Readily available carbohydrate-derived imines and amides as chiral ligands for asymmetric catalysis

Article abstract of DOI:10.1016/S0040-4020(02)00510-0

An easy and diastereoseletive strategy for the synthesis of a new tetrahydrofuranic chiral aldehyde and a new tetrahydrofuranic acid derived from D-ribose is reported. These compounds have been shown to be useful starting materials for obtaining a never d

Full text of DOI:10.1016/S0040-4020(02)00510-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5459±5466
Readily available carbohydrate-derived imines and amides as
chiral ligands for asymmetric catalysis
Maria Cristina Pigro, Gabriella Angiuoni and Giovanni Piancatellip
Á
Dipartimento di Chimica, Universita `La Sapienza' and Centro CNR di Studio per la Chimica delle Sostanze Organiche Naturali,
Piazzale Aldo Moro 5, Box no. 34-Roma 62, 00185 Roma, Italy
Received 28 February 2002; revised 25 April 2002; accepted 16May 2002
AbstractÐAn easy and diastereoseletive strategy for the synthesis of a new tetrahydrofuranic chiral aldehyde and a new tetrahydrofuranic
acid derived from d-ribose is reported. These compounds have been shown to be useful starting materials for obtaining a never described
before class of iminic- and amidic-carbohydrate-based chiral ligands, endowed with stability to puri®cation on silica ¯ash column and to
storage, and characterised by the presence of a stereogenic centre a to the iminic or amidic bond. The ®rst results obtained from the
application of these chiral ligands in a model reaction, conjugate addition of Et2Zn to cyclohexenone, are discussed. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
lacking. An empirical approach to the synthesis of good
substrates could be a valid instrument in order to develop
new chiral ligands, especially for those reactions in which
the mechanism of the asymmetric induction is still unknown
or poorly understood.6 This approach ®nds its driving force
in the ability to make systematically structural changes in
ligand scaffolding, to produce a broad variety of electronic
and stereochemical properties.
Carbohydrates are widespread chiral natural products,
generally cheap and easily obtainable in pure form.1,2
Their great variety of functional groups and stereogenic
centres allows the regio and stereoselective introduction of
different functionalities. As a consequence, carbohydrates
are used as chiral reagents in the synthesis of many chemi-
cally and biologically interesting products: a great variety of
cyclic and linear structures are, in fact, easily obtainable
from them.3 In connection with a program directed to
broaden the application of carbohydrates in organic
chemistry, we focused our attention on the development
of new imine- and amido-carbohydrate-based chiral ligands
for asymmetric catalysis.
Carbohydrates seem to be very suitable for this target. Even
if widely used as starting compounds for the synthesis of
chiral organic molecules, carbohydrates are still considered
exotic as substrates for ligands. Only a few examples are
reported in the literature,7 derived from d-glucose,8
d-mannose,6 d-glucosamine9 and d-xylose.10
A variety of iminic and amidic chiral ligands constituted by
a chiral amino part and an achiral aldehydic or acidic part
can be easily found in the literature.4f,11 Our innovative
work was the synthesis of ligands constituted by a chiral
aldehyde or chiral acid from carbohydrates, and an aromatic
achiral amine, containing a set of different metal binding
sites, with the expectation that such a multidentate array
would favour the formation of organometallic complexes
with well-organised spatial arrangements.
A great variety of chiral ligands are described in the
literature, successfully used in several asymmetric reac-
tions,4a±f such as conjugate additions of organometallic
reagents on linear and cyclic a±b unsatured compounds,
allylic alkylations, Strecker reactions and Diels Alder
reactions.1 They derive from very different substrates5a±c
but many authors underline the importance of using
economic and easily accessible chiral sources for ligands.
Despite ten years of successful studies concerning synthesis
and reactivity of ligands in asymmetric induction, a clear
understanding of the origin of a pronounced dependence of
the enantioselectivity on their electronic properties is still
We found d-ribose as a potential ideal source of substrates
for the synthesis of carbohydrates-based chiral ligands. We
selected this ®ve-membered ring because of its high rigidity
with respect to a six-membered one, such as d-glucose.
Keywords: carbohydrate-based chiral ligands; imines; amides; asymmetric
catalysis.
Corresponding author. Tel.: 139-06-49913861; fax: 139-06-490631; e-
mail: giovanni.piancatelli@uniroma1.it
Previous studies in our laboratory led us to an original
protocol for synthesising new tetrahydrofuran-based chiral
aldehydes (Fig. 1), derived from d-hexopyranoses in six
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00510-0

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M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
Et3N in DMSO. The aldehyde 5 obtained was stable during
puri®cation on silica gel and was isolated in good yield as a
viscous and air-stable oil. We elected aldehyde 5 as a
suitable substrate for the synthesis of new chiral ligands.
Figure 1.
Concerning our synthesis, a signi®cant outcome was the
Scheme 1. (a) TIPSCI, DMF, imidazole, 08C, 80%; (b) NaH, BrBn, DMF, 08C, 60%; (c) TBAF, THF, 08C, 98%; (d) SO3-py, DMSO, Et3N, 70%.
steps with high yields.12 However, this way seemed to be too
long for our purpose: we needed an easy and rapid synthesis
of chiral substrates for ligands in order to synthesise a
library of molecules to be tested in several asymmetric
reactions involving transition metals.
total diastereoselectivity observed in the perbenzylation of
2 to give 3. In the 1H NMR spectrum of compound 3, a well
resolved doublet at dˆ5.06with a coupling constant
J1,2ˆ4.4 Hz corresponds to the proton on the anomeric
position; moreover 13C NMR spectra exhibit a signal at
dˆ99.7, corresponding to the anomeric carbon. These
data indicate that a pure diastereoisomer 3 was obtained.
2. Results and discussion
In order to assign the stereochemistry of the anomeric posi-
tion, we compared the compound 3a, obtained according to
our NaH-based protocol for the monobenzylation of the
TIPS-5-protected-d-ribose 2 (Scheme 2, route a) with the
epimeric compounds 3a and 3b, obtained according to a
different procedure as shown in Scheme 2, route c. These
two diastereoisomers were prepared by a two step sequence
from d-ribose: a ®rst acid-catalysed mono-benzylation
reaction and then a 5-O-protection reaction by TIPSCl. As
is well known, in the acid catalysed mono-benzylation
reaction of 1, the b anomer 2b usually predominates over
the a one 2a.13a,b
The chiral aldehyde 5 was prepared form d-ribose 1
according to the strategy outlined in Scheme 1.
At ®rst, the regioselective protection of the primary OH
group at the C-5 atom was carried out by treatment of
d-ribose 1 with triisopropylsilyl chloride (TIPSCl) to give
compound 2 in good yield. Interestingly, this protection
gave a product in which the a-anomer predominated.
By incorporation of the bulky TIPS protecting group on C-5,
an excellent stereoselectivity was obtained in the direct
perbenzylation of compound 2, providing the a-anomer 3
in good yield. The following step was removal of the silyl
group by treatment with tetrabutylammonium¯uoride
(TBAF) in THF at 08C for 30 min, with formation of the
pure deprotected alcohol 4 in almost quantitative yield.
Finally, an ef®cient oxidation to aldehyde 5 was realised
by reaction of the alcohol 4 with the complex SO3-py and
Then, after the 5-O-protection reaction by the TIPS group
on the anomeric mixture and separation by ¯ash chromato-
graphy of the two epimers 3a and 3b, we found a total
coincidence of 1H NMR and 13C NMR spectra of the
compound 3a prepared according to the two different routes
outlined in Scheme 2. The result clearly indicates that the
Scheme 2. TIPSCI, DMF, 08C; (b) NaH, BrBn, DMF, 08C; (c) BnOH, H1.

M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
5461
Analogously, we used the same versatile synthetic strategy,
described above, for the synthesis of the acid 7, by oxidation
of the alcohol 4 with [bis (acetoxy)iodo]benzene (BAIB)
and TEMPO16a,b in a 1:1 CH3CN/H2O solution. (Scheme 4).
formation of the C-1 a anomer on the 5-O-protected-d-
ribose by the NaH benzylation protocol is a stereocontrolled
reaction.
It can be supposed that the anion derived from 2 during the
benzylation in basic conditions by the NaH-based protocol
exhibits a 4 centre crown ether-like geometry, thus favour-
ing the a-con®guration on C-1.14 (Fig. 2).
Scheme 4. TEMPO, BAIB, CH3CN/H2Oˆ1:1, .99%.
The reaction between the acid 7 with differently functiona-
lised aromatic achiral amines was employed for the
synthesis of new amidic chiral ligands 8 in high yields,
according to a previously described synthetic strategy
applied on analogous substrates.17
Figure 2.
In fact, whereas for the pyranoses the higher nucleophilicity
of the b-oxide can be justi®ed with a stereoelctronic effect
resulting from a repulsion of the lone electron pair or from
an unfavourable dipole dipole interaction, for furanose
substrates steric and chelate effects primarily control the
stereochemistry.15
Moreover, we completed our library of amidic chiral ligands
through a one-pot synthesis of the acid chloride derived
from 7 and its subsequent reaction with various aromatic
achiral amines (Scheme 5 and Table 2).
The aldehyde 5 reacting with differently functionalised
aromatic achiral amines gave a new class of iminic chiral
ligands 6 (Scheme 3 and Table 1).
According to this protocol we obtained a new class of
amidic chiral ligands endowed with the same qualities as
our iminic ligands in terms of stability to puri®cation on
silica ¯ash coloumn, storage and presence of a stereogenic
centre a to the amidic bond; moreover they have the
advantage of being extremely resistant to attack by strong
nucleophilic agents.
In connection with our work devoted to the synthesis of
natural substances, such as lignans, via tandem conjugate
addition±alkylation to furan-2(5H)-one,18 this new class of
ligands has been exploited in the asymmetric Michael
addition to a model a,b-unsatured ketone, cyclohexenone.
Unfortunately, the attempts of Et2Zn conjugate addition to
cyclohexenone in the presence of such ligands with
Cu(OTf)2 as catalyst (5%) gave modest results. We
observed the formation of 3-ethylcyclohexanone in high
yields (.90%), but we found no signi®cant enantiomeric
excess (10±15%) (Scheme 6). However, an important result
was the increased ef®ciency of the catalysis: in the presence
of our chiral ligands, the reaction times are reduced even to
a half of the time observed in the presence of the Cu(OTf)2
only. In fact, diorganozincs smoothly react with enones in
the presence of catalytic amounts of CuI salts and
cosolvents, such as hexamethylphosphonyltriamide
(HMPA) and tetramethylethylenediamine (TMEDA),
which co-ordinate to the metal leading to a marked increase
in the reactivity of these reagents.19
Scheme 3.
Table 1. Reaction of the aldehyde 5 with aromatic amines
Amine
Product
R
Yield (%)
1,2-Phenylenediamine
2-Aminobenzenethiol
2-Aminophenol
6a
6b
6c
6d
NH2
SH
OH
OCH3
70
65
30
35
2-Methoxyphenylamine
Interestingly, our synthetic strategy proceeded stereo-
selectively: we obtained only the E double-bound isomer
of compounds 6. Our iminic ligands present important
peculiarities:
² They are unexpectedly stable: they have been puri®ed by
¯ash chromatography on silica gel column and storedÐ
even for long periodsÐat low temperature under a
nitrogen atmosphere.
² They present a stereogenic centre a to the iminic double
bond which, together with the N atom, is expected to be
responsible for the coordination of transition metal ions
in catalytic asymmetric reactions.
3. Conclusions
In conclusion, we performed a valid, easy and diastereo-
selective strategy for the synthesis of a new tetrahydro-
furanic chiral aldehyde and a new tetrahydrofuranic acid
derived from d-ribose, which have then been converted
into a never described before class of chiral ligands,
endowed with stability to puri®cation on silica ¯ash column

5462
M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
Scheme 5.
Table 2. Reaction of the acid 7 with aromatic amines
Amine
Reaction conditions
Product
Yield (%)
1,2-Phenylenediamine
(1) EDAC, HOBT, 08C, DMF/CH2Cl2ˆ1/2.5, (2) (i-Pr)2NEt, CH2Cl2, amine
(1) (COCl)2, CH2Cl2, (2) amine, Et3N, THF
(1) (COCl)2, CH2Cl2, (2) amine, Et3N, THF
8a
8b
8c
8d
81
40
60
70
2-Diphenylphosphanyl-phenylamine
2-Methylsulfanyl-phenylamine
2,6-Diaminopyridine
(1) (COCl)2, CH2Cl2, (2) amine, Et3N, THF
utilised as purchased. 2-Diphenylphosphanyl-phenyl-
amine21 and 2-methylsulfanyl-phenylamine22 were synthe-
sised and puri®ed according procedures described in the
literature. The enantiomeric excess was determined by gas
chromatography (HP 5890-GC) using a chiral capillary
column with Daetbusililbeta CDX as stationary phase. Opti-
cal rotations were measured at 589 nm on a digital DIP-370
polarimeter (using 1 cm and 10 cm microcells).
Scheme 6. (a) Et2Zn, Cu(OTf)2, ligand.
and to storage, and characterised by the presence of a stereo-
genic centre a to the iminic or amidic bond. The results
obtained from the application of the new chiral ligands in
a model reaction (the Et2Zn conjugate addition to cyclo-
hexenone) are good in terms of increasing the reaction
rate, but the obtained enantiomeric excess was modest.
Studies are in progress to exploit our chiral ligand library
in other asymmetric reactions, involving different transition
metals. It is well known that ligands provided with O, N
substituents are suitable to complex early transition metals
such as Ti or Zr, while the coordination of late transition
metals such as Ni, Cu and Pd is promoted by ligands
provided with P or S binding sites.20
4.1.1. 5-O-Triisopropylsilyl-a-d-ribofuranose 2. Com-
pound 2 was prepared according to the following
procedure.23
A solution of d-ribose (1) (300 mg, 2 mmol) in dry DMF
(5 mL) under argon was treated with imidazole (306mg,
4.5 mmol). The reaction was cooled to 08C and TIPSCl
(307 mg, 1.6mmol) was added dropwise; after an hour,
the same amount of TIPSCl was added again. The reaction
mixture was stirred for 4±5 h until all the d-ribose was
consumed. After dilution with ethyl acetate (20 mL) the
organic layer was washed with water (3£5 mL), brine
(2£10 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was puri®ed by chromatography on silica gel
with hexane/ethylacetate (4:1) to give 2a/bˆ7:1 (490 mg,
1.6mmol, 80%) as a viscous colourless oil. 1H NMR
(CDCl3): dˆ5.35 (d, 1H, H1-a, J1±2ˆ4.4 Hz), 5.02 (s
broad, 1H-b), 4.49 (t, 1H, H3, J3±2ˆJ2±3ˆ5.3 Hz), 4.18±
3.52 (m, 7H, 3OH, H4, H2, 2H5), 3.01 (m, 21H,
3(CH(CH3)2). 13C NMR (CDCl3): dˆ96.97 (C1); 84.57,
71.98, 71.81 (C2, C3, C4), 63.97 (C5), 18.07, 11.95
[CH(CH3)2]. IR (CHCl3): nmaxˆ3410 cm21 (O±H);
2900 cm21 [CH(CH3)2]. Anal. calcd for C14H30O5Si: C,
54.87% H, 9.87%. Found: C, 54.85% H, 9.89%.
4. Experimental
4.1. General
Solvents were puri®ed and dried by standard procedures
before use. Analytical TLC was performed using silica gel
6 0 F254 plates (Merck). Flash chromatography was executed
with Merck Kiesegel 60 (230±400) using a mixture of ethyl
acetate and hexane as eluant. 1H NMR and 13C NMR spectra
were recorded on a Varian Gemini 200 spectrometer at
room temperature with CDCl3 as solvent and as internal
standard. Coupling constants are quoted in Hz. d-Ribose,
1,2-phenylenediamine, 2-aminophenol, 2-aminobenzene-
thiol, 2-methoxyphenylamine, 2,6-diaminopyridine were
4.1.2. 5-O-Triisopropylsilyl-1,2,3-tri-O-benzyl-a-d-ribo-
furanose 3. In a 50 mL ¯amed three necked ¯ask the
compound 2 (1.00 g, 3.26mmol) was dissolved in dry

M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
5463
DMF (12 mL) and cooled to 08C under argon. NaH
(314 mg, 13.04 mmol) was added portionwise throughout
the solution. After stirring for 10 min, BrBn (1.55 mL,
13.04 mmol) was added and the reaction mixture was stirred
for 3 h at 08C. The reaction was quenched by addition of
CH3OH (5 mL) and diluted with hexane (50 mL). The
organic layer was washed with water (3£10 mL), brine
(2£10 mL), dried over Na2SO4 and concentrated in vacuo.
The crude product was puri®ed by ¯ash chromatography
using hexane/ethylacetate (25:1) as eluent to give 3
(CD3OD)ˆ5.03 (d, 1H-b, J1±2ˆ0.7 Hz), 5.12 (d, 0.2 H-a,
J1±2ˆ4.4 Hz). The mixture was used in the next reaction. In
a 25 mL ¯amed three necked ¯ash, the 2a/2b mixture
(2.71 g, 3.85 mmol) was dissolved in 10 mL of dry DMF,
under nitrogen atmosphere.
When the substrate was completely dissolved under stirring,
imidazole (590 mg, 8.66 mmol) was added portionwise.
Then the stirred solution was cooled to 08C under nitrogen
atmosphere and TIPSCl (591 mg, 3.08 mmol) was dropped
during 10 min. After 1 h an identical amount of TIPSCl was
added to the stirred solution, always kept at 08C under
nitrogen atmosphere.
1
(12.270 g, 2.12 mmol, 65%) as colourless viscous oil. H
NMR (CDCl3): dˆ7.52±7.28 (m, 15H, Ph), 5.06(d, 1H,
H1, J1±2ˆ4.4 Hz), 4.97±4.47 (m, 6H, 3CH2Ph), 4.24 (dd,
H3, J3±4ˆ3.3 Hz, J3±2ˆ6.6 Hz), 4.03 (dd, 1H, H4,
J4±3ˆ3.3 Hz, Jwˆ6.4 Hz), 3.82 (dd, 1H, H2, J2±1ˆ4.4 Hz,
J2±3ˆ6.6 Hz), 3.65 (d, 2H, H5, J5±4ˆ3.5 Hz), 1.01 (m, 21H,
3CH(CH3)2) 13C NMR: dˆ138.74, 138.53, 138.18,
(CquatPh), 128.44, 128.38, 128.32, 128.20, 128.15, 127.94,
127.79, 127.64, 127.47 (Ph), 99.7 (C1), 84.01, 78.26, 75.54
(C2, C3, C4), 72.48, 72.34, 68.88 (3CH2Ph), 63.94 (C5);
18.07, 12.00 [CH(CH3)2]. nmaxˆ2945 cm21 [CHCH3)2];
The reaction is completed within 4.5 h, as revealed by TLC
chromatography.
The mixture was poured into a separating funnel, diluted
with EtOAc (150 mL) and washed with H2O until neutrality
(3£10 mL), ®nally with brine (2£10 mL). The organic layer
was dried over Na2SO4 and evaporated in vacuo. The crude
product was puri®ed by ¯ash chromatography on 10 g of
silica gel column to give 776mg (1.96mmol, 52%) of 3b,
as colourless oil, eluted with n-hexane/EtOAcˆ8:1, and
250 mg (0.62 mmol, 16%) of 3a, as colourless oil, eluted
with n-hexane/EtOAcˆ7:1.
20
1119 cm21, 1036cm 21 (CO±C). [a]D ˆ173.38 (c 2.44,
CHCl3). Anal. calcd for C35H48O5Si: C, 72.88% H, 8.39%.
Found: C, 72.89% H, 8.36%.
4.1.3. 1-O-Benzyl-5-O-triisopropylsilyl-a-d-ribofuranose
3a and 1-O-benzyl-5-O-triisopropylsilyl-b-d-ribofura-
nose 3b. 3a (basic conditions): in a 50 mL ¯amed three
necked ¯ask, the compound 2 (1.00 g, 3.26mmol) was
dissolved in dry DMF (8 mL) and cooled to 08C under
argon. NaH (94 mg, 3.91 mmol) was added portionwise to
the solution. After stirring for 10 min, BrBn (0.5 mL,
3.91 mmol) was added and the reaction mixture was stirred
for 3 h at 08C. The reaction was quenched by addition of
CH3OH (5 mL) and diluted with n-hexane. The organic
layer was washed with water (3£10 mL), brine
(2£10 mL), dried over Na2SO4 and concentrated in vacuo.
The crude product was puri®ed by ¯ash chromatography:
after eluting byproducts with hexane/ethylacetateˆ10:1, we
obtained 453 mg (1.41 mmol, 35%) of 3a, as colourless oil,
using hexane/ethylacetateˆ7:1 as eluent.
1H NMR (CHCl3): dˆ7.36±7.28 (m, 5H, Ph), 5.12 (d, 1H,
H1, J1±2ˆ4.4 Hz), 4.75 (d, 1H, JABˆ11.2 Hz), 4.74 (d, 1H,
JA±Bˆ11.2 Hz), 4.24±4.03 (m, 3H, H2, H3, H4), 3.9±3.8
(m, 2H, 2H5), 2.96(s broad, 1H, OH), 2.93 (s broad, 1H,
OH), 1.15±1.01 (m, 21H, 3CH(CH3)2). 13C NMR:
dˆ136.46 (CquatPh), 128.65, 128.63, 128.06 (Ph), 101.20
(C1), 86.23, 72.25, 71.40 (C2,C3,C4), 69.71 (CH2Ph), 63.87
(C5), 18.02, 12.01 [CH(CH3)2]. Anal. calcd for C21H36O5Si:
C, 63.60% H, 9.16%. Found: C, 63.57% H, 9.19%.
1
3b: H NMR (CDCl3): dˆ7.43±7.21 (m, 5H, Ph), 5.03 (d,
1H, H1, J1±2ˆ0.7 Hz), 4.63 (d, 1H, JABˆ11.7 Hz), 4.62 (d,
1H, JABˆ11.7 Hz), 4.43 (q broad, 1H), 4.14 (s broad, 1H),
4.07±3.72 (m, 3H, 2H5, H2), 3.12 (s broad, 1H, OH), 2.74 (s
broad, 1H, OH), 1.15±1.01 (m, 21H, 3CH(CH3)2). 13C
NMR: dˆ136.78 (Cquatarom), 128.49, 128.06, 127.86
(Ph.), 106.33 (C1), 83.16, 75.48, 73.48 (C2, C3, C4),
69.43 (CH2Ph), 65.45 (C5), 18.05, 11.98 [CH(CH3)2].
Anal. calcd for C21H36O5Si: C, 63.60% H, 9.16%. Found: C,
63.57% H, 9.19%.
4.1.4. 1,2,3-Tri-O-benzyl-a-d-ribofuranose 4.24 A solu-
tion of TBAF 1 M in THF (1.3 mL, 1.3 mmol) was added
at 08C to a solution of 3 (501 mg, 0.87 mmol) in dry THF
(5 mL) under argon and the reaction mixture was stirred for
about 1 h until the starting material was consumed. After
dilution with ethyl acetate (20 mL), the organic layer was
washed with water (3£10 mL), brine (2£10 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was puri®ed
by chromatography on silica gel with hexane/ethylacetate
(7:1) as eluent to give 256mg of 4 (0.845 mmol, 98%), as
viscous oil. 1H NMR (CDCl3): dˆ7.50±7.28 (m, 15H, Ph),
5.1 (d, 1H, H1, J1±2ˆ4.4 Hz), 4.24 (dd, 1H, H3,
J3±2ˆ7.3 Hz, J3±4ˆ3.7 Hz), 3.9 (dd, 1H, H2, J2±1ˆ4.4 Hz,
J2±3ˆ7.3 Hz), 3.8±3.65 (m, 2H, H5), 3.48 (dd, 1H, H4,
J4±3ˆ3.7 Hz, Jwˆ12.5 Hz). 13C NMR (CDCl3): dˆ138.47,
138.02 (CquatPh), 128.49, 128.42, 128.26, 128.18, 127.96,
127.88, 127.83, 127.71 (Ph), 99.84 (C1), 83.07, 78.18,
75.24 (C2, C3, C4), 72.75, 72.59, 69.05 [3CH2Ph], 62.72
(C5). Anal. calcd for C26H28O5: C, 74.25% H, 6.72%.
Found: C, 74.29% H, 6.66%.
3a and 3b (acid conditions): to a stirred solution of d-ribose
(2 g, 13.33 mmol) dissolved in neat benzylic alcohol
(60 mL, 580.56 mmol, dˆ1.045 g/mL), a 37% solution of
HCl (1.4 mL, 16.80 mmol) was added dropwise. The
mixture was stirred at room temperature for 12 h. The
excess of benzylic alcohol is removed by distillation
under reduced pressure.13 The crude product is ®nally puri-
®ed via ¯ash chromatography on silica gel (EtOAc ®rst,
then CHCl3/EtOAcˆ3:1) to give 2.71 g (3.85 mmol) of
2b/2aˆ5/1 mixture in 85% overall yield, as viscous oil.
The ratio was assigned by 1H NMR spectroscopy: dH
4.1.5. 1,2,3-Tri-O-benzyl-a-d-ribo-pentodialdo-1,4-fura-
nose 5. Alcohol 4 (150 mg, 0.36mmol) was dissolved in dry
DMSO (1.5 mL) and then Et3N (1.5 mL) and the complex

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M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
SO3-py (273 mg, 1.7 mmol) were added; the reaction
mixture was stirred for 30 min. After dilution with ethyl
acetate (20 mL), the organic layer was washed with water
(3£10 mL), brine (2£10 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was puri®ed by chroma-
tography on silica gel with n-hexane/ethylacetate (3:1) as
eluent to give 106mg of 5 (0.25 mmol, 70%), as colourless
viscous oil. 1H NMR (CDCl3): dˆ9.45 (d, 1H, CHO),
7.46±7.20 (m, 15H, Ph), 5.11 (d, 1H, H1, J1±2ˆ4.4 Hz),
4.90±4.47 (m, 7H, H3, 3CH2Ph), 3.95 (d, 1H, H4,
J4±2ˆ6.6 Hz, J4±3ˆ2.9 Hz), 3.60 (dd, 1H, H2,
J2±1ˆ4.4 Hz, J2±3ˆ6.6 Hz). 13C NMR (CDCl3): dˆ199.6
(CHO), 128.47, 128.40, 128.15, 128.00, 127.91, 127.76
(Ph), 100.01 (C1), 87.18, 77.38, 74.98 (C2, C3, C4),
72.52, 72.48, 69.45 (3CH2Ph). IR (CHCl3): nmaxˆ2700±
(21 mg, 0.19 mmol): 31 mg, 0.06mmol (30%), colourless
oil. 1H NMR (CDCl3): dˆ9.58 (s, 1H, OH), 7.58±6.67 (m,
19H, Ph), 5.35 (d, 1H, H5, J5±4ˆ2.93 Hz), 5.16(d, 1H, H1,
J1±2ˆ4.4 Hz), 5.2±4.3 (m, 7H, H3, 3CH2Ph), 4.00 (dd, 1H,
H4, J4±5ˆ2.9 Hz), 3.64 (dd, 1H, H2, J1±2ˆ4.4 Hz). 13C
NMR (CDCl3): dˆ152.83 (C5), 138.68, 136.23 (CquatPh),
130.59±120.79 (Ph), 100.11 (C1), 82.72, 79.81, 77.29 (C2,
C3, C4), 72.38, 72.21, 69.17 (3CH2Ph). IR (CHCl3):
nmaxˆ1657 cm21. Anal. calcd for C32H31NO5: C, 75.41%
H, 6.14% N 2.75%. Found: C, 75.39% H, 6.17% N,
2.70%.
4.2.4. 5-Deoxy-5-(20-methoxy-phenyl-imino)-1,2,3-tri-O-
benzyl-a-d-ribofuranose 6d. From 2-methoxyphenyl-
amine (24 mg, 0.19 mmol): 35 mg, 0.07 mmol (35%),
1
2820 cm21 (CO±H), 1720 cm21 (CO). [a]D ˆ153.28 (c
20
colourless oil. H NMR (CDCl3): dˆ7.70±6.67 (m, 19H,
Ph), 5.52 (d, 1H, H5, J5±4ˆ4.4 Hz), 5.06(d, 1H, H1,
J1±2ˆ4.4 Hz), 4.75±3.68 (m, 9H, H2, H3, H4, 3CH2Ph),
3.98 (s, 3H, OCH3). 13C NMR (CDCl3): dˆ153.68 (C5),
139.60, 138.68, 136.23, (CquatPh), 131.57±120.12 (Ph),
100.23 (C1), 84.72, 79.61, 77.39 (C2, C3, C4), 72.58,
72.21, 69.74 (3CH2Ph), 55.8 (OCH3). IR (CHCl3):
nmaxˆ1652 cm21. Anal. calcd for C33H33NO5: C, 75.68%
H, 6.36% N, 2.68%. Found: C, 75.70% H, 6.34% N, 2.65%.
3.1, CHCl3). Anal. calcd for C26H26O5: C, 74.61% H,
6.27%. Found: C, 74.59% H, 6.28%.
4.2. General procedure for the synthesis of imines
Imines 6a, 6b, 6c and 6d were prepared according to the
following procedure.
Amine (0.19 mmol) was added to a solution of 5 (100 mg,
0.24 mmol) in absolute ethanol (10 mL) and the reaction
mixture was stirred at 1008C for 24 h. For the work-up,
the solution was concentrated in vacuo and puri®ed by
¯ash chromatography on silica gel (n-hexane/ethyl acetate).
4.2.5. 1,2,3-Tri-O-benzyl-a-d-ribofuranuronic acid 7.
Compound 4 (237 mg, 0.562 mmol), TEMPO (18 mg,
0.112 mmol) and BAIB (398 mg, 1.232 mmol) were
dissolved in CH3CN/H2Oˆ1:1 (2 mL) and the reaction
mixture stirred at room temperature until the starting
material was consumed. After stirring at room temperature
for half an hour, the reaction mixture was worked up at 08C
by adding HCl 2N (2 mL); the solution was diluted with
diethyl ether (20 mL), washed with water (3£10 mL), then
brine (2£10 mL), dried over Na2SO4 and evaporated in
vacuo, giving 7 as a pure colourless oil in quantitative
4.2.1. 5-Deoxy-5-(20-amino-phenyl-imino)-1,2,3-tri-O-
benzyl-a-d-ribofuranose 6a. From 1,2-phenylenediamine
(21 mg, 0.19 mmol): 73 mg, 0.14 mmol, (70%), colourless
oil. 1H NMR (CDCl3): dˆ7.58±7.23 (m, 19H, Ph), 5.44 (d,
1H, H5, J5±4ˆ3.7 Hz), 5.27 (d, 1H, H1, J1±2ˆ4.4 Hz), 5.01±
4.51 (m, 9H, H4, 3CH2Ph, NH2), 4.37 (dd, 1H, H3,
J3±4ˆ4.51 Hz, J3±2ˆ6.6 Hz), 3.90 (dd, 1H, H2,
J2±1ˆ4.4 Hz, J2±3ˆ6.6 Hz). 13C NMR (CDCl3): dˆ152.34
(C5), 137.77, 137.60, 136.80 (CquatPh), 128.68, 128.44,
128.21, 127.94, 126.85, 122.96 (Ph), 100.32 (C1), 79.46,
78.96, 77.29 (C2, C3, C4), 74.47, 72.77, 69.64 (3CH2Ph).
1
yield H NMR (CDCl3): dˆ10.08 (s, 1H, COOH), 7.76
(d, 3H, Ph), 7.51±7.12 (m, 12H, Ph), 5.24 (d, 1H, H1,
J1±2ˆ4.6Hz), 4.99±4.52 (m, 7H, H3, 3CH 2Ph), 4.12 (dd,
1H, H4, J4±3ˆ6.2 Hz, Jwˆ2.6Hz), 3.78 (dd, 1H, H2,
J2±1ˆ4.6Hz, J2±3ˆ5 Hz). 13C NMR (CDCl3): dˆ174.66
(CO), 137.62, 137.59, 137.45, 137.41, 130.34, 128.61,
128.52, 128.44, 128.34, 128.24, 128.15, 128.01, 127.91,
127.80, 127.56(Ph), 100.13 (C1), 81.08, 76.94, 72.45 (C2,
C3, C4), 72.25, 69.53, 65.95 (3CH2Ph). IR (CHCl3):
IR (CHCl3): nmaxˆ1653 cm21
.
Anal. calcd for C32H32O4N2: C, 75.56% H, 6.35% N, 5.51%.
Found: C, 75.59% H, 6.32% N, 5.50%.
nmaxˆ3300±2500 cm21
(O±H);
1710 cm21
(CO).
20
4.2.2. 5-Deoxy-5-(20-mercapto-phenyl-imino)-1,2,3-tri-O-
benzyl-a-d-ribofuranose 6b. From 2-aminobenzenethiol
(24 mg, 0.19 mmol): 68 mg, 0.13 mmol (65%), colourless
oil. 1H NMR (CDCl3): dˆ8.14±7.15 (m, 19H, Ph), 5.61 (d,
1H, H5, J5±4ˆ2.93 Hz), 5.30 (d, 1H, H1, J1±2ˆ4.4 Hz),
5.07±4.47 (m, 7H, H3, 3CH2Ph), 4.24 (dd, 1H, H4,
[a]D ˆ140.08 (c 3.4, CHCl3). Anal. calcd for C26H26O6:
C, 71.86% H, 6.04%. Found: C, 71.90% H, 6.02%.
4.3. General procedures for the synthesis of amides
Compound 8a was prepared according to the following
procedure.17
J3±4ˆ6.6 Hz, J4±5ˆ2.9 Hz), 3.93 (dd, 1H, H2, J1±2
ˆ
4.4 Hz, J2±3ˆ6.6 Hz). 13C NMR (CDCl3): dˆ153.88 (C5),
137.77, 137.68, 137.42 (CquatPh), 128.59±121.84 (9C, Ph),
100.31 (C1), 83.07, 79.41, 77.29 (C2, C3, C4), 72.49, 72.31,
Compound 7 (114 mg, 0.26mmol) was dissolved in dry
DMF/CH2Cl2 (1:2, 6mL) and then EDAC (61 mg,
0.314 mmol) and HOBT (42 mg, 0.312 mmol) were added
at 08C under argon; after half an hour, diisopropylethyl-
amine (0.14 mL, 2.4 equiv.) in CH2Cl2 (2 mL) and 1,2-
phenylenediamine (22 mg, 0.208 mmol) were added and
the reaction mixture stirred until 7 was consumed. The solu-
tion was worked up at 08C by adding HCl 0.5N (1 mL); then
was diluted with diethyl ether (20 mL), washed with water
69.47 (3CH2Ph). IR (CHCl3): nmaxˆ1655 cm21
.
Anal. Calcd for C32H31NO4S: C, 73.12% H, 5.95% N,
2.67%. Found: C, 73.09% H, 5.92% N, 2.64 %.
4.2.3. 5-Deoxy-5-(20-hydroxy-phenyl-imino)-1,2,3-tri-O-
benzyl-a-d-ribofuranose 6c. From 2-aminophenol

M. C. Pigro et al. / Tetrahedron 58 (2002) 5459±5466
5465
(3£10 mL), brine (2£10 mL), dried over Na2SO4, concen-
trated in vacuo and puri®ed by ¯ash chromatography on
column giving the corresponding amide as a colourless oil.
128.68, 128.49, 128.39, 128.21, 127.95, 127.89, 127.83,
126.50, 125.06, 120.75 (Ph), 100.34 (C1), 83.66, 77.35,
76.91 (C2, C3, C4), 72.24, 71.74, 69.69 (3CH2Ph). IR
(CHC13): nmaxˆ1679 cm21 Anal. calcd for C33H33NO5S:
C, 71.32% H, 5.99% N, 2.52%. Found: C, 72.59% H,
6.25% N, 2.50%.
Compounds 8b±8d were prepared according to the follow-
ing procedure.25a,b,c
4.3.4. N-(60-Amino-pyridin-20-yl)-1,2,3-tri-O-benzyl-a-
d-ribofuranuronamide 8d. From 2,6-diaminopyridine:
70% yield, colourless oil. H NMR (CDCl3): dˆ8.53 (s,
To a solution of 7 (140 mg, 0.321 mmol) in dry solvents
(4 mL) was added oxalyl chloride (0.2 mL, 0.321 mmol)
and the reaction mixture was stirred at room temperature
for 12 h under argon. After this time, the solvent was evapo-
rated in vacuo and the residue dissolved in dry THF (4 mL).
Amine (0.321 mmol) and dry Et3N (0.1 mL) were added at
room temperature and the reaction mixture was stirred over-
night. After dilution with CH2Cl2 (20 mL), the organic layer
was washed with water (3£10 mL), brine (2£10 mL), dried
over Na2SO4 and concentrated in vacuo. The residue was
puri®ed by chromatography on silica gel to give the corre-
sponding amides as colourless oils. Yields were calculated
after puri®cation.
1
1H, NH), 7.51±7.25 (m, 19H, Ph); 6.34 (d, 1H, Ph), 5.27
(d, 1H, H1, J1±2ˆ3.2 Hz), 4.94±4.72 (dd, 2H, CH2Ph,
JABˆ11.6Hz), 4.64±4.5 (m, 5H, H3, J2±3ˆ4.5 Hz,
J3±4ˆ4.5 Hz, 2CH2Ph), 4.33 (dd, 1H, H4, J3±4ˆ4.5 Hz,
Jwˆ4.5 Hz), 4.29 (s broad, 2H, NH2), 3.86(dd, 1H, H2,
J1±2ˆ3.2 Hz, J2±3ˆ4.5 Hz). 13C NMR (CDCl3): dˆ169.36
(CO), 157.19 (C10), 148.98, 140.17 (C30), 137.68, 137.62,
137.03, 128.52, 128.33, 128.19, 128.07, 127.94 (Ph),
106.84, 104.75 (C20, C40), 103.13 (C1), 82.21, 81.33,
80.42 (C2, C3, C4), 72.80, 72.59, 71.46(3CH 2Ph). IR
(CHCl3): nmaxˆ1680 cm21 Anal. calcd for C31H31N3O5: C,
70.80% H, 5.94% N, 8.00%. Found: C, 70.83% H, 5.92% N,
7.98%.
4.3.1. N-(20-Amino-phenyl)-1,2,3-tri-O-benzyl-a-d-ribo-
furanuronamide 8a. From 2-phenylenediamine: 81%
1
yield, colourless oil. H NMR (CDCl3): dˆ7.97 (s, 1H,
4.3.5. ZnEt2 Michael addition to cyclohexenone. The
conjugate addition to cyclohexenone was performed accord-
ing to the following procedure.4e A solution of Cu(OTf)2
(14 mg, 0.039 mmol) and a ligand 6a±d or 8a±d
(0.039 mmol) in dry toluene (5 mL) was stirred for half an
hour at room temperature under argon. The solution was
cooled to 2208C and cyclohexenone (75 mg, 0.78 mmol)
followed by Et2Zn (213 mg, 1.72 mmol) were added drop-
wise. After stirring for 5 h at 2208C, the reaction mixture
was worked up. After addition of ethyl acetate (20 mL), the
organic layer was washed with water (3£10 mL), then with
brine (2£10 mL), dried over Na2SO4 and concentrated. An
aliquot of the organic layer was analysed by GC.
NH), 7.5±6.67 (m, 17H, Ph, NH2), 5.11 (d, 1H, H1,
J1±2ˆ4.2 Hz), 4.9±4.67 (m, 5H, H3, J3±2ˆ6.8 Hz,
J3±4ˆ2.5 Hz, CH2Ph, 4.44 (dd, 2H, CH2Ph, JA±B
ˆ
12.5 Hz), 4.12 (dd, 1H, H4, J3±4ˆ2.5 Hz, JWˆ6.5 Hz),
3.65 (dd, 1H, H2, J2±1ˆ4.4 Hz, J2±3ˆ6.8 Hz). 13C NMR
(CDCl3): dˆ168.53 (CO), 137.65, 128.98, 128.48, 128.38,
128.14, 127.98, 127.91, 127.85, 127.39, 124.83 (Ph),
118.44, 100.22, 83.45, 77.75, 77.07 (C2, C3, C4), 72.24,
71.69, 69.58 (3CH2Ph). IR (CHC13): nmaxˆ1678 cm21
Anal. calcd for C32H32O5N2: C, 73.26% H, 6.15% N,
5.34%. Found: C, 73.29% H, 6.11% N, 5.32%.
4.3.2.
N-(20-Diphenylphosphanyl-phenyl)-1,2,3-tri-O-
benzyl-a-d-ribofuranuronamide 8b. From 2-diphenyl-
phosphanyl-phenylamine: 40% yield, colourless oil. 1H
NMR (CDCl3): dˆ9.41 (d, 1H, NH), 8.2 (m, 1H, Ph),
7.5±6.9 (m, 28H, Ph), 5.21 (d, 1H, H1, J1±2ˆ3.3 Hz),
4.91±4.66 (dd, 2H, CH2Ph, JABˆ12.3 Hz), 4.54±4.42 (m,
5H, H3, J3±2ˆ3.8 Hz, J3±4ˆ4.6Hz, CH 2Ph), 4.18 (dd, 1H,
H4, J4±3ˆ4.6Hz, Jwˆ4.6Hz), 3.74 (dd, 1H, H2,
J2±1ˆ3.3 Hz, J2±3ˆ3.8 Hz). 13C NMR (CDCl3): dˆ169.18
(CO), 137.77, 137.29, 134.16, 133.89, 133.77, 133.52,
130.23, 129.27, 128.99, 128.88, 128.74, 128.62, 128.45,
128.18, 128.11, 127.85, 125.27, 122.17 (Ph), 106.32 (C1),
81.95, 81.05, 80.08 (C2, C3, C4), 72.65, 72.45, 71.27
(3CH2Ph). IR (CHCl3): nmaxˆ1675 cm21 Anal. calcd for
C44H40NO5P: C, 76.16% H, 5.81% N, 2.02%. Found: C,
76.19% H, 5.82% N, 2.01%.
Acknowledgements
We thank MURST COFIN 2000 (Roma) for a ®nancial
support and Dr Pietro Passacantilli for helpful discussion.
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