A rapid access to biaryl ether containing macrocycles by pairwise use of Ugi 4CR and intramolecular S(N)Ar-based cycloetherification.

Article abstract of DOI:10.1021/ol0168420

[reaction: see text] From readily accessible starting materials, macrocycles with an endo aryl-aryl ether bond are synthesized in only two operations by combination of the Ugi four-component reaction and an intramolecular S(N)Ar reaction. The nitro group serves as an activator for the macrocyclization and provides a handle for the introduction of functional group diversity. A Ugi reaction promoted by ammonium chloride in aprotic solvent is documented for the first time.

Full text of DOI:10.1021/ol0168420

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4079-4082
A Rapid Access to Biaryl Ether
Containing Macrocycles by Pairwise Use
of Ugi 4CR and Intramolecular
SNAr-Based Cycloetherification
,†
Pierre Cristau,† Jean-Pierre Vors,‡ and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France, and
AVentis CropScience, 14-20 Rue Pierre Baizet, 69009 Lyon, France
zhu@icsn.cnrs-gif.fr
Received October 2, 2001
ABSTRACT
From readily accessible starting materials, macrocycles with an endo aryl−aryl ether bond are synthesized in only two operations by combination
of the Ugi four-component reaction and an intramolecular SNAr reaction. The nitro group serves as an activator for the macrocyclization and
provides a handle for the introduction of functional group diversity. A Ugi reaction promoted by ammonium chloride in aprotic solvent is
documented for the first time.
Macrocycles with an endo aryl-aryl ether bond have been
found in a number of biologically and medicinally important
natural products, such as vancomycin family glycopeptides
(antibiotics),1 RA series (antitumors),2 K-13 (ACE inhibitor),3
piperazinomycine,4 and emestrine5 (both antifungals). Mainly
intrigued by the molecular complexity as well as the synthetic
challenges posed by vancomycin,6 a number of new synthetic
methodologies have been developed during the past decade
that made the construction of illusive biaryl ether containing
macrocycles possible.7,8 The development of efficient syn-
thetic technologies in conjunction with the emergency of high
throughput screening of drug candidates have, on the other
hand, provided opportunities for the production of libraries
of biaryl ether containing macrocycles, inaccessible just a
few years back.9
A stepwise construction of the peptide backbone incor-
porating suitably functionalized side chains followed by an
intramolecular SNAr reaction10 is the main strategy developed
† Institut de Chimie des Substances Naturelles.
‡ Aventis CropScience.
(1) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. Engl. 1999,
38, 1173-1193. (b) Zhu, J. Exp. Opin. Ther. Pat. 1999, 9, 1005-1019.
(2) (a) Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467-1501. (b)
Itokawa, H.; Takeya, K.; Hitotsuyanagi, Y.; Morita, H. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1997; Vol 49, pp 301-
387.
(3) (a) Kase, H.; Kaneko, M.; Yamada, K. J. Antibiot. 1987, 40, 450-
454. (b) Yasuzawa, T.; Shirahata, K.; Sano, H. J. Antibiot. 1987, 40, 455-
458.
(4) (a) Tamai, S.; Kaneda, M.; Nakamura, S. J. Antibiot. 1982, 35, 1130-
1136. (b) Kaneda, M.; Tamai, S.; Nakamura, S.; Hirata, T.; Kushi, Y.; Suga,
T. J. Antibiot. 1982, 35, 1137-1140.
(5) Seya, H.; Nozawa, K.; Nakajima, S.; Kawai, K.-I.; Udagawa, S.-I. J.
Chem. Soc., Perkin Trans. 1 1986, 109-116.
(6) For a review, see: Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.;
Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-2152.
(7) (a) Rao, A. V. R.; Gurjar, M. K.; Reddy, L.; Rao, A. S. Chem. ReV.
1995, 95, 2135-2167. (b) Sawyer, J. S. Tetrahedron 2000, 56, 5045-
5065.
(8) Recent exemples: (a) Decicco, C. P.; Song, Y.; Evans, D. A. Org.
Lett. 2001, 3, 1029-1032. (b) Dinsomore, C. J.; Bogusky, M. J.; Culberson,
J. C.; Bergman, J. M.; Homnick, C. F.; Zartman, C. B.; Mosser, S. D.;
Schaber, M. D.; Robinson, R. G.; Koblan, K. S.; Huber, H. E.; Graham, S.
L.; Hartman, G. D.; Huff, J. R.; Williams, T. M. J. Am. Chem. Soc. 2001,
123, 2107-2108.
(9) Dolle, R. E. J. Comb. Chem. 2000, 2, 383-433.
(10) Zhu, J. Synlett 1997, 133-144.
10.1021/ol0168420 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/10/2001

for the production of the biaryl ether containing macro-
cycles.11,12 In connection with our ongoing project aimed at
the development of step-efficient high throughtput synthesis
of bioactive molecules,13 we envisaged access to the mac-
rocycles of generic structure 6 via a combined use of the
Ugi four-component reaction (Ugi 4CR)14,15 and intra-
molecular SNAr-based cycloetherification. The underlying
principle is shown in the Scheme 1. Thus, the Ugi reaction
established conditions, should cyclize to provide the desired
m,p-cyclophanes (6). A recent communication from Tempest
and Hulme’s group16 employing a similar strategy for the
preparation of heterocycles prompted us to report our own
results in this Letter.
The unknown ethyl R-(4′-fluoro-3′-nitro)phenethyl iso-
cyanoacetate (4a, R ) Et) was synthesized as shown in
Scheme 2. Alkylation of commercially available diethyl
Scheme 1. Two-Step Synthesis of Biaryl Ether Containing
Scheme 2
Macrocycles
formamidomalonate by 4-fluoro-3-nitrobenzyl bromide17
under standard conditions (NaH, DMF) provided 8 in 92%
yield. Partial saponification to the malonate mono ester
followed by heating in 1,4-dioxane18 gave the N-formyl
R-amino ester (9) which was dehydrated (POCl3, Et3N)19 to
the desired isonitrile (4a) in good overall yield.
With the isonitrile in hand, the Ugi 4CR was first
examined.20 At the outset, we were unaware of the compat-
ibility of an amine and a fluoronitro aromatic under Ugi’s
conditions. Indeed, amines and to a lesser extent alcohols,
which are the solvent of choice for the Ugi 4CR, are known
to be good nucleophiles for the intermolecular SNAr reac-
tion.21 Eventually, stirring a methanol solution of heptanal
(1a), butylamine (2a), 3-hydroxyphenylacetic acid (3a), and
4a did provide the desired dipeptide amide (5a), but the yield
was only moderate (34%).22 Therefore, the reaction condi-
tions were reexamined by varying the solvent, temperature,
and additives (Table 1). As shown in the table, the reaction
did not occur in DMF but proceeded smoothly in trifluoro-
ethanol to provide dipeptide 5a in 71% yield (entry 4).23 To
of an aldehyde (1), an amine (2), a ω-(3′-hydroxyphenyl)-
alkanecarboxylic acid (3), and an isonitrile (4) should give
the dipeptide amides (5) which, under our previously
(11) (a) Burgess, K. Lim, D.; Bois-Choussy, M.; Zhu, J. Tetrahedron
Lett. 1997, 38, 3345-3348. (b) Fotsch, C.; Kumaravel, G.; Sharma, S. K.;
Wu, A. D.; Gounarides, J. S.; Nirmala, N. R.; Petter, R. C. Bioorg. Med.
Chem. Lett. 1999, 9, 2125-2130. (c) Goldberg, M.; Smith, L., II; Yamayo,
N.; Kiselyov, A. S. Tetrahedron 1999, 55, 13887-13898. (d) Jefferson, E.
A.; Swayze, E. E. Tetrahedron Lett. 1999, 40, 7757-7760.
(12) TTN-mediated cycloetherification on solid support, see: (a) Naka-
mura, K.; Nishiya, H.; Nishiyama, S. Tetrahedron Lett. 2001, 42, 6311-
6313. (b) Yamamura, S.; Nishiyama, S. J. Synth. Org. Chem. Jpn. 1997,
55, 1029-1039.
(13) Zhao, G.; Sun, X.; Bienayme´, H.; Zhu. J. J. Am. Chem. Soc. 2001,
123, 6700-6701.
(14) (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S.
D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131. (b) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (c) Bienayme´, H.;
Hulme, C.; Oddon, G.; Schmidtt, P. Chem. Eur. J. 2000, 6, 3321-3329.
(15) Selected examples of Ugi 4CR/post functionalization, see: (a)
Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574-
2583. (b) Hulme, C.; Peng, J.; Tang, S. Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. J. Org. Chem. 1998, 63, 8021-8023. (c) Fokas, D.; Ryan,
W. J.; Casebier, D. S.; Coffen, D. G. Tetrahedron Lett. 1998, 39, 2235-
2238. (d) Hulme, C.; Cherrier, M. P. Tetrahedron Lett. 1999, 40, 5295-
5299. (e) Bie´nayme´, H.; Bouzid, K. Tetrahedron Lett. 1999, 40, 2735-
2738. (f) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851-1854. (g)
Hulme, C.; Ma, L.; Cherrier, M.-P.; Romano, J. J.; Morton, G.; Duquenne,
C.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1883-1887.
(h) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712. (i)
Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Do¨mling, A. Org. Lett.
2001, 3, 2875-2878.
(16) Tempest, P.; Ma, V., Kelly, M. G.; Jones, W.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4963-4968.
(17) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.; Zhu,
J. J. Org. Chem. 1994, 59, 5535-5542.
(18) Cooper, M. S.; Seton, A. W.; Stevens, M. F.; Westwell, A. D.
Bioorg. Med. Chem. Lett. 1996, 6, 2613-1616.
(19) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1984, 400-402.
(20) Bowers, M. M.; Carroll, P.; Joullie´, M. M. J. Chem. Soc., Perkin
Trans. 1 1989, 857-865.
(21) Beugelmans, R.; Bigot, A.; Zhu, J. Tetrahedron Lett. 1994, 35,
5649-5652.
(22) The failure of the Ugi reaction in MeOH has been observed in other
cases, see, for example: Neyer, G.; Achatz, J.; Danzer, B.; Ugi, I.
Heterocycles 1990, 30, 863-869.
(23) (a) Bienayme´, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37,
2234-2237. (b) Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.
Tetrahedron Lett. 1998, 39, 7109-7112.
4080
Org. Lett., Vol. 3, No. 25, 2001

Cycloetherification of the dipeptide amide (5) went
smoothly in DMF using potassium carbonate as base.10
Results are summarized in Figure 1. As shown, both 16-
Table 1. Survey of Conditions for Ugi 4CRa
entries
solvent
T, °C
rtc
additive
yield, %b
1
2
MeOH
MeOH
DMFf
none
none
34d
16e
0
60
3
rt
none
4
5
6
7
8
9
10
CF3CH2OH
benzene
toluene
toluene
toluene
toluene
THFf
rt
none
none
none
NH4Cl
NH4Cl
LiBr
71
76
50
60
33h
35
39
refluxg
60
60
rt
60
60
NH4Cl
a 2.2 equiv each of amine, aldehyde, and acid relative to isonitrile was
used. b Total yield of two diastereomers in a 1/1 ratio. c Room temperature.
d 83% conversion of 4a after 24 h. e Isonitrile was consumed rapidly, leading
to a complex reaction mixture. f DMF ) N,N-dimethylformamide, THF )
tetrahydrofurane. g With Dean-Stark. h 63% conversion of 4a after 48 h.
Figure 1.
our surprise, benzene and toluene have also been found to
be good reaction mediums for this four-component conden-
sation. Since aprotic solvents are generally considered to be
an inappropriate solvent for the Ugi 4CR, a more detailed
investigation was carried out.24 The reaction in toluene at
room temperature proceeded slowly and was incomplete after
48 h probably due to the poor solubility of the acid input
(entry 8). While lithium bromide (LiBr) had an adverse effect
(entry 9),25 addition of ammonium chloride (NH4Cl, entry
7) is, on the other hand, beneficial to the reaction. Two points
deserved further comments. First, the R-acyloxy amide
resulting from the potentially competitive Passerini reaction
was not isolated although it is known that nonpolar solvents
favor the latter reaction. Second, ammonium chloride, a
potential donor of NH3,26 did not participate in the Ugi
reaction. To the best of our knowledge, this is the first
example wherein a Ugi reaction was performed in a nonpolar
solvent such as toluene in the presence of ammonium
chloride.27
and 17-membered macrocycles were produced in good yield
regardless the substitution patterns. Except for 6g, two
atropisomers were generally formed from a diastereomeri-
cally pure dipeptide amide due to the creation of a planar
chirality around the biaryl ether linkage. Apparently, the
presence of an endocyclic tertiary amide (R2 residue) did
not have a significant influence on the atropostereoselectiv-
ity.29 In most of the cases, the purity of the crude material
after conventional workup is higher than 75% according to
1H NMR spectrum, and the two atropisomers are readily
separable by preparative TLC. The upfield shift of the proton
Ha is characteristic of the cyclic structure and can be used
for NMR quantification.
While the nitro function served as an efficient activating
group for the key macrocyclization, from the viewpoint of
library diversity, its presence provided an extra handle for
the introduction of functional group diversity. Some repre-
sentative high yield transformations are shown in Scheme
Table 2 lists some representative compounds synthesized
from five amines, five aldehydes, two acids, and two
(24) Since refluxing using Dean-Stark apparatus is inconvenient from
the perspective view of parallel synthesis, only toluene was investigated
further.
(25) Positive effect of LiBr in a three-component synthesis of tetracyclic
tetrahydroisoqunoline, see: Gonzalez-Zamora, E.; Fayol, A.; Bois-Choussy,
M.; Chiaroni, A.; Zhu, J. J. Chem. Soc., Chem. Commun. 2001, 1684-
1685.
Table 2. Representative Examples of Ugi Products 5
R
R1
R2
n
yield, %
(26) (a) Matier, W. L.; Owens, D. A.; Comer, W. T.; Deitchman, D.;
Ferguson, H. C.; Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973, 16,
901-908. (b) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768-1769.
5a Et
5b Et
5c Me Ph
5d Me C2H4NHBoc n-C4H9
5e Me Ph
n-C6H13
Ph
n-C4H9
p-MeO-Ph
benzyl
1
1
1
1
2
2
2
60
65
73
43
55
61a
71
(27) For an earlier study concerning the salt effect on the Ugi reaction,
see: McFarland, J. M. J. Org. Chem. 1963, 28, 2179-2181.
(28) Typical procedure. A solution of heptanal (1a, 56 µL, 0.42 mmol)
and butylamine (2a, 40 µL, 0.42 mmol) in dry toluene (1 mL) was stirred
at room temperature for 1 h. 3-Hydroxyphenylacetic acid (3a, 63.3 mg,
0.42 mmol), isonitrile (4a, 50.3 mg, 0.19 mmol), and NH4Cl (22.2 mg,
0.42 mmol) were then introduced. After being stirred at 60 °C for 20 h, the
reaction mixture was diluted with water and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude residue was purified
by flash chromatography (SiO2, heptane/EtOAc ) 60/40) to afford 5a (67
mg, 60%) as a mixture of two diastereoisomers (1/1 ratio).
(29) For examples of atropselective cycloetherification, see ref 6 and
Bois-Choussy, M.; Neuville, L.; Beugelmans, R.; Zhu, J. J. Org. Chem.
1996, 61, 9309-9322.
benzyl
i-Pr
3,4-dimethoxyphenethyl
5f Me phenethyl
5g Me i-Pr
a A few drops of methanol were added to help dissolve the starting
materials.
isonitriles inputs.28 In all case, the dipeptide amide was
obtained as a mixture of two diastereomers in a ratio of 1/1,
separable by preparative TLC on silica gel.
Org. Lett., Vol. 3, No. 25, 2001
4081

was then converted into the corresponding urea (11) and
methylsulfonamide (12) by its reaction with benzyl iso-
cyanate and methansulfonyl chloride, respectively. Similarly,
macrocycle 6b was transformed into the acetamide 14 and
de-aminated compound 15 in good yield under standard
conditions.
Scheme 3a
In summary, we have developed a two-step synthesis of
biaryl ether containing macrocycles from readily available
starting materials. The sequence of transformations gave rise
to a marked increase in molecular complexity and allowed
for the incorporation of at least three points of diversity. The
presence of the nitro group in macrocycles allowed for the
easy introduction of functional group diversity into the
existing macrocycles, increasing further the molecular di-
versity. In the course of this study, an ammonium chloride
promoted Ugi 4CR in aprotic solvent was documented and
should find application in solid-phase synthesis because of
the good swelling property of toluene.
Acknowledgment. We thank CNRS and Aventis Crop-
Science for financial support. A doctoral fellowship to P.
Cristau from Aventis CropScience is gratefully acknowl-
edged.
a Reagents and conditions: (a) H2, Pd/C, EtOH, 95-99%; (b)
PhCH2NCO, CH2Cl2, 73%; (c) MsCl, Et3N, CH2Cl2, 55%; (d) Ac2O,
Et3N, CH2Cl2, 81%; (e) NaNO2, Cu2O, H3PO2, THF-H2O, 86%.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
3. Thus, hydrogenolysis of 6a under standard conditions (Pd/
C, H2, EtOH) provided the aniline 10 in 99% yield, which
OL0168420
4082
Org. Lett., Vol. 3, No. 25, 2001