Stereoselective Palladium-Catalyzed O-Glycosylation Using Glycals

Article abstract of DOI:10.1021/ja039746y

A highly stereoselective palladium-catalyzed O-glycosylation reaction is described. The reaction of a glycal 3-acetate or carbonate with the zinc(II) alkoxide of acceptors establishes the glycosidic linkage under palladium catalysis to give rise to disaccharides as the product in good yields and with high stereoselectivity. In contrast to the Lewis acid mediated Ferrier procedure, the anomeric stereochemistry of this reaction is controlled by the employed ligand. Whereas the use of a complex of palladium acetate and 2-di(tert-butyl)phosphinobiphenyl as the catalyst results in the exclusive β-glycoside formation, the same reaction using trimethyl phosphite ligand furnishes an α-anomer as the major product. The utility of the 2,3-unsaturation present in the resulting glycoside is demonstrated by the further transformations such as dihydroxylation, hydration, and hydrogenation reactions. Thus, the combination of the glycosylation and subsequent functionalization provides a novel entry to saccharides which are otherwise difficult to prepare. The broad scope of the process, mildness of the reaction conditions, and experimental simplicity should make this method a useful tool in synthetic carbohydrate chemistry. Copyright

Full text of DOI:10.1021/ja039746y

Published on Web 01/15/2004
Stereoselective Palladium-Catalyzed O-Glycosylation Using Glycals
Hahn Kim, Hongbin Men, and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
Received November 23, 2003; E-mail: cblee@princeton.edu
Table 1. Pd-Catalyzed Glycosylation of Benzyl Alcohol with Glycal
1a
Efficient and selective construction of glycosidic linkages
continues to be important due to the critical roles played by various
glycoconjugates in nature.1 Different in modality from the majority
of chemical glycosylations, the Ferrier reaction achieves glycos-
ylation via displacement of the C3 substituent in a glycal system
(eq 1).2 Due to the synthetic versatility of the 2,3-unsaturated
glycoside, this method has proven useful for a wide range of
applications.3 The exceptional synthetic value of the Ferrier process,
however, has not been translated significantly to carbohydrate
chemistry, despite the original conception of the reaction for direct
O-glycosylation. The dominant anomeric effect has limited the
utility of this method largely to the synthesis of R-glycosides using
a stoichiometric Lewis acid. Given the ready availability of glycals
and the synthetic utility of the product, the development of a glycal-
based glycosylation method whose scope transcends the Ferrier
paradigm would represent an important advance.
entry
glycal
ligand
yield (%)b
dr (2r:2â)c
1d
2
3
1a X ) OAc
15% DTBBP
15% dppf
15% dppb
30% P(t-Bu)3
30% P(2-furyl)3
40% PPh3
30% P(OMe)3
15% DTBBP
30% P(OMe)3
92
95
96
92
90
87
90
92
90
<1:25
1:5
1:4
1.5:1
2:1
4:1
7:1
<1:25
5:1
4
5
6e
7
8
1b X ) OtBoc
9f
a All reactions were carried out in THF (1.0 M) at 25 °C for 48 h.
b Isolated yield. c Anomeric ratio determined by 1H NMR. d DTBBP )
di(tert-butyl)-2-biphenylphosphine. e Pd(PPh3)4 was used as the catalyst.
f 91% yield and 2â:2r ) 1:7 when 20 mol % of NH4OAc was added.
afford disaccharides in good yield. The efficiency of the reaction
is well illustrated by the fact that torsional deactivation8 (entries
1-3), the reaction sites of acceptors, or the nature of protecting
groups had little effect on the facility of glycosylation. It is also
noteworthy that glycal 4 fared well in this process despite the
potential complications by its C6 deoxygenation and (L)-configu-
ration (entry 4).9 Similarly, galactal 5 was found to be a viable
substrate for glycosylation (entry 5).10 As demonstrated in the model
study, selective access to the R- or â-linked product from the same
pair of reactants was realized by choice of the ligand (entries 6-10).
The utility of the 2,3-unsaturated product was next explored (eqs
3-5).11 Subjection of 13 to dihydroxylation gave rise to â-alloside
23 as a single diastereomer.5,12 Starting from 21â, a sequence
involving a mercury(II)-mediated hydration furnished 2-deoxysugar
24 with complete regio- and stereocontrol.13 The 2,3,6-trideoxy
system 25 was also readily available by diimide hydrogenation of
16.14
Our approach to glycosylation is to exploit transition metal
catalysis using the allylic feature contained within the glycal
structure (eq 2). However, the poor reactivity of both the glycal
donors and the alcohol acceptors for a η3-metal mediated reaction
has been a major challenge to this approach.4,5 Encouraged by our
recent results,6 we envisioned that the reaction of an acceptor
activated via zinc(II) alkoxide formation with a metal coordinated
cationic donor might accomplish the desired O-glycosylation.
Reported herein is the discovery of a Pd-catalyzed glycosylation
reaction that occurs under mild reaction conditions with the
anomeric configuration controlled by the reagent rather than by
the anomeric or neighboring group effect.
Initial experiments were performed with glycal 1 as the donor
and benzyl alcohol as the acceptor (Table 1). Upon treatment of 1
with a preformed solution of benzyl alcohol (1.0 equiv) and Et2Zn
(50 mol %) in the presence of a palladium catalyst, the reaction
proceeded smoothly to furnish 2 in excellent yield. Notably, the
anomeric stereochemistry depended strongly on the ancillary ligands
at palladium. While moderate selectivities were obtained from the
reactions with common mono- and diphosphines, employment of
DTBBP ligand7 led to complete â-O-glycoside formation, which
cannot be brought about by the traditional Lewis acid mediated
Ferrier procedures (entries 1 and 8). When P(OMe)3 was employed
as the ligand, the R-anomer was generated as the major product in
a 7:1 ratio (entries 7 and 9). Hence, simple alteration of the ligand
provided a switch from â- to R-selective glycosylation.
While a detailed understanding of the present reaction awaits
further studies, a simple mechanistic picture may be advanced,
wherein paths A-D exist for the R-anomer formation (Scheme 1).15
Scheme 1
When P(OMe)3 is used as a ligand, one or more of these paths
may become competitive, whereas the common net retention
mechanism 1 f 2â is believed to be operative in the case of the
DTBBP ligand.16 Regardless of the stereochemical outcome, the
The scope of the new glycosylation was further examined in the
context of disaccharide synthesis (Table 2). An array of monosac-
charide donors and acceptors underwent glycosidic coupling to
9
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J. AM. CHEM. SOC. 2004, 126, 1336-1337
10.1021/ja039746y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Palladium-Catalyzed Synthesis of Disaccharidesa
unnatural carbohydrates and should find useful applications in
carbohydrate chemistry.
Acknowledgment. We thank Princeton University for startup
funding and Hugh Stott Taylor and Atofina Fellowships (H.K.).
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503. (b) Nicolaou,
K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576.
(2) (a) Ferrier, R. J. J. Chem. Soc. C 1964, 5443. (b) Ferrier, R. J.; Ciment,
D. M. J. Chem. Soc. C 1966, 441. (c) Ferrier, R. J.; Prasad, N. J. Chem.
Soc., Chem. Commun. 1968, 476. (d) Ferrier, R. J.; Prasad, N. J. Chem.
Soc. C 1969, 570. (e) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969,
575. (f) Ferrier, R. J. AdV. Carbohydr. Chem. Biochem. 1969, 199. For
reviews, see: (g) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153. (h)
Ferrier, R. J.; Zubkov, O. A. Org. React. 2003, 62, 569.
(3) (a) Fraser-Reid, B. Acc. Chem. Res. 1975, 8, 192; 1985, 18, 347; 1996,
29, 57. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycoside; Pergamon
Press: Tarrytown, NY, 1995. (c) Postema, M. H. D. C-Glycoside
Synthesis; CRC Press: Boca Raton, FL, 1995. (d) Csuk, R.; Schaade,
M.; Krieger, C. Tetrahedron 1996, 52, 6397.
(4) The difficulty of forming a π-allylpalladium species from a glycal system
has been noted, see: (a) RajanBabu, T. V. J. Org. Chem. 1985, 50, 3642.
(b) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406.
(5) For recent examples of Pd-catalyzed O-glycosylation using a more
activated pyranone system, see: (a) Comely, A. C.; Eelkema, R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 8714. (b)
Reference 4b.
(6) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369.
(7) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(8) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen, J. P.
J. Am. Chem. Soc. 1991, 113, 1434.
(9) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. Engl. 1991,
30, 180.
(10) (a) Abdel-Rahman, A. A.-H.; Winterfield, G. A.; Takhi, M.; Schmidt, R.
R. Eur. J. Org. Chem. 2002, 713. (b) Babu, B. S.; Balasubramanian, K.
K. Synth. Commun. 1999, 29, 4299. (c) Grynkiewicz, G.; Priebe, W.;
Zamojski, A. Carbohydr. Res. 1979, 68, 33.
(11) The configuration of the new stereogenic center(s) of the product was
determined by 1H NMR analysis. See Supporting Information.
(12) (a) Murphy, P. V.; O’Brien, J. L.; Smith, A. B. Carbohydr. Res. 2001,
334, 327. (b) Friesen, R. W.; Danishefsky, S. J. Tetrahedron 1990, 46,
103.
(13) (a) Brown, H. C.; Geoghegan, P. J. J. Am. Chem. Soc. 1967, 89, 1522.
(b) Brown, H. C.; Geoghegan, P. J. J. Org. Chem. 1970, 35, 1844.
(14) (a) Servi, S. J. Org. Chem. 1985, 50, 5865. (b) Hart, D. J.; Hong, W. P.;
Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665. (c) Haukaas, M. H.; O’Doherty,
G. A. Org. Lett. 2002, 4, 1771.
(15) Path A: (a) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 581. Path B:
(b) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730.
(c) Ba¨ckvall, J.-E.; Nordberg, R. E. J. Am. Chem. Soc. 1981, 103, 4959.
Path C: (d) Takahashi, T.; Jinbo, Y.; Kitamura, K.; Tsuji, J. Tetrahedron
Lett. 1984, 25, 5921. (e) Granberg, K. L.; Ba¨ckvall, J.-E. J. Am. Chem.
Soc. 1992, 114, 6858. (f) Although Path D for a π-allylpalladium alkoxide
species is unreported, the reductive elimination mechanism of an arylpal-
ladium alkoxide species has been known. See: Widenhoefer, R. A.; Zhong,
H. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6787.
(16) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(17) (a) Steinhuebel, D. P.; Fleming, J. J.; Du Bois, J. Org. Lett. 2002, 4, 293.
(b) In control experiments, both 1 and 1′ failed to undergo the O-
glycosylation in the absence of a Zn(II) ion. Also see refs 4 and 5.
a All reactions were performed with 1.5 equiv of acceptor, 0.8 equiv of
Et2Zn, 10 mol % of Pd(OAc)2, and 15 mol % of DTBBP (entries 1-10) or
b
30 mol % of P(OMe)3 (entries 6-10) in THF at 25 °C for 48 h. 1H NMR
ratio. c Isolated yields. d Single isomer (dr > 25:1). e The donor was slowly
added over 8 h via a syringe pump. f R:â ) 9:1. g R:â ) 12:1. h R:â ) 8:1.
i 20 mol % of Pd(OAc)2/60 mol % of P(OMe)3.
Zn(II) ion in this reaction appears to play an important dual role of
activating both the acceptor for the nucleophilic addition and the
leaving group for the ionization.17
We have developed a new Pd-catalyzed O-glycosylation method
that allows for the direct use of readily available glycal derivatives
as donors. Notably, the anomeric stereochemistry is effectively
controlled by the reagent, independent of the steric and electronic
nature of the substrates. Also demonstrated is the utility of the 2,3-
unsaturated pyranoside product through stereoselective alkene
addition reactions. This combination of the glycosylation and
subsequent elaboration provides a novel entry to natural and
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