Synthesis of 2-iodoglycals, glycals, and 1,1′-disaccharides from 2-deoxy-2-iodopyranoses under dehydrative glycosylation conditions

Article abstract of DOI:10.1021/jo701738m

(Chemical Equation Presented) 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 revea

Full text of DOI:10.1021/jo701738m

SCHEME 1. Glycosylation Procedures from Alkenyl
Sulfanyl Derivatives 1
Synthesis of 2-Iodoglycals, Glycals, and
1,1′-Disaccharides from 2-Deoxy-2-iodopyranoses
under Dehydrative Glycosylation Conditions
Miguel Angel Rodr´ıguez,† Omar Boutureira,†
M. Isabel Matheu,† Yolanda D´ıaz,*,† Sergio Castillo´n,*,† and
Peter H. Seeberger‡
Departament de Qu´ımica Anal´ıtica i Qu´ımica Orga`nica,
UniVersitat RoVira i Virgili, C/ Marcel·l´ı 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
sergio.castillon@urV.cat; yolanda.diaz@urV.cat
ReceiVed August 7, 2007
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).7 The 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.8 This procedure avoids the formation of the 2-iodo-
lactols.
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.3 Initially, 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 CH2Cl2 at
-60 °C. Surprisingly, the product was partially transformed
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.1 This methodology includes itera-
tive,2 orthogonal,3 1,2-cis,4 and catalytic activated5 glycosyla-
(2) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem., Int. Ed. 2001,
40, 414.
(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,
3251.
(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.; D´ıaz, Y.; Castillo´n, S. Synlett 2003, 2143. (b)
Rodr´ıguez, M. A.; Boutureira, O.; Arne´s, X.; Matheu, M. I.; D´ıaz, 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) Rodr´ıguez, M. A.; Boutureira, O.; Matheu, M. I.; D´ıaz, Y.; Castillo´n,
S. Eur. J. Org. Chem. 2007, 2470.
† 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.
10.1021/jo701738m CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007
8998
J. Org. Chem. 2007, 72, 8998-9001

SCHEME 2. Dehydrative Elimination Reaction in
2,6-Dideoxy-2-iodopyranoses
SCHEME 4. Synthesis of 2-Iodoglycals by Dehydrative
Eliminationa
SCHEME 3. Synthesis of Glycals by Dehydrative
Eliminationa
a 2-Deoxy-2-iodopyranoses synthesized from the corresponding phenyl-
sulfanyl alkenes.
a 2-Deoxy-2-iodopyranose synthesized from the corresponding phenyl-
sulfanyl alkenes.
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,9 alkyl sulfides) were
tested, but all yielded the same glycal.
and ∼75 ppm assigned to C1 and C2, respectively, in the 13C
NMR spectra indicated the formation of the 2-iodo-substituted
double bond.
Glycals and 2-iodoglycals are versatile synthetic intermedi-
ates. Insertion of substituents in C1 structures by deprotonation
(C-glycosides, quinones)11 or introduction of C2 vinyl substit-
uents by Heck-type reaction12 yield 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 process15 that
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 bases17 such as TTBP, or
We recently demonstrated that glycals can be easily and
efficiently obtained by treating 2-deoxy-2-iodo-1-thioglycosides
2 under reductive-elimination conditions.10 However, 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
(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.
1
to H1 in the H NMR spectra, and two signals at ∼148 ppm
(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.; Rodr´ıguez, M. A.; Matheu, M. I.; D´ıaz, Y.; Castillo´n,
S. Org. Lett. 2006, 8, 673.
(14) Chemier, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001, 3,
2949.
(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.
J. Org. Chem, Vol. 72, No. 23, 2007 8999

SCHEME 5. Synthesis of 1,1′-Disaccharides by Dehydrative
SCHEME 7. Stereochemical Courses of Dehydrative
Elimination of 2-Deoxy-2-iodopyranoses
Eliminationa
a 2-Deoxy-2-iodopyranose synthesized from the corresponding phenyl-
sulfanyl alkenes.
SCHEME 6. Plausible Mechanism for Product Distribution
during Dehydrative Elimination of 2-Deoxy-2-iodopyranoses
(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
12.
phosphazene P4-t-Bu, that are able to stabilize [I+] species
afforded glycals, while t-BuOK failed and no reaction products
were detected.
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.
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.18 Furthermore, 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 TBS19 group
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 conformation20 such 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.; Rodr´ıguez, M. A.; Campos, P. J. J. Org. Chem. 1990, 55, 3104.
(17) A similar behavior was observed with DBU; see: AÄ 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-
r´ıguez, M. A.; Benito, D.; Matheu, M. I.; D´ıaz, Y.; Castillo´n S. Eur. J.
Org. Chem. 2007, 3564.
9000 J. Org. Chem., Vol. 72, No. 23, 2007

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.
FIGURE 1. Stereochemical features in dehydrative eliminations of
activated 2-iodolactols.
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.
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 Cient´ıfics (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-
edged.
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.
Experimental Section
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
JO701738M
J. Org. Chem, Vol. 72, No. 23, 2007 9001