Solid-phase synthesis of natural product-like macrocycles by a sequence of Ugi-4CR and SNAr-based cycloetherification

Article abstract of DOI:10.1016/S0040-4039(03)01378-9

An on-resin Ugi four-component reaction followed by an intramolecular nucleophilic aromatic substitution (S_NAr) has been developed for the rapid access to biaryl-ether containing macrocycles.

Full text of DOI:10.1016/S0040-4039(03)01378-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5575–5578
Solid-phase synthesis of natural product-like macrocycles by a
sequence of Ugi-4CR and SNAr-based cycloetherification
Pierre Cristau,a Jean-Pierre Vorsb and Jieping Zhua,*
aInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
bBayer CropScience, 14–20 Rue Pierre Baizet, 69009 Lyon, France
Received 12 May 2003; revised 2 June 2003; accepted 3 June 2003
Abstract—An on-resin Ugi four-component reaction followed by an intramolecular nucleophilic aromatic substitution (SNAr) has
been developed for the rapid access to biaryl-ether containing macrocycles.
© 2003 Elsevier Ltd. All rights reserved.
Many macrocycles with a nonsymmetrical endo biaryl
ether bridge have been found in Nature. These com-
pounds range from the monocyclic K-13 (1),1 OF-4949
I-IV (2) (antifungal),2 the bicyclic RA series3 to the
structurally complex polycyclic glycopeptide van-
comycin (3), an important antibiotic used as the last
resort for the treatment of methicillin-resistant Staphyl-
ococcus aureus (MRSA) and other Gram-positive
bacteria4 (Fig. 1). Not surprisingly, non-natural biaryl
ether containing macrocycles have been designed and
compounds with potent bioactivities have been
identified.5
Interested by the molecular complexity as well as the
synthetic challenges posed by vancomycin, a number of
new synthetic methodologies have been developed dur-
ing the past decade that made the construction of the
elusive biaryl ether containing macrocycles possible.4a
In connection with our ongoing project aimed at the
development of step-efficient high throughput synthesis
of potentially bioactive molecules,6 we report in this
letter a solid-phase synthesis of the biaryl ether contain-
ing macrocycles of the generic structure (4) by the
combined use of Ugi-4CR7 and SNAr methodology.8–10
Scheme 1 depicts the synthesis of the resin-bound isocy-
anide (5). Hydrolysis of the N-formyl a-amino ester (6)
under standard conditions (K2CO3, EtOH, H2O) fol-
lowed by esterification with the commercially available
Wang resin (loading 0.9 mmol/g) afforded (8).11 Dehy-
dration of the N-formyl function (POCl3, Et3N) pro-
vided the supported isocyanide (5, loading: 0.74
mmol/g). It is interesting to note that this light yellow
resin could be easily prepared in large scale and has a
long shelf life without any particular precautions.
Figure 1.
Keywords: biaryl ether; macrocycle; multicomponent reaction; SNAr
cycloetherification; solid-phase synthesis; supported isocyanide.
* Corresponding author. Fax: +33-1-69-077247; e-mail: zhu@
icsn.cnrs-gif.fr
With the supported isocyanide (5) in hands, its reaction
with heptanal (9a), butylamine (10a), and 3-hydroxy-
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01378-9

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P. Cristau et al. / Tetrahedron Letters 44 (2003) 5575–5578
phenylacetic acid (11a) was examined (Scheme 2). The
efficiency of the on-resin Ugi-4CR was evaluated by
quantification of dipeptide ester (13a), in turn obtained
by resin cleavage (TFA, CH2Cl2) and esterification
(diazomethane). Following the solution-phase chem-
istry,9 the supported Ugi-4CR was first conducted in
toluene in the presence of NH4Cl (entry 1). However,
no dipeptide ester 13a was isolated after resin cleavage
and esterification. Therefore, we re-investigated the
reaction conditions and the results were summarized in
Table 1.12 Addition of methanol to toluene (entry 2)
dissolved all monomeric reagents and the Ugi reaction
proceeded to afford dipeptide (13a) in 12% yield (calcu-
lated for 5 steps starting from the Wang resin). Replac-
ing the toluene by chloroform increased slight the yield
of dipeptide (entries 3 and 4). To our delight, using
2,2,2-trifluoroethanol13 instead of methanol as co-sol-
vent accelerated the reaction rate to afford (13a) in a
very good overall yield (38%, entry 5). The higher
acidity of TFE may be responsible for the improved
reaction outcome. The ratio of chloroform to TFE (3/1)
seems to be an important factor because an increased
proportion of chloroform has an adverse effect (entry
6).
Scheme 2. Reagents and conditions: (a) see Table 1; (b) TFA,
Ring closure via the intramolecular SNAr reaction on
solid support has been reported and is known to be
very efficient due to a pseudo-dilution effect of the
resin.14 As shown in Scheme 3, the cycloetherification
of polymer-supported dipeptide (12a) in DMF in the
presence of potassium carbonate proceeded smoothly to
provide, after resin cleavage and esterification, the
desired macrocycle (4a) as a mixture of four separable
diastereoisomers. The overall yield of this six-step syn-
thesis was 38% starting from the Wang resin. The low
solubility of potassium carbonate in DMF prompted us
to use a soluble organic base. Gratifyingly, under other-
wise identical conditions, the cyclization promoted by
DBU (DMF, room temperature, 3 days) furnished the
macrocycle (4) in 48% overall yield. To our surprise
only two diastereoisomers were formed. Thermal equi-
librium experiments conducted in DMSO at 160°C
indicated that they are two atropomers. Consequently,
it is hypothesized that chiral centers of the peptide
backbone were epimerized during the DBU promoted
cycloetherification leading to the thermodynamically
more stable diastereomer.
CH2Cl2; (c) CH2N2, Et2O.
Table 1. Survey of conditions for on-resin Ugi-4CRa
Entries
Solvent
Yield (%)b
1
2
3
4
5
6
Toluene/NH4Cl
N.D.c
12
15
17
38
Toluene/MeOH (1/1)d
CHCl3/MeOH (1/1)d
CHCl3/MeOH (3/1)
CHCl3/TFEe (3/1)f
CHCl3/TFE (5/1)
26
a The reaction was followed by IR spectrum until the disappearance
of isonitrile absorption at 2145 cm−1
.
b Isolated yield, calculated from the Wang resin.
c Not determined.
d The reaction was completed after two runs of 48 h.
e TFE=2,2,2-trifluoroethanol.
f The reaction was completed after one run of 72 h.
Scheme 1. Reagents and conditions: (a) K2CO3, EtOH, H2O,
83%; (b) Wang wesin, DCC, DMAP, THF; (c) POCl3, Et3N,
CH2Cl2.
Scheme 3. Reagents and conditions: (a) K2CO3, DMF (38%)
or DBU, DMF (48%); (b) TFA, CH2Cl2; (c) CH2N2, Et2O.

P. Cristau et al. / Tetrahedron Letters 44 (2003) 5575–5578
5577
Acknowledgements
We thank CNRS and Bayer CropScience for financial
support. A doctoral fellowship to P. Cristau from
Bayer CropScience-CNRS is gratefully acknowledged.
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Figure 2 listed the macrocycles synthesized by a
sequence of on-resin Ugi 4CR and intramolecular SNAr
reaction. In all these examples, DBU was used as a base
to promote the cyclization and all macrocycles were
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