Useful sialic acid modifications catalyzed by palladium

Article abstract of DOI:10.1002/chem.200900093

A stereo- and regioselective allylic substitution on simple N-acetylneuraminic acid (Neu5Ac2en) derivatives that ensures the control of the regio- and stereoselectivity and affords the C-2 or C-4 products with high efficiency, was studied. The Neu5Ac2en substrates were easily prepared from the peracetylated methyl ester 9 obtained by standard treatment overnight of the corresponding Neu5Ac methyl ester. Treatment of acetate 10 under Pd⁰-catalyzed allylic substitution conditions using sodium dimethylmalonate as a nucleophile failed to provide any alkylation product. The regioselectivity was largely improved to a synthetically useful level when using a more basic monophosphine ligand. A complete reversal of the regioselectivity occurred when the reaction was performed in the presence of bidentate phosphine. Selective transformations of these products provide easy entry to a variety of modified sialic acid derivatives, which can serve as useful sialyl building blocks for biological research.

Full text of DOI:10.1002/chem.200900093

COMMUNICATION
DOI: 10.1002/chem.200900093
Useful Sialic Acid Modifications ACHTUNTRGNEUNGCatalyzed by Palladium
Chih-Wei Chang,[a] Stꢀphanie Norsikian,[a] and Jean-Marie Beau*[a, b]
The development of efficient synthetic methods for the
preparation of N-acetylneuraminic acid (Neu5Ac) conju-
gates and modified structures for biological research or ther-
apeutic intervention has been a major focus in carbohydrate
chemistry, owing to its significant role in physiological pro-
cesses and diseases.[1,2] This has led to intense research inter-
est in sialic acid chemistry[3] comprising the design of potent
chemotherapeutic agents against the influenza virus.[4] In the
latter area, 2,3-unsaturated N-acetylneuraminic acid (2; 5-
acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d-galacto-non-
2-enoic acid, Neu5Ac2en), first discovered by Meindl and
Tuppy in 1969 as a potent neuraminidase inhibitor,[5] was
highly instrumental as it served as a structural basis for the
discovery and development of two anti-influenza drugs cur-
rently used to treat infected patients, Zanamivir (3) (Re-
lenza) and Oseltamivir phosphate (4) (Tamiflu), both very
potent inhibitors of the influenza neuraminidase
(Figure 1).[4,6] Recent reports on the emergence of drug re-
sistance[7] make, however, the development of new anti-in-
fluenza molecules a priority, using fast and efficient proce-
dures to access to new constructs.[8] Furthermore, the design
and synthesis of selective human neuraminidase inhibitors is
also highly desirable.[9]
Figure 1. Potent neuraminidase inhibitors mimicking the putative high-
energy oxycarbenium intermediate during the neuraminidase cleavage.
couraged by previous failures on substrate 5 (PG=Ac, R=
Me, Scheme 1) equipped with an equatorial allylic substitu-
ent at C-4. This chemistry was rather exploited with the C-4
isomeric substrate 5 undergoing an easy formation of a p-
allyl palladium complex because of the axially disposed
leaving group, thus providing the C-4 products with overall
retention of configuration with the azide ion.[11,12]
Selective transformations at C-2 and C-4 are desirable
goals and because of its broad scope and versatility, palladi-
um(0)-catalyzed allylic substitution[10] would offer an effi-
cient approach for these selective modifications of the allylic
system in Neu5Ac2en derivatives 5 (Scheme 1). Also, a
useful aspect would be the possibility of controlling the
regio- and stereoselectivity of the reaction on the allylic
system. This attractive solution was, however, largely dis-
[a] C.-W. Chang, Dr. S. Norsikian, Prof. J.-M. Beau
Institut de Chimie des Substances Naturelles du CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Scheme 1. Palladium-catalyzed substitution of 2,3-unsaturated sialic acid
[b] Prof. J.-M. Beau
derivatives. Pg=protecting group. L=ligand.
Universitꢀ Paris-Sud 11, Institut de Chimie Molꢀculaire
et des Matꢀriaux associꢀ au CNRS, 91405 Orsay Cedex (France)
Fax : (+33)1-6985-3715
The half-chair conformational flexibility in glycals[13] and
the electronic effects in substrates such as 5 could, however,
be modulated by a simple change of the protecting groups
E-mail: jmbeau@icmo.u-psud.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900093.
Chem. Eur. J. 2009, 15, 5195 – 5199
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5195

(PG). This would facilitate the initial oxidative addition on
5
conformer H6 6, with a pseudo-axial allylic group at C-4, to
the p-allyl palladium complex 7, eventually equilibrating to
the inverted half-chair complex 8. Further, it could be antici-
pated that the regioselectivity of the nucleophilic attack
could be influenced by the nature of the nucleophile[14] as
well as the ligands associated with the allylpalladium com-
plex,[15] thus possibly providing a selective access to the C-2
or the C-4 products. We report here our preliminary results
on the successful development of this approach on simple
Neu5Ac2en derivatives, that ensure the control of the regio-
and stereoselectivity and provide the C-2 or C-4 products
with high efficiency.
Scheme 3. Allylic substitution of Neu5Ac2en derivatives 11 and 12 with
sodium dimethylmalonate.
4 alkylated product 16 (palladium/PPh3 ratio of 1, C-2/C-4
ratio of 25:75, 98%; Scheme 3 and Table 1, entry 1) after a
notably shorter reaction time (0.5 vs. 18 h).
For the purpose of this study, the Neu5Ac2en substrates
were easily prepared from the peracetylated methyl ester 9
obtained by standard treatment (acetic anhydride, pyridine,
cat. 4-(dimethylamino)pyridine, RT, overnight)[16] of the cor-
responding Neu5Ac methyl ester[17] (Scheme 2). Treatment
of ester 9 by trimethylsilyl triflate in ethyl acetate readily in-
duced the b-elimination to the unsaturated derivative 10.
Zemplꢀn de-O-acetylation followed by a 8,9-isopropylidena-
tion[18] furnished a diol which was selectively benzoylated to
the allylic benzoate 11 and silylated to the 7-OTBS deriva-
tive 12 in 88% yield.[19]
Table 1. Regio- and stereoselective allylic substitution of Neu5Ac2en de-
rivative 12 with sodium dimethylmalonate.
Entry
mol% of catalyst,[a] ligand (equiv)[b]
Yield[c] [%]
15/16[d]
1
2
3
4
5
6
7
8
10, PPh3 (1)
10, PCy3 (2)
10, PBu3 (2)
5, PBu3 (2)
10, dppb (2)
10, dppb (1)
10, none
5, dppb (4)
2.5, dppb (4)
10, dppe (2)
10, dppf (2)
98
91
95
95
84
91
66
92
87
88
94
25:75
9:91
5:95
13:87
>95:5
53:47
47:53
>95:5
93:7
9
10
11
>95:5
>95:5
[a] The reaction was carried out at 508C for 0.5–3 h with [Pd2-
(dba)3]·CHCl3 and 2 equiv of sodium dimethylmalonate in degassed sol-
AHCTUNGTRENNUNG
vent at a concentration of 0.08m in THF. [b] Equiv relative to the palladi-
um catalyst. [c] Isolated yield following chromatography. [d] Determined
by 1H NMR spectroscopy of the crude reaction mixture. dppb=1,4-bis-
A
dppe=1,2-bis(diphenylphosphino)ethane.
dppf=1,1’-bis(diphenylphosphino)ferrocene.
The regioselectivity was largely improved to a synthetical-
ly useful level when using a more basic monophosphine
ligand with a C-2/C-4 ratio of 9:91, (91% yield) with P(Cy)3,
or of 5:95, (95% yield) with P(Bu)3 (Table 1, entries 2 and
3). Similar results were obtained with other palladium sour-
Scheme 2. Preparation of Neu5Ac2en derivatives 11 and 12. a) TMSOTf,
AcOEt, 08C to RT, 4 h; 89%; b) NaOMe, MeOH; c) CSA, 2,2-dimeth-
ACHTUNGTRENNUNGoxyACHTUNGTRENNUNGpropane, acetone; d) BzCl, pyridine, CH2Cl2; 72% for the 3 steps;
e) TBSOTf, CH2Cl2, lutidine, RT; 88%.
ces {[PdACHUTTGNERN(NUG OAc)2], [PdCl2ACHTUNGTERN(NNGU PhCN)2], [(allylPdCl)2]} but [Pd2-
AHCTUNGTRENNUNG
Treatment of acetate 10 under Pd0-catalyzed allylic substi-
tution conditions (see below) using sodium dimethylmalo-
nate as a nucleophile failed to provide any alkylation prod-
uct, an observation in agreement with previous work using
similar conditions on this substrate.[11] In contrast, allylic
benzoate 11 readily reacted with sodium dimethylmalonate
crease in the catalyst loading to 5 mol% is possible (C-2/C-4
ratio of 13:87, 95% yield; Table 1, entry 4). Most unexpect-
edly, a complete reversal of the regioselectivity occurred
when the reaction was performed in the presence of biden-
tate phosphines (dppe, dppb, dppf, entries 5, 8–11). With
these ligands, the more substituted anomeric adduct 15 was
largely favored independently of the palladium source
tested, with the best results being obtained with [Pd2-
in the presence of PdACTHNUTRGNE(UGN OAc)2 (20 mol%) in combination
with PPh3 (40 mol%). The reaction, carried out at 508C for
18 h provided regioselectively product 13, alkylated at C-2
on the a face of the sugar (C-2/C-4 ratio of 81:19, 66%
yield; Scheme 3). Different palladium sources {[Pd2-
AHCTUNTGRENGUN(N dba)3]·CHCl3. The proportion of the ligand was crucial
since at least two equivalents of the diphosphine dppb rela-
tive to palladium were needed to attain high regioselectivity
(over 95:5). With only one equivalent of diphosphine per Pd
atom, the reaction led unselectively to 15/16 in a 53:47 ratio
(entry 6), a result very similar to the one obtained without
added ligand (entry 7). The reaction was also performed in
ACHTUNGTRENNUNG(dba)3]·CHCl3, [(allylPdCl)2], etc.} associated with different
ligands (PPh3, PBu3, dppb, etc.) did not significantly improve
this transformation. Surprisingly, silylated allylic benzoate
12 provided regioselectively, under similar conditions, the C-
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Chem. Eur. J. 2009, 15, 5195 – 5199

Sialic Acid Modifications
COMMUNICATION
ed for a selective C-2 alkylation. To better rationalize these
results, the neutral complex 19 and the cationic complex 20
were prepared from the chloro-bridged dimer 18
(Scheme 5).[21] For the neutral complex 19, detailed NMR
analysis readily showed that C-4 is trans to the phosphine
ligand, because of a shift of this carbon to higher frequency
and the large value of the JACTHNUTRGENUGN(P,C4) coupling constant of
Scheme 4. Formation of bicyclic acetal 17.
28 Hz (see Supporting Information for details).[15a,22]
The two complexes 19 and 20 were then engaged in the
stoichiometric reaction with sodium dimethylmalonate in
THF at 508C. The neutral complex 19 led to a 35:65 mixture
of 15 and 16, a selectivity in agreement with the catalytic re-
action, with the favored attack of the nucleophile at C-4,
trans to the best acceptor ligand.[23] The cationic complex 20
also gave a selectivity (a 71:29 mixture of 15 and 16) consis-
tent with the catalytic reaction, with the preferential forma-
tion of the 2-C alkylated compound. This is in line with a
longer Pd C-2 bond as detected by 13C NMR spectroscopy
À
in complex 20.[24]
To complete these preliminary results, a short survey of
the allylic substitution of 12 with other nucleophiles is pre-
sented in Table 2. In contrast with the reaction performed
with sodium dimethylmalonate, the reaction led to the 4-C
adduct as the major regioisomer whatever the ligand
used.[25] For each nucleophile, various conditions were tested
and the best ones are reported in Table 2.
Scheme 5. Preparation of the palladium complexes and their reaction
with sodium dimethylmalonate. Reagents and conditions: a) [PdACTHNUTRGEN(UNG dba)2],
LiCl, THF, RT, 72%; b) PPh3 (2 equiv), CDCl3 then AgOBz (2 equiv);
c) dppb (3 equiv), CDCl3 then AgOTf (2.2 equiv); d) sodium malonate
anion, THF, 508C. dppb=1,4-bis(diphenylphosphino)butane.
Straightforward deprotection of these derivatives was pos-
sible as shown with the morpholine derivative 28 affording
triol 30 (Scheme 6). The malonyl derivatives also offered an
easy entry to a variety of transformations. Thus, hydrogena-
other solvents such as dichloromethane, CH3CN or toluene
with similar trends.
À
The structures of 13–16 were assigned on the basis of
1H NMR analysis.[20] Interestingly, bicyclic derivative 17 was
formed in high yield by treating 11 with the palladium cata-
lyst without an external nucleophile (Scheme 4). This re-
vealed a probable transitory p-allyl palladium complex close
in geometry to 17 and therefore to conformer 7 (Scheme 1).
This explains logically the selec-
tion of the C C double bond in the unsaturated derivative
15 provided the corresponding 4-deoxy-C-glycosyl analogue
32 (Scheme 6).
In addition, decarboxylation[26] of the methyl malonates
15 and 16 opened an efficient entry to the C-2 and C-4-
branched modified sialo-acetic acids, under conditions that
tive formation of the C-2
adduct based on steric grounds,
Table 2. Conditions for the regioselective allylic substitution of 12 with various nucleophiles.
with the bulky side chain at C-6
screening the C-4 attack of the
incoming nucleophile.
The importance of the nature
of the ligands and of the Pd/
ligand ratio in obtaining high
regioselectivities in the alkyla-
tion of the 7-OTBS derivative
12 suggests that different p-allyl
palladium species could be in-
volved. For this substrate, a 1:1
ratio of Pd/PPh3 had to be used
in order to obtain the selectivity
at C-4, which led us to consider
the involvement of a neutral
complex with monophosphine
ligands. In contrast, an excess
Entry
Nucleophile[a]
Solvent
Ligand (equiv)[b]
Additives
AHCTUNGTRENNUNG
(equiv)[c]
Product, Yield [%][d]
1
2
3
4
5
6
7
8
NaCH
NaN3
N
THF
PBu3 (1)
dppb (1)
dppb (2)
dppb (2)
dppb (2)
dppb (2)
dppb (2)
dppb (2)
–
22, 46
23, 65
24, 74
25, 89
26, 82
27, 63
28, 90
29, 88
THF/H2O[e]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Bu4NBr (0.1)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Cs2CO3 (10)
aniline
benzylamine
N-methylbenzylamine
21
morpholine
phenol
[a] The reactions were carried out in a degassed solvent at a concentration of 0.07m with 20 mol% of [Pd2-
(dba)3]·CHCl3 and 3 equiv of the nucleophile at 60–808C for 8–15 h, until TLC showed conversion of the start-
ing material. [b] Equiv relative to the palladium catalyst. [c] Equiv relative to the substrate. [d] Isolated yield
AHCTUNGTRENNUNG
of diphosphines is recommend- following chromatography. [e] As a 4:1 mixture.
Chem. Eur. J. 2009, 15, 5195 – 5199
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www.chemeurj.org
5197

J.-M. Beau et al.
596.2503; found 596.2500; elemental analysis calcd (%) for
C26H43NO11Si: C 54.43, H 7.55, N 2.44; found: C 54.51, H 7.53, N 2.36.
Preparation of 16: In a Schlenk tube, a solution of [Pd2ACTHUNTRGNE(UGN dba)3]·CHCl3
(51 mg, 0.05 mmol) and PBu3 (50 mL, 0.2 mmol) in degassed THF (2 mL)
was added to 12 (281 mg, 0.5 mmol). After stirring for 10 min, a solution
of freshly-prepared sodium dimethyl malonate in THF (3 mL, 1 mmol)
was added and the resulting mixture was heated at 508C for 15 h. After
cooling, the solvents were removed under reduced pressure and the resi-
due was purified by flash column chromatography on silica gel (CH2Cl2/
MeOH 1:0 to 99:1) to give 16 as a colorless solid (261 mg, 92%). M.p.
788C; [a]2D5 =+30.2 (c=1 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
3
d=6.02 (d, J
G
R
1H; NHAc), 4.38 (dd, 3J
6), 4.29 (td, 3J(H-8,H-7)=5.0, 3J
H-8), 4.14 (dd, 3J
(dd, 3J
(H-6,H-7)=1.2, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
Scheme 6. Selective transformations of the allylic substitution products.
a) TBAF, THF, RT, 2 h; 91%; b) aq. NaOH, MeOH, RT, 19 h; c) 80%
AcOH, 808C, 72% for the two steps; d) DMSO, H2O, NaCl, 1508C, 3 h,
62%; e) 10% Pd/C, H2, AcOEt, RT, 24 h; 86%; f) aq. NaOH, MeOH,
1408C, 3 h, 74%.
A
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
provided the di-acid 33 or maintained the ester groups as
with di-ester 31 (Scheme 6). These derivatives represent
suitable precursors for the elaboration of sialo clusters
useful for biological studies.
3H; CH3), 1.30 (s, 3H, CH3), 0.87 (s, 9H; 3ꢂCH3), 0.12 (s, 3H; CH3),
0.11 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=170.2
(CO), 168.7 (CO), 167.9 (CO), 162.3 (CO), 144.1 (C-2), 109.9.1 (C-3),
108.3 (Cq), 77.5 (C-6), 76.3 (C-8), 71.5 (C-7), 65.6 (C-9), 52.8 (OCH3),
52.6 (OCH3), 52.1 (C-malonyl, OCH3), 47.7 (C-5), 38.2 (C-4), 26.6 (CH3),
In conclusion, we have developed a stereo- and regiose-
lective allylic substitution on simple Neu5Ac2en derivatives
that ensures the control of the regio- and stereoselectivity
and affords the C-2 or C-4 products with high efficiency. Se-
lective transformations of these products provide easy entry
to a variety of modified sialic acid derivatives, which can
serve as useful sialyl building blocks for biological research.
26.0 (SiC
(CH3)3), 24.9 (CH3), 23.6 (CH3), 18.4 (SiC), À3.3 (SiCH3),
À4.3 ppm (SiCH3); IR (neat): n˜ =3476 (br), 3267 (br), 2957, 2358, 1735,
1643, 1550, 1433, 1370, 1331, 1246, 1155, 1111, 1058, 1012, 890, 853, 757,
710 cmÀ1
;
ESI HRMS: m/z: calcd for C26H43NO11SiNa [M+Na]+:
596.2503; found 596.2503; elemental analysis calcd (%) for
C26H43NO11Si: C 54.43, H 7.55, N 2.44; found: C 54.31, H 7.54, N 2.38.
Acknowledgements
The authors gratefully acknowledge the National Chiao Tung University
and the Institut FranÅais de Taipei for a Ph.D. grant to C-W.C.
Experimental Section
Detailed experimental procedures have been provided in the Supporting
Information.
Keywords: carbohydrates · palladium · regioselectivity ·
sialic acid · stereoselective catalysis
Preparation of 15: In a Schlenk tube, a solution of [Pd2ACTHUNTRGNE(UGN dba)3]·CHCl3
(5.1 mg, 5 mmol) and dppb (8 mg, 20 mmol) in degassed THF (0.2 mL)
was added to 12 (28.1 mg, 50 mmol). After stirring for 10 min, a solution
of freshly-prepared sodium dimethyl malonate in THF (0.3 mL,
0.1 mmol) was added and the resulting mixture was heated at 508C for
3 h. After cooling, the solvents were removed under reduced pressure
and the residue was purified by flash column chromatography on silica
gel (CH2Cl2/MeOH 1:0 to 49:1) to give 15 as a colorless solid (24 mg,
84%). M.p. 1438C; [a]2D5 =À3.3 (c=1.3 in CHCl3); 1H NMR (300 MHz,
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548.
CDCl3, 258C): d=6.02 (dd, 3J
G
ACHTUNGERTN(NUNG H-3,H-4)=10.4 Hz, 1H;
H-3), 5.99 (dd, 3J
A
ACHTUNGTRENNUNG
3
3
(d, J
(NH,H-5)=7.5 Hz, 1H; NH), 4.36 (ddt, J
(H-5,NH)=7.5, J
G
ACHTUNGTRENNUNG
1.5, 3J
G
N
G
3
7)=3.0, 3J
A
U
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
9’)=7.5 Hz, 1H; H-9’), 3.74 (s, 3H; OCH3), 3.71 (s, 3H; OCH3), 3.70 (s,
3H; OCH3), 1.94 (s, 3H; NHCOCH3), 1.40 (s, 3H; CH3), 1.31 (s, 3H;
CH3), 0.89 (s, 9H; CH3), 0.12 (s, 3H; CH3), 0.11 ppm (s, 3H; CH3);
13C NMR (75 MHz, CDCl3, 258C): d=170.1 (CO), 169.8 (CO), 166.2
(CO), 166.0 (CO), 132.3 (C-4), 125.1 (C-3), 107.7 (Cq), 78.9 (C-2), 77.4
[6] For recent reviews on Tamiflu synthesis, see: a) V. Farina, J. D.
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(C-8), 76.6 (C-6), 70.8 (C-7), 64.7
ACHTUNGTRENNUNG
52.5 (OCH3), 44.3 (C-5), 26.3 (CH3), 26.0 (SiCAHCTUNGTRENNNUG
(CH3 NHCOCH3), 18.2 (SiC), À4.9 (SiCH3), À3.9 ppm (q, SiCH3); IR
(neat): n˜ =2951, 1740, 1646, 1542, 1433, 1243, 1156, 1015, 835, 776,
[7] P. Ward, I. Small, J. Smith, P. Suter, R. Dutkowski, J. Antimicrob.
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714 cmÀ1
;
ESI HRMS: m/z: calcd for C26H43NO11SiNa [M+Na]+:
5198
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Sialic Acid Modifications
COMMUNICATION
[8] Large quantities of Neu5Ac are now available by biotransformation
of the abundant biomass primary product N-acetyl-d-glucosamine;
see: M. J. Dawson, D. Noble, M. Mahmoudian (Glaxo) US 6156544,
2000, and references therein.
[9] For a recent review, see: A. Buschiazzo, P. M. Alzari, Curr. Opin.
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G. B. Kok, M. von Itzstein, J. Chem. Soc. Perkin Trans. 1 1998, 905–
908.
[13] About the conformational flexibility of glycals, see: A. A. Chalmers,
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Santoro. Org. Magn. Res. 1976, 8, 49–55; J. Thiem, P. Ossowski, J.
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Received: January 13, 2009
Published online: April 7, 2009
Chem. Eur. J. 2009, 15, 5195 – 5199
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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