Benzoylurea oligomers: Synthetic foldamers that mimic extended α helices

DOI: 10.1002/anie.200701869

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Angewandte Chemie - International Edition p. 8614 - 8617 (2007)

Update date:2022-08-04

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Authors:

Rodriguez, Johanna M.

Hamilton, Andrew D.

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Article abstract of DOI:10.1002/anie.200701869

Not-so-short and curlies: A new benzoylurea-based foldamer scaffold favors a linear conformation governed by intramolecular hydrogen bonding (see picture, left). The functional groups R are in a staggered arrangement analogous to an α helix. Iterative syn

Full text of DOI:10.1002/anie.200701869

Communications

DOI: 10.1002/anie.200701869

H-Bonded Foldamers

Benzoylurea Oligomers: Synthetic Foldamers That Mimic Extended

a Helices**

Johanna M. Rodriguez and Andrew D. Hamilton*

A key role of a-helical domains within proteins is to act as

rigidifying functionalized scaffolds that define a functional

architecture.^[1]Projection of side chains from the surface of

the a helix allows it to contact other residues intramolecularly

in a folded protein or intermolecularly in mediating protein–

protein or protein–DNA interactions. In some cases, long

stretches of a-helical domains form extended protein struc-

tures through homo- or heterodimerization, as seen in

proteins ranging from transmembrane protein channels to

four-helix bundles.^[2]These interactions are crucial for both

the structural stability and overall function of the protein.

In recent years an idea has taken hold that non-natural

oligomers might take up helical conformations,^[3]and in doing

so, mimic the structure and function of a helices. Particular

progress has been shown with b-amino acid homologues^[4]of

natural peptides, which can be used to inhibit helix–protein

contacts, such as those found in p53/MDM2 (murine double

minute)^[5]and Bak/Bcl-x_L.^[6]Helical conformations have also

been observed in other oligomers based on peptoids,^[7]g-

Figure 1. Structures of oligophenylene 1 and benzoylureas 2–5 in

amino acids,^[8]d-amino acids,^[9]pyridine dicarboxamides,^[10]

comparison to an ideal a helix. N and C refer to the N and to the

C terminus, respectively. R=Bn or H, R¹=R³=R⁵=R⁷=R⁹=CH₃,

R²=R⁴=R⁶=R⁸=iBu.

quinoline oligoamides,^[11]and anthranilamides.^[12]An alter-

native approach to a-helix mimicry ignores the helical

conformation and in its place seeks scaffolds that project

functional side chains in an analogous fashion^[13–15]or mimic

the organizational capabilities of helices.^[16]In this regard,

oligophenylene derivatives have attracted attention owing to

their rigidity and functional stability.^[10,13]

We have previously shown that trisubstituted terphenyl

derivatives can mimic the side-chain projection of two turns

of an a helix and can disrupt various helix–protein interac-

tions.^[14,15,17]The further extension of these mimetics might

involve, for example, a nine-ring differentially substituted

oligophenylene, such as 1, reproducing eight turns of an

a helix and long enough to span a bilayer membrane

(Figure 1). However, the synthesis of 1 would be challenging

and result in a highly hydrophobic product. In searching for

alternatives, we were struck that an acylurea group might

replace certain aryl rings in this scaffold through intra-

molecular hydrogen bonding.^[18]Thus, an oligomer composed

of para-aminobenzoic acid derivatives could form an alter-

nating aromatic ring–hydrogen-bonded acylurea structure,

such as 2, with a similar overall shape to oligophenylene 1

(Figure 1).

An iterative synthesis was developed for the benzoylurea

oligomers using two basic monomer units, a secondary amide

and an isocyanate derived from 4-aminobenzoic acid (see

Supporting Information). A representative cycle of the

synthetic procedure is outlined in Scheme 1. Deprotonation

of amide 6 with LiHMDS followed by nucleophilic attack on

[*] J. M. Rodriguez, Prof. A. D. Hamilton

Department of Chemistry, Yale University

225 Prospect Street, P.O. Box 208107

New Haven, CT 06520-8107 (USA)

Fax: (+1)203-432-6144

E-mail: andrew.hamilton@yale.edu

[**] We thank the National Institutes of Health (GM69850) for financial

support of this work, and Dr. Christopher Incarvito for his

assistance with the X-ray crystallographic analysis.

Scheme 1. Synthesis of 5b. Reagents and conditions: a) LiHMDS,

THF, ꢀ788C, 5 min, then 7, ꢀ788C, 15 min; b) H₂, Pd/C, EtOAc/

MeOH. Bn=benzyl, HMDS=hexamethyldisilazide.

Supporting information for this article is available on the WWW

under http://www.angewandte.org or from the author.

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Angewandte

Chemie

ꢀ

isocyanate 7 gives a bis(benzyl)-protected benzoylurea 5a

tances of 1.87 and 1.78 and N H···O angles of 141.28 and

136.28, respectively.

that is subsequently deprotected to afford the functionalized

benzoylurea 5b in good yield. H NMR spectroscopy experi-

The mimicry of longer helices requires straightforward

and stepwise elongation of the scaffold. To achieve this goal,

amino ester benzoylurea 5a can be treated to further cycles of

the synthetic procedure represented in Scheme 2. However,

prior to hydrogenolytic debenzylation, the benzoylurea group

is protected with Boc to preclude any instability under the

strongly basic conditions. Subsequent reaction of 10 with

triphosgene gave the new isocyanate which could be treated

with secondary amide 6 to give, after full deprotection, the

bis(benzoylurea) 4b containing five substituted ring systems

(see Supporting Information, Scheme S1, for further exper-

imental details of the transformation from 10 to 4b).

The X-ray structure of 4a^[20](Figure 3a) shows intra-

molecular hydrogen bonds between the urea NH groups and

carbonyl oxygen atoms, with interatomic distances of 1.84 and

ments performed on a model benzoylurea compound 9a

(Figure 2a) show little change in the amide-NH resonance of

ꢀ

1.78 and N H···O angles of 141.98 and 136.88 for the

benzoylurea groups nearest to the NBn₂and to the CO₂Me

groups, respectively. Importantly, the five substituents project

in a staggered arrangement from the scaffold in a similar

manner to an a helix. Computational modeling, based on the

X-ray structures of 9b (Figure 2b) and 4a (Figure 3a), shows

that considerable spacer length can be generated through the

elongation of the urea oligomer. Figure 1 shows the variation

of length and helix mimicry. Compound 5, corresponding to

two turns of an a helix, extends a distance of about 14.0

(measured between the aryl-NH and the ester -CO₂Me

atoms). Pentasubstituted 4 adds a further 7.7 (approx.

5 residues, 1.4 turns of a helix) to its length and can potentially

mimic four turns of the helix (length 22.3 ). Further cycles of

Boc-protection, debenzylation, isocyanate formation, reac-

tion with a secondary amide and deprotection have been

carried out to give the homologous hepta- and nonasubsti-

tuted mimetics 3 and 2, respectively. These highly elongated

structures, extending 29.4 and 37.1 , correspond to approx-

Figure 2. a) Structural comparison of terphenyl 8 to benzoylurea scaf-

fold 9. b) X-ray structure of 9b in stereoview. Non-NH hydrogen atoms

omitted for clarity. Red O, blue N, gray C, white H.

the urea in DMSO (Dd = 0.126 ppm)

and in CDCl₃(Dd = 0.015 ppm) when

the concentration of the sample was

varied between 0.005 and 0.5m. In

addition, the temperature-depend-

ence coefficient of 9a in DMSO

was determined from variable tem-

perature (VT) NMR spectroscopy

to be Dd/DT= ꢀ2.9 ppbK^ꢀ1. Taken

together, these data confirm the pres-

ence of an intramolecular hydrogen

bond in the benzoylurea group of 9a

in solution. Additionally, X-ray struc-

tures of 9a and 9b^[20](9b only is

shown in Figure 2b) show that in the

solid state the benzoylurea adopts a

staggered conformation with an intra-

molecular hydrogen bond between

Scheme 2. Synthesis of 4a. Reagents and conditions: a) Boc₂O, DMAP, THF; b) H₂, Pd/C, EtOAc/

MeOH; c) TFA, CH₂Cl₂. Boc=tert-butoxycarbonyl, DMAP=4-(dimethylamino)pyridine, TFA=tri-

fluoroacetic acid.

the urea NH groups and carbonyl

oxygen atoms, with interatomic dis-

Angew. Chem. Int. Ed. 2007, 46, 8614 –8617

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8615

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Communications

function as a-helix mimetics in disrupting the Bcl–x_L/Bak

interaction. These molecules can be readily elongated to

produce extended scaffolds with variable side chain compo-

sition making them attractive for potential applications in

protein recognition and materials design.

Received: April 27, 2007

Published online: October 5, 2007

Keywords: benzoylurea · foldamers · helical structures ·

oligomerization · proteomimetics

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imately 5.4 and 6.8 turns of an a helix, respectively, and

permit the projection of seven and nine substituents in a well-

defined manner from one face of a molecule. Importantly, the

linear synthetic route, by appropriate choice of secondary

amide and aminobenzoate components, allows for each of

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R²¼

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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8614 –8617

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&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Take advantage of blue reference links

&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Angewandte

Chemie

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Angew. Chem. Int. Ed. 2007, 46, 8614 –8617

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

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Article Doi

Benzoylurea oligomers: Synthetic foldamers that mimic extended α helices

DOI: 10.1002/anie.200701869

Source and publish data:

Authors:

Article abstract of DOI:10.1002/anie.200701869

Full text of DOI:10.1002/anie.200701869

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