Palladium-Catalyzed α-Stereoselective O-Glycosylation of O(3)-Acylated Glycals

Article abstract of DOI:10.1021/acs.orglett.7b01092

Pd(MeCN)₂Cl₂ enables the α-stereoselective catalytic synthesis of 2,3-unsaturated O-glycosides from O(3)-acylated glycals without the requirement for additives to preactivate either donor or nucleophile. Mechanistic studies suggest that, unlike traditional (η3-allyl)palladium-mediated processes, the reaction proceeds via an alkoxy-palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is exemplified with the synthesis of a range of glycosides and glycoconjugates of synthetic utility.

Full text of DOI:10.1021/acs.orglett.7b01092

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Stereoselective O‑Glycosylation of
O(3)‑Acylated Glycals
Abhijit Sau and M. Carmen Galan*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, United Kingdom
S
* Supporting Information
ABSTRACT: Pd(MeCN)2Cl2 enables the α-stereoselective
catalytic synthesis of 2,3-unsaturated O-glycosides from O(3)-
acylated glycals without the requirement for additives to
preactivate either donor or nucleophile. Mechanistic studies
suggest that, unlike traditional (η3-allyl)palladium-mediated
processes, the reaction proceeds via an alkoxy-palladium
intermediate that increases the proton acidity and oxygen
nucleophilicity of the alcohol. The method is exemplified with
the synthesis of a range of glycosides and glycoconjugates of synthetic utility.
nterest in the synthesis of oligosaccharides and glycoconju-
gates continues, because of their involvement in many
for the nucleophilic addition, and the leaving group, for the
ionization. More recently, the Nguyen group reported a
palladium-catalyzed Ferrier-type glycosylation using glycal
donors with a trichloroacetimidate leaving group at C-3.
Similarly, prior activation of the glycoside acceptor is required
via a zinc alkoxide for the reaction to proceed.35
Prompted by our interest in the development of catalytic
methods for the synthesis of O-glycosides from glycal starting
materials,36−39 we undertook synthetic studies toward the
palladium catalyzed stereoselective synthesis of 2,3-unsaturated
O-glycosides (Scheme 1). Herein we report an additive-free
Pd(II) stereoselective synthesis of O-glycosides from “dis-
armed” glycals that employs only Pd(MeCN)2Cl2; a reaction
that we propose proceeds via an alkoxypalladation-type
mechanism to yield the glycoside products with high α-
stereocontrol.
I
biological processes, some of which are disease-related1 and
because there is a need to efficiently access glycan-based tools
to study these processes.2,3 The chemical synthesis of complex
carbohydrates generally involves the coupling of a fully
protected glycosyl donor with a suitably protected glycosyl
acceptor (R−OH).4−7 In many instances, these reactions lead
to a mixture of two stereoisomers. Thus, having the ability to
direct the stereoselective formation of glycosidic linkages with
specific reagents in a catalytic manner is highly desirable.
The Ferrier glycosylation reaction involves the allylic
coupling of a nucleophile to a glycal bearing a leaving group
at C3, which leads to the corresponding 2,3-unsaturated
glycoside.8−12 The products of this transformation are versatile
chiral intermediates in the synthesis of a variety of important
compounds from nucleosides and antibiotics to several
biologically active natural products.13−17 Traditionally, a
stoichiometric Lewis acid is required to facilitate the allylic
rearrangement,17 which has limited the utility of this very
attractive transformation. More recently, transition metal
catalysis has been successfully applied to oligosaccharide
synthesis as an improved alternative to traditional glycosylation
promoters, including examples involving glycal starting
materials where the allylic feature is typically exploited for
activation using a metal catalyst.18−30 In this context,
palladium(II)-catalysis has been used for the direct activation
of 1,2-unsaturated glycals to yield the corresponding 2,3-
unsaturated products with good-to-excellent selectivities and
yields, and the reaction is thought to proceed via π-allyl
intermediates.19,26 However, despite employing activated
glycals as the starting materials to facilitate the reaction, the
poor reactivity of both the glycal donors and alcohol acceptors
for an η3-metal-mediated reaction has been a major challenge to
this approach.31−33 Elegant efforts from Lee et al.34 to
overcome this issue employ zinc(II) alkoxides, in addition to
Pd(OAc)2 and ancillary ligands, to activate both the acceptor,
Scheme 1. Palladium-Catalyzed Synthesis of 2,3-Unsaturated
Glycosides
Received: April 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01092
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Organic Letters
Letter
The ligand and counterion in a transition metal catalyzed
reaction plays a key role in stabilizing and activating the central
metal atom and fine-tuning the selectivity of the trans-
formation.40 Thus, our initial studies began by screening a
series of commercial palladium(II) catalysts for their ability to
promote the Ferrier-type stereoselective glycosylation of
peracetylated glucal 1a with glucoside acceptor 2a12 in the
presence of different catalyst loadings and solvents at room
temperature. As summarized in Table 1, 10 mol % proved to be
Table 2. Acceptor Scope in Glycosylation Reactions with
Glucal 1a
Table 1. Initial Catalyst Screen in the Glycosylation of
Glucal 1a
a
time
(h)
yield
(%)
a
entry catalyst (loading mol %)
solvent
α:β
1
2
3
4
Pd(MeCN)2Cl2 (2.5)
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
5
40
52
5:1
5:1
6:1
3:1
c
88
Pd(CH3CN)2(OTs)2
(10)
17
88
b
5
6
Pd(CH3CN)4(OTf)2
(10)
CH2Cl2
CH2Cl2
5
5
N/A
90
N/A
Pd(CH3CN)4(BF4)2
(10)
2.3:1
7
Pd(OAc)2 (10)
CH2Cl2
PhMe
5
N/A
18
−
−
−
N/A
N/A
N/A
8
Pd(MeCN)2Cl2 (10)
Pd(MeCN)2Cl2 (10)
Pd(MeCN)2Cl2 (10)
Pd(MeCN)2Cl2 (10)
24
15
5
9
CH3CN
CH2Cl2
CH2Cl2
traces
d
10
11
12
N/A
e
5
N/A
f
Pd(MeCN)2Cl2 (10)
CH2Cl2
5
N/A
a
b
c
Yield of isolated product. Determined by crude 1H NMR. Reaction
a
b
1
Determined by crude H NMR. Inseparable mixture of products.
c
d
carried out at 50 °C
Isolated yield. Addition of N-phenyl-2-(di-tert-butylphosphino)-
e
pyrrole (0.2 equiv). Addition of tricyclohexylphosphine (0.2 equiv).
f
proceeded smoothly within 3−17 h and in good to excellent
yield and a clear preference for the α-products. These successes
demonstrate that the catalytic system tolerates the presence of
common alcohol and amine protecting groups such as acetals,
ethers, esters, and carbamates. Glycosylations with primary
alcohols 2b−d afforded the corresponding 2,3-unsaturated
glycosides in 90−97% yield within 3−7 h and with a 9:1 α:β
ratio (entries 1−3). Reactions with secondary alcohols such as
glycosides 2e−g (Table 2, entries 4−6) prove to be more
challenging and required longer reactions times (15−17 h).
Moreover, in the case of Boc-protected serine 2h, threonine 2i,
or N-hydroxysuccinimide 2j, besides longer reaction times, a 50
°C reaction temperature was required (entries 7−9). Under
these conditions, the desired products were isolated with
similarly high α selectivity (>99:1 to 3:1, α:β ratio) and yields
of 64−90%, with the lower yields being attributable to the more
hindered nature of the secondary OH nucleophiles.
Addition of Cu(OTf)2 (0.1 equiv). N/A = not applicable.
the optimum catalyst loading for reactions that used
Pd(MeCN)2Cl2 in CH2Cl2 (88% of 3a, entry 3), with reactions
being much slower when lower catalyst loadings were used
(entries 1 and 2). To further investigate the effect of the
catalyst, a series of different Pd(II) catalysts (10 mol %) in
CH2Cl2 were also screened in the glycosylation reaction (Table
1, entries 4−7). It was found that removing or replacing the Cl
counterion by a p-toluenesulfonate was detrimental to the
reaction rate and stereocontrol, while use of tetrafluoroborate
eroded the α-selectivity. The use of trifluoromethanesulfonate
led to an inseparable complex mixture of products. Moreover,
no reaction occurred when Pd(OAc)2 was employed,
demonstrating that Pd(MeCN)2Cl2 was the optimal catalyst.
Next, we decided to explore solvent effects and the addition of
ancilliary additives. The use of acetonitrile or toluene as the
solvent at room temperature was detrimental to yield (entries 8
and 9), as was the addition of phosphine ligands (N-phenyl-2-
(di-tert-butylphosphino)pyrrole or tricyclohexylphosphine) or
Cu(OTf)2 to the reaction (entries 10−12).
Our attention next turned to exploring the scope of the glycal
donor. It has been shown that glycal conformation can
modulate both the reactivity and stereoselectivity of these
reactions.17 It has been proposed that the conformational
equilibria of glycals (4H5 vs H4) are influenced by several
5
Having established the optimum reaction conditions, our
attention turned to exploring the substrate scope of the
coupling reaction between 1a and a range of other OH
nucleophiles 2b−j (Table 2). In all cases, the reactions
contributing factors such as the vinylogous anomeric effect
(VAE),41 which dictates a preferred pseudoaxial orientation of
5
the acyloxy group at C-3, and thus favors a H4 conformation;
also important are 1,3-diaxial interactions, which compete with
B
DOI: 10.1021/acs.orglett.7b01092
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Organic Letters
Letter
the VAE and are influenced by the substituents at C-5, and the
orientation of the C-4 substituent. In the case of galactal, where
C-4 is axial, as opposed to equatorial as in glucals, the
2-deoxyglycoside 8b in 90% yield with high α-selectivity, which
we attribute to the additional constraint imposed by the
siloxane protecting group, which reduces the reactivity of the
glycal toward allylic rearrangement in favor of direct
glycosylation.
To demonstrate the synthetic utility of 2,3-unsaturated
glycosides, reduction of O-linked-N-hydroxysuccinimide 3j was
carried out with 5% Rh−Al2O3/H2 to yield the corresponding
2,3-deoxyglycoside 10 in 80% yield, while treatment of 3j with
Et3SiH and catalytic amounts of 10% Pd/C afforded hydro-
pyran 11 in 76% yield (Scheme 2), which gives access to a
chiral scaffold that can be further developed as a medicinally
active compound.46,47
4
equilibrium is shifted toward the H5 form. Glycal substrates
that favor a bigger shift toward 5H4 conformations (e.g.,
glucals) undergo rearrangement/substitution more readily than
their corresponding counterparts (e.g., galactals).42,43 Further-
more, the use of conformationally constraining protecting
groups can also affect both the reactivity and stereocontrol of
reactions involving glycal donors.38,44,45
To that end, a series of differentially protected deactivated
glycals were prepared. They included peracetylated glucal 1a,
galactal 4a, and L-rhamnal 5, conformationally constrained 1b
and 4b, and all were reacted with 6 as the model acceptor
(Table 3). In general, moderate-to-good yields and α-
Scheme 2. Synthesis of 11 and 10 from Intermediate 3j
Table 3. Reaction of Glycals 1b, 4a, 4b, and 5 with Model
Glycoside Acceptor 6
To probe the mechanism of the palladium-catalyzed Ferrier
reaction, 1H NMR spectroscopy studies of glucal 1a and
Pd(MeCN)2Cl2 in CD2Cl2 did not show any changes in the
spectra (Figure S1, SI), suggesting that the palladium catalyst
does not interact with the alkene functionality in “disarmed”
glycal donors. Indeed, previous results from our group have
shown that mixtures of Pd(MeCN)2Cl2 and perbenzylated
galactal (an “armed” or activated donor) clearly showed
downfield H-shifts associated with alkene protons in the glycal
(from δ 6.37 ppm to 6.20 and 6.03 ppm).40 NMR studies of
acceptor 2a and Pd(MeCN)2Cl2 showed upfield shifts
corresponding to the OH signal in 2a (from 1.86 to 1.75
1
ppm) (Figure S2, SI), while H NMR spectra of a mixture
containing 1a, 2a, and Pd(MeCN)2Cl2 in CD2Cl2, collected
after 10 min and 1 h, showed the disappearance of the OH
proton from 1a and the appearance of new signals
corresponding to the Ferrier product (see SI, Figure S4 for
details). These results suggest that the reaction proceeds via
alkoxypalladation of the OH nucleophile.
As proposed in Scheme 3, palladium-catalyzed allylic
rearrangement of deactivated glycals with alcohol nucleophiles
Scheme 3. Proposed Mechanism
a
b
1
Isolated yield. Determined by H NMR.
selectivities were obtained in most examples leading to the
formation of 2-deoxy and 2,6-dideoxy Ferrier-type products
(entries 1, 2, 3, and 5), with peracetylated glucal 1a affording
the best yields (85%) for the formation of 7a as a 9:1 α:β
mixture, while the 4,6-O-constrained glucal 7b afforded the
product in a lower yield of 54%, with stereoselectivity
unchanged. As predicted, the reaction with galactal 4a was
less selective toward Ferrier rearrangement and gave a mixture
of 2,3-unsaturated product 8a (65%) and 2-deoxyglycoside 8aˈ
(20%) with almost complete α-stereocontrol (>99:1). Un-
expectedly 4,6-O-siloxane protected galactal 4b yielded only the
involves an initial insertion of Pd into the RO-H bond, rather
than the traditional pathway of palladium-mediated alkene
activation,19,26 to produce alkoxypalladium species (A) with
concomitant H+ release from the OH nucleophile.48 Proton
catalyzed allylic rearrangement can now take place, which leads
C
DOI: 10.1021/acs.orglett.7b01092
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01092.
■
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Experimental procedures and characterization data
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: m.c.galan@bristol.ac.uk.
ORCID
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M. Carmen Galan: 0000-0001-7307-2871
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by EPSRC CAF EP/L001926/1
(MCG) and ERC-COG: 648239 (MCG, AS).
■
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