Versatile Glycosyl Sulfonates in β-Selective C-Glycosylation

Article abstract of DOI:10.1002/anie.201914221

C-Glycosides are both a common motif in many bioactive natural products and important glycoside mimetics. We demonstrate that activating a hemiacetal with a sulfonyl chloride, followed by treating the resultant glycosyl sulfonate with an enolate results i

Full text of DOI:10.1002/anie.201914221

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Title: Versatile Glycosyl Sulfonates in b-Selective C-Glycosylation
Authors: Jesse Ling and Clay S Bennett
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Versatile Glycosyl Sulfonates in β-Selective C-Glycosylation
Jesse Ling[a] and Clay S. Bennett*[a]
Abstract: C-Glycosides are both a common motif in many bioactive
natural products and important glycoside mimetics. Here we
demonstrate that activating a hemiacetal with a sulfonyl chloride,
followed by treating the resultant glycosyl sulfonate with an enolate
results in the stereospecific construction of -linked C-glycosides. This
reaction tolerates a range of acceptors and donors, including
disaccharides. The resulting products can be readily derivatized into
C-glycoside analogs of β-glycoconjugates, including C-disaccharide
mimetics.
and Corey–Seebach reaction[13] with excellent -selectivity.
These approaches require an excess of heavy metals, or strongly
oxidizing conditions to unmask the desired products. Radical-
based methods[14] or indirect synthesis through other
intermediates such as glycosyl nitriles[15] and benzothiazole[16]
have also been reported, but they require extra steps or suffer
from low stereoselectivity. Thus, a reliable, unified approach for
the direct preparation of these β-C-alkyl glycosides has yet to be
achieved.
Glycoconjugates are involved in numerous vital biological
functions, ranging from intercellular recognition and the immune
response to modulating the bioactivity of natural products.[1] While
they hold promise as new therapeutic leads and tools for
diagnosis, the inherent instability of many of these species has
limited their utility. Specifically, the glycosidic linkages in many of
these molecules are susceptible to hydrolysis in vivo. One
approach that has been developed to overcome this instability
involves replacing the glycosidic bonds with non-hydrolyzable C–
C bonds. The resulting C-glycosides can act as a robust surrogate
of the native O-glycoconjugate.[2] Indeed, previous studies have
shown that these C-glycosides can even produce enhanced
activities compared to the parent compounds.[3]
One important class of C-glycoconjugates are -C-alkyl
glycosides, which are an important component of both natural
products, and many pharmaceutical compounds.[4] We are
particularly interested in C-homoacyl and C-acyl glycosides, as
they can be modified into a variety of glycoconjugate surrogates.[5]
C-acyl glycosides are also present in some natural products, for
example in the scleropentaside family.[6] Compared to C-aryl
glycosides, however, the stereoselective construction of -C-alkyl
glycosides is challenging. Lewis acid-catalyzed glycosylation
reactions with carbon nucleophiles typically favour the formation
of α-isomers,[4c, 7] which require additional steps to be epimerized
to the β-anomers.[8] The stereochemical outcome and efficiency
of C-glycoside synthesis using other methods, including
4b, 9]
Knoevenagel condensation,[3e,
Mitsunobu reaction,[10] and
Horner–Wadsworth–Emmons
olefination/Michael
addition
cascade[11] of unprotected/peracylated sugars, are highly
dependent on substrates and reaction conditions (Scheme 1A).
For instance, while the condensation of glucose with
acetylacetone proceeds with excellent yield, similar reactions with
aryl β-diketones are much lower yielding.[3e] Alternatively, C-acyl
glycosides have been prepared by transition metal coupling,[5i, 12]
[a]
Dr. J. Ling, Prof. C. S. Bennett
Tufts University
Scheme 1. Methods for the formation of β-C-homoacyl and C-acyl glycosides.
62 Talbot Ave., Medford, MA 02155, USA
E-mail: clay.bennett@tufts.edu
Supporting information for this article is given via a link at the end of
the document.
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Recently, our group has demonstrated that glycosyl sulfonates,
obtained in situ from hemiacetals, undergo highly -selective
glycosylation reactions, provided that the reactivity of the
sulfonate and donor are matched.[17] One major advantage of this
approach is that the electronics of the sulfonate are readily
tunable, permitting SN2 glycosylations with donors that span a
range of reactivities.[18] We envisioned that using strong carbon
nucleophiles (e.g. enolate) in this reaction would permit β-
selective C-glycosylation reactions (Scheme 1C). At the outset,
we were aware that the ambident nucleophilicity and substantially
higher basicity of enolates could pose a challenge. Nevertheless,
we started our investigation of C-glycosylation using
acetophenone and perbenzylated glucose donor 1a as the model
system (Table 1). On the basis of our previous studies,[17d] we
opted to use 3,5-bistrifluromethylbenzenesulfonyl chloride (R = A)
as the promoter. We initially examined lithium and zinc enolate in
order to minimize the formation of O-alkylation product, but they
prove to be ineffective nucleophiles (Entries 1–3). Gratifyingly, the
corresponding sodium enolate provided a moderate yield of
desired product 2 along with minor O-glycoside 3 (Entry 4).
Importantly, both products were obtained exclusively as β-
anomers. After optimizing the temperature and solvent (Entries 5–
11), we observed that reactions at -30 °C in THF/toluene afford
the highest yield of 2. We also investigated the electronic
properties of the sulfonate group (Entries 12–15); however, 3,5-
bistrifluromethylbenzenesulfonyl chloride proved to be the optimal
promoter for 1a. Increasing the stoichiometry of base to promote
complete deprotonation for acetophenone led to a slight increase
in the yield, while reducing the amount of the unwanted O-
glycoside byproduct (Entry 16). These conditions were used for
the remainder of our study.
11
Na/Na
Na/Na
Na/Na
Na/Na
Na/Na
Na/Na
PhMe
PhMe
PhMe
PhMe
THF
-78
-30
-10
-10
0
A
9/0
12[e]
13[e]
14[f]
15[f]
16[g]
4-Ns
4-Ns
Ts
25/4
14/4
12/0
12/0
61/7
B
PhMe
-30
A
[a] Reaction conditions: 1a (1 equiv.) and MN(SiMe3)2 (1.1 equiv.) was
added to RSO2Cl (1.1 equiv.) in THF, temp., 1 h; then acetophenone (2
equiv.) and MN(SiMe3)2 (2.1 equiv.) in co-solvent, -78 °C to temp., 1–2 h.
[b] M for 1a/M for acetophenone. [c] Isolated yields. [d] Generated from Na
enolate and ZnCl2. [e] mixture of α/β anomers (~1:5). [f] mixture of α/β
anomers (~1:1). [g] equiv. of acetophenone/NaHMDS = 1:2.
With the optimized conditions in hand, we proceed to study
the substrate scope of acceptors with 1a (Table 2). In general, we
were able to obtain moderate to good yields of C-glycosides, all
of which were formed exclusively as β-anomers. Both electron
donating (Entries 2 & 3) and withdrawing substituents (Entries 4–
6) on the aryl ring of the enolate are well tolerated. We were
initially concerned that the steric hindrance of ortho substituents
would negatively affect the reaction; however, this proved not to
be an issue (Entry 7). Enolates of heterocyclic ketones are well
tolerated in the reaction (Entries 8 & 9), with 2-acylfuran being
especially interesting as it can serve as a handle for further
derivatization to a C-disaccharide through an Achmatowicz
reaction (vide infra).[19] O-Glycosides were observed as a minor
side product in many cases, all of which were formed exclusively
as β-anomers. The isolation of these latter species was not
always feasible owing to spontaneous hydrolysis under ambient
conditions. We also examined the possible synthesis of C-acyl
glycoside using (trimethylsilyloxy)phenylacetonitrile as the
nucleophile. To our delight, the C-glycosylation of 1a proceeds
smoothly to afford the desired C-acyl glycoside 18 in 56% yield
(Entry 10) after desilylation under mild conditions. This success
allows facile access to perbenzylated Scleropentaside A 19 in a
single-step synthesis, using the corresponding furyl cyanohydrin
(Entry 11).
Table 1. Optimization of C-glycosylation of donor 1a and acetophenone.[a]
Entry
M[b]
Co-
solvent
Temp.
(°C)
R
% Yield[c] of
2 and 3
1
2
3
4
5
6
7
8
9
10
Li/Li
Na/Li
THF
-30
-30
-30
-30
-30
-30
-30
-30
-10
-50
A
A
A
A
A
A
A
A
A
A
0/0
THF
27/15
0/0
Na/Zn[d]
Na/Na
Na/Na
Na/Na
Na/Na
Na/Na
Na/Na
Na/Na
THF
THF
52/11
58/13
45/13
45/15
58/5
Table 2. C-glycosylation of glucose donor 1a[a]
PhMe
Et2O
DME
n-hexane
PhMe
PhMe
48/15
47/0
Entry
Acceptor
Yield of C-glycoside[b]
Yield
glycoside[b]
of
O-
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9
16 60%
0%
0%
0%
1
2
3
4
5
6
7
8
2 61%
3 7%
5 6%
10[d]
17 56%
18 52%
4 65%
6 54%
7 62%
9 52%
11 62%
13 53%
15 60%
11[d]
N.D.[c]
8 11%
10 7%
12 17%
14 11%
N.D.[c]
[a] Reaction conditions: 1a (1 equiv.) and NaHMDS (1.1 equiv.) was added to
RSO2Cl (1.1 equiv.) in THF, -30 °C, 1 h; then acceptor (2 equiv.) and NaHMDS
(2.1–4 equiv.) in co-solvent, -78 °C to -30 °C., 1 h. [b] Isolated yields. Not
determined. [d] C-acyl glycosides 17 and 18 (after desilylation):
[c]
Other glycosyl donors also proved to be competent
electrophiles in the reaction (Scheme 2). C-Glycosylations using
perbenzylated galactose donor 1b proceed in moderate to good
yields. Similarly, reactions with lactose donor 1c proceeded
smoothly, which demonstrates that this reaction is compatible
with more complex sugar donors. As with glucose, the reaction
with both donors only afforded the products exclusively as -
anomers.
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Scheme 2. C-glycosylations of galactose donor 1b and lactose donor 1c.
The ketone in the resultant homoacyl--C-glycosides can
serve as a handle for elaboration to more complex structures. For
example, C-glycoside 2 can be elaborated to the model C-
glycolipid 39 (Scheme 3). To this end, Baeyer–Villiger oxidation
of 2 provides ester 37 in moderate yield.[20] Reduction of 37
using DIBAL then affords alcohol 38. Finally, treatment of 38 with
octanoyl chloride affords C-glycolipid analog 39 in 70% yield.
In addition, we noticed the possibility of transforming the acyl
furan on 15 into a monosaccharide-like structure. Following
O’Doherty’s de novo synthetic protocol,[19b, 19c, 21] ketone 15 was
first reduced using Noyori asymmetrc transfer hydrogenation,[22]
affording alcohol 40 in quantitative yield. This alcohol was
subjected to NBS to generate functionalized enone 41 in 79%
yield. To the best of our knowledge, this is the first Achmatowicz
reaction performed on a carbohydrate substrate, and it expands
the utility of this method to the synthesis of C-disaccharide
analogs.
Scheme 3. Derivatization of C-glycoside 2 into glycolipid mimics.
Scheme 4. Derivatization of C-glycoside 15 by Achmatowicz rearrangement.
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glycosides. The protocol, which employs bench-stable
hemiacetals as donors, tolerates a range of substrates, including
heterocycle-containing nucleophiles. These C-alkyl glycosides
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C-analogs of glycolipids and disaccharides. We anticipate that
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We thank NIGMS (No.: 1U01GM120414) for their generous
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Keywords: carbohydrate• C-glycosides • diastereoselectivity •
C-glycosylation • glycosyl sulfonate
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Entry for the Table of Contents
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Jesse Ling, Clay S. Bennett*
Page No. – Page No.
β-Selective C-Glycosylation
Alkyl C-glycosides are readily prepared
from bench-stable hemiacetals via
glycosyl sulfonate intermediate. This
SN2-like C-glycosylation generates
a
Text for Table of Contents
β-anomers exclusively. The resulting
products undergo facile derivatization
into various C-glycoside mimetics of
β-linked glycoconjugates.
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