Transformation of D-(-)-ribose into a natural product-like scaffold via a Lewis acid catalyzed intramolecular hetero-diels-alder reaction

Article abstract of DOI:10.1080/15257770701490704

Starting from D-(-)-ribose, a tricyclic natural product-like scaffold suitable for combinatorial derivatization was synthesized via an intramolecular hetero-Diels-Alder reaction. Lithium perchlorate was found to enhance the reaction rate and, at the same time, had a pronounced influence on the chemoselectivity of the reaction. The stereochemical course of the reaction, however, was not influenced by the Lewis acid. Copyright Taylor & Francis Group, LLC.

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Transformation of D-(-)-Ribose into a
Natural Product-Like Scaffold via a Lewis
Acid Catalyzed Intramolecular Hetero-
Diels-Alder Reaction
Roland Messer a , Cyril A. Fuhrer a & Robert Häner a
a Department of Chemistry and Biochemistry , University of Bern ,
Bern, Switzerland
Published online: 10 Dec 2007.
To cite this article: Roland Messer , Cyril A. Fuhrer & Robert Häner (2007) Transformation of
D-(-)-Ribose into a Natural Product-Like Scaffold via a Lewis Acid Catalyzed Intramolecular
Hetero-Diels-Alder Reaction, Nucleosides, Nucleotides and Nucleic Acids, 26:6-7, 701-704, DOI:
10.1080/15257770701490704
To link to this article: http://dx.doi.org/10.1080/15257770701490704
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Nucleosides, Nucleotides, and Nucleic Acids, 26:701–704, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701490704
TRANSFORMATION OF D-(-)-RIBOSE INTO A NATURAL
PRODUCT-LIKE SCAFFOLD VIA A LEWIS ACID CATALYZED
INTRAMOLECULAR HETERO-DIELS-ALDER REACTION
Roland Messer, Cyril A. Fuhrer, and Robert Ha¨ner
Department of Chemistry
2
and Biochemistry, University of Bern, Bern, Switzerland
Starting from D-(-)-ribose, a tricyclic natural product-like scaffold suitable for combinatorial
2
derivatization was synthesized via an intramolecular hetero-Diels-Alder reaction. Lithium perchlo-
rate was found to enhance the reaction rate and, at the same time, had a pronounced influence
on the chemoselectivity of the reaction. The stereochemical course of the reaction, however, was not
influenced by the Lewis acid.
Keywords Lewis acid; Hetero-Diels-Alder reaction; bi- and tricyclic structures
INTRODUCTION
The hetero-Diels-Alder reaction has been proven extremely successful
in the construction of heterocyclic six-membered rings.[1] In previous work
aiming at the construction of natural product like scaffolds, we made use
of intramolecular hetero-Diels-Alder reactions to synthesize bi- and tricyclic
structures.[2] Thus, compound 1 is tranformed by cyclization at 100◦C in
toluene within 24 hours into compound 2 in 45% yield (Scheme 1). The
moderate yield is the consequence of an elimination reaction leading to
product 3. The formation of this undesired product proceeds most likely via
a thermal syn elimination pathway,[3] rendering up to 40% of the side ma-
terial. Exploratory experiments showed that at lower reaction temperatures
the elimination process is overproportionally reduced compared to the de-
sired cyclization reaction. The rate and selectivity of Diels-Alder reactions
can be increased drastically by the use of Lewis acids.[4] Lithium perchlorate
in diethylether (LPDE) has gained particular interest as a powerful medium
for Diels-Alder reactions.[5,6] On the other hand, reports describing simi-
lar effects by Lewis acids in hetero-Diels-Alder reactions are sparse. To our
Address correspondence to Robert Ha¨ner, Department of Chemistry and Biochemistry, University
of Bern, Freiestrasse 3, CH 3012 Bern, Switzerland. E-mail robert.haener@ioc.unibe.ch
701

702
R. Messer et al.
O
R''
O
HN
O2N
O
HN
O
O
OMe
O
R'
O
O
O
OMe
H
H
H
O
O
O
O
O
OMe
N
O
hetero-Diels-Alder reaction
2
H
O
O
O
O
D-(-)-ribose
O
OMe
O
O
O
R "
H
O
O
N
OMe
O2N
H
N
O
H
R
O
1
syn-β-elimination reaction
3
SCHEME 1 Intramolecular cyclization of compound 1 via hetero-Diels-Alder reaction leading to prod-
uct 2 and formation of the furan 3 via elimination reaction.
knowledge, only three reports exist in which Lewis acid catalysis of hetero-
Diels-Alder reactions has been investigated—two involving an oxadiene[6,7a]
and one describing the reaction of a nitroso dienophile.[7b] For all reactions,
including one example of an intramolecular hetero Diels Alder reaction,[7a]
a significant acceleration by LPDE was observed. Since the examples with
the oxadiene system[6,7a] are related to the hetero-Diels-Alder of the present
work, we explored the influence of lithium perchlorate on the rate as well
as the selectivity of the reaction shown in Scheme 1.
In preliminary experiments we tested the influence of different Lewis
acids (LiClO4, Mg(ClO4)2, Ti(O-iso-Pr)4, TiCl4) in different solvents on the
course of the cyclisation of 1. The use of lithium perchlorate in acetonitrile
showed the best results. This Lewis acid was, therefore, further investigated
TABLE 1 Influence of lithium perchlorate on the course and reaction rates of the intramolecular
hetero-Diels-Alder reaction of 1
Isolated yield
Entry
Conditions
[LiClO4], M
Ratio 1/2/3
k1 × 106, s−1
of 2 (%)a
1
2
3
4
5
6
toluene/100◦C/24 h
0
0
0.01
0.1
0.5
1.5
0/53/47
100
8.0
7.9
8.4
15.6
34.9
45
b,c
CH3CN/50◦C/72 h
10/55/33
—
—
—
—
b,c
b,c
“
“
“
“
—
c
12/74/9
2/91/7
0/95/5
c
55
aAfter 72 hours.
b Several major byproducts were formed under these conditions.
c Not determined.

Transformation of D-(-)-Ribose
703
FIGURE 1 Reaction rates of the intramolecular hetero-Diels-Alder reaction shown in Scheme 1 against
the lithium perchlorate concentration. (For conditions see Table 1.)
at a reaction temperature of 50◦C. The effect of different concentrations of
lithium perchlorate in acetonitrile was monitored by NMR analysis at differ-
ent times (5, 12, 24, 48, and 72 hours).∗ The proportions of starting material
and products over the course of the reaction were determined by integra-
tion of the corresponding signals. From these measurements the first order
rate constant for the reaction at different lithium perchlorate concentra-
tions was calculated (Table 1). The data show a linear dependence between
the lithium perchlorate concentration and the reaction rate (Figure 1). At
a concentration of 1.5 M, the highest concentration of lithium perchlorate
possible in acetonitrile, a four-fold increase in the rate was observed com-
pared to the uncatalysed reaction at 50◦C. Under the so optimized condi-
tions, 2 was isolated in a 55% yield∗∗ while the amount of the elimination
side reaction 3 was reduced to 5% compared to 33% in the absence of the
Lewis acid.
In conclusion, we have described the Lewis acid catalysis of an in-
tramolecular hetero-Diels-Alder reaction. Using lithium perchlorate in ace-
tonitrile as the reaction medium, a rate increase by a factor of four was
obtained compared to the uncatalyzed reaction. A competing elimination
side reaction was almost entirely suppressed. The use of lithium perchlorate
had no influence on the stereochemical course of the reaction.
∗In toluene as a solvent, the reaction shows no conversion at 50◦C.
∗∗Synthesis of ester 2: To a solution of 1 (100 mg, 0.19 mmol) in acetonitrile (5 ml), lithium perchlo-
rate (798 mg, 7.5 mmol) was added. The glass vial was sealed and held at 50◦C (internal temperature)
for 72 hours. The mixture was worked up as described above and purified by column chromatography
(diethylether/CHCl3/hexane 2:2:1) to give 55 mg, (55%) of 2.

704
R. Messer et al.
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