Intermolecular Pauson-Khand reactions on a galactose scaffold

Article abstract of DOI:10.1016/j.tetlet.2008.02.114

An intermolecular Pauson-Khand reaction involving a carbohydrate scaffold having a pendant alkyne provides galactose derivatives with a cyclopentenone moiety in the C3-position in up to 85% yield.

Full text of DOI:10.1016/j.tetlet.2008.02.114

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2820–2823
Intermolecular Pauson–Khand reactions on a galactose scaffold
Nu´ria Parera Pera a, Ulf J. Nilsson b,*, Nina Kann a,*
a Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-41296 Go¨teborg, Sweden
b Organic Chemistry, Lund University, PO Box 124, SE-22100 Lund, Sweden
Received 19 January 2008; revised 4 February 2008; accepted 21 February 2008
Available online 4 March 2008
Abstract
An intermolecular Pauson–Khand reaction involving a carbohydrate scaffold having a pendant alkyne provides galactose derivatives
with a cyclopentenone moiety in the C3-position in up to 85% yield.
Ó 2008 Elsevier Ltd. All rights reserved.
The Pauson–Khand reaction is a versatile transforma-
tion, involving the reaction of an alkyne, an alkene and
carbon monoxide to furnish a cyclopentenone in one step
while creating three new carbon–carbon bonds.1 Classical
conditions for the reaction involve the use of stoichiometric
amounts of Co2(CO)8 and heating,2 while the use of addi-
tives such as N-oxides,3 amines4 and sulfides5 can facilitate
ligand exchange and promote the reaction. Recent efforts
have been devoted to the development of catalytic versions
of the reaction involving cobalt or other metals such as
titanium, ruthenium, rhodium, iridium or bimetallic spe-
cies.6 However, the catalytic version is as yet mainly limited
to the intramolecular reaction, although development in
this area is likely to continue.
Despite numerous examples of the Pauson–Khand reac-
tion in the total synthesis of natural products and biologi-
cally active molecules,7 there are few examples of its
application to carbohydrate substrates. Lindsell was the
first to prepare a cobalt carbonyl complexed enyne based
on a hex-2-enopyranoside scaffold, but the attempted Pau-
son–Khand reaction did not afford the desired cyclopente-
none product.8 Marco-Contelles9 as well as Voelter10
subsequently reported the successful cyclization of enyne
pyranosides to form bisannulated products under mild
conditions. Borodkin performed Pauson–Khand reactions
on exo-methylene carbohydrate enynes,11 while Isobe and
Takai have described several examples of Pauson–Khand
cyclizations involving tetrahydropyranose substrates.12
Later reports by van Boom13 and Hotha14 focus on the
construction of spiroannulated carbohydrate derivatives,
while Schreiber applied the Pauson–Khand reaction in con-
junction with a Ferrier coupling in diversity orientated syn-
thesis based on a glycal template.15 Following an initial
study on the intramolecular cyclization of sugar azaenynes
prepared from D-glucal and D-galactal,16 Areces performed
the corresponding intermolecular reactions with norborn-
ene and norbornadiene.17 However, to our knowledge,
the publication by Areces is the only report of inter mole-
cular Pauson–Khand reactions involving a sugar deriva-
tive. As part of a study concerning the preparation of
galectin inhibitors, we wanted to see if the Pauson–Khand
reaction could be used to provide galactose scaffolds18
directly derivatized with a cyclopentenone in the 3-position
(Fig. 1). All the galectins have an extended binding site in
close proximity to the galactose 3-position, and attaching
*
Corresponding authors. Tel.: +46 31 7723070; fax: +46 31 7723657
(N.K.); tel.: +46 46 222 8212; fax: +46 46 2228209 (U.J.N.).
E-mail addresses: ulf.nilsson@organic.lu.se (U. J. Nilsson), kann@
chalmers.se (N. Kann).
Fig. 1. Target molecules for the Pauson–Khand reactions.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.114

N. P. Pera et al. / Tetrahedron Letters 49 (2008) 2820–2823
2821
structural elements at C3 of the galactose had proven ear-
lier to be a viable strategy towards galectin-3 inhibitors.19
Different cyclopentenone structures can be accessed by
varying the alkene employed in the reaction, providing
compounds for studying interactions with the galectin
extended binding site near the galactose 3-position. The
cyclopentenone moiety can also be thought of as a scaffold
in itself, suitable for further derivatization by utilizing the
different functionalities contained in the molecule. In this
first preliminary study, a protected galectin functionalized
with an alkyne in the 3-position was investigated in the
Pauson–Khand reaction with a variety of different alkynes.
Methyl 3-O-propargyl-b-D-galactopyranoside (1) was pre-
pared via the activation of methyl b-D-galactopyranoside
with di-n-butyltin oxide, followed by a reaction with prop-
argyl bromide. Compound 1 was subsequently converted
to the benzyl- or acetyl-protected structures 2 and 3
(Scheme 1). Alkynes 1, 2 and 3 were treated with Co2(CO)8
to form cobalt complexes 4, 5 and 6 (Scheme 2). Different
reaction conditions were then investigated for the Pauson–
Khand reaction using norbornadiene as the alkene (Table
1). As mentioned earlier, amine N-oxides are frequently
used as promotors of the Pauson–Khand reaction, and in
the initial reactions the cobalt complex was dissolved in
dichloromethane at ambient temperature, followed by the
addition of norbornadiene and the portionwise addition
of trimethylamine N-oxide (TMANO) or, in one case, N-
methylmorpholine N-oxide (NMO). Reaction of unpro-
tected complex 4 with norbornadiene gave a complex mix-
ture of compounds (entries 1 and 2), and this substrate was
thus abandoned in favour of the protected derivatives.
Reaction of the benzyl-protected complex 5 afforded the
desired product 8 in 27% isolated yield, using toluene as
the solvent (entry 3).
Using the acetyl-protected substrate 6 gave cyclopente-
none 9 in 54% yield after 8 h. A longer reaction time was
found to be detrimental to the reaction. It may be that
excess N-oxide as well as the amine formed in the reaction
gives rise to undesired side products when left for longer
periods of time. For comparison, the reaction was also car-
ried out under thermal conditions without any added pro-
motor. Reflux in toluene afforded 9 in up to 85% yield if the
Scheme 1. Preparation of protected galactoside structures used as precursors in the Pauson–Khand reaction.
Scheme 2. Cobalt complexation followed by Pauson–Khand reactions with norbornadiene.
Table 1
Reaction conditions tested for the Pauson–Khand reactions
Entry
R
Conditions
Temp. (°C)
Time (h)
Product
Yield (%)
a
1
2
3
4
5
6
7
a
H
H
TMANO, CH2Cl2
NMO, CH2Cl2
TMANO, toluene
TMANO, CH2Cl2
TMANO, CH2Cl2
Toluene
rt
rt
rt
rt
rt
110
110
1
3
8
8
17
5
7
7
8
9
9
9
9
—
a
—
Bn
Ac
Ac
Ac
Ac
27
54
25
67
85
Toluene
18
Complex mixture formed.

2822
N. P. Pera et al. / Tetrahedron Letters 49 (2008) 2820–2823
reaction was left for 8–10 h or overnight (entry 7), while a
shorter reaction time gave a slightly lower yield (entry 6).
The appended carbohydrate moiety could, in theory, func-
tion as a chiral auxiliary in these reactions. However, the
presence of two diastereomers in a 1:1 ratio could be seen
by 13C NMR analysis, indicating that no asymmetric
induction occurred.
The observations that the benzyl-protected galactose
substrate was problematic in terms of preparing precursor
2, in the conversion to the cobalt complex 5 and in the
ensuing Pauson–Khand reaction, prompted us to focus
on the acetyl-protected substrate 6 instead, and further
studies of 5 were not pursued.
A set of diverse alkenes with and without heteroatoms
were selected for the thermal Pauson–Khand reaction with
6 (Table 2, Fig. 2). Reaction with norbornene gave similar
results to the reaction with norbornadiene, with a yield of
79% obtained for this reaction (entry 2). Acyclic alkenes
such as allyl benzene, used in entry 3, are generally less effi-
cient in the Pauson–Khand reaction,21 and this was indeed
found to be the case. Product 11 was formed in 30% yield
with the 5-substituted cyclopentenone as the major prod-
uct, as had been observed earlier in Pauson–Khand reac-
tions involving this alkene.21 Cyclopentene performed
well, affording 12 in 68% yield. Electron-deficient alkenes
are generally not good substrates for the Pauson–Khand
reaction, and maleimide-derivatives have been little studied
in this context. Attempted Pauson–Khand reaction of
maleimide showed traces of the desired product according
to MS analysis, but NMR spectra were not in accordance
with the expected product and we thus conclude that the
product was not formed to any great extent in this case.
Indene had been applied earlier in a Pauson–Khand reac-
tion,22 and in our case afforded the corresponding alkene
in high yield (entry 6). 2,3-Dihydrofuran, however, did
not afford the desired product under the thermal reaction
conditions. Degradation of the cobalt complex in this case
seems to be faster than the Pauson–Khand reaction, and a
substantial amount of uncomplexed 3 was recovered after
the reaction. This could be due to the lability of the alkene
towards polymerization under the reaction conditions, lim-
iting the amount of 2,3-dihydrofuran accessible for reac-
tion with the cobalt complex.23 Kerr et al. have reported
alternative reaction conditions for the Pauson–Khand
reaction of 2,3-dihydrofuran with cobalt carbonyl–alkyne
complexes, employing N-oxides in combination with soni-
cation.24 These modified conditions afforded the desired
product 15, albeit in a rather modest 14% yield. 2,5-Dime-
thoxy-2,5-dihydrofuran is a masked dialdehyde and would
provide useful functionalities for further derivatization of
Table 2
Pauson–Khand reactions of 6 with various alkenes20
Entry
1a
Alkene
Time (h)
18
Product
Yield (%)
85
9
2
3
4
10
8
10
11
12
79
30
68
8
5
18
13
n.r.
6
7
10
14
15
74
1.5
14b
8
10
16
55
a
Same as entry 7 in Table 1.
Reaction conditions: TMANOꢀ2H2O, toluene/methanol, sonication,
b
rt.24
Fig. 2. Products from the Pauson–Khand reactions (see Table 2).

N. P. Pera et al. / Tetrahedron Letters 49 (2008) 2820–2823
2823
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the product. Reaction with this alkene proceeded well, pro-
viding 16 in a relatively good yield of 55%, as a mixture of
cis- and trans-isomers.
In summary, we have reported the first examples of
intermolecular Pauson–Khand reactions involving an
alkyne moiety appended to a carbohydrate moiety in its
cyclized form. Cyclic alkenes gave the best results, afford-
ing the desired products in moderate to good yields, while
allyl benzene as well as the sensitive 2,3-dihydrofuran gave
less than satisfactory results. The products formed consti-
tute useful scaffolds for further derivatization and investi-
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Acknowledgements
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We thank the Swedish Foundation for Strategic
Research (SSF) and Chalmers University of Technology
for financial support.
Supplementary data
16. Areces, P.; Carrasco, E.; Plumet, J. Arkivoc 2005, ix, 165–174.
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
02.114.
19. (a) Salameh, B. A.; Sundin, A.; Leffler, H.; Nilsson, U. J. Bioorg.
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20. Typical reaction procedure for the thermal Pauson–Khand reaction
(Table 2, entry 1): Complex 6 (100 mg, 0.152 mmol) and norborna-
diene (80 ll, 0.758 mmol) were dissolved in toluene in a sealable
reaction tube under an argon atmosphere. The tube was sealed with a
cap and heated to 110 °C. After 18 h, the solvent was evaporated and
the crude residue purified by flash chromatography, eluting with
toluene/ethyl acetate 2:1, affording 69 mg of 9 as a brown oil (85%
yield). All the compounds were characterized by NMR, IR and
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21
½aꢂD +15.3 (c 0.014, CH2Cl2); HRMS (ES+) m/z calcd for
C
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