Subtle stereochemical and electronic effects in iridium-catalyzed isomerization of C-allyl glycosides

Article abstract of DOI:10.1021/ol060671n

Stereoselective isomerization of C-allyl glycosides into (E)-C-vinyl glycosides or (2)-exo-glycals was carried out in the presence of the cationic iridium(I) catalyst [(Ph₂MeP)₂Ir(cod)PF₆]. The products of the isomerization were affected by the relative 1,2-stereochemical relationships and by the nature of the protecting groups. These effects are discussed along with a plausible reaction mechanism.

Full text of DOI:10.1021/ol060671n

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2691-2694
Subtle Stereochemical and Electronic
Effects in Iridium-Catalyzed
Isomerization of C-Allyl Glycosides
Ramesh Patnam, Juan M. Jua´rez-Ruiz, and Rene´ Roy*
Department of Chemistry, UniVersite´ du Que´bec a` Montre´al,
P.O. Box 8888, Succ. Centre-Ville, Montreal, (QC) H3C 3P8, Canada
roy.rene@uqam.ca
Received March 17, 2006
ABSTRACT
Stereoselective isomerization of C-allyl glycosides into (E)-C-vinyl glycosides or (Z)-exo-glycals was carried out in the presence of the cationic
iridium(I) catalyst [(Ph2MeP)2Ir(cod)PF6]. The products of the isomerization were affected by the relative 1,2-stereochemical relationships and
by the nature of the protecting groups. These effects are discussed along with a plausible reaction mechanism.
Diverse processes for olefin isomerization continue to be
topics of widespread interest.1 Regio- and stereoselective
double-bond migration in 1,3-dioxepines provides useful
building blocks for polyether synthesis,2 and isomerization
of allyl to enol ethers have been used to remove allyl
protecting groups3 as well as to provide convenient routes
to the enol ether components for Claisen rearrangements.4
Olefin isomerizations to more stable alkenes were reported
with many metal catalysts such as nickel,5 rhodium,6
ruthenium,7 palladium,8 and iridium.9 Iridium(I)-based re-
agents are useful catalysts in chemo- and stereoselective
isomerization of alkenes, particularly in allyl and allyl silyl
ethers.10 Owing to its unique catalytic properties, iridium
[(Ph2MeP)2Ir(cod)PF6]11 catalyzed isomerization reactions
have also been successfully applied in the total synthesis of
natural products12 and in carbohydrate chemistry, to make
R- and â-C-glycosides of N-acetylglucosamine and C-neogly-
copeptides13 and for the deprotection of allyl protecting group.14
In all the above cases, the isomerizations were limited to
affording C-vinyl glycosides only. Consequently, there are still
needs to further develop simple, convenient, and practical
methods to completely isomerize C-allyl glycosides to
(1) (a) Davies, N. R. ReV. Pure Appl. Chem. 1967, 17, 83-93. (b) Hubert,
A. J.; Reimlinger, H. Synthesis 1970, 2, 405-430. (c) Grubbs, R. H. NATO
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10.1021/ol060671n CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/06/2006

prepare the important family of exo-glycals. However, there
is no report of such isomerization processes using iridium
catalysts.
In continuation of our interests in the applications of
organometallic catalysts in carbohydrate chemistry,15 we
report herein a mild and convenient method for the isomer-
ization of C-allyl mannosides and rhamnosides to the
corresponding exo-glycals using iridium catalyst [(Ph2-
MeP)2Ir(cod)PF6] (Scheme 1).
peracetylated ribose21 and the riboside 1920b from 22 by
deacetylation followed by benzylation.
R-Mannoside 1 was initially isomerized using 10% Ir(I)
catalyst pretreated with hydrogen to afford the expected C-
vinyl mannoside 238a in 84% yield after 24 h at room
temperature.
However, when the reaction time was prolonged to 48 h,
an unprecedented, more thermodynamically stable exo-glycal
8 was obtained with exclusive Z-configuration in 80% yield
(Table 1). The protecting group of 1 was then systematically
Scheme 1. Isomerization of C-Allyl Mannosides 1-5
Table 1. Isomerization of C-Allyl Glycosides 1-7 into
(Z)-exo-Glycals
Starting C-allyl glycosides16-22 1-7,17a, 15,17a 16,21a and
1721 were prepared from methyl R-D-glycosides by benzy-
lation16 followed by Sakurai’s C-allylation.17 C-Allyl R-man-
nosides, modified at O-6 (2, 3, 4,18 518c), were prepared by
deacetylation followed by protection using the appropriate
protecting groups. C-Allyl â-mannoside 15 was synthesized
from tetrabenzyl mannopyranose,18 and C-allyl R/â-manno-
side 2018a was prepared using a published procedure.19 The
inseparable anomeric mixture of C-allyl R/â-mannoside 618b
was obtained by deacetylation of 20 followed by acetalation.
Peracetylated â-galactoside 21 was synthesized according
to Taketo et al.,20 and the perbenzylated derivative 1821 was
obtained by deacetylation of 21 followed by benzylation
(NaH, BnBr, DMF). The riboside 2220a was prepared from
(15) (a) Dominique, R.; Roy, R. Tetrahedron Lett. 2002, 43, 39-398.
(b) Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723-2726. (c) Roy,
R.; Das, S. K. Chem. Commun. 2000, 519-529.
a Compound 4 provided 38% of the (Z)-exo-glycal 11 and 53% of the
corresponding vinyl mannoside 11a (see text).
(16) Koto, S.; Morishima, N.; Miyata, Y.; Zen, S. Bull. Chem. Soc. Jpn.
1976, 49, 2639-2640.
(17) (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984,
25, 2383-2386. (b) Bertozzi, C.; Bednarski, M. Carbohydr. Res. 1992,
223, 243-253.
(18) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 4976-4978. (b) Fletcher, S.; Jorgensen, M. R.; Miller, A. D. Org.
Lett. 2004, 6, 4245-4248.
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Van den Elst, H.; Roelen, H. C. P. F.; Van der Marel, G. A.; Van Boom,
J. H. Recl. TraV. Chim. Pays Bas 1990, 109, 583-590. (c) Francisco, C.
G.; Herrera, A. J.; Suarez, E. J. Org. Chem. 2002, 67, 7439-7445. (c)
Hung, S.-C.; Lin, C.-C.; Wong, C.-H. Tetrahedron Lett. 1997, 38, 5419-5422.
(20) Taketo, U.; Thomas, J. W.; Weichyun, W.; Lin, C. C.; Tetsuya, K.;
Maki, T.; Gabriel, W. S.; Tetsuo, A.; Masatoshi, N.; Wong, C. H. Bioorg.
Med. Chem. 1996, 7, 1149-1165.
(21) (a) McDevitt, J. P.; Lansbury, P. T., Jr. J. Am. Chem. Soc. 1996,
118, 3818-3828. (b) Deslongchamps, P.; Dory, Y.; Peterson, M.; Benakli,
K.; Marsault, E.; Ouellet, L.; Ramaseshan, M.; Vezina, M.; Fortin, D.; Lan,
R.; Li, S.; Villeneuve, G.; Hoveyda, H.; Beaubien, S. PTC Int. Appl.
2005012331, 2005; Chem. Abstr. 2005, 142, 219559.
varied at O-6 to investigate its potential role in the outcome
of the reaction. Hence, the corresponding PMB (2), methyl
(3), TBDMS (4), and acetyl (5)-protected analogues, together
with the bis-acetonide 6 and C-allyl R-rhamnoside 7, possess-
ing the same 1,2-trans geometry were similarly treated with
the same general overall outcome (Table 1). Interestingly,
compound 4 provided only 38% of the exo-glycal, accom-
panied by 53% of the partially migrated C-vinyl intermediate
(11a, not shown). Moreover, O-6 acetate-protected manno-
side 5 failed to afford the glycal and gave only the vinyl
analogue 12 in 81% yield (entry 5). These findings suggest
that a bulky TBDMS or carbonyl-protecting groups (acetyl)
have detrimental effects in the anomeric proton abstraction
by the catalyst.
(22) Chen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett. 2004, 6,
4077-4080.
2692
Org. Lett., Vol. 8, No. 13, 2006

To exploit this observation as a general methodology, the
fully benzylated C-allyl mannoside 15 (â-anomer), R-glu-
coside 16, R- and â-galactosides (17, 18), and riboside 19
were subjected to the same isomerization conditions. Surpris-
ingly, none of these C-allyl glycosides were fully isomerized
to give the exo-glycals. Rather, all reactions provided good
yields of the C-vinyl derivatives 24, 25, 26,22 and 27-31
(Table 2). The above observations hold even after exposure
with the formation of exo-glycals resulting from further
isomerization of initially obtained C-vinyl analogues.
After the isomerization of the mannoside derivatives with
the iridium catalyst was done, the same reaction conditions
were attempted with two different palladium catalysts known
to provide analogous isomerization. Both catalysts failed to
fully isomerize mannoside 1 into the corresponding exo-
glycal 8 but succeeded in isomerizing it to the intermediate
C-vinyl mannoside 23, albeit with poorer stereoselectivity.
The results of the isomerization of mannoside 1 with iridium
and palladium catalysts are summarized in Table 3.
Table 2. Isomerization of C-Allyl Glycosides 1 and 8-15 into
(E)-Vinyl Glycosides
Table 3. Isomerization of Mannoside 1 to 23 with Different
Catalysts
time
entry
catalyst
(h)
solvent temp yield (E:Z)
THF rt 80 (>95:0)
benzene8a reflux 84 (2.8:1)
120 toluene8b reflux 75 (4.3:1)
1
2
3
(Ph2MeP)2Ir(cod)PF6 24
PdCl2
18
(PhCN)2PdCl2
The configuration of the double bond in the exo-glycosides
was determined by NOE experiments. For instance, irradia-
tion of the H-2 proton in glycoside 8 at δ 4.01 ppm (d, J ) 3.3
Hz) caused an enhancement (12.4%) of the signal at δ 4.82
ppm (t, J ) 7.2 Hz, H-1′), which indicated that the double
bond in mannoside 8 had the (Z)-configuration (Scheme 1).
The isomerization mechanism of alkenes by iridium
catalysts10a usually involves the oxidative addition of an
allylic C-H bond to the Ir(I) complex to give π-allyliridium
species, followed by reductive elimination to afford the more
stable doubly substituted alkene.
In the case of glycosides 5 and 15-22, abstraction of the
proton at C-1 does not happen because of steric hindrance
or electronic factors, so only the C-vinylic glycosides were
obtained. In the case of C-allyl mannosides 1-4 and 6 and
rhamnoside 7, the observed isomerization into exo-glycals
may be due to chelation between O-2 and the iridium, thus
dominating the steric/electronic factors (Scheme 2);23 hence
the fully isomerized exo-glycals were obtained. In the case
Scheme 2. Proposed Mechanism of Isomerization
to longer reaction time or higher temperature or in the
presence of varied amount of catalyst. Furthermore, to
evaluate the role of the general protecting groups in this
process, the C-allyl tetra-O-acetylated R/â-D-mannoside 20,
tetra-O-acetylated galactoside 21, and tri-O-acetylated ribo-
side 22 were subjected to the isomerization process under
similar reaction conditions, and the results are summarized
in Table 2. Thus, ester protecting groups were not compatible
Org. Lett., Vol. 8, No. 13, 2006
2693

of C-allyl â-D-mannoside 15, similar results were not
observed, presumably because the catalyst could not reach
the axial H-1.In the cases of acetylated mannosides 5 and
20, galactoside 21, and riboside 22, the hypothesized
chelation between the ester carbonyl oxygen and the iridium
may dominate, thus pulling the iridium catalyst away from
the H-1 protons. Consequently, only C-vinylic glycosides
were obtained. In the case of mannoside 4, the exo-
mannoside 11 and C-vinyl mannoside 11a were obtained in
38% and 53% yields, respectively. Here, the bulky substituent
TBDMS lowered the yield of the corresponding exo-
mannoside 11 (Table 1, entry 4). It is postulated herein that
the O-2 configuration as well as the nature of the protecting
groups at O-6 were involved in the complete isomerization
process.
â-D-mannoside 32 (Scheme 3). Hydroboration29 of 8 with
BH3‚THF followed by oxidative workup with NaOH/H2O2
afforded â-mannoside 33 (43%). Hydroboration of 8 with
9-BBN followed by oxidative workup with NaOH/H2O2
afforded â-D-mannoside 33 in only 31% yield. The absolute
stereochemistry of the hydroxyl group on C-2′ in â-D-
mannoside 33 was determined by Mosher’s method,30 which
was consistent with the previously reported hydroboration
reaction.30 Unfortunately, the ruthenium-catalyzed cross
metathesis reactions of exo-mannoside 8 were not successful.
Scheme 3. exo-Glycals as Versatile Intermediates for the
Synthesis of Various Functionalized â-Glycosides
exo-Glycals are valuable synthetic intermediates in natural
product synthesis. However, their syntheses are cumber-
some.24 1-exo-Methylene sugars are accessible by a few
procedures.25,26 Substituted exo-glycals may also be obtained
by Wittig olefination,26 Ramberg-Backlund rearrangement,27
and [2,3]-Wittig sigmatropic rearrangements.28 However, all
of these methods require multiple steps and in some cases
harsh reaction conditions. Additionally, all of the starting
glycosides had the same benzyl protecting groups, which
make further modification of the sugar moieties of exo-
glycals more problematic.
In conclusion, isomerization of C-allyl glycosides mediated
by iridium(I) catalyst has been shown to occur in good yields
and with excellent Z-selectivity, depending on the nature of
the sugars and the protecting groups.
Here we have reported a novel approach to prepare exo-
glycals with different protecting groups under mild condi-
tions. To use the exo-mannosides as chiral intermediates, we
reduced mannoside 8 with Pd/C, which afforded the C-propyl
Acknowledgment. We acknowledge financial support
from Natural Sciences and Engineering Research Council
of Canada (NSERC). We are also thankful to Dr. Mohamed
Touaibia for his assistance in the preparation of the manu-
script.
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Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 8-14 and 24-33.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060671N
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