De novo asymmetric bio- and chemocatalytic synthesis of saccharides - Stereoselective formal O-glycoside bond formation using palladium catalysis

Article abstract of DOI:10.1021/ja0347538

A novel integrated bio- and chemocatalytic approach to the de novo catalytic asymmetric synthesis of saccharides has been developed. Acetoxypyranones obtained enantiopure by enzymatic resolution have been shown to undergo highly stereoselective palladium-catalyzed formal O-glycoside bond formation. The combination of these protocols can be applied to the iterative asymmetric catalytic synthesis of saccharides. Copyright

Full text of DOI:10.1021/ja0347538

Published on Web 06/25/2003
De Novo Asymmetric Bio- and Chemocatalytic Synthesis of Saccharides -
Stereoselective Formal O-Glycoside Bond Formation Using Palladium
Catalysis
Alex C. Comely, Rienk Eelkema, Adriaan J. Minnaard, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received February 19, 2003; E-mail: b.l.feringa@chem.rug.nl
Table 1. Stereoselective Acetal Bond Formation Using Pd
Catalysis
The chemical synthesis of carbohydrate domains in saccharides
and glycoconjugates such as antibiotics, antitumor agents, glyco-
proteins, and glycolipids is now recognized as a major frontier for
organic chemistry.1 Fundamental to the synthesis of such carbo-
hydrates and their derivatives is the selectivity of R- or â-O-
glycoside bond formation which typically entails the coupling of
one nucleophilic (O-donating) glycoside to another electrophilic
glycosyl donor;2,3 anomeric stereoselectivity is a complex issue
usually dependent on the nature of the donor C2 substituent.1
Catalytic stereoselective formation of the acetal linkage onto
pyranones4 of type 1 (Scheme 1) presents a conceptually different
solution to this stereochemical problem by providing a stereodefined
platform whose chiral information can be relayed around the ring.
Such an acetal can be a formal R- or â-glycoside bond depending
on the enantiomer of 1, the stereocontrol in the Pd-catalyzed step,
and the chemistry used to elaborate the ring.5
Scheme 1. Iterative Saccharide Synthesis: Stereoselective Acetal
Bond Formation Using Pd Catalysis
adduct
donor
% yield
% ee/de
adduct
donor
% yield
% dee
2A
2B
2C
2D
2E
2F
2G
(-)-1
(-)-1
(-)-1
(-)-1
(()-1
(-)-1
(-)-1
(-)-3
(+)-3
83
87
98
84
94b
98b,c
99b
98b
ndb,d
97b
94e
2H
(-)-1
(-)-3
(+)-3
(-)-1
(-)-3
(+)-3
(-)-1
65a
57a
61a
70a
71a
76a
60
91
92
96
97
82
95
f
2I
69
78a
77a
88a
96a
2J
94e
98e
a Isolated yield of unique stereoisomer. b 10% Pd(OAc)2, P(OPh)3, DCM,
-30 °C; stereoselectivities were determined by chiral HPLC analysis.
c Enantiomeric excess before chromatography. d Coupled to racemic 1 only.
e 5% Pd2(dba)3, PPh3, DCM, -10 °C; diastereoselectivities were determined
Here, we present a novel integrated approach to the de novo
catalytic asymmetric synthesis of saccharides uniting two proto-
cols: the enzymatic resolution of racemic acetoxypyranones 16 with
a highly stereoselective palladium-catalyzed acetal bond formation
onto this embryonic sugar (Scheme 1). Resulting from subsequent
steps to elaborate the ring into a diversity of natural and unnatural
sugars, a free hydroxyl group can be stereoselectively coupled again
to 1, giving rise to an iterative catalytic asymmetric saccharide
synthesis. A blank slate for saccharide synthesis, the versatility of
this cyclic enone platform has been appreciated for some time.7
Despite the widespread use of phenols as nucleophiles in the
palladium-catalyzed allylic substitution reaction,8 aliphatic alcohols
have received scant attention.9,10 During early investigations,
however, we found that the substitution reaction of enantiomerically
pure 6-acetoxy-2H-pyran-3(6H)-one (-)-16 with simple primary
and secondary aliphatic alcohols as solvent proceeded with nearly
complete retention of stereochemistry.11
1
from H NMR. f Mixture of isomers.
and 94% ee. Particularly rewarding were the still higher yields and
ee’s for anisyl nucleophiles B and C and the ortho-nitrobenzyl
alcohol D, useful mimics of benzyl linkers1b,13 applied to the solid-
phase synthesis of saccharides.14 In preliminary experiments to
apply the protocol to the solid-phase, photocleavable E, immobilized
onto phenolic polystyrene, was also coupled efficiently to racemic
1. Representative of Mucin-type glycosylation found in the glyco-
peptides of mammals and other eukaryotes,15 adduct 2F was also
prepared with excellent stereoselectivity.
Key to the feasibility of the protocol is the success of a first
iteration: a stereoselective coupling reaction of enantiopure glycosyl
donor with a sugar derivative. The results are illustrated in Table
1. Initial attempts using the Pd(OAc)2/P(OPh)3 catalyst system
failed, but, to our relief, use of Pd2(dba)3/PPh3 successfully mediated
formation of the desired adducts 2G-2J. Primary alcohol G, a
6-deprotected glucopyranose, underwent coupling with (-)-1 and
both (R)-(-)-3 and (S)-(+)-316 to afford the stereoisomers of the
Efforts to improve the viability of this methodology resulted in
the coupling depicted in Table 1. The use of 10 mol % Pd(OAc)2
and triphenyl phosphite in DCM at -30 °C12 was found to convert
pyranone (-)-1 into the benzyl alcohol adduct 2A in high yield
9
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J. AM. CHEM. SOC. 2003, 125, 8714-8715
10.1021/ja0347538 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
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products with excellent yield (77-96%) and diastereoselectivity
(94-98%). Crucially, similar success was found with the more
sterically demanding substrates 4-deprotected glucopyranose H and
3-deprotected glucofuranose I bearing a secondary alcohol moiety,
and good yields (57-76%) and excellent stereoselectivities (82-
97%) were obtained during both R- and S-acetal bond formation.
All adducts were isolated as unique diastereomers by simple column
chromatography with the exception of that with J, deprotected at
the anomeric center.
References
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A preliminary application of our iterative approach is depicted
in Scheme 2. Diastereoselective catalytic cis-dihydroxylation of
enone adduct 2C was effected by RuCl3/NaIO4,17 and the resulting
diol was protected to the dioxolane 4C under standard conditions.
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18
Subsequent reduction using Zn(BH4)2 gave 5C, a â-L-ribose.19
Coupling of this sugar under the catalytic conditions previously
described successfully afforded the disaccharide precursor 6C with
96% de.20
(7) For a review, see: Holder, N. L. Chem. ReV. 1982, 82, 287. For selected
examples, see: (a) Plaumann, D. E.; Fitzsimmons, B. J.; Ritchie, B. M.;
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Vranken, D. L. Chem. ReV. 1996, 96, 395. For examples using phenols,
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3534 and references therein.
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Scheme 2. Preliminary Application of Iterative Saccharide
Synthesisa
a (i) RuCl3‚3H2O (20 mol %), NalO4; (ii) 2,2-DMP, acetone, PTSA; (iii)
Zn(BH4)2; (iv) (-)-1, Pd2(dba)3 (5 mol %), PPh3, CH2Cl2.
Unsuccessful endeavors to alkylate the methylene position of
4C led to an appraisal of prefunctionalized pyranone substrate 7 in
the palladium-catalyzed allylic substitution reaction (Scheme 3).
Prepared enantiopure employing a Sharpless dihydroxylation
protocol,7j 7 indeed underwent substitution with complete retention
of stereochemistry, giving 8. 4,4-Dimethyl-substituted pyranone
(10) Glycosides have been allyl protected using a Pd-catalyzed allylic substitu-
tion reaction: Lakhmiri, R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1989,
30, 4669.
(11) Van der Deen, H.; Van Oeveren, A.; Kellogg, R. M.; Feringa, B. L.
Tetrahedron Lett. 1999, 40, 1755.
9,7i,16 applicable to the asymmetric synthesis of L-noviose,21
a
(12) Racemates of compounds 2A-2F were prepared using (()-1 and 5 mol
% Pd(OAc)2 at ambient temperature. Higher catalyst loading and reduced
temperature were found necessary for high stereoselectivities.
(13) Roussel, F.; Takhi, M.; Schmidt, R. R. J. Org. Chem. 2001, 66, 8540.
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Osborn, H. M. I.; Khan, T. H. Tetrahedron 1999, 55, 1807.
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(16) (()-3 and (()-9 were separated by preparative chiral HPLC.
(17) Murphy, P. V.; O’Brien, J. L.; Smith, A. B., III. Carbohydr. Res. 2001,
334, 327.
constituent of the antibiotic novobiocin, also participated with high
stereoselectivity to afford 10.
Scheme 3 . C4-Substituted Glycosyl Donors
(18) Gensler, W. J.; Johnson, F. A.; Sloan, A. D. B. J. Am. Chem. Soc. 1960,
82, 6074.
(19) Achmatowicz, O.; Grynkiewicz, G. Carbohydr. Res. 1977, 54, 193.
(20) Preliminary steps toward a disaccharide from glucofuranose adduct 2I
proceeded also with complete diastereoselectivity to give 4I, albeit so far
with low yield.
Efforts to elaborate on this chemistry by providing a view of an
iterative catalytic solid-phase protocol are ongoing.
Acknowledgment. We thank Dr. Richard van Delden for the
preparative HPLC separation. Financial support from NRSC-C
Catalysis and the Dutch Ministry of Economic Affairs under the
EET scheme (grant nos. EETK97107 and EETK99104) is gratefully
acknowledged.
(21) (a) Achmatowicz, O., Jr.; Grynkiewicz, G.; Szechner, B. Tetrahedron 1976,
32, 1051. (b) Ferroud, D.; Collard, J.; Klich, M.; Dupuis-Hamelin, C.;
Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem.
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