Selective Solid Phase Synthesis of Ureas and Hydantoins from Common Phenyl Carbamate Intermediates

Article abstract of DOI:10.1021/jo971087i

An efficient method for selective, solid phase synthesis of unsymmetrical ureas and hydantoins from a common phenyl carbamate dipeptide intermediate is decribed. Reaction of phenyl carbamate 6 with primary or secondary amines (R₃R₄NH) in THF results in selective formation of ureas 8, whereas its treatment with a tertiary amine base (iPr₂NEt or DBU) in DMF affords clean conversion to hydantoins 10.

Full text of DOI:10.1021/jo971087i

6
968
J . Org. Chem. 1997, 62, 6968-6973
Selective Solid P h a se Syn th esis of Ur ea s a n d Hyd a n toin s fr om
Com m on P h en yl Ca r ba m a te In ter m ed ia tes
†
‡
,‡
Xiao-yi Xiao, Khehyong Ngu, Corinne Chao, and Dinesh V. Patel*
Affymax Research Institute, 3410 Central Expressway, Santa Clara, California 95051
Received J une 16, 1997X
An efficient method for selective, solid phase synthesis of unsymmetrical ureas and hydantoins
from a common phenyl carbamate dipeptide intermediate is decribed. Reaction of phenyl carbamate
6
3 4
with primary or secondary amines (R R NH) in THF results in selective formation of ureas 8,
whereas its treatment with a tertiary amine base (iPr
2
NEt or DBU) in DMF affords clean conversion
to hydantoins 10.
In tr od u ction
Ureas are typically prepared in solution or solid phase
6
by treatment of isocyanates or p-nitrophenyl carbamates
In the era of rational drug design, it has become
(
PNP)7 with amines. This relatively simple method
relatively easy to discover peptidic leads for therapeuti-
cally important enzyme or receptor targets. While such
compounds by themselves may usually find limited utility
because of poor metabolic stability, bioavailability, and
absorption, they do provide a good starting point for drug
discovery projects. The next critical step in de novo drug
design is to transform such peptidic leads into more
stable and bioavailable nonpeptidic molecules. This
strategy has been extensively persued in the last decade
and has led to the culmination of a wide variety of
works well for single amino esters but is inappropriate
for insertion of urea linkages as amide bond isosteres in
a peptidic framework. This is because of the susceptibil-
ity of reactive isocyanate or PNP carbamate intermedi-
ates to nucleophilic attack by adjacent amide group
resulting in formation of hydantoin as a side product.
Hydantoins have been independently prepared on solid
support from R-urea esters which in turn are derived
from R-amino esters and isocyanates. The final step
involves N-cyclization of ureas to the immobilized ester
group, resulting in simultaneous cleavage from the resin
to generate hydantoins in solution.8 This strategy is well
suited for synthesis of individual hydantoins, but not
appropriate for their inclusion as nonpeptidic surrogates
in a peptide framework because of the mandatory re-
quirement of an ester linker adjacent to the urea group.
Herein, we report an efficient method for selective, SPS
of both unsymmetrical ureas or hydantoins from common
linear dipeptide intermediates 6. Phenyl carbamate 7
derived from dipeptide 6 on solid support serves as the
activated intermediate which can be treated with pri-
nonpeptidic replacements for peptide amide bonds and
secondary structures of peptides.1
In this paper, we would like to describe an efficient
and practical solid phase synthesis (SPS) of ureas and
hydantoins from a common intermediate. The urea
functionality has attracted considerable attention as a
stable, nonhydrolyzable replacement for amide bonds of
peptides.2 The five-membered hydantoins represent a
cyclic scaffold displaying conformationally constrained
dipeptide motifs. An obvious advantage with the solid
phase methodology for these peptidomimetic motifs is
3
their potential utility in the area of combinatorial chemis-
try.4 In order to effectively utilize the “split and pool”
mary or secondary amines (R
metrical ureas 8, or alternatively with a tertiary amine
base (iPr NEt or DBU) to form hydantoins 10. Phenyl
3 4
R NH) to form unsym-
protocol in a combinatorial format, it has become in-
creasingly necessary to develop equivalent solid phase
2
carbamates have been occasionally used as intermediates
for solution synthesis of ureas.9 They are more stable
than p-nitrophenyl carbamates or isocyanates, and at the
same time, they are reactive enough and more prone to
nucleophilic attack by primary or secondary amines than
simple alkyl carbamates. Thus, they may offer the right
balance of stability and reactivity for selective conversion
to either ureas or hydantoins by appropriate choice of
reagents and reaction conditions. This study represents
the first example of SPS of ureas or hydantoins from
common phenyl carbamate intermediates.
chemistries of various traditional solution phase reac-
tions.5
†
Current address: IRORI Quantum Microchemistry, 11025 N.
Torrey Pines Rd., #100 La J olla, CA 92037.
‡
Current address: VERSICOR Inc., 34790 Ardentech Ct., Arden-
wood Business Park, Fremont, CA 94555. e-mail: dpatel@versicor.com.
X
Abstract published in Advance ACS Abstracts, September 15, 1997.
(
1) Morgan, B. A.; Gainor, J . A. Annual Reports in Medicinal
Chemistry; Allen, R. C., Ed.; Academic Press Inc.: New York, 1989;
43.
2) (a) Kempf, D. J .; Marsh, K. C.; Paul, D. A.; Knigge, M. F.;
2
(
Norbeck, D. W.; Kohlbrenner, W. E.; Codacovi, L.; Vasavanonda, S.;
Bryant, P.; Wang, X. C.; Wideburg, N. E.; Clememt, J . J .; Plattner, J .
J .; Erickson, J . W. Antimicrob. Agents Chemother. 1991, 35, 2209. (b)
Getman, D. P.; DeCrescenzo, G. A.; Henitz, R. M.; Reed, K. L.; Talley,
J . J .; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, R. R.; Mueller,
R. A.; Vazquez, M. L.; Shien, H. S.; Sallings, W. C.; Stegeman, R. A. J .
Med. Chem. 1993, 36, 288. (c) Norwick, J . S.; Abdi, M.; Bellamo, K.
A.; Love, J . A.; Martinez, E. J .; Noroha, G.; Smith, E. M.; Ziller, J . W.
J . Am. Chem. Soc. 1995, 117, 89.
(5) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron
1996, 52, 4527.
(6) (a) Majer, P.; Randad, R. S. J . Org. Chem. 1994, 59, 1937 and
references cited therien. (b) Norwick, J . S.; Holmes, D. L.; Noronha,
G.; Smith, E. M.; Nguyen, T. M.; Huang, S.-L. J . Org. Chem. 1996, 61,
3929 and references cited therien.
(
3) The five-membered hydantoins and six-membered diketo-
(7) (a) Izdebski, J .; Pawlak, D. Synthesis 1989, 423. (b) Hutchins,
S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055.
(8) DeWitt, S. H.; Kiely, J . S.; Stankovic, C. J .; Schroeder, M. C.;
Cody, D. M.; and Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A., 90, 6909-
6913 (1993).
(9) (a) Adamiak, R. W.; Stawinski, J . Tetrahedron Lett. 1977, 1935.
(b) Waldner, A.; De Mesmaeker, H.; Lebreton, J . Fritsch, V.; Wolf, R.
M. Synlett 1994, 1, 57-61.
piperazines are two common examples of cyclic dipeptidomimetic
motifs.
(4) (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gallop, M. A. J . Med. Chem. 1994, 37, 1385. (b) Thompson, L. A.;
Ellman, J . A. Chem. Rev. 1996, 96, 555. (c) Gordon, E. M.; Gallop, M.
A., Patel , D. V. Acc. Chem. Res. 1996, 29, 144. (d) Patel D. V., Gordon,
E. M. Drug Disc. Today 1996, 1, 134.
S0022-3263(97)01087-6 CCC: $14.00 © 1997 American Chemical Society

Solid Phase Synthesis of Ureas and Hydantoins
J . Org. Chem., Vol. 62, No. 20, 1997 6969
Sch em e 1. Un sym m etr ica l Ur ea s a n d Hyd a n toin s
fr om P h en yl Ca r ba m a tes
Ta ble 1. Effect of Solven t on Ur ea vs Hyd a n toin
F or m a tion
solvent
CH2Cl2
THF
Ph(CH2)2NH2a
iPr2NEtb
36%
100%
31%
100%
100%
100%
44%
1%
0.3%
97%
93%
90%
1
,4-dioxane
CH3CN
DMF
DMSO
a
Percentage of phenol release after 1 h of treatment of phenyl
b
carbamate 1 with Ph(CH2)2NH2 in a particular solvent. Per-
centage of phenol release after 1 h of treatment of phenyl
carbamate 1 with iPr2NEt in a particular solvent.
is not surprising because more nucleophilic and less
hindered amines such as phenethylamine will be more
likely to attack the activated carbamate to yield ureas
(path a), whereas a relatively more basic and more
hindered amine such as iPr
2
NH, especially under condi-
tions unoptimized for urea formation, is more likely to
act as a general base (path b) and yield hydantoins
(Scheme 1). These observations prompted us to thor-
oughly investigate the factors influencing formation of
ureas and hydantoins from common peptidic phenyl
carbamate intermediates on solid support.
Effect of Solven ts on Hyd a n toin vs Ur ea F or m a -
tion . A striking observation made during the early
experiments was that phenyl carbamate 1 was formed
from the corresponding dipeptide amine by treatment
with phenyl isocyanate and iPr
dioxane and found to be stable. Thus, despite the fact
that iPr NEt is a strong, non-nucleophilic tertiary amine,
2
NEt in aqueous 1,4-
2
there was no hydantoin cyclization observed in 1,4-
dioxane during the rather long reaction times (12 h). This
is in sharp contrast to the smooth cyclization to hydan-
2
toin observed for the same intermediate 1 with iPr NH
in DMF. This led us to speculate that, besides the steric
nature of phenyl carbamate intermediate and basicity of
amine, solvents may play an important role in directing
the reaction of amines with phenyl carbamates on solid
support. For example, the above observation suggested
that DMF may strongly favor hydantoin formation,
whereas 1,4-dioxane would tend to disfavor cyclization.
This led us to investigate the effect of solvents on selec-
tive urea and hydantoin formation from phenyl carbam-
ates on solid support (Table 1). Six different solvents
Resu lts a n d Discu ssion
Resin-bound phenyl carbamate dipeptide PhOCONH-
Val-Phe-NH-resin 1 was designed to be the substrate for
initial studies (Scheme 1). The valine residue provides
a sterically demanding situation for the reaction, while
the chromophoric phenylalanine group facilitates HPLC
identification of the final cleavage product. Additionally,
UV absorption of the released phenol (288 nm, emax
)
(
DCM, acetonitrile, THF, 1,4-dioxane, DMF, and DMSO)
were included in the study. For each solvent, phenethy-
lamine and iPr
NEt were used at a 0.5 M concentration
-
1
-1
2
600 M cm ) provides a convenient and reliable tool
to monitor the progress of these displacement reactions.
Dipeptide NH -Val-Phe-NH-resin was synthesized on
2
2
to react with resin-bound phenyl carbamate 1. The rate
of reaction was monitored by quantitative spectrophoto-
metric measurement of the amount of phenol released
after 1 h. Reaction with phenethylamine should give a
measure of the extent of urea formation, whereas the
1
0
TentaGel S AM resin (90 mmol) using conventional
Fmoc deprotection/HATU-coupling chemistry. It was
treated with excess phenyl chloroformate (5-10-fold) and
diisopropylethylamine (10-20-fold) in aqueous 1,4-diox-
1
1
ane at room temperature for 4 h. The resulting phenyl
carbamate intermediate 1 on resin is stable at room
temperature and can be stored dry for several weeks
without any noticeable decomposition. Resin-bound phen-
yl carbamate 1 was treated separately with either excess
phenethylamine or diisopropylamine in DMF (0.2-0.5 M)
at room temperature. Within 1 h, measurement of the
released phenol in the supernatant (diluted in 0.1 N
aqueous KOH) indicated completion of reaction. Stan-
dard TFA cleavage of the resulting resin yielded pre-
dominantly the anticipated urea product 2 for the phen-
ethylamine reaction. However, only the internally cyclized
hydantoin 3 and none of the urea 4 was obtained from
the diisopropylamine reaction. In retrospect, this result
2
phenol release from iPr NEt reaction should reflect the
12
degree of hydantoin cyclization.
The resulting data provides us with good choice for
selective urea or hydantoin transformations (Table 1).
Thus, urea formation is sluggish in CH Cl (36%) and
2 2
(
10) TentaGel S resin is from RAPP Polymere: 90 µ. Initial
loading: 0.23 mmol/g. AM: acid cleavable linker.
11) The reaction was usually continued until the resin became
(
ninhydrin negative, signifying the disappearance of starting amine.
Later experiments suggested that the carbamate formation was usually
complete in 1 h.
(12) Simple hydrolysis of phenyl carbamate 1 would also result in
the release of phenol accompanied by the formation of corresponding
free amine of 1. This possibility was ruled out because the final
resin was ninhydrin negative. Therefore, it was appropriate to view

6
970 J . Org. Chem., Vol. 62, No. 20, 1997
Xiao et al.
Sch em e 2. Solid P h a se Syn th esis of Un sym m etr ica l Ur ea s a n d Hyd a n toin s
Ta ble 2. Solid P h a se Syn th esis of Un sym m etr ica l Ur ea s
1
,4-dioxane (31%) but proceeds very efficiently in THF,
3
CH CN, DMF, and DMSO (100%), whereas hydantoin
cyclization is observed to proceed very poorly in THF (1%)
and 1,4-dioxane (0.3%). This makes THF the most
discriminatory and ideal solvent for selective urea forma-
tion, whereas a choice of several different solvents
3
(CH CN, DMF, and DMSO) is available for preparing
hydantoins. In the latter case, DMF was chosen for
effecting cyclizations based on convenience, toxicity, and
resin-swelling ability. With THF as the optimum solvent
for urea and DMF for hydantoin formation, structurally
diverse dipeptide phenyl carbamate intermediates on
resin were treated with a series of primary, secondary,
and tertiary amines under the above established condi-
tions to investigate the scope and selectivity of these
transformations (Scheme 2, Table 2).
Solid P h a se Syn th esis of Un sym m etr ica l Ur ea s
8
fr om P h en yl Ca r ba m a tes 7. Formation of unsym-
metrical ureas 8 vs competing internal cyclization to
hydantoins 10 from common phenyl carbamate interme-
diate 6 can be expected to be influenced by the steric and
electronic nature of the two reacting partners, i.e. the
incoming nucleophilic reagent R
3 4 2
R NH and the R sub-
stituents on carbamate 6 (Scheme 2, Table 2). Starting
with phenethylamine as a representative example of a
simple primary amine, the urea reaction was studied
with various phenyl carbamates 6 bearing different R
2
groups (Table 2). Resin-bound dipeptides 5 were con-
verted to phenyl carbamates 6 and individually treated
2
with phenethylamine (entry a-e, Table 2) and iPr NEt
in THF for 1 h. The crude products 8a -8e obtained after
TFA cleavage were reasonably pure as judged by HPLC
1
(
72-94%), and analysis of the H NMR spectra confirmed
that urea formation proceeded with high selectivity (>14:
). The tolerance for sterically hindered (8b, R ) iPr),
acidic (8d , R ) (CH CO H), and basic (8e, R
CH NH ) substituents serves to illustrate the struc-
selectivity (8f, 93%, 25:1 urea vs hydantoin). The selec-
tivity is slightly compromised with secondary amines
such as cyclohexylamine (8g, 79%, 8:1 urea vs hydantoin)
and the highly hindered diisopropylamine (8h -j, 83-97%,
1
2
2
2
)
2
2
2
)
(
2
)
4
2
tural flexibility for the R
preparing ureas.
2
site afforded by this route for
7
to 9:1 urea vs hydantoin). These results highlight the
anticipated trend that as the incoming amine R NH
3 4
R
Next, we investigated the scope of substituents on the
other nitrogen of urea moiety (R and R ) by treating
phenyl carbamates 6 with more sterically demanding
amines (R NH). The reaction of a primary amine such
gets sterically demanding, the dipeptide phenyl carbam-
ate intermediate 6 becomes more susceptible to cyclizing
to the hydantoin side product. Nevertheless, even worse
case combinations of having bulky substituents on both
3
4
3
R
4
as isobutylamine proceeds with excellent conversion and
nitrogens in urea products such as 8j (R
2
) R
3
) R )
4
the amount of phenol release from 1 upon DIEA treatment as an
indication of the extent of cyclization to hydantoin. Similarly, since
phenyl carbamate 1 was reasonably stable to storage, phenol release
upon reaction with phenethylamine was used as a measure of urea
formation.
iPr) can be achieved in excellent yields with adequate
selectivity (97%, 7:1 urea vs hydantoin).
Solid P h a se Syn th esis of Hyd a n toin s 10 fr om
P h en yl Ca r ba m a tes 6. In hydantoin synthesis, the

Solid Phase Synthesis of Ureas and Hydantoins
J . Org. Chem., Vol. 62, No. 20, 1997 6971
Ta ble 3. Solid P h a se Syn th esis of Hyd a n toin s 10
an activated carbamoyl intermediate with the right
balance of stability and chemical reactivity such that it
can be selectively converted to either ureas or hydantoins
by the appropriate choice of nucleophile/base and sol-
vents. Thus, reaction of dipeptide derived phenyl car-
bamate 6 with primary or secondary amines (R
in THF leads to selective formation of ureas 8, whereas
its treatment with a tertiary amine base (iPr NEt or
3 4
R NH)
2
DBU) in DMF affords clean conversion to hydantoins 10.
Since a wide variety of substituents are well tolerated
in both instances, it permits the syntheses of hydantoins
and ureas with an adequate degree of structural diver-
sity. The current method should facilitate the utility of
ureas and hydantoins as peptide amide-bond surrogates
and dipeptidomimetic scaffolds respectively in the field
of drug discovery. In general, maneuvering the outcome
of common reactive intermediates to different products
in a predictable manner is a very useful chemical
strategy. It can be expected to facilitate the application
of solid phase methodologies to combinatorial preparation
of structurally diverse chemical libraries of various
scaffolds and pharmacophores.
Exp er im en ta l Section
Gen er a l. TentaGel S AM resin was from RAPP Polymere,
Germany. Wang hydroxy resin was from Advanced ChemTech.
All reagents and solvents were from either Aldrich Chemi-
cal Co. or VWR and were used as received without any
additional treatment. 1H and C NMR spectra were obtained
possibility of competetive urea formation is eliminated
by choosing a tertiary base such as DIEA or DBU for
effecting the cyclization reaction. The normal protocol
is to treat the immobilized dipeptide phenyl carbamate
13
3 3
on a 400 MHz Varian spectrometer, with CDCl or CD OD as
the solvent and internal reference. Low-resolution mass
spectra were obtained on an Electron Spray mass spectrom-
eter. Final TFA cleavage products were normally lyophilized
from benzene (if solubility was a problem, 5-10% meth-
anol was added). Fmoc numbers and phenol concentra-
tions were measured on a HP8452A diode array spectropho-
tometer.
P r ep a r a tion of Dip ep tid e P h en yl Ca r ba m a te 1. TGS
AM resin (2.10 g, 0.48 mmol) was suspended in DMF (10 mL).
DIEA (0.84 mL, 4.83 mmol, 10 equiv), L-Fmoc-Phe-OH (0.94
g, 2.42 mmol, 5 equiv), and PyBOP (1.26 g, 2.42 mmol, 5 equiv)
were added. The reaction mixture was shaken at room
temperature for 1 h and washed with DMF (10 mL × 4). The
resin was subjected to a second coupling under identical
conditions. Kaiser test of the resin was negative. The
resulting resin (400 mg) was treated with 20% piperidine/DMF
6
with DIEA in DMF and monitor the course of reaction
by spectrophotometric measurement of the released
phenol. Typically, cyclization was found to be complete
within 1 h for the amide-linked products derived from
Tentagel S Resin (X ) NH), whereas much longer
reaction times (24 h) were required for ester-linked
products from hydroxyl Wang resin (X ) O). The reasons
for such an influence of linker and nature of immobilized
support are not clear, and these examples serve to
highlight the importance of such commonly ignored
physical parameters in solid phase organic synthesis. In
all instances, the crude products were obtained in almost
quantitative yields and good purity (89-95%). In the
case of 10e (R
2
) iPr, R ) Me), incomplete cyclization
1
(4 mL) at room temperature for 30 min, giving an Fmoc
was observed even after prolonged treatment (<50% yield
after 24 h) under standard conditions, but a dramatic
enhancement in efficiency and extent of conversion was
realized by employing DBU in place of DIEA as a base
number of 192. The resin was then washed with DMF (5 mL
× 3), MeOH (5 mL × 3), and ether (5 mL × 3) and coupled
with L-Fmoc-Val-OH under the above standard conditions. The
final resin was negative to Kaiser test. The Fmoc protecting
group (400 mg) was removed under the standard conditions
described above. The resulting dipeptide amine H N-Val-Phe-
2
NH-TGS was treated with DIEA (0.28 mL, 1.6 mmol, 20 equiv)
and phenyl chloroformate (0.10 ml, 0.8 mmol, 10 equiv) in 9:1
(
essentially quantitative mass recovery of crude product
1
3
with 92% purity after 1 h). The possibility of epimer-
ization during DBU treatment was eliminated on the
basis of 1H NMR and HPLC analysis of the hydan-
1
,4-dioxane/water at room temperature for 1 h. Kaiser test
toin product 10e. Similarly, 10f (R
2
) R
1
) CH
2
Ph)
indicated completion of reaction. The resin was washed with
1,4-dioxane (5 mL × 4) and ether (5 mL × 4) and dried under
vacuum to give 1.
underwent smooth cyclization with DBU. These re-
sults (10e and 10f) point to the possibility of DBU as
being a more effective base than DIEA for preparing
hydantoins.
P r ep a r a tion of Ur ea 2. Immobilized phenyl carbamate
dipeptide 1 (200 mg) was treated with 0.5 M phenethylamine/
DMF at room temperature for 1 h. Measurement of the
released phenol indicated that the reaction was 99% complete.
Standard TFA cleavage (room temperature, 30 min) yielded
Con clu sion
1
urea 2 as a white solid (14 mg, quantitative): H NMR (400
In summary, we have described the first examples of
a simple and efficient method for selectively synthesizing
either unsymmetrical ureas or hydantoins from common
phenyl carbamate intermediates. Phenyl carbamate is
MHz, CDCl
3
)
3
) δ 0.62 (d, J ) 8.0 Hz, 3 H), 0.74 (d, J ) 6.9 Hz,
H), 1.86-1.95 (m, 1 H), 2.65 (t, J ) 7.1 Hz, 2 H), 2.88 (dd, J
8.0, 14.1 Hz, 1 H), 3.08 (dd, J ) 6.0, 14.1 Hz, 1 H), 3.20-
3.32 (m, 2 H), 4.64 (dd, J ) 6.0, 8.0 Hz, 1 H), 5.79 (br d, J )
6
.2 Hz, 1 H), 7.06-7.38 (m, 10 H); 13C NMR (100 MHz, CDCl
3
)
(13) Other organic bases like triethylamine and N-methylmorpholine
δ 17.17, 19.09, 30.17, 36.25, 37.36, 41.22, 53.76, 59.97, 70.34,
126.36, 126.86, 128.52, 128.74, 129.12, 136.50, 139.20, 173.05,
were also tested and and found to give less satisfactory results.

6
972 J . Org. Chem., Vol. 62, No. 20, 1997
73.20, 190.05; LRMS calcd for C23 (M + H) 411.5,
Xiao et al.
1
H
31
N
4
O
3
13C NMR (100 MHz, CDCl
3
) δ 17.64, 19.88, 28.86, 37.20, 47.49,
50.35, 53.76, 126.89, 128.52, 129.22, 136.66, 159.01, 174.30,
found 411.2.
+
P r ep a r a tion of Hyd a n toin 3. Immobilized phenyl car-
bamate dipeptide 1 (200 mg) was suspended in DMF (2 mL)
and treated with diisopropylamine (0.5 M) at room tempera-
ture for 1 h. Measurement of the released phenol indicated
that the reaction was 99% complete. Standard TFA cleavage
174.43; HRMS (C17
335.2085.
H
26
N
4
O
3
+ H) calcd 335.2083, found
(P ip er id ylca r ba m oyl)-Ala -L-P h e-NH
(400 MHz, CDCl
2
(8g): 1H NMR
3
) δ 1.29 (d, J ) 7.1 Hz, 3 H), 1.44-1.64 (m,
6 H), 3.08-3.38 (m, 6 H), 4.14 (q, J ) 7.1 Hz, 1 H), 4.66 (dd,
(room temperature, 30 min) yielded hydantoin 3 as a white
J ) 6.3, 14.2 Hz, 1 H), 6.65 (br s, 1 H), 6.96 (br s, 1 H), 7.15-
1
13
solid (15 mg, quantitative): H NMR (400 MHz, CDCl
3
) δ 0.38
7.35 (m, 5 H); C NMR (100 MHz, CDCl
3
) δ 17.86, 24.26, 25.63,
(
1
d, J ) 6.8 Hz, 3 H), 0.75 (d, J ) 7.0 Hz, 3 H), 1.80-1.92 (m,
37.08, 37.51, 45.27, 50.16, 51.60, 54.01, 127.36, 128.95, 129.42,
H), 3.34 (dd, J ) 5.2, 14.0 Hz, 1 H), 3.48 (dd, J ) 12.0, 14.1
136.29, 157.57, 174.46, 175.66; LRMS calcd for C18
+ H) 347.4, found 347.2.
H
27
N
4
O
3
(M
Hz, 1 H), 3.74 (d, J ) 3.8 Hz, 1 H), 4.86 (dd, J ) 5.2, 12.0 Hz,
H), 7.09-7.22 (m, 5 H); 13C NMR (100 MHz, CDCl
8.52, 29.95, 34.31, 55.48, 70.45, 127.10, 128.77, 129.06,
36.50, 171.80, 173.90, 213.00; LRMS calcd for C14 Na
) δ 15.45,
(8i): 1
H
1
1
1
3
(N,N′-Diisop r op ylca r ba m oyl)-L-Gly-L-P h e-NH
2
NMR (400 MHz, CDCl
3
) δ 0.98 (d, J ) 6.8 Hz, 6 H), 1.00 (d, J
) 6.9 Hz, 6 H), 2.84-3.00 (m, 4 H), 3.50-3.58 (m, 2 H), 4.43
(dd, J ) 5.8, 7.2 Hz, 1 H), 6.95-7.12 (m, 5 H); C NMR (100
MHz, CDCl ) δ 20.20, 33.31, 36.98, 43.69, 45.56, 53.40, 126.38,
128.03, 128.68, 136.20, 157.50, 171.28, 174.30; HRMS
21 3 2
H N O
1
3
(M + Na) 312.3, found 311.9.
Gen er a l P r oced u r e for Syn th esis of Ur ea s on Solid
3
Su p p or ts. Immobilized dipeptide phenyl carbamate 6 was
prepared in the same manner as described for 1 and treated
overnight with 0.5 M primary or secondary amine in THF at
room temperature, at which time the phenol release was
essentially found to be complete. The resulting intermediate
resin 7 was subjected to standard TFA cleavage treatment
described above to yield the desired ureas 8.
+
(C18
H
28
N
4
O
3
+ H) calcd 349.2240, found 349.2232.
(N,N′-Diisop r op ylca r ba m oyl)-Ala -L-P h e-NH
NMR (400 MHz, CDCl ) δ 1.14 (d, J ) 6.8 Hz, 6 H), 1.16 (d, J
(8j): 1H
2
3
) 6.9 Hz, 6 H), 1.35 (d, J ) 7.2 Hz, 3 H), 3.03 (dd, J ) 5.9,
14.0 Hz, 1 H), 3.37 (dd, J ) 5.9, 14.0 Hz, 1 H), 3.65-3.80 (m,
2 H), 4.08 (dq, J ) 3.5, 7.2 Hz, 1 H), 4.42 (br d, J ) 3.5 Hz, 1
H), 4.74 (dt, J ) 5.9, 8.8 Hz, 1 H), 5.33 (br s, 1 H), 6.46 (br d,
N-(P h en eth ylcar bam oyl)-L-Gly-L-P h e-NH
400 MHz, CDCl ) δ 2.55 (t, J ) 7.3 Hz, 2 H), 2.78 (dd, J )
.9, 13.9 Hz, 1 H), 2.94 (dd, J ) 5.8, 13.9 Hz, 1 H), 3.15 (t, J
(8a): 1H NMR
2
1
3
(
7
)
3
J ) 8.8 Hz, 1 H), 7.10 (br s, 1 H), 7.16-7.30 (m, 5 H);
NMR (100 MHz, CDCl ) δ 18.14, 21.37, 21.54, 39.96, 45.88,
51.80, 53.15, 127.20, 128.90, 129.54, 136.40, 157.10, 173.30,
C
3
7.3 Hz, 2 H), 3.50 (s, 2 H), 4.41 (dd, J ) 5.8, 7.9 Hz, 1 H),
.95-7.10 (m, 5 H); 13C NMR (100 MHz, CD
OD) δ 37.57,
173.83; HRMS (C19
363.2394.
H
N
O
+ H) calcd 363.2396, found
+
6
3
1
3
30
4
3
8.88, 42.90, 44.61, 55.59, 127.41, 127.93, 128.80, 129.62,
29.98, 130.44, 138.39, 140.90, 161.00, 173.10, 176.05; HRMS
(N,N′-Diisop r op ylca r ba m oyl)-L-Va l-L-P h e-NH
2
(8k ): 1
H
+
(C
20
H
24
N
4
O
3
+ H) calcd 369.1927, found 369.1923.
NMR (400 MHz, CDCl ) δ 0.79 (d, J ) 6.9 Hz, 3 H), 0.86 (d, J
3
N-(P h en eth ylcar bam oyl)-L-Val-L-P h e-NH
400 MHz, CDCl ) δ 0.49 (d, J ) 6.3 Hz, 3 H), 0.62 (d, J ) 6.2
2
(8b): 1H NMR
) 6.8 Hz, 3 H), 1.13 (d, J ) 6.8 Hz, 6 H), 1.15 (d, J ) 6.8 Hz,
6 H), 1.98-2.08 (m, 1 H), 3.06 (t, J ) 6.6 Hz, 2 H), 3.75-3.84
(m, 2 H), 3.92-3.96 (m, 1 H), 4.57-4.65 (m, 1 H), 7.12-7.22
(
3
Hz, 3 H), 1.75-1.84 (m, 1 H), 2.53 (t, J ) 7.0 Hz, 2 H), 2.75
(
dd, J ) 8.2, 13.0 Hz, 1 H), 2.97 (dd, J ) 5.3, 13.0 Hz, 1 H),
3
5
(m, 5 H); 13C NMR (100 MHz, CDCl
3
) δ 18.15, 19.70, 21.39,
21.51, 30.89, 37.45, 45.62, 53.74, 60.47, 127.20, 128.86, 129.47,
.04-3.20 (m, 2 H), 3.65 (d, J ) 4.4 Hz, 1 H), 4.42 (dd, J )
.3, 8.2 Hz, 1 H), 6.95-7.25 (m, 10 H); 13C NMR (100 MHz,
136.78, 157.51, 172.79, 174.26; HRMS (C21
391.2709, found 391.2713.
+
34 4 3
H N O + H) calcd
CDCl
1
1
3
) δ 16.52, 18.44, 29.78, 35.83, 36.94, 40.85, 53.49, 59.75,
25.84, 126.34, 128.02, 128.26, 128.66, 136.50, 138.80, 160.20,
Gen er a l P r oced u r e for Syn th esis of Hyd a n toin s on
Solid Su p p or ts. Immobilized dipeptide phenyl carbamate 6
was treated with 0.5 M DIEA or DBU in DMF at room
temperature for the indicated time (Table 2) to give resin 9.
Standard TFA treatment of resin 9 yielded the desired
hydantoins 10.
+
73.00, 174.00; HRMS (C23
30 4 3
H N O + H) calcd 411.2396,
found 411.2394.
N-(P h en eth ylcar bam oyl)-L-P h e-L-P h e-NH
400 MHz, CDCl
(8c): 1H NMR
2
(
8
3
) δ 2.50 (t, J ) 7.2 Hz, 2 H), 2.61 (dd, J )
.0, 14.0 Hz, 1 H), 2.70-2.83 (m, 2 H), 2.90 (dd, J ) 5.8, 14.0
Hz, 1 H), 3.10-3.20 (m, 2 H), 4.16 (dd, J ) 5.8, 8.0 Hz, 1 H),
(5S)-5-Meth yl-3-[(2S)-1-a m in o-1-oxo-3-p h en ylp r op -2-yl-
4
(
1
1
.40 (dd, J ) 5.8, 7.6 Hz, 1 H), 6.90-7.13 (m, 15 H); 13C NMR
100 MHz, CDCl ) δ 35.67, 36.77, 37.37, 40.76, 53.41, 55.20,
25.65, 126.19, 126.24, 127.84, 127.92, 128.12, 128.59, 128.65,
36.30, 138.70, 158.50, 172.80, 173.90; HRMS (C27
]h yd a n toin (10a ): 1H NMR (400 MHz, CDCl
3
) δ 0.95 (d, J )
3
7.0 Hz, 3 H), 3.35-3.48 (m, 2 H), 3.86 (q, J ) 7.0 Hz, 3 H),
1
3
4.84 (dd, J ) 5.8, 11.6 Hz, 1 H), 7.10-7.23 (m, 5 H); C NMR
(100 MHz, CDCl ) δ 17.58, 34.99, 52.88, 56.38, 127.38, 128.91,
H
30
N
4
O
3
+
3
+
H) calcd 459.2396, found 459.2391.
129.31, 136.20, 156.60, 174.10, 177.50; HRMS (C13
H
15
N
3
O
3
+
+
N-(P h en eth ylca r ba m oyl)-L-Glu -L-P h e-NH
2
a m m on iu m
H) calcd 262.1192; found 262.1192.
1
sa lt (8d ): H NMR (400 MHz, CDCl
3
) δ 1.50-1.70 (m, 1 H),
(5S)-5-Isop r op yl-3-[(2S)-1-a m in o-1-oxo-3-p h en ylp r op -
1
.70-1.80 (m, 1 H), 2.08 (t, J ) 7.3 Hz, 2 H), 2.59 (t, J ) 7.3
Hz, 2 H), 2.82 (dd, J ) 8.3, 14.0 Hz, 1 H), 3.03 (dd, J ) 5.7,
4.0 Hz, 1 H), 3.10-3.25 (m, 3 H), 3.91 (dd, J ) 5.7, 8.3 Hz, 1
2-yl]h yd a n toin (10b): 1H NMR (400 MHz, CDCl
3
) δ 0.38 (d,
J ) 6.8 Hz, 3 H), 0.75 (d, J ) 7.0 Hz, 3 H), 1.80-1.92 (m, 1
H), 3.34 (dd, J ) 5.2 14.0 Hz, 1 H), 3.48 (dd, J ) 12.0, 14.0
Hz, 1 H), 3.75 (d, J ) 3.8 Hz, 1 H), 4.86 (dd, J ) 5.2, 12.0 Hz,
1
1
3
H), 7.00-7.18 (m, 10 H); C NMR (100 MHz, CDCl
3
) δ 26.89,
9.72, 35.96, 37.07, 41.08, 53.50, 53.68, 126.03, 126.50, 128.71,
28.31, 128.42, 128.70, 128.75, 128.86, 136.50, 138.86, 158.65,
2
1
1
4
1 H), 7.09-7.21 (m, 5 H); 13C NMR (100 MHz, CDCl
3
) δ 15.45,
18.52, 29.95, 34.30, 55.48, 62.44, 127.10, 128.7, 129.06, 136.30,
+
+
72.76, 173.76, 174.22; HRMS (C23
41.2138, found 441.2146.
H
28
N
4
O
5
+ H) calcd
157.80, 171.90, 173.80; HRMS (C15
290.15047, found 290.15115.
H
19
N
3
O
3
+ H) calcd
N-(P h en eth ylcar bam oyl)-L-Lys-L-P h e-NH
400 MHz, CDCl
2
2
(8e): 1H NMR
(5S)-5-Isop r op yl-3-[(1S)-1-ca r b oxy-2-p h en ylet h yl]h y-
(
3
) δ 1.05-1.15 (m, 2 H), 1.30-1.53 (m, 4 H),
.62 (t, J ) 7.0 Hz, 2 H), 2.70 (t, J ) 7.0 Hz, 2 H), 2.86 (dd, J
8.6, 14.2 Hz. 1 H), 3.09 (dd, J ) 5.5, 14.2 Hz, 1 H), 3.21 (t,
J ) 7.3 Hz, 2 H), 3.85 (dd, J ) 5.1, 7.9 Hz, 1 H), 4.48 (dd, J )
.5, 8.6 Hz, 1 H), 7.05-7.20 (m, 10 H); 13C NMR (100 MHz,
CDCl ) δ 21.76, 26.51, 30.91, 36.33, 37.12, 39.10, 41.42, 54.08,
4.45, 126.36, 126.89, 128.50, 128.56, 128.71, 129.01, 129.06,
29.16, 136.69, 139.14, 159.25, 173.96, 174.69; HRMS
d a n toin (10c): 1H NMR (400 MHz, CDCl
3
) δ 0.66 (d, J ) 8.1
Hz, 3 H), 0.98 (d, J ) 8.0 Hz, 3 H), 2.09-2.18 (m, 1 H), 3.62-
3.65 (m, 2 H), 3.96 (d, J ) 5.3 Hz, 1 H), 5.11 (dd, J ) 9.1, 12.1
)
Hz, 1 H), 7.25-7.38 (m, 5 H); 13C NMR (100 MHz, CDCl
) δ
3
5
15.57, 18.70, 30.08, 34.08, 53.41, 126.95, 128.71, 129.12,
+
3
136.80, 162.50, 170.90, 173.20; HRMS (C15
291.13448, found 291.13443.
18 2 4
H N O + H) calcd
5
1
(5S )-5-B e n zy l-3-[(1S )-1-c a r b o x y -2-m e t h y lp r o p y l]-
+
h yd a n toin (10d ): 1H NMR (400 MHz, CDCl
(
C
24
H
33
N
5
O
3
+ H) calcd 440.2662, found 440.2663.
N-(Isobu tylca r ba m oyl)-L-Ala -L-P h e-NH
(8f): 1H NMR
400 MHz, CDCl ) δ 0.77 (d, J ) 6.6 Hz, 6 H), 1.11 (d, J ) 7.2
3
) δ 0.78 (d, J )
2
8.0 Hz, 3 H), 1.16 (d, J ) 7.0 Hz, 3 H), 2.61-2.71 (m, 1 H),
3.01-3.08 (m, 1 H), 3.38 (dd, J ) 5.0, 15.0 Hz, 1 H), 4.40 (d,
J ) 11.5 Hz, 1 H), 4.48 (dd, J ) 5.0, 11.6 Hz, 1 H), 7.31-7.47
(
3
Hz, 3 H), 1.56 (m, 1 H), 2.75-2.85 (m, 2 H), 2.97 (dd, J ) 7.6,
4.0 Hz, 1 H), 3.07 (dd, J ) 5.9, 14.0 Hz, 1 H), 3.95 (q, J ) 7.2
Hz, 1 H), 4.49 (dd, J ) 5.9, 7.6 Hz, 1 H), 7.11-7.20 (m, 5 H);
1
(m, 5 H); 13C NMR (100 MHz, CDCl
3
) δ 19.15, 20.93, 28.03,
36.83, 37.80, 58.47, 127.48, 128.89, 129.68, 135.10, 163.21,

Solid Phase Synthesis of Ureas and Hydantoins
+ H)+ calcd 291.13448,
5S )-5-Isop r op yl-3-[(1S )-1-ca r b oxye t h yl]H yd a n t oin
J . Org. Chem., Vol. 62, No. 20, 1997 6973
1
70.80, 173.30; HRMS (C15
H
18
N
2
O
4
8.6 Hz, 1H), 2.88 (dd, J ) 4.5, 9.5 Hz, 1H), 3.31 (m, 3H), 4.17
(dd, J ) 3.85, 4.67, Hz, 1H), 7.22 (m, 10H); HRMS (C H N O
found 291.13405.
1
9
18
2
4
+
(
+ H) calcd 339.13448, found 339.13353.
1
(
1
(
6
1
10e): H NMR (400 MHz, CDCl
.21 (d, J ) 7.9 Hz, 3 H), 1.77 (d, J ) 7.5 Hz, 3 H), 2.36-2.45
m, 1 H), 4.13 (d, J ) 4.0 Hz, 1 H), 4.95 (q, J ) 7.5 Hz, 1 H),
3
) δ 1.08 (d, J ) 8.1 Hz, 3 H),
Ack n ow led gm en t. We would like to thank Bill
Fitch and Nikhil Shah at Affymax for providing high-
and low-resolution mass spectral data on the compounds
described in this paper.
.63 (br d, 10.5 Hz, 1 H); 13C NMR (100 MHz, CDCl
6.27, 19.11, 30.70, 48.09, 158.10, 164.00, 172.95; LRMS calcd
) δ 14.99,
3
+
for C
9 15 2 4
H N O (M + H) 215.1, found 215.0.
5S)-5-Ben zyl-3-[(1S)-1-ca r boxy-2-p h en yleth yl]h yd a n -
(
1
toin (10f): H NMR (400 MHz, CD
3
OD) δ 2.37(dd, J ) 5.5,
J O971087I