Stereoselective michael-type addition of organocopper reagents to enones derived from glycals in the synthesis of 2-phosphono-α-C-glycosides

Article abstract of DOI:10.1002/ejoc.200500149

Michael-type additions of various organocopper reagents to the novel carbohydrate-derived 2-(diethoxyphosphoryl)hex-1-en-3-uloses are described. The reactions have proved to be rapid, clean and stereoselective, giving rise to the formation of 3-oxo-2-phos

Full text of DOI:10.1002/ejoc.200500149

SHORT COMMUNICATION
Stereoselective Michael-Type Addition of Organocopper Reagents to Enones
Derived from Glycals in the Synthesis of 2-Phosphono-α-C-Glycosides
Francesca Leonelli,*[a] Marinella Capuzzi,[a] Vincenzo Calcagno,[a] Pietro Passacantilli,[a]
and Giovanni Piancatelli*[a]
Keywords: C-Glycosides / Carbohydrates / Michael addition / Phosphorylation / 3-Oxo-2-phosphono α-C-glycosides /
Organocopper reagents
Michael-type additions of various organocopper reagents to
the novel carbohydrate-derived 2-(diethoxyphosphoryl)hex-
1-en-3-uloses are described. The reactions have proved to be
rapid, clean and stereoselective, giving rise to the formation
of 3-oxo-2-phosphono-α-C-glycosides or the corresponding
enol acetates. These compounds are direct precursors of 2-
phosphono-α-C-glycosides, a very interesting class of mole-
cules never described before.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
additions.[5] Compounds 1a and 1b were prepared from gly-
cals, such as d-glucal 2a and the d-galactal 2b, according
to the synthetic procedure reported in Scheme 1.
Introduction
Michael-type addition to activated double bonds of
carbohydrate derivatives has recently become a powerful
tool for the functionalization of monosaccharides.[1]
Among the various examples, one of the most interesting is
the preparation of C-glycosides,[1a–1c,1g,2] carbohydrate ana-
logues in which the C–O glycosidic linkage is substituted by
a C–C bond. During the last three decades, the synthesis of
these compounds has attracted the interest of chemists and
biochemists thanks to their stability towards enzymes, acids
and bases and because the C-glycoside moiety is contained
in several bioactive natural products.[3]
C-Glycosylphosphonates are known as important enzy-
matic inhibitors[1h,4] (the C–P bond cannot be hydrolysed
by “ordinary” enzymes) and are able to act as stable biomi-
metics of the corresponding glycosyl phosphates, which
have turned out to be the main metabolic precursors and
the key glycosylating agents in the biosynthesis of glycocon-
jugates. We therefore believe that the preparation of new C-
glycosides containing the phosphonate group is quite valu-
able.
Here we describe a simple procedure for the preparation
of the novel 3-oxo-2-phosphono-α-C-glycosides through
Michael-type additions of organocopper reagents, starting
from 2-(diethoxyphosphoryl)hex-1-en-3-uloses 1a and 1b.
The presence of the carbonyl function α to the phosphonate
group was necessary because of the well documented low
reactivity of nonactivated vinyl phosphonates towards 1,4-
Scheme 1. Reagents and conditions: a) NaH, BnBr, THF/DMF
(4:1), 4 h, 60 °C, 90%. b) CH3CN, 3-Å molecular sieves, BAIB,
TsOH, 2 h, room temp., 40% for 4a, 60% for 4b. c) I2, CCl4/Py
(1:1), 2 h, room temp., 74% for 5a, 60% for 5b. d) P(OEt)3, NiCl2,
150 °C, 60%.
The tri-O-benzyl-d-glycals 3a and 3b, obtained by per-
benzylation of the starting d-glucal 2a and d-galactal 2b
with sodium hydride/benzyl bromide, were selectively oxid-
ized to enones 4a and 4b with bis(acetoxy)iodobenzene
(BAIB) and TsOH by a well known synthetic procedure.[6]
The pyranones 4 were then converted in good yields into
the vinyl iodides 5 by treatment with molecular iodine in a
CCl4/Py (1:1) solution.[7] Unexpectedly, initial attempts to
perform the cross-coupling reaction for the formation of
the C–P bonds in phosphonate compounds 1 with various
[a] Dipartimento di Chimica and Istituto di Chimica Biomolecol-
are del CNR - Sezione di Roma, Università “La Sapienza”,
Piazzale Aldo Moro 5, 00185 Roma, Italy
Fax: +39-06-490631
E-mail: francesca.leonelli@uniroma1.it
giovanni.piancatelli@uniroma1.it
Eur. J. Org. Chem. 2005, 2671–2676
DOI: 10.1002/ejoc.200500149
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Leonelli, M. Capuzzi, V. Calcagno, P. Passacantilli, G. Piancatelli
SHORT COMMUNICATION
Pd-based catalysts and diethyl hydrogen phosphite failed in good yields and with almost complete α diastereoselectiv-
completely. We therefore considered Kazankova’s method[8] ity[9,10] and proved to be extremely rapid (the starting enone
for converting vinyl halides into phosphonates by a modi- had disappeared by TLC in less than 3 minutes). These re-
fied Arbuzov reaction catalysed by triethyl phosphite sults show the remarkable accelerating effect of the phos-
nickel(0) complex. When this reaction was performed in tri- phonate group on the reaction rate. The effect is clearly
ethyl phosphite at 150 °C in the presence of NiCl2 as a cata- evident on reference to the conjugate addition on the enone
lyst the desired products 1 were obtained in fair yields.
4a, for which we observed no product under the same reac-
Initial experiments involving addition of the organocop- tion conditions (Table 1, entry 4).[11]
per reagents were carried out with the d-glucal-derived en-
The addition of Ph2CuLi to 1a gave a 7:3 mixture of the
one 1a as shown in Table 1. The reactions resulted in the ketonic and enolic derivatives, which was treated without
formation of the 3-oxo-2-phosphono-α-C-glycosides 6a–8a purification with Ac2O in Py to give the enol acetate 9a
quantitatively with an α/β diastereoisomeric ratio of 88:12
(Scheme 2). This result was in agreement with previous
studies regarding the conjugate addition of phenylcopper
Table 1. Stereoselective Michael-type addition to 2-(diethoxyphos-
phoryl)hex-1-en-3-ulose 1a and enone 4a.
reagents to hex-1-enopyran-3-uloses.[1c]
Such behaviour was also noticed with the d-galactal-de-
rived enone 1b (Table 2): conjugate addition of all the orga-
nocopper reagents almost exclusively gave α-C-glycosides[12]
in enolic form, and these were transformed into the enol
acetates 6b–9b as described previously. In this case the C(4)-
galacto configuration probably forced all the addition com-
pounds to be in enolic form, presumably less crowded than
the corresponding ketonic one. As in the case of compound
1a, the phosphonate group also accelerates the reaction
rates for 1b (Table 2, entry 5).[13]
The α-C-glycoside configurations in the addition prod-
ucts 6a–8a were established by the presence of clear NOE
signals between H-(5) and CH2R at C(1) (Scheme 3). The
assignment of the C(2) configuration was defined by the
presence of NOE signals between H-(2) and CH2R at C(1)
(Scheme 3) and by coupling constant analysis (J1,2 Ϸ 3 Hz).
The presence of a NOE between H-(5) and CH2R at C(1)
also confirmed the α-C-glycoside configuration in the gal-
actal-derived addition products 6b–8b. Furthermore we
were able to rule out C(4) epimerization[14] in compounds
6–9 because the values of J4,5 were large (Ϸ 10 Hz) in prod-
ucts 6a–9a, indicating an axial-axial relationship, and
smaller (Ϸ 3 Hz) in 6b–9b because of an equatorial-axial
relationship.
In conclusion, Michael-type organocopper addition to 2-
(diethoxyphosphoryl)hex-1-en-3-uloses 1 has been shown
here to be stereoselectively α and has allowed us to prepare
the novel compounds 6–9, which can in turn be trans-
formed into 2-phosphono-α-C-glycosides by means of the
well known stereoselective reduction of the carbonyl
group[1d,1g,15] (for 6a–8a) or the reduction of the enol ace-
tate function (for 6b–9b and 9a).[16]
[a] R2CuLi (2.5 equiv.), –78 °C, 3 min, 75%. [b] Diastereoisomeric
ratios were determined by integration of the corresponding 2-H
signal in the 200-MHz 1H NMR spectra and by HPLC analysis of
the crude reaction mixtures. [c] The epimeric mixtures were treated
with Ac2O in Py to give the two corresponding α- and β-enol ace-
tates in unchanged diastereoisomeric ratios.
Scheme 2. a) Ph2CuLi (2.5 equiv.), Et2O/THF (1:1), –78 °C, 3 min. b) Ac2O, Py, 40 °C, 12 h, 60% (after two steps)..
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Eur. J. Org. Chem. 2005, 2671–2676

Stereoselective Michael-Type Addition of Organocopper Reagents to Enones
SHORT COMMUNICATION
sured at the sodium d line on a DIP 370 Jasco digital polarimeter.
Yields are given for isolated products after column chromatography
showing a single spot on TLC and no detectable impurities in the
1H NMR spectrum. All reactions were performed under Ar in
flame-dried glassware. All reactions were monitored by thin-layer
chromatography (TLC) carried out on Merck F-254 silica glass
plates and viewed with the aid of UV light and heat-gun treatment
with 2 n H2SO4 solution. Column chromatography was performed
with Merck silica gel 60 (70–230 mesh). HPLC analysis Shimadzu
LC-10AD; RID detector, 250/4 Nucleosil 100-5 column (Mach-
erey–Nagel), at a flow of 0.8 mLmin–1; tR in min.
Table 2. Stereoselective Michael-type addition to 2-(diethoxyphos-
phoryl)hex-1-en-3-ulose 1b and enone 4b.
Tri-O-benzyl-D-glucal 3a: Glucal 2a (Aldrich, 1.00 g, 6.84 mmol)
was added slowly at 0 °C to a 4:1 THF/DMF mixture (50 mL)
containing NaH (1.09 g, 27.38 mmol, 60% suspension in mineral
oil). BnBr (3.2 mL, 27.38 mmol) was then added and the reaction
mixture was heated at 60 °C for 4 h. After the reaction mixture had
cooled, Et2O (20 mL) and H2O (5 mL, slowly) were added and a
stream of CO2 was passed through the solution until neutrality.
The organic layer was washed with brine, dried (Na2SO4) and con-
centrated under reduced pressure. The residue was then purified by
column chromatography (SiO2; n-hexane/AcOEt, 95:5) to give pure
3a[17] (2.56 g, 6.15 mmol, 90%).
Tri-O-benzyl-D-galactal 3b: This compound was prepared from gal-
actal 2b (Aldrich, 0.50 g, 3.42 mmol) as in the procedure described
for 3a. The crude product was purified by column chromatography
(SiO2; n-hexane/AcOEt, 95:5) to give pure 3b[18] (1.28 g, 3.07 mmol,
90%).
Hex-1-enopyran-3-ulose 4a: Powdered molecular sieves (3 Å, 1.67
g) were added to a solution of 3a (2.56 g, 6.15 mmol) in anhydrous
CH3CN (120 mL), and the suspension was stirred at 0 °C for 5
min. BAIB (2.38 g, 7.38 mmol) was then added in one portion and
the mixture was stirred for 10 min at room temp. TsOH (1.40 g,
7.38 mmol) was added slowly and the stirring was continued for
another 75 min. The suspension was then filtered through a pad of
Celite, and the residue was washed with CH2Cl2. The combined
filtrate and washings were washed with s.s. NaHCO3 (30 mL) and
brine (30 mL), dried (Na2SO4) and concentrated under reduced
pressure. The residue was then rapidly purified by column
chromatography (SiO2; n-hexane/AcOEt, 90:10) to give pure 4a[6]
(0.80 g, 2. 46 mmol, 40%).
[a] i) R2CuLi (2.5 equiv.), –78 °C, 3 min. ii) Ac2O, Py, room temp.,
12 h, 70% (after the two steps). [b] Diastereoisomeric ratios were
determined by integration of the corresponding 1-H in the 200-
MHz 1H NMR spectra and by HPLC analysis of the crude reaction
mixtures.
Hex-1-enopyran-3-ulose 4b: This compound was prepared from 3b
(1.28 g, 3.07 mmol) as in the procedure described for 4a. The crude
product was purified by column chromatography (SiO2; n-hexane/
AcOEt, 90:10) to give pure 4b[3] (0.60 g, 1.84 mmol, 60%).
Vinyl Iodide 5a: Iodine (1.31 g, 5.18 mmol), dissolved in CCl4/pyri-
dine (1:1, 10 mL), was added dropwise at 0 °C to a solution of 4a
(0.80 g, 2.46 mmol) in CCl4/pyridine (1:1, 10 mL). The mixture was
stirred for 2 h at room temp., diluted with CH2Cl2 (30 mL) and
then washed in a separating funnel with H2O (15 mL), 1 n HCl
(2×15 mL) and 20% aqueous Na2S2O3 (15 mL), dried (Na2SO4)
and concentrated under reduced pressure. The crude product was
purified by column chromatography (SiO2; hexanes/Et2O, 80:20) to
give pure 5a (0.82 g, 1.82 mmol, 74%) as a viscous oil. Data for 5a.
Scheme 3. NOE signals in glucal derivatives 6a–8a and in galactal
derivatives 6b–8b.
1
[α]D = +253.6 (c = 3.2, CHCl3). H NMR: δ = 7.71 (s, 1 H, 1-H),
7.28–7.44 (m, 10 H, 2 Ph), 5.07 (A of AB, JAB = 10.9 Hz, 1 H, HA
of CH2Ph), 4.61 (B of AB, JBA = 10.9 Hz, 1 H, HB of CH2Ph),
Experimental Section
1
General: H NMR (200 MHz) and 13C NMR (50.3 MHz) spectra 4.59 (A of AB, JAB = 12.0 Hz, 1 H, HA of CH2Ph), 4.56 (A of
were recorded on a Varian Gemini 200 spectrometer with CDCl3
as the solvent and as the internal standard; δ in ppm. IR spectra:
Shimadzu-470 scanning infrared spectrophotometer; values given
in cm–1. HRMS spectra were recorded with a Micromass Q-TOF
micro Mass Spectrometer (Waters). Optical rotations were mea-
ABX2, JAB = 11.3, JAX = 3.0 Hz, 1 H, 5-H), 4.53 (B of AB, JBA =
12.0 Hz, 1 H, HB of CH2Ph), 4.40 (B of AB, JBA = 11.3 Hz, 1 H,
4-H), 3.82 (d, J6,5 = 3.0 Hz, 2 H, 6-HA, 6-HB) ppm. 13C NMR: δ
= 188.1 (C-3), 164.8 (C-1), 137.3, 136.9 (Cquat, Ph), 128.4, 128.0,
127.8, 127.6 (Ph), 81.7 (C-H), 74.5 (CH2Ph), 73.9 (C-H), 73.5
Eur. J. Org. Chem. 2005, 2671–2676
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Leonelli, M. Capuzzi, V. Calcagno, P. Passacantilli, G. Piancatelli
SHORT COMMUNICATION
(CH Ph), 67.5 (C-6). IR (CHCl ): ν = 1693, 1578 cm–1. HRMS:
Et2O (3 mL) were then added to the reaction mixture. The organic
layers were washed with saturated aqueous NH4Cl (3×1 mL) and
brine (3 mL), dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy (SiO2; n-hexane/AcOEt, 1:1) to give 6a (26 mg, 0.06 mmol,
75%) as a viscous oil and as a 96:4 inseparable mixture of α/β
diastereomers. Data for 6a. 1H NMR: δ = 7.20–7.42 (m, 10 H, 2
Ph), 4.81–5.04 (m, 1 H, 1-H), 4.86 (A of AB, JAB = 11.3 Hz, 1 H,
HA of CH2Ph), 4.61 (d, J4,5 = 9.2 Hz, 1 H, 4-H), 4.43–4.57 (m, 2
H, CH2Ph), 4.40 (B of AB, JBA = 11.3 Hz, 1 H, HB of CH2Ph),
4.01–4.24 (m, 4 H, 2 OCH2CH3), 3.93 (dt, J5,4 = 9.2, J5,6 = 3.0 Hz,
1 H, 5-H), 3.70 (d, J6,5 = 3.0 Hz, 2 H, 6-HA, 6-HB), 3.02 (dd, J =
23.3, J2,1 = 4.0 Hz, 1 H, 2-H), 1.33 (pt, J = 7.0 Hz, 6 H, CH3,
OCH2CH3), 1.19 (t, J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR:
δ = 202.0 (C-3), 138.0, 137.3 (Cquat, Ph), 128.4, 128.3, 128.0, 127.7,
127.6 (Ph), 78.0 (C-H), 75.3 (C-H), 73.4, 73.3 (CH2Ph), 70.5 (d, J
= 2.7 Hz, C-1), 69.9 (C-6), 63.2 (d, J = 6.9 Hz, OCH2CH3), 62.9
(d, J = 6.9 Hz, OCH2CH3), 58.7 (d, J = 125.1 Hz, C-2), 20.4 (d, J
˜
2
3
calcd. for C20H19IO4 [M + Na]+: 473.0226; found 473.0229.
Vinyl Iodide 5b: This compound was prepared from 4b (0.60 g,
1.84 mmol) as in the procedure described for 5a. The crude product
was purified by column chromatography (SiO2; hexanes/Et2O,
80:20) to give pure 5b[1f] (0.52 g, 1.10 mmol, 60%) as a white solid.
Data for 5b. M.p. 126–128 °C (n-hexane/Et2O). [α]D = +71.0 (c =
1.5, CHCl3). 1H NMR: δ = 7.78 (s, 1 H, 1-H), 7.21–7.45 (m, 10 H,
2 Ph), 4.70 (A of AB, JAB = 11.8 Hz, 1 H, HA of CH2Ph), 4.59–
4.67 (m, 1 H, 5-H), 4.58 (A of AB, JAB = 11.9 Hz, 1 H, HA of
CH2Ph), 4,52 (B of AB, JBA = 11.9 Hz, 1 H, HB of CH2Ph), 4.46
(B of AB, JBA = 11.8 Hz, 1 H, HB of CH2Ph), 4.00 (d, J4,5 = 2.4 Hz,
1 H, 4-H), 3.91 (A of ABX, JAB = 10.2, JAX = 6.8 Hz, 1 H, 6-HA),
3.75 (B of ABX, JBA = 10.2, JBX = 5.6 Hz, 1 H, 6-HB) ppm. 13C
NMR: δ = 184.0 (C-3), 165.3 (C-1), 137.2, 136.5 (Cquat, Ph), 128.4,
128.3, 128.1, 127.9, 127.7 (Ph), 81.3 (C-H), 74.7 (C-2), 73.6
(CH2Ph), 73.5 (C-H), 72.2 (CH2Ph), 67.1 (C-6) ppm. IR (CHCl3):
ν = 1679, 1574 cm–1. HRMS: calcd. for C H IO [M + Na]+:
˜
20 19
4
= 10.7 Hz, CH ), 16.3, 16.2 (OCH CH ) ppm. IR (CHCl ): ν =
˜
3
2
3
3
473.0226; found 473.0223.
1723 cm–1. HPLC (n-hexane/AcOEt 1:1): tRα 18.6 (96%), tRβ 22.8
(4%). HRMS: calcd. for C25H33O7P [M + H]+: 477.2042; found
477.2029.
Enone 1a: A stirred mixture of NiCl2 (12 mg, 0.09 mmol) in P(OEt)
(1 mL, 5.83 mmol) was heated at reflux for 1 h. After that time
3
the black solution became clear and 5a (0.82 g, 1.82 mmol) was
added. After 5 h the solution was cooled, diluted with Et2O,
washed with H2O and brine, dried (Na2SO4) and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography (SiO2; n-hexane/AcOEt, 1:1) to give pure 1a
3-Oxo-2-phosphono-α-C-glycoside 7a: This compound was pre-
pared from 1a (30 mg, 0.06 mmol) as in the procedure described
for 6a, followed by column chromatography (SiO2; n-hexane/Ac-
OEt, 1:1) to give 7a (24 mg, 0.05 mmol, 75%) as a viscous oil and
as a 96:4 inseparable mixture of α/β diastereomers. Data for 7a. 1H
NMR: δ = 7.20–7.40 (m, 10 H, 2Ph), 4.87 (A of AB, JAB = 11.2 Hz,
1 H, HA of CH2Ph), 4.59–4.68 (m, 1 H, 1-H), 4.57 (d, J4,5 = 9.5 Hz,
(0.50 g, 1.09 mmol, 60%) as a viscous oil. Data for 1a. [α]D
=
+189.4 (c = 7.2, CHCl ). IR (CHCl ): ν = 1695, 1585 cm–1. 1H
˜
3
3
NMR: δ = 8.04 (d, J = 9.1 Hz, 1 H, 1-H), 7.21–7.44 (m, 10 H, 2
Ph), 4.99 (A of AB, JAB = 11.0 Hz, 1 H, HA of CH2Ph), 4.41–4.58
(m, 4 H, HB of CH2Ph, CH2Ph, 5-H), 3.96–4.27 (m, 5 H, 4-H, 2
OCH2CH3), 3.73–3.88 (m, 2 H, 6-HA, 6-HB), 1.31 (t, J = 7.0 Hz,
3 H, OCH2CH3), 1.29 (t, J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C
NMR: δ = 189.6 (C-3), 171.0 (d, J = 18.7 Hz, C-1), 137.1, 136.9
(Cquat, Ph), 128.4, 128.3, 128.0, 127.8, 127.6 (Ph), 105.8 (d, J =
191.5 Hz, C-2), 81.8, (C-H), 74.1 (CH2Ph), 73.6 (d, J = 8.8 Hz, C-
H), 73.56 (CH2Ph), 67.7 (C-6), 62.4, 62.3 (OCH2CH3), 16.2, 16.1
(OCH2CH3) ppm. HRMS: calcd. for C24H29O7P [M + H]+:
461.1729; found: 461.1721.
1 H, 4-H), 4.41–4.53 (m, 2 H, CH2Ph), 4.43 (B of AB, JBA
=
11.2 Hz, 1 H, HB of CH2Ph), 4.03–4.24 (m, 4 H, 2 OCH2CH3),
3.86 (dt, J5,4 = 9.5, J5,6 = 3.0 Hz, 1 H, 5-H), 3.72 (d, J6,5 = 3.0 Hz,
2 H, 6-HA, 6-HB), 3.05 (dd, J = 23.4, J2,1 = 2.7 Hz, 1 H, 2-H),
1.47–1.81 (m, 2 H, CH2CH3), 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH3),
1.19 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.95 (t, J = 7.3 Hz, 3 H,
CH2CH3) ppm. 13C NMR: δ = 201.9 (C-3), 138.1, 137.4 (Cquat
,
Ph), 128.4, 128.34, 128.30, 128.0, 127.7, 127.6 (Ph), 78.1 (C-H),
75.6 (d, J = 3.4 Hz, C-1), 74.7 (C-H), 73.5, 73.4 (CH2Ph), 69.9 (C-
6), 63.2 (d, J = 6.5 Hz, OCH2CH3), 62.7 (d, J = 6.5 Hz,
OCH2CH3), 57.4 (d, J = 125.9 Hz, C-2), 26.3 (d, J = 12.2 Hz,
CH2CH3), 16.3, 16.2 (OCH2CH3), 9.7 (CH2CH3) ppm. IR
Enone 1b: This compound was prepared from 5b (0.52 g,
1.10 mmol) as in the procedure described for 1a. The crude product
was purified by column chromatography (SiO2; n-hexane/AcOEt,
1:1) to give pure 1b (0.30 g, 1.10 mmol, 60%) as a viscous oil. Data
(CHCl ): ν = 1720 cm–1. HPLC (n-hexane/AcOEt 1:1): t 13.0
˜
3
Rα
(96%), tRβ 11.7 (4%). HRMS: calcd. for C26H35O7P [M + Na]+:
513.2018; found 513.2026.
1
for 1b. [α]D = +6.8 (c = 1.3, CHCl3). H NMR: δ = 8.07 (d, J =
3-Oxo-2-phosphono-α-C-glycoside 8a: This compound was pre-
pared from 1a (35 mg, 0.08 mmol) as in the procedure described
for 6a, followed by column chromatography (SiO2; n-hexane/Ac-
OEt, 1:1) to give 8a (30 mg, 0.06 mmol, 75%) as a viscous oil and
as a 96:4 inseparable mixture of α/β diastereomers. Data for 8a. 1H
NMR: δ = 7.19–7.41 (m, 10 H, 2Ph), 4.87 (A of AB, JAB = 11.2 Hz,
1 H, HA of CH2Ph), 4.59–4.78 (m, 1 H, 1-H), 4.58 (d, J4,5 = 9.4 Hz,
1 H, 4-H), 4.54 (A of AB, JAB = 11.8 Hz, 1 H, HA of CH2Ph), 4.46
(B of AB, JBA = 11.8 Hz, 1 H, HB of CH2Ph), 4.43 (B of AB, JBA
= 11.2 Hz, 1 H, HB of CH2Ph), 4.03–4.25 (m, 4 H, 2 OCH2CH3),
3.87 (dt, J5,4 = 9.4, J5,6 = 3.0 Hz, 1 H, 5-H), 3.71 (d, J6,5 = 3.0 Hz,
2 H, 6-HA, 6-HB), 3.04 (dd, J = 23.4, J2,1 = 2.9 Hz, 1 H, 2-H),
1.24–1.84 [m, 6 H, (CH2)3CH3], 1.32 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.19 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.87 [t, J =
9.3 Hz, 1 H, 1-H), 7.18–7.46 (m, 10 H, 2 Ph), 4.41–4.74 (m, 5 H,
2 CH2Ph, 5-H), 4.00–4.27 (m, 4 H, 2 OCH2CH3), 3.70–3.98 (m, 3
H, 4-H, 6-HA, 6-HB), 1.33 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.28 (t,
J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR: δ = 186.7 (C-3),
171.1 (d, J = 19.1 Hz, C-1), 137.1, 136.4 (Cquat, Ph), 128.3, 128.1,
128.0, 127.8, 127.6 (Ph), 105.5 (d, J = 191.5 Hz, C-2), 81.2 (C-H),
73.5 (CH2Ph), 73.3 (d, J = 6.5 Hz, C-H), 71.9 (CH2Ph), 66.9 (C-
6), 62.3 (d, J = 6.0 Hz, OCH2CH3), 62.2 (d, J = 6.0 Hz,
OCH2CH3), 16.1 (d, J = 3.0 Hz, OCH2CH3), 16.0 (d, J = 3.0 Hz,
OCH CH ) ppm. IR (CHCl ): ν = 1684, 1581 cm–1. HRMS: calcd.
˜
2
3
3
for C24H29O7P [M + H]+: 461.1729; found 461.1731.
3-Oxo-2-phosphono-α-C-glycoside 6a: A 1.6 m solution of MeLi in
Et2O (Fluka, 0.2 mL, 0.36 mmol of MeLi) was added at 0 °C to a
stirred slurry of CuI (34 mg, 0.18 mmol) in dry Et2O (0.7 mL). 7.1 Hz, 3 H, (CH2)3CH3] ppm. 13C NMR: δ = 201.9 (C-3), 138.1,
After 10 min the mixture was cooled to –78 °C and a solution of
1a (33 mg, 0.07 mmol) in dry THF (0.7 mL) was added. After only
3 min TLC analysis (AcOEt) showed the complete disappearance
of the starting material. Saturated aqueous NH4Cl (1 mL) and
137.3 (Cquat, Ph), 128.4, 128.33, 128.27, 127.9, 127.7, 127.6 (Ph),
78.1, 74.8 (C-H), 74.2 (d, J = 3.4 Hz, C-1), 73.5, 73.4 (CH2Ph),
69.9 (C-6), 63.0 (d, J = 6.5 Hz, OCH2CH3), 62.7 (d, J = 6.5 Hz,
OCH2CH3), 57.6 (d, J = 125.5 Hz, C-2), 32.9 (d, J = 11.4 Hz,),
2674
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2671–2676

Stereoselective Michael-Type Addition of Organocopper Reagents to Enones
SHORT COMMUNICATION
27.4, 22.1 [(CH2)3CH3], 16.3, 16.2 (OCH2CH3), 13.9 (CH3) ppm. JAX = 6.4 Hz, 1 H, 6-HA), 3.72 (B of ABX, JBA = 9.6, JBX
=
IR (CHCl ): ν = 1721 cm–1. HPLC (n-hexane/AcOEt 1:1): t 7.8 6.4 Hz, 1 H, 6-HB), 2.05 (s, 3 H, OCOCH3), 1.65–2.04 (m, 2 H,
˜
3
Rα
(96%), tRβ 7.1 (4%). HRMS: calcd. for C28H39O7P [M + H]+: CH2CH3), 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.29 (t, J = 7.0 Hz,
519.2512; found 519.2526.
3 H, OCH2CH3), 1.04 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C
NMR: δ = 168.9 (C=O), 154.2 (d, J = 4.2 Hz, C-3), 138.0, 137.9
(Cquat, Ph), 128.36, 128.33, 128.1, 127.8, 127.6 (Ph), 123.5 (d, J =
171.3 Hz, C-2), 75.2 (d, J = 14.1 Hz, C-1), 73.6, 73.1 (CH2Ph), 70.5
(d, J = 9.9 Hz, C-4), 70.0 (C-5), 68.8 (C-6), 62.2 (d, J = 5.3 Hz,
OCH2CH3), 62.0 (d, J = 5.7 Hz, OCH2CH3), 24.5 (CH2CH3), 20.8
(CH3), 16.3 (d, J = 4.2 Hz, OCH2CH3), 16.1 (d, J = 4.9 Hz,
2-Phosphono-α-C-glycoside 9a: This compound was prepared from
1a (50 mg, 0.11 mmol) as in the procedure described for 6a. The
crude product, consisting of a mixture of ketonic and enolic com-
pounds, was treated with Ac2O (0.01 mL, 0.1 mmol) in Py (1 mL)
at 40 °C for 12 h. The solution was washed with H2O and brine,
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography (SiO2; n-hexane/AcOEt, 1:1) of the crude com-
pound gave 9a (38 mg, 0.06 mmol) as a viscous oil and as a 88:12
inseparable mixture of α/β diastereomers. Data for 9a. 1H NMR: δ
= 7.16–7.58 (m, 15 H, 3Ph), 5.58 (d, J = 5.0 Hz, 1 H, 1-H), 4.31–
4.62 (m, 5 H, 2 CH2Ph, 4-H), 3.63–4.06 (m, 5 H, 2 OCH2CH3, 5-
H), 3.56 (A of ABX, JAB = 10.9, JAX = 3.7 Hz, 1 H, 6-HA), 3.44
(B of ABX, JBA = 10.9, JBX = 2.7 Hz, 1 H, 6-HB), 2.18 (s, 3 H,
OCOCH3), 1.24 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.97 (t, J =
7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR: δ = 168.6 (C=O), 156.8
(d, J = 3.4 Hz, C-3), 137.8, 137.7, 137.6 (Cquat, Ph), 129.5, 128.5,
128.4, 128.3, 128.2, 128.0, 127.94, 127.89, 127.7 (Ph), 119.2 (d, J =
178.5 Hz, C-2), 75.7 (d, J = 11.8 Hz, C-1), 74.2, 73.3 (CH2Ph), 71.3
(d, J = 10.7 Hz, C-4), 70.4 (C-5), 68.7 (C-6), 62.2 (d, J = 5.7 Hz,
OCH2CH3), 62.0 (d, J = 5.7 Hz, OCH2CH3), 20.9 (CH3), 16.1 (d,
J = 6.5 Hz, OCH2CH3), 15.9 (d, J = 6.5 Hz, OCH2CH3) ppm. IR
OCH CH ), 10.7 (CH ) ppm. IR (CHCl ): ν = 1756 cm–1. HPLC
˜
2
3
3
3
(n-hexane/AcOEt, 1:1): tRα 15.9 (100%). HRMS: calcd. for
C28H37O8P [M + Na]+: 555.2124; found 555.2112.
2-Phosphono-α-C-glycoside 8b: This compound was prepared from
1b (50 mg, 0.11 mmol) as in the procedure described for 6b, fol-
lowed by column chromatography (SiO2; n-hexane/AcOEt, 60:40)
to give 8b (43 mg, 0.08 mmol, 70%) as a viscous oil and as an 94:6
1
inseparable mixture of α/β diastereomers. Data for 8b. H NMR: δ
= 7.21–7.42 (m, 10 H, 2 Ph), 4.49–4.69 (m, 5 H, 2 CH2Ph, 1-H),
4.18 (td, J5,6 = 6.3, J5,4 = 2.5 Hz, 1 H, 5-H), 3.96–4.15 (m, 4 H, 2
OCH2CH3), 4.02 (d, J4,5 = 2.5 Hz, 1 H, 4-H), 3.79 (A of ABX, JAB
= 9.8, JAX = 6.3 Hz, 1 H, 6-HA), 3.69 (B of ABX, JBA = 9.8, JBX
= 6.3 Hz, 1 H, 6-HB), 2.05 (s, 3 H, OCOCH3), 1.37–2.02 [m, 6 H,
(CH2)3CH3], 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.29 (t, J =
7.0 Hz, 3 H, OCH2CH3), 0.90 [t, J = 7.0 Hz, 3 H, (CH2)3CH3] ppm.
13C NMR: δ = 168.9 (C=O), 154.1 (d, J = 3.8 Hz, C-3), 138.0,
137.9 (Cquat, Ph), 128.3, 128.1, 127.7, 127.6 (Ph), 123.5 (d, J =
171.7 Hz, C-2), 73.8 (d, J = 13.7 Hz, C-1), 73.5, 73.1 (CH2Ph), 70.6
(d, J = 9.9 Hz, C-4), 70.0 (C-5), 68.8 (C-6), 62.1 (d, J = 5.3 Hz,
OCH2CH3), 61.9 (d, J = 5.7 Hz, OCH2CH3), 30.7, 28.3, 22.1
[(CH2)3CH3], 20.8 (CH3), 16.2 (d, J = 3.8 Hz, OCH2CH3), 16.1 (d,
(CHCl ): ν = 1757 cm–1. HPLC (n-hexane/AcOEt 1:1): t 17.4
˜
3
Rα
(88%), tRβ 19.8 (12%). HRMS: calcd. for C32H37O8P [M + H]+:
581.2304; found 581.2313.
2-Phosphono-α-C-glycoside 6b: This compound was prepared from
1b (35 mg, 0.08 mmol) as in the procedure described for 6a. The
crude product, consisting of a mixture of ketonic and enolic com-
pounds, was treated with Ac2O (0.01 mL, 0.1 mmol) in Py (1 mL)
at room temp. for 12 h. The solution was washed with H2O and
brine, dried (Na2SO4) and concentrated under reduced pressure.
Column chromatography (SiO2; n-hexane/AcOEt, 1:1) of the crude
compound gave 6b (29 mg, 0.06 mmol) as a viscous oil and as an
98:2 inseparable mixture of α/β diastereomers. Data for 6b. 1H
NMR: δ = 7.18–7.44 (m, 10 H, 2Ph), 4.67–4.83 (m, 1 H, 1-H), 4.63
(s, 2 H, CH2Ph), 4.59 (A of AB, JAB = 11.9 Hz, 1 H, HA of
CH2Ph), 4.51 (B of AB, JBA = 11.9 Hz, 1 H, HB of CH2Ph), 4.22
(td, J5,6 = 6.4, J5,4 = 2.6 Hz, 1 H, 5-H), 3.93–4.18 (m, 4 H, 2
OCH2CH3), 3.99 (d, J4,5 = 2.6 Hz, 1 H, 4-H), 3.73 (A of ABX, JAB
= 9.7, JAX = 6.4 Hz, 1 H, 6-HA), 3.69 (B of ABX, JBA = 9.7, JBX
J = 4.6 Hz, OCH CH ), 13.9 (CH ) ppm. IR (CHCl ): ν =
˜
2
3
3
3
1756 cm–1. HPLC (n-hexane/AcOEt, 1:1): tRα 12.6 (94%), tRβ 14.2
(6%). HRMS: calcd. for C30H41O8P [M + Na]+: 583.2437; found
583.2422.
2-Phosphono-α-C-glycoside 9b: This compound was prepared from
1b (50 mg, 0.11 mmol) as in the procedure described for 6b, fol-
lowed by column chromatography (SiO2; n-hexane/AcOEt, 60:40)
to give 9b (44 mg, 0.08 mmol, 70%) as a viscous oil and as an 97:3
1
inseparable mixture of α/β diastereomers. Data for 9b. H NMR: δ
= 7.10–7.58 (m, 15 H, 3 Ph), 5.61 (d, J = 5.3 Hz, 1 H, 1-H), 4.7 (s,
2 H, CH2Ph), 4.39 (A of AB, JAB = 11.7 Hz, 1 H, HA of CH2Ph),
4.35 (B of AB, JBA = 11.7 Hz, 1 H, HB of CH2Ph), 3.97–4.16 (m,
4 H, OCH2CH3, 4-H, 5-H), 3.67–3.92 (m, 2 H, HA of OCH2CH3,
6-HA), 3.42–3.64 (m, 2 H, HB of OCH2CH3, 6-HB), 2.14 (s, 3 H,
OCOCH3), 1.29 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.88 (t, J =
7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR: δ = 169.4 (C=O), 155.8
(d, J = 3.4 Hz, C-3), 137.9, 137.8, 137.1 (Cquat, Ph), 129.4, 128.5,
128.35, 128.27, 128.2, 127.8, 127.7, 127.6 (Ph), 121.4 (d, J =
176.6 Hz, C-2), 75.9 (d, J = 12.2 Hz, C-1), 73.6, 73.2 (CH2Ph), 70.6
(d, J = 9.9 Hz, C-4), 69.8 (C-5), 68.3 (C-6), 62.3 (d, J = 5.7 Hz,
OCH2CH3), 62.1 (d, J = 5.7 Hz, OCH2CH3), 20.8 (CH3), 16.2 (d,
J = 6.5 Hz, OCH2CH3), 15.8 (d, J = 6.1 Hz, OCH2CH3) ppm. IR
= 6.4 Hz, 1 H, 6-HB), 2.05 (s, 3 H, OCOCH3), 1.50 (d, JMe,1
=
6.6 Hz, 1 H, CH3), 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.29 (t, J
= 7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR: δ = 169.0 (C=O), 154.2
(d, J = 3.8 Hz, C-3), 138.0, 137.9 (Cquat, Ph), 128.4, 128.3, 128.2,
127.83, 127.77, 127.7 (Ph), 123.9 (d, J = 171.3 Hz, C-2), 73.6, 73.4
(CH2Ph), 70.5 (d, J = 9.9 Hz, C-4), 70.3 (C-5), 70.2 (d, J = 13.7 Hz,
C-1), 68.6 (C-6), 62.2 (d, J = 5.3 Hz, OCH2CH3), 62.0 (d, J =
5.3 Hz, OCH2CH3), 20.8 (CH3), 18.5 (CH3), 16.3 (d, J = 3.8 Hz,
OCH CH ), 16.1 (d, J = 4.2 Hz, OCH CH ) ppm. IR (CHCl ): ν
˜
2
3
2
3
3
= 1758 cm–1. HPLC (n-hexane/AcOEt, 1:1): tRα 20.5 (98%), tRβ
18.2 (2%). HRMS: calcd. for C27H35O8P [M + Na]+: 541.1967;
found 541.1973.
(CHCl ): ν = 1758 cm–1. HPLC (n-hexane/AcOEt, 1:1): t 15.8
˜
3
Rα
(97%), tRβ 18.3 (3%). HRMS: calcd. for C32H37O8P [M + H]+:
581.2304; found 581.2302.
2-Phosphono-α-C-glycoside 7b: This compound was prepared from
1b (45 mg, 0.10 mmol) as in the procedure described for 6b, fol-
lowed by column chromatography (SiO2; n-hexane/AcOEt, 60:40)
to give 7b (37 mg, 0.07 mmol, 70%) as a viscous oil. Data for 7b.
Acknowledgments
1
[α]2D0 = –93.2 (c = 2.3, CHCl3). H NMR: δ = 7.20–7.40 (m, 10 H,
The financial support of “La Sapienza” University, Rome is grate-
fully acknowledged. We thank Prof. M. Delfini of “La Sapienza”
University, Rome and Dr. G. Mancini of CNR “Istituto di Meto-
2 Ph), 4.50–4.68 (m, 4 H, 2 CH2Ph), 4.37–4.50 (m, 1 H, 1-H), 3.91–
4.26 (m, 6 H, 2 OCH2CH3, 4-H, 5-H), 3.76 (A of ABX, JAB = 9.6,
Eur. J. Org. Chem. 2005, 2671–2676
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2675

F. Leonelli, M. Capuzzi, V. Calcagno, P. Passacantilli, G. Piancatelli
SHORT COMMUNICATION
[6] A. Kirschning, J. Org. Chem. 1995, 60, 1228–1232.
[7] C. R. Johnson, J. P. Adams, M. P. Braun, C. B. W. Senanayake,
P. M. Wovkulich, M. R. Uskokovic´, Tetrahedron Lett. 1992, 33,
917–918.
[8] M. A. Kazankova, I. G. Trostyanskaya, S. V. Lutsenko, I. V. Ef-
imova, I. P. Beletskaya, Russ. J. Org. Chem. 1999, 35, 428–434.
[9] The α/β diastereoselectivity was improved when the reactions
were carried out in a 1:1 Et2O/THF solution instead of only
Et2O (Table 1, entries 2 and 3).
[10] We obtained a single diastereoisomer at C(2) as demonstrated
by the diastereoisomeric ratios of the acetalization reactions
performed on 7a and 8a (note c, Table 1).
[11] Partial conversion of the starting enone 4a was achieved only
at higher temperatures and longer reaction times.
[12] The presence of THF in the reaction mixture also improved
the α/β diastereoselectivity in this case (Table 2, entry 4).
[13] The addition reaction on enone 4b required higher tempera-
tures and longer times as in the case of 4a.
dologie Chimiche-Sezione Meccanismi di Reazione” for helpful
discussions about NOESY experiments.
[1] Inter alia: a) T. E. Goodwin, C. M. Crowder, R. B. White, J. S.
Swanson, F. E. Evans, W. L. Meyer, J. Org. Chem. 1983, 48,
376–380 and references cited therein; b) H. Kunz, B. Müller, J.
Weissmüller, Carbohydr. Res. 1987, 171, 25–34; c) V. Bellosta,
S. Czernecki, Carbohydr. Res. 1987, 171, 279–288; d) K.
Michael, H. Kessler, Tetrahedron Lett. 1996, 37, 3453–3456 and
references cited therein; e) A. Kirschning, J. Harders, Synlett
1996, 772–774; f) A. K. Sanki, T. Pathak, Tetrahedron 2003, 59,
7203–7214 and references cited therein; g) J. M. Gardiner, R.
Mills, T. Fessard, Tetrahedron Lett. 2004, 45, 1215–1217; h) K.
Pachamuthu, I. Figueroa-Perez, I. A. I. Ali, R. Schmidt, Eur.
J. Org. Chem. 2004, 3959–3961 and references cited therein.
[2] K. Pachamuthu, A. Gupta, J. Das, R. R. Schmidt, Y. D. Van-
kar, Eur. J. Org. Chem. 2002, 1479–1483.
[3] For reviews see: D. E. Levy, C. Tang, The Chemistry of C-Gly-
cosides, Pergamon, 1995, vol. 13; M. H. D. Postema, C-Glyco-
side Synthesis CRC Press: London, UK, 1995.
[14] H. Paulsen, H. Büensch, Chem. Ber. 1978, 111, 3484–3496.
[15] C.-W. T. Chang, Y. Hui, B. Elchert, Tetrahedron Lett. 2001, 42,
7019–7023 and references cited therein.
[4] Inter alia: a) R. Engel, Chem. Rev. 1977, 77, 349–367 and refer-
ences cited therein; b) H. D. Junker, W. D. Fessner, Tetrahedron
Lett. 1998, 39, 269–272 and references cited therein; c) A. Don-
doni, A. Marra, C. Pasti, Tetrahedron: Asymmetry 2000, 11,
305–317 and references cited therein; d) F. Orsini, A. Caselli,
Tetrahedron Lett. 2002, 43, 7259–7261 and references cited
therein.
[16] V. Bellosta, S. Czernecki, M. C. Perlat, J. Carbohydr. Chem.
1988, 7, 141–149.
[17] A. Fürstner, Liebigs Ann. Chem. 1993, 1211–1217.
[18] G. Capozzi, C. Falciani, S. Menichetti, C. Nativi, B. Raffaelli,
Chem. Eur. J. 1999, 5, 1748–1754.
Received: March 01, 2005
Published Online: May 24, 2005
[5] a) T. Minami, J. Motoyoshiya, Synthesis 1992, 333–349; b) T.
Hayashi, T. Senda, Y. Takaya, M. Ogasawara, J. Am. Chem.
Soc. 1999, 121, 11591–11592.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2671–2676