Rapid and diverse route to natural product-like biaryl ether containing macrocycles

Article abstract of DOI:10.1016/j.tet.2003.08.031

A two-step sequence involving an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution (S_NAr) has been developed for the rapid access to biaryl-ether containing macrocycles. In the course of this study, we documented that ammonium chloride can promote the Ugi-4CR in non-polar aprotic solvent (toluene) without the interference of an alternative Passerini reaction. Solid phase synthesis of macrocycles by this two-step sequence was also developed using polymer (Wang resin) supported α-(4′-fluoro-3′-nitro)phenethyl isocyanoacetate as one of the inputs.

Full text of DOI:10.1016/j.tet.2003.08.031

Tetrahedron 59 (2003) 7859–7870
Rapid and diverse route to natural product-like biaryl ether
containing macrocycles
Pierre Cristau,a Jean-Pierre Vorsb and Jieping Zhua
,
*
aInstitut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, cedex 91198, France
bBayer CropScience, 14-20 Rue Pierre Baizet, Lyon 69009, France
Received 11 August 2003; accepted 19 August 2003
Abstract—A two-step sequence involving an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution (SNAr)
has been developed for the rapid access to biaryl-ether containing macrocycles. In the course of this study, we documented that ammonium
chloride can promote the Ugi-4CR in non-polar aprotic solvent (toluene) without the interference of an alternative Passerini reaction. Soli0d
phase synthesis of macrocycles by this two-step sequence was also developed using polymer (Wang resin) supported a-(40-fluoro-3 -
nitro)phenethyl isocyanoacetate as one of the inputs.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
thallium trinitrate promoted intramolecular oxidative
coupling,9 intramolecular Ullmann reaction10 nucleophilic
aromatic substitution (SNAr) reaction11 and Cu-assisted
O-arylation of arylboronic acid12 have been developed. The
mild cyclization condition in conjunction with the high
chemical yield and generality made the SNAr based
cyclization methodology one of the most efficient tech-
nologies for the access of aryl-ether containing macro-
cycles. Indeed, a number of natural products including
K-13,13 RA-VII,14 aceroside IV,15 sanjoinine G1,16 vanco-
mycin,17 and teicoplanin18 have been synthesized by using
this cycloetherification reaction as a key step.
Many macrocycles with a non-symmetrical endo biaryl
ether bridge have been found in nature. These compounds
range from the monocyclic K-13 (1) (ACE inhibitor),1 the
bicyclic piperazinomycin (2) (antifungal),2 the RA VII (3)
(antitumor antibiotics)3 to the structurally complex poly-
cyclic glycopeptide vancomycin (4), an important antibiotic
used as a last resort for the treatment of methicillin-resistant
Staphylococcus 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
The development of efficient synthetic tools in conjunction
with the emergency of high throughput screening of drug
candidates have provided opportunities for the library
production of biaryl ether containing macrocycles,
inaccessible just a few years back. Since the initial report
on the solid phase synthesis of OF-4949 analogs by SNAr-
based macrocyclization reaction,19 a number of aryl ether
containing macrocyclic compound libraries with a peptide
tether have been synthesized.20,21 While on-resin SNAr
macrocyclization worked nicely to provide the expected
macrocycles, the cyclization precursors in these studies
have been prepared by a stepwise peptide coupling strategy,
elongating thus the overall synthetic sequence.
Mainly intrigued by the molecular complexity as well as the
synthetic challenges posed by vancomycin, a number of
new synthetic methodologies have been developed during
the past decade that made the construction of the elusive
biaryl ether containing macrocycles possible. From the view
point of retro-synthetic analysis, two strategies are among
the most obvious for the synthesis of above-mentioned
macrocycles.6,7 The first one involves the formation of the
functionalized biaryl ether unit, followed by macrolactami-
zation that has been successfully applied to the total
synthesis of K-13 (1) and OF4949-III.8 The second strategy
consists of the construction of the suitably functionalized
peptide backbone followed by the ring closure with
concomitant formation of the biaryl ether bridge. To
implement this latter strategy, few methodologies including
In connection with our ongoing project aimed at the
development of step-efficient high throughput synthesis of
potentially bioactive molecules,22 we envisaged the syn-
thesis of the biaryl ether containing macrocycles of generic
structure (5) by combined use of Ugi-4CR23 and SNAr
methodology.24,25 The underlying principle is shown in the
Scheme 1. Thus, the Ugi reaction of an aldehyde (7), an
Keywords: multicomponent reaction; Ugi-4CR; intramolecular SNAr
reaction; cycloetherification; marcrocycles; diaryl ether.
*
Corresponding author. Tel.: þ33-1-69-82-31-31; fax: þ33-1-69-07-72-
47; e-mail: zhu@icsn.cnrs-gif.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.031

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P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
Figure 1. Natural products with endo aryl–aryl ether bond.
amine (8), a v-(30-hydroxyphenyl)alkanecarboxylic acid
(9), and a suitably functionalized isonitrile (10) should give
the dipeptide (6) which under our previously established
conditions, should cyclize to provide the desired m,p-
cyclophanes (5).26 We detail herein the successful
implementation of this strategy using both solution and
solid phase synthesis technologies. Tempest, Hulme and
their co-workers have independently developed the similar
approach for the synthesis of fused 7-membered hetero-
cycles.27
2. Results and discussion
2.1. Solution phase synthesis of biaryl ether containing
macrocycles (5)
At the outset of this work, we were unaware of the
compatibility of an ortho fluoronitro aromatic compound
and an amine under the Ugi’s reaction conditions. Indeed,
amines and low-molecular-weight alcohols, which are
usually the solvent of choice for Ugi-4CR are known to
be good nucleophiles for the intermolecular SNAr reac-
tion.28 In order to evaluate the feasibility of our approach,
the reaction of the known 4-fluoro-3-nitrobenzaldehyde
(7a),29 butylamine (8a), 3-(30-hydroxyphenyl) propionic
acid (9a) and the commercially available tert-butyl
isocyanide (11) in MeOH was carried out. As shown in
Scheme 2, Ugi reaction occurred smoothly at the expense of
SNAr process to provide exclusively the a-amino acylamide
(12) in 82% yield.
To proceed the projected reaction sequence, two
unknown isonitriles, namely, ethyl a-(40-fluoro-30-nitro)-
phenethyl isocyanoacetate (10a) and the 2-acetoxy
(40-fluoro-30-nitro)phenethyl isocyanide (10b) have to be
synthesized. This is shown in Scheme 3. Alkylation of
the commercially available diethyl formamidomalonate
with 4-fluoro-3-nitrobenzyl bromide (13, NaH, DMF)30
provided 14 in 92% yield. Selective hydrolysis of one of the
carboxylic ester functionalities followed by decarboxylation
in 1,4-dioxane31 afforded the corresponding racemic
Scheme 1.

P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
Table 1. Survey of conditions for Ugi-4CR
7861
Entries
Solvent
T (8C)
Additive
Yielda (%)
1
2
3
4
5
6
7
8
9
10
MeOH
MeOH
DMFe
rtb
60
rt
None
None
None
None
None
None
NH4Cl
NH4Cl
LiBr
34c
16d
0
71
76
50
60
33g
35
39
TFEe
rt
Benzene
Toluene
Toluene
Toluene
Toluene
THFe
Refluxf
60
60
rt
60
60
NH4Cl
2.2 equiv. each of amine, aldehyde, and acid relative to isonitrile was used.
a
Total yield of two diastereomers in a 1/1 ratio.
Room temperature.
83% conversion of 10a after 24 h.
Isonitrile was consumed rapidly, leading to a complex reaction mixture.
b
c
d
Scheme 2.
e
DMF¼N,N-dimethylformamide, TFE¼2,2,2-trifluoroethanol, HF¼
tetrahydrofurane.
With Dean–Stark.
63% conversion of 10a after 48 h.
f
g
using isonitrile (10a), heptanal (7b), butylamine (8a) and
3-hydroxyphenylacetic acid (9b) as inputs. Stirring a
methanol solution of 10a, 7b, 8a, and 9b did provide the
desired dipeptide amide (6a), but the yield was only
moderate (16–34%, entry 1 and 2, Table 1). Therefore,
the reaction conditions were re-examined varying the
solvent, temperature and additives (Table 1).
As is seen, the reaction did not occur in DMF (entry 3) but
proceeded smoothly in 2,2,2-trifluoroethanol (TFE) (entry
4) to provide the desired dipeptide (6a) in 71% yield. To our
surprise, non-polar solvents such as benzene or toluene gave
better results than methanol leading to the desired dipeptide
(6a) in 76 and 50% yield, respectively (entries 5 and 6).
Since aprotic solvents are generally considered to be
inappropriate for the Ugi reaction, a more detailed
investigation was carried out. In the perspective view of
library production, and because Dean–Stark apparatus are
not convenient for parallel synthesis, only toluene was
investigated further.34 While lithium bromide (LiBr) had an
adverse effect (entry 9), addition of ammonium chloride
(entry 7) is, on the other hand beneficial to the reaction. This
observed beneficial effect has also been demonstrated in our
laboratory where a three-component synthesis of oxazole in
toluene was significantly promoted by addition of
ammonium chloride.35 To the best of our knowledge, this
was the first example wherein the effect of ammonium
chloride in promoting the Ugi reaction in aprotic solvent
was demonstrated.36 Two points deserved further com-
ments. First, the a-acyloxy amide resulting from the
potentially competitive Passerini reaction37 was not isolated
although it is known that non-polar solvents favor the latter
reaction.38 Second, ammonium chloride, a potential donor
of NH3,39 did not participate in the Ugi reaction. Keeping in
mind the potential application of the Ugi-4CR/SNAr
sequence to the solid phase synthesis of macrocycles (5)
and the good swelling property of toluene, we decided to
exploit these new conditions for the synthesis of dipeptides
(6). From five amines, five aldehydes, two acids and three
isonitriles inputs (Fig. 2), some representative dipeptides
synthesized are listed in Figure 3. As expected, all the
dipeptides (6) were obtained as a mixture of two
Scheme 3.
N-formyl a-amino ester (15). Dehydration of the N-formyl
group was performed under Ugi’s conditions (POCl3,
Et3N)32 to provide the desired isonitrile (10a) in good
overall yield. The isonitrile (10b) was synthesized starting
from the racemic 2-amino-1-(40-fluoro-30-nitro)phenyl-
ethanol (16).33 Formylation of the amine function was
carried out under standard conditions (HCOOH, EDC) to
provide 17 in 90% yield. Acetylation of the hydroxyl group
followed by dehydration of the N-formyl function afforded
the desired isonitrile (10b) in good yield.
With these isonitriles in hands, the Ugi-4CR was examined

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P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
viously for natural product synthesis (DMF, 0.01 M,
K2CO3, room temperature). As shown in Figure 4, both
16- and 17-membered macrocycles (n¼1 or 2) were
produced in good yields regardless the substitution patterns.
Except for 5g, two atropisomers were generally formed
from a diastereomerically pure dipeptide due to the creation
of a planar chirality around the biaryl ether linkage.
Apparently, the presence of a tertiary amide function did
not have a significant influence on the atropstereoselectivity.
In most of the cases, the two atropisomers were readily
separable by preparative TLC on silica gel. The upfield shift
of the proton Ha in a 16-membered macrocycle is
characteristic of the cyclic structure and can be used for
NMR quantification.40
To further increase the structural and functional diversity of
the biaryl ether containing macrocycles (5), the selective
chemical transformation of the nitro group was exploited.
As shown in Scheme 4, hydrogenolysis of 5a under standard
conditions (Pd/C, H2, EtOH) provided the aniline (19) in
very good yield, which was then converted into the
corresponding urea (20) and N,N-dimethylsulfonamide
(21) by its reaction with benzyl isocyanate and methan-
sulfonyl chloride, respectively. Similarly, macrocycle (5b)
was transformed into the aniline (22), acetamide (23) and
de-aminated compound 24 in good yield under standard
conditions.
Figure 2. Inputs of Ugi-4CR.
diastereoisomers in a ratio of 1/1, separable by preparative
TLC on silica gel.
The ready availability of aldehydes, amines and acids
components allow the easy introduction of structural
diversity into the newly formed peptide backbone. For the
aldehyde part, aromatic and aliphatic aldehyde including
sterically hindered, and functionalized aldehyde were
suitable substrates. Both aliphatic amine and aniline
participated well in this process. Two different spacer
sizes between the tertiary amide function and the phenol
moiety have been introduced by using either the 3-(30-
hydroxyphenyl) propionic acid (9a) (n¼2) or the
3-hydroxyphenylacetic acid (9b) (n¼1).
The hydroxyl group in benzylic position represents an
important structural feature of many natural biaryl ether
containing macrocycles like the complex glycopeptide
vancomycin (4).4 As shown in Scheme 5 the m,p-
cyclophane (5e) prepared from isonitrile (10b), could be
easily transformed into 25 by mild hydrolysis (K2CO3,
MeOH/H2O) of the ester functionality.
2.2. Solid phase synthesis of biaryl ether containing
macrocycles (5)
Our next goal was to apply the Ugi-4CR/SNAr sequence to
the solid phase synthesis of macrocycle (5). Scheme 6
depicted the synthesis of the resin-bound isonitrile (28).
Hydrolysis of the N-formyl a-amino ester (15) under
Cycloetherification of the dipeptide amide (6) was next
examined. Compound 6 cyclized smoothly to afford the
m,p-cyclophane under the conditions we developed pre-
Figure 3. Structure of dipeptides obtained by Ugi-4CR.

P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
7863
Scheme 5.
Scheme 6.
standard conditions (K2CO3, EtOH, H2O) followed by
esterification with the commercially available Wang resin41
(loading 0.9 mmol/g) afforded 27. Dehydration of the
N-formyl function (POCl3, Et3N) provided the supported
isonitrile (28). This last reaction could be easily monitored
by Infrared spectra. Indeed, as the reaction progressed, the
intensity of the amide carbonyl absorption at 1685 cm21
decreased with concomitant appearance of isonitrile signal
at 2145 cm21. Microanalysis of this resin-bound isonitrile
(28) indicated a loading of 0.74 mmol/g (theoretical:
0.75 mmol/g).42 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 4. Structure of macrocycles obtained by a sequence of Ugi-4CR and
cycloetherification.
With the supported isonitrile (28) in hands, its reaction with
heptanal (7b), butylamine (8a), and 3-hydroxyphenylacetic
acid (9b) was examined (Scheme 7).43 The reaction was
followed by Infrared spectra until complete disappearance
of the sharp and strong signal at 2145 cm21 of the isonitrile
function. The efficiency of the on-resin Ugi-4CR was
evaluated by quantification of dipeptide ester (6i), in turn
obtained by resin cleavage (TFA, CH2Cl2) and esterification
reactions (diazomethane, ether).
As shown in Table 2, Ugi-4CR conducted in toluene in the
presence of NH4Cl (entry 1) was not investigated due to the
poor solubility of the acid component 9b in toluene and by
the presence of ammonium chloride that entail a multi-
phases reaction medium, unfavorable to the polymer-
supported reactions. Therefore, the solvent system was
investigated. Addition of methanol to toluene (entry 2)
dissolved all monomeric reagents and the Ugi reaction
proceeded to afford dipeptide (6i) in 12% yield (calculated
for five steps starting from the Wang resin). The yield of
dipeptide increased slightly using chloroform instead of
toluene as solvent (entries 3 and 4). To our delight, using
2,2,2-trifluoroethanol instead of methanol as co-solvent
Scheme 4.

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P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
carbonate proceeded smoothly to provide the desired
macrocycle (5i) as a mixture of four diastereoisomers 5i1,
5i2, 5i3 and 5i4 separable by chromatography on silica gel.
The overall yield of this six-step synthesis was 38% starting
from the Wang resin. The low solubility of potassium
carbonate in DMF prompted us to use a soluble organic
base. Gratefully, under otherwise identical conditions, the
cyclization promoted by DBU20 (DMF, room temperature,
3 days) furnished the macrocycle 5i in 48% overall yield. To
our surprise only two diastereoisomers 5i1 and 5i3 were
formed. Thermal equilibrium experiments conducted in
DMSO at 1608C indicated that 5i1 and 5i3 are two
atropisomers. Moreover, when the diastereoisomerically
pure 5i1 was resubmitted to the cyclization conditions, no
equilibrium to 5i3 was observed. On the other hand, the
diastereoisomer 5i2, obtained from potassium carbonate
promoted cyclization, was readily converted into 5i1 upon
treating with DBU in DMF at room temperature. These
control experiments indicated that the cyclization step
carried out with DBU is under kinetic control leading to two
atropisomers. However, the chiral centers of the peptide
backbone were epimerized to provide the thermodynami-
cally more stable compounds. While no detailed studies
have been carried out, the relative stereochemistry of 5i1
and 5i3 was tentatively assigned as is P*R*R* and
M*R*R*, respectively, according to NOE experiments
(Fig. 5).
Scheme 7.
Table 2. On-resin Ugi-4CR, survey of conditions
Entries
Solvent
Yielda(%)
1
2
3
4
5
6
Toluene/NH4Cl
NCb
12
15
17
38
26f
Toluene/MeOH (1/1)c
CHCl3/MeOH (1/1)c
CHCl3/MeOH (3/1)
CHCl3/TFEd (3/1)e
CHCl3/TFE (5/1)
Figure 5. Stereochemistry of two atropisomers.
Figure 6 listed the macrocycles synthesized on polymer
support using DBU as base. As is seen, the sequence is
generally applicable to various types of amines and
aldehydes. In most of the cases, macrocycles were isolated
as a mixture of two atropisomers in good overall yields.45
For macrocycle 5m, a diketopiperazine derivative 31 was
isolated in 4% yield. Although an intramolecular transami-
dation can account for the formation of 31, no experiments
have been designed to probe whether the diketopiperazine
unit was produced before or after the macrocyclization.
a
Isolated yield, calculated from the Wang resin.
b
Not calculated due to very poor solubility of the acid component and
ammonium chloride: these conditions are not suitable to solid phase.
The reaction was completed after two runs of 48 h.
TFE¼2,2,2-trifluoroethanol.
c
d
e
f
The reaction was completed after one run of 72 h.
Not optimized.
accelerated the reaction rate to afford 6i in a very good
overall yield (38%, entry 5).44 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).
3. Conclusion
The novel Ugi-4CR/SNAr cycloetherification sequence
reported in this article allowed the rapid access to a wide
range of functionalized biaryl ether containing macrocycles
starting from readily available inputs. Moreover, the
presence of nitro group in the macrocycles allowed the
introduction of further structural diversities. Thus, our
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. As shown in
Scheme 7, the cycloetherification of polymer-supported
dipeptide (29) in DMF in the presence of potassium

P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
7865
4.1.1. Compound 10a. 1.6 g, 91% as a yellow solid: IR
(CHCl3) 2995, 2153, 1746, 1624, 1540, 1353, 998 cm21; 1H
NMR (250 MHz, CDCl3) 7.96 (dd, 1H, J¼6.9, 2.2 Hz), 7.57
(ddd, 1H, J¼8.4, 4.1, 2.2 Hz), 7.30 (dd, 1H, J¼10.4,
8.5 Hz), 4.51 (dd, 1H, J¼6.1, 5.7 Hz), 4.29 (q, 2H,
J¼7.1 Hz), 3.28 (dd, 1H, J¼14.1, 5.7 Hz), 3.26 (dd, 1H,
J¼14.1, 6.1 Hz), 1.31 (t, 3H, J¼7.1 Hz); 13C NMR
(62.5 MHz, CDCl3) 165.2, 161.8, 155.0 (d, J¼264 Hz),
137.1 (d, J¼6 Hz), 136.7 (d, J¼9 Hz), 131.5 (d, J¼3 Hz),
126.7, 118.8 (d, J¼21 Hz), 63.2, 57.2, 37.1, 13.8; MS (IE):
m/z 267 (MþH)þ.
4.1.2. Acetic acid 1-(4-fluoro-3-nitro-phenyl)-2-isocyano
ethyl ester 10b. IR (CHCl3) 3029, 3013, 2155, 1753, 1624,
1
1544, 1351, 1226 cm21; H NMR (250 MHz, CDCl3) 8.11
(dd, 1H, J¼6.8, 2.4 Hz), 7.71 (ddd, 1H, J¼9.0, 4.1, 2.4 Hz),
7.37 (dd, 1H, J¼10.3, 8.5 Hz), 5.97 (t, 1H, J¼5.4 Hz), 3.82
(d, 2H, J¼5.4 Hz), 2.21 (s, 3H); 13C NMR (75 MHz,
CDCl3) 169.3, 160.4, 155.7 (d, J¼264 Hz), 137.6, 133.8 (d,
J¼9 Hz), 133.1, 124.3, 119.2 (d, J¼22 Hz), 70.5, 46.1, 20.8;
MS (ESþ): m/z 275 (MþNa)þ, 291 (MþK)þ.
4.1.3. 3-(4-Fluoro-3-nitro-phenyl)-2-isocyano-propionic
acid methyl ester 10c. IR (CHCl3) 3072, 3021, 2958,
2888, 2151, 1752, 1624, 1593, 1537, 1503, 1439, 1355,
1255, 1220, 1137, 1090, 1051, 1024 cm21 1H NMR
;
Figure 6. Macrocycles synthesized by a sequence of on-resin Ugi-4CR and
cycloetherification.
(250 MHz, CDCl3) 7.96 (dd, 1H, J¼6.9, 2.4 Hz), 7.57
(ddd, 1H, J¼8.5, 4.1, 2.4 Hz), 7.29 (dd, 1H, J¼10.5,
8.5 Hz), 4.57 (dd, 1H, J¼7.6, 4.9 Hz), 3.82 (s, 3H), 3.30 (dd,
1H, J¼14.2, 4.9 Hz), 3.19 (dd, 1H, J¼14.2, 7.6 Hz); 13C
NMR (62.5 MHz, CDCl3) 165.7, 161.8, 154.9 (d,
J¼263 Hz), 137.1, 136.7 (d, J¼8 Hz), 131.4 (d, J¼3 Hz),
126.7, 118.9 (d, J¼21 Hz), 57.1, 53.6, 37.1; MS (IE): m/z
253 (MþH)þ.
synthesis allowed the introduction of at least four-point of
diversity and generated significant molecular complexity in
an operationally simple two-step sequence.
The development of chemistry amenable to the introduction
of multiple diversities while still creating molecules of
drug-like properties in minimum steps remained a
challenging task to synthetic chemists. The combination
of multicomponent reaction with other highly efficient
transformation, especially cyclization methodologies, has
been demonstrated to be one of the highly promising
approaches to the problem.46 Indeed, such a step-economic
approach introduced naturally the molecular diversity,
complexity and drug likeness of the compounds (hetero-
cycles, macrocycles). Further application of MCR/SNAr
cycloetherification sequence to the synthesis of other natural
product-like compound libraries is in progress and will be
reported in due course.47
4.2. General procedure of Ugi-4CR
To a solution of heptanal (58 mL, 0.416 mmol) in dry
toluene (1 mL), butylamine (41 mL, 0.416 mmol) was
added. The resulting mixture was stirred at room tempera-
ture for 1 h then 3-hydroxyphenyl acetic acid (63.3 mg,
0.416 mmol) followed by isonitrile 10a (50.3 mg,
0.189 mmol) and NH4Cl (22.2 mg, 0.416 mmol) were
added. The reaction mixture was stirred at 608C for 20 h.
The reaction mixture was cooled to room temperature then
water was added and the aqueous layer was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude residue was
purified by flash chromatography (SiO2, Heptane/
EtOAc¼60/40) to afford 6a (67 mg, 60%) as a mixture of
two diastereoisomers.
4. Experimental
4.1. General procedure of dehydration
4.2.1. Compound 6a. Mixture of two diastereoisomers (50/
50): IR (CHCl3) 3027, 2954, 1732, 1687, 1621, 1542, 1497,
1456, 1353, 1332, 1140 cm21; 1H NMR (250 MHz, CDCl3)
7.87 (dd, 0.5H, J¼7.0, 2.3 Hz), 7.79 (dd, 0.5H, J¼7.0,
2.3 Hz), 7.72 (s broad, 0.5H), 7.44 (ddd, 0.5H, J¼8.6, 4.2,
2.3 Hz), 7.39 (ddd, 0.5H, J¼8.6, 4.2, 2.3 Hz), 7.28 (d, 1H,
J¼8 Hz), 7.07–7.26 (m, 2H), 6.90 (s broad, 0.5H), 6.83 (s
broad, 0.5H), 6.68–6.75 (m, 2H), 6.51 (s broad, 0.5H),
4.73–4.88 (m, 2H), 4.16–4.26 (m, 2H), 3.62–3.79 (m, 2H),
2.93–3.26 (m, 4H), 1.00–1.99 (m, 17H), 0.73–1.00 (m,
6H); MS (IE): m/z 587 (M)þ.
To a solution of 15 (1.88 g, 6.62 mmol) and Et3N (4.59 mL,
33.2 mmol) in dry CH2Cl2 (90 mL) was added dropwise at
2258C POCl3 (0.94 mL, 9.96 mmol). The reaction mixture
was stirred for 5 h at 2258C. A saturated solution of
Na2CO3 was added and the aqueous layer was extracted
with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and evaporated to dryness. The crude
residue was purified by flash chromatography (SiO2,
Heptane/EtOAc¼70/30) to afford 3-(4-fluoro-3-nitro-
phenyl)-2-isocyano-propionic acid ethyl ester (10a).

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P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
4.3. General procedure of SNAr cycloetherification
115.8, 113.0, 62.0, 56.6, 52.1, 45.2, 40.1, 36.7, 33.2, 31.5,
31.1, 29.1, 26.2, 22.5, 20.3, 14.2, 14.0, 13.6; MS (IE): m/z
567 (M)þ, 568 (MþH)þ.
To a solution of dipeptide 6a (327 mg, 0.557 mmol) in dry
DMF (56 mL) was added K2CO3 (384 mg, 2.78 mmol). The
reaction mixture was stirred at room temperature for 3 h. A
saturated solution of NH4Cl was added and the aqueous
layer was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude residue was purified by flash chromato-
graphy (SiO2, Heptane/AcOEt¼70/30) to afford 9,12-
dioxo-2-oxa-10-butyl-11-hexyl-14-ethoxycarbonyl-18-
nitro-10,13-diazatricycle[14.2.2.13,7]-heneicosa-3,5,
7(21),16,18,19-hexaene (5a) (250 mg, 79%) as a brown oil.
The four diastereoisomers were separated by preparative
TLC (SiO2, Toluene/EtOH¼95/5).
4.3.4. Diastereoisomer 5a4. IR (CHCl3) 3027, 2931, 1739,
1662, 1624, 1591, 1534, 1444, 1349, 1241 cm21; 1H NMR
(250 MHz, CDCl3) 7.90 (d, 1H, J¼2.0 Hz), 7.18–7.30 (m,
4H), 7.14 (dd, 1H, J¼8.2, 2.3 Hz), 6.76 (d, 1H, J¼7.3 Hz),
5.50 (s, 1H), 4.65 (m, 1H), 4.31 (mþq, 3H, J¼7.2 Hz), 3.61
(s, 2H), 3.51 (dd, 1H, J¼14.6, 4.9 Hz), 3.38 (dd, 1H,
J¼14.6, 5.3 Hz), 2.98 (m, 2H), 1.75–2.00 (m, 2H), 1.07–
1.40 (mþt, 15H, J¼7.2 Hz), 0.77–0.89 (m, 6H); 13C NMR
(62.5 MHz, CDCl3) 172.1, 171.8, 170.9, 160.4, 149.7,
143.1, 136.3, 134.9 (2C), 129.9, 127.3, 126.7, 122.6, 116.2,
114.2, 62.0, 54.2, 49.7, 41.3, 35.8 (2C), 31.6, 31.0, 29.7,
29.0, 26.5, 22.5, 19.9, 14.3, 14.0, 13.5; MS (IE): m/z 567
(M)þ, 568 (MþH)þ.
4.3.1. Diastereoisomer 5a1. IR (CHCl3) 3424, 3020, 2959,
2931, 1738, 1679, 1624, 1591, 1536, 1490, 1445, 1351,
1226 cm21
;
1H NMR (300 MHz, CDCl3) 7.91 (d, 1H,
4.4. Procedures for post-transformations
J¼1.7 Hz), 7.18–7.25 (m, 2H), 7.04 (dd, 1H, J¼8.1,
2.6 Hz), 6.98 (d, 1H, J¼8.5 Hz), 6.79 (d, 1H, J¼7.7 Hz),
6.49 (d, 1H, J¼8.1 Hz), 5.69 (s, 1H), 4.97 (t, 1H, J¼7.7 Hz),
4.79 (m, 1H), 4.20 (q, 2H, J¼7.3 Hz), 3.81 (d, 1H,
J¼15.8 Hz), 3.46 (dd, 1H, J¼13.2, 12.8 Hz), 3.41 (mþd,
2H, J¼15.8 Hz), 3.06 (dt, 1H, J¼15.8, 7.7 Hz), 2.64 (t, 1H,
J¼13.2 Hz), 1.70 (m, 1H), 1.48 (m, 1H), 1.03–1.30 (mþt,
15H, J¼7.3 Hz), 0.72–0.82 (m, 6H); 13C NMR (62.5 MHz,
CDCl3) 172.0, 171.1, 171.0, 160.0, 148.3, 143.2, 137.4,
136.1, 134.4, 129.9, 125.8, 125.6, 123.2, 115.9, 113.5, 61.9,
55.7, 52.8, 45.2, 39.4, 37.2, 33.4, 31.6, 31.2, 29.1, 26.1,
22.5, 20.2, 14.2, 14.0, 13.5; MS (IE): m/z 567 (M)þ, 568
(MþH)þ.
4.4.1. 9,12-Dioxo-2-oxa-10-butyl-11-hexyl-14-ethoxycar-
bonyl-18-amino-10,13-diazatricycle[14.2.2.13,7]-henei-
cosa-3,5,7(21),16,18,19-hexaene (19a). To a solution of
5a2 (22.1 mg, 0.039 mmol) in EtOH (0.8 mL) was added a
catalytic amount of Pd/C (10%). The reaction mixture was
purged several times with argon then stirred under H2
atmosphere for 20 min. The mixture was filtered on celite
and the solvent removed under vacuum to afford aniline 19a
(20.7 mg, Yield: 99%) as a brown oil: 1H NMR (300 MHz,
CDCl3) 7.22 (d, 1H, J¼7.6 Hz), 7.07 (dd, 1H, J¼8.1,
2.4 Hz), 6.85 (d, 1H, J¼8.1 Hz), 6.78 (d, 1H, J¼7.6 Hz),
6.57 (dd, 1H, J¼8.1, 2.4 Hz), 6.40 (d, 1H, J¼2.4 Hz), 5.61
(s, 1H), 4.64–4.75 (m, 2H), 4.26 (m, 2H), 3.82 (d, 1H,
J¼16.2 Hz), 3.77 (s, 2H), 3.42 (d, 1H, J¼16.2 Hz), 3.34 (dd,
1H, J¼14.3, 3 Hz), 3.01–3.18 (m, 3H), 1.93 (m, 1H), 1.65
(m, 1H), 1.11–1.50 (mþt, 15H, J¼7.1 Hz), 0.84 (m, 6H).
4.3.2. Diastereoisomer 5a2. IR (CHCl3) 3300, 3019, 2960,
2932, 1738, 1662, 1623, 1535, 1501, 1465, 1444, 1351,
1298, 1238 cm21; 1H NMR (250 MHz, CDCl3) 7.66 (d, 1H,
J¼2.6 Hz), 7.44 (dd, 1H, J¼8.5, 2.6 Hz), 7.30 (dd, 1H,
J¼8.5, 7.2 Hz), 7.18 (dd, 1H, J¼8.5, 2.4 Hz), 7.13 (d, 1H,
J¼8.5 Hz), 6.81 (d, 1H, J¼7.2 Hz), 5.47 (s, 1H), 4.73 (m,
1H), 4.56 (m, 1H), 4.33 (m, 2H), 3.77 (d, 1H, J¼16.6 Hz),
3.48 (dd, 1H, J¼14.1, 4.3 Hz), 3.47 (d, 1H, J¼16.6 Hz),
3.28 (dd, 1H, J¼14.1, 5.5 Hz), 3.06 (m, 2H), 1.95 (m, 1H),
1.64 (m, 1H), 1.38 (t, 3H, J¼7.3 Hz), 1.26 (m, 12H), 0.84
(m, 6H); 13C NMR (62.5 MHz, CDCl3) 172.4, 171.9, 170.5,
160.9, 150.6, 143.9, 136.7, 136.1, 133.9, 129.8, 127.2,
125.1, 123.2, 116.5, 116.2, 62.1, 53.6, 47.1, 40.4, 35.8 (2C),
31.9, 31.5, 29.0, 28.7, 26.3, 22.5, 20.1, 14.2, 14.0, 13.5; MS
(IE): m/z 568 (MþH)þ.
4.4.2. Compound 19b (prepared from 5a3 in 99% yield).
1H NMR (300 MHz, CDCl3) 7.25 (m, 1H), 7.04 (m, 1H),
6.86 (d, 1H, J¼8.5 Hz), 6.78 (d, 1H, J¼7.3 Hz), 6.66 (d, 1H,
J¼7.9 Hz), 6.63 (s, 1H), 6.09 (d, 1H, J¼7.3 Hz), 5.81 (s,
1H), 5.02 (t, 1H J¼7.3 Hz), 4.63 (m, 1H), 4.24 (q, 2H,
J¼7.3 Hz), 3.84 (d, 1H, J¼15.9 Hz), 3.78 (s, 2H), 3.50 (d,
1H J¼15.9 Hz), 3.31–3.44 (m, 2H), 3.11 (m, 1H), 2.56 (t,
1H, J¼13.4 Hz), 1.82 (m, 1H), 1.49 (m, 1H), 1.05–1.35
(mþt, 15H, J¼7.3 Hz), 0.77–0.88 (m, 6H).
4.4.3. 9,12-Dioxo-2-oxa-10-(40-methoxyphenyl)-11-
phenyl-14-ethoxycarbonyl-18-amino-10,13-diazatri-
cycle[14.2.2.13,7]-heneicosa-3,5,7(21),16,18,19-hexaene
(22) (prepared from 5b3 in 91% yield). IR (CHCl3) 3041,
1737, 1693, 1645, 1603, 1511, 1443, 1372, 1337, 1297,
4.3.3. Diastereoisomer 5a3. IR (CHCl3) 3418, 3011, 2931,
1734, 1683, 1623, 1537, 1490, 1458, 1445, 1352,
1281 cm21
;
1H NMR (250 MHz, CDCl3) 7.84 (d,
1
1H, J¼2.2 Hz), 7.60 (dd, 1H, J¼8.3, 2.2 Hz), 7.27 (dd,
1H, J¼8.0, 7.3 Hz), 7.14 (d, 1H, J¼8.3 Hz), 7.11 (dd, 1H,
J¼8.0, 2.4 Hz), 6.80 (d, 1H, J¼7.3 Hz), 6.60 (d, 1H,
J¼9.0 Hz), 5.66 (s, 1H), 4.96 (m, 1H), 4.84 (t,
1H, J¼7.3 Hz), 4.26 (q, 2H, J¼7.1 Hz), 3.74 (d, 1H,
J¼15.8 Hz), 3.59 (dd, 1H, J¼13.9, 5.1 Hz), 3.55 (d, 1H,
J¼15.8 Hz), 3.46 (m, 1H), 3.00 (m, 1H), 2.86 (dd,
1H, J¼13.9, 14.3 Hz), 1.78 (m, 1H), 1.60 (m, 1H), 1.08–
1.36 (mþt, 15H, J¼7.1 Hz), 0.77–0.89 (m, 6H); 13C NMR
(62.5 MHz, CDCl3) 171.6, 171.1, 170.7, 160.1, 148.7,
142.8, 136.9, 134.9, 134.6, 129.9, 127.1, 126.4, 122.8,
1265 cm21; H NMR (250 MHz, CDCl3) 6.89–7.23 (m,
9H), 6.56–6.62 (mþs, 4H), 6.53 (d, 1H, J¼7.4 Hz), 6.42 (s
broad, 1H), 6.27 (s, 1H), 6.06 (mþd, 2H, J¼8.8 Hz), 5.00
(m, 1H), 4.14 (m, 2H), 3.68 (s, 3H), 3.43 (m, 1H), 3.41 (d,
1H, J¼15.8 Hz), 3.26 (d, 1H, J¼15.8 Hz), 2.59 (dd, 1H,
J¼13.4, 12.5 Hz), 1.20 (t, 3H, J¼7.2 Hz); 13C NMR
(62.5 MHz, CDCl3) 171.8, 171.3, 168.8, 159.7, 159.0,
141.6, 139.8, 137.8, 134.8, 133.9, 131.5, 129.9 (4C), 129.2,
128.41, 128.35 (3C), 123.1, 122.1, 121.1, 116.9, 114.8,
113.9, 113.3, 61.6, 60.4, 55.2, 53.2, 40.3 39.0, 14.1; MS
(ESþ): m/z 580 (MþH)þ, 602 (MþNa)þ, 618 (MþK)þ.

P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
7867
4.4.4. Compound 20. To a solution of 19a (19 mg,
0.035 mmol) in dry CH2Cl2 (0.8 mL) was added at 08C
benzyl isocyanate (5 mL, 0.040 mmol). The reaction
mixture was stirred at room temperature for 1 h. Water
was added at 08C and the aqueous layer was extracted with
CH2Cl2. The organic layer was washed with brine, dried
over MgSO4, and evaporated to dryness. The resulting crude
solid was purified by preparative TLC (SiO2, Toluene/
EtOH¼90/10) to afford 20 (17.2 mg, 73%) as a brown oil:
IR (CHCl3) 3621, 3416, 3006, 2976, 2933, 1735, 1684,
1629, 1601, 1532, 1506, 1446, 1391, 1347, 1242 cm21; 1H
NMR (300 MHz, CDCl3) 7.64 (d, 1H, J¼1.9 Hz), 7.15–
7.26 (m, 7H), 7.04 (dd, 1H, J¼7.6, 1.9 Hz), 6.93 (d, 1H,
J¼8.1 Hz), 6.88 (dd, 1H, J¼8.1, 1.9 Hz), 6.76 (d, 1H,
J¼7.6 Hz), 6.65 (s, 1H), 5.47 (s broad, 2H), 4.70 (m, 1H),
4.40 (dd, 1H, J¼15.3, 6.2 Hz), 4.22–4.39 (m, 4H), 3.63 (d,
1H, J¼16.7 Hz), 3.33 (m, 2H), 2.93–3.11 (m, 3H), 1.91 (m,
1H), 1.63 (m, 1H), 1.07–1.41 (mþt, 15H, J¼7.2 Hz), 0.80–
0.88 (m, 6H); 13C NMR (62.5 MHz, CDCl3) 172.19, 171.50
(2C), 160.4, 154.9, 145.9, 139.0, 137.1, 133.5, 133.2, 129.5,
128.5 (2C), 127.3 (2C), 127.1, 125.4, 124.0, 122.9, 121.3,
115.8, 115.5, 61.8, 54.6, 52.9, 47.3, 44.2, 39.5, 36.4, 32.2,
31.6, 29.0, 28.9, 26.2, 22.6, 20.1, 14.2, 14.0, 13.6; MS
(ESþ): m/z 693 (MþNa)þ, (ES2): m/z 670 (M)2, 669
(M2H)2.
1H NMR (300 MHz, CDCl3) 8.57 (s, 1H), 7.72 (s broad,
1H), 7.50 (s broad, 1H), 7.07–7.23 (m, 5H), 6.86–6.98 (m,
4H), 6.68 (mþd, 2H, J¼7.6 Hz), 6.60 (s, 1H), 6.43 (mþs,
2H), 6.10 (m, 1H), 5.96 (d, 1H, J¼7.6 Hz), 4.83 (m, 1H),
4.14 (m, 2H), 3.67 (s, 3H), 3.49 (d, 1H, J¼15.7 Hz), 3.46
(dd, 1H, J¼12.9, 3.3 Hz), 3.18 (d, 1H, J¼15.7 Hz), 2.51 (dd,
1H, J¼12.9, 12.4 Hz), 2.23 (s, 3H), 1.22 (t, 3H, J¼7.2 Hz);
MS (ESþ): m/z 622 (MþH)þ, 644 (MþNa)þ.
4.4.7. 9,12-Dioxo-2-oxa-10-(40-methoxyphenyl)-11-
phenyl-14-ethoxycarbonyl-10,13-diazatricycle-
[14.2.2.13,7]-heneicosa-3,5,7(21),16,18,19-hexaene (24).
To a solution of 22 (24 mg, 0.041 mmol) in a 1:1 mixture
of THF/H2O (0.8 mL) was added at 08C a solution of
aqueous H3PO2 (50%) (16 mL, 0.154 mmol), followed by a
catalytic amount of Cu2O and NaNO2 (3.7 mg, 0.054 mmol)
dissolved in water (0.2 mL). The reaction mixture was
stirred at room temperature for 2 h. A saturated solution of
Na2CO3 was added and the aqueous layer was extracted
with AcOEt. The organic layer was washed with brine, dried
over MgSO4, and evaporated to dryness. The crude residue
was purified by preparative TLC (SiO2, Heptane/
EtOAc¼50/50) to afford 24 (20 mg, 86%) as a brown oil:
IR (KBr) 3032, 2930, 1686, 1653, 1588, 1536, 1508, 1489,
1442, 1372, 1352, 1291 cm21; 1H NMR (300 MHz, CDCl3)
7.54 (dd, 1H, J¼8.4, 2.2 Hz), 7.38 (m, 1H), 7.11–7.24 (m,
6H), 6.98 (m, 4H), 6.50–6.63 (mþs, 3H), 6.37 (m, 1H), 6.26
(s, 1H), 6.04 (mþd, 2H, J¼8.6 Hz), 4.95 (m, 1H), 4.13 (m,
2H), 3.66 (s, 3H), 3.42 (mþd, 2H, J¼15.9 Hz), 3.20 (d, 1H,
J¼15.9 Hz), 2.56 (dd, 1H, J¼13.2, 12.6 Hz), 1.19 (t, 3H,
J¼7.1 Hz); 13C NMR (62.5 MHz, (CD3)2CO) 171.9, 169.7,
169.7, 161.7, 159.9, 155.9, 139.5, 137.2, 135.1, 133.5,
133.3, 133.1, 132.1, 131.6, 130.7 (2C), 129.9, 128.9 (2C),
128.7, 123.1, 122.8, 122.7, 116.3, 115.5, 114.0, 113.7, 61.6,
60.9, 55.6, 53.9, 40.7, 38.5, 14.4; MS (ESþ): m/z 565
(MþH)þ, 587 (MþNa)þ, 603 (MþK)þ.
4.4.5. Compound 21. To a solution of 19b (26 mg,
0.048 mmol) in dry CH2Cl2 (0.8 mL) was added at 08C
Et3N (50 mL, 0.361 mmol) followed by methanesulfonyl
chloride (15 mL, 0.193 mmol). The reaction mixture was
stirred at room temperature for 20 h then a saturated solution
of Na2CO3 was added and the aqueous layer was extracted
with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4, and evaporated to dryness. The crude
residue was purified by preparative TLC (SiO2, Heptane/
EtOAc¼60/40) to afford 21 (16.3 mg, 49%) as a brown oil:
IR (CHCl3) 3621, 3461, 3010, 2976, 1734, 1676, 1630,
1603, 1504, 1488, 1447, 1391, 1373, 1250 cm21; 1H NMR
(250 MHz, CDCl3) 7.26–7.36 (m, 2H), 7.18 (m, 2H), 7.06
(d, 1H, J¼8.5 Hz), 6.84 (d, 1H, J¼7.5 Hz), 6.19 (d, 1H,
J¼7.2 Hz), 5.91 (s, 1H), 4.78–4.88 (m, 2H), 4.28 (m, 2H),
3.79 (d, 1H, J¼15.9 Hz), 3.58 (dd, 1H, J¼14, 6.1 Hz), 3.50
(d, 1H, J¼15.9 Hz), 3.41 (s, 3H), 3.06–3.38 (m, 2H), 3.01
(s, 3H), 2.96 (dd, 1H, J¼14, 10.4 Hz), 1.77–1.86 (m, 1H),
1.40–1.58 (m, 1H), 1.12–1.37 (mþt, 15H, J¼7.3 Hz), 0.86
(m, 6H); 13C NMR (75 MHz, CDCl3) 171.2, 170.8, 170.3,
160.4, 153.9, 137.7, 133.8, 133.3, 131.8, 130.1, 127.2,
125.3, 123.3, 116.0, 114.7, 61.9, 56.2, 52.2, 44.7, 43.6, 42.5,
39.8, 35.4, 33.2, 31.5, 31.0, 29.0, 25.8, 22.5, 20.2, 14.2,
14.0, 13.7; MS (ESþ): m/z 716 (MþNa)þ, 732 (MþK)þ.
4.4.6. 9,12-Dioxo-2-oxa-10-(40-methoxyphenyl)-11-
phenyl-14-ethoxycarbonyl-18-acetamido-10,13-diazatri-
cycle[14.2.2.13,7]-heneicosa-3,5,7(21),16,18,19-hexaene
(23). To a solution of 22 (11 mg, 0.019 mmol) in dry
CH2Cl2 (0.6 mL) was added Et3N (6 mL, 0.043 mmol)
followed by acetic anhydride (4 mL, 0.042 mmol). The
reaction mixture was stirred at room temperature for 17 h.
Water was added and the aqueous layer was extracted with
CH2Cl2. The organic layer was washed with brine, dried
over MgSO4, and evaporated to dryness. The resulting crude
solid was purified by preparative TLC (SiO2, Heptane/
EtOAc¼50/50) to afford 23 (9.6 mg, 81%) as a brown oil:
4.4.8. 9,12-Dioxo-2-oxa-10-butyl-11-hexyl-14-ethoxycar-
bonyl-15-hydroxyl-18-nitro-10,13-diazatricycle-
[14.2.2.13,7]-heneicosa-3,5,7(21),16,18,19-hexaene (25).
To a solution of 5e (23.6 mg, 0.0426 mmol) in a mixture
of methanol and water (0.5 mL, methanol/water: 8/2),
K2CO3 (11.7 mg, 0.0852 mmol) was added. The reaction
mixture was stirred at room temperature for 1 h. The
reaction mixture was acidified with a solution of HCl 10%
then extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and evaporated to dryness.
The resulting crude solid was purified by preparative TLC
(SiO2, Heptane/EtOAc¼50/50) to afford 25 (21 mg, 96%)
as a colorless oil: IR (CHCl3) 3284, 2961, 2930, 2859, 1649,
1617, 1591, 1535, 1489, 1458, 1444, 1360, 1232,
1084 cm21 1H NMR (250 MHz, CD3OD) 8.28 (d, 1H,
;
J¼1.9 Hz), 7.99 (broad d, 1H, J¼8.3 Hz), 7.60 (dd, 1H,
J¼8.5, 1.9 Hz), 7.31 (t, 1H, J¼7.8 Hz), 7.14 (d, 1H,
J¼8.5 Hz), 7.07 (dd, 1H, J¼7.8, 1.9 Hz), 6.88 (d, 1H,
J¼7.8 Hz), 5.73 (s, 1H), 5.18 (broad s, 1H), 4.88 (m, 1H),
4.12–4.23 (m, 1H), 3.88 (d, 1H, J¼16.4 Hz), 3.43–3.56
(mþd, 2H, J¼16.4 Hz), 3.20 (dd, 1H, J¼14.4, 2.7 Hz), 3.05
(ddd, 1H, J¼15.6, 10.5, 5.1 Hz), 1.56–1.77 (m, 2H), 1.11–
1.42 (m, 12H), 0.88 (t, 3H, J¼7.3 Hz), 0.84 (t, 1H,
J¼7.3 Hz); 13C NMR (75 MHz, CD3OD) 173.8, 173.2,
161.4, 149.0, 144.0, 142.1, 138.6, 134.3, 131.0, 126.4,
124.4, 123.9, 116.5, 113.5, 70.8, 57.5, 47.1, 46.8, 40.7, 34.2,

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P. Cristau et al. / Tetrahedron 59 (2003) 7859–7870
32.8, 32.3, 30.1, 27.3, 23.6, 21.3, 14.4, 13.9; MS (ESþ): m/z
512 (MþH)þ, 534 (MþNa)þ, 550 (MþK)þ, 573
(MþNaþK)þ.
3.13 (m, 1H), 2.76 (dd, 1H, J¼13.2, 12.9 Hz), 1.76–1.83
(m, 1H), 1.36–1.65 (m, 1H), 1.12–1.38 (m, 12H), 0.81–
0.91 (m, 6H); 13C NMR (75 MHz, CDCl3) 172.0, 171.4,
171.2, 159.9, 148.4, 143.3, 137.4, 135.9, 134.3, 129.9,
126.0, 125.7, 123.2, 115.9, 113.6, 55.9, 52.8 (2C), 45.3,
39.4, 37.3, 33.4, 31.6, 31.1, 29.1, 26.2, 22.5, 20.3, 14.0,
13.5; MS (ESþ): m/z 554 (MþH)þ, 576 (MþNa)þ, 1129
(2MþNa)þ.
4.4.9. Procedure for the preparation of the resin-bound
isonitrile (28). To a suspension of Wang resin (100 mg,
loading: 0.9 mmol / g) in dry THF (2.5 mL), DCC (92.8 mg,
0.45 mmol), followed by DMAP (2.2 mg, 0.018 mmol) and
26 (115.2 mg, 0.45 mmol) were added. The resulting
suspension was stirred for 2 days at room temperature.
After filtration, the resulting yellow resin 27 was washed
four times with THF, then DMF/water (2/1) (to remove
excess DCC and DCU), methanol and ether: IR (KBr) 3386,
3060, 3026, 2924, 1736, 1686, 1611, 1541, 1509, 1492,
1451, 1382, 1349, 1248, 1171, 1114, 1028, 819, 756,
4.5.2. Diastereoisomer 5i3. IR (CHCl3) 3021, 3015, 1744,
1677, 1624, 1535, 1444, 1350, 1218 cm21 1H NMR
;
(300 MHz, CDCl3) 7.84 (d, 1H, J¼1.8 Hz), 7.61 (dd, 1H,
J¼8.1, 1.8 Hz), 7.29 (m, 1H), 7.14 (mþd, 2H, J¼8.5 Hz),
6.82 (d, 1H, J¼7.7 Hz), 6.51 (d, 1H, J¼7.7 Hz), 5.67 (s,
1H), 4.98 (ddd, 1H, J¼12.9, 8.8, 5.5 Hz), 4.82 (t, 1H,
J¼7.4 Hz), 3.84 (s, 3H), 3.75 (d, 1H, J¼16.2 Hz), 3.54–
3.63 (mþd, 2H, J¼16.2 Hz), 3.37–3.51 (m, 1H), 2.96–3.03
(m, 1H), 2.90 (dd, 1H, J¼14.0, 12.5 Hz), 1.79–1.88 (m,
1H), 1.52–1.70 (m, 1H), 1.07–1.45 (m, 12H), 0.82–0.90
(m, 6H); 13C NMR (75 MHz, CDCl3) 171.6, 171.2, 171.1,
160.1, 148.7, 142.8, 136.9, 134.9, 134.6, 129.9, 127.1,
126.4, 122.8, 115.8, 113.0, 56.7, 52.7, 52.1, 45.3, 40.1, 36.6,
33.2, 31.6, 31.2, 29.1, 26.2, 22.5, 20.2, 14.0, 13.6; MS
(ESþ): m/z 554 (MþH)þ, 576 (MþNa)þ, 1129 (2MþNa)þ.
697 cm21
.
To a suspension of resin 27 (106.1 mg) in dry CH2Cl2
(3 mL), Et3N (0.163 mL, 1.179 mmol) was added. Then
POCl3 (37 mL, 0.397 mmol) was added dropwise at 08C.
The resulting suspension was stirred for 5 h 30 min at 08C.
The yellow resin 28 was filtered and washed four times with
CH2Cl2, then methanol and ether. Microanalysis of this
resin-bound isonitrile indicated a loading of 0.74 mmol/g
based on the percentage of nitrogen (theoretical: 0.75 mmol/
g): IR (KBr) 3483, 3060, 3026, 2923, 2145, 1752, 1611,
1541, 1511, 1492, 1451, 1350, 1172, 1113, 818, 757,
Acknowledgements
698 cm21
.
We thank CNRS and Bayer CropScience for financial
support. A doctoral fellowship to P. Cristau from Bayer
CropScience is gratefully acknowledged.
4.5. General procedure for the solid supported Ugi-
4CR/SNAr sequence
To a suspension of resin 28 (100 mg, 0.074 mmol) in a
mixture of chloroform and 2,2,2-trifluoroethanol (3/1,
1 mL), 3-hydroxyphenyl acetic acid (225.1 mg,
1.48 mmol) was added. A solution of preformed imine
(1 mL of a solution 1.48 M of heptanaldehyde and
butylamine in chloroform and 2,2,2-trifluoroethanol: 3/1)
was added and the suspension was stirred 3 days at room
temperature. After filtration, the resin was washed succes-
sively with CH2Cl2, methanol, ether and dried under
vacuum. The dry resin was suspended in DMF (3 mL),
and DBU (55 mL, 0.37 mmol) was added. The suspension
was stirred for 3 days at room temperature then filtered. The
resin was washed four times with CH2Cl2, then methanol
and ether. The solid supported macrocycle was suspended in
dry CH2Cl2 (1.5 mL) and TFA (150 mL) was added. The
mixture was stirred at room temperature for 30 min then
methanol was added. The resin was filtered and washed four
times with methanol. The crude filtrate was treated at 08C
with an excess of diazomethane (solution in ether) and
purified by preparative TLC (SiO2, Heptane/EtOAc¼50/50)
to afford 6.9 mg of diastereoisomer 5i1 and 13.0 mg of
diastereoisomer 5i3 (total yield: 48%).
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