α-Selective organocatalytic synthesis of 2-deoxygalactosides

Article abstract of DOI:10.1002/anie.201204505

Alpha rules: A thiourea acts as an efficient organocatalyst for the glycosylation of protected galactals to form oligosaccharides containing a 2-deoxymonosaccharide moiety (see scheme). The reaction is highly stereoselective for α-linkages and proceeds by way of a syn-addition mechanism. Copyright

Full text of DOI:10.1002/anie.201204505

Angewandte
Chemie
DOI: 10.1002/anie.201204505
Organocatalysis
a-Selective Organocatalytic Synthesis of 2-Deoxygalactosides**
Edward I. Balmond, Diane M. Coe, M. Carmen Galan,* and Eoghan M. McGarrigle*
The stereoselective synthesis of acetals is of great interest,
especially because of the abundance of cyclic acetals in
nature.[1,2] Recently, there have been several reports of
organocatalytic approaches to stereoselective acetal forma-
tion.[2b–d] Organocatalysis has become a powerful synthetic
tool[3] and is attractive because the reactions are often
tolerant of water and air, and tend to be relatively simple to
perform. Arguably, the most important acetals are carbohy-
drates, of which 2-deoxysugars form an important and
synthetically challenging subclass. They occur widely in
natural products[1] and are frequently present in antibiotics,
Scheme 1. Catalytic acetal formation from enol ethers.[10,13] PG=pro-
tecting group; THF=tetrahydrofuran.
anti-cancer, and cardiotonic agents[1,4] where the deoxysugar
component is often crucial for the bioactivity of the drug.[5]
Herein, we describe our efforts to develop an organocatalytic
method for the synthesis of 2-deoxygalactosides.
Glycosylation reactions involving glycals tend to give
better stereoselectivities under mild conditions.[10] Organo-
catalysts often work under such conditions and tend to be
more tolerant of sensitive functional groups.[11,12] Recently,
Kotke and Schreiner reported the use of thiourea 1 to catalyze
the protection of alcohols with dihydropyran (DHP) under
mild conditions (Scheme 1b).[13,14] We reasoned that if glycals
could be used in place of DHP, it could provide a more
efficient glycosylation method than is currently available.
Modification of Schreinerꢀs reaction for use in stereoselective
glycosylations was not a trivial task, as the physical properties
and solubilities of our substrates were not amenable to the
methods described.[13] We optimized the reaction of protected
galactal 2a[15] (1.2 equiv.) with model acceptor 3a and found
that 1 mol% of catalyst 1, in a solution of CH2Cl2 heated to
reflux, gave excellent results. Disaccharide 4a was produced
in 90% yield in under six hours, exclusively as the a-glycoside
(Table 1, entry 1).[16] The high selectivity is not the result of
a postglycosylational anomerization (see below).
Considerable efforts have been made to develop stereo-
selective chemical methods for the assembly of oligosacchar-
ides containing 2-deoxysugars.[4,6] However, the absence of
groups at C-2 that can act to direct the coupling reaction often
leads to syntheses of 2-deoxyglycosides as mixtures of
anomers. Another concern is that 2-deoxyglycosides tend to
be more difficult to manipulate compared to the C-2
hydroxylated analogues because of their greater susceptibility
to hydrolysis.[7] Using directing groups at C-2 that are later
removed is inherently inefficient.[6,8] Many direct methods
rely on stoichiometric promoters and/or precursors that
require several steps to synthesize.[9] Catalyzing the direct
addition of an alcohol to a glycal (2) is the most atom-efficient
route to 2-deoxyglycosides.[10] Existing methods (Scheme 1a)
tend to be mostly confined to primary alcohol acceptors and
give either moderate yields or variable selectivities.[10] Herein,
we describe a highly atom-efficient method for the direct
reaction of readily available galactals with alcohols to give a-
linkages with high stereoselectivity using an organocatalyst.
Having shown that thiourea 1 could be used as an efficient
and mild catalyst in our test reaction, we studied its use with
galactals bearing a range of different protecting groups. Thus
galactals 2b–f bearing ethyl, allyl, benzyl, methoxymethyl
ether (MOM), and silyl ether protecting groups were
prepared[17] and subjected to the optimized reaction condi-
tions with 3a as acceptor (Table 1). In all cases, high yields
and excellent selectivities for a-linked glycosides were
obtained, albeit with longer reaction times being required
for substrates with bulkier protecting groups. In the case of
acetate-protected galactal 2g,[18] no reaction was detected
after two days. Substrates 2h and 2j show that acetates can be
tolerated by the reaction but not in close proximity to the
reacting alkene, as is the case for 2h with an acetate at C-3
(Table 1, entry 8). We attribute the lack of reactivity of 2g to
the deactivation of the double bond.[19] Entries 8 and 9 in
Table 1 also show that the reaction is not sensitive to the
conformational restrictions imposed by the cis-decalin
system.
[*] E. I. Balmond, Dr. M. C. Galan, Dr. E. M. McGarrigle[+]
School of Chemistry, University of Bristol
Cantock’s Close, Bristol BS8 1TS (UK)
E-mail: m.c.galan@bristol.ac.uk
Dr. D. M. Coe
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage SG1 2NY (UK)
[+] Current address: Centre for Synthesis and Chemical Biology, UCD
School of Chemistry and Chemical Biology, University College
Dublin
Belfield, Dublin 4 (Ireland)
E-mail: eoghan.mcgarrigle@ucd.ie
[**] We thank GSK and the EPSRC-funded Bristol Chemical Synthesis
Doctoral Training Centre for a PhD studentship (E.I.B.) (EP/
G036764/1) and The Royal Society for a DHF and EPSRC for a CAF
(M.C.G.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204505.
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Table 1: Reaction of galactals 2a–j with model acceptor 3a.[a]
or thiophenyl as the anomeric substituents gave yields of the
isolated product of 87–98% and a-selectivity (Table 2,
entries 1, 2, 8, 9).
This high selectivity was maintained regardless of the
position of the free hydroxy group on the acceptor. Couplings
to secondary hydroxy groups[21] at C-2, C-3, or C-4 proceeded
extremely well with yields of the isolated product of 83–96%
and complete a-stereocontrol (Table 2, entries 3–7). These
reactions were also independent of the configuration of the
OH group (axial vs. equatorial). For instance, galactoside 3h
with an axial secondary hydroxy group (Table 2, entry 7) gave
an excellent yield of 85%, which is comparable to the result
obtained for glycosyl acceptor 3d (89%). Individual optimi-
zation of the reaction conditions was not required except in
the case of 3g. Because of its lower solubility in CH2Cl2 this
reaction was run at a higher dilution of 3g with 2 equiv. of
galactal 2d and 2 mol% catalyst 1.
These results highlight that the organocatalyzed reaction
is tolerant of most commonly used alcohol protecting groups,
that is, benzyl and silyl ethers, benzoyl esters, and acetals.
Furthermore, the reaction works well across a range of
reactivity profiles[22] and the overall mild nature of the
reaction conditions makes this procedure remarkably general.
Having found that thioacetals were inert under the
Entry
R1
R2
R3
t [h] Yield [%][b]
a:b[c]
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Me
Et
Allyl
Bn
TBS
MOM
Ac
Ac
MOM
Bn
Me
Et
Me
Et
6
90
92
96
96
72
96
0
a
a
a
a
a
a
-
a
a
a
18
18
24
48
18
48
48
24
24
Allyl
Bn
TBS
MOM
Ac
Si(tBu)2
Si(tBu)2
Bn
Allyl
Bn
TBS
MOM
Ac
Si(tBu)2
Si(tBu)2
Ac
14
92
89
2j
[a] 1.2 equiv. of 2a–j were used. [b] Yield of isolated product. No Ferrier
rearranged product was observed. [c] Determined by 1H NMR spectros-
copy.
Encouraged by these results, the scope of other common
glycosyl acceptors was investigated (Table 2). To that end,
perbenzylated galactal 2d was used as a model donor and
reacted with a range of differentially protected glycosyl
acceptors 3b–3j under the optimized reaction conditions.
Glycosyl acceptors with a primary alcohol[20] and either
benzyl or benzoyl protecting groups, as well as either methoxy
organocatalytic
glycosylation
conditions
(Table 2,
entries 8,9), we evaluated the new method in a three-compo-
nent, one-pot synthesis of trisaccharide 6 (Scheme 2). Thus,
Table 2: Scope of acceptor in the glycosylation of galactals.
ROH
Yield [%][a]
98
ROH
Yield [%][a]
83[b]
Scheme 2. One-pot trisaccharide synthesis.
1
2
3
6
7
8
9
galactal 2d was reacted with thioglycoside 3j under our
standard conditions. Following disaccharide formation,
acceptor 3a was added to the same pot along with N-
iodosuccinimide (NIS) and catalytic trimethylsilyl trifluoro-
methanesulfonate (TMSOTf).[23] This stepwise, one-pot addi-
tion reaction afforded trisaccharide 6 in 58% yield with
complete stereoselectivity.
98
85
92
87
89[c]
To probe the mechanism of this reaction,[24] an a/b-
mixture of disaccharide 5b was subjected to the reaction
conditions and showed no change in the anomeric ratio,
indicating that the high a-selectivity is not the result of
anomerization. Moreover, the reaction with deuterated
galactal 7 yielded disaccharide 8 with the newly formed
4
5
94[d]
96
À
À
bonds cis to each other (Scheme 3), thus the C O and the C
H bond formation steps are both diastereoselective. We
hypothesize that an alcohol–thiourea complex delivers the
proton selectively to the less hindered face of the enol ether
(A) followed by rapid collapse of the ion pair (B) to give 8.
[a] Yield of isolated product. [b] 30 h; 2 equiv. of 2d and 2 mol% catalyst 1 with
respect to 3g was used; 0.4m ROH (all other reactions were approximately
0.8m). [c] 18 h. [d] Product was isolated as the desilylated disaccharide for
purification purposes.
À
The selective C H bond formation may be dictated by steric
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À
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In conclusion, we have described the first example, to our
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with a wide range of glycosyl acceptors using a readily
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selectivity for the a-anomer with only 1.2 equiv. of the
galactal donor. Furthermore, we have exemplified the versa-
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tive synthesis of a trisaccharide. Work is currently underway
to extend this method to the stereoselective synthesis of other
deoxyglycosides. The simplicity of the method, mild condi-
tions, high yields, and stereoselectivity should make this
diastereoselective acetal formation a valuable addition to
synthetic chemistry with applications in, and beyond, the field
of carbohydrates.
Experimental Section
The monosaccharide acceptor (0.50 mmol) was weighed into a round-
bottom flask and placed under vacuum for 1 h. Then the flask was
filled with N2, followed by the addition of the galactal (1.2 equiv.) and
a stock solution of thiourea 1 (0.6 mL, 1 mol%) in anhydrous
dichloromethane. The solutions were then heated at reflux under N2
until the reaction was determined to be complete by either TLC or
NMR spectroscopy analysis of the crude material. The solution was
then concentrated under vacuum and purified by column chromatog-
raphy.
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Received: June 11, 2012
Published online: && &&, &&&&
Keywords: acetals · deoxyglycosides · diastereoselectivity ·
.
organocatalysis · thiourea
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Organocatalysis
E. I. Balmond, D. M. Coe, M. C. Galan,*
E. M. McGarrigle*
&&&& — &&&&
a-Selective Organocatalytic Synthesis of
2-Deoxygalactosides
Alpha rules: A thiourea acts as an
saccharide moiety (see scheme). The
efficient organocatalyst for the glycosyla-
tion of protected galactals to form oligo-
saccharides containing a 2-deoxymono-
reaction is highly stereoselective for a-
linkages and proceeds by way of a syn-
addition mechanism.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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These are not the final page numbers!