 3f (0.044
g, 80%).
4.3. Typical procedure for the sub-stoichiometric reac-
tion mediated by (Me3P)4Co (procedure B)
Compound 3f: colourless thick oil; [h]D=−25.45 (c 12.2
mg/mL, CHCl3); 1H NMR (CDCl3): l 1.15 (d, 3H,
J=6.5 Hz), 1.25 (t, 6H, J=7.5 Hz), 1.9 (ddd, 1H,
J=16.0, 16.0, 8.5 Hz), 2.3 (ddd, 1H, J=18.0, 16.0, 2.5
Hz), 3.53 (bq, 1H, J=6.5), 3.60 (ddd, 1H, J=9.0, 8.5,
2.5 Hz), 3.6–3.7 (m, 3H), 3.98–4.1 (m, 4H), 4.65–4.75
(4H), 4.95–5 (2H), 7.25–7.40 (15H); 13C NMR (CDCl3):
l 16.24 (q), 16.35 (q), 17.17 (q), 28.70 (dt, J=140.74),
61.44 (dt, JCP=21.9), 61.54 (dt, JCP=21.9), 72.49 (t),
74.38 (d), 74.69 (d), 74.88 (t), 75.09 (t), 76.75 (d), 78.44
(d), 85.02 (d), 127.62 (d), 4×127.89 (d), 4×128.186 (d),
4×128.104 (d), 128.30 (s), 2×138.58 (s). 31P NMR
(CDCl3): l 30.30; MS, m/z: 477 (M+−PhCH2), 416
A 1 M solution of trimethylphosphine in dry THF (1
mL) was added to a mixture of activated magnesium
turnings (0.3 g) and anhydrous CoCl2 (0.032 g, 0.25
mmol).13b The mixture was stirred at room temperature
until the yellow-brown colour of the cobalt(0) complex
developed. To the mixture a THF solution (10 mL) of
lactone (1 mmol) and diethyl-a-iodomethylphosphonate
(1.2 mmol, 0.2 mL) were added dropwise under stirring.
The speed of addition was adjusted so as to minimise
the time of persistence of the blue colour (Co(II) com-
plex) developed during the addition. At the end of the
reaction, indicated by the persistence of the yellow-
brown colour of the original Co(0) complex, the mag-
nesium was filtered off and the resulting solution was
stirred under air until a blue colour developed. For
water-insoluble compounds (procedure A) the reaction
mixture was diluted with ethyl acetate and poured into
aqueous HCl (5%, 2–3 mL). The aqueous phase was
extracted with ethyl acetate (3×15 mL). The organic
layers were collected, dried (Na2SO4), and evaporated
to dryness. Occasionally, a light blue or green colour
still persistent in the crude material was eliminated by
dissolving in ethyl acetate and by washing with a
sutured EDTA (bis-sodium salt) solution.
(M+−CH3P(O)(OEt)2,
310
(417−PhCH2O),
152
[CH2P(O)(OEt)2], 91 (PhCH2). Anal. calcd for
C32H41O7P: C, 67.61; H, 7.22. Found: C, 67.71; H,
7.22%.
Acknowledgements
National Research Council (CNR) and Ministero della
Ricerca Scientifica
e
Tecnologica (MURST) are
acknowledged for financial support. Dr. Marinella Fer-
rari is gratefully acknowledged for computer-assisted
bibliographic research.
For partially soluble-compounds, the reaction mixture
was filtered through silica gel, eluting with ethyl ace-
tate:petroleum ether to remove cobalt salts.
The crude material was chromatographed on silica gel,
eluting with ethyl acetate:petroleum ether 7:3 and ethyl
acetate:methanol 9:1, to separate the product from
unreacted starting lactone.
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after use.
19. Magnesium was activated by adding a few drops of
1,2-dichloroethane to metal turnings (0.5 g) in THF (3
mL) so that a vigorous reaction ensued. After a few
minutes the mixture was ice-cooled, the solvent was
removed and the magnesium was washed three times with
THF (2 mL each time).
20. The solution can also be warmed with an external bath at
ca. 50°C to speed the reduction of Co(II) to Co(0).
Warming may be useful when triphenylphosphine is used
instead of trimethylphosphine.
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9. Co(PMe3)4 is a well-identified complex, that can be con-
veniently obtained by reducing a mixture of Co(II) chlo-
ride and trimethylphosphine (1:4 mole ratio) with
magnesium metal in THF. Trimethylphosphine can be
conveniently replaced by triphenylphosphine without
affecting the course of the reaction.