Neo-glycoconjugates: Stereoselective synthesis of α-glycosyl amides via Staudinger ligation reactions

Article abstract of DOI:10.1016/j.tetasy.2004.11.055

α-Glycosyl azides can be transformed in the corresponding α-glycosyl amides with good yields and selectivity via reduction-acylation (Staudinger ligation) reactions using funtionalised phosphines 1a-f. The limits and scope of this approach for the synthes

Full text of DOI:10.1016/j.tetasy.2004.11.055

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 381–386
Neo-glycoconjugates: stereoselective synthesis of a-glycosyl
amides via Staudinger ligation reactions
Aldo Bianchi, Andrea Russo and Anna Bernardi*
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Received 3 November 2004; accepted 22 November 2004
Available online 5 January 2005
Abstract—a-Glycosyl azides can be transformed in the corresponding a-glycosyl amides with good yields and selectivity via reduc-
tion–acylation (Staudinger ligation) reactions using funtionalised phosphines 1a–f. The limits and scope of this approach for the
synthesis of a-glycosyl amides are reported.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the product, and to synthesise a-glycosyl amides avoid-
ing the formation of the intermediate free amines.2–7
Much work has been devoted to the Staudinger ligation
reaction, that is, the reduction of glycosyl azides with
trialkyl or triarylphosphines in the presence of carbox-
ylic acids or derivatives, which can trap the aza-ylide
(iminophosphorane) intermediate before the free amine
is formed. However, in most cases, anomerisation
remains a significant problem also for Staudinger inter-
mediates and b-amides or mixtures of anomers are
obtained.5
It has been recently shown that the conformation of the
peptide in a-and b-N-linked glycopeptides is uniquely
influenced by the attached sugar in ways that depend
on the configuration of the carbohydrate–peptide link-
age.1 The stereoselective synthesis of neo-glycoconju-
gates in the ꢀunnaturalꢁ a configuration has therefore
become of great interest as a means of designing glyco-
peptide mimetics, which can be useful as probes or
inhibitors of glycosyltransferases. The stereoselective
synthesis of a-glycosyl amides has proven difficult be-
cause glycosyl amines are not configurationally stable
and undergo easy anomerisation (Scheme 1).
We have recently reported8 the first general methodol-
ogy for reductive acetylation of a-glycosyl azides that
proceeds with complete retention of configuration at
the anomeric carbon using the functionalised phosphine
1a.9,10 The reaction could be applied to O-benzyl glycos-
yl azides in the fuco-, gluco- and galacto-series with
good yield and selectivity (Scheme 2).8
O
O
O
RO
RO
RO
N3
NH2
NHCOR'
PPh2
OBn
O
OBn
O
O
O
OAc
NHCOR'
NH2
RO
RO
BnO
BnO
BnO
BnO
+
BnO
N3
BnO
NHAc
Scheme 1. a ! b Isomerisation of anomeric amines precludes the
stereoselective synthesis of a-glycosyl amides.
1a
3a
2
Scheme 2. Stereoselective synthesis of a-glycosyl acetamides.
Various methods have been proposed to circumvent this
process, which destroys the stereochemical integrity of
We have now explored the limits and scope of this ap-
proach for the synthesis of other a-glycosyl amides
and our results are reported herein.
*
Corresponding author. Tel.: +39 02 50314092; fax: +39 02 50314072;
e-mail: anna.bernardi@unimi.it
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.055

382
A. Bianchi et al. / Tetrahedron: Asymmetry 16 (2005) 381–386
PPh2
PPh2
OMOM
OMOM
O
R
BuLi, TMEDA
Ph2PCl
1. HCl in MeOH
2. RCOCl, TEA
O
1b R: -(CH2)3CH3
1c R: -CH2CH(CH3)2
1d R: -CH(CH3)2
4
5
1e R: -CH=C(CH3)2
Scheme 3. Synthesis of acyl phosphines 1b–e.
2. Results and discussion
(no cross-peak) and in the proton decoupled 13C
NMR APT spectrum (a singlet for C-1). Similarly, the
minor compound m shows a broad doublet at
5.36 ppm (JH1–H2 = 4.1 Hz) for H-1 correlated to a peak
at 80.1 ppm for C-1 in the 13C spectrum. The phospho-
rus nucleus of m gives a signal at 27.1 ppm, which shows
no correlation to H-1 or C-1.
The functionalised phosphines 1b–e (Scheme 3) were
synthesised as previously reported8–11 starting from
o-diphenylphosphinophenol. All the reagents are easily
synthesised and handled, and can be conserved at 4 °C
for several weeks, either pure or as a 1 M solution in
toluene.
The accepted mechanism for the Staudinger reduction of
azides with phosphines12 requires the formation of two
different intermediates: initially, a phosphotriazene
(phosphotriazadiene) is formed by nucleophilic attack
of phosphorus on the distal nitrogen of the azide
(Scheme 5, 6). This intermediate is stabilised by electron
donating groups on the phosphine, or electron with-
drawing groups on the azide, or sterically hindering
groups on both phosphine and azide.13 Phosphotriaza-
dienes have been isolated from Staudinger azide reduc-
tions and characterised by X-ray crystallography and
other techniques:5,12–14 they all have been found to be
consistent with a zwitterionic structure corresponding
to 7 (Scheme 5) displaying a partial double bond charac-
ter of the central N–N linkage. The E configuration of
the N–N double bond (Scheme 5, 7-E) is generally ob-
served. In the reaction mixture 7-E can isomerise to
the Z isomer 7-Z, which spontaneously decomposes to
afford N2 and the iminophosphorane 8. Glycosyl imino-
phosphoranes are rather stable, and some have been isol-
ated and characterised by NMR spectroscopy.5 In the
presence of acylating agents, the iminophosphorane re-
acts at nitrogen, to give, after hydrolysis, the corre-
sponding amide. In the present case, intramolecular
trapping of the iminophosphorane should occur to af-
ford 9. Likely, this process is faster than anomeric equili-
bration of 8, thus allowing for retention of the anomeric
configuration of the starting azide. Decomposition of 9,
either spontaneous or induced by water quenching, af-
fords the desired a-glycosylamide 3 and the phosphinox-
ide by-product.
The a-glucosyl azide 2 was chosen as the model sub-
strate for the Staudinger ligation reaction (Scheme 4).
Our previous studies had shown8 that 2 reacts with 1a
in various solvents (CCl4, toluene, CHCl3) to give the
a-glucosyl acetamide 3a in 77% yield after 24 h at
70 °C. Under the same conditions the reaction between
2 and the n-pentanoate 1b afforded only 24% of the ex-
pected n-pentanamide 3b. The major reaction product
was
a stable, phosphorus-containing intermediate,
which could be isolated by flash chromatography on sil-
ica gel. Once purified, the intermediate spontaneously
evolved to the desired a-pentanamide 3b in a few hours
at room temperature, but the transformation could not
be induced in the reaction mixture under various condi-
tions of solvent (CCl4, CHCl3, toluene), temperature, or
time (up to 36 h at 70 °C).
OBn
O
OBn
O
PPh2
BnO
BnO
O
R
BnO
BnO
+
BnO
N3
BnO
NHCOR
O
1b R: -(CH2)3CH3
1c R: -CH2CH(CH3)2
1d R: -CH(CH3)2
3b R: -(CH2)3CH3
3c R: -CH2CH(CH3)2
3d R: -CH(CH3)2
2
1e R: -CH=C(CH3)2
3e R: -CH=C(CH3)2
Scheme 4. Staudinger ligation of 1-azido-2,3,4,6-tetra-O-benzyl-a-D-
glucopyranose 2 with phosphines 1b–e.
NMR analysis of the isolated intermediate revealed two
compounds, M and m, in 84:16 ratio. The two com-
pounds could not be separated by chromatography
and, once isolated, appeared (by NMR spectroscopy)
to transform to the final product without appreciable
modification of their initial ratio. In the 31P NMR spec-
trum the major isomer M is characterised by a signal at
27.4 ppm. In the 1H NMR spectrum its anomeric proton
appears as a doublet at 5.07 ppm (JH1–H2 = 4.1 Hz)
The NMR data collected for the intermediate M and m
in the reaction between 2 and 1b are consistent with the
phosphotriazadiene structure 7, because no coupling is
observed between the phosphorus nucleus and either
the anomeric proton or carbon. Coupling constants
JC1–P and JH1–P of ca. 20 Hz have been reported in the
literature for glycosyl iminophosphoranes.5 The JH1–H2
values observed for both intermediates is of ca. 4 Hz,
consistent with the expected value for a cis relationship
between H-1 and H-2 in both compounds. Hence M and
m do not appear to be anomeric epimers of 7. It is there-
fore likely that the two compounds correspond to the
1
correlated in the Hetcor H–13C spectrum to a peak at
83.5 ppm. Neither the anomeric proton (H-1) nor the
anomeric carbon (C-1) display any correlation to the
31P signal, as shown in the Hetcor 1H–31P spectrum

A. Bianchi et al. / Tetrahedron: Asymmetry 16 (2005) 381–386
383
OBn
O
OBn
O
PPh2
BnO
BnO
BnO
BnO
O
R
+
BnO
BnO
O
N
N3
N
PPh2
N
6
2
ROCO
ROCO
Ph2P
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
N
N
N
N
N
PPh2
N
ROCO
7-Z
7-E
N2
OBn
O
OBn
O
OBn
O
COR
O
BnO
BnO
BnO
BnO
O
H2O
BnO
BnO
BnO
BnO
N
N
Ph2P
BnO
NHCOR
ROC Ph2P
O
3
8
9
PPh2
OH
Scheme 5. Proposed mechanism for the intramolecular Staudinger ligation of 2.
two isomers 7-E and 7-Z of the phosphotriazadiene
intermediate. MALDI and ESI mass spectrometry show
for the 84:16 M and m mixture a single molecular ion at
m/z 922.3 (M+Na+), which is consistent with the imino-
phosphorane structure. However, considering the results
of the NMR analysis, it is likely that this compound is
obtained in the spectrometer upon ionisation-induced
nitrogen loss.
Table 1. Staudinger ligation of the glycosyl azide 2 with phosphines
1b–ea
Phosphine
Product
Yield (%)
a/b ratiob
1b
1c
1d
1e
3b
3c
3d
3e
60
70
40c
65
84:16
83:17
84:16
85:15
a Reactions were run at 70 °C in CHCl3 (0.1 M). After disappearance
of the starting material (ca. 1 h), the mixtures were irradiated with a
sunlamp for 1 h at 70 °C.
Although this partial analysis was not sufficient to fully
characterise the reaction intermediates, it suggested that
the phosphotriazadiene–iminophosphorane rearrange-
ment and nitrogen loss, that appeared to occur sponta-
neously and at room temperature from the isolated
triazadiene, is inhibited by some unknown element in
the reaction mixture. Efforts to identify the inhibiting
agent or to accelerate the nitrogen loss by increasing
the reaction temperature, or by providing acid catalysis
(to accelerate E to Z isomerisation of the phosphotriaza-
diene) were unsuccessful. We found, however, that sun-
light appeared to accelerate the decomposition of the
intermediates, and indeed when the Staudinger ligation
of 2 with 1b was carried out in CHCl3, at 70 °C and un-
der an ordinary sunlamp (Philips HPL 250 W, mercury
with magnesium arsenate), clean conversion to the prod-
uct amide 3b occurred in 1 h. After flash chromatogra-
phy, the reaction product was isolated in 60% yield as
a 84:16 a/b mixture. Under the same conditions, conver-
sion could be obtained also with the other phosphines
1c–e (see Table 1) to give the corresponding a-amides
in good to moderate yields. The reaction appears to be
rather sensitive to steric and electronic factors. For in-
b Determined by 1H NMR.
c After 24 h irradiation. 15% of triazadiene intermediate was also
isolated.
stance, synthesis of the i-butanamide 3d required a much
longer irradiation time (24 h) to achieve modest yields
(40%). On the contrary, the 3,3-dimethylacriloyl substi-
tuted phosphine 1e reacted much faster with 2 and the
reaction product 3e could be obtained also without irra-
diation (data not shown).
In all cases, the a-amide was the prevailing product in
the reaction crude, as judged by H NMR. Chromato-
1
graphic purification of the a isomer was generally possi-
ble using flash chromatography. Amides 1b–e (like 1a)
appear to adopt a 4C1 conformation, and their anomeric
configuration could be assigned based on the H1–H2
coupling constant, which is, in all cases of ca. 5 Hz.
N-Linked glycopeptides are connected to the pep-
tide aglycon via the side chain of an Asn residue.15

384
A. Bianchi et al. / Tetrahedron: Asymmetry 16 (2005) 381–386
PPh2
OBn
O
OH
O
PPh2
O
2
EDC
O
10
BnO
BnO
O
NHCbz
OMe
OMe
NHCbz
BnO
NH
O
+
HO
O
OMe
NHCbz
1f
3f
O
11
Scheme 6. Synthesis of 3f.
N-Glycosylation of aspartic acid side chain appears
therefore particularly useful to obtain neo-glycopep-
tides. For this purpose o-diphenylphosphinophenol 10
was acylated with Cbz-L-aspartic acid 1-methyl ester
11 using N-(3-dimethylaminopropyl)-N0-ethylcarbodi-
imide (EDC) as the condensing agent. The correspond-
ing acyl phosphine 1f was used for the reduction–
acylation of 2 (Scheme 6).
chain to be ligated appears to slow down the reaction,
whereas transfer of unsaturated acyl chains appears to
be very facile. The low reactivity of the acylating agent
can often be overcome by irradiating the reaction mix-
ture with a simple sunlamp. When irradiation fails to
achieve the desired effect, the most efficient procedure
for the Staudinger ligation consists in isolating the reac-
tion intermediate (likely, a mixture of phosphotriazadi-
enes) and allowing it to evolve spontaneously to the
amide products.
In this case, acyl transfer appeared to be particularly
sluggish. After 10 h irradiation at 70 °C in toluene, only
10–20% of 3f was isolated together with a 1:1 mixture of
two intermediates. NMR spectroscopy of the intermedi-
ates showed two anomeric protons: the first one as a
doublet at 5.35 ppm (JH1–H2 = 4.1 Hz) with no correla-
tion with the phosphorous atom (no cross-peak in the
4. Experimental
Solvents were dried by standard procedures. Solvents
used to synthesise and manipulate phosphines were
degassed and saturated with Ar. Reactions requiring
anhydrous conditions were performed under Ar. 1H,
13C and 31P NMR spectra were recorded at 300 K, un-
less otherwise noted, on a Bruker AVANCE-500, Bru-
ker AVANCE-400 or Bruker AC-200 spectrometer.
1
Hetcor H–31P spectrum), the second one as a doublet
of doublets at 4.92 ppm with JH1–H2 = JH1–P = 1.5 Hz.
This value for the JH1–P coupling constant is not consis-
tent with an iminophosphorane structure.5 Therefore
the two isolated intermediates could be again assigned
as the two phosphotriazadiene isomers. This hypothesis
was confirmed by the analysis of the 13C NMR spec-
trum, which showed two singlets (at 80.2 and
82.6 ppm) for the two anomeric carbons.
1
Chemical shifts d for H and 13C are expressed in ppm
relative to internal Me4Si as standard. Chemical shifts
d for 31P are expressed in ppm relative to internal
H3PO4 as standard. Signals were abbreviated as s, sin-
glet; bs broad singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. Mass spectra were obtained with a MAL-
DI-TOF (OMNIFLEX Bruker) or an ESI (LCQ
Advantage Termofinnigan) apparatus. Optical rotations
were measured in a cell of 1 dm pathlength and 1 mL
capacity with a Perkin–Elmer 241 polarimeter. IR spec-
tra were recorded on a JASCO FT/IR-300E spectro-
meter, and frequencies are expressed in cmÀ1. Thin layer
chromatography (TLC) was carried out with precoated
Merck F254 silica gel plates. Flash chromatography
(FC) was carried out with Macherey–Nagel silica gel
60 (230–400 mesh). The O-benzyl glucosyl azide 2,8,16
the methoxymethylphenyl ether 417 and the phosphine
511a were synthesised as described in the literature.
Further experimentation failed to uncover appropriate
conditions to induce the transfer in the reaction mix-
ture.ꢂ However, as already observed in the synthesis of
3b, also in this case conversion of the intermediates oc-
curred spontaneously after chromatographic isolation.
Thus the best conditions for conversion of 2 in 3f in-
volve treatment with 1f at 70 °C for 1 h, followed by
chromatographic isolation of the intermediates, which
are then converted to 3f (86:14 a/b) by stirring over
night in CHCl3 (75% yield from 2).
3. Conclusion
In conclusion, phosphines 1 have been shown to be gen-
eral-scope Staudinger ligation agents for a-glycosyl
azides and to afford the corresponding a-amides with
good stereoselectivity for a broad range of acyl chains.
Thus the first general method for the stereoselective syn-
thesis of a-glycosyl amides from the corresponding a-
azides has been established. Steric hindrance of the acyl
4.1. Synthesis of the o-diphenylphosphinophenol 10
Five millilitres of dry methanol were saturated with gas-
eous HCl. Methoxymethyl o-diphenylphosphinophenyl
ether 5 (760 mg, 2.36 mmol) was added at room temper-
ature and under Ar. The resulting solution was stirred for
1 h then the solvent was evaporated giving a yellow oil.
The residue was dissolved in AcOEt and washed with
saturated NaHCO3.11b The organic layer was dried over
Na2SO4 and concentrated. The residue was dissolved in
dry MeOH (3 mL), then water was added until the cloud
point was reached. The solution was stirred under Ar
while cooling, and the resulting white solid was filtered
ꢂ The conditions tried include: increasing the reaction temperature to
110 °C, changing the solvent from toluene to CHCl3, irradiating the
mixture at 70 °C with a Xenon lamp, using different protecting
groups on the amino acid.

A. Bianchi et al. / Tetrahedron: Asymmetry 16 (2005) 381–386
385
1
to give 10 in 77% yield. H NMR (400 MHz, CDCl3):
7.43–7.26 (m, 11H), 7.05–6.86 (m, 3H), 6.42 (bs, 1H,
o-diphenylphosphinophenol 10 (1 equiv), the protected
amino acid 11 (1.2 equiv) and DMAP (0.1 equiv) in
dry CH2Cl2 (0.1 M) was added, at room temperature
and under Ar. The mixture was stirred at room temper-
ature for 2 h, monitoring by TLC (6:4 hexane/AcOEt).
The reaction mixture was diluted with CH2Cl2 and ex-
tracted with 10% HCl and water: the organic layer was
dried over Na2SO4 and concentrated. The crude product
was purified by flash chromatography using 6:4 hexane/
AcOEt as the eluent to afford 1f in 85% yield. 1H NMR
(400 MHz, CDCl3): 7.39–7.24 (m, 11H), 7.17–7.08 (m,
2H), 6.86 (m, 1H), 5.77 (d, 1H, NH, J = 8.9 Hz), 5.17
(d, 1H, CH2–Ph, J = 12.3 Hz), 5.12 (d, 1H, CH2–Ph,
J = 12.3 Hz), 4.61 (m, 1H, CH), 3.70 (s, 3H, COOMe),
3.04 (dd, 1H, CH2–COO, J = 5.1, 17.4 Hz), 2.75 (dd,
1H, CH2–COO, J = 4.4, 17.0 Hz); 13C NMR
(50.3 MHz, CDCl3): 171.1, 169.3, 156.2, 152.8, 152.5,
136.4, 135.6, 135.5, 135.4, 135.3, 134.3, 134.2, 133.91,
133.88, 130.5, 130.3, 130.2, 129.4, 129.3, 128.9, 128.8,
128.7, 128.4, 128.3, 126.7, 122.61, 122.57, 67.3, 53.0,
50.4, 36.6; 31P NMR (161 MHz, CDCl3): À15.65
(+28.2 oxide).
OH). 31P NMR (160 MHz, CDCl3): À26.6 (+40.7 oxide).
4.2. General procedure for the synthesis of the 2-diphen-
ylphosphanyl-phenyl esters 1b–e
To a solution of the o-diphenylphosphinophenol 10
(1 equiv) in dry CH2Cl2 (0.1 M) at room temperature
and under Ar, dry Et3N (1.1 equiv) and the acyl chloride
(1.1 equiv) were added. The reaction mixture was stirred
at room temperature and monitored by TLC (9:1 hex-
ane/AcOEt) until disappearance of 10 (ca. 1 h). The sol-
vent was then evaporated under reduced pressure and
the residue was diluted with AcOEt and extracted with
5% NaHCO3 and water. The organic layer was dried
over Na2SO4 and concentrated. The crude product
was used for the Staudinger ligation. Analytical samples
were purified by flash chromatography using 8:2 hexane/
AcOEt as the eluent.
4.2.1.
2-Diphenylphosphanyl-phenyl
pentanoate
1
1b. Yield = 96%; H NMR (400 MHz, CDCl3): 7.40–
7.31 (m, 11H), 7.19–7.12 (m, 2H), 6.86–6.82 (m, 1H),
2.28 (t, 2H, CH2, J = 7.5 Hz), 1.51 (m, CH2), 1.29 (m,
CH2), 0.89 (t, 3H, CH3, J = 7.5 Hz); 13C NMR
(50.3 MHz, CDCl3): 171.8, 153.2, 134.7, 134.5, 134.0,
133.9, 133.8, 132.2, 131.8, 130.1, 129.2, 128.9, 128.8,
128.7, 126.2, 125.9, 125.7, 122.8, 33.9, 26.7, 22.3, 13.9;
31P NMR (161 MHz, CDCl3): À14.8 (+27.2 oxide).
4.4. General procedure for the synthesis of the a-glucosyl
amides 3b–e
To a solution of 2 (1 equiv) in CHCl3 (0.1 M) a 1 M
solution in dry toluene of the acylphosphine 1b–e
(1.2 equiv) was added. The mixture was heated to
70 °C for 1 h (until disappearance of 2 from the TLC
plate; 8:2 toluene/AcOEt) and then irradiated for 1 h
with a Philips HPL 250W sunlamp (24 h for product
3d). The crude was diluted with AcOEt, stirred with
H2O for a few minutes, then the phases were separated
and the organic layer washed with water. The solution
was dried over Na2SO4, and the solvent evaporated to
yield crudes that were purified by flash chromatography
(7:3 petroleum ether/AcOEt) to give the a-glucosyl
amides with the yields and anomeric ratios reported in
Table 1.
4.2.2. 2-Diphenylphosphanyl-phenyl 3-methyl-butanoate
1c. Yield = 97%; H NMR (400 MHz, CDCl3): 7.42–
1
7.32 (m, 11H), 7.20–7.12 (m, 2H), 6.88–6.83 (m, 1H),
2.17 (d, 2H, CH2, J = 7.0 Hz), 2.05 (m, 1H, CH), 0.94
(d, 6H, 2CH3, J = 7.0 Hz); 13C NMR (50.3 MHz,
CDCl3): 171.1, 134.2, 133.9, 132.0, 131.8, 130.1, 129.2,
128.9, 128.8, 128.7, 126.2, 122.74, 122.71, 43.0, 25.5,
22.6; 31P NMR (161 MHz, CDCl3): À15.0 (+27.1 oxide).
4.2.3. 2-Diphenylphosphanyl-phenyl i-butanoate 1d.
Yield = 87%; 1H NMR (400 MHz, CDCl3): 7.42–7.26
(m, 11H), 7.18–7.12 (m, 2H), 6.83–6.78 (m, 1H), 2.55
(m, 1H, CH, J = 7.0 Hz), 1.10 (d, 6H, 2CH3,
J = 7.0 Hz); 13C NMR (50.3 MHz, CDCl3): 175.0,
134.4, 133.8, 130.1, 129.2, 129.1, 128.8, 128.7, 126.2,
122.64, 122.61, 34.3, 18.82, 18.80; 31P NMR
(161 MHz, CDCl3): À15.05 (+28.9 oxide).
4.4.1. 3b. 1H NMR (400 MHz, CDCl3): 7.43–7.12 (m,
20H, aromatics), 6.09 (d, 1H, NH, J1-NH = 6.8 Hz),
5.85 (dd, 1H, H1, J1-NH = 6.8 Hz, J1–2 = 5.5 Hz), 4.97–
4.79 (m, 4H, –CH2Ph), 4.69–4.47 (m, 4H, –CH2Ph),
0
3.88–3.60 (m, 6H, H2, H3, H4, H5, H6 and H6 ), 2.25
(t, 2H, –CH2–, J = 6.8 Hz), 1.64 (m, 2H, –CH2–), 1.37
(m, 2H, –CH2–), 0.92 (t, 3H, –CH3, J = 6.8 Hz); 13C
NMR (50.3 MHz, CDCl3): 174.2, 138.7, 138.2, 137.4,
129.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9,
82.3, 75.7, 75.3, 74.5, 73.8, 72.7, 71.3, 68.5, 36.8, 29.9,
4.2.4. 2-Diphenylphosphanyl-phenyl 3-methyl-but-2-eno-
ate 1e. Yield = 84%; 1H NMR (400 MHz, CDCl3):
7.43–7.32 (m, 11H), 7.22–7.12 (m, 2H), 6.93–6.86 (m,
1H), 5.69 (m, 1H, CH@C(CH3)2), 2.09 (d, 3H, CH3,
J = 1.2 Hz), 1.90 (d, 3H, CH3, J = 1.2 Hz); 13C NMR
(50.3 MHz, CDCl3): 164.3, 159.9, 134.4, 134.0, 133.83,
183.80, 130.0, 129.0, 128.8, 128.7, 128.6, 128.5, 126.0,
123.04, 122.99, 115.0, 27.7, 20.6; 31P NMR (161 MHz,
CDCl3): À14.8 (+26.8 oxide).
27.8, 22.6, 14.0; ESI-MS: 646.6 (M+Na+); IR (Nujol):
25
D
3426, 1654; ½aŠ ¼ þ47:6 (c 1.0, CHCl3).
4.4.2. 3c. 1H NMR (400 MHz, CDCl3): 7.38–7.14 (m,
20H, aromatics), 6.21 (d, 1H, NH, J1-NH = 6.7 Hz),
5.88 (dd, 1H, H1, J1-NH = 6.7 Hz, J1–2 = 5.0 Hz), 4.98–
4.49 (m, 8H, –CH2Ph), 3.90–3.63 (m, 6H, H2, H3, H4,
0
H5, H6 and H6 ), 2.20–2.11 (m, 3H, –CH2– and –CH–),
4.3. Synthesis of 1f
0.97 (d, 6H, 2 –CH3); 13C NMR (50.3 MHz, CDCl3):
173.5, 138.5, 138.1, 137.3, 128.8, 128.6, 128.4, 128.1,
128.0, 127.8, 127.7, 86.2, 82.1, 77.6, 77.5, 76.5, 75.5,
75.2, 74.6, 74.5, 73.6, 72.5, 71.2, 68.3, 46.1, 26.2, 22.5;
To a suspension of EDCÆHCl (1.4 equiv) and dry
i-Pr2EtN (1.4 equiv) in dry CH2Cl2, a solution of the

386
A. Bianchi et al. / Tetrahedron: Asymmetry 16 (2005) 381–386
ESI-MS 624.5 (M+H+), 646.7 (M+Na+), 662.5 (M+K+);
IR (Nujol): 3383, 1652; ½aŠ ¼ þ56:3 (c 0.5, CHCl3).
4.4.3. 3d. 1H NMR (400 MHz, CDCl3): 7.37–7.12 (m,
20H, aromatics), 6.12 (d, 1H, NH, J1-NH = 6.6 Hz),
5.83 (dd, 1H, H1, J1-NH = 6.6 Hz, J1–2 = 5.0 Hz), 5.01–
4.43 (m, 8H, –CH2Ph), 3.93–3.58 (m, 6H, H2, H3, H4,
COOMe), 2.97 (dd, 1H, CH2–COO, J = 5.1, 15.7 Hz),
2.75 (dd, 1H, CH2–COO, J = 4.7, 15.7 Hz); 13C NMR
(50.3 MHz, CDCl3): 171.6, 171.5, 171.0, 138.6, 138.2,
138.1, 137.3, 129.2, 129.1, 129.0, 128.8, 128.7, 128.63,
128.60, 128.4, 128.3, 128.2, 128.1, 128.0, 127.92,
127.89, 82.1, 79.6, 78.6, 77.7, 77.1, 76.6, 75.7, 75.2,
73.7, 72.9, 71.5, 68.5, 67.3, 53.0, 50.9, 38.3; MALDI-
25
D
H5, H6 and H6 ), 2.42 (m, 1H, Ha), 1.25 (d, 6H,
TOF-MS: 825.93 (M+Na+), 841.84 (M+K+); IR
0
25
D
2–CH3, JCH -a = 6.9 Hz); 13C NMR (50.3 MHz, CDCl3):
(Nujol): 3361, 1733, 1716, 1653; ½aŠ ¼ þ37:9 (c 0.5,
3
178.1, 138.6, 138.2, 137.4, 128.8, 128.62, 128.55, 128.34,
128.26, 128.2, 128.0, 127.93, 127.86, 82.2, 78.8, 77.1,
75.7, 75.3, 74.8, 73.8, 72.6, 71.3, 68.4, 36.0, 19.7, 19.6;
CHCl3).
ESI-MS: 610.4 (M+H+), 632.6 (M+Na+); IR (Nujol):
25
D
References
3421, 1646; ½aŠ ¼ þ46:2 (c 0.5, CHCl3).
4.4.4. 3e. 1H NMR (400 MHz, CDCl3, 328 K) 7.33–
7.22 (m, 20H, aromatics), 6.01 (d, 1H, NH,
J1-NH = 6.85 Hz), 5.82 (bs, 1H, H1), 5.64 (m, 1H, Hb),
4.93–4.86 (m, 1H, –CH2Ph), 4.81–4.76 (m, 2H,
–CH2Ph), 4.63–4.46 (m, 5H, –CH2Ph), 3.82 (dd, 1H,
H2, J1–2 = 5.4 Hz, J2–3 = 9.3 Hz), 3.79–3.63 (m, 5H,
1. Bosques, C. J.; Tschampel, S. M.; Woods, R. J.; Imperiali,
B. J. Am. Chem. Soc. 2004, 126, 8421–8425.
2. Nair, L. G.; Fraser-Reid, B.; Szardenings, A. K. Org. Lett.
2001, 3, 317–319, and references cited therein.
3. Mizuno, M.; Muramoto, I.; Kobayashi, K.; Yaginuma,
H.; Inazu, T. Synthesis 1999, 162–165, and references cited
therein.
0
H3, H4, H5, H6 and H6 ), 2.17 (s, 3H, CH3), 1.85 (s,
4. Boullanger, P.; Maunier, V.; Lafont, D. V. Carbohydr.
Res. 2000, 324, 97–106.
3H, CH3); 13C NMR (50.3 MHz, CDCl3): 167.5,
154.2, 138.7, 138.3, 138.2, 137.2, 129.1, 128.7, 128.60,
128.56, 128.3, 128.2, 128.1, 128.0, 127.94, 127.90,
117.9, 82.4, 78.0, 77.2, 75.7, 75.3, 74.9, 73.8, 72.6,
71.2, 68.5, 27.6; ESI-MS: 622.4 (M+H+), 644.5
¨
5. Kovacs, L.; Osz, E.; Domokos, V.; Holzer, W.; Gyo¨rgy-
´
deak, Z. Tetrahedron 2001, 57, 4609–4621, and references
´
cited therein.
6. Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125,
4408–4409.
7. Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams,
L. J. J. Am. Chem. Soc. 2003, 125, 7754–7755.
8. Bianchi, A.; Bernardi, A. Tetrahedron Lett. 2004, 45,
2231–2234.
(M+Na+), 660.3 (M+K+); IR (Nujol): 3419, 1634;
25
D
½aŠ ¼ þ74:1 (c 1.0, CHCl3).
4.5. Synthesis of 3f
9. Nillson, B. L.; Kiessling, L. K.; Raines, R. T. Org. Lett.
2000, 2, 1939–1941.
10. Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett.
2000, 2, 2141–2143.
11. (a) Rauchfuss, T. B. Inorg. Chem. 1977, 16, 2966–2968; (b)
Grotjahn, D. B.; Joubran, C.; Combs, D. J. Organomet.
Chem. 1999, 589, 115–121.
12. Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48,
1353–1406, and references cited therein.
13. Widauer, C.; Grutzmacher, H.; Shevchenko, I.; Gramlich,
¨
To a solution of 2 (1 equiv) in dry toluene (0.1 M) a 1 M
solution in dry toluene of the acylphosphine 1f was
added (1.2 equiv). The mixture was heated to 70 °C for
ca. 1 h, until disappearance of 2 from the TLC plate
(8:2 toluene/AcOEt). The solvent was evaporated and
the intermediates isolated by flash chromatography
(7:3 toluene/AcOEt). The isolated intermediates were
stirred overnight at room temperature in CHCl3, before
adding water. The mixture was diluted with AcOEt, the
phases separated. The organic phase was washed with
water, dried over Na2SO4 and evaporated. The crude
was purified by flash chromatography (8:2 toluene/
AcOEt) to afford 3f as a 86:14 a/b mixture in 75% yield.
1H NMR (400 MHz, CDCl3): 7.40–7.21 (m, 23H, aro-
matics), 7.13–7.11 (m, 2H, aromatics), 6.33 (d, 1H,
NH, J = 6.3 Hz), 5.99 (d, 1H, NH, J = 8.1 Hz), 5.68
(dd, 1H, H1, J = 5.1, 8.1 Hz), 5.15–5.03 (m, 2H, CH2–
Ph), 4.92–4.89 (m, 1H, CH2–Ph), 4.80–4.76 (m, 2H,
–CH2Ph), 4.68–4.38 (m, 6H, –CH2Ph, CH), 3.81–3.57
V. Eur. J. Inorg. Chem. 1999, 1659–1664, and references
cited therein.
´
14. Molina, P.; Lopez-Leonardo, C.; Llamas-Botıa, J.; Foces-
Foces, C.; Fernandez-Castan˜o, C. Tetrahedron 1996, 52,
´
´
´
´
9629–9642; Alajarın, M.; Molina, P.; Lopez-Lazaro, A.;
Foces-Foces, C. Angew. Chem., Int. Ed. 1997, 36, 67–
70.
15. Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem.
Rev. 2000, 100, 4495–4537.
´
16. Gyo¨rgydeak, Z.; Szitagyi, L.; Paulsen, H. J. Carbohydr.
Chem. 1993, 12, 139–163, and references cited therein.
17. Jeganathan, S.; Tsukamoto, M.; Schlosser, M. Synthesis
1990, 109–111.
0
(m, 6H, H2, H3, H4, H5, H6 and H6 ), 3.70 (s, 3H,