One-step synthesis of natural product-inspired biaryl ether-cyclopeptoid macrocycles by double ugi multiple-component reactions of bifunctional building blocks

Article abstract of DOI:10.1002/ejoc.200600354

Isonitrile-functionalized biaryl ethers can serve as key building blocks for the highly efficient one-step production of natural product inspired-macrocycles, with six or even twelve new bonds and rings with up to 50 members being formed in total yields o

Full text of DOI:10.1002/ejoc.200600354

FULL PAPER
DOI: 10.1002/ejoc.200600354
One-Step Synthesis of Natural Product-Inspired Biaryl Ether-Cyclopeptoid
Macrocycles by Double Ugi Multiple-Component Reactions of Bifunctional
Building Blocks
Dirk Michalik,[a,b] Angela Schaks,[a] and Ludger A. Wessjohann*[a]
Keywords: Multiple component reaction / Biaryl ether / Macrocyclization / Cyclopeptide / Ugi reaction / Peptoid
Isonitrile-functionalized biaryl ethers can serve as key build-
ing blocks for the highly efficient one-step production of nat-
ural product inspired-macrocycles, with six or even twelve
new bonds and rings with up to 50 members being formed
in total yields of up to 51%. Aliphatic diamine and diacid
tethers give access to two different classes of N-substituted
biaryl ether cyclopeptides, suitable for library construction.
As part of a conceptual work on MiBs (multiple multicompo-
nent macrocyclizations/macrocycles including bifunctional
building blocks), the influence of length and type of flexible
tethers on the propensity for cyclization is studied.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tives in very few steps from commercially available sub-
stances, through the use of an Ugi-MCR strategy. In con-
trast with transition metal-catalyzed C–C bond-forming
macrocyclization[5] or SNAr-based cycloetherification[6] ap-
proaches to biaryl ether-containing macrocycles, our strat-
egy differs substantially from the known methods in that
the combinatorial synthesis of linear precursors and the
macrocyclization step are combined in a powerful strategy
termed MiB (multiple multicomponent macrocyclization in-
cluding bifunctional building blocks). Details of the theo-
retical concept of MiBs, such as directionality, transition
state geometries, etc., are discussed elsewhere.[2d] An ap-
proach to biaryl ether-containing cyclopeptoids should best
be carried out by use of an Ugi-MCR with two different
bifunctional substrates, one of them a bisisonitrilo biaryl
ether.[3,7] The term peptoid refers in this context to partially
N-substituted peptides (i.e., it is used in a broader sense
then the strictly N-substituted polyglycine definition, which
excludes additional Cα-substituents).
For our initial study on one-pot syntheses of biaryl ether
cyclopeptoids we chose two routes based on the diisonitriles
4 and 11, each representing a biaryl ether moiety with either
an aryl-aryl (Scheme 1) or an aryl-alkyl (Scheme 2) substi-
tution pattern. Each diisocyanide was allowed to react
either with an aliphatic diacid or with an aliphatic diamine,
complemented with amine/aldehyde or a carboxylic acid/
aldehyde, respectively, to form macrocycles containing two
Introduction
Macrocycles containing biaryl ether moieties in their ring
systems are present in many natural products, such as the
vancomycin aglycon, K-13, bouvardin, OF4949-III, or bi-
phenomycin-A.[1] These compounds have antibiotic and an-
titumor properties, and enterprising approaches to their to-
tal syntheses and mimetic structures have been described in
the last decade.[2,3] Because of the increasing need for po-
tent antibiotics caused by, for example, multiply resistant
bacteria, the search for and discovery of new lead candi-
dates and efficient synthetic methods by which to obtain
natural product-like or natural product-inspired libraries is
an ongoing process (cf. “chemical genetics” and “biology
oriented synthesis”, BIOS).[2c,2j] Rapid creation of diversity-
oriented libraries based on biaryl ether-containing cyclic
peptide mimics, in combination with modern high-through-
put screening techniques, is desirable for lead discovery.[4]
In addition, larger members of the biaryl ether macrocycle
class may serve as potential hosts in supramolecular chem-
istry, utilizing the lipophilic, π-interaction, and thermal sta-
bility properties of a biaryl ether moiety.
Results and Discussion
We have investigated a new and efficient approach by
which to obtain potentially bioactive cyclopeptide deriva-
[a] Leibniz Institute of Plant Biochemistry, Department of Bioor- dipeptoid units.
ganic Chemistry,
The synthesis of the aryl-aryl diisocyanide 4[8] started
Weinberg 3, 06120 Halle (Saale), Germany
from the commercially available bis(4-aminophenyl) ether
(1). Formylation with ethyl formate was accomplished un-
der reflux conditions after several days; although the reac-
tion time is long, the reaction can be regarded as very mild,
E-mail: wessjohann@ipb-halle.de
[b] Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 149–157
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149

D. Michalik, A. Schaks, L. A. Wessjohann
FULL PAPER
(K2CO3) to yield 8 (61%, two steps). After hydrogenation
of 8 with Raney-Ni under hydrogen, 9 was obtained in high
yield (97%), N-formylated with ethyl formamide to afford
10, and dehydrated by treatment with phosphorus oxychlor-
ide to give the diisocyanide 11 (78%, two steps, Scheme 2).
Macrocyclizations were achieved by the envisioned
double Ugi-MCRs, ideally under pseudo-dilution condi-
tions.[2b,2d,11] Thus, a solution of the biaryl diisocyanide (4
or 11) was slowly added by syringe pump to a reaction mix-
ture containing the other three components. Long-chain ali-
phatic diamines and diacids served as second bifunctional
units to allow ring-closure, resulting in macrocycles with
exo- and endocyclic dipeptoid units, respectively (Scheme 3
and Scheme 4). Theoretically, an ideal pseudo-dilution
setup would involve simultaneous addition of both bifunc-
tional building blocks; in some combinations[2d] this is even
essential. However, after some experience with the combi-
nation studies here and for practical reasons, we chose to
only add the diisocyanide slowly, because the reaction is
speeded up if larger amounts of intermediate iminium salts
and acid are present. This is possible with aryl ether isoni-
triles because the (second) aromatic isocyanide usually re-
acts more slowly than the first or much more slowly than
the aliphatic one, so double-Ugi diacid formation (cf. 14)
and possible tetra-Ugi macrocycle formation (cf. 17) is in-
trinsically reduced.
In order to study the importance of tether length, the
aryl-aryl diisocyanide 4 was treated with isobutyraldehyde,
isopropylamine, and diacids of varying chain length (12).
Scheme 1.
with clean conversion being achieved. Even in the case of Use of the short-chain diacids (oxalic acid, succinic acid,
an incomplete conversion, the presence of residual mono- glutaric acid) resulted in acyclic, linear bis-Ugi diacids (14,
N-formylated intermediate 2 does not disturb the next step, avg. crude yield Ͼ 50%; the formation of diacids 14a–d
and its separation from the bis-N-formyl derivative 3[9] is and sometimes of minor amounts of cyclodimeric tetra-Ugi
not required. Diisocyanide 4 is obtained in acceptable yield macrocycles could be unambiguously determined by mass
(62% overall over two steps, Scheme 1) either from pure 3 spectrometry, though we performed no further characteri-
or from the mixture of 2 and 3, by dehydration with phos- zation of these products because of our focus on the mono-
phorus oxychloride and purification by crystallization.
meric macrocyclizations). Attempts to force the cyclisation
The synthesis of the aryl-alkyl diisocyanide 11 started with glutaric acid by its very slow addition simultaneously
from tyramine (5), which was N-formylated[10] to give 6 and with diisocyanide did only result in minute amounts of the
coupled to p-fluoronitrobenzene (7) under basic conditions monomeric cycle. The reaction is shifted to increased
Scheme 2.
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Synthesis of Biaryl Ether-Cyclopeptoid Macrocycles
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Scheme 3. Italic numbers in brackets after the compound number denominate the ring size. 13a: The macrocycle is isolated as a mixture
with a subsequently formed Mannich–Gattermann product (see text).
Scheme 4. Italic numbers in brackets after the compound number denominate the ring size.
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151

D. Michalik, A. Schaks, L. A. Wessjohann
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amounts of the corresponding cyclodimeric MiB – a com- higher configurational flexibility, and thus probably lower
mon product if the cyclomonomer is too strained or the ring tension, within the diamine-derived products (e.g.,
precursor folding is unfavorable (cf., e.g., 17).[2d,12] Adipic 16a). Two of the four amide bonds in 16a are exocyclic,
acid (C6) is a borderline case, with the corresponding 23- compared to four endocyclic amide bonds in 13a
membered macrocycle 13a (n = 4, 8%) being obtained in (Scheme 3, Figure 1).[11] This is important both for strain
very low yield. The forced, lengthy reaction causes the sub- and for acyclic prefolding, because the s-trans amide config-
sequent Mannich–Gattermann aminomethylation of one uration usually is also preferred in the cyclic MiBs. Further-
aromatic ring of 13a, i.e. appending a CH2NHiPr residue, more, it also needs to be considered that it is not only the
to give a mixture. The longer-chain diacids, as might be final product that is a limiting factor for the formation of
expected, gave increasing yields of the desired cyclomono- the macrocycles. As discussed earlier,[2d] the formation of
meric MiBs, as demonstrated by products 13b (n = 6, 16%) the intermediate α adduct is crucial: here the macrocycle is
and 13c (n = 10, 30%).
formed initially (Figure 1). Furthermore, conversion of the
The Ugi reaction is not diastereoselective, so the two dia- α adduct into the final product proceeds through a 1,3-
stereomers of 13a–c are in all cases formed in almost equal ansa-like intermediate that should cause additional ring
amounts. Although this feature is highly desirable for lead- strain in both variations. To form a ring of the same final
finding studies, it is inconvenient for method development size when using a diacid, however, requires intermediates
and analytics, so we investigated the substitution of isobu- with one ring atom fewer than the final macrocycle and,
tyraldehyde by paraformaldehyde, a less usual and often depending on the overall strain and conformational rigidity
not so well behaved aldehyde in Ugi reactions because of of the system used, this may result in a disadvantaging of
its propensities towards polymerization and side reactions. the diacid version, whereas the diamine version does not
With isopropylamine and dodecandioic acid, however, the suffer from smaller intermediates. This, though, is only im-
reaction proceeded smoothly, affording the glycine-contain- portant for borderline cases: intermediate or product strain
ing cyclopeptoid 13d in 37% yield, which can be considered becomes less important with increasing length or flexibility
very efficient in view of the fact that six new bonds are of the bifunctional building blocks, and is overruled or even
formed, including a macrocyclization with a very flexible inverted in preference by the increasing statistical disadvan-
endocyclic C10-alkyl chain.
tage common to all flexible-chain macrocyclizations.
In a second series utilizing diamines, diisonitrile 4 was
Treatment of 4 with paraformaldehyde, diamine 15,
treated with isobutyraldehyde, 1,8-octadiamine (15), and and acetic acid gave only a small amount of the expected
acetic acid. The resulting 25-membered macrocycle 16a was product 16b (1%), with the 50-membered macrocycle
obtained in higher yield (24%) than the likewise 25-mem- 17 (11%) containing eight newly formed peptide bonds
bered 13b. Although the diisocyanide/diamine combination and having double the molecular mass of 16b instead
is only slightly more efficient than the diisocyanide/diacid being obtained as the main product. Here, 12 building
one with otherwise equal parameters, this trend was ob- blocks have been engaged in 16 reactions, corresponding to
served in several cases (v.i.). The difference in the product almost 87% for each bond formation (including the macro-
yields of these two combinations is probably a result of the cyclization).
Figure 1. Macrocyclic intermediates, ring strain change, and resulting diamide constitution in MiBs of diisocyanide/diacid vs. diisocyanide/
diamine combinations. Boxes represent the first (acyclic) Ugi dipeptide.
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Synthesis of Biaryl Ether-Cyclopeptoid Macrocycles
FULL PAPER
300 MHz) and 13C NMR spectra (75.5 or 125.7 MHz) were re-
corded with VARIAN Inova 500, Mercury 400, and Mercury 300
spectrometers, respectively, at 300 K if not indicated otherwise. δH
(ppm) and δC (ppm) values are referred to the solvent signals:
CDCl3 (δH = 7.26, δC = 77.0), [D6]DMSO (δH = 2.50, δC = 39.7)
and MeOD (δH = 3.30, δC = 49.0). EI mass spectrometry was per-
formed on an AMD 402 (AMD Intectra GmbH) instrument. The
high-resolution positive ion ESI mass spectra were obtained with
a Bruker Apex 70e Fourier transform ion cyclotron resonance mass
spectrometer (Bruker Daltonics, Billerica, USA) fitted with an In-
The aryl-alkyl diisocyanide 11 (Scheme 4) was treated in
the same way as 4 with isobutyraldehyde, isopropylamine,
and diacids 12 to produce macrocycles 18a (n = 1, 38%),
18b (n = 2, 42%), and 18c (n = 4, 51%). The aliphatic isocy-
anide portion reacts more rapidly than the aromatic one.
Overall yields in this system are much higher, because the
additional ethylene group creates more flexibility in the cy-
cle and lowers the ring tension of the α adduct and the
resulting product.[2d]
Treatment of 11 with isobutyraldehyde, acetic acid, and finity cell,
a 7.0 Tesla superconducting magnet (Bruker,
Karlsruhe, Germany), an RF-only hexapole ion guide, and an ex-
ternal electrospray ion source (Agilent). IR spectra were measured
with a Bruker IFS 28 spectrometer. Elemental analyses were per-
formed on a CHNS automatic elemental analyzer Flash EA
(ThermoQuest). All compounds for which elemental analytical
data are not available were chromatographically homogeneous, and
NMR and mass spectroscopic data were in full agreement with the
assigned structures.
aliphatic diamine 19 provided the macrocycle 20a in 46%
yield (Scheme 4). The ring flexibility of 20a is higher and
ring formation is slightly preferred in comparison with 18b,
for the reasons discussed above (Figure 1), though with in-
creased flexibility these strain-based preferences become
less important, or may even invert, with too much flexibility
being detrimental. Interestingly, the 27-membered rings 18c
and 20b appear to retain methanol solvent quite well.
Both conversions of 11 were also performed with para-
formaldehyde. With suberic acid, paraformaldehyde, and
isopropylamine, compound 18d was obtained in 7% yield,
while with diamine 15, paraformaldehyde, and acetic acid,
macrocycle 20b was obtained in 11% yield. Obviously, the
use of paraformaldehyde decreases the yield in most cases
(16, 18, 20). Although decreased formation or polymeriza-
tion of the intermediate imine cannot be excluded, the more
probable reason is the higher flexibility of the acyclic pre-
cursor, thus reducing the propensity towards macrocycliza-
tion. This appears most likely because the use of paraform-
aldehyde can even improve the yield in cases in which
macrocyclization is problematic due to very high overall ri-
gidity[11] or strain (cf. 13c vs. 13d vs. 14). Rigidity and strain
are factors easily influenced by the Ugi oxo component,[12]
and the use of an element such as formaldehyde gives gly-
cine amides, which in such cases avoids putting two sets
of vicinal and transannularily interfering α-amino acid side
chains (e.g., two isopropyl groups) in a tight macrocycle.
Bis(4-isocyanophenyl) Ether (4): A mixture of bis(4-aminophenyl)
ether (1, 10 g, 50 mmol) in ethyl formate (200 mL) was heated at
reflux for 5 d. After the starting material had been converted (TLC
monitoring), solvent and formed alcohol were removed under re-
duced pressure and the residue (11.4 g, mixture from 2 and 3) was
dried in vacuo, and then dissolved in THF (350 mL). After ad-
dition of NEt3 (64 mL, 460 mmol), a solution of POCl3 (12 mL,
130 mmol) in THF (50 mL) was added dropwise to the reaction
mixture at –60 °C over 2 h, and stirring was continued for 5 h at
room temp. The mixture was poured into ice/water and extracted
with diethyl ether, and the combined organic layers were washed
with water, dried (Na2SO4), filtered, and concentrated. Recrystalli-
zation from ethanol gave 4 as light-brown needles (6.8 g, 62%);
m.p. 144–145 °C; TLC (CHCl3/MeOH 9:1) Rf = 0.79 (4), 0.26 (3),
and 0.17 (2).
1
Compound 4: H NMR (400 MHz; CDCl3): δ = 7.39 (m, 4 H, m-
Ph), 7.01 (m, 4 H, o-Ph) ppm. 13C NMR (125.7 MHz; CDCl3): δ
= 164.1 (br., NC), 156.5 (i-Ph), 128.2 (m-Ph), 119.6 (o-Ph), 122.3
(brt, p-Ph) ppm. IR:
ν
=
2125 cm–1 (NC). EI-MS of
(KBr)
˜
C14H8N2O (M, 220.1): m/z = 220 [M]+. HRMS of C14H8N2O
220.0615; calcd. 220.0637. The diisonitrile is reactive, elemental
analysis was varying under normal conditions.
1
Compound 2: H NMR (300 MHz; [D6]DMSO, δ of minor isomer
in brackets): δ = 10.11 (brs, 1 H, NHcis); (10.03) (d, 1 H, NHtrans);
Conclusions
(8.63) (d, JNH,CHO = 11.3 Hz, 1 H, CHOtrans); 8.20 (d, JNH,CHO
=
In summary, we have devised a very short and straight-
forward route to macrocycles containing biaryl ether com-
ponents through double (and quadruple) Ugi MCRs. The
importance of the spans of the bifunctional building blocks,
the pseudo-dilution conditions, and the influence of formal-
dehyde have been discussed. In view of the fact that eight
bonds are formed in each double MCR, a total yield of,
say, 43% equates to a ca. 90% yield for each bond-forming
step, including the macrocyclization.
1.9 Hz, 1 H, CHOcis); 7.54 (7.17) (m, 2 H, m-Ph); 6.94 (6.94) (m,
2 H, o-Ph) ppm. 13C NMR (125.7 MHz; [D6]DMSO, δ of minor
isomer in brackets): δ = 159.7 (163.0) (CHO); 153.0 (153.6) (i-Ph);
133.9 (133.9) (p-Ph); (121.2), 121.2 (m-Ph); (120.0), (119.7), (119.6),
(119.1), 119.1 (o-Ph) ppm. EI-MS of C14H12N2O3 (M, 256.1): m/z
= 256 [M]+. HRMS of C14H12N2Na1O3 [M + Na]: 279.0743; calcd.
279.0740. C14H12N2O3 (256.26): calcd. C 65.62, H 4.72, N 10.93;
found C 65.82, H 4.81, N 10.59.
1
Compound 3: H NMR (300 MHz; [D6]DMSO, δ of minor isomer
in brackets): δ = 10.02 (brs, 1 H, NHcis); (9.95) (d, 1 H, NHtrans);
(8.63) (d, JNH,CHO = 11.0 Hz, 1 H, CHOtrans); 8.17 (d, JNH,CHO
=
1.9 Hz, 1 H, CHOcis); 7.46 (7.10) (m, 2 H, mЈ-Ph); 6.81 (6.81) (m,
2 H, oЈ-Ph); 6.71 (6.71) (m, 2 H, o-Ph); 6.57 (6.57) (m, 2 H, m-Ph);
4.85 (brs, 2 H, NH2) ppm. 13C NMR (125.7 MHz; [D6]DMSO, δ
of minor isomer in brackets): δ = 159.4 (162.7) (CHO); 154.7
(155.4) (i-Ph); 146.4 (146.4), 145.0 (145.1) (iЈ-Ph, pЈ-Ph); 132.5
(132.4) (p-Ph); 121.0, 120.4 (m, mЈ-Ph); (119.9), (117.9), 117.2 (o-
Ph); 115.2 (oЈ-Ph) ppm. EI-MS of C13H12N2O2 (M, 228.1): m/z =
Experimental Section
General: Reactions were monitored by TLC on 60 F254 silica gel
(Merck) with detection either by UV light or by charring with 10%
H2SO4 in EtOH. Solutions were concentrated under reduced pres-
sure at 40 °C. Column chromatography was performed on silica
gel 60 (0.063–0.200 mm, Merck). 1H NMR spectra (500, 400 or
Eur. J. Org. Chem. 2007, 149–157
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153

D. Michalik, A. Schaks, L. A. Wessjohann
FULL PAPER
228 [M]+. HRMS of C13H12N2Na1O2 [M + Na]: 251.0794; calcd.
251.0791. C13H12N2O2 (228.25): calcd. C 68.41, H 5.30, N 12.27;
found C 68.07, H 5.13, N 12.09.
0.87 g, 3.4 mmol) in ethyl formate (100 mL) was heated at reflux
for 24 h. After the starting material had been consumed, solvent
and alcohol formed were removed under reduced pressure. Column
chromatography of the residue on silica (CHCl3/MeOH 9:1) gave
10 as a brown solid (0.88 g, 91%). TLC (CHCl3/MeOH 9:1) Rf =
0.20. 1H NMR (400 MHz; MeOD): δ = 8.22 (8.60) (s, 1 H,
C6H4NHCHO); 8.00 (7.75) (s, 1 H, CH2NHCHO); 7.54 (m, 2 H,
mЈ-Ph); 7.21 (m, 2 H, m-Ph); (7.16) (m, 2 H, m-Ph); (6.96) (m, 2
N-[2-(4-Hydroxyphenyl)ethyl]formamide (6): A mixture of tyramine
(5, 5 g, 36 mmol) in ethyl formate (50 mL) was heated at reflux for
24 h. After the starting material had been converted (tlc monitor-
ing), the solvent and formed alcohol were removed under reduced
pressure. Crystallization of the residue from ethanol gave 6 as light
brown crystals (4.95 g, 82%). M.p. 96–97 °C; TLC (CHCl3/MeOH
H, m-Ph); 6.91 (m, 4 H, o,oЈ-Ph); 3.44 (t, JCH
= 7.3 Hz, 2 H,
,
2 CH2
CH2N); 2.79 (t, 2 H, CH2CH2N) ppm. 13C NMR (125 MHz;
MeOD): δ = 163.6, 161.2 (167.1, 164.7) (CHO); 157.2 (157.1), 155.1
(155.9) (i-, iЈ-Ph); 135.1 (135.2), 134.2 (134.5) (p-, pЈ-Ph); 131.0
(131.4) (m-Ph); 122.5 (121.5) (mЈ-Ph); 120.0 (120.7), 119.6 (119.6)
(o-, oЈ-Ph); 40.6 (44.5) (CH2); 35.7 (37.6) (CH2) ppm. EI-MS of
1
4:1) Rf = 0.47. H NMR (400 MHz; [D6]DMSO): δ = 7.94 (brs, 1
H, CHO); 6.98 (m, 2 H, m-Ph); 6.65 (m, 4 H, o-Ph); 3.23 (dt,
JCH
= JCH
= 7.0 Hz, 2 H, CH2NH); 2.58 (t, 2 H,
,
2,NH
2 CH2
CH2CH2NH) ppm. 13C NMR (125.7 MHz; [D6]DMSO, δ of minor
isomer in brackets): δ = 161.3 (164.6) (CHO); 155.6 (i-Ph); 129.5
(129.8) (m-Ph); 129.4 (128.9) (p-Ph); 115.2 (115.2) (o-Ph); 39.3
(43.0) (CH2); 34.3 (36.4) (CH2) ppm. EI-MS of C9H11NO2 (M,
165.1): m/z = 165 [M]+. HRMS of C9H11N1Na1O2 [M + Na]:
188.0685; calcd. 188.0682. C9H11N1O2 (165.19): calcd. C 65.44, H
6.71, N 8.48; found C 65.56, H 6.86, N 8.44.
C16H16N2O3 (M, 284.1): m/z
=
284 [M]+. HRMS of
C16H16N2Na1O3 [M + Na]: 307.1055; calcd. 307.1053. C16H16N2O3
(284.31): calcd. C 67.59, H 5.67, N 9.85; found C 67.32, H 5.70, N
9.66.
4-[4-(2-Isocyanoethyl)phenoxy]phenyl Isocyanide (11): A solution of
POCl3 (0.6 mL, 6.2 mmol) in THF (10 mL) was added dropwise
at –60 °C over 2 h to a mixture of N-{4-[4-(2-formylaminoethyl)-
phenoxy]phenyl}formamide (10, 0.72 g, 2.6 mmol) and NEt3
(3.5 mL, 25 mmol) in THF (10 mL). Stirring was continued for 5 h
at room temp., and the mixture was then poured into ice/water
and extracted with diethyl ether. The combined organic layers were
washed with water, dried (Na2SO4), filtered, and concentrated, and
11 was obtained as a dark brown oil (0.55 g, 86%). TLC (CHCl3/
N-{2-[4-(4-Nitrophenoxy)phenyl]ethyl}formamide (8): A mixture of
N-[2-(4-hydroxyphenyl)ethyl]formamide (6, 5 g, 30 mmol), p-fluo-
ronitrobenzene (7, 3.5 mL, 33 mmol), and K2CO3 (5 g) in N,N-di-
methylformamide (35 mL) was stirred for 24 h at room temp. The
mixture was poured into ice/water and extracted with chloroform,
and the combined organic layers were washed with water, dried
(Na2SO4), filtered, and concentrated. Recrystallization from etha-
nol gave 8 as a light brown solid (6.41 g, 74%). M.p. 96–97 °C;
1
MeOH 9:1) Rf = 0.73. H NMR (400 MHz; CDCl3): δ = 7.33 (m,
1
TLC (CHCl3/MeOH 9:1) Rf = 0.37. H NMR [400 MHz; CDCl3,
2 H, mЈ-Ph); 7.24 (m, 2 H, m-Ph); 6.97 (m, 4 H, o-, oЈ-Ph); 3.63 (t,
δ of minor isomer (15%) in brackets]: δ = 8.20 (m, 3 H, mЈ-Ph,
CHO); (7.97) (d, JCHO,NH = 12.1 Hz, 1 H, CHO); 7.29–7.23 (m, 2
H, m-Ph); 7.08–6.98 (m, 4 H, o-, oЈ-Ph); 5.63 (5.73) (brs, 1 H, NH);
JCH
= 7.0 Hz, 2 H, CNCH2); 2.98 (t, 2 H,CNCH2CH2) ppm.
,
2 CH2
13C NMR (125 MHz; CDCl3): δ = 163.2 (br., CNCar); 156.6 (t,
CNCH2); 157.9, 154.7 (i-Ph); 132.7 (p-Ph); 130.2 (m-Ph); 127.8 (mЈ-
Ph); 121.0 (brm, pЈ-Ph); 119.9 (o-Ph); 118.5 (oЈ-Ph); 43.0 (t,
3.61 (dt, JCH
= JCH
= 6.8 Hz, 2 H, CH2NH); (3.53) (dt,
,
2,NH
2 CH2
JCH
= JCH
= 6.6 Hz, 2 H, CH2NH); 2.89 (2.87) (t, 2 H,
,
2,NH
2 CH2
CNCH ); 34.9 (CNCH CH ) ppm. IR: ν
= 2151 cm–1 (–NC);
˜
(KBr)
2
2
2
CH2CH2NH) ppm. 13C NMR (125 MHz; CDCl3, δ of minor iso-
mer in brackets): δ = 161.3 (164.5) (CHO); 163.3 (163.2) (iЈ-Ph);
153.3 (153.3) (i-Ph); 142.5 (pЈ-Ph); 135.6 (134.6) (p-Ph); 130.5
(130.7) (m-Ph); 125.9 (mЈ-Ph); 120.7 (120.8), 116.9 (117.0) (o-, oЈ-
Ph); 39.3 (43.1) (CH2); 34.9 (36.9) (CH2) ppm. EI-MS of
2130 cm–1 (–NC). EI-MS of C16H12N2O (M, 248.1): m/z = 248
[M]+. The diisonitrile is reactive, elemental analysis was varying
under normal conditions (cf. 4).
9,10,19,20-Tetraisopropyl-2-oxa-7,10,19,22-tetraazatricyclo[21.2.
2.23,6]nonacosa-1(26),3(29),4,6(28),23(27),24-hexaene-8,11,18,21-tet-
raone (13b): A solution of isobutyraldehyde (0.19 mL, 2 mmol) and
isopropylamine (0.18 mL, 2 mmol) in methanol (130 mL) was
stirred for 1 h at room temp., suberic acid (87 mg, 0.5 mmol) was
then added, and stirring was continued for another 30 min. After-
wards, a solution of diisonitrile 4 (110 mg, 0.5 mmol) in methanol
(10 mL) was slowly added to the reaction mixture by syringe pump
(flow rate 0.1 mLh–1). The reaction mixture was concentrated un-
der reduced pressure, and column chromatography of the residue
on silica (CHCl3/MeOH 9:1) gave 13b as a diastereomeric mixture,
isolated as an amorphous solid (50 mg, 16%). TLC (EtOAc) Rf =
C15H14N2O4 (M, 286.1): m/z
=
286 [M]+. HRMS of
C15H14N2Na1O4 [M + Na]: 309.0849; calcd. 309.0846. C15H14N2O4
(286.28): calcd. C 62.93, H 4.93, N 9.77; found C 62.68, H 4.97, N
9.80.
N-{2-[4-(4-Aminophenoxy)phenyl]ethyl}formamide (9): A suspen-
sion of Raney nickel in water (approx. 2 g wet) was washed with
water until the washings remain neutral. After washing with meth-
anol
a
solution of N-{2-[4-(4-nitrophenoxy)phenyl]ethyl}-
formamide (8, 1.0 g, 3.5 mmol) in methanol (100 mL) was added
and the reaction mixture was stirred under hydrogen for 24 h and
then filtered through Celite. Concentration of the filtrate gave 9 as
a pale yellow syrup (0.87 g, 97%). TLC (CHCl3/MeOH 9:1) Rf =
0.25; 1H NMR (300 MHz; [D6]DMSO): δ = 8.04 (brs, 1 H,
NHCHO); 7.98 (d, JCHO,NH = 1.6 Hz, 1 H, NHCHO); 7.13 (m, 2
H, mЈ-Ph); 6.75 (m, 4 H, o-, oЈ-Ph); 6.57 (m, 2 H, m-Ph); 4.96 (brs,
1
0.53. H NMR (500 MHz; CDCl3): δ = 10.60, 10.50, 10.42, 10.08
(broad signals, NH); 7.48, 7.35, 7.30, 7.07, 6.99, 6.90 (2), 6.73 (sev-
eral multiplets from Ar); 4.97 (d, J = 11.0 Hz, CHCHMe2); 4.12–
3.96 (m, NCHMe2); 3.17–3.09 (m, CHCHMe2); 2.67–2.20, 1.80–
1.10 (brm, CH2); 1.40–1.10 [m, NCH(CH3)2]; 1.07 (d, J = 6.2 Hz),
1.06 (d, J = 6.3 Hz), 0.98 (d, J = 6.3 Hz), 0.87 m, 0.76 (d, J =
6.6 Hz) [CHCH(CH3)2] ppm. 13C NMR (125 MHz; CDCl3): δ =
174.9, 173.0, 172.4, 172.1, 171.3, 171.1, 170.4 (CO); 158.4, 156.8,
154.2 (i-Ar); 134.7, 134.3, 130.4 (p-Ar); 129.9, 121.3, 120.8, 120.5,
120.0, 119.4 (o-, m-Ar); 70.3, 57.8 [CHCH(CH3)2]; 50.7, 50.5
[NCH(CH3)2]; 36.6, 35.6, 35.2 (CH2CO); 30.9, 30.5, 30.4, 29.1
(CH2); 27.6, 27.5, 27.3 (2) (CHCHMe2); 26.2, 25.8 (CH2); 22.7,
22.1, 21.6, 21.5, 21.2, 21.0 (2) [NCH(CH3)2]; 20.3, 20.1, 20.0, 19.7,
18.4, 14.2 [CHCH(CH3)2] ppm. ESI-MS of C36H52N4O5 (M,
2 H, NH2); 3.27 (dt, J
= JCH
= 7.1 Hz, 2 H, CH2NH);
,
2,NH
CH2 CH2
2.65 (t, 2 H, CH2CH2NH) ppm. 13C NMR (75.5 MHz; [D6]DMSO,
δ of minor isomer in brackets): δ = 160.8 (CHO); 157.2 (i-Ph);
145.5, 145.2 (i-, p-Ph); 132.3 (pЈ-Ph); 129.6 (129.9) (mЈ-Ph); 120.7
(m-Ph); 116.2, 114.7 (o-, oЈ-Ph); 38.9 (42.8) (CH2); 34.2 (36.3)
(CH2) ppm. C15H16N2O4 (288.30): calcd. C 70.29, H 6.29, N 10.93;
found C 69.74, H 6.39, N 10.75.
N-{4-[4-(2-Formylaminoethyl)phenoxy]phenyl}formamide (10):
A
mixture of N-{2-[4-(4-aminophenoxy)phenyl]ethyl}formamide (9,
154
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 149–157

Synthesis of Biaryl Ether-Cyclopeptoid Macrocycles
620.4): m/z = 621.6 [M + H]+, 643.4 [M + Na]+. HRMS of then added, and stirring was continued for another 30 min. After
FULL PAPER
C36H52N4Na1O5 [M + Na]: 643.3830; calcd. 643.3830. C36H54N4O6
(638.84): calcd. C 67.68, H 8.52, N 8.77; found C 67.13, H 8.33, N
8.65.
addition of methanol (100 mL), a solution of diisonitrile 4 (110 mg,
0.5 mmol) in methanol (10 mL) was slowly added to the reaction
mixture by syringe pump (flow rate 0.1 mLh–1) and the reaction
mixture was concentrated under reduced pressure. Column
chromatography of the residue on silica (CHCl3/MeOH 9:1) gave
16a as a diastereomeric mixture, isolated as an amorphous solid
(72 mg, 24 %). TLC (CHCl3/MeOH 95:5) Rf = 0.58. 1H NMR
(300 MHz, CDCl3): δ = 8.10 (br., NH); 7.44 (m, 4 H, Ar); 6.87 (m,
4 H, Ar); 4.20 (br., 2 H, CHN); 3.27 (br., 4 H, 2ϫCH2NAc); 2.60
(br., 2 H, 2ϫCHMe2); 2.16, 2.14 (2ϫs, 6 H, 2ϫAc); 2.00–1.05
[br m, 12 H, (CH2)6]; 1.03, 0.86 (2 ϫ d, J = 6.5 Hz, 12 H,
4ϫCH3) ppm. 13C NMR (75.5 MHz; CDCl3): δ = 172.6, 172.5,
168.9 (CO); 153.3 (i-Ar); 133.4 (p-Ar); 121.2, 121.1, 119.0, 118.9
(o-, m-Ar); 63.0 (br., CHN); 48.0 (br., NCH2); 37.9, 33.9, 30.4 (br),
29.3, 29.1 (2), 29.0 (br) [(CH2)6]; 26.9 (br), 20.0, 19.1 (br) [CHMe2,
CH(CH3)2, COCH3] ppm. FAB MS of C34H48N4O5 (M, 592.4): m/z
= 592 [M]+. HRMS of C34H48N4Na1O5 [M + Na]: 615.3530; calcd.
615.3517. M + H2O, C34H50N4O6 (610.78): calcd. C 66.86, H 8.25,
N 9.17 and C34H48N4O5 (592.77): calcd. C 68.89, H 8.16, N 9.45;
found C 66.05, H 8.16, N 9.45.
9,10,23,24-Tetraisopropyl-2-oxa-7,10,23,26-tetraazatricyclo[25.2.2.
23,6]tritriaconta-1(30),3(33),4,6(32),27(31),28-hexaene-8,11,22,25-
tetraone (13c): A solution of isobutyraldehyde (0.19 mL, 2 mmol)
and isopropylamine (0.18 mL, 2 mmol) in methanol (130 mL) was
stirred for 1 h at room temp., dodecanedioic acid (115 mg,
0.5 mmol) was added, and stirring was continued for another
30 min. Afterwards, a solution of diisonitrile 4 (110 mg, 0.5 mmol)
in methanol (10 mL) was slowly added to the reaction mixture by
syringe pump (flow rate 0.1 mLh–1). The reaction mixture was con-
centrated under reduced pressure, and column chromatography of
the residue on silica (CHCl3/MeOH 9:1) gave 13c as a dia-
stereomeric mixture, isolated as an amorphous solid (102 mg,
30%). TLC (CHCl3/MeOH 9:1) Rf = 0.31. 1H NMR (500 MHz;
CDCl3, δ of minor isomer in brackets): δ = 10.60, 10.40 (2ϫbr,
2ϫNH); 7.46 (7.39) (m, 4 H, Ar); (6.90) 6.88 (m, 4 H, Ar); 4.15
(m, 2 H, NCHMe2); 3.19 (br., 4 H, CHCHMe2); 2.65 (m, 2 H),
2.29 (m, 2 H) (CH2CO); 1.72 (m, 2 H), 1.54 (m, 2 H) (CH2CH2CO);
1.34–1.12 [m, 12 H, (CH2)6]; 1.28 (d, J = 6.6 Hz, 6 H), 1.23 (d, J
= 6.6 Hz, 6 H) [NCH(CH3)2]; 1.10 (d, J = 6.3 Hz, 6 H), 0.90 (d, J
= 6.3 Hz, 6 H) [CHCH(CH3)2] ppm. 13C NMR (75.5 MHz; CDCl3,
δ of minor isomer in brackets): δ = 175.7, 171.1 (CO); 154.2 (i-Ar);
134.3 (p-Ar); 120.6, 119.5 (119.7) (o-, m-Ar); 70.4 (CHCHMe2);
50.9 (NCHMe2); 35.0 (CH2CO); 30.0, 29.9 (3), 29.6 (2) [(CH2)6];
27.3 (CHCHMe2); 26.5 (CH2CH2CO); 21.5, 21.1 [NCH(CH3)2];
20.3, 20.1 [CHCH(CH3)2] ppm. FAB MS of C40H60N4O5 (M,
676.5): m/z = 676 [M]+. HRMS of C40H60N4Na1O5 [M + Na]:
699.4461; calcd. 699.4456. C40H60N4O5 (676.93): calcd. C 70.97, H
8.93, N 8.28; found C 71.09, H 8.33, N 8.65.
10,19-Diacetyl-2-oxa-7,10,19,22-tetraazatricyclo[21.2.2.23,6]nona-
cosa-1(26),3(29),4,6(28),23(27),24-hexaene-8,21-dione (16b): A mix-
ture of paraformaldehyde (60 mg, 2 mmol), 1,8-diaminooctane (15,
144 mg, 1 mmol), and sodium sulfate (2 g) in methanol (30 mL)
was stirred for 2 h at room temp., methanol (100 mL) and acetic
acid (0.12 mL, 2 mmol) were then added, and stirring was contin-
ued for another 30 min. Afterwards, a solution of diisonitrile 4
(220 mg, 1 mmol) in methanol (10 mL) was slowly added to the
reaction mixture by syringe pump (flow rate 0.1 mLh–1), and the
reaction mixture was filtered and concentrated under reduced pres-
sure. Column chromatography of the residue on silica (CHCl3/
MeOH 9:1) gave 16b as an amorphous solid (4.3 mg, 1%). TLC
10,23-Diisopropyl-2-oxa-7,10,23,26-tetraazatricyclo[25.2.2.23,6]tri-
triaconta-1(30),3(33),4,6(32),27(31),28-hexaene-8,11,22,25-tetraone
(13d): A mixture of paraformaldehyde (120 mg, 4 mmol), isopro-
pylamine (0.36 mL, 4 mmol) and sodium sulfate (2 g) in methanol
(40 mL) was stirred for 2 h at room temp., methanol (130 mL) and
dodecanedioic acid (230 mg, 1 mmol) were then added, and stirring
was continued for another 30 min. Afterwards, a solution of diiso-
nitrile 4 (220 mg, 1 mmol) in methanol (10 mL) was slowly added
to the reaction mixture by syringe pump (flow rate 0.1 mLh–1) and
the reaction mixture was filtered and concentrated under reduced
pressure. Column chromatography of the residue on silica (CHCl3/
MeOH 9:1) gave 13d as an amorphous solid (220 mg, 37%). TLC
1
(CHCl3/MeOH 9:1) Rf = 0.30. H NMR (500 MHz; [D6]DMSO):
δ = 10.20 (br., 1 H, NH); 9.65 (br., 1 H, NH); 7.38 (br., 4 H, Ar);
7.00 (br., 4 H, Ar); 4.10–3.90 (br., 4 H, 2ϫCOCH2); 3.15 (br., 4
H, 2ϫCH2CH2N); 2.00 (brs, 6 H, 2ϫAc); 1.40–0.90 (brm, 12 H,
6ϫCH2); (at 120 °C): δ = 9.40 (br., 2 H, NH); 7.36 (m, 4 H, Ar);
6.98 (m, 4 H, Ar); 3.95 (s, 4 H, 2ϫCOCH2); 3.20 (t, J = 7.0 Hz, 4
H, 2ϫCH2CH2N); 2.03 (s, 6 H, 2ϫAc); 1.30 (brs, 4 H, 2ϫCH2);
1.03 (brs, 8 H, 4ϫCH2) ppm. 13C NMR (125 MHz; [D6]DMSO):
δ = 170.5, 170.0, 167.2 (CO); 152.5, 152.3, 151.8 (i-Ar); 139.3,
134.4, 134.2 (p-Ar); 128.0, 124.8, 120.8 (2), 118.5 (o-, m-Ar); 51.5,
49.5, 49.0, 46.2 (NCH2); 35.0–20.0 (several signals from CH2 and
CH3); (at 120 °C): δ = 169.6, 168.0 (CO); 155.6 (i-Ar); 133.5 (p-
Ar); 123.9 (br), 119.7 (br) (o-, m-Ar); 35.0–20.0 (several broad sig-
nals) ppm. ESI-MS of C28H36N4O5 (M, 508.6): m/z = 509.3 [M +
H]+, 531.4 [M + Na]+. HRMS of C28H36N4O5Na [M + Na]:
531.2579; calcd. 531.2578.
1
(CHCl3/MeOH 9:1) Rf = 0.60. H NMR (500 MHz; [D6]DMSO, δ
of minor isomer in brackets): δ = 10.05 (9.52) (br., 2 H, 2ϫNH);
7.50 (m, 4 H, Ar); 6.91 (m, 4 H, Ar); 4.71 (4.15) (m, 2 H, CHMe2);
4.00 (3.80) (s, 4 H, 2 ϫ NCH2 CO); (2.36) 2.03 (m, 4 H,
CH2CH2CO); 1.42 (m, 4 H, CH2CH2CO); 1.20–1.00 [m, 24 H,
(CH2)6, 4 ϫ Me] ppm. 13C NMR (75.5 MHz; [D6]DMSO): δ =
172.2, 168.1 (CO); 153.9 (i-Ar); 134.0 (p-Ar); 121.3, 121.2, 119.9,
119.2, 118.6 (o-, m-Ar); 47.6, 45.2, 44.6, 43.8 (NCH2CO, CHMe2);
32.7, 31.9, 29.6, 29.1, 28.9, 25.0, 24.7, 20.7, 19.6 [(CH2)6,
4ϫMe] ppm. ESI-MS of C34H48N4O5 (M, 592.7): m/z = 593.7 [M
+ H]+, 615.6 [M + Na]+. HRMS of C34H48N4O5Na [M + Na]:
615.3511; calcd. 615.3517. C34H48N4O5 (592.77): calcd. C 68.89, H
8.16, N 9.45; found C 69.00, H 8.36, N 9.51.
10,19,35,44-Tetraacetyl-2,27-dioxa-7,10,19,22,32,35,44,47-octaaza-
pentacyclo[42.2.2.23,6.223,26.228,31]octapentaconta-1(51),
3(54),4,6(53),23,25,28,30,48(52),49,55,57-dodecaene-8,21,33,46-tet-
raone (17): Amorphous solid (55 mg, 11%). TLC (CHCl3/MeOH
1
9:1) Rf = 0.20. H NMR (500 MHz; [D6]DMSO, room temp.): δ =
10.20 (br., 2 H, NH); 9.95 (br., 2 H, NH); 7.58 (br., 8 H, Ar); 6.96
(br., 8 H, Ar); 4.15 (s, 4 H, 2ϫCOCH2); 4.05 (s, 4 H, 2ϫCOCH2);
3.40–3.20 (2 ϫ t, 8 H, 2 ϫ CH2CH2N); 2.20–1.90 (4 ϫ s, 12 H,
4ϫAc); 1.60–1.20 (brm, 24 H, 12 CH2) ppm. 13C NMR (125 MHz;
[D6]DMSO, room temp.): δ = 170.4 (2), 169.9, 167.2 (2) (CO);
152.7, 152.6, 152.5, 152.4, 151.5 (i-Ar); 139.2, 134.6, 134.5, 134.2
(2) (p-Ar); 128.0, 124.9, 120.8, 120.7, 118.8, 118.7 (o-, m-Ar); 51.7
(br), 49.6, 49.0, 46.4 (br) (NCH2); 35.0–20.0 (several signals from
CH2 and CH3) ppm. ESI-MS of C56H72N8O10 (M, 1017.2): m/z =
10,19-Diacetyl-9,20-diisopropyl-2-oxa-7,10,19,22-tetraazatricyclo-
[21.2.2.23,6]nonacosa-1(26),3(29),4,6(28),23(27),24-hexaene-8,21-di-
one (16a): A solution of isobutyraldehyde (0.19 mL, 2 mmol) and
1,8-diaminooctane (15, 144 mg, 1 mmol) in methanol (30 mL) was
stirred for 1 h at room temp., acetic acid (0.12 mL, 2 mmol) was
Eur. J. Org. Chem. 2007, 149–157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
155

D. Michalik, A. Schaks, L. A. Wessjohann
FULL PAPER
1039.7 [M + Na]+. HRMS of C56H72N8O10Na [M + Na]:
1039.5280; calcd. 1039.5264.
(18d): A mixture of paraformaldehyde (60 mg, 2 mmol), isopro-
pylamine (0.18 mL, 2 mmol), and sodium sulfate (2 g) in methanol
(40 mL) was stirred for 2 h at room temp., methanol (130 mL) and
octanedioic acid (174 mg, 1 mmol) were then added, and stirring
was continued for another 30 min. Afterwards, a solution of 4-[4-
(2-isocyanoethyl)phenoxy]phenyl isocyanide (11, 248 mg, 1 mmol)
in methanol (20 mL) was slowly added to the reaction mixture by
syringe pump (flow rate 0.1 mLh–1), and the reaction mixture was
filtered and concentrated under reduced pressure. Column
chromatography of the residue on silica (CHCl3/MeOH 9:1) gave
18d as an amorphous solid (40 mg, 7%). TLC (CHCl3/MeOH 9:1)
Rf = 0.72. 1H NMR (300 MHz; CDCl3, δ of minor isomer in brack-
ets): δ = (9.50) 9.34 (br., NH); (7.48) 7.44 (m, 2 H, Ar); 7.09 (7.02)
(m, 2 H, Ar); 6.92 (m, 4 H, Ar); 4.19 (m, 1 H, CHMe2); 4.08 (s, 2
H, COCH2N); 3.98 (m, 1 H, CHMe2); 3.86 (s, 2 H, COCH2N);
2.74 (t, 2 H, CH2Ar); 2.51, 2.23 (2ϫt, 4 H, 2ϫCOCH2); 1.80–1.00
[brm, 8 H, (CH2)4]; 1.27 (d, J = 6.7 Hz, 6 H, Me); 1.15 (d, J =
6.7 Hz, 6 H, Me) ppm. 13C NMR (75.5 MHz; CDCl3, δ of minor
isomer in brackets): δ = 174.5, (173.9), 173.2, 170.7, 168.5, (167.2)
(CO); (156.1), 155.9, (154.3), 154.0 (i-, iЈ-Ar); 134.2, (134.1), 133.4
(132.3) (p-, pЈ-Ar); 130.1, (129.9), (121.0), 120.4, (119.8), 119.5,
118.9 (o-, oЈ-, m-, mЈ-Ar); 49.8, (48.8), 48.7 (CHMe2); 46.7, 45.8,
40.5, (40.4), 34.7, (33.7), 33.5, 33.0, 30.3, (29.5), 29.4, 26.1, (25.4),
25.3 (CH2); 21.1, (20.8), 20.7, (20.4) (Me) ppm. ESI-MS of
C32H44N4O5 (M, 564.7): m/z = 565.5 [M + H]+, 587.3 [M + Na]+.
HRMS of C38H58N4O5 [M + H]: 565.3375; calcd. 565.3385.
C32H44N4O5 (564.72): calcd. C 68.06, H 7.85, N 9.92; found C
68.03, H 7.95, N 9.97.
9,10,16,17-Tetraisopropyl-2-oxa-7,10,16,19-tetraazatricyclo[20.2.
2.23,6]octacosa-1(25),3(28),4,6(27),22(26),23-hexaene-8,11,15,18-tet-
raone (18a): A solution of isobutyraldehyde (0.19 mL, 2 mmol) and
isopropylamine (0.18 mL, 2 mmol) in methanol (130 mL) was
stirred for 1 h at room temp., glutaric acid (66 mg, 0.5 mmol) was
then added, and stirring was continued for another 30 min. After-
wards, a solution of 4-[4-(2-isocyanoethyl)phenoxy]phenyl isocya-
nide (11, 124 mg, 0.5 mmol) in methanol (20 mL) was slowly added
to the reaction mixture by syringe pump (flow rate 0.1 mLh–1),
and the reaction mixture was concentrated under reduced pressure.
Column chromatography of the residue on silica (CHCl3/MeOH
9:1) gave 18a as a diastereomeric mixture, isolated as an amorphous
solid (116 mg, 38%). TLC (EtOAc) Rf = 0.31. 1H NMR (500 MHz;
CDCl3): δ = 10.53, 10.21 (2 broad signals, ArNH); 8.29–7.95 (5
broad signals, CH2NH); 7.48–6.74 (several multiplets, Ar); 5.06 (d,
J = 11.0 Hz, CHCHMe2); 4.18–3.75 (m), 3.42 (m), 3.20–2.00 (sev-
eral multiplets, CHCHMe2, NCHMe2, CH2); 1.90–0.70 (several
multiplets from Me) ppm. 13C NMR (125 MHz; CDCl3): δ = 174.5,
174.0; 173.8, 173.3, 173.1, 172.8, 171.9, 171.5, 171.4, 171.3, 171.1,
170.9 (CO); 158.5, 157.0, 156.7, 156.3 (2), 156.1 (i-Ar); 135.1, 134.4,
134.2, 132.3, 130.7 (p-Ar); 130.5, 130.3, 130.1, 130.0, 129.9, 129.8,
123.2, 120.9, 120.6, 120.5, 119.9, 118.3, 116.7 (o-, m-Ar); 70.4 (br),
68.7 (br), 68.4 (br), 68.3, 61.2, 61.1, 58.0 (br., COCHN); 51.0 (br),
50.1 (br), 50.0, 49.6, 47.6, 47.2, 45.4 (br) (NCHMe2); 41.0, 40.8,
40.3, 40.2, 35.5, 35.2 (2), 35.1, 34.9, 34.7, 34.4, 33.6, 32.6, 32.0
(CH2); 28.3, 28.1, 27.4 (br), 27.0 (br), 26.6, 26.4 (CHCHMe2); 22.6–
18.5 (several signals from Me) ppm. ESI-MS of C35H50N4O5 (M,
606.4): m/z = 607.4 [M + H]+, 629.3 [M + Na]+. HRMS of
C35H50N4Na1O5 [M + Na]: 629.3656; calcd. 629.3673.
10,17-Diacetyl-9,18-diisopropyl-2-oxa-7,10,17,20-tetraazatricyclo-
[21.2.2.23,6]nonacosa-1(26),3(29),4,6(28),23(27),24-hexaene-8,19-di-
one (20a): A solution of isobutyraldehyde (0.19 mL, 2 mmol) and
1,6-diaminohexane (19, 116 mg, 1 mmol) in methanol (30 mL) was
stirred for 1 h at room temp., acetic acid (0.12 mL, 2 mmol) was
then added, and stirring was continued for another 30 min. After
addition of methanol (100 mL), a solution of 4-[4-(2-isocyanoethyl)
phenoxy]phenyl isocyanide (11, 124 mg, 0.5 mmol) in methanol
(10 mL) was slowly added to the reaction mixture by syringe pump
(flow rate 0.1 mLh–1), and the reaction mixture was concentrated
under reduced pressure. Column chromatography of the residue on
silica (CHCl3/MeOH 9:1) gave 20a as a diastereomeric mixture,
isolated as an amorphous solid (136 mg, 46 %). TLC (CHCl3/
9,10,19,20-Tetraisopropyl-2-oxa-7,10,19,22-tetraazatricyclo[23.2.
2.23,6]hentriaconta-1(28),3(31),4,6(30),25(29),26-hexaene-8,11,
18,21-tetraone (18c): A solution of isobutyraldehyde (0.19 mL,
2 mmol) and isopropylamine (0.18 mL, 2 mmol) in methanol
(130 mL) was stirred for 1 h at room temp., octanedioic acid
(87 mg, 0.5 mmol) was then added, and stirring was continued for
another 30 min. Afterwards, a solution of 4-[4-(2-isocyanoethyl)
phenoxy]phenyl isocyanide (11, 124 mg, 0.5 mmol) in methanol
(10 mL) was slowly added to the reaction mixture by syringe pump
(flow rate 0.1 mLh–1), and the reaction mixture was concentrated
under reduced pressure. Column chromatography of the residue on
silica (CHCl3/MeOH 9:1) gave 18c as a diastereomeric mixture, iso-
lated as an amorphous solid (165 mg, 51%) that can contain meth-
1
MeOH 95:5) Rf = 0.49. H NMR (300 MHz; CDCl3): δ = 7.50 (m,
2 H, Ar); 7.04 (m, 2 H, Ar); 6.94 (m, 2 H, Ar); 6.83 (m, 2 H,
Ar); 4.80 (br., 2 H, CHN); 3.80 (br., 2 H, NCH2); 3.30 (br., 4 H,
2 ϫCH2NAc); 2.95–2.30 (br m, 4 H, CH2Ar, 2ϫCHMe2); 2.19,
1.78 (2ϫs, 6 H, 2ϫAc); 1.60–1.10 [brm, 8 H, (CH2)4]; 1.05, 0.92,
0.84, 0.78 (4 ϫ d, J = 6.6 Hz, 12 H, 4 ϫ CH3) ppm. 13C NMR
(75.5 MHz; CDCl3): δ = 172.4, 172.1, 170.6, 169.3 (br) (CO); 156.9,
154.0 (i-, iЈ-Ar); 134.1, 133.3 (p-, pЈ-Ar); 129.4, 120.7, 120.5, 118.7
(o-, oЈ-, m-, mЈ-Ar); 62.1 (br., CHN); 48.2, 44.4 (2ϫbr, NCH2);
37.9, 33.9, 30.4 (br), 29.1, 27.9, 26.7, 25.7 (br) [(CH2)4, CHMe2];
26.4, 22.0, 20.0, 19.9, 19.7, 18.5 (br) (CHCH3, COCH3) ppm. EI-
MS of C34H48N4O5 (M, 592.4): m/z = 592 [M]+. HRMS of
C34H49N4O5 [M + H]: 593.3696; calcd. 593.3697.
10,19-Diacetyl-2-oxa-7,10,19,22-tetraazatricyclo[23.2.2.23,6]hentria-
conta-1(28),3(31),4,6(30),25(29),26-hexaene-8,21-dione (20b): A
mixture of paraformaldehyde (60 mg, 2 mmol), 1,8-diaminooctane
(15, 144 mg, 1 mmol) and sodium sulfate (2 g) in methanol (40 mL)
was stirred for 2 h at room temp., methanol (130 mL) and acetic
acid (0.12 mL, 2 mmol) were then added, and stirring was contin-
ued for another 30 min. Afterwards, a solution of 4-[4-(2-isocyano-
ethyl)phenoxy]phenyl isocyanide (11, 248 mg, 1 mmol) in methanol
(20 mL) was slowly added to the reaction mixture by syringe pump
1
anol. TLC (EtOAc) Rf = 0.39. H NMR (300 MHz; CDCl3): δ =
10.56, 8.26 (2ϫbr, 2ϫNH); 7.45 (m, 2 H, Ar); 7.13 (m, 2 H, Ar);
6.91 (m, 4 H, Ar); 4.10–3.90 (brm, 4 H, CHN); 3.10–2.10 (broad
signals, 10 H, NCH2, 2ϫCOCH2, CH2Ar, 2ϫCHMe2); 1.90–1.10
[broad signals, 8 H, (CH2)4]; 1.26 (d, J = 6.6 Hz, 6 H, Me); 1.15
(d, J = 6.5 Hz, 3 H, Me); 1.08 (d, J = 6.2 Hz, 6 H, Me); 1.02 (d, J
= 6.5 Hz, 3 H, Me); 0.88 (d, J = 6.2 Hz, 3 H, Me); 0.74 (d, J =
6.5 Hz, 3 H, Me) ppm. 13C NMR (75.5 MHz; CDCl3): δ = 174.8,
173.7, 173.2 (br), 170.9 (CO); 155.7, 154.2 (i-, iЈ-Ar); 134.7, 133.6
(p-, pЈ-Ar); 130.1, 120.7, 119.7, 118.6 (o-, oЈ-, m-, mЈ-Ar); 70.1, 68.5
62.1 (br., COCHN); 50.6, 49.9 (NCHMe2); 40.3, 35.3, 34.3, 30.3,
29.5, 25.8, 25.7 (CH2); 27.5, 26.5 (CHCHMe2); 21.5, 21.1, 20.6,
20.4, 20.3 (2), 20.0 (2) (Me) ppm. EI-MS of C38H57N4O5 (M,
648.4): m/z = 648 [M]+. HRMS of C38H58N4O5 [M + H]: 649.4314;
calcd. 649.4323. M+MeOH; C39H60N4O6 (680.92): calcd. C 68.79,
H 8.88, N 8.23; found C 69.03, H 8.76, N 8.41.
10,19-Diisopropyl-2-oxa-7,10,19,22-tetraazatricyclo[23.2.2.23,6]hen-
triaconta-1(28),3(31),4,6(30),25(29),26-hexaene-8,11,18,21-tetraone
156
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Eur. J. Org. Chem. 2007, 149–157

Synthesis of Biaryl Ether-Cyclopeptoid Macrocycles
FULL PAPER
(flow rate 0.1 mLh–1), and the reaction mixture was filtered and
concentrated under reduced pressure. Column chromatography of
the residue on silica (CHCl3/MeOH 9:1) gave 20b as an amorphous
solid (62 mg, 11 %) that can contain methanol. TLC (CHCl3/
MeOH 9:1) Rf = 0.37. 1H NMR (300 MHz; CDCl3, δ of minor
isomer in brackets): δ = 9.30 (9.11) (s, NH); 7.45 (m, 2 H, Ar); 7.05
(m, 2 H, Ar); 6.91 (m, 2 H, Ar); 6.83 (m, 2 H, Ar); (4.12) 4.10,
3.83 (2ϫs, 4 H, COCH2N); 3.50 (m, 4 H), (3.06) 2.98 (t, 2 H), 2.80
(t, 2 H) (ArCH2, 3ϫNCH2); 2.21, 1.95 (2ϫs, 6 H, 2 ϫMe); 1.75–
1.00 [brm, 12 H, (CH2)6] ppm. 13C NMR (75.5 MHz; CDCl3, δ of
minor isomer in brackets): δ = 172.6, 171.0, (170.9), 169.2, (168.6),
186.4, (167.8) (CO); (156.9), 156.4, 153.3 (i-, iЈ-Ar); 133.5, 133.2,
(132.6) (p-, pЈ-Ar); 129.9, (121.8), 121.4, 119.8, (118.7), 118.1 (o-,
oЈ-, m-, mЈ-Ar); (58.4), 54.2, (52.5), 52.4, (52.0), 50.9, 50.2, (46.6),
(40.4), 39.5 (NCH2); (34.1), 34.0, 30.2, (29.9), (29.5), 29.1, 28.9,
28.4, (27.5), (27.0), 26.7, 26.5 (CH2); 21.9, 21.1 (2ϫMe) ppm. ESI-
MS of C30H40N4O5 (M, 536.3): m/z = 537.5 [M + H]+, 559.4 [M
+ Na]+. HRMS of C30H40N4O5Na [M + Na]: 559.2887; calcd.
559.2891. M + MeOH, C31H44N4O6 (568.70): calcd. C 65.47, H
7.80, N 9.85; found C 65.33, H 7.40, N 9.85.
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Received: April 24, 2006
Published Online: November 6, 2006
Eur. J. Org. Chem. 2007, 149–157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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