The formation of trans-fused macrocycles from N3,N 3′-polymethylenebis-(hydantoins) by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.200700836

A straightforward ring transformation giving polymethylenebis(hydantoins) was extended, as these are HMBA analogues. Firstly, ethyl or allyl pyroglutamate was carbamoylated with a diisocyanate. Upon treatment with KOtBu in allyl alcohol the bis(carbamoyll

Full text of DOI:10.1002/ejoc.200700836

FULL PAPER
DOI: 10.1002/ejoc.200700836
The Formation of trans-Fused Macrocycles from N3,N3Ј-Polymethylenebis-
(hydantoins) by Ring-Closing Metathesis
Diederica D. Claeys,[a][‡] Christian V. Stevens,*[a] and Nicolai Dieltiens[a]
Keywords: Nitrogen heterocycles / Lactams / Macrocycles / Rearrangement / Pyroglutamates / Hydantoins / Ring-closing
metathesis / Isocyanates
A straightforward ring transformation giving polymethyl-
second-generation Grubbs’ catalyst to form macrocycles con-
enebis(hydantoins) was extended, as these are HMBA ana- taining the ester functionality in the ring. It was established
logues. Firstly, ethyl or allyl pyroglutamate was carbamo-
ylated with a diisocyanate. Upon treatment with KOtBu in
allyl alcohol the bis(carbamoyllactam) rearranged to give the
hydantoin, which was followed by the ring-opening of the
by HSQC experiments with inverse detection that only the E
isomers were formed in the cases of the 24- and 26-mem-
bered heterocycles.
pyrrolidinone with formation of the allyl ester. These com- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
pounds were subsequently ring-closed in the presence of
Germany, 2008)
Introduction
Hydantoins, first identified as products of undesired side-
reactions in peptide chemistry, have attracted much interest
in drug discovery because of their wide range of therapeutic
properties, which include, among others, antiarrhythmic,[1]
anticonvulsant,[2] antitumour,[3] antidiabetic[4] and antimus-
carinic[5] activities. Several clinically important pharmaceu-
ticals, such as phenytoin (1, Figure 1), which is used to treat
certain types of epileptic seizures,[6] and nilutamide (2), an
antiandrogen medication used in the treatment of prostate
cancer, are based upon this heterocyclic scaffold. Hydan-
toins are useful not only for human medicine, but also in
agriculture. Hydantocidin (3) is a naturally occurring spiro-
hydantoin with herbicidal activities,[7] while iprodion (4) is
a commercially used fungicide.
Figure 1. Phenytoin (1), nilutamide (2), hydantocidin (3) and ipro-
Hydantoins may be regarded as cyclic ureides of α-amino dion (4).
acids, and these two types of compounds are readily in-
terconvertible. A number of methods to synthesise hydan-
toins exist.[8,9] Treatment of α-amino acids, nitriles or
from amino acids or derivatives with carbonic acid deriva-
amides with alkali cyanates is used mainly for the prepara-
tion of hydantoins with substituents at their C-5 positions,
but also for N1-substituted hydantoins. Treatment of free α-
amino acids, esters or nitriles with isocyanates is valuable
when hydantoins substituted at their N-3 positions are de-
sired. Urea can be treated with α-amino acids, α-hydroxy
acids, α-hydroxy nitriles, α-dicarbonyl compounds or unsat-
urated acids. Further, a range of other methods starting
tives such as phosgene, alkyl chloroformates or 1,1Ј-carbon-
yldiimidazole (CDI) have been described, while another ge-
neral method is the Bucherer–Bergs synthesis of 5-substi-
tuted hydantoins from aldehydes and ketones through the
action of potassium cyanide and ammonium carbonate.
New synthetic methods are still being developed or older
ones further investigated; they include palladium-catalysed
reactions,[10] rearrangement reactions of 2,3-epoxydiaryl
ketones[11] and modified Bucherer–Bergs reactions with ni-
triles and organometallic reagents.[12] In solid-phase synthe-
sis the hydantoins are mostly synthesised from natural and
unnatural acyclic α-amino acids or dipeptides as starting
materials.[13]
[a] Research group SynBioC, Department of Organic Chemistry,
Faculty of Bioscience Engineering, Ghent University,
Coupure links 653, 9000 Ghent, Belgium
Fax: +32-9-2646243
E-mail: chris.stevens@ugent.be
[‡] Ph.D. fellow of the Research Foundation – Flanders (FWO).
Eur. J. Org. Chem. 2008, 171–179
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171

D. D. Claeys, C. V. Stevens, N. Dieltiens
FULL PAPER
Several N3,N3Ј-polymethylenebis(hydantoins) have been activity at a concentration of 10 µ,[21] the allyl esters of the
evaluated as hexamethylenebis(acetamide) (HMBA) ana- bis(hydantoins) were synthesised and further ring-closed by
logues. HMBA is a compound that induces cancer cells to ring-closing metathesis (RCM).[22,23] In this library of com-
differentiate to a less malignant phenotype, which provides pounds, the ester function is incorporated in the macro-
an attractive area for the development of new anticancer cyclic ring, endowing the molecule with lower polarity. Es-
drugs. These differentiation agents are expected to exhibit terification is also a bioreversible chemical derivatisation
reduced toxicity relative to conventional chemotherapeutic and is most popular for drugs containing carboxy or hy-
agents, since the mechanism is not primarily based on cyto- droxy functions. This was used in, for example, the synthe-
toxity. HMBA had some modest success in a phase II clin- sis of prodrugs to -prolines, where ester derivatives as well
ical trial.[14] Relatively high drug concentrations, of the or- as further macrocyclic ring-closed products were evalu-
der of 5 m, are required, but HMBA suffers from dose- ated.[24]
related toxicity and has a short biological lifetime as it un-
For the macrocycles that we have previously synthesised
dergoes rapid deacetylation and rapid renal clearance.[15] it was shown that only the trans isomers were formed.[19]
The bis(hydantoin) 5a (Figure 2) was about 10 times more This was also evaluated for the 24- and 26-membered rings
potent than HMBA. The phenytoin analogue 5b was very described below. As these ring structures are symmetrical
insoluble, which may have limited its activity.[16,17]
entities, JH,H coupling constants do not appear in the H
3
1
NMR spectra of these compounds, but can be recovered by
1
using H- and 13C-correlated spectra obtained by inverse
detection techniques.[25]
Results and Discussion
The hydantoins 11 were synthesised by the previously de-
scribed two-step protocol,[19] since the more straightforward
one-step ring-closing ring-opening (Scheme 1) did not go to
completion in THF and some side reactions resulting from
the attack of the alkoxide anions on the isocyanates oc-
curred. NaH was therefore added to a mixture of allyl pyro-
glutamate, synthesised by a Dean–Stark esterification reac-
tion, and diisocyanate in dry ether (Scheme 2). Almost im-
mediately after the addition of the base, a white precipitate
was formed. The reaction was quenched with saturated
NH4Cl solution after two hours. Stirring of the bis(carb-
amoyllactam) 11a in allyl alcohol with 2.1 equiv. KOtBu
afforded the bis(hydantoin) 12a.
Figure 2. Bis(hydantoins) as HMBA analogues.
The bis(hydantoins) were synthesised through N-3-selec-
tive alkylation of the hydantoins with 1,6-dihalohexanes.
The associated problems of selectivity and the low yields
can be circumvented using the protocol described below.
Recently we reported on the pyroglutamate–hydantoin
rearrangement:[18] when a solution of pyroglutamate and
iso(thio)cyanate is treated with NaH in THF, ring-closure
to the hydantoin occurs, with simultaneous ring-opening of
the pyrrolidinone (Scheme 1). With this reaction in ether as
a solvent, the intermediate sodium salt of the N-carbamo-
ylated pyroglutamate precipitates and can be easily isolated.
These products of the double ring-transformation can be
converted into bicyclic hydantoin derivatives[18] and macro-
cycles.[19]
In view of the promising results of earlier biotesting by
chick heart invasion assay,[20] in which some bis(hydantoins)
with hexa- and octamethylene spacers showed anti-invasive
Scheme 1.
Scheme 2.
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Macrocycles from Bis(hydantoins)
It was investigated whether one could start from ethyl to the formation of carbamic acids, which after decarboxyl-
pyroglutamate and perform a transesterification simulta- ation produce amines, which add to isocyanates to form
neously with the pyroglutamate–hydantoin rearrangement urea derivatives. These can be precipitated in ether, but col-
(Table 1). For this purpose the ethyl pyroglutamate was car- umn chromatography is needed to achieve complete purity.
bamoylated in ether with 1,6-diisocyanatohexane and then
The obtained hydantoins can be further derivatised by
rearranged in allyl alcohol by treatment with KOtBu. This alkylation at nitrogen (Scheme 3). To introduce N-benzyl
sequence resulted in pure bis(hydantoin) 12b in a slightly groups, the imidazolidinediones 12 were heated at reflux
higher yield – 85% in comparison with 71% – for the com- overnight in acetone with an excess of electrophile (mostly
plete sequence in Scheme 2. Unfortunately, though, this the corresponding bromide) and finely ground K2CO3. The
protocol could not be used successfully for diisocyanates alkylation had a 100% conversion, but the chromatographic
with longer alkyl chains, since not only carbamoylation, but removal of the excess of electrophile caused the yield to
also rearrangement had started even during the intended drop. For the methylation, iodomethane and NaH in DMF
preparation of 11d. This is in contrast with our previous were used. The yields presented in Scheme 3 are those after
results with short-chain alkylisocyanates and arylisocyan- purification of 13.
ates, which did not rearrange even after stirring overnight
The N-alkylation also serves as protection methodology
in ether. After workup, the hydantoin, which in this case is for the N-lactam to prevent deactivation of the catalyst used
the side-product, could be precipitated in diethyl ether for the cyclisation. RCM is a powerful method to synthesise
(34% yield) while the carbamoylated product had to be macrocyclic products; substrates devoid of any conforma-
purified by column chromatography (48% yield, 11d). The tional constraints can be cyclised by it. Neither the confor-
rearrangement resulted in 12d in high yield.
mational predisposition of the substrates nor the ring-size
play a decisive role, but the presence of polar relay substitu-
ents, their distance from the alkene groups and low steric
hindrance close to the double bond are important.[26] The
ring-closure was carried out by use of 5 mol-% of second-
generation Grubbs’ catalyst 16 (Figure 3).[27] Simply heating
the compounds at reflux overnight together with the ruthe-
nium catalyst resulted in quantitative conversion to the
macrocycles.
Table 1. Yields of carbamoylation and rearrangement of pyrogluta-
mate 6.
n
Path A, R = allyl
Path B, R = ethyl
Carbamoylation Rearrangement Carbamoylation Rearrangement
1
3
7
11a 83%
11e 91%
12a 86%
11b 93%
12b 91%
12d 96%
12c 86%[a]
12e 49%[c]
11d 48%[b]
[a] Product 11c was not purified from the mixture with 12c. [b]
Drop in yield due to purification of 11d from the crude mixture
with the hydantoin by column chromatography. [c] Purified by col-
umn chromatography.
Also in the case of allyl pyroglutamate, prolonged stir-
ring in ether causes the sodium salts of the carbamoylated
lactams (11c and 11e) to rearrange partially to the hydan-
toins (12c and 12e), though the crude mixtures could be
further used for the rearrangement in allyl alcohol. The re-
arrangement in ether can be limited by shortening the reac-
Figure 3. First- and second-generation Grubbs’ catalysts.
Usually RCM results in mixtures of E and Z isomers,
tion time to 30 minutes and by using a 0.1 to 0.2  concen- but in some cases only E isomers have been formed.[28] The
tration of the pyroglutamate. The limited reaction time is use of the fully saturated second-generation Grubbs’ cata-
important, as side reactions occur with, for example, the lyst 16 affords much higher E/Z ratios than the use of the
nucleophilic alkoxide anions. Moreover, it is very important standard Grubbs’ carbene 15.[29] This is caused by the abil-
to work under dry conditions, as the presence of water leads ity of 16 to isomerise the initial product under the reaction
Scheme 3.
Eur. J. Org. Chem. 2008, 171–179
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173

D. D. Claeys, C. V. Stevens, N. Dieltiens
FULL PAPER
of compound between two sodium chloride plates. Crystalline com-
pounds were mixed with KBr and pressed in a transparent plate.
Melting points of crystalline compounds were measured with a
Büchi 540 apparatus and have not been corrected. The elemental
analysis was performed with a Perkin–Elmer 2400 Elemental Ana-
lyzer. The purification of reaction mixtures was performed by col-
umn chromatography in a glass column with silica gel (Across, par-
ticle size 0.035–0.070 mm, pore diameter ca. 6 nm). Removal of the
Grubbs’ catalyst was achieved by preparative thin-layer chromatog-
raphy.
conditions, thereby progressively enriching the mixture in
the thermodynamically favoured E isomer.[30]
Also in this case, two separate signals for the alkene pro-
tons of derivatives 14 were observed. Since these macro-
cycles 14 have two chiral centres, these can be diastereomers
as well. Usually the E and Z isomers are distinguished
through their 3JH,H NMR coupling constants, but these are
3
absent as the macrocycles are symmetrical. These JH,H
coupling constants, however, can be recovered when an
H,C-inverse-detection spectrum is acquired without car-
bon-decoupling during acquisition. In the inverse-detected
H,C-correlation spectra, the major component due to sig-
nals coming from H bonded to 12C, which represents 99%
of the total number of C atoms in normal 1H NMR spectra,
In the next part the procedures and spectroscopic data are given
for the different types of reaction. The amounts in grams were used
for the synthesis of the products that are given just underneath the
procedures.
Typical Experimental Procedure for the Carbamoylation of Pyro-
glutamates at Nitrogen: The pyroglutamate ester (2.48 g,
14.66 mmol) was dissolved in dry diethyl ether (70 mL, freshly dis-
tilled from Na metal), the diisocyanate (1.24 g, 7.37 mmol) was
added by syringe, and the mixture was briefly stirred. After ad-
3
is suppressed. By doing this, the JH,H coupling constants
between equivalent protons can be observed.[25]
The diastereomers of 14a and 14c were separated by pre-
parative thin-layer chromatography (TLC), though
chromatography again caused a large drop in yield. For 14c, dition of NaH (0.36 g, 15.00 mmol) the reaction mixture was
stirred under nitrogen for 0.5 to 2 hours, while a white precipitate
formed. The reaction was then quenched with saturated NH4Cl
solution until the pH was neutral or slightly acidic. The mixture
was extracted three times with EtOAc, and the organic layers were
dried with MgSO4 and filtered. Compound 11c was further purified
by column chromatography. The allyl ester derivatives can be used
without purification in the subsequent rearrangement reaction, as
they appear with the rearranged product.
coupling constants of 17.4 and 18.1 Hz were observed,
pointing to trans geometries for both isomers.
Further evidence that a mixture of diastereomers rather
than E and Z isomers is formed was provided by an experi-
ment in which one of the diastereomers of 13e was isolated
in pure form by column chromatography. This so-called
“diastereomer” is actually a mixture of two enantiomers,
which cannot be distinguished in the NMR spectra. Heat-
ing of this diastereomer at reflux with Grubbs’ catalyst 16
gave one product in the 13C NMR spectrum, so only the E
or the Z isomer was formed, as otherwise two products
should have been observed in the 13C NMR spectrum. The
coupling constant of 14e was 17.7 Hz, again pointing to the
formation of the E isomer.
Allyl 1-{6-[(2-Allyloxycarbonyl-5-oxopyrrolidin-1-ylcarbonyl)-
amino]hexylcarbamoyl}-5-oxopyrrolidine-2-carboxylate (11a): Yield
1
83%, 3.08 g. H NMR (300 MHz, CDCl3): δ = 1.30–1.40 (m, 4 H,
CH2CH2), 1.50–1.60 (m, 4 H, 2ϫCH2CH2N), 2.01–2.11 (m, 2 H,
2ϫCHaHb, ring), 2.28–2.42 (m, 2 H, 2ϫCHaHb, ring), 2.57 (ddd,
J = 17.7, 9.4, 3.3 Hz, 2 H, 2 ϫ CHaHbCO), 2.75 (dt, J = 17.7,
9.9 Hz, 2 H, 2ϫCHaHbCO), 3.18–3.37 (m, 4 H, 2ϫNCH2), 4.68
(brd, J = 5.7 Hz, 4 H, 2ϫOCH2), 4.82 (dd, J = 9.6, 2.8 Hz, 2 H,
2ϫCH), 5.26 (ddd, Jcis = 10.5, 2.3, 1.1 Hz, 2 H, 2ϫ=CHaHb), 5.35
(ddd, Jtrans = 17.3, 2.3, 1.4 Hz, 2 H, 2ϫ=CHaHb), 5.92 (ddt, Jtrans
= 17.3 Hz, Jcis = 10.5 Hz and Jvic = 5.7 Hz, 2 H, 2ϫCH=CH2),
8.28 (t, J = 5.2 Hz, 2 H, 2 ϫ NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.25 (2 ϫ CH2, ring), 26.46 (CH2CH2), 29.47
Conclusions
The pyroglutamate hydantoin rearrangement has been
used to construct N3,N3Ј- polymethylenebis(hydantoins),
which are HMBA analogues and showed anti-invasive ac- (2 ϫ CH2CH2N), 31.83 (2 ϫ CH2CO), 39.80 (2 ϫ NCH2), 58.10
(2 ϫ CH), 66.14 (2 ϫ OCH2 ), 118.89 (2 ϫ =CH2 ), 131.43
(2ϫCH=CH2), 152.18 (2ϫC=O, urea), 171.17 (2ϫC=O, ester),
tivity in the chick heart assay. The biological data will be
published in due course. After N-alkylation or N-arylation,
the bis(hydantoins) were ring-closed to form 24- to 30-
membered macrocycles, again indicating the power of ring-
closing metathesis. The use of second-generation Grubbs’
catalyst 16 resulted in exclusive formation of the trans iso-
mers, as was confirmed by undecoupled HSQC.
176.32 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1651 (C=C),
˜
max
1689 (C=O), 1719 (C=O), 1745 (C=O), 3317 (NH) cm–1. MS: m/z
(%) = 507 (100) [M + H]+. C24H34N4O8 (506.55): calcd. C 56.91,
H 6.77, N 11.06; found C 57.14, H 6.41, N 11.38.
Ethyl 1-{6-[(2-Ethoxycarbonyl-5-oxopyrrolidin-1-ylcarbonyl)-
amino]hexylcarbamoyl}-5-oxopyrrolidine-2-carboxylate (11b): Yield
93 %, 1.43 g, white powder, m.p. 79 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.29 (t, J = 7.2 Hz, 6 H, 2ϫCH3), 1.32–1.38 (m, 4 H,
CH2CH2), 1.50–1.59 (m, 4 H, 2ϫCH2CH2N), 1.99–2.09 (m, 2 H,
2ϫCHaHb, ring), 2.27–2.41 (m, 2 H, 2ϫCHaHb, ring), 2.57 (ddd,
J = 17.6, 9.4, 3.3 Hz, 2 H, 2 ϫ CHaHbCO), 2.74 (dt, J = 17.6,
9.9 Hz, 2 H, 2ϫCHaHbCO), 3.18–3.37 (m, 4 H, 2ϫNCH2), 4.24
(q, J = 7.2 Hz, 4 H, 2ϫOCH2), 4.78 (dd, J = 9.4, 2.8 Hz, 2 H,
2 ϫ CH), 8.28 (t, J = 5.5 Hz, 2 H, 2 ϫ NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.21 (2 ϫ CH3), 21.37 (2 ϫ CH2, ring),
26.58 (CH2CH2), 29.60 (2ϫCH2CH2N), 31.98 (2ϫCH2CO), 39.91
(2ϫNCH2), 58.26 (2ϫCH), 61.80 (2ϫOCH2), 152.32 (2ϫC=O,
urea), 171.61 (2ϫC=O, ester), 176.49 (2ϫC=O, lactam) ppm. IR
Experimental Section
General Remarks: High-resolution 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were run with a Jeol EX300 Eclipse NMR
spectrometer. Peak assignments were obtained with the aid of 2D-
HSQC, 2D-HMBC and 2D-COSY spectra. The compounds were
diluted in deuterated solvents, and the solvent used is indicated for
each compound. Low-resolution mass spectra were recorded with
an Agilent 1100 Series VS (ES = 4000 V) mass spectrometer. IR
spectra were obtained with a Perkin–Elmer Spectrum One infrared
spectrometer. The samples were collected by preparing a thin film
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Macrocycles from Bis(hydantoins)
(NaCl): ν
= 1693 (C=O), 1722 (C=O), 1742 (C=O), 3320
(t, J = 7.2 Hz, 4 H, 2 ϫ CH2CO), 3.48 (t, J = 7.2 Hz, 4 H,
˜
max
(NH) cm–1. MS: m/z (%) = 483 (100) [M + H]+. C22H34N4O8 2ϫNCH2), 4.10 (brt, J = 5.8 Hz, 2 H, 2ϫCH), 4.60 (d, J = 5.8 Hz,
(482.53): calcd. C 54.76, H 7.10, N 11.61; found C 54.47, H 7.26,
N 11.45.
4 H, 2ϫOCH2), 5.26 (dq, Jcis = 10.5, 1.1 Hz, 2 H, 2ϫ=CHaHb),
5.32 (dq, Jtrans = 17.1, 1.5 Hz, 2 H, 2ϫ=CHaHb), 5.91 (ddt, Jtrans
= 17.1, Jcis = 10.5, Jvic = 5.8 Hz, 2 H, 2ϫCH=CH2), 6.00 (brs, 2
H, 2 ϫ NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.12
(CH2CH2), 26.81 (2ϫCH2CH2CO), 27.82 (2ϫCH2CH2N), 29.68
(2 ϫ CH2 CO), 38.51 (2 ϫ NCH2 ), 56.25 (2 ϫ CH), 65.65
(2 ϫ OCH2), 118.83 (2 ϫ =CH2), 131.78 (2 ϫ CH=CH2), 157.28
(2ϫC=O, urea), 172.45 (2ϫC=O, ester), 173.54 (2ϫC=O, lac-
The mixture of 11c and the rearranged product was used without
purification.
Ethyl 1-{6-[(2-Ethoxycarbonyl-5-oxopyrrolidin-1-ylcarbonyl)-
amino]octylcarbamoyl}-5-oxopyrrolidine-2-carboxylate (11d): Yield
48%, 0.50 g; the rearranged product was also formed. 1H NMR
(300 MHz, CDCl3): δ = 1.26–1.32 (m, 14 H, 2ϫCH3, CH2CH2),
1.50–1.58 (m, 4 H, 2ϫCH2CH2N), 2.00–2.10 (m, 2 H, 2ϫCHaHb,
ring), 2.28–2.42 (m, 2 H, 2ϫCHaHb, ring), 2.57 (ddd, J = 17.6, J
= 9.4, 3.3 Hz, 2 H, 2ϫCHaHbCO), 2.75 (dt, J = 17.6, 9.9 Hz, 2 H,
2ϫCHaHbCO), 3.19–3.36 (m, 4 H, 2ϫNCH2), 4.24 (q, J = 7.2 Hz,
4 H, 2ϫOCH2), 4.77 (dd, J = 9.4, 2.8 Hz, 2 H, 2ϫCH), 8.29 (t, J
= 5.5 Hz, 2 H, 2ϫNH) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.08 (2ϫ CH3), 21.22 (2 ϫCH2, ring), 26.70 (CH2CH2), 29.09
(CH2CH2CH2CH2), 29.51 (2ϫCH2CH2N), 31.85 (2 ϫCH2CO),
39.85 (2 ϫ NCH2), 58.14 (2 ϫ CH), 61.62 (2 ϫ OCH2), 152.19
(2ϫC=O, urea), 171.48 (2ϫC=O, ester), 176.39 (2ϫC=O, lac-
tam) ppm. IR (KBr): ν
= 1650 (C=C), 1732 (C=O), 1771
˜
max
(C=O), 3234 (NH) cm–1. MS: m/z (%) = 505 (100) [M + H]+.
C24H34N4O8 (506.55): calcd. C 56.91, H 6.77, N 11.06; found C
56.82, H 6.82, N 10.99.
Allyl 3-(1-{8-[4-(2-Allyloxycarbonylethyl)-2,5-dioxoimidazolidin-1-
yl]octyl}-2,5-dioxoimidazolidin-4-yl)propionate (12c and 12d): Yield
86%, 1.05 g from 6a and 96%, 50 mg, white powder, m.p. 89 °C.
1H NMR (300 MHz, CDCl3): δ = 1.22–1.35 [m, 8 H, 2ϫN(CH2)2-
(CH2)2], 1.54–1.64 (m, 4 H, 2ϫNCH2CH2), 1.99–2.10 (m, 2 H,
2ϫCHaHbCH), 2.18–2.29 (m, 2 H, 2ϫCHaHbCH), 2.51 (t, J =
7.2 Hz, 4 H, 2ϫCH2CO), 3.47 (t, J = 7.3 Hz, 4 H, 2ϫNCH2),
4.10 (brt, J = 5.4 Hz, 2 H, 2ϫCH), 4.59 (brd, J = 5.8 Hz, 4 H,
2ϫOCH2), 5.26 (dq, Jcis = 10.4, 1.4 Hz, 2 H, 2ϫ=CHaHb), 5.32
tam) ppm. IR (NaCl): ν
= 1692 (C=O), 1721 (C=O), 1744
˜
max
(C=O), 3316 (NH) cm–1. MS: m/z (%) = 511 (100) [M + H]+.
Chromatography: Rf = 0.20 (PE/EtOAc, 1:1). C24H38N4O8
(510.58): calcd. C 56.46, H 7.50, N 10.97; found C 56.59, H 7.51,
N 11.04.
(dq, Jtrans = 17.2, 1.4 Hz, 2 H, 2ϫ=CHaHb), 5.91 (ddt, Jtrans
=
17.2, Jcis = 10.4, Jvic = 5.8 Hz, 2 H, 2ϫCH=CH2), 6.31 (s, 2 H,
2ϫNH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.64 [2ϫN(CH2)3-
CH2 ], 26.93 (2 ϫ CH2 CH), 28.06 (2 ϫ NCH2 CH2), 29.02
[2ϫN(CH2)2CH2], 29.69 (2ϫCH2CO), 38.79 (2ϫNCH2), 56.32
(2 ϫ CH), 65.74 (2 ϫ OCH2 ), 118.90 (2 ϫ =CH2 ), 131.91
(2ϫCH=CH2), 157.65 (2ϫC=O, urea), 172.54 (2ϫC=O, ester),
Allyl 1-{6-[(2-Allyloxycarbonyl-5-oxopyrrolidin-1-ylcarbonyl)-
amino]dodecylcarbamoyl}-5-oxopyrrolidine-2-carboxylate (11e):
Yield 91%, 0.63 g. 1H NMR (300 MHz, CDCl3): δ = 1.25–1.36 [m,
16 H, 2ϫN(CH2)2(CH2)4], 1.49–1.56 (m, 4 H, 2ϫCH2CH2N), 2.07
(ddt, J = 13.1, J = 9.8, 2.9 Hz, 2 H, 2ϫCHaHb, ring), 2.28–2.42
(m, 2 H, 2ϫCHaHb, ring), 2.57 (ddd, J = 17.6, J = 9.3, 3.2 Hz, 2
H, 2ϫCHaHbCO), 2.75 (dt, J = 17.6, 9.8 Hz, 2 H, 2ϫCHaHbCO),
3.19–3.37 (m, 4 H, 2ϫNCH2), 4.66–4.69 (m, 4 H, 2ϫOCH2), 4.82
(dd, J = 9.6, 2.9 Hz, 2 H, 2ϫCH), 5.27 (dbrq, J = 10.6, 1.4 Hz, 2
H, 2 ϫ =CHa Hb ), 5.35 (dbr q, Jtran s = 17.2, 1.4 Hz, 2 H,
2ϫ=CHaHb), 5.92 (ddt, Jtrans = 17.2, Jcis = 10.6, Jvic = 5.7 Hz, 2 H,
2ϫCH=CH2), 8.28 (t, J = 5.2 Hz, 2 H, 2ϫNH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.25 (2 ϫ CH2, ring), 26.86 (CH2CH2),
29.27 (2 ϫ CH2), 29.51 (2 ϫ CH2), 29.54 (2 ϫ CH2), 29.57
(2 ϫ CH2CH2N), 31.86 (2 ϫ CH2CO), 39.99 (2 ϫ NCH2), 58.11
(2 ϫ CH), 66.14 (2 ϫ OCH2 ), 118.91 (2 ϫ =CH2 ), 131.41
(2ϫCH=CH2), 152.16 (2ϫC=O, urea), 171.20 (2ϫC=O, ester),
173.73 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1649 (C=C),
˜
max
1706 (C=O), 1774 (C=O), 3310 (NH) cm–1. MS: m/z (%) = 535
(100) [M + H]+. C26H38N4O8 (534.60): calcd. C 58.41, H 7.16, N
10.48; found C 58.14, H 7.33, N 10.39.
Allyl 3-(1-{12-[4-(2-Allyloxycarbonylethyl)-2,5-dioxoimidazolidin-1-
yl]dodecyl}-2,5-dioxoimidazolidin-4-yl)propionate (12e): Yield 49%,
1
0.16 g, oil. H NMR (300 MHz, CDCl3): δ = 1.22–1.28 [m, 16 H,
2ϫN(CH2)2(CH2)4], 1.47–1.64 (m, 4 H, 2ϫCH2CH2N), 1.99–2.11
(m, 2 H, 2ϫCHaHbCH), 2.17–2.30 (m, 2 H, 2ϫCHaHbCH), 2.51
(t, J = 7.3 Hz, 4 H, 2 ϫ CH2CO), 3.47 (t, J = 7.2 Hz, 4 H,
2ϫNCH2), 4.11 (t, J = 5.9 Hz, 2 H, 2ϫCH), 4.59 (brd, J = 5.8 Hz,
4 H, 2ϫOCH2), 5.25 (dq, Jcis = 10.4, 1.4 Hz, 2 H, 2ϫ=CHaHb),
5.32 (dq, Jtrans = 17.1, 1.4 Hz, 2 H, 2ϫ=CHaHb), 5.91 (ddt, Jtrans
= 17.1, Jcis = 10.4, Jvic = 5.8 Hz, 2 H, 2ϫCH=CH2), 6.74 (s, 2 H,
2ϫNH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.74 [2ϫN(CH2)2-
CH2 ], 26.87 (2 ϫ CH2 CH), 28.09 (2 ϫ CH2CH2 N), 29.16
[2ϫN(CH2)3CH2], 29.49 [2ϫCH2CO and 2 ϫN(CH2)4(CH2)2],
38.78 (2 ϫ NCH2), 56.21 (2 ϫ CH), 65.62 (2 ϫ OCH2), 118.72
(2ϫ=CH2), 131.88 (2ϫCH=CH2), 157.84 (2ϫC=O, urea), 172.40
176.32 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1695 (C=O),
˜
max
1722 (C=O), 1745 (C=O), 3323 (NH) cm–1. MS: m/z (%) = 591
(100) [M + H]+. C30H46N4O8 (590.71): calcd. C 61.00, H 7.85, N
9.48; found C 60.62, H 7.62, N 9.41.
Typical Experimental Procedure for the Rearrangement of Carbamo-
ylated Pyroglutamates 11 to Hydantoins 12: The pyroglutamate es-
ter 11 (1.40 g, 2.76 mmol) was dissolved in allyl alcohol (20 mL)
and KOtBu (0.65 g, 5.79 mmol) was added. The mixture was stirred
at room temperature for 1 hour, protected from moisture with a
CaCl2 tube. The reaction mixture was quenched with a saturated
NH4Cl solution, extracted with EtOAc, dried with MgSO4 and fil-
tered. Removal of the solvent yielded the product. Product 12a was
crystallised from EtOAc, 12b and 12c were crystallised from dry
acetone, and 12e was further purified by column chromatography.
(2ϫC=O, ester), 173.78 (2ϫC=O, lactam) ppm. IR (NaCl): ν
˜
max
= 1651 (C=C), 1710 (C=O), 1733 (C=O), 1774 (C=O), 3337
(NH) cm–1. MS: m/z (%) = 591 (100) [M + H]+. Chromatography:
Rf = 0.01 (PE/EtOAc, 5:2). C30H46N4O8 (590.71): calcd. C 61.00,
H 7.85, N 9.48; found C 61.19, H 7.87, N 9.30.
Typical Procedure for the N-Alkylation of Hydantoins. Synthesis of
13a: The bis(hydantoin) (0.12 g, 0.24 mmol) was dissolved in THF
Allyl 3-(1-{6-[4-(2-Allyloxycarbonylethyl)-2,5-dioxoimidazolidin-1- (7 mL). Iodomethane (0.10 g, 0.70 mmol) was added by syringe,
yl]hexyl}-2,5-dioxoimidazolidin-4-yl)propionate (12a and 12b): Yield
followed by NaH (0.02 g, 0.83 mmol). The mixture was stirred
overnight, protected from moisture with a CaCl2 tube. The reaction
86%, 1.20 g and 91%, 0.42 g, white crystals, m.p. 99–103 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.28–1.39 (m, 4 H, CH2CH2), 1.56– was quenched with a saturated NH4Cl solution, extracted with
1 . 6 8 ( m , 4 H , 2 ϫ C H 2 C H 2 N ) , 1 . 9 8 – 2 . 1 0 ( m , 2 H , EtOAc, dried with MgSO4, filtered and coated on silica for column
2ϫCHaHbCH2CO), 2.17–2.29 (m, 2 H, 2ϫCHaHbCH2CO), 2.51 chromatography.
Eur. J. Org. Chem. 2008, 171–179
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
175

D. D. Claeys, C. V. Stevens, N. Dieltiens
Allyl 3-(1-{6-[4-(2-Allyloxycarbonylethyl)-3-methyl-2,5-dioxoimid- H, 2ϫ=CHaHb), 5.26–5.34 (m, 2 H, 2ϫ=CHaHb), 5.89 (ddt, Jtrans
FULL PAPER
azolidin-1-yl]hexyl}-3-methyl-2,5-dioxoimidazolidin-4-yl)propionate
(13a): Yield 55 %, 71 mg, yellowish oil. 1H NMR (300 MHz,
CDCl3): δ = 1.27–1.37 (m, 4 H, CH2CH2), 1.54–1.64 (m, 4 H,
= 16.7, Jcis = 10.3, Jvic = 5.8 Hz, 2 H, 2ϫCH=CH2), 7.16 (d, J =
8.4 Hz, 4 H, 4ϫCHar), 7.48 (d, J = 8.4 Hz, 4 H, 4ϫCHar) ppm.
13C NMR (75 MHz, CDCl3): δ = 23.81 (2ϫCH2CH2CO), 26.36
2ϫCH2CH2N), 2.02–2.19 (m, 2 H, 2ϫCHaHbCH2CO), 2.20–2.34 (CH2CH2), 28.10 (2 ϫ CH2CH2N), 28.20 (2 ϫ CH2CO), 39.09
(m, 2 H, 2ϫCHaHbCH2CO), 2.30–2.53 (m, 4 H, 2ϫCH2CO), 2.93
(s, 6 H, 2ϫNCH3), 3.47 (brt, J = 7.3 Hz, 4 H, 2ϫNCH2), 3.91
(dd, J = 6.5, 3.2 Hz, 2 H, 2ϫCH), 4.58 (brd, J = 5.8 Hz, 4 H,
2ϫOCH2), 5.25 (dbrq, J = 10.5, 1.2 Hz, 2 H, 2ϫ=CHaHb), 5.32
(dbrq, J = 17.2, 1.2 Hz, 2 H, 2ϫ=CHaHb), 5.90 (ddt, Jtrans = 17.2,
Jcis = 10.5, Jvic = 5.8 Hz, 2 H, 2 ϫ CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.73 (2ϫCH2CH2CO), 26.18 (CH2CH2),
27.85 (2ϫCH3), 27.93 (2ϫCH2CH2N), 28.11 (2ϫCH2CO), 38.78
(2 ϫ NCH2, alkyl), 60.05 (2 ϫ CH), 65.55 (2 ϫ OCH2), 118.68
(2ϫ=CH2), 131.89 (2ϫCH=CH2), 156.62 (2ϫC=O, urea), 171.98
(2ϫNCH2, alkyl), 44.34 (2ϫNCH2, benzyl), 57.67 (2ϫCH), 65.78
(2 ϫ OCH2), 118.93 (2 ϫ =CH2), 122.44 (2 ϫ Car,quat.), 130.21
(4 ϫ CHar), 132.07 (2 ϫ CH=CH2), 132.39 (4 ϫ CHar), 134.94
(2 ϫ Car,quat.), 156.88 (2ϫ C=O, urea), 172.12 (2 ϫC=O, ester),
172.40 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1705 (C=O),
˜
max
1732 (C=O), 1768 (C=O) cm–1. MS: m/z (%) = 843/845/847 (100)
[M + H]+. Chromatography: Rf = 0.17 (PE/EtOAc, 5:3).
C38H44Br2N4O8 (844.59): calcd. C 54.04, H 5.25, N 6.63; found C
53.81, H 5.29, N 6.32.
Allyl 3-(1-{8-[4-(2-Allyloxycarbonylethyl)-3-(4-chlorobenzyl)-2,5-di-
oxoimidazolidin-1-yl]octyl}-3-(4-chlorobenzyl)-2,5-dioxoimid-
azolidin-4-yl)propionate (13d): Yield 68 %, 51 mg. 1H NMR
(300 MHz, CDCl3): δ = 1.22–1.34 [m, 8 H, 2ϫN(CH2)2(CH2)2],
1.56–1.66 (m, 4 H, 2 ϫ NCH2 CH2 ), 1.98–2.10 (m, 2 H,
2ϫCHaHbCH), 2.17–2.26 (m, 2 H, 2ϫCHaHbCH), 2.24–2.45 (m,
4 H, 2ϫCH2CO), 3.50 (td, J = 7.4, 1.8 Hz, 4 H, 2ϫNCH2, alkyl),
3.81 (dd, J = 6.5, 2.9 Hz, 2 H, 2ϫCH), 4.11 (d, J = 15.3 Hz, 2 H,
2ϫNCHaHb, benzyl), 4.56 (d, J = 5.8 Hz, 4 H, 2ϫOCH2), 4.90 (d,
J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 5.25 (brd, Jcis = 10.8 Hz, 2
H, 2ϫ=CHaHb), 5.31 (brd, Jtrans = 16.9 Hz, 2 H, 2ϫ=CHaHb),
5.89 (ddt, Jt ra n s = 16.9, Jc i s = 10.8, Jv i c = 5.8 Hz, 2 H,
2ϫCH=CH2), 7.22 (d, J = 8.3 Hz, 4 H, 4ϫCHar), 7.32 (d, J =
8.3 Hz, 4 H, 4 ϫ CHar) ppm. 13C NMR (75 MHz, CDCl3): δ =
2 3 . 6 3 ( 2 ϫ C H 2 C H ) , 2 6 . 7 1 [ 2 ϫ N ( C H 2 ) 3 C H 2 ] , 2 8 . 0 3
(2 ϫ NCH2 CH2 or 2 ϫ CH2CO), 28.09 (2 ϫ NCH2CH2 or
2 ϫCH2CO), 29.03 [2ϫN(CH2)2CH2], 39.13 (2ϫNCH2, alkyl),
44.12 (2 ϫ NCH2, benzyl), 57.51 (2 ϫ CH), 65.65 (2 ϫ OCH2),
118.78 (2ϫ=CH2), 129.29 (4 ϫCHar), 129.76 (4ϫCHar), 131.93
(2ϫCH=CH2), 134.19 (2ϫCar,quat.), 134.31 (2ϫCar,quat.), 156.80
(2 ϫ C=O, urea), 172.01 (2 ϫ C=O, ester or lactam), 172.30
(2ϫC=O, ester), 172.36 (2ϫC=O, lactam) ppm. IR (NaCl): ν
˜
max
= 1709 (C=O), 1732 (C=O), 1770 (C=O) cm–1. MS: m/z (%) = 535
(100) [M + H]+. Chromatography: Rf = 0.01 (PE/EtOAc, 4:1).
C26H38N4O8 (534.60): calcd. C 58.41, H 7.16, N 10.48; found C
58.37, H 7.18, N 10.14.
Typical Procedure for the N-Alkylation of Hydantoins. Synthesis of
13b–e: The bis(hydantoin) (0.32 g, 0.63 mmol) was dissolved in dry
acetone (6 mL, dried with K2CO3 and distilled). The aryl bromide
(0.32 g, 1.87 mmol) and K2CO3 (0.52 g, 3.76 mmol) were added
and the mixture was heated at reflux overnight, protected from
moisture with a CaCl2 tube. The solution was cooled to room tem-
perature, and the precipitate was filtered and coated on silica for
column chromatography.
Allyl 3-(1-{6-[4-(2-Allyloxycarbonylethyl)-3-benzyl-2,5-dioxoimid-
azolidin-1-yl]hexyl}-3-benzyl-2,5-dioxoimidazolidin-4-yl)propionate
1
(13b): Yield 73%, 0.52 g, yellow oil. H NMR (300 MHz, CDCl3):
δ = 1. 31–1 . 4 2 (m, 4 H , C H2 CH2 ) , 1 . 5 8– 1. 68 (m, 4 H,
2ϫCH2CH2N), 2.01–2.13 (m, 2 H, 2ϫCHaHbCH2CO), 2.16–2.27
(m, 2 H, 2ϫCHaHbCH2CO), 2.25–2.42 (m, 4 H, 2ϫCH2CO), 3.51
(brt, J = 7.2 Hz, 4 H, 2ϫNCH2, alkyl), 3.82 (dd, J = 6.2, 2.9 Hz,
2 H, 2ϫCH), 4.10 (d, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl),
4.55 (brd, J = 5.8 Hz, 4 H, 2ϫOCH2), 4.97 (d, J = 15.3 Hz, 2 H,
2 ϫ NCHaHb, benzyl), 5.23 (dbr q, Jcis = 10.5, 1.2 Hz, 2 H,
2ϫ=CHaHb), 5.30 (dbrq, Jtrans = 17.2, 1.2 Hz, 2 H, 2ϫ=CHaHb),
5.89 (ddt, Jt ra n s = 17.2, Jc i s = 10.5, Jv i c = 5.8 Hz, 2 H,
2 ϫCH=CH2), 7.25–7.37 (m, 10 H, 10 ϫCHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.45 (2ϫCH2CH2CO), 26.13 (CH2CH2),
27.86 (2 ϫ CH2CH2N or 2 ϫ CH2CO), 27.95 (2 ϫCH2CH2N or
2ϫCH2CO), 38.79 (2ϫNCH2, alkyl), 44.59 (2ϫNCH2, benzyl),
57.31 (2 ϫ CH), 65.42 (2 ϫ OCH2), 118.54 (2 ϫ =CH2), 128.09
(2 ϫ CHar), 128.20 (4 ϫ CHar), 128.96 (4 ϫ CHar), 131.90
(2 ϫ CH=CH2), 135.59 (2 ϫ Car,quat.), 156.63 (2 ϫ C=O, urea),
171.84 (2ϫC=O, ester), 172.28 (2ϫC=O, lactam) ppm. IR (NaCl):
(2ϫC=O, lactam or ester) ppm. IR (NaCl): ν
= 1708 (C=O),
˜
max
1733 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 781/783/785 (100)
[M – H]+. Chromatography: Rf = 0.37 (PE/EtOAc, 4:3).
C40H48Cl2N4O8 (783.74): calcd. C 61.30, H 6.17, N 7.15; found C
61.23, H 6.44, N 6.84.
Allyl 3-(1-{8-[4-(2-Allyloxycarbonylethyl)-3-(4-bromobenzyl)-2,5-di-
oxoimidazolidin-1-yl]octyl}-3-(4-bromobenzyl)-2,5-dioxoimidazol-
1
idin-4-yl)propionate (13e): Yield 54%, 0.16 g. H NMR (300 MHz,
CDCl3): δ = 1.24–1.38 [m, 8 H, 2ϫN(CH2)2(CH2)2], 1.56–1.66 (m,
4 H, 2ϫNCH2CH2), 1.98–2.10 (m, 2 H, 2ϫCHaHbCH), 2.17–2.26
(m, 2 H, 2ϫCHaHbCH), 2.24–2.45 (m, 4 H, 2ϫCH2CO), 3.43–
3.57 (m, 4 H, 2ϫNCH2, alkyl), 3.82 (dd, J = 6.6, 3.0 Hz, 2 H,
2ϫCH), 4.10 (d, J = 15.4 Hz, 2 H, 2ϫNCHaHb, benzyl), 4.56
(dt, J = 5.8, 1.4 Hz, 4 H, 2ϫOCH2), 4.89 (d, J = 15.4 Hz, 2 H,
2 ϫ NCHaHb, benzyl), 5.25 (dq, Jcis = 10.5, 1.2 Hz, 2 H,
2ϫ=CHaHb), 5.31 (dq, Jtrans = 17.1, 1.4 Hz, 2 H, 2ϫ=CHaHb),
5.89 (ddt, Jt ra n s = 17.1, Jc i s = 10.5, Jv i c = 5.8 Hz, 2 H,
2ϫCH=CH2), 7.16 (d, J = 8.4 Hz, 4 H, 4ϫCHar), 7.47 (d, J =
8.4 Hz, 4 H, 4 ϫ CHar) ppm. 13C NMR (75 MHz, CDCl3): δ =
2 3 . 5 3 ( 2 ϫ C H 2 C H ) , 2 6 . 6 0 [ 2 ϫ N ( C H 2 ) 3 C H 2 ] , 2 7 . 9 3
(2 ϫ NCH2 CH2 or 2 ϫ CH2CO), 27.97 (2 ϫ NCH2CH2 or
ν
= 1649 (C=C), 1707 (C=O), 1734 (C=O), 1768 (C=O) cm–1.
˜
max
MS: m/z (%) = 687 (100) [M + H]+. Chromatography: Rf = 0.02
(PE/EtOAc, 4:1). C38H46N4O8 (686.79): calcd. C 66.45, H 6.75, N
8.16; found C 66.10, H 6.46, N 8.09.
Allyl 3-(1-{6-[4-(2-Allyloxycarbonylethyl)-3-(4-bromobenzyl)-2,5-
dioxoimidazolidin-1-yl]hexyl}-3-(4-bromobenzyl)-2,5-dioxoimidazol-
idin-4-yl)propionate (13c): Yield 78 %, 0.17 g, yellowish oil. 1H
NMR (300 MHz, CDCl3): δ = 1.31–1.40 (m, 4 H, CH2CH2), 1.57– 2 ϫCH2CO), 28.92 [2ϫN(CH2)2CH2], 39.01 (2ϫNCH2, alkyl),
1 . 6 7 ( m , 4 H , 2 ϫ C H 2 C H 2 N ) , 1 . 9 7 – 2 . 0 9 ( m , 2 H , 44.08 (2 ϫ NCH2, benzyl), 57.41 (2 ϫ CH), 65.52 (2 ϫ OCH2),
2ϫCHaHbCH2CO), 2.16–2.25 (m, 2 H, 2ϫCHaHbCH2CO), 2.25– 118.66 (2ϫ=CH2), 122.18 (2ϫCar,quat.), 129.98 (4ϫCHar), 131.84
2.45 (m, 4 H, 2ϫCH2CO), 3.50 (brt, J = 7.2 Hz, 4 H, 2ϫNCH2,
alkyl), 3.82 (dd, J = 6.6, 3.0 Hz, 2 H, 2ϫCH), 4.10 (d, J = 15.3 Hz,
2 H, 2ϫNCHaHb, benzyl), 4.56 (brd, J = 5.8 Hz, 4 H, 2ϫOCH2),
4.88 (d, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 5.22–5.28 (m, 2
(2ϫCH=CH2), 132.13 (4ϫ CHar), 134.74 (2 ϫCar,quat.), 156.68
(2 ϫ C=O, urea), 171.87 (2 ϫ C=O, ester or lactam), 172.15
(2ϫC=O, lactam or ester) ppm. IR (NaCl): ν
= 1706 (C=O),
˜
max
1734 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 871/873/875 (100)
176
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 171–179

Macrocycles from Bis(hydantoins)
[M + H]+. Chromatography: Rf = 0.11 (PE/EtOAc, 2:1).
C40H48Br2N4O8 (872.64): calcd. C 55.05, H 5.54, N 6.42; found C
55.45, H 5.93, N 6.05.
27.96 (2 ϫ CH2 CH2 N or 2 ϫ CH3 or 2 ϫ CH2 CO), 28.08
(2 ϫ CH2CH2N or 2 ϫ CH3 or 2 ϫ CH2CO), 38.96 (2 ϫ NCH2,
alkyl), 60.49 (2ϫCH), 63.88 (2ϫOCH2), 127.49 (2ϫ=CH), 156.73
(2ϫC=O, urea), 171.95 (2ϫC=O, ester), 172.30 (2ϫC=O, lac-
Allyl 3-(1-{12-[4-(2-Allyloxycarbonylethyl)-3-benzyl-2,5-dioxoimid-
azolidin-1-yl]dodecyl}-3-benzyl-2,5-dioxoimidazolidin-4-yl)propio-
nate (13f): Yield 55%, 52 mg, oil. 1H NMR (300 MHz, CDCl3):
δ = 1.22–1.34 [m, 16 H, 2ϫN(CH2)2(CH2)4], 1.57–1.67 (m, 4 H,
2ϫCH2CH2N), 2.01–2.13 (m, 2 H, 2ϫCHaHbCH), 2.17–2.28 (m,
2 H, 2ϫCHaHbCH), 2.30–2.26 (m, 4 H, 2ϫCH2CO), 3.51 (td, J
= 7.4, 2.2 Hz, 4 H, 2ϫNCH2), 3.81 (dd, J = 6.2, 3.2 Hz, 2 H,
2ϫCH), 4.08 (d, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 4.56
(dt, J = 5.8, 1.4 Hz, 4 H, 2ϫOCH2), 5.00 (d, J = 15.3 Hz, 2 H,
2 ϫ NCHaHb, benzyl), 5.24 (dq, Jcis = 10.5, 1.4 Hz, 2 H,
2ϫ=CHaHb), 5.30 (dq, Jtrans = 17.1, 1.4 Hz, 2 H, 2ϫ=CHaHb),
5.91 (ddt, Jt ra n s = 17.1, Jc i s = 10.5, Jv i c = 5.8 Hz, 2 H,
2 ϫCH=CH2), 7.24–7.38 (m, 10 H, 10 ϫCHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.47 (2ϫCH2CH), 26.75 [2ϫN(CH2)2-
CH2 ], 27.99 (2 ϫ CH2 CO), 28.08 (2 ϫ CH2CH2 N), 29.15
[2ϫN(CH2)3CH2], 29.50 [2ϫN(CH2)4(CH2)2], 39.09 (2ϫNCH2,
alkyl), 44.63 (2 ϫ NCH2 , benzyl), 57.32 (2 ϫ CH), 65.50
(2 ϫ OCH2), 118.60 (2 ϫ =CH2), 128.16 (2 ϫ CHar, para), 128.24
(4 ϫ CHar), 129.02 (4 ϫ CHar), 131.90 (2 ϫ CH=CH2), 135.63
(2 ϫ Car,quat.), 156.76 (2ϫ C=O, urea), 171.93 (2 ϫC=O, ester),
tam) ppm. IR (NaCl) of the reaction mixture: νmax = 1708 (C=O),
˜
1733 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 507 (100) [M +
H]+. Chromatography: Rf = 0.21 (EtOAc/Et2O, 1:1). C24H34N4O8
(506.55): calcd. C 56.91, H 6.77, N 11.06; found C 57.14, H 6.88,
N 10.73.
10,25-Dibenzyl-15,20-dioxa-1,8,10,25-tetraazatricyclo[22.2.1.18,11]-
octacos-17-ene-9,14,21,26,27,28-hexaone (14b): Mixture of dia-
1
stereomers. Yield 95%, 0.10 g, oil. H NMR (300 MHz, CDCl3): δ
= 1.28–1.43 (m, 4 H, CH2CH2), 1.56–1.74 (m, 4 H, 2ϫCH2CH2N),
2.14–2.41 (m, 8 H, 2ϫCH2CH2CO), 3.41–3.65 (m, 4 H, 2ϫNCH2,
alkyl), 3.78–3.81 (m, 2 H, 2ϫCH), 3.98 (dd, J = 15.3, 8.1 Hz, 2 H,
2ϫNCHaHb, benzyl), 4.54–4.72 (m, 4 H, 2ϫOCH2), 5.00 (brd, J
= 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 5.79 (t, J = 2.8 Hz, 2 H,
2 ϫ =CH), 7.22–7.38 (m, 10 H, 10 ϫ CHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.07 and 23.16 (2ϫCH2CH2CO), 26.55
(CH2CH2), 27.83 and 27.93 (2 ϫ CH2CH2N), 28.08 and 28.22
(2ϫCH2CO), 39.04 and 39.16 (2ϫNCH2, alkyl), 44.45 and 44.52
(2ϫNCH2, benzyl), 57.38 and 57.47 (2 ϫCH), 63.85 and 63.96
(2 ϫ OCH2), 127.47 and 127.75 (2 ϫ =CH), 128.19, 128.32 and
128.34 (6ϫCHar), 129.03 (4ϫCHar), 135.47 (2ϫCar,quat.), 156.73
and 156.83 (2ϫC=O, urea), 172.00 and 172.12 (2ϫC=O, ester),
172.38 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1709 (C=O),
˜
max
1735 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 771 (100)
[M + H]+. Chromatography: Rf = 0.29 (PE/EtOAc, 2:1).
172.30 (2ϫC=O, lactam) ppm. IR (NaCl): ν
= 1708 (C=O),
˜
max
1733 (C=O), 1768 (C=O) cm–1. MS: m/z (%) = 659 (100) [M + H]+.
Chromatography: Rf = 0.6 (PE/EtOAc, 1:4). C36H42N4O8 (658.74):
calcd. C 65.64, H 6.43, N 8.51; found C 65.79, H 6.76, N 8.15.
C
44H58N4O8 (770.95): calcd. C 68.55, H 7.58, N 7.27; found C
68.47, H 7.90, N 7.19.
Typical Procedure for the Ring-Closing Metathesis Reaction of Bis-
(hydantoins) 14: Bis(hydantoin) 14 (0.11 g, 0.16 mmol) was dis-
solved in benzene (20 mL) and brought to reflux temperature. Then
the second-generation Grubbs’ catalyst (0.0068 g, 0.008 mmol) was
added. The reaction was heated at reflux overnight, shielded from
moisture with a CaCl2 tube. Traces of catalyst were removed by
preparative thin layer chromatography (TLC) and in the cases of
compounds 14a and 14c diastereomers were separated; 14d yielded
one single diastereomer.
10,25-Bis(4-bromobenzyl)-15,20-dioxa-1,8,10,25-tetraazatricyclo-
[22.2.1.18,11]octacos-17-ene-9,14,21,26,27,28-hexaone (14c): Yield
(before TLC) 99%, 83 mg.
Diastereomer 1: Oil. 1H NMR (300 MHz, CDCl3): δ = 1.25–1.43
(m, 4 H, CH2CH2), 1.56–1.72 (m, 4 H, 2ϫCH2CH2N), 2.11–2.46
(m, 8 H, 2ϫCH2CH2CO), 3.43–3.52 (m, 2 H, 2ϫNCHaHb, alkyl),
3.55–3.66 (m, 2 H, 2 ϫ NCHaHb, alkyl), 3.76–3.80 (m, 2 H,
2ϫCH), 3.95 (d, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 4.57
(brd, J = 11.6 Hz, 2 H, 2ϫOCHaHb), 4.67 (brd, J = 11.6 Hz, 2
H, 2ϫOCHaHb), 4.92 (d, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl),
5.78 (t, J = 2.9 Hz, 2 H, 2 ϫ =CH), 7.12 (d, J = 8.3 Hz, 4 H,
4 ϫ CHar), 7.47 (d, J = 8.3 Hz, 4 H, 4 ϫ CHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.05 (2ϫCH2CH2CO), 26.51 (CH2CH2),
27.77 (2 ϫ CH2CH2N or 2 ϫ CH2CO), 28.17 (2 ϫCH2CH2N or
2ϫCH2CO), 39.19 (2ϫNCH2, alkyl), 43.85 (2ϫNCH2, benzyl),
57.50 (2ϫ CH), 63.99 (2ϫ OCH2), 122.28 (2 ϫCar,quat.), 127.72
(2 ϫ = CH), 130.07 (4 ϫ CHar), 132.21 (4 ϫ CHar), 134.47
(2ϫCar,quat.), 156.80 (2ϫC=O, urea), 172.12 (4ϫC=O, ester and
10,25-Dimethyl-15,20-dioxa-1,8,10,25-tetraazatricyclo[22.2.1.18,11]-
octacos-17-ene-9,14,21,26,27,28-hexaone (14a): Yield (before TLC)
99%, 80 mg.
Diastereomer 1: Oil. 1H NMR (300 MHz, CDCl3): δ = 1.27–1.40
(m, 4 H, CH2CH2), 1.54–1.69 (m, 4 H, 2ϫCH2CH2N), 2.14–2.49
(m, 8 H, 2ϫCH2CH2CO), 2.87 (s, 6 H, 2ϫNCH3), 3.39–3.49 (m,
2 H, 2ϫNCHaHb, alkyl), 3.51–3.62 (m, 2 H, 2ϫNCHaHb, alkyl),
3.89 (t, J = 3.7 Hz, 2 H, 2ϫCH), 4.55 (brd, J = 10.9 Hz, 2 H,
2ϫOCHaHb), 4.63 (brd, J = 10.9 Hz, 2 H, 2ϫOCHaHb), 5.76 (t,
J = 2.9 Hz, 2 H, 2ϫ=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
23.42 (2ϫCH2CH2CO), 26.55 (CH2CH2), 27.83 (2ϫCH2CH2N),
28.06 and 28.18 (2ϫCH3, 2ϫCH2CO), 39.09 (2ϫCH2N), 60.81
(2ϫCH), 63.94 (2ϫOCH2), 127.73 (2ϫ= CH), 156.90 (2ϫC=O,
urea), 172.03 (2ϫC=O, ester), 172.25 (2ϫC=O, lactam) ppm. IR
lactam) ppm. IR (NaCl): ν
= 1706 (C=O), 1733 (C=O), 1768
˜
max
(C=O) cm–1. Chromatography: Rf = 0.29 (PE/EtOAc, 1:1).
Diastereomer 2: Oil. 1H NMR (300 MHz, CDCl3): δ = 1.25–1.41
(m, 4 H, CH2CH2), 1.56–1.72 (m, 4 H, 2ϫCH2CH2N), 2.15–2.40
(m, 8 H, 2ϫCH2CH2CO), 3.45–3.62 (m, 4 H, 2ϫNCH2, alkyl),
3.79 (t, J = 3.9 Hz, 2 H, 2 ϫ CH), 3.99 (d, J = 15.4 Hz, 2 H,
2ϫNCHaHb, benzyl), 4.59–4.60 (m, 4 H, 2ϫOCH2), 4.91 (d, J =
15.4 Hz, 2 H, 2ϫNCHaHb, benzyl), 5.78 (brt, J = 2.8 Hz, 2 H,
(NaCl): ν
= 1706 (C=O), 1732 (C=O), 1768 (C=O) cm–1. MS:
˜
max
m/z (%) = 507 (100) [M + H]+. Chromatography: Rf = 0.26 (EtOAc/
Et2O, 1:1). C24H34N4O8 (506.55): calcd. C 56.91, H 6.77, N 11.06;
found C 57.26, H 7.11, N 10.71.
Diastereomer 2: Oil. 1H NMR (300 MHz, CDCl3): δ = 1.28–1.37 2ϫ=CH), 7.14 (d, J = 8.3 Hz, 4 H, 4ϫCHar), 7.48 (d, J = 8.3 Hz,
(m, 4 H, CH2CH2), 1.51–1.70 (m, 4 H, 2ϫCH2CH2N), 2.23–2.38
(m, 8 H, 2ϫCH2CH2CO), 2.90 (s, 6 H, 2ϫNCH3), 3.41–3.59 (m,
4 H, 2ϫNCH2, alkyl), 3.88–3.91 (m, 2 H, 2ϫCH), 4.50–4.66 (m,
4 H, 2ϫOCH2), 5.78 (brt, J = 2.9 Hz, 2 H, 2ϫ=CH) ppm. 13C
NMR (75 MHz, CDCl3) by difference spectrum reaction mixture
and first fraction: δ = 23.48 (2ϫCH2CH2CO), 26.52 (CH2CH2),
4 H, 4 ϫ CHar) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.16
(2 ϫ CH2CH2CO), 26.46 (CH2CH2), 27.88 (2 ϫ CH2CH2N or
2 ϫ CH2CO), 28.02 (2 ϫ CH2CH2N or 2 ϫ CH2CO), 39.06
(2ϫNCH2, alkyl), 43.96 (2ϫNCH2, benzyl), 57.45 (2ϫCH), 63.90
(2 ϫ OCH2), 122.28 (2 ϫ Car,quat.), 127.43 (2 ϫ =CH), 130.04
(4 ϫ CHar), 132.22 (4 ϫ CHar), 134.51 (2 ϫ Car,quat.), 156.71
Eur. J. Org. Chem. 2008, 171–179
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
177

D. D. Claeys, C. V. Stevens, N. Dieltiens
FULL PAPER
(2ϫC=O, urea), 171.98 (2ϫC=O, ester), 172.12 (2ϫC=O, lac-
benzyl), 57.35 (2ϫCH), 64.22 (2ϫOCH2), 128.06 and 128.26
(2ϫ=CH), 128.38 and 129.10 (10ϫCHar), 135.55 (2ϫCar,quat.),
156.92 (2ϫC=O, urea), 171.96 (2ϫC=O, ester), 172.30 (2ϫC=O,
tam) ppm. IR (NaCl): ν
= 1706 (C=O), 1733 (C=O), 1768
˜
max
(C=O) cm–1. Chromatography: Rf = 0.23 (PE/EtOAc, 1:1). MS: m/z
(%) = 813/815/817 (100) [M – H]+. C36H40Br2N4O8 (816.53): calcd.
C 52.95, H 4.94, N 6.86; found C 53.34, H 5.23, N 6.54.
lactam) ppm. IR (NaCl): ν
= 1709 (C=O), 1736 (C=O), 1769
˜
max
(C=O) cm–1. MS: m/z (%) = 743 (100) [M + H]+. Chromatography:
Rf = 0.3 (PE/EtOAc, 1:1). C42H54N4O8 (742.90): calcd. C 67.90, H
7.33, N 7.54; found C 68.17, H 7.55, N 7.28.
12,27-Bis(4-chlorobenzyl)-17,22-dioxa-1,10,12,27-tetraazatricyclo-
[24.2.1.110,13]triacont-19-ene-11,16,23,28,29,30-hexaone (14d): Mix-
1
ture of diastereomers. Yield (before TLC) 99%, 39 mg. H NMR
(300 MHz, CDCl3): δ = 1.22–1.37 [m, 8 H, 2ϫN(CH2)2(CH2)2],
1.58–1.68 (m, 4 H, 2 ϫ NCH2 CH2 ), 2.14–2.37 (m, 8 H,
2ϫCH2CH2CO), 3.43–3.55 (m, 2 H, 2ϫNCHaHb, alkyl), 3.52–
3.66 (m, 2 H, 2ϫNCHaHb, alkyl), 3.80 (brs, 2 H, 2ϫCH), 3.99
(brd, J = 15.3 Hz, 2 H, 2ϫNCHaHb, benzyl), 4.47–4.71 (m, 4 H,
2ϫOCH2), 4.94 (dd, J = 15.3, 2.6 Hz, 2 H, 2ϫNCHaHb, benzyl),
5.80 (t, J = 2.9 Hz, 2 H, 2 ϫ =CH), 7.19 (d, J = 7.8 Hz, 4 H,
4 ϫ CHar), 7.32 (d, J = 7.8 Hz, 4 H, 4 ϫ CHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.02 (2ϫCH2CH), 26.87 [2ϫN(CH2)3-
CH2], 27.81 (2ϫNCH2CH2 or 2ϫCH2CO), 27.97 (2ϫNCH2CH2
or 2ϫCH2CO), 29.19 [2ϫN(CH2)2CH2], 39.30 (2ϫNCH2, alkyl),
43.94 (2 ϫ NCH2, benzyl), 57.54 (2 ϫ CH), 64.21 (2 ϫ OCH2),
127.79 (2ϫ=CH), 129.35 (4ϫCHar), 129.82 (4ϫ CHar), 134.08
(2ϫCar,quat.), 134.29 (2ϫCar,quat.), 156.89 (2ϫC=O, urea), 172.10
Acknowledgments
The authors are indebted to the Research Foundation – Flanders
(FWO) for financial support of this research.
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(4ϫC=O, lactam and ester) ppm. IR (NaCl): ν
= 1707 (C=O),
˜
max
1735 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 755/757/759 (100)
[M + H]+ . Chromatography: Rf = 0.3 (PE/EtOAc, 1:1).
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diastereomer. Yield (before TLC) 99 %, 0.12 g, oil. 1H NMR
(300 MHz, CDCl3): δ = 1.25–1.37 [m, 8 H, 2ϫN(CH2)2(CH2)2],
1.57–1.69 (m, 4 H, 2 ϫ NCH2 CH2 ), 2.14–2.35 (m, 8 H,
2ϫCH2CH2CO), 3.43–3.52 (m, 2 H, 2ϫNCHaHb, alkyl), 3.55–
3.64 (m, 2 H, 2ϫNCHaHb, alkyl), 3.80 (brs, 2 H, 2ϫCH), 3.97
(brd, J = 15.2 Hz, 2 H, 2ϫNCHaHb, benzyl), 4.47–4.70 (m, 4 H,
2ϫOCH2), 4.92 (dd, J = 15.2, 2.3 Hz, 2 H, 2ϫNCHaHb, benzyl),
5.80 (t, J = 2.9 Hz, 2 H, 2 ϫ =CH), 7.13 (d, J = 8.4 Hz, 4 H,
4 ϫ CHar), 7.47 (d, J = 8.4 Hz, 4 H, 4 ϫ CHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.89 (2ϫCH2CH), 26.77 [2ϫN(CH2)3-
CH2], 27.71 (2ϫNCH2CH2 or 2ϫCH2CO), 27.86 (2ϫNCH2CH2
or 2ϫCH2CO), 29.09 [2ϫN(CH2)2CH2], 39.19 (2ϫNCH2, alkyl),
43.87 (2 ϫ NCH2, benzyl), 57.42 (2 ϫ CH), 64.11 (2 ϫ OCH2),
122.28 (2ϫCar,quat.), 127.67 (2ϫ=CH), 130.04 (4ϫCHar), 132.21
(4ϫCHar), 134.47 (2ϫCar,quat.), 156.77 (2ϫC=O, urea), 171.98
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= 1710 (C=O),
˜
max
1737 (C=O), 1769 (C=O) cm–1. MS: m/z (%) = 843/845/847 (100)
[M + H]+. Chromatography: Rf = 0.35 (PE/EtOAc, 1:1).
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[28.2.1.114,17]tetratriacont-23-ene-15,20,27,32,33,34-hexaone (14f):
1
Mixture of diastereomers. Yield (before TLC) 99%, 54 mg, oil. H
NMR (300 MHz, CDCl3): δ = 1.22–1.34 [m, 16 H, 2ϫN(CH2)2-
(CH2)4], 1.59–1.69 (m, 4 H, 2ϫCH2CH2N), 2.14–2.33 (m, 8 H,
2ϫCH2CH2CO), 3.45–3.63 (m, 4 H, 2ϫNCH2), 3.79–3.81 (m, 2
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4.67 (m,
4 H, 2ϫOCH2), 5.00 (brd, J = 15.1 Hz, 2 H,
2ϫNCHaHb, benzyl), 5.81 (t, J = 2.8 Hz, 2 H, 2ϫ=CH), 7.23–
7.37 (m, 10 H, 10ϫCHar) ppm. 13C NMR (75 MHz, CDCl3): δ =
23.08 (2ϫCH2CH), 26.47 [2ϫN(CH2)2CH2], 27.67 (2ϫCH2CO),
27.88 (2ϫCH2CH2N), 28.98 [2ϫN(CH2)3CH2], 29.02 and 29.12
[2ϫN(CH2)4(CH2)2], 39.09 (2ϫNCH2, alkyl), 44.61 (2ϫNCH2,
178
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 171–179

Macrocycles from Bis(hydantoins)
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Eur. J. Org. Chem. 2008, 171–179
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179