Elaboration of D-(-)-ribose into a tricyclic, natural product-like scaffold

Article abstract of DOI:10.1021/jo048351+

The construction of natural product-like, tricyclic compounds is reported. Starting from a D-(-)-ribose-derived dihydrofurane, the tricyclic scaffold is prepared via an intramolecular hetero-Diels-Alder reaction. The reaction proceeds with very high diast

Full text of DOI:10.1021/jo048351+

SCHEME 1. Structural Similarity of a
D-(-)-Ribose Derived Tricyclic Scaffold (A) to
Selected Natural Compounds (euplotins,15
ent-udoteatrial,16 and plumericin17)
Elaboration of D-(-)-Ribose into a Tricyclic,
Natural Product-like Scaffold
Roland Messer, Andrea Schmitz, Luzia Moesch, and
Robert Ha¨ner*
Department of Chemistry and Biochemistry, University of
Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
robert.haener@ioc.unibe.ch
Received September 17, 2004
Abstract: The construction of natural product-like, tricyclic
compounds is reported. Starting from a D-(-)-ribose-derived
dihydrofurane, the tricyclic scaffold is prepared via an
intramolecular hetero-Diels-Alder reaction. The reaction
proceeds with very high diastereoselectivity through an endo
transition state, as established on the basis of X-ray struc-
tural analysis of the products. Further modification and
derivatization of the obtained products is described.
SCHEME 2. Synthetic Approach to a Tricyclic
Scaffold through Hetero-Diels-Alder Reaction of
D-(-)-ribose Derived Precursorsa
Natural products have had a large impact on drug
discovery. Many natural products, or derivatives thereof,
are used in modern medicine. Furthermore, the large
structural diversity of natural compounds has always
served medicinal scientists as a source of inspiration in
the search for new molecular entities with pharmacologi-
cal activity.1 The synthesis of natural product analogues,
therefore, represents a key challenge for medicinal
chemists.2-4 In addition, combinatorial methods are
increasingly applied for the generation of derivatives of
natural products and natural product-like scaffolds.5-7
During our work aimed at the synthesis of natural
product-like scaffolds, we became attracted to a group of
compounds belonging to the iridoid family (see Scheme
1). These tricyclic compounds, which have a common
perhydrofuropyrane core,8,9 possess a variety of interest-
ing biological activities. The synthetic scaffold A shows
a high degree of structural similarity to these compounds.
This scaffold, in turn, should be accessible through an
intramolecular hetero-Diels-Alder reaction of a simple,
D-(-)-ribose-derived precursor. The hetero-Diels-Alder
reaction is one of the most important reactions for the
construction of heterocyclic six-membered rings.10-14 Its
a Reagents and conditions: (a) Et3N, pivaloyl chloride, DMAP,
2 h, 0 °C.
concerted character allows the selective formation of up
to three stereogenic centers in a single reaction step.
Therefore, we investigated the usefulness of the intramo-
lecular hetero-Diels-Alder reaction for the construction
of the synthetic scaffold A. Here, we report the synthesis
and further derivatization of this scaffold.
The precursors for the hetero-Diels-Alder reaction
were readily prepared according to literature procedures.
Following the method by Schmidt et al.,18 the dihydro-
furanoside 1 was obtained in five steps from D-(-)-ribose
* To whom correspondence should be addressed.
(1) Dewick, P. M. Medicinal Natural Products, 2nd ed.; J. Wiley &
Sons: Chichester, UK, 2003.
(2) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int.
Ed 2003, 42, 3996-4028.
(3) Lee, K. H. J. Nat. Prod. 2004, 67, 273-283.
(4) Mehta, G.; Singh, V. Chem. Soc. Rev. 2002, 31, 324-334.
(5) Nielsen, J. Curr. Op. Chem. Biol. 2002, 6, 297-305.
(6) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int.
Ed. 2002, 41, 2879-2890.
(7) Boldi, A. M. Curr. Op. Chem. Biol. 2004, 8, 281-286.
(8) Alonso, F.; Lorenzo, E.; Melendez, J.; Yus, M. Tetrahedron 2003,
59, 5199-5208.
(9) Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron Lett. 2000, 41,
1661-1665.
(15) Guella, G.; Dini, F.; Pietra, F. Helv. Chim. Acta 1996, 79, 710-
717.
(10) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10-23.
(11) Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651-692.
(12) Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250-259.
(13) Waldmann, H. Synthesis 1994, 535-551.
(16) Ge, Y. T.; Kondo, S.; Katsumura, S.; Nakatani, K.; Isoe, S.
Tetrahedron 1993, 49, 10555-10576.
(17) Kupchan, S. M.; Desserti. A.; Blaylock, B. T.; Bryan, R. F. J.
Org. Chem. 1974, 39, 2477-2482.
(14) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558-3588.
10.1021/jo048351+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004
8558
J. Org. Chem. 2004, 69, 8558-8560

TABLE 1. Hetero-Diels-Alder Reactions of D-(-)-Ribose Derived Acylacrylate Estera
3a-h
4a-h
yield (%)
R1
R2
yield (%)a
conditions
a
b
c
d
e
f
methyl
H
H
H
H
H
benzyl
pentyl
acetyl
61
69
67
63
78
75
60
b
53
73
o-xylene, reflux, 16 h
o-xylene, reflux, 5 h
o-xylene, reflux, 18 h
toluene, reflux, 20 h
o-xylene, reflux, 3 h
toluene, 170 °C,d 3 h
toluene, 170 °C,d 5 h
1,2-dichloroethane, rt, 20 h
phenyl
4-bromophenyl
3-nitrophenyl
4-nitrophenyl
methyl
methyl
methyl
45
(96)c
(99)c
24
30
51
g
h
a Reaction conditions: see Scheme 2. b Intermediate was not isolated; cyclization takes place spontaneously. c Crude material was directly
used in the next step (see Scheme 3). d The reaction was carried out in a sealed, Teflon-coated steel autoclave.
with an overall yield of 35%. The acrylic acids 2a-h were
also prepared according to literature procedures.19,20 The
esterification of alcohol 1 (Scheme 2 and Table 1) with
the different acids was best carried out via the mixed
anhydrides obtained with pivaloyl chloride. Isolated
yields of the esters 3a-g varied between 60% and 80%.
These esters were subsequently treated in high-boiling
aromatic hydrocarbons or, alternatively, in a sealed steel
autoclave at 170 °C with toluene as the solvent. Ester
3h behaved exceptionally in this reaction. Isolation of this
compound was not possible, since cyclization took place
under the conditions of esterification, i.e., at room tem-
perature in 1,2-dichloroethane. This observation of a
faster reaction is in good agreement with the expected
influence of an electron-withdrawing substituent at the
diene moiety in this inverse electron-demand hetero-
Diels-Alder reaction.21 Table 1 shows the tricyclic de-
rivatives 4a-h formed in the cyclization reaction. Yields
were in the range of 50-70%, except for the two deriva-
tives 4f and 4g, which were isolated in low yields, due to
partial decomposition at 170 °C. The two compounds 4d
and 4e were not purified but were directly used for
further modifications (see below).
The stereochemical outcome of the hetero-Diels-Alder
reaction was, of course, of particular interest. On the
basis of the 1H NMR spectra of the crude materials only
a single diastereomer was formed in all reactions.
Structural analysis (1H NMR nuclear Overhauser experi-
ments) as well as X-ray structures of compounds 4a,b,g
revealed that the hetero-Diels-Alder reaction must fol-
low the pathway shown in Scheme 2. Only if the two
substituents R1 and R2 are arranged endo to the sugar
are the respective diastereomers formed. The reaction
proceeds, thus, with endo selectivity as commonly ob-
served in inverse electron-demand hetero-Diels-Alder
reactions.12,14
In a recent report, Aungst and Funk22 reported on the
total synthesis of (()-euplotin A using a hetero-Diels-
Alder reaction as a key step in the synthesis. The
stereochemical outcome, however, was different from the
one observed here. The difference is most likely a result
of the altered substitution pattern of the dihydrofurane,
leading to changed steric and electronic parameters in
the transition state. On the other hand, Kim and co-
workers described an analogous stereochemical course
in an intermolecular Diels-Alder reaction between cy-
clopentadiene and a cyclic, sugar-derived dienophile.23
Furthermore, we observed the same course in the in-
tramolecular hetero-Diels-Alder reaction of acyclic allylic
alcohols of acylacrylates.24
The obtained tricyclic compounds 4d and 4e, contain-
ing 3- and 4-nitrophenyl groups in position R1, were
further derivatized as shown in Schemes 3 and 4. Cata-
lytic hydrogenation with palladium on charcoal under a
hydrogen atmosphere led to the reduction of the nitro
group as well as the double bond (Scheme 3). Although
the corresponding products 5a and 5b could be isolated
and purified, we observed some instability during the
purification process. It turned out to be advantageous to
directly use the crude material in the subsequent acyla-
tion reaction with the different electrophiles. In this way,
considerably higher yields of the products 6 and 7 were
obtained. The overall yields over three steps varied
between 30% and 50% (Scheme 3).
In general, the 3-acylamino derivatives (6a-e) were
obtained in higher yields than the corresponding 4-acyl-
amino compounds (7a-e). Somewhat unexpectedly, the
stereochemistry of the hydrogenation reaction (4 f 5) did
not proceed with complete selectivity. Compounds 5a and
5b were obtained with selectivities of 93:7 and 84:16,
respectively. After acylation in the subsequent step,
(21) See e.g.: Fleming, L. Frontier Orbitals and Organic Chemical
Reactions; Wiley: London, UK, 1977.
(18) Schmidt, R. R.; Heermann, D.; Jung, K. J. Liebigs Ann. Chem.
1974, 1856-1863.
(22) Aungst, R. A.; Funk, R. L. J. Am. Chem. Soc. 2001, 123, 9455-
9456.
(19) Bourguignon, J. J.; Schoenfelder, A.; Schmitt, M.; Wermuth,
C. G.; Hechler, V.; Charlier, B.; Maitre, M. J. Med. Chem. 1988, 31,
893-897.
(23) Kim, K. S.; Cho, I. H.; Joo, Y. H.; Yoo, I. Y.; Song, J. H.; Ko, J.
H. Tetrahedron Lett. 1992, 33, 4029-4032
(24) Fuhrer, C.; Messer, R.; Ha¨ner, R. Tetrahedron Lett. 2004, 45,
4297-4300.
(20) Papa, D.; Schwenk, E.; Villani, F.; Klingsberg, E. J. Am. Chem.
Soc. 1948, 70, 3356-3357.
J. Org. Chem, Vol. 69, No. 24, 2004 8559

SCHEME 3. Reduction of Tricyclic Products 4d,e
and Further Derivatization of the Obtained
Aromatic Amines 5a,b with Various Acyl
Chloridesa,b
SCHEME 4. Selective Reduction of the Nitro
Group in 4d Followed by Acylation of the
Resulting Anilinea
a Reagents and conditions: (a) Pd/C (10%), HCOONH4, MeOH.
(b) R3COCl, DMAP, pyridine.
benzoyl and 1-naphthoyl chloride to give the correspond-
ing compounds 9a and 9b.
In summary, the tricyclic scaffold A is accessible via
an intramolecular hetero-Diels-Alder reaction of D-(-)-
ribose-derived esters of different acylacrylic acids. The
cyclization reaction proceeds in a highly stereoselective
manner. The tricyclic intermediates can be further modi-
fied and derivatized with various reagents. The natural
product-like compounds are being tested for their biologi-
cal activities in cellular assays.
a Reagents and conditions: (a) Pd/C (10%), MeOH. (b) R3COCl,
DMAP, pyridine. bYields given for products 6 and 7 are over three
steps starting from esters 3d and e, respectively.
Acknowledgment. This work was supported by the
Swiss National Foundation (grant 200021-101861/1).
We gratefully acknowledge the generous gift of com-
pound 1 and the structure elucidation of compound 6e
by Novartis Institutes of Biomedical Research (NIBR),
Basel, Switzerland.
however, the major isomers were isolated after column
chromatography in pure form. The spacial orientation of
the aminophenyl substituents shown for compounds 6
and 7 was confirmed by 1H NMR spectroscopic methods.
To increase the diversity of potential new types of
structures, we also tried to preserve the enol double bond
present in compounds 4, i.e., to selectively reduce the
nitro to the amino group in the presence of the enol ether.
This worked best by using ammonium formiate as the
hydrogen source in the catalytic reduction. Scheme 4
shows the conversion of compound 4d to the correspond-
ing aminophenyl derivative 8, in which the enol ether
still exists. Due to partial reduction of the enol double
bond, the yield is modest. Nevertheless, the compound
was obtained and could readily be further reacted with
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org. Crystallographic data (excluding structure
factors) for 4a, 4b, and 4g have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publications numbers CCDC 248308, CCDC 248309, and
CCDC 248310, respectively.
JO048351+
8560 J. Org. Chem., Vol. 69, No. 24, 2004