Direct umpolung of glycals and related 2,3-unsaturated n-acetylneuraminic acid derivatives using samarium diiodide

Article abstract of DOI:10.1002/anie.201402891

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate-derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reac

Full text of DOI:10.1002/anie.201402891

Angewandte
Chemie
DOI: 10.1002/anie.201402891
Umpolung
Direct Umpolung of Glycals and Related 2,3-Unsaturated
N-Acetylneuraminic Acid Derivatives Using Samarium Diiodide**
Tien Xuan Le, Caroline Papin, Gilles Doisneau,* and Jean-Marie Beau*
In memory of Robert (Robin) J. Ferrier and Jean-Louis Namy
Abstract: The umpolung of glycals with samarium diiodide
offers a simple route to novel carbohydrate-derived nucleo-
philic reagents in a single step using a readily available
reductant. The corresponding allyl samarium reagent that
arises from the hexose series reacts with ketones at the
C3 position with high stereoselectivity; carbon–carbon bond
formation takes place only anti to the substituent at the
Scheme 1. Electrophilic or nucleophilic intermediates from glycals (1,5-
C4 position of the dihydropyran ring. For the sialic acid series,
the completely regio- and stereoselective coupling process of
the samarium reagent occurs at the anomeric carbon atom and
provides a new approach to the a-C-glycosides of N-acetyl
neuraminic acid.
anhydrohex-1-enitols) 1. El=electrophile, Nu=nucleophile, Pg=pro-
tecting group.
has not been reported to date. Using samarium diiodide as the
reducing agent,[4–6] existing methods typically rely on the
umpolung of preformed electrophilic palladium[7] (or iri-
dium)[8] p-allyl complexes, as reported for simple allylic
alcohol derivatives (esters, carbonates, phosphates).
Herein, we reveal that samarium diiodide alone can
perform the direct and selective umpolung of glycals without
the need for intermediary p-allyl transition-metal com-
plexes.[9] This was demonstrated for the coupling reaction
with appropriate carbonyl compounds under Barbier con-
ditions. Furthermore, we show that the high regio- and
stereoselectivity of this transformation can be fine-tuned by
the structure of the substrates.
G
lycals (1,5-anhydrohex-1-enitols)[1] are carbohydrate
derivatives that are extensively used for the preparation of
important complex carbohydrates and glycoconjugates as
well as non-carbohydrate natural products,[2] most notably
through a Lewis acid induced allylic oxocarbenium ion that
reacts with appropriate nucleophiles mainly at the anomeric
center (known as the Ferrier I rearrangement; Scheme 1).[3]
These useful substrates could also provide new types of
nucleophilic carbohydrate-derived allylation reagents by
polarity inversion (umpolung). However, such a reaction
The direct reductive coupling of such substrates was
initially studied with simple dihydropyranyl allylic esters.
Therefore, treatment of acetate 3 or benzoate 4[10] with SmI2
alone at room temperature in the presence of a carbonyl
compound provided only (entries 1–5 and 7, Table 1) or very
predominantly (entries 6 and 8–10) the C4-coupling products
5a–f. The highest yields were obtained with allylic benzoate 4
(entries 2, 3, 5, 7, and 9; 77–95% yield), suggesting that this
group was first reduced to generate the initial allylic radical
intermediate. The intracyclic oxygen atom of the dihydro-
pyran ring is essential for the reaction to occur as allylic
cyclohex-2-enyl acetate did not react under identical reaction
conditions.[9b,11]
This procedure was then extended to more functionalized
glycals. Surprisingly, commercial tri-O-acetyl-d-glucal did not
react under the above conditions, which revealed that the
reduction of the allylic acetate in this substrate was signifi-
cantly more difficult than for dihydropyran substrates. How-
ever, orthogonally protected d-glucal derivatives 7b–e, which
are equipped with an allylic carbonate,[9a] all reacted with
SmI2 at room temperature under Barbier conditions, giving
exclusively the C3-products 8a–g (carbohydrate numbering)
in 54–63% yield (entries 2–8, Table 2). Only di-O-benzyl
substrate 7a was very reactive (reaction at 08C for 2 h), but
[*] T. X. Le, C. Papin, G. Doisneau, J.-M. Beau
Universitꢀ Paris-Sud and CNRS
Laboratoire de Synthꢁse de Biomolꢀcules
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay, UMR 8182
91405 Orsay (France)
E-mail: gilles.doisneau@u-psud.fr
jean-marie.beau@u-psud.fr
T. X. Le
Department of Chemical Engineering
HCMC University of Technology, VNU-HCM
268 Ly Thuong Kiet, District 10, Ho Chi Minh City (Vietnam)
C. Papin
Molecular NeuroImaging LLC
60 Temple Street, New Haven, CT 06510 (USA)
J.-M. Beau
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles du CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
[**] We thank the Ministry of Education and Training of Vietnam for
a PhD fellowship to T.X.L. and the French Agency for Research
(ANR-2010-BLAN-708-1) and the Institut Universitaire de France
(IUF) for financial support of this study. The CHARM3AT Labex
program is also acknowledged for its support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402891.
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Table 1: SmI2-induced umpolung of dihydropyranyl allylic esters 3 and
4.[a]
Table 2: SmI2-induced umpolung of d-glucal derivatives 7a–e.[a]
Entry Substrate
Ketone
Product Yield
[%][b]
Entry Substrate Ketone
C4-Adduct
(yield)[b]
C2-Adduct
(yield)[b]
1
2
3
4
5
3
4
4
3
4
n=2 5a (64%)
n=2 5a (77%)
n=1 5b (82%)
n=0 5c (51%)
n=0 5c (87%)
6a (<1%)
6a (<1%)
6b (nd)
6c (<1%)
6c (<1%)
1
7a
7b
cyclohexanone
8a
8b
8c
33[c]
5d (69%)[c] 6d (6%)
5d (95%)[c] 6d (nd)
2
3
cyclohexanone
cyclohexanone
63
6
7
3
4
7c
R=Et
8
9
3
4
5e (61%)
5e (86%)
6e (6%)
6e (10%)
60
4
5
6
7
7c
7c
7c
7d
cyclopentanone
cyclobutanone
N-Boc-piperidin-4-one 8 f
8d
8e
56
54
55
63
10
4
pentan-3-one
5 f (68%)
6 f (10%)
[a] Conditions: SmI2 (3 equiv), ketone (2 equiv), THF, 2 h, room
temperature. [b] Yield after purification by column chromatography on
silica gel. [c] Obtained as a 1:2.6 mixture of isomers. Boc=tert-
butyloxycarbonyl, nd=not detected. Pyran numbering is used.
cyclohexanone
8c
R=Ph
8
7e
cyclohexanone
8g
56
provided a low 33% yield of 8a (entry 1) because of the
competitive formation of unidentified side products.
[a] Reaction conditions: SmI2 (5 equiv), ketone (3 equiv), THF, 1–2 days
at room temperature. [b] Yield after purification by column chromatog-
raphy on silica gel. [c] Reaction performed at 08C for 2 h. Carbohydrate
numbering is used.
The reduction rate of 7b–e was also much slower than
above (1–2 days versus 2 h for the dihydropyrans; Table 1).
Remarkably, all homoallylic alcohols 8a–g were formed as
single C3-regioisomers with the 3,4-trans configuration only,
for example, with an overall retention of configuration at the
C3 position. This trans relationship with an equatorial ori-
À
entation of the newly formed C C bond was determined by
1H NMR analysis (strong nuclear Overhauser effect (nOe)
between the H3 and H5 hydrogen atoms and large J3,4 values
of 8.6–9.4 Hz).
This study was also conducted with the d-galactal
derivatives 9a and 9b to identify the structural features that
control the stereochemical outcome of the reaction
(Scheme 2). Again, the homoallylic alcohols 10a and 10b
were formed as single C3-regioisomers from 9a and 9b with
the 3,4-trans configuration only, for example, with an overall
inversion of configuration at the C3 position. The reductive
coupling of isopropylidene derivative 9b was very slow (21%
yield after 3 days with 44% of recovered starting material
9b).[12]
The chiral center at the C4 position strictly controls the
stereochemical outcome of the coupling reaction as the
trapping of the allylic samarium species occurred anti to the
substituent at the C4 position. This was further confirmed by
the reductive coupling of 4-deoxyglycal 11 with cyclohex-
anone (Scheme 2). In the absence of a substituent at the
Scheme 2. SmI2-induced umpolung of d-galactal derivatives 9a and 9b
and 4-deoxyglycal 11. Bn=benzyl, Bz=benzoyl.
À
C4 position (11), the C C bond at the C3 position in
product 12 was formed with no selectivity (isomer ratio of
This study was completed with coupling reactions of an
2:3; Scheme 2).
important glycal that is derived from N-acetyl neuraminic
2
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Table 3: SmI2-induced umpolung of glycals from N-acetyl neuraminic acid (Neu5-
Ac2en) derivatives 13a–c.[a]
The high reactivity of peracetylated 13c is
remarkable as this compound does not react under
palladium catalysis, because the formation of the p-
allyl palladium complex is too difficult.[13,19] The
reduction of glycals 7a–e, which belong to the hexose
series, is thought to proceed through a selective
electron transfer to the carbonyl group of the allylic
moiety, leading to allylic radical A, which is further
Entry Substrate
Ketone
Product Yield[b]
[%]
reduced to the allylic samarium derivative
B
(Scheme 4). This explains why allylic benzoates and
carbonates are more efficient substrates than ace-
tates (Table 1 and Table 2).
1
13a cyclohexanone
14a
14b
14c
97
97
96
Because of the very different reaction conditions,
it is likely that the mechanism for the reduction of
Neu5Ac2en derivatives 13 involves a distinct mech-
anism, which explains the excellent reactivity of
peracetylated 13c.[20] We suggest that the trans-
formation may start with the formation of radical
enolate C,[6,21] which is possibly facilitated by chela-
tion of the samarium atom by the endocyclic oxygen
atom. This radical is further reduced to the dianionic
species D, which undergoes elimination to form E.
Subsequent coupling with the ketone then proceeds
with the same a stereoselectivity that was already
observed with similar samarium enolates derived
from NeuAc derivatives.[22,23] Further work is needed
to clarify this point.
In summary, the umpolung of glycals proceeds
under simple experimental conditions (SmI2 in THF)
and in a chemoselective fashion in the presence of
many other reducible groups (O-acyl and NHAc
moieties). For the hexose series, the corresponding
allyl samarium reagent reacts with ketones at the
C3 position with high stereoselectivity, which is
2
3
13b cyclohexanone
13c cyclohexanone
4
5
6
13c cyclopentanone
13c cyclobutanone
13c 4-tert-butylcyclohexa- 14 f
14d
14e
97
96
88
none
7
13c N-Boc-piperidin-4-
one
14g
96
8
9
13c propanone
13c butan-2-none
14h
14i
92
91[c]
[a] Reaction conditions: SmI2 (3 equiv), ketone (2 equiv), THF, 1 h, À788C. [b] Yield
after purification by column chromatography on silica gel. [c] Isolated as a 1:1.2
mixture of diastereomers. TBS=tert-butyldimethylsilyl.
acid (Neu5Ac2en). A selective umpolung approach would
offer useful modifications of the allylic system in Neu5Ac2en
derivatives. With these derivatives, the umpolung reaction
with SmI2 was facile, and after optimization, it was found that
the best method was to run the reaction under the Barbier
conditions at À788C for one hour (Table 3). Under these
conditions, the allylic benzoates 13a and 13b[13] provided
exclusively the C2-products 14a and 14b in 97% yield each.
Readily available peracetylated Neu5Ac2en 13c[13,14] was also
an excellent substrate and afforded the C2-coupling products
Scheme 3. SmI2-induced intramolecular coupling with peracetylated
Neu5Ac2en 13c. Reaction conditions: a) H2, Pd/C (5%), AcOEt, RT,
24 h; b) MeONa, MeOH, RT.
14c–i in 88–97% yield (entries 3–9). The structures of the C2-
products 14 were assigned by NMR analysis.[15]
Furthermore, their structures were confirmed by NMR
analysis of the reduction product (H2, Pd/C, AcOEt) of 14 f
after deprotection (15, Scheme 3).[13,16] This compound cor-
responds to a 4-deoxy-a-C-glycosyl analogue of N-acetyl
neuraminic acid.
Without an external ketone, bicyclic derivative 16 was
formed in 59% yield by treating glycal 13c with SmI2 under
identical conditions (Scheme 3).[17,18] This intramolecular
coupling reaction revealed that the C4 position of the allylic
system acts as a nucleophile when no intermolecular coupling
partner is available.
controlled by the substituent at the C4 position. For the
sialic acid series, the completely regio- and stereoselective
coupling process at the anomeric carbon atom provides a new
approach to a-C-glycosides, which complements our previ-
ously described samarium-promoted routes from the anome-
ric 2-thiopyridyl and acetyl derivatives.[22] Further work to
elucidate the mechanism of this transformation and to extend
this method to the preparation of modified C-sialosides,
which are useful for an exploration of their interactions with
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Scheme 4. Proposed mechanism for the SmI2-induced umpolung of
hexose glycals 7a–e and methyl ulosonate glycals 13a–c.
À
C O bond at the C3 position to assume a pseudoaxial orienta-
tion (5H4 conformation; as in 7a and 9a), the faster the reduction
rate (stereoelectronic control of the homolytic cleavage of the
C3 O3 bond). For the glycals 7b–e and 9b, a 4H5 to 5H4
conformational change is constrained by a 4,6-cyclic protecting
group; these substrates were thus only very slowly reduced by
SmI2.
À
sialo-binding proteins, is currently underway in our laborato-
ries.
Received: February 28, 2014
Revised: March 27, 2014
Published online: && &&, &&&&
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[15] This was based on the J values for the H4 and H5 atoms in
a 6H5 half-chair conformation; see also Ref. [13].
[16] Diagnostic for the configuration determination of the quater-
Keywords: carbohydrates · reductive coupling · samarium ·
sialic acids · umpolung
.
nary center at the C2 position is the large value of the
3
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4
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Chemie
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Umpolung
T. X. Le, C. Papin, G. Doisneau,*
J.-M. Beau*
&&&& — &&&&
Direct Umpolung of Glycals and Related
2,3-UnsaturatedN-Acetylneuraminic Acid
Derivatives Using Samarium Diiodide
Samarium can do it alone: Without the
help of transition metals, samarium(II)
iodide induces a chemoselective reduc-
tive coupling of carbonyl compounds
with glycals. The high regioselectivity and
stereoselectivity of the transformation are
controlled by the structure of the sub-
strates.
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These are not the final page numbers!