Triurea derivatives of diethylenetriamine as potential templates for the formation of artificial β-sheets

Article abstract of DOI:10.1021/ja9536072

This paper describes synthetic and structural studies of triurea derivatives of an N,N_-disubstituted diethylenetriamine. Diethylenetriamine triureas 1 (PhN(CONHR₁)CH₂CH₂N(CONHR₂)CH₂CH₂

Full text of DOI:10.1021/ja9536072

1066
J. Am. Chem. Soc. 1996, 118, 1066-1072
Triurea Derivatives of Diethylenetriamine as Potential
Templates for the Formation of Artificial â-Sheets1
James S. Nowick,* Sami Mahrus, Eric M. Smith, and Joseph W. Ziller
Contribution from the Department of Chemistry, UniVersity of California, IrVine,
IrVine, California 92717-2025
ReceiVed October 27, 1995X
Abstract: This paper describes synthetic and structural studies of triurea derivatives of an N,N"-disubstituted
diethylenetriamine. Diethylenetriamine triureas 1 (PhN(CONHR1)CH2CH2N(CONHR2)CH2CH2N(CONHR3)CH2-
CH2CN; 2a, R1 ) R2 ) R3 ) Ph; 2b, R1 ) R2 ) R3 ) CH3; 2c, R1 ) (S)-CH(CH2Ph)CO2CH3, R2 ) (S)-CH(i-
Pr)CO2CH3, R3 ) (S)-CH((S)-s-Bu)CO2CH3)) are efficiently prepared in five or six steps from N-phenylethylene-
1
diamine. Infrared spectroscopy, H NMR spectroscopy, and X-ray crystallography indicate that triureas 1 adopt
intramolecularly hydrogen-bonded conformations, both in chloroform solution and in the solid state. The three urea
groups form a hydrogen-bonded network: The carbonyl group of urea NCONHR1 is hydrogen bonded to the NH
group of urea NCONHR2, and the carbonyl group of urea NCONHR2 is hydrogen bonded to the NH group of urea
NCONHR3. The three R groups are aligned along the triurea backbone, pointing in roughly the same direction, like
three fingers on a hand. Molecular modeling suggests that the triurea backbone will be a suitable template for the
creation of artificial â-sheets. When molecular mechanics energy minimization calculations are performed upon a
triurea bearing three N-terminally linked peptide strands, a parallel â-sheet is formed.
Although â-sheets are fundamental elements of protein
and a peptide strand to create artificial antiparallel â-sheets.5
Subsequent reports have described parallel â-sheets that incor-
porate this template.6 Since 1991, Kelly and co-workers have
described a series of antiparallel â-sheet models in which a
dibenzofuran template holds two peptide strands in proximity,
while hydrophobic interactions between the template and peptide
side chains help stabilize â-sheet formation.7 Within the past
year, a number of other templates capable of bringing two
peptide strands together and inducing â-sheet structure have
been reported.8 Complementary to these strategies, which rely
upon peptidomimetic surrogates to help stabilize protein struc-
ture, are systems that are wholly peptide-based. These systems
include “template-assembled synthetic proteins” (TASPs),9 small
naturally occurring â-sheet proteins,10 and de novo designed
proteins.11
structure, their structure and stability remain poorly understood.
One approach to studying protein structure and stability involves
the design, synthesis, and study of peptidomimetic model
systems.2 Over the past decade, a number of research groups
have developed chemical models for â-sheets in which a
synthetic template (turn unit) holds two peptide strands or a
peptide strand and a peptide strand mimic in proximity.
Beginning in 1986, Feigel and co-workers have employed
several aromatic templates to form two-stranded antiparallel and
parallel â-sheet structures in cyclopeptides.3 While earlier
studies had focused upon the mimicry and induction of â-turns,4
Feigel’s work marked the beginning of interest in the mimicry
of â-sheets. In 1988, Kemp and co-workers reported using an
epindolidione â-strand mimic in conjunction with a â-turn unit
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) Paper 5 in the series Molecular Scaffolds.
(5) (a) Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077.
(b) Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5081. (c) Kemp,
D. S.; Bowen, B. R.; Muendel, C. C. J. Org. Chem. 1990, 55, 4650.
(6) Kemp, D. S. Studies of template-nucleated â-sheets and R-helices.
Presented at the 203rd National Meeting of the American Chemical Society,
San Fransisco, CA, April 1992; paper ORGN 151.
(7) (a) Diaz, H.; Kelly, J. W. Tetrahedron Lett. 1991, 32, 5725. (b) Diaz,
H.; Espina, J. R.; Kelly, J. W. J. Am. Chem. Soc. 1992, 114, 8316. (c)
Diaz, H.; Tsang, K. Y.; Choo, D.; Espina, J. R.; Kelly, J. W. J. Am. Chem.
Soc. 1993, 115, 3790. (d) Diaz, H.; Tsang, K. Y.; Choo, D.; Kelly, J. W.
Tetrahedron 1993, 49, 3533. (e) Tsang, K. Y.; Diaz, H.; Graciani, N.; Kelly,
J. W. J. Am. Chem. Soc. 1994, 116, 3988.
(8) For examples, see: (a) Winningham, M. J.; Sogah, D. Y. J. Am.
Chem. Soc. 1994, 116, 11173. (b) LaBrenz, S. R.; Kelly, J. W. J. Am Chem.
Soc. 1995, 117, 1655. (c) Schneider, J. P.; Kelly, J. W. J. Am. Chem. Soc.
1995, 117, 2533. (d) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am.
Chem. Soc. 1995, 117, 3280. (e) Kemp, D. S.; Li, Z. Q. Tetrahedron Lett.
1995, 36, 4175. (f) Kemp, D. S.; Li, Z. Q. Tetrahedron Lett. 1995, 36,
4179.
(9) (a) Mutter, M.; Altmann, E.; Altmann, K.-H.; Hersperger, R.; Koziej,
P.; Nebel, K.; Tuchscherer, G.; Vuilleumier, S.; Gremlich, H.-U.; Mu¨ller,
K. HelV. Chem. Acta 1988, 71, 835. (b) Mutter, M.; Vuilleumier, S. Angew.
Chem., Int. Ed. Engl. 1989, 28, 535. (c) Tuchscherer, G.; Do¨rner, B.; Sila,
U.; Kabmer, B.; Mutter, M. Tetrahedron 1993, 49, 3559.
(2) For reviews, see: (a) Kemp, D. S. Trends Biotechnol. 1990, 8, 249.
(b) Ho¨lzemann, G. Kontakte 1991, 3. (c) Ho¨lzemann, G. Kontakte 1991,
55. (d) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278. (e)
Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bo¨s, M.; Cook, C. M.; Fry, D.
C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.; Vincent, G. P.; Voss, M. E. J.
Med. Chem. 1993, 36, 3039. (f) Wiley, R. A.; Rich, D. H. Med. Res. ReV.
1993, 13, 327. (g) Chorev, M.; Goodman, M. Acc. Chem. Res. 1993, 26,
266. (h) Zuckermann, R. N. Curr. Opin. Struct. Biol. 1993, 3, 580. (i) Kahn,
M. Synlett 1993, 821. (j) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1244. (k) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1699. (l) Liskamp, R. M. J. Recl. TraV. Chim. Pays-Bas 1994, 113, 1. (m)
Adang, A. E. P.; Hermkens, P. H. H.; Linders, J. T. M.; Ottenheijm, H. C.
J.; van Staveren, C. J. Recl. TraV. Chim. Pays-Bas 1994, 113, 63. (n) Beeley,
N. Trends Biotechnol. 1994, 12, 213. (o) Schneider, J. P.; Kelly, J. W.
Chem. ReV. 1995, 95, 2169.
(3) (a) Feigel, M. J. Am. Chem. Soc. 1986, 108, 181. (b) Brandmeier,
V.; Feigel, M.; Bremer, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 486.
(c) Brandmeier, V.; Feigel, M. Tetrahedron 1989, 45, 1365. (d) Feigel, M.
Liebigs Ann. Chem. 1989, 459. (e) Wagner, G.; Feigel, M. Tetrahedron
1993, 49, 10831. (f) Brandmeier, V.; Sauer, W. H. B.; Feigel, M. HelV.
Chim. Acta 1994, 77, 70.
(4) For early examples, see: (a) Veber, D. F.; Holly, F. W.; Paleveda,
W. J.; Nutt, R. F.; Bergstrand, S. J.; Torchiana, M.; Glitzer, M. S.;
Saperstein, R.; Hirschmann, R. Proc. Natl. Acad. Sci U.S.A. 1978, 75, 2636.
(b) Freidinger, R. M; Veber, D. F.; Perlow, D. S. Brooks, J. R.; Saperstein,
R. Science 1980, 210, 656.
(10) (a) Kim, C. A.; Berg, J. M. Nature 1993, 362, 267. (b) Minor, D.
L., Jr.; Kim, P. S. Nature 1994, 367, 660. (c) Smith, C. K.; Withka, J. M.;
Regan, L. Biochemistry 1994, 33, 5510. (d) Minor, D. L.; Kim, P. S. Nature
1994, 371, 264. (e) Otzen, D. E.; Fersht, A. R. Biochemistry 1995, 34,
5718.
0002-7863/96/1518-1066$12.00/0 © 1996 American Chemical Society

Triurea DeriVatiVes of Diethylenetriamine
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1067
At present, none of the template-based strategies have allowed
the development of artificial â-sheets comprising more than two
peptide strands and exhibiting patterns of hydrogen bonding
characteristic of â-sheet structures. With the goal of creating
artificial â-sheets of greater size and complexity than those that
have been prepared previously, we are developing a new
approach in which an oligourea template holds multiple peptide
strands in proximity. Since 1992, we have reported the
development of amino acid ester isocyanate and peptide
isocyanate building blocks12 and the creation of oligourea
templates, which we have termed “molecular scaffolds”.13
Recently, we have synthesized and studied a small artificial
â-sheet comprising a diurea molecular scaffold and two peptide
strands14 and a second small artificial â-sheet comprising a
diurea molecular scaffold, a peptide strand, and a â-strand
mimic.15 We now report synthetic and structural studies of a
triurea molecular scaffold (1) tailored for the creation of three-
stranded artificial parallel â-sheets.
tivity.17 Diureas 4 are converted to triureas 1 by removal of
the tert-butyloxycarbonyl protective group to generate amines
5, conjugate addition of the primary amino group to acrylonitrile
to form secondary amines 6, and reaction of the secondary amino
group with the appropriate isocyanate. The triureas were
obtained as analytically pure samples by recrystallization or
column chromatography. The yields for the various steps shown
in eq 1 are not optimized but are generally good. The yields
associated with the synthesis of triurea 1c are probably most
representative: 3 f 4c, 97%; 4c f 6c, 72%; and 6c f 1c,
99%. The methyl ureas (b series) were generated in lower yields
because these compounds are water soluble, hygroscopic, and
thus more difficult to handle.
Results
Synthesis of Triureas 1. Triureas 1 were synthesized from
N-phenylethylenediamine (2) as shown in eq 1. Reductive
alkylation of N-phenylethylenediamine with Boc-glycinal16
affords diamine 3. Diamine 3 reacts with isocyanates to
generate diureas 4. Diurea 4a (R1 ) R2 ) Ph) was prepared
by treatment of 3 with an excess of phenyl isocyanate; diurea
4b (R1 ) R2 ) CH3) was prepared by using an excess of methyl
isocyanate. The aliphatic amino group of diamine 3 is
substantially more basic and nucleophilic than the aromatic
amino group, allowing the regioselective synthesis of diureas
bearing different substitutents. Thus, diurea 4c (R1 ) (S)-
CH(CH2Ph)CO2Me, R2 ) (S)-CH(i-Pr)CO2Me) was prepared
by sequential treatment of diamine 3 with 0.95 equiv of L-valine
methyl ester isocyanate and 1.2 equiv of L-phenylalanine methyl
ester isocyanate.12a 1H NMR analysis of the unpurified reaction
mixture indicates that L-valine methyl ester isocyanate reacts
with the upper amino group with complete (>98:2) regioselec-
Infrared and 1H NMR Spectroscopic Studies of Triureas
1. IR and 1H NMR spectroscopic studies of triureas 1 indicate
that these compounds adopt intramolecularly hydrogen-bonded
conformations in chloroform solution. To aid in the interpreta-
tion of the data, the spectra were compared to those of
monoureas 7 and 8. Monoureas 7 bear two ethyl groups on
one nitrogen atom and resemble the “upper” two urea groups
of triureas 1. Monoureas 8 have a phenyl group and an ethyl
group on one nitrogen atom and are comparable to the “lower”
urea group of triurea 1. Studies of related diureas have been
described in detail in ref 13b, and the reader is directed to this
paper for a discussion in greater detail than is presented here.
(11) (a) Pessi, A.; Bianchi, E.; Crameri, A.; Venturini, S.; Tramontano,
A.; Sollazzo, M. Nature 1993, 362, 367. (b) Yan, Y.; Erickson, B. W.
Protein Sci. 1994, 3, 1069. (c) Quinn, T. P.; Tweedy, N. B.; Williams, R.
W.; Richardson, J. S.; Richardson, D. C. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 8747.
(12) (a) Nowick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha, G. J.
Org. Chem. 1992, 57, 7364. (b) Nowick, J. S.; Holmes, D. L.; Noronha,
G.; Smith, E. M.; Nguyen, T. M.; Huang, S.-L. Submitted to J. Org. Chem.
(13) (a) Nowick, J. S.; Powell, N. A.; Martinez, E. J.; Smith, E. M.;
Noronha, G. J. Org. Chem. 1992, 57, 3763. (b) Nowick, J. S.; Abdi, M.;
Bellamo, K. A.; Love, J. A.; Martinez, E. J.; Noronha, G.; Smith, E. M.;
Ziller, J. W. J. Am. Chem. Soc. 1995, 117, 89.
The IR spectra of triureas 1a,b and monoureas 7a,b and 8a,b
are shown in Figure 1 (10 mM solutions in CHCl3). Triurea
1a exhibits a non-hydrogen-bonded NH stretching band at 3425
cm-1 and a hydrogen-bonded NH stretching band at 3305 cm-1
.
The band at 3425 cm-1 is similar in position, intensity, and
shape to that of monourea 8a (3428 cm-1) and is attributed to
the “bottom” NH group of 1a, which is not hydrogen bonded.
(14) Nowick, J. S.; Smith, E. M.; Noronha, G. J. Org. Chem. 1995, 60,
7386.
(15) Nowick, J. S.; Holmes, D. L.; Mackin, G.; Noronha, G.; Shaka, A.
J.; Smith, E. M. Submitted to J. Am. Chem. Soc.
(16) Dueholm, K. L.; Egholm, M.; Buchardt, O. Org. Prep. Proc. Int.
1993, 25, 457.
(17) The regiochemical course of the reaction of diamine 3 with L-valine
methyl ester isocyanate is readily apparent because the ortho and para 1H
NMR resonances of the aromatic ring shift downfield by ca. 0.5 ppm when
the aromatic amino group reacts with an isocyanate to form a urea.

1068 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Nowick et al.
alanine NH resonance appears at 4.68 ppm. Under the con-
ditions of the IR and 1H NMR studies, no evidence of
intermolecular hydrogen bonding is detected, and the NH groups
of triureas 1 exhibit no significant differences in chemical shift
(e0.01 ppm) at varying concentrations (1 and 10 mM).
X-ray Crystallographic Studies of Triureas 1. Triureas
1a,b afforded small crystals suitable for X-ray crystallography.
Crystals of 1a were obtained from a warm mixture of dimethyl
sulfoxide and water (ca. 4:1), while crystals of 1b were produced
by slow evaporation of a mixture of methylene chloride and
petroleum ether. Triurea 1c was obtained as a viscous oil, which
began to solidify over a period of months but resisted our most
valiant efforts to grow crystals for X-ray crystallography.
Figure 2 shows the X-ray crystallographic structures of
triureas 1a,b. In these structures the carbonyl group of the
“bottom” urea is hydrogen bonded to the NH group of the
“middle” urea, and the carbonyl group of the “middle” urea is
hydrogen bonded to the NH group of the “top” urea. Triurea
1b crystallized as a monohydrate, and its structure was refined
to a wR2 value of 13.4% as a 65:35 ratio of two superimposed
conformers differing only in the geometry of the diethylenetri-
amine backbone. Triurea 1a was refined to a wR2 value of
27.2% as a single conformer. The distances, angles, and thermal
parameters involving atoms C2, C3, N2, C4, and C5 of 1a are
not consistent with a well-ordered model. Attempts to refine
the structure as a disordered model with two or more compo-
nents for each of the above atoms proved unsatisfactory.
Figure 1. Infrared spectra (3150-3550 cm-1) of ureas 1a,b, 7a,b,
and 8a,b. Spectra were recorded at 295 K using a 10 mM solution in
CHCl3 (1.0 mm path length) against a CHCl3 reference.
The band at 3305 cm-1 arises from the “upper” two NH groups.
The position of this band indicates that these groups are
hydrogen bonded. The absence of a band at ca. 3464 cm-1 (the
NH stretching frequency of 7a) indicates the absence of a
detectable population in which one or both of the “upper” two
NH groups of 1a are not hydrogen bonded. Compound 1a also
Discussion and Conclusions
Triureas of the general structure 1 are remarkably easy to
synthesize by the route shown in eq 1. In five straightforward
and efficient steps, diamine 3 can be converted to a triurea in
which three different groups are presented along a well-
structured backbone. Because of their structure and ease of
preparation, triureas of this sort may be of interest in combi-
natorial approaches to drug discovery19 and in the construction
exhibits bands at 3255 (a shoulder), 3199, and 3142 cm-1
.
Although the origin of these bands is unclear, similar bands
are apparent in every hydrogen-bonded di- and triurea with
phenyl substituents that we have studied. (Related examples
are described in ref 13.) Apparently these bands are associated
with interactions between the hydrogen-bonded NH groups and
the adjacent phenyl substituents. Triurea 1b also exhibits
hydrogen-bonded and non-hydrogen-bonded NH stretching
bands, at 3327 and 3456 cm-1, respectively. The non-hydrogen-
bonded band is similar in position, intensity, and shape to that
of monourea 8b (3460 cm-1). The absence of a band at ca.
3487 cm-1 (the NH stretching frequency of 7b) indicates the
absence of a detectable population of a non-hydrogen-bonded
conformation of 1b. The infrared spectrum of triurea 1c (not
shown in Figure 1) also shows hydrogen-bonded and non-
hydrogen-bonded bands (3300 and 3425 cm-1, respectively).
These studies indicate that triureas 1 are intramolecularly
hydrogen bonded in CHCl3 solution.
1H NMR spectroscopic studies corroborate the IR studies.
In 1.0 mM CDCl3 solution, the NH resonances of 1a appear at
9.21, 9.02, and 6.25 ppm, respectively, at 295 K. Under
comparable conditions, the NH resonances of controls 7a and
8a appear at 6.24 and 6.08 ppm.18 Similarly, the NH resonances
of 1b appear at 6.86, 6.77, and 4.24 ppm, while those of 7b
and 8b appear at 4.32 and 4.06 ppm. These shifts indicate that
two of the NH groups of 1 are hydrogen bonded and are
consistent with our previous observation that intramolecularly
hydrogen-bonded urea NH resonances shift downfield by about
2.5 ppm.13 Triurea 1c exhibits a similar pattern of shifting in
the 1H NMR spectrum; the isoleucine and valine NH resonances
appear at 6.84 and 6.56 ppm, respectively, while the phenyl-
(18) At the suggestion of one of the referees, the temperature depend-
encies of the 1H NMR chemical shifts of the NH resonances of 1a, 7a, and
8a were determined. In 1.0 mM CDCl3 solution, over the range of 253-
293 K, the following values were observed, 1a (most downfield NH), -4.5
ppb/K; 1a (next most downfield NH), -3.8 ppb/K; 1a (upfield NH), -0.9
ppb/K; 7a, -1.4 ppb/K; 8a, -0.8 ppb/K. The greater temperature depend-
encies of the downfield NH resonances of urea 1a provide further evidence
that these NH groups are hydrogen bonded and that the upfield group is
not. (In peptides and related amides, hydrogen-bonded NH groups generally
exhibit greater temperature dependencies of chemical shifts than non-
hydrogen-bonded NH groups. For examples, see: (a) Ribeiro, A. A.;
Goodman, M.; Naider, F. Int. J. Pept. Protein Res. 1979, 14, 414. (b)
Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J. Am. Chem.
Soc. 1980, 102, 7048. (c) Gellman, S. H.; Adams, B. R. Tetrahedron Lett.
1989, 30, 3381.)
(19) For related examples, see: (a) Hagihara, M.; Anthony, N. J.; Stout,
T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6568. (b)
Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jewell, D.
A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.; Marlowe, C. K.;
Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.;
Bartlett, P. A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367. (c) Zuckermann,
R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992,
114, 10646. (d) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114,
10997. (e) Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor,
S. P. A.; Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science
1993, 261, 1303. (f) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett.
1994, 35, 4055. (g) Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek,
J., Jr. Angew. Chem., Int. Ed. Engl. 1994, 33, 2059. (h) Carell, T.; Wintner,
E. A.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1994, 33, 2061. (i) Bunin,
B. A.; Plunkett, M. J.; Ellman, J. A. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 4708. (j) Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116,
11580. (k) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1995, 36,
2583. (l) Carell, T.; Wintner, E. A.; Sutherland, A. J.; Rebek, J., Jr.;
Dunayevskiy, Y. M.; Vouros, P. Chem. Biol. 1995, 2, 171. (m) Moran, E.
J.; Wilson, T. E.; Cho, C. Y.; Cherry, S. R.; Schultz, P. G. Biopolymers
1995, 37, 213. (n) Burgess, K.; Linthicum, D. S.; Shin, H. W. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 907.

Triurea DeriVatiVes of Diethylenetriamine
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1069
Figure 2. X-ray crystallographic structures of triureas 1a,b. Triurea 1b crystallized as the monohydrate (water shown). The major (65%) and
minor (35%) conformers of 1b are shown middle and right, above.
of “molecular tweezers”20 or related structures consisting of three
groups appended to a rigid scaffold.21 Preliminary studies
suggest that it may be possible to prepare even larger oligourea
homologs (e.g., tetra- and pentaureas) by an iterative route
involving the reductive alkylation of amines 5 with Boc-glycinal.
A number of intramolecularly hydrogen-bonded systems that
are related to triureas 1 have been reported. We previously
described the propylene homolog of 1a (PhN(CONHPh)CH2-
CH2CH2N(CONHPh)CH2CH2CH2N(CONHPh)CH2CH2-
CN).13a IR studies indicated this compound to adopt both
hydrogen-bonded and non-hydrogen-bonded conformations in
CHCl3 solution. In the main conformer, the “upper” two NH
groups are hydrogen bonded; however, there is a significant
population that lacks one or both hydrogen bonds. In contrast,
the IR spectrum of 1a shows this compound to be wholly
hydrogen bonded. We have also previously described diurea
derivatives of 1,2-diaminoethane.13b These compounds adopt
hydrogen-bonded conformations in which the urea groups form
nine-membered, hydrogen-bonded rings that are similar in
structure to those seen in triureas 1. Gellman and co-workers
have extensively studied intramolecular hydrogen bonding in
di- and triamides and found intramolecularly hydrogen-bonded
nine-membered rings to be especially stable in these systems.22
Araka and co-workers have determined that the hexaphenylurea
derivative of pentaethylenehexamine is intramolecularly hydro-
gen bonded in chloroform solution.23
Two structural elements of triureas 1 deserve comment: the
phenyl group at the “bottom” of the triurea backbone and the
cyanoethyl group at the “top” of the triurea backbone. In
N-phenyl-N-alkyl amides and ureas, there is a strong bias for
the phenyl group to be s-trans to the carbonyl group.24 This
bias makes the “lower” carbonyl group point “upward”;
intramolecular hydrogen bonding then aligns the “upper” two
carbonyl groups. For the “top” carbonyl group to align properly,
the “top” backbone urea nitrogen must have two alkyl substit-
uents. The cyanoethyl group provides a convenient “cap” for
this nitrogen atom because the reaction of primary amines (e.g.,
4) with acrylonitrile generally proceeds with high yield and
selectivity for monoaddition.25 From the observed selectivity,
we estimate that the rate of reaction of primary amines 5 with
acrylonitrile is about 102 times greater than the rate of addition
of the resulting secondary amine adducts (6) to acrylonitrile.
To avoid overaddition, we generally monitor the reaction by
thin-layer chromatography.
The solid-state structures of triureas 1a,b are remarkable. The
three urea groups and pendant substituents (R1, R2, and R3 in
structure 1) are approximately coplanar, resembling in geometry
a hand with three fingers. The shape of the triureas can best
be seen by inspection of space-filling models (e.g., 1a, shown
in Figure 3). The diethylenetriamine backbone curves, arraying
the substituents in a slightly divergent fashion. The divergence
of the substituents can be quantified by the angles between the
vectors of the N-R bonds. The vectors of the “lower” and
“middle” bonds (N-R1 and N-R2) of 1a form an angle of 48°,
while those of the “middle” and “upper” bonds (N-R2 and
N-R3) form an angle of 52°. In 1b, the angles are 50° and
(20) (a) Zimmerman, S. C.; Wu, W. J. Am. Chem. Soc. 1989, 111, 8054.
(b) Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J. Am. Chem.
Soc. 1991, 113, 183. (c) Zimmerman, S. C.; Wu, W.; Zeng, Z. J. Am. Chem.
Soc. 1991, 113, 196.
(21) For examples, see: (a) Gala´n, A.; de Mendoza, J.; Toiron, C.; Bruix,
M.; Deslongchamps, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1991, 113, 9424.
(b) Huang, C.-Y.; Cabell, L. A.; Lynch, V.; Anslyn, E. V. J. Am. Chem.
Soc. 1992, 114, 1900. (c) Maitra, U.; D'Souza, L. J. J. Chem. Soc., Chem.
Commun. 1994, 2793.
(22) (a) Gellman, S. H.; Adams, B. R. Tetrahedron Lett. 1989, 30, 3381.
(b) Dado, G. P.; Desper, J. M.; Gellman, S. H. J. Am. Chem. Soc. 1990,
112, 8630. (c) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R. J.
Am. Chem. Soc. 1991, 113, 1164. (d) Liang, G.-B.; Dado, G. P.; Gellman,
S. H. J. Am. Chem. Soc. 1991, 113, 3994. (e) Dado, G. P.; Desper, J. M.;
Holmgren, S. K.; Rito, C. J.; Gellman, S. H. J. Am. Chem. Soc. 1992, 114,
4834. (f) Liang, G.-B.; Desper, J. M.; Gellman, S. H. J. Am. Chem. Soc.
1993, 115, 925. (g) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1993,
115, 4228.
(23) Araki, T.; Kubo, Y.; Yasuda, Y. Chem. Express 1989, 4, 605.
(24) (a) Ganis, P.; Avitabile, G.; Benedetti, E.; Pedone, C.; Goodman,
M. Proc. Natl. Acad. Sci. U.S.A. 1970, 67, 426. (b) Itai, A.; Toriumi, Y.;
Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K. Tetrahedron Lett.
1989, 30, 6177. (c) Yamaguchi, K.; Matsumura, G.; Kagechika, H.;
Azumaya, I.; Ito, Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991, 113,
5474. (d) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am.
Chem. Soc. 1992, 114, 10649. (e) Azumaya, I.; Kagechika, H.; Yamaguchi,
K.; Shudo, K. Tetrahedron 1995, 51, 5277.
(25) (a) Bergeron, R. J.; Burton, P. S.; McGovern, K. A.; Kline, S. J.
Synthesis 1981, 732. (b) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.; Phillips,
D.; Rosnack, K. J.; Saccomano, N. A.; Stroh, J. G.; Volkmann, R. A. J.
Am. Chem. Soc. 1990, 112, 6696.

1070 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Nowick et al.
Figure 4. Model of a three-stranded artificial parallel â-sheet consisting
of three tripeptide strands attached to the triurea molecular scaffold.
The model is in a minimum energy conformation (local minimum) as
calculated using MacroModel V5.0 with the AMBER* force field.27
Hydrogen atoms that are attached to carbon atoms are omitted for
clarity.
than the sum of the van der Waals radii of these groups,
however, and the observed conformers do not appear to be
disfavored.
Figure 3. Space-filling representation of the X-ray crystallographic
structure of diurea 1a. Atoms are displayed at 85% of their van der
Waals radii.
The structures of triureas 1 in chloroform solution are similar
in several ways to the solid-state structures. The 1H NMR and
IR spectroscopic studies described in the Results section indicate
that the molecules are intramolecularly hydrogen bonded.
Analysis of the coupling patterns associated with several of the
1H NMR resonances of the diethylenetriamine backbones of
triureas 1 reveals vicinal coupling constants of 5 and 10 Hz.
These coupling constants indicate that the N-C-C-N groups
of the backbone adopt anti conformations in solution, as in the
solid state. (A similar, but more detailed, treatment of the
solution-phase conformation of related diureas is described in
ref 13b.) From the IR and NMR data, it is not possible to
determine whether the “terraced” conformer or crystallographi-
cally observed conformers are present, and there is little reason
to believe that any one of the backbone conformers shown in
Chart 1 should be present exclusively.
Chart 1
Molecular modeling suggests that the triurea backbone will
be a suitable template for the creation of artificial â-sheets.
Beginning with the crystallographic geometry of the major
conformer of 1b, a model for the “terraced” conformation was
prepared, three tripeptide strands (Ala-Ala-Ala-NHMe) were
introduced, and an energetic minimum (local minimum) was
located using MacroModel V5.0 and the AMBER* force field.27
The model adopts a hydrogen-bonded parallel â-sheet confor-
mation and is shown in Figure 4. In this model, the N-C-
C-N torsion angles are 138°.28 The diminished torsion angles
reduce the angles between the N-R vectors to 22° and the
distance between the R substituents on the triurea backbone (the
attached peptide R-carbons in Figure 4) to 4.9-5.1 Å.29 This
distance is similar to the separation of peptide strands in parallel
51°, respectively. Related diureas that we have studied exhibit
a similar divergence, with angles ranging from 41° to 62°.13b
The crystallographically observed conformations of the
diethylenetriamine backbones of triureas 1a,b are also note-
worthy. Each 1,2-diaminoethane unit adopts an anti conforma-
tion, with N-C-C-N torsion angles ranging from 166° to
170°. The related diureas that we have studied also adopt anti
conformations in the solid state, with torsion angles ranging
from 159° to 169°.13b In each structure, the central CH2CH2-
NCH2CH2 unit of the diethylenetriamine backbone resembles
the g+g- conformer of pentane.26 This relationship is easily
seen when the triureas are viewed in profile, as shown in Chart
1. Because severe steric interactions disfavor g+g- pentane,
the observed conformations of the diethylenetriamine backbone
might have been thought to be unstable, and the “terraced”
conformation shown in Chart 1 might have been anticipated.
The distance between the proximal methylene groups in the
crystallographically observed conformers (3.6-3.9 Å) is larger
(27) (a) McDonald, D. Q.; Still, W. C. Tetrahedron Lett. 1992, 33, 7743.
(b) McDonald, D. Q.; Still, W. C. Tetrahedron Lett. 1992, 33, 7747.
(28) The calculated torsion angles of 138° (-138°, to be more specific)
seem somewhat small, particularly in light of the values that we have
observed crystallographically (159-170°) for various di- and triureas. The
calculated values may reflect the absence of high-quality parameters for
the N-C-C-N torsion angle and the treatment of hydrogen bonding in
the AMBER* force field. If the N-C-C-N torsion angles are constrained
to a larger value (e.g., -150°), a well-formed parallel â-sheet is still
generated upon minimization.
(26) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 603-605.
(29) In 1b, the distance between adjacent methyl groups is 6.5 Å.

Triurea DeriVatiVes of Diethylenetriamine
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1071
Hz, 2 H); HRMS (FAB) m/e for C27H31N6O2 (M + H)+ calcd 471.2508,
found 471.2510.
â-sheets (ca. 4.9 Å).30 This model may be viewed as a working
hypothesis, which we will evaluate and refine through future
experimental studies.
Triurea 1a (PhN(CONHPh)CH2CH2N(CONHPh)CH2CH2N-
(CONHPh)CH2CH2CN). A solution of amine 6a (0.166 g, 0.353
mmol) and phenyl isocyanate (0.043 mL, 0.39 mmol) in 3 mL of 1,2-
dichloroethane was heated at reflux for 16 h and then concentrated by
rotary evaporation to afford 0.219 g of a foamy tan solid. Column
chromatography on silica gel (EtOAc-hexanes, 3:1), followed by
recrystallization from methanol, yielded 0.123 g (59%) of triurea 1a
as white crystals: mp 177.5-178.8 °C; IR (CH2Cl2) 3421, 3305, 2251,
1659 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1 H), 9.01 (s, 1 H),
7.74 (app t, J ) 8.7 Hz, 4 H), 7.53 (t, J ) 7.7 Hz, 2 H), 7.47 (t, J )
7.2 Hz, 1 H), 7.31 (app t, J ) 7.5 Hz, 10 H), 7.09-7.02 (m, 3 H), 6.25
(s, 1 H), 3.85-3.83 (m, 2 H), 3.75-3.73 (m, 2 H), 3.59 (t, J ) 6.2 Hz,
2 H), 3.58-3.47 (m, 4 H), 2.69 (t, J ) 6.1 Hz, 2 H); HRMS (FAB)
m/e for C34H36N7O3 (M + H)+ calcd 590.2879, found 590.2874. Anal.
Calcd for C34H35N7O3: C, 69.25; H, 5.98; N, 16.63. Found: C, 69.35;
H, 6.18; N, 16.44.
Diurea 4b (PhN(CONHCH3)CH2CH2N(CONHCH3)CH2CH2-
NHCO2-t-Bu). A solution of diamine 3 (0.307 g, 1.10 mmol) and
methyl isocyanate (0.38 mL, 6.6 mmol) in 3 mL of methylene chloride
was stirred for 11 h and then concentrated by rotary evaporation to
afford 0.406 g of a foamy deliquescent tan solid. Column chroma-
tography on silica gel (CH3OH-EtOAc, gradient from 5:95 to 10:90)
afforded 0.325 g (75%) of diurea 4b as a deliquescent foamy white
solid: IR (CH2Cl2) 3454, 3336, 1705, 1645 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.45 (app t, J ) 7.6 Hz, 2 H), 7.37 (app t, J ) 7.3 Hz, 1 H),
7.18 (d, J ) 7.1 Hz, 2 H), 6.60 (br s, 1 H), 5.22 (br s, 1 H), 4.26 (app
q, J ) 4.4 Hz, 1 H), 3.67-3.62 (m, 2 H), 3.46-3.40 (m, 2 H), 3.34 (t,
J ) 6.1 Hz, 2 H), 3.17 (q, J ) 5.6 Hz, 2 H), 2.87 (d, J ) 4.4 Hz, 3 H),
2.74 (d, J ) 4.7 Hz, 3 H), 1.40 (s, 9 H); HRMS (FAB) m/e for
C19H32N5O4 (M + H)+ calcd 394.2454, found 394.2445.
Experimental Section
General. Reaction mixtures were magnetically stirred under a
nitrogen atmosphere, unless otherwise noted. Commercial grade
reagents and solvents were used without further purification. IR studies
were performed using hydrocarbon-stabilized chloroform that was
passed through furnace-dried Al2O3 prior to use. 1H NMR resonances
of aliphatic amino groups that were coincident with the H2O resonance
(δ 1.6) in CDCl3 are not reported in the 1H NMR spectra. Samples of
triureas 1 were dried under vacuum (ca. 50 °C, 0.01 mmHg) prior to
elemental analysis.
Diamine 3 (PhNHCH2CH2NHCH2CH2NHCO2-t-Bu). A 500-mL,
three-necked, round-bottomed flask equipped with a nitrogen inlet
adapter, a glass stopper, a gas inlet adapter fitted with a hydrogen
balloon, and a magnetic stirring bar was charged with 200 mL of
methanol, Boc-glycinal16 (6.6 g, 41 mmol), N-phenylethylenediamine
(5.0 mL, 38 mmol), and 6.1 g of 10% Pd/C. The flask was evacuated
and filled with nitrogen twice and then evacuated, filled with hydrogen,
and maintained under a hydrogen atmosphere for 16 h. The reaction
mixture was filtered, concentrated by rotary evaporation, and chro-
matographed on silica gel (CH3OH-EtOAc, 1:9) to afford 6.9 g (65%)
1
of diamine 3 as a light brown oil: IR (CHCl3) 3452, 1706 cm-1; H
NMR (300 MHz, CDCl3) δ 7.18 (dd, J ) 8.5, 7.4 Hz, 2 H), 6.71 (app
t, J ) 7.3 Hz, 1 H), 6.64 (dd, J ) 8.6, 0.9 Hz, 2 H), 4.89 (br s, 1 H),
4.07 (br s, 1 H), 3.24-3.19 (m, 4 H), 2.88 (app t, J ) 5.8 Hz, 2 H),
2.75 (app t, J ) 5.9 Hz, 2 H), 1.45 (s, 9 H); HRMS (FAB) m/e for
C15H26N3O2 (M + H)+ calcd 280.2025, found 280.2024.
Diurea 4a (PhN(CONHPh)CH2CH2N(CONHPh)CH2CH2NHCO2-
t-Bu). A solution of diamine 3 (0.755 g, 2.70 mmol) and phenyl
isocyanate (0.88 mL, 8.1 mmol) in 5 mL of 1,2-dichloroethane was
heated at reflux for 21 h and then concentrated by rotary evaporation
to afford 1.80 g of a dark yellow oil. Column chromatography on
silica gel (EtOAc-hexanes, 3:2) afforded 1.108 g (79%) of diurea 4a
Amine 5b (PhN(CONHCH3)CH2CH2N(CONHCH3)CH2CH2NH2).
A solution of diurea 4b (0.309 g, 0.785 mmol) in 12 mL of methylene
chloride and 1.2 mL of trifluoroacetic acid was stirred for 3 h and then
concentrated by rotary evaporation to afford a yellow oil. The oil was
dissolved in 50 mL of methylene chloride, and the solution was washed
with 150 mL of a saturated aqueous Na2CO3 solution. The aqueous
phase was extracted with three 50-mL portions of methylene chloride,
concentrated to 90 mL by rotary evaporation, and extracted with three
100-mL portions of methylene chloride. The combined organic layers
were concentrated to afford 0.201 g (87%) of amine 5b as a yellow
oily solid: IR (CH2Cl2) 3454, 3338, 1643 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.44 (app t, J ) 7.4 Hz, 2 H), 7.34 (app t, J ) 6.8 Hz, 1 H),
7.20 (d, J ) 7.2 Hz, 2 H), 6.63 (app q, J ) 4.0 Hz, 1 H), 4.39 (app q,
J ) 4.3 Hz, 1 H), 3.70-3.65 (m, 2 H), 3.47-3.42 (m, 2 H), 3.29 (t, J
) 6.2 Hz, 2 H), 2.84 (d, J ) 4.4 Hz, 3 H), 2.79-2.73 (m, 5 H); HRMS
(FAB) m/e for C14H24N5O2 (M + H)+ calcd 294.1930, found 294.1923.
Amine 6b (PhN(CONHCH3)CH2CH2N(CONHCH3)CH2CH2-
NHCH2CH2CN). A solution of amine 5b (0.192 g, 0.655 mmol) and
acrylonitrile (0.065 mL, 0.99 mmol) in 10 mL of methanol was stirred
for 26 h and then concentrated by rotary evaporation to afford 0.210 g
of a yellow oil. Column chromatography on silica gel (i-PrOH-CHCl3,
1:1) yielded 0.133 g (58%) of amine 6b as a viscous yellow oil: IR
as a foamy white solid: IR (KBr) 3423, 3307, 1708 (sh), 1660 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1 H), 7.69 (d, J ) 8.2 Hz, 2
H), 7.52 (t, J ) 7.5 Hz, 2 H), 7.43 (t, J ) 7.2 Hz, 1 H), 7.33-7.24 (m,
8 H), 7.06-6.98 (m, 2 H), 6.29 (s, 1 H), 5.12 (br s, 1 H), 3.87-3.82
(m, 2 H), 3.70-3.65 (m, 2 H), 3.46 (app t, J ) 6.2 Hz, 2 H), 3.28 (app
q, J ) 5.8 Hz, 2 H), 1.40 (s, 9 H); HRMS (FAB) m/e for C29H36N5O4
(M + H)+ calcd 518.2767, found 518.2768.
Amine 5a (PhN(CONHPh)CH2CH2N(CONHPh)CH2CH2NH2).
A solution of diurea 4a (1.108 g, 2.140 mmol) in 11 mL of methylene
chloride and 3.3 mL of trifluoroacetic acid was stirred for 4 h and then
concentrated by rotary evaporation to afford a dark yellow oil. The
oil was dissolved in 100 mL of methylene chloride, and the solution
was washed with 100 mL of a mixture of equal volumes of saturated
aqueous NaCl solution and saturated aqueous NaHCO3 solution and
then with three 50-mL portions of saturated aqueous NaHCO3 solution.
The organic layer was concentrated by rotary evaporation to yield 0.881
g (99%) of amine 5a as a foamy white solid: IR (CH2Cl2) 3423, 3307,
1664 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.53 (br s, 1 H), 7.54-7.47
(m, 4 H), 7.43-7.23 (m, 9 H), 7.02 (t, J ) 7.2 Hz, 1 H), 6.97 (t, J )
7.4 Hz, 1 H), 6.43 (s, 1 H), 3.92-3.87 (m, 2 H), 3.68-3.63 (m, 2 H),
3.44 (t, J ) 5.5 Hz, 2 H), 2.95 (t, J ) 5.5 Hz, 2 H); HRMS (FAB) m/e
for C24H28N5O2 (M + H)+ calcd 418.2243, found 418.2238.
1
(CH2Cl2) 3454, 3338, 2250, 1645 cm-1; H NMR (300 MHz, CDCl3)
δ 7.45 (app t, J ) 7.4 Hz, 2 H), 7.36 (app t, J ) 8.0 Hz, 1 H), 7.21 (d,
J ) 7.2 Hz, 2 H), 6.56 (app q, J ) 4.3 Hz, 1 H), 4.33 (app q, J ) 4.6
Hz, 1 H), 3.70-3.65 (m, 2 H), 3.49-3.42 (m, 2 H), 3.34 (t, J ) 6.1
Hz, 2 H), 2.90 (t, J ) 6.6 Hz, 2 H), 2.84 (d, J ) 4.4 Hz, 3 H), 2.77-
2.73 (m, 5 H), 2.46 (t, J ) 6.6 Hz, 2 H); 1.89 (br s, 1 H); HRMS
(FAB) m/e for C17H27N6O2 (M + H)+ calcd 347.2195, found 347.2197.
Triurea 1b (PhN(CONHCH3)CH2CH2N(CONHCH3)CH2CH2N-
(CONHCH3)CH2CH2CN). A solution of amine 6b (0.133 g, 0.382
mmol) and methyl isocyanate (0.068 mL, 1.15 mmol) in 2 mL of
methylene chloride was stirred for 4.5 h and then concentrated by rotary
evaporation to afford 0.173 g of a hygroscopic foamy white solid.
Repeated recrystallization from CH2Cl2-petroleum ether, followed by
column chromatography on silica gel (0.7% MeOH in CH2Cl2), afforded
0.085 g (55%) of triurea 1b as a hygroscopic foamy white solid: IR
Amine 6a (PhN(CONHPh)CH2CH2N(CONHPh)CH2CH2NH-
CH2CH2CN). A solution of amine 5a (0.201 g, 0.481 mmol) and
acrylonitrile (0.0475 mL, 0.722 mmol) in 10 mL of methanol was stirred
for 28 h and then concentrated by rotary evaporation to afford 0.215 g
(95%) of amine 6a as a foamy white solid: IR (CH2Cl2) 3421, 3307,
1
2252, 1662 cm-1; H NMR (300 MHz, CDCl3) δ 8.95 (s, 1 H), 7.59
(d, J ) 7.8 Hz, 2 H), 7.52 (app t, J ) 7.4 Hz, 2 H), 7.43 (app t, J )
7.3 Hz, 1 H), 7.37-7.23 (m, 8 H), 7.06-6.97 (m, 2 H), 6.29 (s, 1 H),
3.92-3.87 (m, 2 H), 3.70-3.66 (m, 2 H), 3.47 (t, J ) 5.9 Hz, 2 H),
2.95 (t, J ) 6.6 Hz, 2 H), 2.87 (t, J ) 5.9 Hz, 2 H), 2.48 (t, J ) 6.5
1
(CH2Cl2) 3452, 3323, 2249, 1645 cm-1; H NMR (300 MHz, CDCl3)
(30) (a) Pauling, L.; Corey, R. B. Proc. Natl. Acad. Sci. U.S.A. 1953,
39, 253. (b) Ashida, T.; Tanaka, I.; Yamane, T. Int. J. Pept. Protein Res.
1981, 17, 322.
δ 7.47 (app t, J ) 7.4 Hz, 2 H), 7.38 (t, J ) 7.3 Hz, 1 H), 7.18 (d, J
) 7.1 Hz, 2 H), 6.86 (app q, J ) 3.7 Hz, 1 H), 6.78 (app q, J ) 4.3

1072 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Nowick et al.
Hz, 1 H), 4.29 (app q, J ) 4.5 Hz, 1 H), 3.63-3.58 (m, 2 H), 3.49 (t,
J ) 6.2 Hz, 2 H), 3.45-3.40 (m, 2 H), 3.29 (app s, 4 H), 2.89 (d, J )
4.4 Hz, 3 H), 2.83 (d, J ) 4.4 Hz, 3 H), 2.75 (d, J ) 4.7 Hz, 3 H),
2.59 (t, J ) 6.2 Hz, 2 H); HRMS (FAB) m/e for C19H30N7O3 (M +
H)+ calcd 404.2410, found 404.2409. Anal. Calcd for C19H29N7O3:
C, 56.56; H, 7.24; N, 24.30. Found: C, 56.73; H, 7.37; N, 24.04.
Diurea 4c (PhN(CONH-(S)-CH(CH2Ph)CO2CH3)CH2CH2N-
(CONH-(S)-CH(i-Pr)CO2CH3)CH2CH2NHCO2-t-Bu). A solution of
diamine 3 (0.180 g, 0.645 mmol) and L-valine methyl ester isocyanate12a
(0.096 g, 0.61 mmol) in 15 mL of methylene chloride was stirred for
13 h and then concentrated by rotary evaporation to afford a light brown
oil. Column chromatography on silica gel (EtOAc-hexanes, 2:1)
afforded 0.259 g (97%) of PhNHCH2CH2N(CONH-(S)-CH(i-Pr)CO2-
CH3)CH2CH2NHCO2-t-Bu as a colorless oil: IR (CHCl3) 3462, 3365,
chromatography on silica gel (CH3OH-EtOAc, 1:9) yielded 0.180 g
(72% from 4c) of amine 6c as a colorless oil: IR (CHCl3) 3425, 3305,
1
2251, 1740, 1651 cm-1; H NMR (500 MHz, CDCl3) δ 7.35 (t, J )
7.5 Hz, 2 H), 7.29 (t, J ) 6.8 Hz, 1 H), 7.21-7.19 (m, 3 H), 7.11 (d,
J ) 7.6 Hz, 2 H), 6.96-6.95 (m, 2 H), 6.72 (d, J ) 8.1 Hz, 1 H), 4.73
(d, J ) 7.8 Hz, 1 H), 4.67 (app q, J ) 6.7 Hz, 1 H), 4.25 (dd, J ) 8.3,
5.7 Hz, 1 H), 3.78-3.70 (m, 2 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 3.54-
3.48 (m, 1 H), 3.44-3.36 (m, 2 H), 3.33-3.28 (m, 1 H), 3.05 (dd,
ABX pattern, JAB ) 13.8 Hz, JAX ) 5.5 Hz, 1 H), 2.94-2.88 (m, 3
H), 2.80-2.75 (m, 2 H), 2.51-2.48 (m, 2 H), 2.19-2.12 (m, 1 H),
1.79 (br s, 1 H), 0.96 (d, J ) 6.7 Hz, 6 H); 13C NMR (75 MHz, CDCl3)
δ 174.0, 173.5, 159.0, 156.5, 141.5, 136.0, 130.0, 128.9, 128.3, 127.7,
126.8, 119.0, 59.3, 54.2, 52.0, 51.6, 48.8, 48.3, 46.2, 45.2, 37.9, 30.3,
19.2, 18.3.
1
1734, 1703, 1643 cm-1; H NMR (500 MHz, CDCl3) δ 7.16 (t, J )
Triurea 1c (PhN(CONH-(S)-CH(CH2Ph)CO2CH3)CH2CH2N-
(CONH-(S)-CH(i-Pr)CO2CH3)CH2CH2N(CONH-(S)-CH((S)-s-Bu)-
CO2CH3)CH2CH2CN). A solution of amine 6c (0.180 g, 0.303 mmol)
and L-isoleucine methyl ester isocyanate12a (0.054 g, 0.31 mmol) in 10
mL of methylene chloride was stirred for 20 h and then concentrated
by rotary evaporation. The residue was purified by column chroma-
tography on silica gel (CH3OH-EtOAc, 1:9) to yield 0.231 g (99%)
of triurea 1c as a colorless oil: IR (CHCl3) 3425, 3305, 2249, 1740,
7.7 Hz, 2 H), 6.70 (t, J ) 7.3 Hz, 1 H), 6.63 (d, J ) 8.1 Hz, 2 H), 5.95
(d, J ) 7.5 Hz, 1 H), 5.16 (br s, 1 H), 4.39 (br s, 1 H), 4.30 (dd, J )
8.4, 5.6 Hz, 1 H), 3.72 (s, 3 H), 3.62 (dt, J ) 14.8 Hz, 6.1 Hz, 1 H),
3.48-3.40 (m, 2 H), 3.35-3.20 (m, 5 H), 2.11-2.04 (m, 1 H), 1.42
(s, 9 H), 0.93 (d, J ) 6.8 Hz, 3 H), 0.85 (d, J ) 6.6 Hz, 3 H); HRMS
(FAB) m/e for C22H37N4O5 (M + H)+ calcd 437.2764, found 437.2750.
A solution of PhNHCH2CH2N(CONH-(S)-CH(i-Pr)CO2CH3)CH2-
CH2NHCO2-t-Bu (0.178 g, 0.407 mmol) and L-phenylalanine methyl
ester isocyanate12a (0.098 g, 0.48 mmol) in 5 mL of 1,2-dichloroethane
was heated at reflux for 45 h and then concentrated by rotary
evaporation to give a brown oil. Column chromatography on silica
gel (EtOAc-CH2Cl2, 9:1) afforded 0.262 g (100%) of diurea 4c as a
colorless oil: IR (CHCl3) 3458 (sh), 3427, 3325, 1740, 1703, 1649
1
1643 cm-1; H NMR (500 MHz, CDCl3) δ 7.38 (t, J ) 7.5 Hz, 2 H),
7.33 (t, J ) 7.3 Hz, 1 H), 7.22-7.20 (m, 3 H), 7.08 (d, J ) 7.4 Hz, 2
H), 6.97-6.95 (m, 2 H), 6.86 (br s, 1 H), 6.58 (d, J ) 7.7 Hz, 1 H),
4.72-4.66 (m, 2 H), 4.24 (dd, J ) 7.6, 6.0 Hz, 1 H), 4.20 (app t, J )
6.6 Hz, 1 H), 3.75 (ddd, J ) 13.1, 10.5, 5.0 Hz, 1 H), 3.70 (s, 3 H),
3.684 (s, 3 H), 3.680 (s, 3 H), 3.60-3.47 (m, 3 H), 3.43-3.32 (m, 5
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.35 (app t, J ) 7.5 Hz, 2 H),
H), 3.25-3.20 (m, 1 H), 3.07 (dd, ABX pattern, JAB ) 13.8 Hz, JAX
)
7.29 (app t, J ) 7.4 Hz, 1 H), 7.22-7.19 (m, 3 H), 7.07 (app d, J )
7.7 Hz, 2 H), 6.98-6.94 (m, 2 H), 6.59 (d, J ) 5.5 Hz, 1 H), 5.19 (br
s, 1 H), 4.72-4.66 (m, 2 H), 4.26 (dd, J ) 8.0, 6.2 Hz, 1 H), 3.77
(ddd, J ) 13.4, 10.5, 5.2 Hz, 1 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.65-
3.56 (m, 1 H), 3.55-3.46 (m, 1 H), 3.45-3.32 (m, 2 H), 3.29-3.12
(m, 3 H), 3.06 (dd, ABX pattern, JAB ) 13.8 Hz, JAX ) 5.1 Hz, 1 H),
2.91 (dd, ABX pattern, JAB ) 13.8 Hz, JAX ) 6.3 Hz, 1 H), 2.22 (octet,
J ) 6.7 Hz, 1 H), 1.39 (s, 9 H), 1.03 (d, J ) 6.8 Hz, 3 H), 1.00 (d, J
) 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 173.4, 172.2, 158.2,
156.0, 141.1, 135.7, 129.8, 128.7, 128.1, 127.5, 127.3, 126.6, 78.6,
59.6, 54.0, 51.7, 51.3, 48.5, 46.7, 45.8, 39.7, 37.6, 29.9, 28.0, 18.9,
18.3; HRMS (FAB) m/e for C33H48N5O8 (M + H)+ calcd 642.3503,
found 642.3505.
5.2 Hz, 1 H), 2.91 (dd, ABX pattern, JAB ) 13.8 Hz, JAX ) 6.4 Hz, 1
H), 2.65 (dt, J ) 16.8 Hz, J ) 6.9 Hz, 1 H), 2.51 (dt, J ) 16.9, 5.9
Hz, 1 H), 2.23-2.17 (m, 1 H), 1.95-1.90 (m, 1 H), 1.55-1.50 (m, 1
H), 1.32-1.26 (m, 1 H), 1.00 (d, J ) 6.9 Hz, 3 H), 0.97 (d, J ) 6.8
Hz, 3 H), 0.922 (d, J ) 6.8 Hz, 3 H), 0.920 (t, J ) 7.3 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 173.6, 173.5, 172.4, 158.3, 157.6, 156.4,
141.4, 136.0, 130.3, 129.0, 128.4, 128.0, 127.6, 126.9, 118.8, 59.7,
58.9, 54.3, 52.1, 51.6, 49.3, 47.9, 47.0, 46.8, 45.3, 38.1, 36.8, 30.4,
25.7, 19.2, 18.4, 17.6, 15.6, 11.4; HRMS (FAB) m/e for C39H56N7O9
(M + H)+ calcd 766.4139, found 766.4141. Anal. Calcd for
C39H55N7O9: C, 61.16; H, 7.24; N, 12.80. Found: C, 60.97; H, 7.43;
N, 12.62.
Amine 5c (PhN(CONH-(S)-CH(CH2Ph)CO2CH3)CH2CH2N-
(CONH-(S)-CH(i-Pr)CO2CH3)CH2CH2NH2). A solution of diurea
4c (0.271 g, 0.422 mmol), 1.3 mL of trifluoroacetic acid, and 0.02 mL
of water in 8 mL of methylene chloride was stirred for 45 min.
Saturated aqueous NaHCO3 solution was then added gradually, with
stirring, until the bubbling ceased (ca. 10 mL). The phases were
separated, the aqueous phase was extracted with two 5-mL portions of
methylene chloride, and the combined organic layers were washed with
20 mL of saturated aqueous NaCl solution, dried over MgSO4, filtered,
and concentrated by rotary evaporation to yield 0.242 g (106%) of amine
Acknowledgment. This work was supported by the National
Institutes of Health Grant GM-49076, Zeneca Pharmaceuticals
Group, The Upjohn Co., and Hoffman-La Roche Inc. S.M.
thanks the National Science Foundation for support in the form
of an REU fellowship. J.S.N. thanks the following agencies
for support in the form of awards: the Camille and Henry
Dreyfus Foundation (New Faculty Award), the American Cancer
Society (Junior Faculty Research Award), the National Science
Foundation (Young Investigator Award, Presidential Faculty
Fellowship), and the Arnold and Mabel Beckman Foundation
(Young Investigator Award).
1
5c as a colorless oil: IR (CHCl3) 3425, 3296, 1740, 1649 cm-1; H
NMR (500 MHz, CDCl3) δ 7.34 (t, J ) 7.5 Hz, 2 H), 7.28 (t, J ) 7.1
Hz, 1 H), 7.20-7.19 (m, 3 H), 7.10 (d, J ) 7.8 Hz, 2 H), 7.03-6.94
(m, 3 H), 4.77 (d, J ) 7.8 Hz, 1 H), 4.68 (app q, J ) 6.6 Hz, 1 H),
4.23 (dd, J ) 7.8, 5.8 Hz, 1 H), 3.81-3.73 (m, 1 H), 3.70-3.63 (m,
1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 3.56-3.48 (m, 1 H), 3.41-3.32 (m,
2 H), 3.31-3.22 (m, 1 H), 3.05 (dd, ABX pattern, JAB ) 13.7 Hz, JAX
) 5.6 Hz, 1 H), 2.92 (dd, ABX pattern, JAB ) 13.8 Hz, JAX ) 6.9 Hz,
1 H), 2.84 (br s, 2 H), 2.27 (br s, 2 H), 2.20-2.13 (m, 1 H), 0.96 (d,
J ) 6.8 Hz, 6 H).
Amine 6c (PhN(CONH-(S)-CH(CH2Ph)CO2CH3)CH2CH2N-
(CONH-(S)-CH(i-Pr)CO2CH3)CH2CH2NHCH2CH2CN). A solution
of 0.242 g of amine 5c (from above) and acrylonitrile (0.042 mL, 0.64
mmol) in 8 mL of methanol was stirred for 65 h and then concentrated
by rotary evaporation to afford 0.214 g of a yellow oil. Column
Supporting Information Available: Experimental details
of the X-ray crystallographic structure determination, tables of
distances, angles, fractional coordinates, and thermal parameters,
and thermal ellipsoid plots for triureas 1a, b (32 pages). This
material is contained in many libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS, can be downloaded
from the Internet; see any current masthead page for ordering
information and Internet access instructions.
JA9536072