Mixed S/P ligands from carbohydrates: Synthesis and utilization in asymmetric catalysis

Article abstract of DOI:10.1080/10426500590911449

New chiral mixed sulfur/phosphorus ligands derived from carbohydrates are reported. These ligands were found to be efficient catalyst precursors for palladium-catalyzed asymmetric substitution of 1,3-diphenylpropenyl acetate with dimethyl malonate or benz

Full text of DOI:10.1080/10426500590911449

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Mixed S/P Ligands from
Carbohydrates: Synthesis and
Utilization in Asymmetric
Catalysis
Noureddine Khiar a , Belén Suárez a , Michaela Stiller
a , Victoria Valdivia b & Inmaculada Fernández b
a Instituto de Investigaciones Químicas, CSIC-
Universidad de Sevilla, Isla de la Cartuja , Spain
b Departamento de Química Orgánica y
Farmacéutica, Facultad de Farmacia, Universidad de
Sevilla , Spain
Published online: 16 Aug 2006.
To cite this article: Noureddine Khiar , Belén Suárez , Michaela Stiller , Victoria
Valdivia & Inmaculada Fernández (2005) Mixed S/P Ligands from Carbohydrates:
Synthesis and Utilization in Asymmetric Catalysis, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:5-6, 1253-1258, DOI: 10.1080/10426500590911449
To link to this article: http://dx.doi.org/10.1080/10426500590911449
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Phosphorus, Sulfur, and Silicon, 180:1253–1258, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590911449
Mixed S/P Ligands from Carbohydrates: Synthesis
and Utilization in Asymmetric Catalysis
Noureddine Khiar
´
´
Belen Suarez
Michaela Stiller
Instituto de Investigaciones Qu´ımicas, CSIC-Universidad de Sevilla,
Isla de la Cartuja, Spain
Victoria Valdivia
Inmaculada Fernandez
´
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de
Farmacia, Universidad de Sevilla, Spain
New chiral mixed sulfur/phosphorus ligands derived from carbohydrates are re-
ported. These ligands were found to be efficient catalyst precursors for palladium-
catalyzed asymmetric substitution of 1,3-diphenylpropenyl acetate with dimethyl
malonate or benzylamine (up to 96% ee), and for rhodium-catalyzed methyl ac-
etamidocinnamate hydrogenation (up to 92% ee).
Keywords Carbohydrates; P/S ligands; Pd-catalyzed; enantioselective allylic substitu-
tion; rh-catalyzed enantioselective hydrogenation
INTRODUCTION
The enormous effort in the area of enantioselective asymmetric synthe-
sis has resulted in the accrual of structurally diverse ligands.1 Never-
theless, the inability to predict the structural requirements of a ligand
for generating efficient catalyst explains the need for new ligands that
combine easy synthesis and high effectiveness. An early rationalization
in this field, directed toward the restriction of the diastereomeric tran-
sition states, has resulted in the use of the C2-symmetry as successful
ligand design.2 Nevertheless, recently, the trans effect resulting from
the use of heterodonor ligands with different donor–acceptor properties
Received July 9, 2004; accepted October 5, 2004.
Address correspondence to Noureddine Khiar, Instituto de Investigaciones Qu´ımicas,
CSIC-Universidad de Sevilla, c/. Ame´rico Vespucio, 49, Isla de la Cartuja, 41092-Sevilla,
Spain. E-mail: khiar@iiq.csic.es
1253

1254
N. Khiar et al.
of the chelating atom, has demonstrated itself as an effective control
of the stereochemical restrictions needed for high enantioselectivity.3−5
In our continuing interest in the synthesis and utilization in asym-
metric synthesis of chiral sulfur compounds,6 we have recently re-
ported the preparation of C2-symmetric bis-thioglycosides as new
sulfur/sulfur (S/S) ligands using carbohydrates as cheap starting
material.7 These ligands were used in Pd(0)-catalyzed allylic alkylation
of 1,3-diphenylpropenylacetate with dimethyl malonate affording the
desired product in up to 90% enantiomeric-excess (ee). In this commu-
nication we report on the use of mixed sulfur/phosphorus (S/P) ligands
derived from carbohydrates and their application in the palladium-
catalyzed asymmetric substitution as well as in the Rh-catalyzed hy-
drogenation of enamides.
RESULTS
Our synthetic design (Figure 1) is based on the use of thioglycosides I
having a phosphinite moiety at the 2-position of the pyranose ring.
The premise of this study is that upon coordination to the metal
the stereochemistry of the sulfur in the six-member ring would be effi-
ciently controlled through steric bias. Accordingly, the chelation of the
metal through the pro Rlp of the sulfur leads to a complex II where the
sulfur substituent R and the endocyclic oxygen are in an unfavorable
syn relationship. On the other hand, the chelation of the metal through
the Pro-Slp leads to the anti diastereoisomer III presenting less steric
FIGURE 1 Ligand design.

Mixed S/P Ligands from Carbohydrates
1255
interactions and thus more favored. Additionally, the strong trans influ-
ence of the phosphinite vs. the thioether places the more labile site LA
of the metal complex in the proximity of the stereogenic sulfur atom.4
On the other hand, it is worthy of mention that ligands type I are highly
tuneable, as the sulfur substituent, the phosphorus substituents, and
the sugar backbone can all be changed easily. Another advantage of
these polyhydroxylated ligands is that they can give either lipophilic
or hydrophilic catalysts. The different nature of the hydroxyl groups
(primary and secondaries) may be used to easily link these ligands to a
solid support.
Galactose with cis hydroxyl groups at the 3 and 4 positions offers
an ideal platform for the rapid construction of these ligands. Accord-
ingly, the synthesis of phosphinite thioglycosides has been carried out
in only five high-yielding steps starting from commercially available
galactose pentaacetate 1 (Scheme 1). Condensation of a thiol with 1
in the presence of boron trifluoride afforded the corresponding thio-
glycoside 2 in high chemical yields (85–90%). Surprisingly, while this
reaction is generally highly diastereoselective, leading to the 1,2-trans-
thioglycoside, we found that the use of tert-butanethiol as glycosyl ac-
ceptor afforded the corresponding α- and β-thioglycosides in a 2:1 ratio.
On the other hand, taking into account that this reaction is under a
thermodynamic control and that both anomers are easily separable by
column chromatography, α- and β-anomers can be prepared in high
yield at will. A Zemplen deacetylation, followed by acid-catalyzed ac-
etallation with 2,2-dimethoxy propane (DMP), afforded the 3,4-acetal 3
in 75–80% yield. A regioselective acetylation of primary alcohol using
collidine as base at −78◦C afforded the monoalcohol 4 in 80–85% yield.
The installation of the phosphinite moiety has been carried out in a
1:1 mixture THF:NEt3, using DMAP as catalyst in 80–90% yield. Thus
in only five high-yielding steps the phosphinite thioglycosides were ob-
tained in a multigram scale.
SCHEME 1

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N. Khiar et al.
SCHEME 2
Application of Phosphinite Thioglycosides
to Palladium-Catalyzed Allylic Substitution
The ability of the prepared phosphinite thioglycosides (5–8) to act as
chiral ligands in asymmetric catalysis was first assayed in palladium-
catalyzed allylic alkylation of 1,3-diphenyl propenyl acetate with dime-
thyl malonate (Scheme 2). The reactions were conducted under Trost’s
conditions in ethylene chloride using 2 mol% of the Pd and 2.8 mol%
of ligands, and stopped upon completion of the reaction. The desired
calculated product was always obtained in high chemical yield and in
variable ee, depending mainly on the stereochemistry of the anomeric
center and on the substituent of the sulfur substituent atom. Signif-
icantly, while β-thioglycosides 5–7 afforded the desired product with
good yield and variable ee, α-thioglycoside 8 lead to the racemic product.
The aromatic thioglycosides, either hindered 5 or unhindered 6, af-
forded the same moderate enantioselectivity around 60% ee. Bulkier
alkyl thioglycosides, such as the tert-butyl thioglycoside 7, afforded the
desired product in 92% ee.
The optimization of the reaction conditions shows that using 2 mol%
of the palladium, 2.8% of the ligand in methylene chloride at −20◦C
afforded the allylic alkylation product in 96% ee. Using the same condi-
tion and benzylamine as nucleophile afforded the allyl amine product in
94% ee and quantitative yield, Scheme 3. At the onset of this study was
the determination of the sulfur stereocontrol upon coordination to the
metal. To address this problem we synthesized the corresponding Pd(II)
SCHEME 3

Mixed S/P Ligands from Carbohydrates
1257
complex by treatment of 7 with palladium bis-chloro bis-acetonitrile.
The complex was obtained in 90% yield as a single isomer, as shown
by dynamic proton and phosphorus nuclear magnetic resonance (NMR)
study, indicating an efficient control of the sulfur chirality. The nuclear
overhauser effect spectroscopy (NOESY) study of the complex shows
that, beside the usual NOE contacts between the H1-H3-H5 that indi-
cate a 4C1 conformation of the pyranose ring, there is an intense NOE
contact between the anomeric proton and the tert-butyl group. Addition-
ally, as no NOE contact between tert-butyl group and the H-2 proton
was detected, we conclude that sulfur configuration is S as predicted.
Application of Phosphinite Thioglycosides
to Rhodium-Catalyzed Asymmetric Hydrogenation
Owing to the good results of the ligand 7 in asymmetric allylic substi-
tution, we decided to evaluate its activity in asymmetric hydrogenation
of enamides. The Pd and Rh complexes employed in these processes
are structurally homologous square planar d8 metals complexed by a
common ligand family. Accordingly, the origins of the setereoinduction
may be owed to the interplay of the trans influence and metal-induced
sulfur chirality. The model reaction we chose was the hydrogenation of
methylacetamido cinnamate, leading to the protected phenylalanine. A
large number of effective chiral bis-phosphines are available for this
transformation. Nevertheless mixed ligands have been scarcely used,
all of which lead to low reactivity or selectivity or both. To start this
study we developed a well-defined catalyst precursor. Treatment of 1
equiv. of 7 with 1 equiv. of [(cod)2Rh]SbF6 afforded the cationic complex
9 in 90% yield (Scheme 4).
SCHEME 4
The utilisation of 1 mol% of 9 in THF at room tempertaure (rt) un-
der only 1 atm of hydrogen afforded the (S)-acetamido-phenyl alanine
methyl ester in quantitative yield and in 92% ee. The use of more hydro-
gen pressure (4 atm) afforded the product with the same enantiomeric
excess.

1258
N. Khiar et al.
One of the drawbacks when using carbohydrates in asymmetric syn-
thesis in general, and as chiral ligands in asymmetric catalysis, is the
difficulties to accede to the other enantiomer. Accordingly, although the
price of D-glucose is low (1.2 Eu/mol), L-glucose is prohibitively expen-
sive (8650 Eu /mol), ruling out any possibility of using L-sugars even
in catalytic processes. In order to solve this problem we have noticed
that α-D-arabinose 10, a cheap commercially available D-pentopyranose,
which exists mainly in the 1C4 conformation, is a quasi-mirror image of
β-galactose. The synthesis of 2-phosphinite tert-butyl-thioarabinoside
11 has been carried out in four high-yielding steps from arabinose
tetraacetate (Scheme 5). Using 2 mol% of the palladium, 2.8% of the
SCHEME 5
ligand in methylene chloride at −20◦C afforded the opposite enantiomer
of the allylic alkylation product in 96% ee. Additionally the use of 1 mol%
of the cationic Rh(I) complex 12 in the hydrogenation of methylcinna-
mate afforded the R-isomer in 92% ee. Thus even though belonging to
the D-serie, ligand 7 and ligand 11 behave as enantiomers.
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