Synthesis of 2-iodoglycals, glycals, and 1,1'-disaccharides from 2-Deoxy-2-iodopyranoses under dehydrative glycosylation conditions.
ABSTRACT Treatment of 2-deoxy-2-iodopyranoses under dehydrative glycosylation conditions afforded pyranose glycals, 2-iodoglycals, and 1,1'-disaccharides instead of the expected glycoside products. While the product distribution revealed that this reaction is very sensitive to the configuration of the 2-deoxy-2-iodopyranose, 2-iodopyranoid glycals can be obtained almost exclusively in good yields by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group. The behavior of 2-deoxy-2-iodopyranoses during the dehydrative elimination reaction has been analyzed in detail.
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ABSTRACT: The detection of tuberculosis currently relies upon insensitive and unspecific techniques; newer diagnostics would ideally co-opt specific bacterial processes to provide real-time readouts. The trehalose mycolyltransesterase enzymes (antigens 85A, 85B and 85C (Ag85A, Ag85B, Ag85C)) serve as essential mediators of cell envelope function and biogenesis in Mycobacterium tuberculosis. Through the construction of a systematically varied sugar library, we show here that Ag85 enzymes have exceptionally broad substrate specificity. This allowed exogenously added synthetic probes to be specifically incorporated into M. tuberculosis growing in vitro and within macrophages. Even bulky substituents, such as a fluorescein-containing trehalose probe (FITC-trehalose), were incorporated by growing bacilli, thereby producing fluorescent bacteria; microscopy revealed selective labeling of poles and membrane. Addition of FITC-trehalose to M. tuberculosis-infected macrophages allowed selective, sensitive detection of M. tuberculosis within infected mammalian macrophages. These studies suggest that analogs of trehalose may prove useful as probes of function and for other imaging modalities.Nature Chemical Biology 03/2011; 7(4):228-35. · 12.95 Impact Factor
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ABSTRACT: Iodosulfonamidation of peracetylated glycals was investigated using either a combination of N-iodosuccinimide/iodine or iodine chloride as a source of iodonium ion. 1,2-trans- and 1,2-cis-2-deoxy-2-iodo-1-sulfonamido hexoses were, respectively, obtained depending on the reagent system used. Both series of isomers were successfully converted to 1,2-di-nitrogenated compounds, for example, 1-azido-1,2-dideoxy-2-sulfonamido sugars, which are useful intermediates for the synthesis of N-linked glycoproteins or glycoconjugates.Carbohydrate research 01/2011; 346(5):577-87. · 2.03 Impact Factor
Synthesis of 2-Iodoglycals, Glycals, and
1,1′-Disaccharides from 2-Deoxy-2-iodopyranoses
under Dehydrative Glycosylation Conditions
Miguel Angel Rodrı ´guez,†Omar Boutureira,†
M. Isabel Matheu,†Yolanda Dı ´az,*,†Sergio Castillo ´n,*,†and
Peter H. Seeberger‡
Departament de Quı ´mica Analı ´tica i Quı ´mica Orga `nica,
UniVersitat RoVira i Virgili, C/ Marcel·lı ´ Domingo s/n, 43007
Tarragona, Spain, and Laboratorium fu ¨r Organische Chemie,
Swiss Federal Institute of Technology, ETH Zu ¨rich, HCI F315,
Wolfgang-Pauli Strasse 10, 8093 Zu ¨rich, Switzerland
ReceiVed August 7, 2007
Treatment of 2-deoxy-2-iodopyranoses under dehydrative
glycosylation conditions afforded pyranose glycals, 2-
iodoglycals, and 1,1′-disaccharides instead of the expected
glycoside products. While the product distribution revealed
that this reaction is very sensitive to the configuration of
the 2-deoxy-2-iodopyranose, 2-iodopyranoid glycals can be
obtained almost exclusively in good yields by employing
3,4-O-isopropylidene as a cyclic bifunctional protecting
group. The behavior of 2-deoxy-2-iodopyranoses during the
dehydrative elimination reaction has been analyzed in detail.
Dehydrative glycosylation is an efficient glycosylation pro-
cedure that uses 1-hydroxysugars as glycosylating agents and
diphenyl sulfoxide and triflic anhydride as activators to produce
glycosides and disaccharides in good yields. These glycosyla-
tions proceed via an oxosulfonium intermediate that may evolve
to an oxocarbenium ion with concomitant regeneration of
diphenyl sulfoxide. The nucleophilic acceptor subsequently adds
to the anomeric center to yield the desired glycosylated product
in a one-pot procedure. Activated or deactivated glycosyl donors
react equally well, and the procedure also allows for the
N-glycosylation of amides.1This methodology includes itera-
tive,2orthogonal,31,2-cis,4and catalytic activated5glycosyla-
tions, but generally, preactivation of the glycosylating agent is
required prior to addition of the acceptor.6
Recently, we reported the synthesis of 2-deoxy-2-iodohexo-
pyranosyl thioglycosides 2 that are efficient glycosylating agents
for the stereoselective synthesis of 2-deoxy-2-iodoglycosides
and oligosaccharides 4. The key step in the synthesis of these
donors was the cyclization of alkenyl sulfanyl derivatives 1 with
iodonium reagents (Scheme 1, path a).7The reaction time and
temperature had to be carefully controlled. Forcing reaction
conditions to ensure full conversion usually resulted in the
activation of the already formed thioglycoside 2. Thus, variable
amounts of the corresponding 2-iodolactol 3 were recovered
usually after workup in unoptimized experiments with labile
substrates. The reaction can be also performed in one-pot fashion
from the sulfanyl alkene 1 by cyclization and in situ activation
of the thioglycoside in the presence of the corresponding
alcohol.8This procedure avoids the formation of the 2-iodo-
We considered that the corresponding 2-iodolactols 3 could
be directly obtained when performing the cyclization reaction
in the presence of small amounts of water. 2-Iodolactols could
be used for the dehydrative glycosylation procedure (Scheme
1, path b), in order to expand the synthetic scope of the 2-iodo
derivatives and provide the basis for orthogonal glycosylation
procedures.3Initially, phenylsulfanylalkene 5 was reacted with
NIS in wet CH3CN to access 2,6-dideoxy-2-iodopyranose 6, a
precursor in the synthesis of oligosaccharides present in natural
products such as digitoxine. Compound 6 was treated with Tf2O,
Ph2SO, and 2,4,6-tri-tert-butylpyrimidine (TTBP) in CH2Cl2at
-60 °C. Surprisingly, the product was partially transformed
†Universitat Rovira i Virgili.
‡Swiss Federal Institute of Technology.
(1) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122,
4269. (c) Nguyen, H. M.; Chen, Y.; Duron, S. G.; Gin, D. Y. J. Am. Chem.
Soc. 2001, 123, 8766.
(2) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem., Int. Ed. 2001,
(3) Codee ´, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1947.
(4) Codee ´, J. D. C.; Hossain, L. H.; Seeberger, P. H. Org. Lett. 2005, 7,
(5) (a) Boebel, T. A.; Gin, D. Y. Angew. Chem., Int. Ed. 2003, 42, 5874.
(b) Boebel, T. A.; Gin, D. Y. J. Org. Chem. 2005, 70, 5818.
(6) Codee ´, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der Marel, G. A.
Tetrahedron 2004, 60, 1057.
(7) (a) Arne ´s, X.; Dı ´az, Y.; Castillo ´n, S. Synlett 2003, 2143. (b)
Rodrı ´guez, M. A.; Boutureira, O.; Arne ´s, X.; Matheu, M. I.; Dı ´az, Y.;
Castillo ´n, S. J. Org. Chem. 2005, 70, 10297. (c) Ko ¨ve ´r, A.; Matheu, M. I.;
Diaz, Y.; Castillo ´n, S. ArkiVoc 2007, 364.
(8) Rodrı ´guez, M. A.; Boutureira, O.; Matheu, M. I.; Dı ´az, Y.; Castillo ´n,
S. Eur. J. Org. Chem. 2007, 2470.
Sulfanyl Derivatives 1
Glycosylation Procedures from Alkenyl
J. Org. Chem. 2007, 72, 8998-9001
10.1021/jo701738m CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007
within a few minutes into a new compound, even before adding
a nucleophile. Glycal 7 was obtained in excellent yield after 1
h (Scheme 2). To avoid this elimination, lower temperatures
(-80 to -100 °C), less base (1 to 3 equiv of TTBP), and
different dehydrative promoters (BSP,9alkyl sulfides) were
tested, but all yielded the same glycal.
We recently demonstrated that glycals can be easily and
efficiently obtained by treating 2-deoxy-2-iodo-1-thioglycosides
2 under reductive-elimination conditions.10However, glycal 7
must be formed via a completely different mechanism. To
elucidate the reaction mechanism we prepared a set of 2-deoxy-
2-iodo-pyranoses with gulo-8, allo-10, 13, talo-15, 17, 22, and
manno-20 configuration by treating the corresponding phenyl
sulfanyl alkenes7b(or glycals) with NIS in wet CH3CN.
Thus, 2-iodolactols 8 and 10 were subjected to dehydrative
conditions to afford the corresponding glycals 9 and 11 (Scheme
3). In the case of ribo derivative 10, 2-iodoglycal 12 was
obtained in minor amounts (22% yield). In order to confirm
that glycal 11 was not derived from 2-iodoglycal 12, following
isolation, 12 was submitted to dehydrative elimination condi-
tions. Recovery of iodoglycal 12 indicated that it was formed
in a irreversible way.
Interestingly, isopropylidene-protected iodolactols 13 and 15
rendered exclusively the 2-iodoglycals 14 and 16 in good to
excellent yield (Scheme 4). In the case of 2-deoxy-2-iodopy-
ranose 17, minor amounts of 2-iodoglycal 18 were also obtained,
together with 1,1′-disaccharide 19. The presence of the iso-
proylidene group is crucial for obtaining 2-iodoglycals in good
yield as can be deduced by comparing the configurationally
identical compounds 10 and 13. A singlet at ∼6.8 ppm assigned
to H1 in the1H NMR spectra, and two signals at ∼148 ppm
and ∼75 ppm assigned to C1 and C2, respectively, in the13C
NMR spectra indicated the formation of the 2-iodo-substituted
Glycals and 2-iodoglycals are versatile synthetic intermedi-
ates. Insertion of substituents in C1 structures by deprotonation
(C-glycosides, quinones)11or introduction of C2 vinyl substit-
uents by Heck-type reaction12yield iso-C-glycosides. Iodine is
preferable over chlorine or bromine for these reactions.13
However, only one synthesis dealing with 2-iodoglycals has
been disclosed to date.14
Manno-20 and talo-22 derivatives were reacted under the
same conditions to give 1,1′-disaccharides 21 and 23, respec-
tively, resulting from the self-condensation of the starting
2-iodolactols (Scheme 5).
The conversion of compound I to III (Scheme 6) represents
an overall base-assisted hydroxyl elimination process15that
might be occurring through the initial 1-OH activation followed
by elimination of Ph2SO and tri-tert-butylpyrimidinium triflate
(TTBPHOTf) to render 2-iodoglycal III. Similarly, the produc-
tion of IV might be explicable in terms of nitrogen assisted
iodine elimination in II to afford the corresponding glycal16
(Scheme 6). Further credence to this hypothesis is provided by
the fact that only N-containing bases17such as TTBP, or
(9) For the use of benzensulfinylpiperidine (BSP) in glycosylation, see:
(a) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015. (b) Crich,
D.; Li, H. J. Org. Chem. 2001, 67, 4640.
(10) Boutureira, O.; Rodrı ´guez, M. A.; Matheu, M. I.; Dı ´az, Y.; Castillo ´n,
S. Org. Lett. 2006, 8, 673.
(11) Hallett, M. R.; Painter, J. E.; Quayle, P.; Ricketts, D.; Patel, P.
Tetrahedron Lett. 1998, 39, 2851.
(12) (a) Go ´mez, A. M.; Danelo ´n, G. O.; Pedregosa, A.; Valverde, S.;
Lo ´pez, J. C. Chem. Commun. 2002, 2024. (b) Go ´mez, A. M.; Pedregosa,
A.; Barrio, A.; Valverde, S.; Lo ´pez, J. C. Tetrahedron Lett. 2004, 45, 6307.
(13) (a) R. F. Heck, Acc. Chem. Res., 1979, 12, 146. (b) Turner, W. R;
Suto, M. J. Tetrahedron Lett. 1993, 34, 281.
(14) Chemier, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001, 3,
(15) For a similar outcome in exo-glycals with IDCP as a base, see:
Noort, D.; Veeneman, G. H.; Boons, G.-J. P. H.; Van der Marel, G. A.;
Mulder, G. J. van Boom, J. H. Synlett 1990, 205.
Dehydrative Elimination Reaction in
Synthesis of Glycals by Dehydrative
a2-Deoxy-2-iodopyranoses synthesized from the corresponding phenyl-
Synthesis of 2-Iodoglycals by Dehydrative
a2-Deoxy-2-iodopyranose synthesized from the corresponding phenyl-
J. Org. Chem, Vol. 72, No. 23, 2007 8999
phosphazene P4-t-Bu, that are able to stabilize [I+] species
afforded glycals, while t-BuOK failed and no reaction products
According to these results, the chairlike oxocarbenium
intermediates Ia-d and IIa-d (Scheme 7) play an important
role for the chemoselectivity of dehydrative elimination reac-
tions. Moreover, intermediates Ia,b (allo and gulo) and IIc,d
(manno and talo) that contain axial iodine are likely to be more
stable than the corresponding equatorial iodine conformers due
to stabilizing hyperconjugative interactions between σC-I and
π*C-O of the oxocarbenium.18Furthermore, during the E1
elimination reaction, the new double bond can only form when
the vacant p orbital of the carbocation and the breaking C-H
or C-I bond are aligned in parallel. Therefore, the group to be
eliminated must be in the axial position. Consistent with this
view, dehydrative elimination of the gulo-configured 2-deoxy-
2-iodopyranose 8 proceeded through the more stable conformer
Ib and elimination of the axial iodide provided glycal 9 in
excellent yield. Similarly, axial iodine elimination of allo-
configured 2-deoxy-2-iodopyranose 6 in the more stable con-
formation Ia rendered exclusively glycal 7. In this case, the
equilibrium between conformers is considerably shifted toward
Ia due to destabilizing gauche effects between the TBS19group
(OR2) and the C-6 substituent (OR1) in conformer IIa. In the
case of tri-O-benzyl-protected allo-configured 2-deoxy-2-
iodopyranose 10, the elimination mainly proceeded through the
more stable intermediate Ia to render glycal 11. However, a
minor amount of conformer IIa also reacted to give 2-iodoglycal
Dehydrative glycosylation of 2-deoxy-2-iodo-pyranoses of
manno (20) and talo (22) configurations afforded the 1,1′-
disaccharides 21 and 23, respectively, as single R-anomers. In
this case, self-condensation of the 2-deoxy-2-iodopyranoses from
the more stable conformer IIc,d is faster than elimination.
Particularly, allo- and gulo-configured glycosylating agents
afforded only glycals and 2-iodoglycals, while manno and talo
sugars yielded disaccharides. This finding can be explained by
the presence of steric interactions between the C-6 substituent
(OR1) and the incoming nucleophile in the most stable con-
former Ia,b (allo and gulo) when compared with IIc,d (manno
and talo), where such destabilizing interactions do not exist
(Scheme 7). These findings highlight the critical role the
2-deoxy-2-iodopyranose configuration exerts on this new de-
hydrative elimination process.
Finally, in order to rationalize the observed chemoselectiviy
of the 2-deoxy-2-iodopyranoses bearing a 3,4-O-isopropylidene
protecting group, we considered that the reaction might operate
by way of a constrained conformation20such as III and IV,
upon which highly favored proton elimination may occur instead
of the opposite iodine abstraction (Figure 1).21
In summary, despite the fact that dehydrative glycosylation
has proved to be an efficient and general glycosylation method,
its application to 2-deoxy-2-iodopyranoses did not always afford
the expected products. The treatment of 2-deoxy-2-iodopyra-
(16) Stabilization/elimination of [I+] by the nitrogen atom has been
reported previously: (a) Mongin, F.; Rebstock, A.-S.; Tre ´court, F.;
Que ´guiner, G.; Marsais, F. J. Org. Chem. 2004, 69, 6766. (b) Roux, M.-
C.; Paugam, R.; Rousseau, G. J. Org. Chem. 2001, 66, 4304. (c) Barluenga,
J.; Rodrı ´guez, M. A.; Campos, P. J. J. Org. Chem. 1990, 55, 3104.
(17) A similar behavior was observed with DBU; see: A Ä lvarez de
Cienfuegos, L.; Mota, A. J.; Robles, R. Org. Lett. 2005, 7, 2161.
(18) Billings, S. B.; Woerpel, K. A. J. Org. Chem. 2006, 71, 5171.
(19) (a) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997,
53, 8825. (b) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121,
3541. (c) Okada, Y.; Mukae, T.; Okajima, K.; Taira, M.; Fujita, M.; Yamada,
H. Org. Lett. 2007, 9, 1576.
(20) For a review dealing with the use of cyclic bifunctional protecting
groups, see: Litjens, R. E. J. N.; van den Bos, L. J.; Code ´e, J. D. C.;
Overkleeft, H. S.; van der Marel, G. A. Carbohydr. Res. 2007, 342, 419.
(21) A similar behavior was observed in the selenium induced cylization
of 3,4-O-isopropylidene-protected alkenyl sulfides: Boutureira, O.; Rod-
rı ´guez, M. A.; Benito, D.; Matheu, M. I.; Dı ´az, Y.; Castillo ´n S. Eur. J.
Org. Chem. 2007, 3564.
Synthesis of 1,1′-Disaccharides by Dehydrative
a2-Deoxy-2-iodopyranose synthesized from the corresponding phenyl-
during Dehydrative Elimination of 2-Deoxy-2-iodopyranoses
Plausible Mechanism for Product Distribution
Elimination of 2-Deoxy-2-iodopyranoses
Stereochemical Courses of Dehydrative
9000 J. Org. Chem., Vol. 72, No. 23, 2007
noses using dehydrative glycosylation conditions afford glycals,
2-iodoglycals, and self-condensation disaccharides depending
on the configuration of the starting 2-deoxy-2-iodopyranoses
and the protecting groups. Thus, allo- and gulo-configured
compounds afforded glycals, while manno and talo derivatives
gave glycosylated products. Moreover, 2-iodopyranose glycals
can be obtained in mostly good yield by employing 3,4-O-
isopropylidene protecting groups. A detailed analysis of the fate
of 2-deoxy-2-iodopyranoses during dehydrative glycosylations
provided insight into the mechanism of this process.
General Procedure for Dehydrative Elimination from 2-
Iodopyranoses. A mixture of the 2-iodolactol product (1.0 mmol),
prepared by treating sulfanyl alkenes or glycals with NIS-water
in acetonitrile, Ph2SO (2.0 mmol), and TTBP (3.0 mmol) in CH2-
Cl2(0.04 M to iodolactol) were stirred over flame-dried molecular
sieves for 30 min, after which the reaction mixture was cooled to
-60 °C. Tf2O (1.0 mmol) was added, and the mixture was first
brought to -40 °C and then slowly warmed to the completion of
the reaction (TLC). The reaction was quenched by the addition of
Et3N (10 mmol) and concentrated in vacuo. The crude product was
purified by chromatographic techniques.
Acknowledgment. We acknowledge the financial support
of DGESIC, CTQ2005-03124 (Ministerio de Educacio ´n, Spain)
and the ETH Zurich. We thank I. Cobo for preliminary studies
and Servei de Recursos Cientı ´fics (URV) for technical as-
sistance. Fellowships from DURSI (Generalitat de Catalunya)
and Fons Social Europeu to O.B. and M.A.R are also acknowl-
Supporting Information Available: General experimental
methods, experimental procedures, compound characterization data,
and NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
FIGURE 1. Stereochemical features in dehydrative eliminations of
J. Org. Chem, Vol. 72, No. 23, 2007 9001