A palladium-catalyzed glycosylation reaction: The de novo synthesis of natural and unnatural glycosides

Article abstract of DOI:10.1021/ja037097k

A highly stereoselective and sterospecific palladium-catalyzed glycosylation reaction of a variety of alcohols is reported. The reaction selectively converts α-2-substituted 6-carboxy-2H-pyran-3(6H)-ones into α-2-substituted 6-alkoxy-2H-pyran-3(6H)-ones with complete retention of configuration and similarly converts the pyranones with β-carboxy groups into pyranones with β-alkoxy groups. The reaction works equally well with both amino acid- and carbohydrate-based alcohols. To demonstrate the utility of this process for carbohydrate chemistry several of the products were selectively converted into α-manno-pyranosides in two additional steps. Because the 2-substituted 6-carboxy-2H-pyran-3(6H)-ones are prepared by asymmetric synthesis, this reaction can be used for the preparation of either d- or l-pyranones. Copyright

Full text of DOI:10.1021/ja037097k

Published on Web 09/23/2003
A Palladium-Catalyzed Glycosylation Reaction: The de Novo Synthesis of
Natural and Unnatural Glycosides
Ravula Satheesh Babu and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
Received July 6, 2003; E-mail: george.odoherty@mail.wvu.edu
Scheme 2
In an effort to improve upon the seminal work of Sharpless and
Masamune1 in their use of asymmetric catalysis for the enantiose-
lective synthesis of the hexoses, we developed an alternative de
novo approach to various hexoses.2 Our approach relied upon the
use of the Achmatowicz reaction in conjunction with the catalytic
asymmetric synthesis of furan alcohols.2,3 To further improve the
scope of our approach, we desired to develop a route that would
use diastereoselective catalysis to control coupling at the anomeric
center and in turn allow for the de novo preparation of oligosac-
charides.
For this de novo synthesis of natural and unnatural oligosac-
charides, we were interested in investigating the use of palladium-
catalyzed allylation reactions.4 In contrast to typical glycosylation
reactions, Pd π-allyl reactions customarily proceed with excellent
stereocontrol. In addition to being a catalytic reaction, the reaction
has the added advantage that it can be accomplished under quite
mild conditions without the stoichiometric use of strong Lewis acid
presumably more electrophilic Pd π-allyl intermediate 8 from the
corresponding pyranones 6a-c (Scheme 2).8,11
To our delight, success was achieved for alcohol nucleophiles
when using the more oxidized pyrans 6a and 6b with benzoate12
or pivaloate leaving groups.5 Our final reaction optimization
involved changing the C-1 leaving group to a tert-butyl carbonate,
which in general lead to significantly faster and cleaner reactions
(6c, Scheme 3).13 For instance, when the pyranone 6cR was treated
with a slight excess of alcohol (1.2 equiv) in the presence of
catalytic amounts of Pd2(dba)3‚CHCl3 and PPh3 (∼1:1 ratio),
pyranones with an R-alkoxy group 10R were formed in excellent
promoters.
yields (Table 1). Similarly, the â-pyranone 6câ reacted under
Herein we describe our discovery of a palladium(0)-catalyzed
reaction that selectively converts 2-substituted 6-tert-butoxycarboxy-
2H-pyran-3(6H)-ones into 2-substituted 6-alkoxy-2H-pyran-3(6H)-
ones. Recently, Feringa reported a similar palladium-catalyzed trans-
formation.5,6 Finally we demonstrate that the 2-alkoxy-substituted
pyranone products can be transformed into typical pyranohexoses
identical conditions to afford pyranones with a â-alkoxy group
10â.14
The reaction is very general in terms of alcohol steric hindrance.
For instance, both methanol and t-BuOH couple to form either of
the desired R- or â-C-1 acetal in excellent yields (Table 1). There
seems to be little difference between the R- or â-substrates (6cR
by a simple reduction/oxidation sequence.
vs 6câ) in terms of reaction time or yield.15 The reaction occurs
We initially tried to generate a diastereomeric Pd π-allyl
rapidly (<30 min) at temperatures from 0 °C to room temperature
and in solvents, such as Et2O, THF, and CH2Cl2. The reaction can
be catalyzed with various sources of palladium(0); however, Pd2-
(dba)3‚CHCl3 is our preferred Pd(0) precursor. A palladium/
intermediate of 5 from the triacetoxy glucal 1 but were unsuccessful
at ionizing the C-3 equatorial acetate under typical Pd π-allyl-
forming conditions (Scheme 1).7 We next investigated pyrans 3a
and 3b in the reaction hopeful that an axial leaving group at the
C-1 position would be more conducive for Pd π-allyl formation.
We had previously prepared pyrans 3a and 3b in various stereoi-
someric forms via asymmetric catalysis and thus decided to use
them for our investigation.8,9 Fortuitously, moving the leaving group
to C-1 proved to be the solution for generating both diastereomeric
phosphine ratio of 1:2.5 appears to be ideal with the effective
catalyst (Pd(PPh3)2) loading in the range of 0.5-5 mol %, which
consistently yields products in the range of 70-89%.16
The coupling reaction works equally well for various chiral al-
cohols, such as: menthol 9e (Table 1), the three amino acids 9h-j
(Table 2), and the three D-sugars 9k-m (Table 2). In all of these
Pd π-allyl intermediates from either C-1 axial or equatorial
cases no diastereomers were observed when optically pure enones
carboxylates. Evidence for this ionization can be seen when the
were used.17
Pd intermediates are reacted with the traditional Pd π-allyl
A possible explanation for the improved reactivity of the
nucleophiles (i.e. various anions of malonates and phenols) products
pyranones with tert-butoxycarboxy leaving groups is that the
reaction does not generate a carboxylic acid as the reaction proceeds;
instead, t-BuOH and CO2 are generated.18 Evidence for this
are formed with net retention of stereochemistry.10 Unfortunately,
in our hands the same Pd π-allyl intermediates did not react with
the simplest of alcohols. Thus, we decided to try to generate the
decarboxylation reaction can be seen when more hindered alcohols
Scheme 1
Scheme 3
9
12406
J. AM. CHEM. SOC. 2003, 125, 12406-12407
10.1021/ja037097k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1
In summary, we have developed a practical palladium catalyzed
glycosylation reaction. This three-step protocol allows for the
incorporation of either D- or L-manno-pyranose on to an assortment
of alcohols with excellent stereocontrol. We believe this route is
amenable to multigram-scale preparation of various natural and
unnatural glycosides and are currently investigating this approach
for the preparation of unnatural oligosaccharides. We feel this new
efficient route to unnatural glycosides will be very beneficial for
the synthesis of natural and unnatural oligosaccharides.
c
alcohol
9a−g
acetal
10a−g
yield of
10R (%)
yield of
10â (%)
yield of
entry
10fâ (%)
1b
2
CH3OH
BnOH
PhOH
CyOH
menthol
t-BuOH
adamantol
10a
10b
10c
10d
10e
10f
87
89
85
88
82
78
54
85
85
76
80
72
75
52
0
0
2
2
3
4
5
12
NA
34
6
7d
10g
a Typical reaction conditions were performed with a 1:1.2 ratio of 6c to
9 at room temperature and in a 0.5 M CH2Cl2 solution. b This reaction was
run in a 0.5 M THF solution. c The reactions with 6câ were more prone to
t-BuOH glycosylation. d The byproducts 10fR is also formed (34%) when
6cR is reacted with adamantol.
Acknowledgment. We thank the Arnold and Mabel Beckman
Foundation and the NIH (1R01 GM63150-01A1) for supporting
our research and the NSF-EPSCoR (0314742) for a 600 NMR at
WVU.
Table 2
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) Sharpless, K. B.; Masamune, S. Science 1983, 220, 949. (b) For a
good review: Zamoiski, A.; Banaszek, A.; Grynkiewicz, G. AdV.
Carbohydr. Chem. Biochem. 1982, 40, 1.
(2) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999,
64, 2982-2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young,
V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36.
(3) An Achmatowicz reaction is the oxidative rearrangement of furfuryl
alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones. (a) Achma-
towicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176. (b) Grapsas,
I., K.; Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem. 1990, 64,
823-826. For its use in carbohydrate synthesis see: ref 2 and (c)
Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863-866. (d)
Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033-4036.
(4) Recently, both the poor reactivity in Pd-catalyzed allylation reaction of
alcohols as well as a nice solution to this problem was reported, see: Kim,
H.; Lee, C. Org. Lett. 2002, 4, 4369.
alcohol
9h−n
glycoside
10h−n
yield of
10R (%)
yield of
10â (%)
yield of
10fâ (%)
1
9h
9i
9j
9k
9l
9m
10h
10i
10j
10k
10l
10m
87
90
90
82
82
85
85
84
86
79
79
83
1
2
0
0
0
0
2
3
4
5b
6
(5) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2003, 125, 8714.
(6) In this communication, we report the Pd-catalyzed glycosylation reaction
for 6-substituted pyranones and for the first time demonstrate the reaction’s
high selectivity for both R- and â-glycosylation.
(7) RajanBabu had previously noted the resistance of 1 toward Pd π-allyl
formation, see: (a) RajanBabu, T. V. J. Org. Chem. 1985, 50, 3642.
(8) Pyranones 3 and 6 can easily be prepared from furan alcohols 13 by an
Achmatowicz reaction followed by hemiacetal protection. The more
reactive axial anomeric alcohols can be acylated selectively (>20:1) at
-78 °C. Alternatively at room temperature, a 1:1 mixture of anomers
can be produced.
a Typical reaction conditions were performed with a 2:1 ratio of 6c to 9
at room temperature and in a 0.5 M CH2Cl2 solution. b Products 10l were
isolated as a 2:1 (C2:C3) mixture of monoglycosides.
are used as nucelophiles. When the tertiary alcohol adamantol was
used, a significant amount of the tert-butyl acetal byproduct 10f
was formed (34% in both the R and â case). This result is consistent
with the formation of the less reactive tert-butyl alcohol as the
reaction proceeds. This problem could easily be solved in terms of
glycosylation yield by adding additional enone 6cR or 6câ (see
Table 2), or by switching to the pyranones with the less reactive13
pivaloate leaving group (6bR or 6bâ).19
The glycoside products can easily be converted into either L- or
D-hexopyranoses by a two-step reduction/oxidation sequence. This
was demonstrated for six of the Pd catalyzed glycosylation products
10R(a, b, g, h, i, k) by exposure to NaBH4 at -78 °C in CH2Cl2
and CH3OH (Scheme 4). The NaBH4 reduction produced equatorial
alcohols 11R with complete stereocontrol and high yields (78-
96%, Table 3). Similarly, the resulting allylic alcohols 11R could
be diastereoselectively oxidized to give the manno-triols 12R in
excellent yields (72-89%) with complete stereocontrol.
(9) Compounds similar to 3 with a C-1 acetate can also be prepared from
glycols, see: Collins, P.; Ferrier, R. Monosaccharides. Their Chemistry
and Their Roles in Natural Products; Wiley: U.K., 1995.
(10) Stabilized anions such as these are the optimum coupling partners for
Pd-π-allyls, see: Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96,
395-422.
(11) It should be noted that we have prepared both antipodes of 6a-c and are
only presenting the enantiomer that leads to L-sugars in this report.
(12) Feringa has shown one example of coupling with the 6-substituted
pyranone 6a using a Pd(OAc)2/POPh3 catalyst system.
(13) Typical reaction times for 6a/6b were 8-10 h versus 0.5 h for 6c under
identical conditions.
(14) The reaction is both highly steroselective and stereospecific, that is to
say, the pyranone with an R-tert-butoxycarboxy group reacts to give only
pyranones with R-alkoxy groups and pyranones with a â-tert-butoxycar-
boxy groups react to give only pyranones with â-alkoxy groups, which is
consistant with a π-allyl palladium intermediate.
Scheme 4
(15) A significant difference between the R- and â-glycosylation reactions is
that the reactions with â-pyranone 6câ produce a small amount of tert-
butyl acetal byproduct 10fâ (Table 1).
(16) Higher yields are observed when greater than 1.2 equiv of alcohol is used.
While the yield of adamantol glycoside appears to be less than 70%, this
is due to the competitive formation of the tert-butyl glycoside 10f. Thus,
the total yield of glycosylated products is in excess of 80%.
(17) In contrast, Feringa observed some loss of stereospecificity (2-10%) with
unsubstituted pyranones.
(18) Alternatively the ionization step could be rate limiting. It is known that
carbonates are better leaving groups in π-allyl Pd reactions, see ref 10.
(19) Thus, exposing pyranone 6bR to 1.2 equiv of adamantol and 5% catalyst
proceed to give product 10gR in a 76% yield.
Table 3
enone
yield of
11R (%)
yield of
12R (%)
enone
6R
yield of
11R (%)
yield of
12R (%)
6R
1
2
3
a
b
g
84
90
78
72
84
83
4
5
6
h
i
k
87
91
96
78
73
89
JA037097K
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J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12407