β-Rhamnosides from 6-thio mannosides

Article abstract of DOI:10.1039/c2cc17623h

Upon condensation of 6-thio-6-deoxy-mannosyl donors 1,2-cis products are obtained with a high degree of stereoselectivity. Subsequent reductive removal of the 6-thio functionality gives 1,2-cis rhamnosides. The 1,2-cis-selectivity can be rationalized with

Full text of DOI:10.1039/c2cc17623h

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COMMUNICATION
b-Rhamnosides from 6-thio mannosidesw
Alphert E. Christina, Daan van der Es, Jasper Dinkelaar, Hermen S. Overkleeft,
´
Gijsbert A. van der Marel* and Jeroen D. C. Codee*
Received 6th December 2011, Accepted 17th January 2012
DOI: 10.1039/c2cc17623h
Upon condensation of 6-thio-6-deoxy-mannosyl donors 1,2-cis
products are obtained with a high degree of stereoselectivity.
Subsequent reductive removal of the 6-thio functionality gives
1,2-cis rhamnosides. The 1,2-cis-selectivity can be rationalized
with a product forming 3H4-oxocarbenium, which is in equilibrium
with a bridged sulfonium intermediate.
Neighboring group participation is a powerful means to steer the
stereochemical course of a synthetic transformation. Especially in
the area of carbohydrate chemistry it takes up a prominent
position and the placement of a participating N- or O-acyl
function at the C-2 position is commonly used to secure the
stereoselective formation of 1,2-trans glycosidic bonds.1 C-2-thio-
and C-2-seleno-ethers have also been exploited to direct the
stereochemical outcome of glycosylation reactions and various
groups have reported on their use for the construction of 1,2-trans
linkages.2–4 Recently, Boons and co-workers developed a chiral
auxiliary for the stereoselective formation of 1,2-cis glucosyl and
galactosyl linkages based on a participating chiral thioether
grafted on the C-2-hydroxyl of the donor.5 Turnbull and
co-workers have reported on glycosylations of bicyclic methyl
sulfonium xylofuranosides which, upon reaction with an acceptor
nucleophile, provided the a-linked disaccharides with moderate
selectivity.6 The rate of success of participating thio functions seems
to depend on the relative stability of the sulfonium species on
the one hand and the corresponding oxocarbenium ions on the
other, in combination with the ease of substitution of both
species.2,7 As Woerpel and co-workers have convincingly
demonstrated, the intermediate sulfonium ions can serve as a
reservoir for the corresponding oxocarbenium ions, which often
are more reactive and react in a distinct stereochemical manner.8
Based on these precedents we reasoned that activation of a
mannosyl donor (such as 1, Scheme 1), equipped with a thio
ether at C-6, can lead to the formation of a bicyclic sulfonium
ion 2. This sulfonium ion can serve as a reservoir for the
structurally related but more reactive oxocarbenium ion–triflate
anion pairs 3a and 3b. The 3H4 oxocarbenium ion 3a should be
Scheme 1 Strategy for the synthesis of b-rhamnosides.
favored over its 4H3 counterpart 3b, because the former places
all ring substituents in a favorable spatial orientation.9 As
indicated by Woerpel and co-workers, the C-2 alkoxy group
preferentially takes up a pseudo equatorial position in a
pyranosyl oxocarbenium ion half chair, thereby allowing for
hyperconjugative stabilization of the cation by donation of
electron density of the perpendicular sC–H bond. Besides,
alkoxy substituents at C-3 and C-4 prefer to occupy a pseudo axial
orientation to minimize their electron-withdrawing effect,10 and to
allow for the donation of electron density from the heteroatom
lone pairs to the electron-deficient oxocarbenium ion.9 We
hypothesize that the C-5 methylene thioether in a pseudo axial
orientation contributes to the relative stability of 3a with respect to
3b by stabilizing the anomeric positive charge by the sulfur lone
pair electrons. An incoming nucleophile preferentially attacks
oxocarbeniums 3a or 3b on the diastereotopic faces leading to
the chair product to give the b- or a-product, respectively. Like 3b,
nucleophilic attack on bicyclic sulfonium ion 2 will result in the
formation of the a-product. Thus, although the product forming
intermediates 2, 3a and 3b occur in a dynamic equilibrium, the
involvement of the C-5 methylene thioether in the stereochemical
outcome can be deduced from the formation of b-product 4.
Desulfurization of this b-6-thio mannoside can then provide the
corresponding b-D-rhamnoside 5 in a straightforward manner.11,12
To investigate the stereodirecting effect of a mannosyl C-5
thioether, a panel of N-phenyltrifluoroacetimidate donors13
8–14 was combined with three acceptors (15a,b,c) in a series of
condensation reactions.w A variety of C-6 thioethers, a C-6-
selenoether, and a C-6-iodide2,14 were probed, because all these
functionalities have previously been used as participating groups.
The perbenzylated mannosyl donor 6 and the C-6 deoxy donor 7
were included as reference donors. Table 1 records the outcome of
the glycosylations. As expected perbenzylated imidate 6 provided
little to moderate b-selectivity, depending on which acceptor
was used.15 Condensations of rhamnose donor 7 proceeded
with low selectivity with all three acceptors, also in line with
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55,
2333 CC Leiden, The Netherlands.
E-mail: marel_g@chem.leidenuniv.nl, jcodee@chem.leidenuniv.nl;
Tel: +31 715274280X
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterisation of all new compounds. See DOI:
10.1039/c2cc17623h
c
2686 Chem. Commun., 2012, 48, 2686–2688
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Table 1 Condensations of donors 6–14
Scheme 2 Formation and reactions of bicyclic sulfonium ion 25.
15a
15b
15c
16c
Product (yield a/b)a
used here, triflate intermediates are probably not the major product
forming species.17b,c
Entry Donor
1
2
3
4
5
6
7
8
9
6, X = OBn
16a
16b
Because the C-6-S-phenyl donor 8 performed best in the
model glycosylations, is easier to synthesize than its C-6-seleno
counterpart 13 and more stable than 6-iodo mannoside 14 we
continued our studies with donor 8. The formation of the bridged
sulfonium ion 25 from donor 8 and its reactivity was assessed in a
variable temperature NMR experiment (Scheme 2). Treatment of
8 with an equimolar amount of triflic acid (TfOH) at ꢀ80 1C in
CD2Cl2 led to the near instantaneous formation of 25, tentatively
assigned as the exo-sulfonium isomer. This species proved to be
stable up to room temperature (decomposition set in after several
hours at room temperature) and treatment of the mixture with
excess MeOH-d4 led, after 16 hours, to the formation of methyl
mannoside 26 as an anomeric mixture (a/b = 1 : 1). Interestingly,
sulfonium ion 25 could also be generated from the C-6-OH
b-S-phenyl mannoside 27 by treating this thiomannoside with a
catalytic amount of diphenylsulfoxide (Ph2SO) and equimolar triflic
anhydride (Tf2O).18,19 The outcome of the latter experiment
substantiated the result of the former pre-activation experiment.
It also shows that the primary alcohol in 27 is more nucleophilic
towards diphenylsulfonium bistriflate than the anomeric thiophenyl
functionality19 and that a catalytic amount of Ph2SO can be
used for complete activation of donor 27. Addition of acceptor
15a and di-tert-butylmethylpyridine (DTBMP) to sulfonium
ion 25, generated from 27 at room temperature, provided
disaccharide 18a as a 1 : 1 a/b mixture in 42% yield. A similar
stereochemical result was obtained when 8 was preactivated
with an equimolar amount of TfOH at ꢀ80 1C followed by reaction
with 15a in the presence of DTBMP at room temperature.20
Importantly, b-selectivity was restored when the coupling reaction
was executed at low temperature: generation of 25 from 8
using an equimolar amount of TfOH at ꢀ80 1C, and ensuing
reaction with acceptor 15a at ꢀ60 1C delivered 18a in a 1 : 4
a/b-ratio (67% yield). These results can be rationalized by the
mechanistic proposal in Scheme 1. The equilibrium of bridged
sulfonium ion 2 (with R = Ph) and oxocarbenium ions 3a and 3b
lies to the side of the sulfonium ion. At low temperatures this
species is not reactive enough to react with an incoming nucleo-
phile, in line with the recent results obtained by Woerpel et al.8 and
Turnbull et al.6 Reaction takes place from the more reactive
oxocarbenium ion 3a, the formation of which is favored over the
alternative half chair oxocarbenium ion 3b, to produce the b-linked
product in a Curtin–Hammett type kinetic scenario. At higher
temperatures sulfonium ion 2 and/or oxocarbenium ions 3a,b can
be attacked, leading to the demise of stereoselectivity.
(94%, 1 : 3.5) (88%, 1 : 1) (99%, 1 : 4)
17a 17b 17c
(91%, 1 : 2.5) (87%, 1 : 1.5) (90%, 1 : 1)
18a 18b 18c
(90%, 1 : 7) (89%, 1 : 11) (87%, 1 : 5)
19a 19b 19c
(86%, 1 : 5) (56%, 1 : 8) (89%, 1 : 3.5)
10, X = S-pMeOPh 20a 20b 20c
(85%, 1 : 5) (58%, 1 : 7) (88%, 1 : 4.5)
11, X = S-pNO2Ph 21a 21b 21c
(79%, 1 : 7) (91%, 1 : 4) (90%, 1 : 4)
22a 22b 22c
(80%, 1 : 4) (86%, 1 : 3.5) (78%, 1 : 1.5)
23a 23b 23c
(99%, 1 : 7) (96%, 1 : 10) (92%, 1 : 3)
24a 24b 24c
(84%, 1 : 7) (95%, 1 : 6) (87%, 1 : 3)
7, X = H
8, X = SPh
9, X = STol
12, X = SEt
13, X = SePh
14, X = I
a
Isolated yield after size exclusion chromatography. The anomeric
ratio is based on 1H NMR of the diastereomeric mixture. The anomeric
configuration of the mannosidic linkages has been established using
C10–H10 coupling constants.
our previous results.15 The C-6-thio, seleno and iodo mannosyl
donors 8–14 on the other hand, all preferentially provided the
1,2-cis linked disaccharides, with the C-6-S-phenyl donor 8
performing best and the C-6-S-ethyl mannoside 12 showing
least selectivity. Although, these results indicate that for these
3
donors the H4-oxocarbenium ion 3b can be the main product
forming intermediate, no simple correlation between the nature
of the C-6-thio-, C-6-seleno, or C-6-iodo functionality and
stereochemical outcome of the reactions can be distilled from
Table 1. Small changes in the dynamic equilibrium of the
reactive intermediates 2, 3a and 3b, as a result of the different
C-6 functionalities in combination with the different nucleo-
philicity of the three acceptors, contribute to the observed
variation in stereoselectivity. Although direct SN2 displacement
of the activated imidate donors (having predominantly the
a-configuration) by the acceptors is conceivable, this reaction
mode is excluded as a major pathway because the variation in
the amount of the b-product in the different glycosylations,
including the role of the C-thio/iodo/seleno function, cannot be
accounted for by this pathway. Illustrative of this is the finding
that most condensations with secondary acceptor 15b proceed
with better b-selectivity than the corresponding couplings with
primary alcohol 15a. The same reasoning holds for the inter-
mediacy of a-triflates that have been shown to be product
forming intermediates in glycosylations using 4,6-O-benzylidene
mannosyl donors16 and mannosides equipped with electron
withdrawing substituents.17 Given the reactive (‘‘armed’’) and
conformationally unconstrained nature of the mannosyl donors
To explore the use of C-6-S-phenyl mannosyl donors in the
context of complex oligosaccharide synthesis, we undertook
the assembly of tetrasaccharide 37, containing alternating
c
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´
Scheme 3 Assembly of a Xanthomonas campestris tetrasaccharide.
a- and b-D-rhamnosides (Scheme 3). Tetrasaccharide 37
represents two repeating units of the O-specific polysaccharide
of the LPS of the phytopathogen Xanthomonas campestris
pathovar campestris,21 the causative agent of a devastating
disease affecting cruciferous crops such as cabbage and broccoli.22
The synthesis of 37 started with the condensation of 6-S-Ph
mannoside 28 and rhamnosyl acceptor 29. To keep the
stereoelectronic effects in building block 28 as similar as
possible to those in donor 8, we used a naphth-2-ylmethyl ether
as a selectively removable protecting group at the C-3 of 28.
Disaccharide 30 was obtained in 72% yield, highlighting the
b-directing capacities of the 6-S-phenyl group in donor 28.
Removal of the naphth-2-ylmethyl ether liberated the C-300-OH,
which was glycosylated with rhamnoside 32 to provide the
a-linked trimer 33, by virtue of the participating acetyl function in
donor 32. Deacetylation of 33 then set the stage for the introduction
of the second b-mannosidic bond. Reaction of the trimer acceptor
and mannosyl donor 8 at ꢀ60 1C led to the formation of the target
tetramer 35, which was obtained as a mixture of anomers, in which
the desired b-isomer prevailed (82%, a/b = 1 : 3). This result
shows that also elaborate acceptors can be b-mannosylated with
productive selectivity. Desulfurization of tetramer 35 under the
agency of Raney-nickel proceeded uneventfully to deliver the
perbenzylated tetrarhamnoside 36 in 96% yield. Reductive removal
of all benzyl ethers completed the synthesis of tetramer 37.
Chem., 2009, 74, 4982–4991.
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´
e and G. A. van der
´
In conclusion, the installation of a thiophenyl ether at C-6 of
a mannosyl donor leads to a 1,2-cis-mannosylating agent, which
can be used as a precursor in the synthesis of b-D-rhamnosides.
The stereoselectivity in the cis-mannosylation reaction can be
rationalized with a Curtin–Hammett kinetic scenario in which
´
R. E. J. N. Litjens, H. S. Overkleeft, J. H. van Boom and G. A.
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´
e, R. E. J. N. Litjens, L. J. van den Bos,
1
the quasi-stable bicyclic C4-sulfonium ion intermediate is in
´
equilibrium with the more reactive and b-selective mannosyl
3H4-oxocarbenium, which places all ring-substituents in an
electronically favorable position.
Litjens, R. den Heeten, H. S. Overkleeft, J. H. van Boom and
G. A. van der Marel, Org. Lett., 2003, 5, 1519–1522.
20 (a) Isomerisation of the b-product into the a-product does not occur
under these conditions, excluding this as a pathway leading to the
a-product; (b) While the formation of 25 from 8 was instanteneous,
the condensation reactions required overnight, excluding direct
intermolecular substitution of the activated imidates. See ESIw.
21 (a) A. Molinaro, A. Silipo, R. Lanzetta, M.-A. Newman, J. Maxwell
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Notes and references
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c
2688 Chem. Commun., 2012, 48, 2686–2688
This journal is The Royal Society of Chemistry 2012