Stereoselective synthesis of 2-deoxy-2-phenylselenenyl glycosides from furanoses: Implication of the phenylselenenyl group in the stereocontrolled preparation of 2-deoxy-ribo- and 2-deoxy-xylo-oligosaccharides

Article abstract of DOI:10.1002/ejoc.200700161

A series of 2-deoxy-2-phenylselenenyl-1-thioglycosides were evaluated as a class of glycosyl donors that provide access to 2-deoxyglycosides from furanoses. This short synthetic route involves olefination, selenonium ion mediated 6-endo cyclization and gl

Full text of DOI:10.1002/ejoc.200700161

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DOI: 10.1002/ejoc.200700161
Stereoselective Synthesis of 2-Deoxy-2-phenylselenenyl Glycosides from
Furanoses: Implication of the Phenylselenenyl Group in the Stereocontrolled
Preparation of 2-Deoxy-ribo- and 2-Deoxy-xylo-oligosaccharides
Omar Boutureira,[a] Miguel A. Rodríguez,[a] David Benito,[a] M. Isabel Matheu,[a]
Yolanda Díaz,*[a] and Sergio Castillón*[a]
Keywords: Carbohydrates / Cyclization / Glycosylation / Selenium
A series of 2-deoxy-2-phenylselenenyl-1-thioglycosides were
evaluated as a class of glycosyl donors that provide access to
2-deoxyglycosides from furanoses. This short synthetic route
involves olefination, selenonium ion mediated 6-endo cycli-
zation and glycosylation reactions. The cyclization reaction
proceeds with complete regio- and stereoselectivity, which
are enhanced by employing 3,4-O-isopropylidene as a cyclic
bifunctional protecting group. The implication of the phenyl-
selenenyl group at C-2 in the stereocontrolled preparation of
2-deoxyoligosaccharides is discussed. Its presence gives
some insights into the likely pathway of glycosylation reac-
tions by using 2-deoxy-2-phenylselenenyl-1-thioglycosyl do-
nors in comparison with the previously described 2-deoxy-2-
iodo derivatives. We also demonstrated that the glycosylation
of 2-deoxy-2-phenylselenenyl-1-thioglycosides is highly sub-
strate dependent, as well as particularly effective in provid-
ing 2-deoxy-2-phenylselenenyl-β-D-gulo- and -β-D-allo-gly-
cosides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
2-Deoxy- and 2,6-dideoxy carbohydrates are structurally
As recently reported in our group, 2-deoxy-2-iodo-1-thio-
important motifs present in many biologically active natu- glycosides[8] were synthesized from pentoses and used as
ral products.[1] The stereocontrolled formation of 2-deoxy- glycosyl donors for the stereocontrolled synthesis of 2-de-
glycosidic linkages represents one of the most challenging oxy-2-iododisaccharides. This short synthetic route involves
synthetic problems in carbohydrate chemistry.[2] Although olefination, iodonium ion mediated 6-endo cyclization and
in recent years a wide variety of methods[3,4] for the stereo- glycosylation reactions, and provides access to 2-deoxy-β-
selective synthesis of 2-deoxy- and 2,6-dideoxyglycosides hexo-glycosides of -ribo and -xylo configuration
have been developed, those involving special glycosyl do- (Scheme 1). Motivation to develop this new procedure
nors[5] and 2-deoxy-2-X-glycosyl donors (X = Br, I, SPh prompted us to investigate 2-deoxy-2-phenylselenenyl-1-thio-
and SePh) are still valuable and attractive[6,7]
glycosides as a new class of glycosyl donors and evaluate
Scheme 1. Stereoselective synthesis of 2-deoxy- and 2,6-dideoxyglycosides of -lyxo, -arabino, -ribo and -xylo configurations through
an olefination–cyclization–glycosylation sequence.
[a] Departament de Química Analítica i Química Orgànica, Uni-
the effect of the phenylselenenyl[9] group in the stereochemi-
cal outcome of the glycosylation reaction since there are no
examples reported with 2-deoxy-2-phenylselenenyl--gulo
and --allo glycosides.
versitat Rovira i Virgili,
C/ Marcelí Domingo s/n, 43007 Tarragona, Spain
Fax: +34-977558446
E-mail: yolanda.diaz@urv.cat,
sergio.castillon@urv.cat
3564
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Stereoselective Synthesis of 2-Deoxy-2-phenylselenenyl Glycosides
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the cyclic bifunctional protecting group.[21] However, it is
less obvious why phenylselenenyl-promoted cyclization led
Results and Discussion
The first step in the proposed synthesis of 2-deoxy-2- to such a different product distribution (thioglycosides, gly-
phenylselenenyl-1-thioglycosides was the electrophile-in-
duced cyclization (Scheme 1). For this purpose, vinyl sul-
fides 1, 3, 4, 8 and 9 were easily prepared in one step from
the corresponding protected furanoses and used as the
starting materials.[8c]
In this context, functionalization of double bonds pro-
moted by electrophilic selenium species was employed suc-
cessfully for the synthesis of different versatile building
blocks in organic synthesis.[10] When the alkene moiety is
tethered to a nucleophilic substituent, intramolecular attack
of the latter upon the intermediate selenonium ion takes
place, leading to the corresponding cyclized product. Al-
though different alkene derivatives, reagents and reaction
conditions were employed for this general transforma-
tion,[11–13] no publication dealing with the electrophilic se-
lenenylation reaction of carbohydrate-based vinyl sulfides
has been reported to date.
Scheme 2. Cyclization of tri-O-benzyl-protected alkenyl sulfides 1,
3 and 4 to obtain 2-deoxy-2-phenylselenenylthioglycosides 2 and
5–7.
Table 1. Cyclization of 3,4-O-isopropylidene-protected alkenyl sul-
The reaction conditions for cyclization were optimized fides 8–10 induced by electrophilic selenium containing reagents.
by starting from derivative 1 (Scheme 1). Initial attempts
under basic conditions with the use of phenylselenenyl trifl-
ate (PhSeOTf)[14] proved ineffective as this selenenylating
agent gave an inseparable mixture of products. However,
when N-(phenylselenenyl)phthalimide (NPSP)[15] was em-
ployed without a promoter, expected product 2 was ob-
tained in yields lower than 11% but with total regio- and
stereoselectivity.[16]
[17]
Cyclization with NPSP and ZnI2 as the promoter led
to desired product 2 in a similar yield (Ͻ15%) maintaining
the same regio- and stereoselectivity. The presence of the
promoter allows the reaction to proceed under milder con-
ditions. Other promoters such as (Ϯ)-camphor-10-sulfonic
[19]
acid (CSA),[14] Mg(ClO4)2,[18] SnCl4 and I2[20] resulted in
unsuccessful cyclization reactions. Other alkenyl sulfides
such as -arabino 3 and -ribo 4 derivatives also reacted
with similar selectivity, but the reactions were sluggish with
yields lower than 15% (Scheme 2).The synthetic scope of
the current cyclization method was examined by changing
the structural patterns of the alkenyl sulfides (Table 1). The
cyclization of 3,4-O-isopropylidene-protected derivative 8
proceeded smoothly and afforded desired thioglycoside 11
with complete α-selectivity in good yield (Table 1, Entry 1).
Forcing the reaction conditions in the absence of ZnI2 led
to the formation of 2-phenylselenenyl glycal 12 in 34% yield
together with small amounts of 11 (Table 1, Entry 2). Cycli-
zation of 3,4-O-isopropylidene-protected -lyxo 9 and -
ribo 10 derivatives also afforded thioglycosides 13 and 15,
respectively, in moderate yields (15–33%) and complete
selectivity together with glycals 14 (60%) and 16 (74%) as
major products (Table 1, Entries 3 and 4). These cyclization
assays revealed that the cyclization conditions are very sen-
sitive to the configuration, as well as the nature, of the hex-
[a] Determined by integration of the anomeric proton signals in the
enyl sulfide protecting groups. These experiments estab-
1H NMR spectrum after chromatographic purification. [b] Solvent
lished that hydroxy hexenyl sulfides 8–10 undergo a com-
pleted 6-endo regioselective electrophilic selenium-induced
= CH2Cl2. [c] Determined by integration of the anomeric proton
signals in the 1H NMR spectrum of the crude reaction mixture. [d]
cyclization enhanced by employing 3,4-O-isopropylidene as 10% of the corresponding glycal was also obtained.
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Y. D íaz, S. Castillón et al.
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cals and 2-phenylselenenyl glycals) related to the alkene have the reactivity characteristics that we desired. Thus, we
substrate, although being performed under similar condi- found that the glycosylation of 11 with several promoters,
tions.
such as NIS/TfOH, NIS/TMSOTf and dimethyl(methythio)-
A plausible explanation for the observed product distri- sulfonium fluoroborate (DMTSF) proceed smoothly at low
bution is outlined in Scheme 3. The conversion of com- temperature to give corresponding 2-deoxy-2-phenylse-
pound I into III represents an overall base-promoted lenenyl-glycoside 18 with high stereocontrol (α/β ratio range
PhSSePh elimination process, and might be occurring from 7:1 to 40:1) in moderate-to-good yields (21–68%). The
through initial S-phenylselenenylation followed by the eli- results are summarized in Table 2. In NIS-promoted glyco-
mination of a “phenylselenol equivalent” PhSSePh in II to sylations the use of toluene/dioxane (1:3) enhanced α-selec-
give a 2-phenylselenenyl glycal. Similarly, the production of tivity[23] (Table 2, Entries 1 and 2). However, the most dra-
IV might be explained in terms of reductive elimination of matic effect in terms of anomeric ratio is the nature of the
PhSSePh–PhSeI in II to afford the corresponding glycal.[22] promoter, as well as the counterion of the Lewis acid that
activates the NIS. The best selectivities were obtained when
DMTSF (Table 2, Entry 4) was used, followed by NIS/
TMSOTf and TfOH, respectively (Table 2, Entries 2 and 3).
Unfortunately, DMTSF and NIS/TMSOTf led to low yields
of 18.
Accordingly, glycosylation reactions of 2, 5–7 and 15
were performed by treating a mixture of the 2-deoxy-2-
phenylselenenyl-1-thioglycosyl donor (1 equiv.) and glycosyl
acceptor 17 (2 equiv.) with NIS (2.2 equiv.) and TfOH
(0.2 equiv.) in toluene/dioxane (1:3) in the presence of 4 Å
molecular sieves (Table 3). This procedure typically pro-
vides the desired products in good yields (50–70%). When
Scheme 3. Plausible mechanism for the observed product distribu-
tion during the cyclization of 3,4-O-isopropylidene-protected alk-
enyl sulfides induced by electrophilic selenium species.
Having our target donor thioglycosides in hand, we
turned our attention to the investigation of their glycosyla-
tion properties. On the basis of our experience with 2-de-
oxy-2-iodo-1-thioglycosides[8c] we anticipated that 2-deoxy-
2-phenylselenenyl-1-thioglycosides 2, 5–7, 11 and 15 would
Table 3. Stereoselective glycosylation of 17 from 2-deoxy-2-phenyl-
selenenyl-1-thioglycosides 2, 5–7 and 15.
Table 2. Optimization of the stereoselective glycosylation condi-
tions of 2-deoxy-2-phenylselenenyl-1-thioglycoside 11 to obtain 18
containing reagents.
[a] Glycosyl donor (1 equiv.), glycosyl acceptor (ROH) 17
(2 equiv.), NIS (2.2 equiv.), TfOH (20 mol-%), 4 Å MS, toluene/di-
oxane (1:3). [b] Determined by H NMR spectroscopy in the pres-
ence of an internal standard unless otherwise indicated. [c] Deter-
mined by integration of the anomeric proton signals in the 1H
NMR spectrum of the crude reaction mixture. [d] Isolated yield.
[a] Glycosyl donor 11 (1 equiv.) and glycosyl acceptor 17 (2 equiv.)
were stirred with 4 Å MS at –78 or 0 °C for 1 h unless otherwise
indicated. [b] Determined by integration of the anomeric proton
signals in the 1H NMR spectrum of the crude reaction mixture. [c]
The reaction mixture was stirred from –78 to –50 °C for 2 h.
1
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Stereoselective Synthesis of 2-Deoxy-2-phenylselenenyl Glycosides
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compared with 5, 6 and 15 (Table 3, Entries 2, 3 and 5), activity of each conformer, as mandated by Curtin–Ham-
glycosyl donors 11 (Table 2) and 7 (Table 3, Entry 4) pro- met/Winstein–Holness kinetics[26] (Scheme 4). Thus, ac-
vided improved stereoselectivities. These results are in cording to the results reported by Billings and coworkers,[27]
agreement with those reported by Roush and coworkers for PhSe-axial intermediates IIa,b (-manno and -talo) and
the glycosylation of 2-deoxy-2-iodo-manno- and 2-deoxy-2- Ic–e (-gluco, -allo and -gulo) are likely to be more stable
talo-pyranosyl acetates.[7i] However, an interesting result than the corresponding PhSe-equatorial conformers due to
was obtained with gulose derivative 2 (Table 3, Entry 1). In stabilizing hyperconjugative interactions between σC–Se and
this case, even using toluene/dioxane (1:3) as solvent sys- π*C–O of the oxocarbenium. Besides, it is known that nucle-
tem, the high β-selectivity observed is comparable to 11 ophilic attack on the oxocarbenium cations along a pseu-
(Table 2, Entry 2) and 7 (Table 3, Entry 4), as well as to that doaxial trajectory to maximize overlap of the nucleophile
previously observed for analogous glycosylation reactions HOMO with the LUMO of the oxocarbenium ion occurs
of 2-deoxy-2-iodo-1-thio-gulo-glycosyl donors in CH2Cl2 with a facial preference to give a chair-like transition state.
(α/β, 1:16).[8c] Interestingly, a similar behaviour was issued According to this stereoelectronic effect, the reaction of
in previous studies with 2-deoxy-2-iodo-glucosyl trichlo- each conformer is expected to provide a different dia-
roacetimidates in which no improvement in the α/β ratio stereomer of the product. However, the selectivity obtained
was found by changing solvent properties.[7d] Glycosyl do- in the glycosylation experiments cannot only be addressed
nor 6 displayed no β-selectivity in agreement with prior in terms of relative conformer population but developing
studies with 2-phenylsulfanyl- and 2-phenylselenenyl-gluco- destabilizing interactions in the transition state (transition-
pyranosyl donors which indicated that selectivity was highly state effects) should also be accounted for. Thus, the reac-
substrate dependent, and the 2-iodo substituent was found tivity of the oxocarbenium conformers towards nucleophilic
to be the more general stereodirecting group[9b,9c,24] attack may be affected by steric interactions between the C-
(Table 3, Entry 3). Other glycosyl donors bearing an equa- 3 alkoxy substituent and the incoming nucleophile.
torial phenylselenenyl group such as 5 and 15 provided
modest β-selectivities (Table 3, Entries 2 and 5).
Consistent with this, glycosylation of -manno 7 and -
gulo 2 derivatives provided excellent α- and β-selectivities,
In light of these results, we envisioned that oxocarbenium respectively; by far the more stable axial PhSe conformers
intermediates play an important role in the stereoselectivity IIa (-manno) and Id (-gulo) are also the more reactive
of the glycosylation reactions of 2-deoxy-2-phenylselenenyl- ones towards nucleophilic attack. The -allo derivative 5
1-thioglycosides rather than the corresponding selenonium showed moderate β-selectivity. When compared with the -
ion intermediates.[7a,25] The selectivity is determined by gulo derivative 2, the lower selectivity magnitude obtained
both the ground-state conformational preferences of oxo- could be explained by ground-state conformational prefer-
carbenium intermediates Ia–e and IIa–e and the relative re- ence variations.
Scheme 4. Stereochemical courses of glycosylation reactions of 2-deoxy-2-phenylselenenyl-1-thioglycosyl donors.
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