Solid-support synthesis of natural product-like compounds derived from D-(-)-ribose

Article abstract of DOI:10.1055/s-2005-872684

The synthesis of natural product-like compounds on solid support is described. Starting from a readily accessible D-(-)-ribose derivative, a tricyclic scaffold is prepared in five steps. After coupling onto solid supports bearing different substituents (P

Full text of DOI:10.1055/s-2005-872684

LETTER
2441
Solid-Support Synthesis of Natural Product-like Compounds Derived from
D-(–)-Ribose
N
atural Product-L
o
ike Compou
l
nds and Messer,a Xavier Pelle,b Andreas L. Marzinzik,b Hansjörg Lehmann,b Jürg Zimmermann,b Robert Häner*a
a
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
Fax +41(31)6318057; E-mail: robert.haener@ioc.unibe.ch
b
Novartis Institutes of BioMedical Research, 4002 Basel, Switzerland
Received 3 August 2005
Abstract: The synthesis of natural product-like compounds on
solid support is described. Starting from a readily accessible D-(–)-
ribose derivative, a tricyclic scaffold is prepared in five steps. After
coupling onto solid supports bearing different substituents (PAL
resins), the scaffold can be further derivatised at two diversity
points. Representative derivatives obtained by this diversity-orient-
ed procedure are described.
Key words: solid-phase synthesis, hetero Diels–Alder reactions,
medicinal chemistry, combinatorial, furans
Many existing drugs are either natural products or are
derived from naturally occurring compounds.1 It is, thus,
not surprising that a considerable effort in the search for
new lead compounds is devoted to the synthesis of natural
product-like libraries.2 Tricyclic iridoid-derived struc-
tures, such as euplotin and udoteatrial, represent an inter-
esting class of compounds with a variety of biological
activities.3 Therefore, they serve as a guiding motif for the
synthesis of natural product-like compounds. We have
recently described the synthesis of a tricyclic scaffold
with a high structural similarity to these natural products
starting from D-(–)-ribose.4 The key step of the synthesis
involves a highly selective intramolecular hetero Diels–
Scheme 1 Preparation and derivatisation of a solid-support-bound
tricyclic intermediate synthesised from a D-(–)-ribose derivative
Scheme 2 Preparation of the unsaturated furanoside 3. Reagents
Alder reaction leading to a single diastereomeric product. and conditions: a) 0.5 N LiOH, dioxane–H2O (5:1), quant.; b) glycine
benzylester, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), N,N-diisopropylethylamine, MeCN, r.t.,
4 h, 97%
We also showed that the scaffold was amenable to further
derivatisation in solution-phase. For the preparation of
larger compound libraries, however, the synthesis on
solid-phase has practical advantages.5 In this letter we
wish to report the elaboration of a solid-phase synthesis was directly converted into the amide 3 in 97% overall
enabling the generation of multi-dimensional compound yield.
libraries, as illustrated in Scheme 1.
Next, the oxadiene moiety required for the hetero Diels–
Starting point of the synthesis was the unsaturated furano- Alder reaction was introduced. The nitro-derived benzoyl
side 1, which is easily accessible from D-(–)-ribose.6 Di- acrylic acids 4 were chosen for this purpose. Both, the me-
rect attachment to a solid support through the carboxylic ta- and the para-isomers were prepared as described in the
acid function of 1 was, however, not advised since steric literature.7 Esterification involved formation of the mixed
hindrance in the later tricyclic derivatives was likely to anhydride of the acids 4 with pivaloyl chloride, which
lead to problems. To avoid these difficulties, an additional were further reacted with 3 in the presence of N,N-di-
glycine linker was introduced early in the synthesis methyl-4-aminopyridine (Scheme 3). The moderate
(Scheme 2). Thus, compound 1 was treated with one yields of the esters 5a and 5b obtained with both acids
equivalent of lithium hydroxide in a mixture of dioxane (45% in each case) are mostly due to the lability of the
and water (5:1) to give the lithium carboxylate 2, which acrylic acids under the conditions required for esterifi-
cation.8
Esters 5a and 5b underwent cyclisation in toluene at
SYNLETT 2005, No. 16, pp 2441–2444
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872684; Art ID: G21805ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
5
100 °C within 24 hours to give the corresponding prod-
ucts 6a and 6b in yields of approximately 45%.9 In both

2442
R. Messer et al.
LETTER
cases, the intramolecular hetero Diels–Alder reaction
gave a single product, which is in agreement with the high
stereoselectivity observed with a similar derivative.4 Hy-
drogenation of the scaffolds 6a and 6b involved cleavage
of the benzyl ester, reduction of the nitro group as well as
of the enol ether. Again, compounds 7a and 7b were ob-
tained as single diastereomers. The hydrogenation was
carried out in THF due to slow trans-esterification if
methanol was used as solvent. Without further purifica-
tion, the anilines 7a and 7b were protected with Fmoc-Cl
to give products 8a and 8b after crystallisation from
methyl tert-butyl ether and methanol in yields of 78%
based on 6a and 52% based on 6b, respectively.
For the synthesis of combinatorial compound libraries we
decided to use N-substituted PAL resins.10 The N-substi-
tuted PAL resin features the advantage of derivatising the
carboxylic acid moiety in the coupling step by secondary
amide formation, thus providing a third possibility of
introducing diversity. Two examples of solid-support-
mediated libraries were made from the Fmoc-protected
scaffold 8a. In these model libraries, the two N-substi-
tuted PAL resins A and B (Scheme 4) were used contain-
ing a benzyl amine and a 2-methoxy ethylamine residue,
respectively. The immobilisation of 8a worked best using
a combination of HCTU11 and 1-hydroxybenzotriazole
(HOBT) in N-methyl pyrrolidone (NMP). The immobi-
lized aniline 8a was deprotected with 20% piperidine in
N,N-dimethyl acetamide (DMA). Quantification by UV
spectrometry indicated a loading of approximately 60%.12
Each batch of the functionalised solid supports A and B
was split into two unequal portions of 1/4 and 3/4.
Acylation was then performed as shown in Scheme 4
using different acyl chlorides in pyridine–dichloro-
methane. The smaller portions were cleaved from the
support directly after acylation, leading to the products 9
and 11. The larger portions were split again into three
equal portions. One portion of each kind (A and B) was
Scheme 3 Synthesis of the Fmoc-protected aniline acid scaffolds 8a
and 8b. Reagents and conditions: a) pivaloyl chloride, Et3N, N,N-di-
methyl-4-aminopyridine, 1,2-dichloroethane, 0 °C, 2 h, 45% (for 5a
and b); b) toluene, 100 °C, 24 h (6a: 45%; 6b: 44%); c) Pd/C (10%),
H2, THF; d) Fmoc-Cl, NaHCO3, dioxane–H2O (8a: 78%; 8b: 52%
over two steps)
Scheme 4 Schematic illustration of combinatorial synthesis of compounds 9–16. Intermediate 8a was linked to PAL resins A and B contai-
ning a benzyl and a 2-methoxy aminoethyl moiety, respectively. Reagents and conditions: a) HCTU–1-hydroxybenzotriazole, N,N-diisopropyl-
ethylamine (DIPEA), N-methyl pyrrolidone; b) piperidine–N,N-dimethylacetamide (1:4); c) pyridine–CH2Cl2 1:4; d) H2O–TFA–CH2Cl2
(1:19:80); e) 2-hydroxy pyridine (5 equiv), THF
Synlett 2005, No. 16, 2441–2444 © Thieme Stuttgart · New York

LETTER
Natural Product-Like Compounds
2443
Table 1 Products Synthesized through Derivatisation of the Solid-Support-Bound Intermediate 8a
Product
R1
R2
R3
Yield (%)a
9
10
11
12
Benzyl
Benzyl
2-Methoxyethyl
2-Methoxyethyl
Butyl
–
–
–
–
55
54
59
71
Isobutyryl
Benzoyl
2-Furanyl
13
14
15
16
Benzyl
Benzyl
2-Methoxyethyl
2-Methoxyethyl
Isobutyryl
Isobutyryl
2-Furanyl
2-Furanyl
Benzyl
Butyl
Benzyl
Butyl
46
39
70
63
a Overall yields [steps c)–e), see Scheme 4] isolated after HPLC purification.
cleaved from the support to give the products 10 and 12. PAL resins. The immobilised scaffold, bearing six stereo-
The remaining two portions of each support were further centres, was shown to be amenable to derivatisation in a
submitted to aminolysis of the lactone leading to the prod- diversity-oriented manner. Two small exemplary libraries
ucts 13–16. The structures of the eight products obtained were prepared to demonstrate the usefulness of this ap-
in this way are shown in Table 1. Aminolysis of the lac- proach.
tone was best achieved by the use of 2-hydroxy pyridine.13
Simple treatment with an amine in the absence of the cat-
alyst did not lead to formation of the desired amides.
Cleavage from the solid support was carried out using a Functionalisation of the PAL-Resins
General Procedure
Resin A or B (150 mg) containing 0.6–0.7 mmol of available amino
mixture of aqueous trifluoroacetic acid in dichlo-
romethane.
groups per gram were placed into a syringe containing a filter. The
resin was suspended in NMP (3 mL), agitated well and allowed to
swell for 30 min. After displacement of the solvent, a solution of 8a
(148 mg, 240 mmol), HCTU (100 mg, 240 mmol) and HOBT (33
mg, 240 mmol) in NMP (2 mL) was added to the resin followed by
DIPEA (148 ml, 880 mmol). The suspension was gently agitated
over night. The solution was displaced and the resin was treated
with the same reagents [HCTU (68 mg, 165 mmol) together with
HOBT (22 mg, 165 mmol) and 8a (101 mg, 165 mmol) dissolved in
2 mL NMP followed by DIPEA (148 mL, 880 mmol)] a second time
(5 h). The resin was washed successively with degassed DMA
(5 × 1 mL), i-PrOH (1 mL), DMA (3 × 1 mL), i-PrOH (5 × 1 mL),
CH2Cl2 (2 × 1 mL) and degassed DMA (2 × 1 mL). The resin was
flushed continuously with 30 mL of a 20% solution of piperidine in
DMA over a period of 30 min. The eluent was collected and diluted
with MeOH to 100 mL for UV spectrophotometric quantification of
the loading.12
The crude products were finally purified using normal
phase HPLC to obtain the individual compounds shown in
Table 1.
It is important to note here that no signs of decomposition
were observed under the acidic conditions required for re-
lease of the products from the solid support. Since the ob-
tained, highly functionalised polycyclic compounds are
based on acetal-type structures, this might well be expect-
ed. The hydrolytic stability of the scaffolds is, further-
more, an important aspect for potential medicinal
applications. Both acetal groups present in the scaffold
were, however, completely resistant to treatment with
aqueous trifluoro acetic acid at room temperature for one
day.
Derivatisation of the Functionalised Supports by Acylation
The resin derivatised with 8a was washed by repeating the proce-
dure described in the previous step followed by an additional final
washing step with CH2Cl2. The resin was suspended in a minimally
required amount of CH2Cl2 (1 mL) and split into 2 portions of 1/4
and 3/4. Each portion was treated separately with an excess of the
corresponding acyl chloride (20 equiv, see Scheme 4) in CH2Cl2–
pyridine (8:2, 0.4 or 1.2 mL, respectively). The suspensions were
gently agitated for 3 h. The resins were again washed in the typical
In conclusion, a polycyclic scaffold with high structural
similarity to several natural products has been elaborated
to meet the requirements of solid-phase synthesis. The
scaffold was constructed from a D-(–)-ribose-derived in-
termediate through an intramolecular hetero Diels–Alder
reaction. The obtained tricyclic derivative was further
transformed by straightforward chemical reactions into a
substrate suitable for immobilisation on N-substituted
Synlett 2005, No. 16, 2441–2444 © Thieme Stuttgart · New York

2444
R. Messer et al.
LETTER
procedure including an additional final washing step with CH2Cl2 (1
mL). The portions carrying compounds 9 and 11 were put aside for
the final cleaving step. The remaining two portions were again sus-
pended in CH2Cl2 (1.5 mL). The material was split into 3 equal frac-
tions. One fraction of each series (containing compounds 10 and 12)
was again saved for final cleavage from the support. The two re-
maining portions of each series were further derivatised as de-
scribed below.
169.2, 157.0, 149.3, 146.0, 143.8, 140.1, 139.6, 129.5, 129.4, 129.1,
128.4, 129.1, 127.9, 123.0, 120.3, 119.0, 115.3, 113.0, 112.2, 106.4,
78.5, 76.0, 71.8, 58.7, 55.7, 43.8, 42.8, 42.0, 41.4, 39.7, 34.3. ESI-
MS (positive mode): 674 [M+ + Na+], 651 [M+], 621, 620. HRMS:
m/z calcd for C33H38N4O10Na: 637.2485; found: 673.2480.
Acknowledgment
Financial support by the Swiss National Foundation (grant 200021-
101861/1) is gratefully acknowledged. We thank L. Moesch for ex-
cellent technical assistance.
Aminolysis of the Lactone
The remaining portions of resin obtained as described above were
treated with an excess of the corresponding amine (20 equiv) in the
presence of 2-hydroxy pyridine (4 equiv) in 0.5 mL THF.
References
Cleavage of the Products from the Supports
(1) Newmann, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod.
2003, 1022.
(2) Messer, R.; Fuhrer, C. A.; Häner, R. Curr. Opin. Chem. Biol.
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(3) (a) Guella, G.; Dini, F.; Pietra, F. Helv. Chim. Acta 1996,
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The compounds so obtained were cleaved from the support by five
repetitive treatments with 0.6 mL of a mixture of H2O–TFA–
CH2Cl2 (1:19:80) for 15 min. The thus obtained solutions contain-
ing the products were collected in round-bottom flasks and concen-
trated. The obtained crude materials (purity generally >80%) were
re-dissolved in MeOH and concentrated again before purification
by normal phase HPLC (LiChrospher® Si 60, 10 mm) using isocratic
elution with MeCN.
(2R,2aR,4aS,6S,7aS,7bS)-6-{3-[(Furan-2-carbonyl)amino]phe-
nyl}-2-methoxy-4-oxohexahydro-1,3,7-trioxacyclopenta[cd]in-
dene-7a-carboxylic Acid [(2-Methoxyethyl-carbamoyl)meth-
yl]amide (12)
Yield 6.0 mg (71%). TLC (MeCN): Rf = 0.46; HPLC: tR = 8.55,
l
max = 276 nm. 1H NMR (300 MHz, acetone-d6): d = 9.46 (1 H, br),
7.94–7.90 (1 H,), 7.76–7.75 (1 H, m), 7.69 (1 H, m), 7.73 (1 H, br),
7.37–7.31 (1 H, t, J = 7.9 Hz), 7.24–7.23 (1 H, m), 7.19–7.16 (1 H,
m), 7.10 (1 H, br), 6.66–6.64 (1 H, m), 5.28 (1 H, s), 4.93 (1 H, d,
J = 6.2 Hz), 4.81 (1 H, dd, J = 9.7, 6.5 Hz), 4.01–3.86 (3 H, m), 3.42
(7) Papa, D.; Schwenk, E.; Villani, F.; Klingsberg, E. J. Am.
Chem. Soc. 1948, 3356.
(8) Other conditions and different coupling reagents were tried
but did not result in an improvement of the yields.
(9) In a preliminary experiment, the yield could be improved
using different conditions. Thus, the use of lithium
perchlorate (1.5 M) in MeCN as a catalyst allowed
cyclisation of 5a at a temperature of 50 °C in 50 h.
Compound 6a was isolated in a 55% yield. Further
experiments in this direction are ongoing.
(3 H, s), 3.42–3.34 (5 H, m), 3.24 (3 H, s), 2.44–2.19 (2 H, m). 13
C
NMR (75 MHz, acetone-d6): d = 178.1, 169.6, 169.2, 157.1, 146.0,
143.4, 139.8, 129.7, 122.7, 120.5, 120.4, 119.2, 115.4, 113.0, 107.7,
84.9, 73.4, 71.8, 58.7, 55.9, 43.3, 39.8, 39.0, 36.4, 28.3. ESI-MS
(positive mode): 566 [M+ + Na+], 544 [M+], 512. HRMS: m/z calcd
for C26H29N3O10Na: 566.1750; found: 566.1769.
(10) Sharma, S. K.; Songster, M. F.; Colpitts, T. L.; Hegyes, P.;
Barany, G.; Castellino, F. J. J. Org. Chem. 1993, 58, 4993.
(11) HCTU: N-[(1H-6-chlorobenzotriazol-1-yl)(dimethyl-
amino)methylene]-N-methylmethanaminium hexafluoro-
phosphate N-oxide.
(12) The loading efficiency was determined by UV spectrometric
quantification of the dibenzofulvene–piperidine adduct
formed during deprotection (lmax = 302 nm, e = 7800), see:
Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 3404.
(13) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J.
Am. Chem. Soc. 1998, 8565.
(2R,3R,3aS,4S,6S,7aS)-6-{3-[(Furan-2-carbonyl)amino]phe-
nyl}-3-hydroxy-2-methoxyhexahydrofuro[2,3-b]pyran-4,7a-di-
carboxylic Acid 4-Benzylamide 7a-{[(2-methoxyethyl-
carbamoyl)methyl]amide} (15)
Yield 7.0 mg (70%). TLC (EtOAc): Rf = 0.15; HPLC: tR = 8.61,
l
max = 277 nm. 1H NMR (300 MHz, acetone-d6): d = 9.47 (1 H, br),
8.26 (1 H, br), 7.92–7.88 (1 H, m), 7.77 (1 H, m), 7.75–7.74 (1 H,
m), 7.73–7.72 (1 H, m), 7.37–7.18 (9 H, m), 6.65–6.63 (1 H, m),
5.13 (1 H, s), 4.92 (1 H, dd, J = 11.9, 2.3 Hz), 4.49 (2 H, s), 4.28 (1
H, d, J = 6.0 Hz), 3.98–3.82 (2 H, m), 3.38–3.36 (5 H, m), 3.36 (3
H, s), 3.24 (3 H, s), 2.93–2.89 (2 H, m), 2.43–2.31 (1 H, m), 1.88–
1.82 (1 H, m). 13C NMR (75 MHz, acetone-d6): d = 175.0, 169.8,
Synlett 2005, No. 16, 2441–2444 © Thieme Stuttgart · New York