Aromatic oligoamides with a rare ortho-connectivity: Synthesis and study of ortho-arylopeptoids

FULL PAPER

DOI: 10.1002/ejoc.201300398

Aromatic Oligoamides with a Rare ortho-Connectivity: Synthesis and Study of

ortho-Arylopeptoids

Thomas Hjelmgaard*^[a][‡]and John Nielsen*^[b]

Keywords: Aromatic oligoamides / Synthetic methods / Solid-phase synthesis / Conformation analysis

Even though aromatic oligoamides composed of aromatic

amino acids in a “one-way sequence” attract ever increasing

research interest, backbones connected through ortho-linked

aromatics remain rare. Herein, we present the first synthesis

and study of N-alkylated ortho-aminomethyl-benzamides

termed “ortho-arylopeptoids”. The ortho-arylopeptoids may,

with a few exceptions, be synthesized either in solution or on

solid-phase using unique and highly efficient submonomer

methods with similar levels of high generality and efficiency

to those previously demonstrated for meta- and para-arylo-

peptoids. NMR studies indicated a more restricted rotation

about the amide bonds in ortho-arylopeptoids, presumably

due to a more congested backbone structure resulting from

the ortho-connectivity pattern. Intriguingly, tert-butyl and

phenyl side chains offer complete control over the amide

conformations; whereas arylopeptoid residues with tert-butyl

side chains adopt a 100% cis amide conformation, the oppo-

site 100% trans amide conformation was observed in arylo-

peptoids with phenyl side chains. The tert-butyl moiety can

furthermore serve as a protecting group during synthesis,

which can later be removed to allow the amide to adopt a

100% trans conformation instead.

ruplex ligands^[5j]have all been reported. Increased struc-

tural diversity at the expense of reduced rigidity may be

achieved by insertion of aliphatic carbon atoms into the

aromatic oligoamide backbone, which has been demon-

strated in aminomethylbenzamides,^[7]aminomethylpyrid-

Introduction

Structural and functional mimicry of biopolymers is a

research area of high interest, and aryl-based foldamers

have proven to be well-suited for this purpose.^[1]Aromatic

oligoamides assembled from aromatic amino acids in a

“one-way sequence” constitutes a subgroup of these folda-

mers that receives ever increasing attention.^[2]The most

well-studied foldamers of this genre include benzanilides,^[3]

pyridylamides,^[3c,3k,4]and oligoamides of quinolines^[5]and

naphthyridines (Figure 1, top row).^[6]The lack of aliphatic

backbone carbon atoms in these constructs necessitates

comparably more rigorous coupling conditions during their

syntheses but results in the formation of relatively rigid

structures. These may be further stabilized by the capacity

of their backbone amide protons to participate in intra-

molecular hydrogen bonding. Accordingly, spherand or

crown ether-like structures,^[3n,3q]crescent or helical struc-

tures,^{[3i,3r–3t,4a–4d,5,6]}rod-like structures,^[3g,3h,3p]as well as

their use as α-helix mimetics^{[3c,3e,3h,3k,3m,4e–4f]}and G-quad-

[a] Department of Chemistry, Section for Chemical Biology and

Nanobioscience, Faculty of Science, University of Copenhagen,

Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark

[b] Department of Drug Design and Pharmacology, Faculty of

Health and Medical Sciences, University of Copenhagen,

Universitetsparken 2, 2100 Copenhagen Ø, Denmark

E-mail: john.nielsen@sund.ku.dk

[‡] Current address: Rockwool International A/S, Group Research

and Development

Hovedgaden 584, Entrance C, 2640 Hedehusene, Denmark

Fax: +45-46-563311

E-mail: thomas.hjelmgaard@rockwool.com

Homepage: http://ww w .rockwool.com

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300398.

Figure 1. “One-way sequence” aromatic oligoamides.

3574

Eur. J. Org. Chem. 2013, 3574–3589

Synthesis and Study of ortho-Arylopeptoids

ylamides,^[8]oligoamides of aminophenoxy acetic acid,^[9]of an entirely new type of aromatic oligoamides with ortho

and oligoamides of aminomethylphenyl acetic acid (Fig- connection patterns in their backbone aromatics: ortho-ary-

ure 1, mid row).^[10]

lopeptoids.

The syntheses of these oligoamides involve comparatively

more reactive aliphatic amines and carboxylic acids and

therefore require less demanding coupling conditions. How-

ever, although the formation of crescent or helical struc-

tures has been documented,^[9,10]they remain less well

studied. A different approach that may greatly increase the

structural diversity of aromatic oligoamides is alkylation of

the backbone amide nitrogen atoms (Figure 1, bottom

row), in this case at the expense of losing the possibility for

backbone participation in intramolecular hydrogen bond-

ing. This strategy has been applied in N-alkylated benzanil-

ides,^[3d,11]and N-alkylated naphthanilides,^[3d]which do not

contain any aliphatic backbone carbon atoms. Interestingly,

even in the absence of backbone amide protons, crescent or

helical structures,^[11g]as well as the use as α-helix mi-

metics^[11b]of these oligoamides have still been reported. We

focus on this intriguing strategy in our research program on

N-alkylated meta- and para-aminobenzamides termed

“meta-arylopeptoids” and “para-arylopeptoids”, respec-

tively.^[12]Interestingly, this strategy has recently been ex-

tended to heteroaromatic backbones.^[13]The N-alkylated

meta- and para-aminomethyl-benzamides were originally

conceived as a subclass of the peptidomimetic pepto-

ids,^[14,15](N-alkylated glycines and β-alanines) in which

each backbone residue is “extended” with a phenyl ring.

However, after being briefly mentioned for the first time in

a few patents back in the mid and late 90’s,^[16]they had,

until recently, only received further attention in a single let-

ter in 2007.^[17]Since then, we have begun to unveil the po-

tential of this promising class of aromatic oligoamides by

developing greatly improved synthetic methods and under-

taking the first conformational studies. Thus, we have re-

cently developed the first convenient solution-phase synthe-

sis of meta- and para-arylopeptoids using bromomethyl

benzoyl bromides in the coupling steps,^[12c]and two solid-

phase methodologies based on the use of either COMU-

activated chloromethylbenzoic acids^[12b]or chlorometh-

ylbenzoyl chlorides^[12a]in the coupling steps. These meth-

ods all rely on “submonomer” approaches wherein the aryl-

opeptoid residues are created in an iterative manner directly

on the growing oligoamide chains using a unique acylation-

substitution cycle. In principle, any primary amine may be

used in the substitution steps for installing the side chains,

whereby a great diversity of arylopeptoids may be envi-

sioned. Overall, only inexpensive, commercially available

reagents are required and the combination of our methods

makes it possible both to synthesize large and diversified

libraries of meta- and para-arylopeptoids as well as to ac-

cess target meta- and para-arylopeptoids on a gram scale.

However, in spite of the ever increasing research efforts

on “one-way sequence” aromatic oligoamides, the demon-

stration of backbones connected through ortho-linked aro-

matics is, to the best of our knowledge, limited to as few

Results and Discussion

Solution-Phase Synthesis

We initiated our work on ortho-arylopeptoids by study-

ing the feasibility of solution-phase submonomer synthesis

(Scheme 1). We opted for the use of tert-butyl 2-(bromo-

methyl)benzoate (1)^[18]as starting material because the

tert-butyl group may eventually serve in selective postsyn-

thesis removal and modification as we have previously dem-

onstrated in both peptoids and arylopeptoids.^[12c,19]Three

series were studied, originating from the use of three dif-

ferent simple aliphatic amines in the substitution steps:

series a carrying the least bulky ethyl side chains, series b

decorated with the moderately bulky isopropyl side chains,

and series c, carrying the highly bulky tert-butyl side chains

(Scheme 1 and Table 1). We chose not to synthesize oligo-

mers longer than trimers 4a–c.

Scheme 1. Iterative submonomer solution-phase synthesis of ortho-

arylopeptoids. Reagents and conditions: (a) R-NH₂, Et₃N, THF,

0 °C to room temp., overnight; (b) BrCH₂ArCOBr, Et₃N, THF,

0 °C, 1 h; see Table 1 for yields.

Table 1. Isolated yields (HPLC purity Ն 97%) after column

chromatography for iterative solution-phase synthesis of ortho-

arylopeptoids (see Scheme 1).

Entry

n

Et [%]^[a]

iPr [%]^[a]

tBu [%]^[b]

1

2

3

1

2

3

2a: 62^[c]

3a: 81

4a: 85

2b: 88

3b: 86

4b: 84

2c: 89

3c: 85

4c: 78

[a] 1.05 equiv. of acylating reagent was used and the synthesis of

each residue was performed as a one-pot procedure. [b] 2.0 equiv.

of acylating reagent was used and the acylated intermediates were

purified by column chromatography. [c] 2-Ethyl-2,3-dihydro-1H-

isoindol-1-one (26%), formed by cyclization of 2a, was also iso-

lated.

We have previously developed a convenient one-pot pro-

as three examples.^[3v,9,10]Inspired by the sparse literature cedure for solution-phase synthesis of meta- and para-

precedence, we herein present the first synthesis and study arylopeptoid residues using 3- and 4-(bromomethyl)benzoyl

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T. Hjelmgaard, J. Nielsen

FULL PAPER

bromide (1.05 equiv.) and Et₃N (1.05 equiv.) in tetra-

hydrofuran (THF) at 0 °C in the coupling steps, followed

directly by substitution with the required primary amine

(10.0 equiv.) in the presence of further Et₃N (2.0 equiv.) at

0 °C to room temp. overnight.^[12c]We were satisfied to find

that this method could be adapted directly to the synthesis

of ortho-arylopeptoids 2a–4a and 2b–4b simply by using 2-

(bromomethyl)benzoyl bromide instead. The residues were

synthesized and isolated in comparably high yields (81–

85%), except for monomer 2a, which was isolated in a lower

yield (62%) due to formation of the corresponding isoindol-

inone. In the case of ortho-arylopeptoids 2c–4c, with the

highly bulky tert-butyl side chains, each acylated intermedi-

ate had to be purified because a greatly increased excess of

acylation reagent (2.0 equiv.) was needed for the reactions

to proceed to completion. This was also necessary for the

corresponding meta- and para-arylopeptoids,^[12c]and with

this modification each residue was formed in comparably

high yield (78–89%). Solution-phase synthesis is useful for

accessing products on gram-scale and, overall, the methods

previously developed by us for solution-phase synthesis of

meta- and para-arylopeptoids could be adapted directly to

the synthesis of ortho-arylopeptoids.

Scheme 2. Solution-phase model studies. Reagents and conditions:

(a) ClCH₂ArCOOH (1 m), coupling reagent, DIPEA, NMP, room

temp. or ClCH₂ArCOCl (0.5 m), DIPEA, CH₂Cl₂, room temp., fur-

ther conditions in Table 2. (b) iPrNH₂(20 equiv., 2 m), DMSO,

50 °C, 7.5 min or room temp., 30 min.

gous para-substituted model system,^[12b]and in both studies

we found COMU (entry 1) to be the best coupling reagent.

However, compared with a reaction time of 5 min found

in the para-arylopeptoid study, the reaction on the ortho-

arylopeptoid backbone required no less than one hour to

reach completion, presumably as a result of increased steric

Solid-Phase Synthesis – A Model Study

A small solution-phase study of the substitution and hindrance. Furthermore, the extended reaction time caused

coupling conditions was carried out prior to the develop- the formation of minor amounts of unidentified impurities.

ment of a solid-phase methodology. The study was carried Using our most recently developed conditions,^[12a]we then

out with monomer 2b, chloromethyl intermediate 5, and di- found that monomer 2b could be converted cleanly into in-

mer 3b, carrying the moderately bulky isopropyl side chain, termediate 5 in less than 2 min by reaction with 2-(chloro-

as a model system (Scheme 2, Table 2, and the Supporting methyl)benzoyl chloride (3.0 equiv.) as a 0.5 m solution in

Information for details).^[12b]

CH₂Cl₂in the presence of DIPEA (Table 2, entry 6). Al-

The potential use of the corresponding bromomethyl in- though it may therefore be possible to synthesize ortho-

termediate was quickly discarded; although we found that arylopeptoids using 2-(chloromethyl)benzoic acid in combi-

2-(chloromethyl)benzoic acid and 2-(bromomethyl)benzoic nation with a peptide coupling reagent, the use of the corre-

acid were transformed into the derived phthalide in under sponding acid chloride is much more efficient.

2 min in N-methyl-2-pyrrolidinone (NMP) and CH₂Cl₂

In the analogous para-arylopeptoid study, we found reac-

when DIPEA was added, transformation into an active spe- tion with isopropylamine (20 equiv.) as a 2 m solution in

cies by use of a coupling reagent was only fast enough to dimethyl sulfoxide (DMSO) at 50 °C to be the optimal con-

compete with phthalide formation in the case of 2- ditions for the substitution step.^[12b]When adapted directly

(chloromethyl)benzoic acid.

to the conversion of intermediate 5 into ortho-arylopeptoid

We first tested the use of a selection of peptide type cou- dimer 3b, we found that the reaction proceeded four times

pling reagents in combination with 2-(chloromethyl)benzoic faster than in the para-arylopeptoid study; the reaction was

acid (3.0 equiv. activated species) as 1.0 m solutions in NMP complete within 30 min at room temp. or 7.5 min at 50 °C.

in the presence of DIPEA (Table 2, entries 1–5). We have We suggest that this is brought about by a neighboring

previously tested these coupling conditions on the analo- group effect from the adjacent amide.

Table 2. Optimization of coupling step from 2b to give 5.

Entry

Coupling method (equiv.)

Reaction time [min]^[a]

Comments

1

2

3

4

5

6

ClCH₂ArCOOH (3.0)/COMU (3.5)/DIPEA (7.0)

ClCH₂ArCOOH (6.0)/DIC (3.0)/DIPEA (7.0)

ClCH₂ArCOOH (3.0)/HATU (3.5)/DIPEA (7.0)

ClCH₂ArCOOH (3.0)/PyBOP (3.5)/DIPEA (7.0)

ClCH₂ArCOOH (3.0)/HBTU (3.5)/DIPEA (7.0)

ClCH₂ArCOCl (3.0)/DIPEA (6.0)

60

slightly impure reaction to 5

93% conv. after 60 min

59% conv. after 60 min

53% conv. after 60 min

36% conv. after 60 min

clean reaction to 5

Ͼ 60

Ͻ 2

[a] Reactions monitored by analytical HPLC.

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Synthesis and Study of ortho-Arylopeptoids

Solid-Phase Synthesis – A Free Acid at the C-Terminus

studied using hexamer 6b, carrying the moderately bulky

isopropyl side chain, as the model target (Table 3, entries

The promising results obtained in the above model study 1–4). When using the Rink acid linker and performing the

thus indicated that we could adapt our previously devel- substitution steps at room temp., hexamer 6b was isolated

oped methods for solid-phase synthesis of meta- and para- in excellent crude purity (93%) and the purified product

arylopeptoids based on the use of chloromethylbenzoyl was likewise obtained in excellent yield after preparative

chlorides in the coupling steps directly to the synthesis of HPLC (97%, Ͼ99% purity, entry 1). Performing the substi-

ortho-arylopeptoids. These methods are derived from the tution reactions at 50 °C resulted in a slight increase in

optimal conditions found in the model studies, albeit with crude purity (99%) but concomitantly also resulted in a

extended reaction times in both the acylation steps (20 min) dramatic decrease in yield of crude material and, thus, puri-

and the substitution steps (1 h at 50 °C) because this proved fied 6b (29%, Ͼ99% purity, entry 2). This dramatic loss of

advantageous.^[12a,12b]Using these methods as a starting product during synthesis can most likely be explained by an

point, we then investigated the solid-phase synthesis of a increase in aminolysis of the growing arylopeptoid chain

selection of model ortho-arylopeptoid hexamers 6a–h with from the Rink acid linker when raising the temperature dur-

free acids at the C-terminus (Scheme 3 and Table 3). We ing the substitution steps.

have previously used the highly acid labile 2-chlorotrityl

For comparison, aminolysis of arylopeptoids from the

chloride polystyrene resin (cleavage in HFIP/CH₂Cl₂, 1:4) more bulky 2-chlorotrityl chloride linker only appeared to

for solid-phase synthesis of the analogous meta- and para- be a problem when using extended reaction times (3 h) or

arylopeptoids.^[12a,12b]However, we found that the rapid DMSO/water mixtures in the substitution steps.^[12a,12b]Iso-

conversion of 2-(chloromethyl)benzoic acid into the derived indolinone formation after the first substitution step could

phthalide under basic conditions excluded the use of the 2- represent an additional or alternative explanation. How-

chlorotrityl chloride linker. Instead, we tested the use of the ever, a test reaction showed that the previously synthesized

likewise highly acid labile Rink acid linker (cleavage in monomer 2b (also of the isopropyl series, see Scheme 1) re-

HFIP/CH₂Cl₂, 1:4) and the moderately acid labile HMPB mained completely stable when subjected to the solid-phase

linker (cleavage in TFA/water, 95:5). After some experimen- substitution conditions (monitored by analytical HPLC).

tation, we found that the loading of these linkers was best As would then be expected, we found that the use of the

carried out by reaction with 2-(chloromethyl)benzoyl chlor- less hindered HMPB linker resulted in substantial decreases

ide (3.0 equiv.) as a 0.5 m solution in CH₂Cl₂in the presence in purified yields of hexamer 6b compared with the Rink

of DIPEA (3.0 equiv.) and 4-(dimethylamino)pyridine acid linker (67 vs. 97% and 16 vs. 29%, Ͼ99% purity, en-

(DMAP) (3.0 equiv.); loading did not proceed efficiently in tries 3–4). We therefore chose to concentrate our efforts on

the absence of DMAP, whereas the use of 6.0 equiv. DMAP the use of the Rink acid polystyrene resin. For the synthesis

caused the formation of trace amounts of impurities. The of hexamer 6a, decorated with ethyl side chains (Table 3,

efficiencies of the Rink acid and HMPB linkers were first entry 5), we unfortunately only isolated trace amounts of

Scheme 3. Solid-phase submonomer synthesis of ortho-arylopeptoid hexamers with free acids at the C-terminus. Reagents and conditions:

(a) ClCH₂ArCOCl (3.0 equiv., 0.5 m), DMAP (3.0 equiv.), DIPEA (3.0 equiv.), CH₂Cl₂, room temp., 20 min. (b) 6a–g: R-NH₂(20 equiv.,

2.0 m), DMSO, room temp. or 50 °C, 1 h; 6h: R-NH₂(20 equiv., 4.0 m), DMSO, 50 °C, 3 h. (c) 6a–b and 6d–h: ClCH₂ArCOCl (3.0 equiv.,

0.5 m), DIPEA (6.0 equiv.), CH₂Cl₂, room temp., 20 min; 6c: ClCH₂ArCOCl (6.0 equiv., 1.0 m), DIPEA (12.0 equiv.), CH₂Cl₂, room

temp., 180 min. (d) 6a–b and 6d–h: BzCl (3.0 equiv., 0.5 m), DIPEA (6.0 equiv.), CH₂Cl₂, room temp., 20 min; 6c: BzCl (6.0 equiv., 1.0 m),

DIPEA (12.0 equiv.), CH₂Cl₂, room temp., 180 min. (e) Rink acid polystyrene resin: HFIP/CH₂Cl₂, 1:4, room temp., 1 h. HMPB-MBHA

polystyrene resin: TFA/water, 95:5, room temp., 1 h. See Table 3 for further details, yields and purities.

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T. Hjelmgaard, J. Nielsen

Table 3. Results for solid-phase submonomer synthesis of ortho-arylopeptoid hexamers with free acids at the C-terminus.

FULL PAPER

Entry Hexamer Linker

Substitution conditions

Conc. [m] Temp. [°C] t [h]

Acylation conditions

ArCOCl [equiv.] Conc. [m] t [min]

Crude yield Crude purity Pure yield

[%]

[%]^[a]

93

[%]^[b]

97

1

2

6b

Rink

acid

Rink

acid

2

r.t.

50

1

3

0.5

20

101

35

99

29

3

4

5

6b

6a

HMPB

Rink

acid

Rink

acid

Rink

acid

Rink

acid

Rink

acid

Rink

acid

Rink

acid

Rink

acid

2

r.t.

50

r.t.

1

3

0.5

20

96

35

trace

92

86

–

67

16

–

6

6c

6d

6e

6f

2

4

r.t.

50

r.t.

50

r.t.

50

r.t.

50

1

3

6

3

1.0

0.5

40

180

20

33

54

trace^[c]

23^[d]

–

7

8

trace

16

–

9

76

10

23

2

10

11

12

13

14

15

86

36

6f

11

32

[e]

6g

6h

97

50

–

Rink

acid

Rink

acid

Rink

acid

92

98

94^[f]

–

48

trace^[g]

91

7

5

[a] Determined by analytical HPLC. [b] Yield of product isolated in Ͼ99% purity after preparative HPLC. [c] LC-MS revealed only trace

amounts of oligomers longer than trimer length. [d] Major impurities: pentamer and tetramer (LC-MS). [e] HPLC purification hindered

due to poor solubility. [f] Purified by aqueous extraction due to poor solubility in HPLC solvents. [g] Complex HPLC; LC-MS showed

the presence of all oligomer lengths.

crude product, presumably as a result of even more favor- in 10 and 23% yield (Ͼ99% purity) when performing the

able aminolysis and/or isoindolinone formation when in- substitution reactions at room temp. Attempts to improve

stalling this small side chain. To accommodate the expected on the crude purity of 6f by performing the substitution

difficult acylations in the synthesis of hexamer 6c, with the reactions at 50 °C proved futile and, as expected, caused a

highly bulky tert-butyl side chains, we first doubled the con- dramatic decrease in yield to 2% (entry 11). When per-

centrations and number of equivalents of reagents as well as forming the substitution reactions at room temp., hexamer

the reaction time of these steps,^[12a]whereas the substitution 6g, with the bulky (S)-N-(1-phenylethyl) (spe) side chains,

steps were performed at room temp. (entry 6). This proved was first isolated in 92% crude yield and 50% crude purity

not to suffice, however, because the crude product con- (entry 12). Due to poor solubility, this product could not be

tained only trace amounts of oligomers longer than trimers. purified by preparative reverse-phase HPLC. However, we

The reaction time of the acylation steps was therefore ex- found that hexamer 6g could be obtained in 94% yield and

tended to 3 h and the substitution steps were performed at 98% purity by performing the substitution steps at 50 °C

50 °C, which allowed for isolation of hexamer 6c in 7% and purifying the crude product by aqueous extraction (en-

yield (Ͼ99% purity, entry 7). The next hexamers studied, try 13). The final ortho-arylopeptoid of this model study,

6d–g, followed the same trend as above; the lower the en- hexamer 6h, decorated with phenyl side chains, was obtained

cumbrance of the primary amine used in the substitution through the use of unreactive aniline in the substitution

steps, the lower the yield, presumably due to more facile steps. Compensating for this low reactivity by using 4 m

aminolysis and/or isoindolinone formation.

solutions of aniline in DMSO at room temp., in combina-

Thus, attempts at the synthesis of hexamer 6d, with phen- tion with reaction times extended to 3 h in the substitution

ylbutyl side chains, produced only trace amounts of crude steps,^[12a]first afforded a crude product containing a com-

products even though the substitution steps were performed plex mixture of all oligomer lengths between monomer and

at room temp. (Table 3, entry 8). More success was achieved hexamer (48% crude yield, entry 14). Performing the substi-

in the syntheses of the water soluble oligomers 6e and 6f, tution steps at 50 °C caused a dramatic decrease in crude

with 2-morpholinoethyl and pyridinylmethyl side chains, yield (7%) but allowed for isolation of 5% of the desired

respectively (entries 9–10). These oligomers were obtained hexamer 6h (entry 15).

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Synthesis and Study of ortho-Arylopeptoids

Solid-Phase Synthesis; Primary Amide at the C-Terminus

all substitution reactions were carried out at 50 °C. The first

two ortho-hexamers, 7b of the isopropyl series and 7a of the

ethyl series, were isolated in 96 and 81% yields, respectively

(Ͼ99% purity, Table 4, entries 1 and 2). For comparison,

the yield of hexamer 7b was approximately 25% higher than

what was previously achieved in the synthesis of the analo-

gous para-hexamer using identical conditions.^[12a]The

harsh cleavage conditions (TFA/water, 95:5, 2 h) was antici-

pated to cause concomitant removal of any tert-butyl side

chains installed on the backbone amides. Indeed, when

using tert-butylamine in the substitution steps we isolated

the derived hexamer 7i with free backbone amide protons in

101% crude yield and 48% crude purity (entry 3). Although

poor solubility hindered purification by preparative HPLC,

the crude product was soluble enough to allow analysis by

HPLC and HRMS. This is the first time we have been able

to establish that the tert-butyl group can be used as a

masked free amide proton in arylopeptoid synthesis; the na-

ture of the crude products obtained in the analogous syn-

theses of the corresponding meta- and para-hexamers could

not be established due to complete insolubility in any useful

organic solvent.^[12a]Hexamer 7d, with phenylbutyl side

chains, and the water soluble hexamer 7e, with 2-morphol-

inoethyl side chains, were isolated in crude purities and

purified yields (76 and 63%, entries 4 and 5) similar to

those previously obtained in the synthesis of the analogous

meta- and para-hexamers.^[12a]Although hexamer 7g, with

spe side chains, was also obtained in a crude purity reminis-

cent of what was obtained for the corresponding meta- and

para-hexamers,^[12a]the desired product was only isolated in

23% yield (Ͼ99% purity, entry 7), presumably due to loss

of product during preparative HPLC purification caused by

low solubility. It should be noted that the cleavage time was

Although selected oligomers of ortho-arylopeptoids with

free acids at the C-terminus may be synthesized using the

Rink acid linker, the limited stability of this linker pre-

vented comparison of the efficiency of the chain elongation

process in ortho-arylopeptoids with that of the correspond-

ing meta- and para-arylopeptoids. To enable this compari-

son, we therefore synthesized ortho-hexamers 7a–h, which

carry a primary amide at the C-terminus (Scheme 4 and

Table 4). As in our previous syntheses of the meta- and

para-counterparts,^[12a]these ortho-arylopeptoids were syn-

thesized on the highly stable Rink amide polystyrene resin

(cleavage in TFA/water, 95:5), for which the risk of amino-

lysis and/or isoindolinone formation is minimal. The only

modification to the submonomer chain growth procedures

compared with synthesis on the Rink acid linker was that

Table 4. Results for solid-phase submonomer synthesis of ortho-

arylopeptoid hexamers with primary amides at the C-terminus.

Entry Hexamer Crude yield Crude purity

Purified yield

[%]^[b]

[%]

[%]^[a]

1

2

3

4

5

6

7

8

7b

7a

7i^[c]

7d

7e

141

132

101

117

107

106

104

106

99

91

48

92

84

96

81

–

76

63

[d]

7f

28

20

7g

7h

80

23^[e]

35

50^[f]

[a] Determined by analytical HPLC. [b] Yield of product isolated

in Ͼ99% purity after preparative HPLC. [c] tert-Butylamine used

in the substitution steps. [d] HPLC purification hindered due to

poor solubility. [e] Low purified yield presumably due to low solu-

bility of crude and pure product. [f] Major byproducts: pentamer

and tetramer.

Scheme 4. Solid-phase submonomer synthesis of ortho-arylopeptoid hexamers with primary amides at the C-terminus. Reagents and

conditions: (a) piperidine/NMP, 1:4, room temp., 2 and 15 min; then ClCH₂ArCOCl (3.0 equiv., 0.5 m), DIPEA (6.0 equiv.), CH₂Cl₂, room

temp., 20 min. (b) 7a–g and 7i: R-NH₂(20 equiv., 2.0 m), DMSO, 50 °C, 1 h; 7h: R-NH₂(20 equiv., 4.0 m), DMSO, 50 °C, 3 h. (c) 7a–

h: ClCH₂ArCOCl (3.0 equiv., 0.5 m), DIPEA (6.0 equiv.), CH₂Cl₂, room temp., 20 min; 7i: ClCH₂ArCOCl (6.0 equiv., 1.0 m), DIPEA

(12.0 equiv.), CH₂Cl₂, room temp., 180 min. (d) 7a–h: BzCl (3.0 equiv., 0.5 m), DIPEA (6.0 equiv.), CH₂Cl₂, room temp., 20 min; 7i: BzCl

(6.0 equiv., 1.0 m), DIPEA (12.0 equiv.), CH₂Cl₂, room temp., 180 min. (e) TFA/water, 95:5, room temp., 2 h (2ϫ 10 min for 7g). See

Table 4 for yields and purities.

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T. Hjelmgaard, J. Nielsen

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reduced to 2ϫ 10 min in the case of hexamer 7g to mini- very broad signals were observed for the benzylic protons

mize degradation of the crude product.^[12a]The last two adjacent to the amide moieties (CONCH₂Ar). We propose

hexamers, 7f of the water soluble pyridinylmethyl series and that this is a result of the environment around these protons

7h of the phenyl series, were isolated in lower crude purities undergoing conformational changes in the intermediate

compared with the corresponding meta- and para-hexa- time regime on the NMR time scale. In the case of dimer

mers,^[12a]however, the purified products were still isolated 3c, the broad signal was furthermore split into two broad

in comparable yields (20 and 35%, respectively, Ͼ99% pu- signals of equal size. We suggest this signal splitting is a

rity, entries 6 and 8). These results using the Rink amide result of the highly encumbered environment, which may

linker demonstrate that when adapting the methods we pre- cause these benzylic protons to have different dihedral

viously developed for solid-phase synthesis of meta- and angles to the surrounding substituents. This effect is then

para-arylopeptoids^[12a]to the synthesis of the corresponding most clearly observed in dimer 4c, which only contains a

ortho-arylopeptoids, similar levels of efficiencies may be ob- single amide moiety. Furthermore, dimers with ethyl side

tained. The most prominent exception is when installing the chains (3a) or isopropyl side chains (3b) produced NMR

tert-butyl side chain in ortho-arylopeptoids, in which case spectra with sharp signals even though cis/trans-amide mix-

much extended reaction times were needed in the acylation tures were present. At trimer length (4a–b), the complexity

steps.

increased and the hexamers (6 and 7), in general, all pro-

duced spectra that were considerably more complex than

their meta- and para-counterparts. These observations indi-

cate that the rotation about each amide bond in ortho-aryl-

opeptoids is, as expected, more restricted than for their

Conformational Studies

We have previously undertaken the first conformational meta- and para-counterparts. The combination of the re-

studies of meta- and para-arylopeptoids by means of NMR stricted rotation and the more “congested” backbone struc-

spectroscopy.^[12a,12c]Intriguingly, we found that the tert-bu- ture resulting from the ortho-connectivity pattern in ortho-

tyl and phenyl side chains represented particularly interest- arylopeptoids then offers a plausible explanation for the

ing cases because only single, sharp sets of signals were ob- highly complex NMR spectra observed for the longer oligo-

served in the spectra of meta- and para-arylopeptoids carry- mers.

ing these side chains. NOESY experiments revealed that the

To enable more detailed NMR studies of ortho-arylo-

highly bulky tert-butyl side chain invoked a 100% cis con- peptoids, we therefore synthesized model monomers 8b

formation about the amide bond, presumably as a result of (isopropyl side chain), 8c (tert-butyl side chain), 8g (spe side

steric effects, whereas the phenyl side chain resulted in a chain), 8h (phenyl side chain), and 8i (free backbone amide

100% trans conformation.^[12a,12c]The latter observation was proton) as illustrated in Figure 2. These model monomers

in agreement with results reported on closely related N-alk- all consisted of an arylopeptoid residue with a free acid at

ylated benzanilide monomers^[3d]and N-methyl-N-phenyl the C-terminus and a 2-methylbenzoyl capping group at the

acetamides.^[20]For the N-methyl-N-phenylacetamides, ab N-terminus that served as a simple model for a continuing

initio molecular orbital calculations indicated that this pref- ortho-arylopeptoid backbone. The model monomers were

erence may be due to a combination of the N-phenyl side synthesized as described above using the Rink acid linker,

chain being less bulky than the N-methylbenzyl group and in all cases performing the substitution reaction at 50 °C.

electronic repulsions between the carbonyl lone pair and

the phenyl π-electrons.^[20b]The tert-butyl and phenyl side

chains thus enabled a rarely seen complete control over the

amide conformations in meta- and para-arylopeptoids. For

meta- and para-arylopeptoids with any other type of side

chain we observed NMR spectra with very broad signals,

indicating that these oligomers underwent conformational

changes in the intermediate time regime on the NMR time

scale. Furthermore, due to the presence of cis/trans amide

mixtures, the NMR spectra of these meta- and para-arylo-

peptoids contained partly overlapping sets of signals for

carbons and/or protons in close proximity to the amide ni-

trogen atom(s).^[12a,12c]In general, no distinct length-

dependent changes to the spectra of meta- and para-arylo-

peptoids were observed.

Interestingly, the NMR spectra of the ortho-arylopepto-

ids synthesized herein (see the Supporting Information)

showed very different characteristics to those of the corre-

sponding meta- and para-arylopeptoids. Thus, although di-

mer 3c and trimer 4c, with tert-butyl side chains, as ex-

pected, showed the presence of only a single set of signals, correlations if applicable.

Figure 2. Model monomer arylopeptoids and observed NOESY

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Synthesis and Study of ortho-Arylopeptoids

The correlations observed in the NOESY spectrum of major conformer in model monomer 8b (as well as in dimer

8c (tert-butyl side chain) in CDCl₃at room temp. were, as 3b) therefore most likely corresponded to the cis-conformer.

expected, indicative of a 100% cis conformation (see Fig- It is worth noting that these ratios are similar to those pre-

ure 2 and the Supporting Information); the methyl substitu- viously observed for the analogous meta- and para-di-

ent on the N-capping group correlated with both the benz- mers.^[12c]

ylic protons and the aromatic protons of the arylopeptoid

The spe side chain is interesting because it has been used

residue, whereas the tert-butyl side chain showed no corre- extensively in conformational studies of peptoids.^[15,19,21]

lations with the aromatic part of the capping group. As a Model monomer 8g existed as a 75:25 mixture of two con-

result of the congested backbone structure of the cis-amide formers in CDCl₃at room temp. (see the Supporting Infor-

conformation, a correlation between the tert-butyl side mation), which is similar to what was observed in the analo-

chain and the methyl substituent of the N-capping group gous meta- and para-arylopeptoids with spe side chains,^[12a]

was also observed. Previous attempts to study the meta- but extensive overlap in the NOESY spectrum hindered fur-

and para-arylopeptoids with free backbone amide proton(s) ther analysis. For the corresponding meta- and para-arylo-

were hindered because of insolubility.^[12a]We were therefore peptoids, we have, however, previously deduced that the

satisfied to find that model monomer 8i, with a free back- major conformer may correspond to the trans conform-

bone amide proton, was sufficiently soluble to allow for er.^[12a]To investigate the presence of any length-dependent

NMR analysis in [D₆]DMSO as well as in MeOD. Only one behavior in ortho-arylopeptoids carrying the spe side chain,

conformer was observed in both solvents, and the NOESY we synthesized monomer 9g and trimer 10g (Figure 3) and

spectrum was indicative of a 100% trans amide conforma- compared the NMR spectra (CDCl₃at room temp.) to

tion. Correlations between the backbone amide proton and those obtained for hexamer 6g. The corresponding non-

the aromatic protons of the N-capping group were ob- amer was also synthesized but the crude product was dis-

served, whereas no correlations were observed between the carded due to insolubility.

methyl group of the N-capping group and the benzylic or

aromatic protons of the arylopeptoid residue (see Figure 2

and the Supporting Information). Interestingly, overall, this

means that the tert-butyl side chain can be used both for

invoking a 100% cis conformation in arylopeptoids and

serve as a protecting group during synthesis, which can later

be removed to allow the amide group(s) to adopt a 100%

Figure 3. The spe series ortho-arylopeptoids; the yields are of prod-

ucts isolated in more than 99% purity after preparative HPLC.

trans amide conformation instead. Model monomer 8h,

which carries a phenyl side chain, was likewise expected to

adopt a 100% trans amide conformation and, indeed, only

a single conformer was observed in the NMR spectrum of

8h in CDCl₃at room temp., but overlap in the aromatic

region of the NOESY spectra unfortunately did not allow

as many correlations to be identified as in the case of 8i

(see Figure 2 and the Supporting Information). The absence

of correlations between the methyl group of the N-capping

group and the benzylic or aromatic protons of the arylo-

peptoid residue did, however, still indicate the presence of

the expected 100% trans amide conformation. NMR spec-

tra of model monomer 8b of the isopropyl series revealed

the presence of two conformers in ca. 80:20 ratio in CDCl₃

at room temp. (see the Supporting Information). Overlap in

The spe-series of ortho-arylopeptoids was found to follow

the same pattern as the rest of the ortho-arylopeptoid fam-

ily; monomer 9g produced simple NMR spectra with sharp

signals, whereas increased complexity was observed for tri-

mer 10g and highly complex spectra were obtained in the

case of hexamer 6g (see the Supporting Information). We

are currently studying these spe-series ortho-arylopeptoids

by means of circular dichroism spectroscopy.

Conclusions

Examples of “one-way sequence” aromatic oligoamides

the aromatic region of the NOESY spectra unfortunately constructed of aromatic amino acids that are connected

hindered the extraction of any additional information. through ortho-linked aromatics are very rare. Herein, we

However, in general, we observed the following: (1) the have presented the first synthesis and studies of ortho-arylo-

highly bulky tert-butyl side chain was shown to invoke a peptoids as an entirely new type of aromatic oligoamides

100% cis conformation; (2) dimer 3b, with the least hin- with an ortho-connection pattern in the backbone. These

dered ethyl side chain, existed as a ca. 50:50 mixture of cis oligoamides may be synthesized both in solution and on

and trans amides (see the Supporting Information); (3) in solid-phase by using unique and highly efficient submon-

the NMR spectra of model monomer 8b as well as dimer omer methods wherein the residues are created directly on

3b, which both carry the moderately bulky isopropyl side the growing chain in an iterative manner. Only commer-

chain, we observed the existence of mixtures of two con- cially available reagents are needed and our methods allow

formers in ca. 80:20 ratio (see the Supporting Information). the synthesis of target arylopeptoids on a gram scale as well

In cases with simple alkyl side chains, these observations as synthesis of highly diversified libraries. The methods we

suggest that increasing bulk of the side chain resulted in an have used are reminiscent of those we have previously devel-

increasing proportion of cis-amide conformation, and the oped for meta- and para-arylopeptoids, although the ortho-

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3581

T. Hjelmgaard, J. Nielsen

FULL PAPER

shifts are referenced to the residual solvent peak and J values are

given in Hz. The following multiplicity abbreviations are used: sing-

let (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad

(br). Where applicable, assignments were based on COSY, HMBC,

HSQC and J-mod experiments. TLC analyses were performed on

Merck TLC aluminum sheets (silica gel 60, F₂₅₄). Progress of reac-

tions was, when applicable, followed by HPLC, NMR and/or TLC.

Visualizing spots on TLC was effected with UV-light and/or nin-

hydrin in EtOH/AcOH. Flash chromatography was performed with

silica gel 60 (35–75 μm), purchased from Fluka. Unless otherwise

arylopeptoids show a slightly different reaction pattern. Ex-

ceptions include longer reaction times in the acylations of

ortho-arylopeptoids carrying the highly bulky tert-butyl side

chain as well as a necessitated change from the 2-chloro-

trityl chloride linker to the Rink acid linker in the solid-

phase synthesis of ortho-arylopeptoids with a free acid at

the C-terminus. The latter change reduced the synthetic

scope in some cases, in particular when synthesizing ortho-

arylopeptoids with small side chains. In general, however,

it was shown that the efficiency of the chain growth process stated, flash chromatography was performed in the eluent system

for which the R_fvalues are given. HRMS were recorded with a

Micromass LCT apparatus equipped with an AP-ESI probe cal-

ibrated with Leu-Enkephalin.

in ortho-arylopeptoids was similar to that of the corre-

sponding meta- and para-arylopeptoids. The ortho-arylo-

peptoids were studied by NMR spectroscopy and were

shown to display different length-dependent trends to those

of their meta- and para-counterparts; whereas the NMR

spectra of shorter oligomers showed sharp signals, longer

oligomers produced highly complex NMR spectra. These

observations indicate that there is more restricted rotation

about the amide bonds in ortho-arylopeptoids, presumably

due to a more congested backbone structure resulting from

the ortho-connectivity pattern. Model studies showed that

the tert-butyl and phenyl side chains offer a rarely seen

complete control over the amide conformations; (short) or-

tho-arylopeptoids with tert-butyl side chains adopt a 100%

cis conformation, whereas the presence of a phenyl side

chain resulted in the complete opposite 100% trans amide

conformation. We furthermore found that the tert-butyl

side chain can be used both for invoking a 100% cis confor-

mation in arylopeptoids and to serve as a protecting group

during synthesis, which can later be removed to allow the

amide(s) to adopt a 100% trans amide conformation in-

stead.

Solution-Phase Synthesis

Method A. General Procedure for Synthesis of the First Arylopeptoid

Residue: To a solution of 1^[18](1.0 equiv., 0.2 m in THF) at 0 °C

under N₂was added Et₃N (2.0 equiv.) and then the chosen primary

amine (10.0 equiv., either neat or as a 2 m solution in THF). After

stirring overnight at room temp., the resulting mixture was concen-

trated under reduced pressure. The residue was taken up in EtOAc

and washed with satd. aq. NaHCO₃(1ϫ) and brine (1ϫ). The com-

bined aqueous layers were extracted with EtOAc (1ϫ) and the com-

bined organic layers were dried with Na₂SO₄, filtered, and concen-

trated under reduced pressure. Flash chromatography of the residue

yielded the desired product.

Method B. General Procedure for Synthesis of Arylopeptoid Resi-

dues (except for tert-butyl side chain): To a solution of the second-

ary amine (1.0 equiv., 0.2 m in THF) at 0 °C under N₂was added

Et₃N (1.05 equiv.) and then 2-(bromomethyl)benzoyl bromide

(1.05 equiv.). After stirring for 1 h at 0 °C, Et₃N (2.0 equiv.) and

then the chosen primary amine (10.0 equiv., either neat or as a 2 M

solution in THF) were added. After stirring overnight at room

temp., the resulting mixture was concentrated under reduced pres-

sure. The residue was taken up in EtOAc (dimers) or CH₂Cl₂(tri-

mers) and washed with satd. aq. NaHCO₃(1ϫ) and brine (1ϫ).

The combined aqueous layers were extracted with EtOAc (dimers,

1ϫ) or CH₂Cl₂(trimers, 1ϫ) and the combined organic layers were

dried with Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Flash chromatography of the residue gave the desired product.

The development of ortho-arylopeptoids presented

herein greatly increases the possible scope for design and

diversity in the field of arylopeptoids. We will continue to

study and explore all aspects of this intriguing family of

aromatic oligoamides and will report our findings in due

course.

Method C. General Procedure for Synthesis of Arylopeptoid Resi-

dues with tert-Butyl Side Chain: To a solution of the secondary

amine (1.0 equiv., 0.2 m in THF) at 0 °C under N₂was added Et₃N

(2.0 equiv.) and then 2-(bromomethyl)benzoyl bromide (2.0 equiv.).

After stirring for 1 h at 0 °C, the resulting mixture was concen-

trated under reduced pressure. The residue was taken up in CH₂Cl₂

and washed with satd. aq. NaHCO₃/brine, 1:1 (1ϫ). The aqueous

layer was extracted with CH₂Cl₂(1ϫ) and the combined organic

layers were dried with Na₂SO₄, filtered, and concentrated under

reduced pressure. The residue was passed through a short silica gel

column to give the sufficiently pure acylated intermediate. To a

solution of the acylated intermediate (1.0 equiv., 0.2 m in THF) at

0 °C under N₂was added Et₃N (2.0 equiv.) and then tert-

butylamine (10.0 equiv.). After stirring overnight at room temp.,

the resulting mixture was concentrated under reduced pressure. The

residue was taken up in CH₂Cl₂and washed with satd. aq.

NaHCO₃(1ϫ) and brine (1ϫ). The combined aqueous layers were

extracted with CH₂Cl₂(1ϫ) and the combined organic layers were

dried with Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Flash chromatography of the residue gave the desired product.

Experimental Section

General Methods: CH₂Cl₂, Et₃N and THF used in reactions were

dried with 4 Å molecular sieves. Technical grade 2-(bromomethyl)-

benzoyl bromide obtained from Matrix Scientific was distilled un-

der reduced pressure before use. All other chemicals obtained from

commercial sources (Alfa Aesar, Fluka, Merck and Sigma–Aldrich)

were used as received. Rink amide copoly(styrene-1% DVB) resin

(100–200 mesh) with a listed loading of 0.74 mmol/g, Rink acid

copoly(styrene-1% DVB) resin (100–200 mesh) with a listed load-

ing of 0.55 mmol/g, and HMPB-MBHA copoly(styrene-1% DVB)

resin (100–200 mesh) with a listed loading of 0.71 mmol/g were

purchased from Merck. Primary amines (2.0 or 4.0 m in DMSO)

used in the substitution steps during solid-phase synthesis were pre-

pared from the neat, free amines, except in the case of ethylamine

for which a saturated aqueous solution was used as a source of the

amine. Melting points were determined with a Mettler Toledo

MP70 melting point system and are referenced to the melting

points of benzophenone and benzoic acid. NMR spectra were re-

corded with a Bruker Avance 300 MHz spectrometer. Chemical

tert-Butyl 2-[(Ethylamino)methyl]benzoate (2a): Treatment of 1^[18]

(543 mg, 2.00 mmol) by Method A with ethylamine (2 m) in THF

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Synthesis and Study of ortho-Arylopeptoids

yielded 2a (290 mg, 62%, Ͼ99% purity) as a pale-yellowish oil. R_f

129.7, 129.7, 129.2, 129.2, 128.9, 128.8, 128.8, 128.2, 127.8, 127.6,

(EtOAc/MeOH, 95:5) = 0.08. ¹H NMR (300 MHz, CDCl₃): δ = 127.2, 127.1, 127.0, 127.0, 126.9, 126.8, 126.7, 126.6, 126.3, 126.2,

7.82–7.77 (m, 1 H, o-C₆H₄COO), 7.46–7.37 (m, 2 H, p-C₆H₄COO

and mЈ-C₆H₄COO), 7.31–7.25 (m, 1 H, m-C₆H₄COO), 3.97 (s, 2 H,

HNCH₂Ar), 2.66 (q, J = 7.1 Hz, 2 H, HNCH₂CH₃), 1.89–1.82 (br.

126.0, 125.7, 125.7, 125.4, 125.3, 125.2, 125.2 (12CH), 131.3, 131.2,

130.3 (C_q), 81.6, 81.5, 81.5, 81.4 (C_q), 51.7, 51.6, 51.5, 51.5 (CH₂,

HNCH₂Ar), 49.8, 49.7, 48.8, 48.8, 44.9, 44.1 (2ϫ CH₂, 2ϫ CON-

s, 1 H, NH), 1.60 (s, 9 H, OtBu), 1.12 (t, J = 7.1 Hz, 3 H, CH₂Ar), 43.7, 43.0, 42.8, 40.2, 40.1, 40.0, 39.7 (3ϫ CH₂,

HNCH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 167.2 (C_q, HNCH₂CH₃and 2ϫ CONCH₂CH₃), 28.2, 28.1 (3ϫ CH₃), 15.2,

COO), 141.0 (C_q, oЈ-C₆H₄COO), 131.9 (C_q, ipso-C₆H₄COO), 131.3 13.7, 13.5, 13.4, 12.4, 12.2, 12.0, 12.0 (3CH₃) ppm. HRMS (TOF

(CH, p-C₆H₄COO), 130.6 (CH, mЈ-C₆H₄COO), 130.4 (CH, o- MS, ES⁺): m/z calcd. for C₃₄H₄₄N₃O₄[M + H]⁺558.3326; found

C₆H₄COO), 126.8 (CH, m-C₆H₄COO), 81.4 (C_q, OtBu), 52.5 (CH₂,

HNCH₂Ar), 43.5 (CH₂, HNCH₂CH₃), 28.2 (3ϫ CH₃, OtBu), 15.3

(CH₃, HNCH₂CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₁₃H₂₀NO₂[M + H]⁺236.1645; found 236.1647.

558.3327.

tert-Butyl 2-[(Propan-2-ylamino)methyl]benzoate (2b): Treatment of

1^[18](543 mg, 2.00 mmol) by Method A with isopropylamine

yielded 2b (441 mg, 88%, Ͼ99% purity) as a pale-yellowish oil. R_f

(EtOAc/MeOH, 95:5) = 0.19. ¹H NMR (300 MHz, CDCl₃): δ =

7.78 (d, J = 7.78 Hz, 1 H, o-C₆H₄COO), 7.46–7.36 (m, 2 H, p-

C₆H₄COO and mЈ-C₆H₄COO), 7.32–7.23 (m, 1 H, m-C₆H₄COO),

3.97 (s, 2 H, HNCH₂Ar), 2.88–2.74 [m, 1 H, HNCH(CH₃)₂], 1.97–

1.86 (br. s, 1 H, NH), 1.60 (s, 9 H, OtBu), 1.09 [d, J = 6.2 Hz, 6

H, HNCH(CH₃)₂] ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 167.2

(C_q, COO), 141.2 (C_q, oЈ-C₆H₄COO), 132.0 (C_q, ipso-C₆H₄COO),

131.4 (CH, p-C₆H₄COO), 130.6 (CH, mЈ-C₆H₄COO), 130.3 (CH,

o-C₆H₄COO), 126.7 (CH, m-C₆H₄COO), 81.3 (C_q, OtBu), 50.0

(CH₂, HNCH₂Ar), 47.7 [CH, HNCH(CH₃)₂], 28.2 (3ϫ CH₃,

OtBu), 22.9 [2ϫ CH₃, HNCH(CH₃)₂] ppm. HRMS (TOF MS,

ES⁺): m/z calcd. for C₁₅H₂₄NO₂[M + H]⁺250.1802; found

250.1797.

Also isolated was 2-ethyl-2,3-dihydro-1H-isoindol-1-one (84 mg,

26%) as a pale-yellowish solid; m.p. 40–43 °C. R_f(EtOAc/MeOH,

95:5) = 0.58. ¹H NMR (300 MHz, CDCl₃): δ = 7.83–7.79 (m, 1 H),

7.53–7.38 (m, 3 H), 4.35 (s, 2 H), 3.65 (q, J = 7.3 Hz, 2 H), 1.25

(t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 168.1

(C_q), 141.0 (C_q), 133.0 (C_q), 131.0 (CH), 127.9 (CH), 123.5 (CH),

122.6 (CH), 49.2 (CH₂), 36.9 (CH₂), 13.5 (CH₃) ppm. HRMS (TOF

MS, ES⁺): m/z calcd. for C₁₀H₁₂NO [M + H]⁺162.0913; found

162.0910.

Arylopeptoid Dimer 3a: Treatment of 2a (236 mg, 1.00 mmol) by

Method B with ethylamine (2 m) in THF yielded 3a (323 mg, 81%,

Ͼ99% purity) as a pale-yellowish oil. R_f(EtOAc/MeOH, 80:20) =

1

0.21. H NMR (300 MHz, CDCl₃): δ = 7.86 (m, J = 7.8, 1.2 Hz,

0.49 H, o-C₆H₄COO, minor isomer), 7.83 (dd, J = 7.8, 1.3 Hz, 0.51

H, o-C₆H₄COO, major isomer), 7.57–7.19 (m, 6 H), 7.09–7.04 (m,

1 H), 5.19 (s, 1.02 H, CONCH₂Ar, major isomer), 4.74 (s, 0.98 H,

CONCH₂Ar, minor isomer), 3.80–3.10 (br., 0.98 H, CONCH₂CH₃,

minor isomer), 3.78, 3.76 (2ϫ s, 2 H, HNCH₂Ar), 3.15 (q, J =

7.1 Hz, 1.02 H, CONCH₂CH₃, major isomer), 2.70–2.60 (m, 2 H,

HNCH₂CH₃), 2.11–2.04 (br. s, 1 H, NH), 1.59 (s, 4.59 H, OtBu,

major isomer), 1.48 (s, 4.41 H, OtBu, minor isomer), 1.25 (t, J =

7.1 Hz, 1.47 H, CONCH₂CH₃, minor isomer), 1.11, 1.08 (2ϫ t, J

= 7.1 and 7.1 Hz, 3 H, HNCH₂CH₃), 1.02 (t, J = 7.1 Hz, 1.53 H,

CONCH₂CH₃, major isomer) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 171.7, 171.6 (C_q, CON), 166.6, 165.9 (C_q, COO), 138.6, 138.6

(C_q, oЈ-C₆H₄COO), 137.0, 136.9, 136.5, 136.0 (2ϫ C_q, ipso-

C₆H₄CON and oЈ-C₆H₄CON), 131.9, 131.7 (CH), 131.1, 130.4 (C_q,

ipso-C₆H₄COO), 130.9, 130.5, 129.9, 129.8, 128.8, 128.8, 127.7,

126.8, 126.8, 126.7, 126.6, 126.6, 125.7, 125.1 (7CH), 81.5, 81.4 (C_q,

OtBu), 51.7, 51.5 (CH₂, HNCH₂Ar), 50.0 (0.49ϫ CH₂, CON-

CH₂Ar, minor isomer), 44.6 (0.51ϫCH₂, CONCH₂Ar, major iso-

mer), 43.7, 43.6, 43.4 (1.51ϫ CH₂, HNCH₂CH₃and

CONCH₂CH₃, major isomer), 40.0 (0.49ϫ CH₂, CONCH₂CH₃,

minor isomer), 28.1, 28.0 (3ϫ CH₃, OtBu), 15.1 (2ϫ CH₃,

HNCH₂CH₃), 13.6 (0.51ϫ 2CH₃, CONCH₂CH₃), 12.0 (0.49ϫ

2CH₃, CONCH₂CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₂₄H₃₃N₂O₃[M + H]⁺397.2486; found 397.2479.

Arylopeptoid Dimer 3b: Treatment of 2b (374 mg, 1.50 mmol) by

Method B with isopropylamine yielded 3b (550 mg, 86%, Ͼ99%

purity) as a pale-yellowish oil. R_f(EtOAc/MeOH, 90:10) = 0.19.

¹H NMR (300 MHz, CDCl₃): δ = 7.89 (dd, J = 7.8, 1.2 Hz, 0.78

H, o-C₆H₄COO, major isomer), 7.75 (dd, J = 7.8, 1.2 Hz, 0.22 H,

o-C₆H₄COO, minor isomer), 7.60–7.15, 7.06–6.95 (2ϫ m, 7 H),

5.18 (d, J = 17.2 Hz, 0.78 H, CONCHHAr, major isomer), 5.04 (d,

J = 17.2 Hz, 0.78 H, CONCHHAr, major isomer), 4.80–4.57 [m,

0.66 H, CONCH(CH₃)₂, minor isomer and CONCH₂Ar, minor

isomer], 4.05–3.90 [m, 0.78 H, CONCH(CH₃)₂, major isomer], 3.81

(s, 1.56 H, HNCH₂Ar, major isomer), 3.71 (s, 0.44 H, HNCH₂Ar,

minor isomer), 2.92–2.77 [m, 1 H, HNCH(CH₃)₂], 1.61 (s, 7.02 H,

OtBu, major isomer), 1.49 (s, 1.98 H, OtBu, minor isomer), 1.33–

1.22, 1.13–1.01 [2ϫ m, 12 H, HNCH(CH₃)₂, CONCH-

(CH₃)₂] ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 172.5 (0.22ϫ C_q,

CON, minor isomer), 171.6 (0.78ϫ C_q, CON, major isomer), 166.7

(0.78ϫ C_q, COO, major isomer), 166.0 (0.22ϫ C_q, COO, minor

isomer), 140.2 (C_q, oЈ-C₆H₄COO), 137.4, 136.9, 136.8, 136.7 (2ϫ

C_q, ipso-C₆H₄CON, oЈ-C₆H₄CON), 131.5, 131.3, 130.0, 129.5,

128.8, 128.6, 127.4, 126.9, 126.8, 126.6, 126.5, 126.2, 125.4, 125.1

(7ϫ CH), 130.6 (0.22ϫ CH, o-C₆H₄COO, minor isomer), 130.6

(0.78ϫ CH, o-C₆H₄COO, major isomer), 129.9 (0.78ϫ C_q, ipso-

C₆H₄COO, major isomer), 129.8 (0.22ϫ C_q, ipso-C₆H₄COO,

minor isomer), 81.4 (0.22ϫ C_q, OtBu, minor isomer), 81.3 (0.78ϫ

C_q, OtBu, major isomer), 50.6 [0.78ϫ CH, CONCH(CH₃)₂, major

isomer], 49.6 (0.78ϫ CH₂, HNCH₂Ar, major isomer), 49.1 (0.22ϫ

Arylopeptoid Dimer 4a: Treatment of 3a (238 mg, 0.60 mmol) by

Method B with ethylamine (2 m) in THF yielded 4a (285 mg, 85%,

Ͼ99% purity) as a pale-yellowish oil. R_f(EtOAc/MeOH, 70:30) = CH₂, HNCH₂Ar, minor isomer), 48.5 [0.78ϫ CH, HNCH(CH₃)₂,

1

0.24. H NMR (300 MHz, CDCl₃): δ = 7.91–7.78 (m, 1 H), 7.63–

6.98 (m, 11 H), 5.28–4.20 (m, 4 H, 2ϫCONCH₂Ar), 4.05–3.02 (m,

6

major isomer], 48.1 [0.22ϫ CH, HNCH(CH₃)₂, minor isomer],

47.4 [0.22ϫ CH, CONCH(CH₃)₂, minor isomer], 47.3 (0.22ϫ

CH₂, CONCH₂Ar, minor isomer), 41.6 (0.78ϫ CH₂, CONCH₂Ar,

H, HNCH₂Ar and CONCH₂CH₃), 2.70–2.58 (m, 2 H,

HNCH₂CH₃), 1.90–1.70 (br. s, 1 H, NH), 1.60, 1.58, 1.50 (3ϫ s, 9 major isomer), 28.2 (0.78ϫ 3CH₃, OtBu, major isomer), 28.1

H), 1.32–0.92 (m, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = (0.22ϫ 3CH₃, OtBu, minor isomer), 22.9 [0.22ϫ 2CH₃,

171.7, 171.6, 171.6, 171.5, 171.1, 171.0, 170.4, 170.3 (2C_q), 166.6,

166.5, 165.9, 165.7 (C_q), 138.5, 138.4, 138.3, 138.3, 137.1, 137.0,

136.9, 136.3, 136.3, 136.2, 136.1, 136.0, 135.1, 134.9, 134.5, 134.2,

133.8 (5C_q), 131.9, 131.9, 131.8, 131.6, 131.0, 130.7, 130.6, 129.8,

HNCH(CH₃)₂, minor isomer], 22.8 [0.78ϫ 2CH₃, HNCH(CH₃)₂,

major isomer], 21.4, 20.9, 20.1 [2ϫ CH₃, CONCH(CH₃)₂] ppm.

HRMS (TOF MS, ES⁺): m/z calcd. for C₂₆H₃₇N₂O₃[M + H]⁺

425.2799; found 425.2799.

Eur. J. Org. Chem. 2013, 3574–3589

www.eurjoc.org

3583

T. Hjelmgaard, J. Nielsen

FULL PAPER

Arylopeptoid Trimer 4b: Treatment of 3b (446 mg, 1.05 mmol) by

Method B with isopropylamine yielded 4b (530 mg, 84%, 97% pu-

rity) as a colorless solid. R_f(EtOAc/MeOH, 80:20) = 0.23; m.p.

52–55 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.94–7.74 (m, 1 H),

7.68–6.98 (br. m, 11 H), 5.30–3.64 [m, 8 H, 2ϫ CONCH₂Ar, 2ϫ

purity) as a colorless solid. Acylated intermediate: R_f(heptane/

EtOAc, 75:25) = 0.28. Data for 4c: R_f(EtOAc/MeOH, 90:10) =

0.15; m.p. 70–73 °C. H NMR (300 MHz, CDCl₃): δ = 7.78 (d, J

= 7.5 Hz, 1 H), 7.59–7.42 (m, 4 H), 7.35–7.19 (m, 3 H), 7.10–6.95

(m, 4 H), 5.10–4.00 (br. s, 4 H, 2ϫ CONCH₂Ar), 3.71 (s, 2 H,

1

CONCH(CH₃)₂, HNCH₂Ar], 3.00–2.72 [m, 1 H, HNCH(CH₃)₂], HNCH₂Ar), 1.56 (s, 9 H), 1.51 (s, 9 H), 1.41 (s, 9 H), 1.18 (s, 9

2.20–1.94 (br. s, 1 H, NH), 1.62, 1.61, 1.59, 1.50 (4ϫ s, 9 H), 1.38–

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 173.5 (C_q), 172.0 (C_q),

0.90 (br. m, 18 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 172.5, 165.7 (C_q), 141.5 (C_q), 138.2 (C_q), 136.8 (C_q), 136.2 (C_q), 135.7

172.2, 171.8, 171.8, 171.5, 170.6 (2ϫ C_q), 166.8, 166.6, 166.1 (C_q), (C_q), 131.4 (CH), 130.9 (CH), 129.9 (CH), 129.1 (C_q), 128.8 (CH),

140.4, 140.3, 140.1, 140.0, 137.6, 137.0, 136.9, 136.8, 136.2, 135.8,

135.5, 135.3, 135.2, 134.8 (5ϫ C_q), 131.6, 131.6, 131.4, 130.8, 130.7,

130.4, 130.3, 129.9, 129.8, 129.0, 128.9, 128.8, 128.7, 127.7, 127.4,

127.2, 127.0, 126.8, 126.7, 126.6, 126.5, 126.4, 126.3, 125.6, 125.6,

125.5, 125.4, 125.2, 125.1 (12ϫ CH), 130.1, 130.0 (C_q), 81.7, 81.4

(C_q), 51.1, 50.8, 50.6, 48.9, 48.6, 48.3, 48.0, 47.8, 47.7 [3ϫ CH, 2ϫ

CONCH(CH₃)₂and HNCH(CH₃)₂], 49.6, 49.5, 49.2, 47.3, 47.2,

41.8, 41.7, 41.4, 41.1, 40.6 (3ϫ CH₂, HNCH₂Ar and 2ϫ CON-

CH₂Ar), 28.3, 28.2 (3ϫ CH₃), 22.8, 22.7, 21.8, 21.3, 21.1, 20.9,

20.7, 20.3, 20.3 (6ϫ CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd.

for C₃₇H₅₀N₃O₄[M + H]⁺600.3796; found 600.3805.

128.2 (CH), 127.0 (CH), 126.7 (CH), 126.6 (CH), 126.5 (CH), 126.3

(CH), 124.4 (CH), 124.1 (CH), 81.2 (C_q), 58.3 (C_q), 58.2 (C_q), 50.8

(C_q), 48.9 (CH₂, CONCH₂Ar), 48.6 (CH₂, CONCH₂Ar), 44.6

(CH₂, HNCH₂Ar), 29.1 [3ϫ CH₃, HNC(CH₃)₃], 28.7 [3ϫ CH₃,

CONC(CH₃)₃], 28.5 [3ϫ CH₃, CONC(CH₃)₃], 28.1 (3ϫ

CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for C₄₀H₅₆N₃O₄[M

+ H]⁺642.4265; found 642.4265.

Chloromethyl Intermediate 5: To

a solution of 2b (100 mg,

0.42 mmol) in THF (2.0 mL) at 0 °C under N₂was added Et₃N

(0.059 mL, 0.42 mmol) and then 2-(chloromethyl)benzoyl chloride

(79 mg, 0.42 mmol). After stirring for 1 h at 0 °C, the resulting mix-

ture was concentrated under reduced pressure at room temp. The

residue was taken up in EtOAc (10 mL) and the mixture was

washed with satd. aq. NaHCO₃(5 mL) and brine (5 mL). The com-

bined aqueous layers were extracted with EtOAc (5 mL) and the

combined organic layers were dried with Na₂SO₄, filtered and con-

centrated under reduced pressure. Flash chromatography of the res-

idue gave 5 (150 mg, 93%, Ͼ99% purity) as a colorless oil. R_f

tert-Butyl 2-[(tert-Butylamino)methyl]benzoate (2c): Treatment of

1^[18](488 mg, 1.80 mmol) by Method A with tert-butylamine

yielded 2c (420 mg, 89%, Ͼ99% purity) as a pale-yellowish oil. R_f

(EtOAc/MeOH, 95:5) = 0.15. ¹H NMR (300 MHz, CDCl₃): δ =

7.73 (dd, J = 7.7, 1.4 Hz, 1 H, o-C₆H₄COO), 7.47 (dd, J = 7.7,

1.4 Hz, 1 H, mЈ-C₆H₄COO), 7.41 (ddd, J = 7.7, 7.7, 1.4 Hz, 1 H,

p-C₆H₄COO), 7.25 (ddd, J = 7.7, 7.7, 1.4 Hz, 1 H, m-C₆H₄COO),

3.91 (s, 2 H, HNCH₂Ar), 1.69–1.62 (br. s, 1 H, NH), 1.60 (s, 9 H,

OtBu), 1.18 [s, 9 H, HNC(CH₃)₃] ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 167.3 (C_q, COO), 142.1 (C_q, oЈ-C₆H₄COO), 132.1 (C_q,

ipso-C₆H₄COO), 131.5 (CH, p-C₆H₄COO), 130.4 (CH, mЈ-

C₆H₄COO), 129.9 (CH, o-C₆H₄COO), 126.5 (CH, m-C₆H₄COO),

81.1 (C_q, OtBu), 50.7 [C_q, HNC(CH₃)₃], 45.6 (CH₂, HNCH₂Ar),

29.1 [3ϫ CH₃, HNC(CH₃)₃], 28.2 (3ϫ CH₃, OtBu) ppm. HRMS

(TOF MS, ES⁺): m/z calcd. for C₁₆H₂₆NO₂[M + H]⁺264.1958;

found 264.1959.

1

(heptane/EtOAc, 75:25) = 0.30. H NMR (300 MHz, CDCl₃): δ =

7.91 (dd, J = 7.8, 1.3 Hz, 0.79 H, o-C₆H₄COO, major isomer), 7.78

(dd, J = 7.8, 1.2 Hz, 0.21 H, o-C₆H₄COO, minor isomer), 7.64–

7.20 (m, 6.58 H), 7.09–7.01 (m, 0.42 H), 5.13 (s, 1.58 H, CON-

CH₂Ar, major isomer), 4.93 (d, J = 11.2 Hz, 0.79 H, ClCHHAr,

major isomer), 4.80–4.52 [m, 1.84 H, ClCH₂Ar, minor isomer,

CONCH₂Ar, minor isomer and CONCH(CH₃)₂, minor isomer and

ClCHHAr, major isomer], 4.10–3.94 [m, 0.79 H, CONCH(CH₃)₂,

major isomer], 1.63 (s, 7.11 H, OtBu, major isomer), 1.49 (s, 1.89

H, OtBu, minor isomer), 1.38–1.26 [m, 1.26 H, CONCH(CH₃)₂,

minor isomer], 1.20–1.05 [m, 4.74 H, CONCH(CH₃)₂, major iso-

mer] ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 171.4 (0.21ϫ C_q,

CON, minor isomer), 170.4 (0.79ϫ C_q, CON, major isomer), 166.7

(0.79ϫ C_q, COO, major isomer), 166.3 (0.21ϫ C_q, COO, minor

isomer), 140.0 (0.21ϫ C_q, oЈ-C₆H₄COO, major isomer), 139.6

(0.79ϫ C_q, oЈ-C₆H₄COO, minor isomer), 137.2, 134.7, 133.8 (2ϫ

C_q, ipso-C₆H₄CON and oЈ-C₆H₄CON), 131.6, 131.2, 130.9, 130.3,

129.3, 129.1, 128.3, 128.1, 127.3, 126.9, 126.7, 126.2, 125.8, 125.0

(7ϫ CH), 130.7 (CH, o-C₆H₄COO), 130.4 (0.21ϫ C_q, ipso-

C₆H₄COO, minor isomer), 129.9 (0.79ϫ C_q, ipso-C₆H₄COO, major

isomer), 81.7 (0.21ϫ C_q, OtBu, minor isomer), 81.3 (0.79ϫ C_q,

OtBu, major isomer), 50.7 [0.79ϫ CH, CONCH(CH₃)₂, major iso-

mer], 48.2 (0.21ϫ CH₂, CONCH₂Ar, minor isomer), 48.1 [0.21ϫ

CH, CONCH(CH₃)₂, minor isomer], 43.4 (0.21ϫ CH₂, ClCH₂Ar,

minor isomer), 43.3 (0.79ϫ CH₂, ClCH₂Ar, major isomer), 42.0

(0.79ϫ CH₂, CONCH₂Ar, major isomer), 28.3 (0.79ϫ 3CH₃,

OtBu, major isomer), 28.1 (0.21ϫ 3CH₃, OtBu, minor isomer),

21.2, 20.9 [0.79ϫ 2CH₃, CONCH(CH₃)₂, major isomer], 20.1

[0.21ϫ 2CH₃, CONCH(CH₃)₂, minor isomer] ppm. HRMS (TOF

MS, ES⁺): m/z calcd. for C₂₃H₂₉ClNO₃[M + H]⁺402.1830; found

402.1829.

Arylopeptoid Dimer 3c: Treatment of 2c (369 mg, 1.40 mmol) by

Method C with tert-butylamine yielded 3c (541 mg, 85%, Ͼ99%

purity) as a pale-yellowish oil. Acylated intermediate: R_f(heptane/

EtOAc, 75:25) = 0.41. Data for 3c: R_f(EtOAc/MeOH, 90:10) =

1

0.21. H NMR (300 MHz, CDCl₃): δ = 7.77 (dd, J = 7.7, 1.4 Hz,

1 H, o-C₆H₄COO), 7.68 (d, J = 7.7 Hz, 1 H, mЈ-C₆H₄COO), 7.53

(ddd, J = 7.7, 7.7, 1.4 Hz, 1 H, p-C₆H₄COO), 7.40 (d, J = 7.7 Hz,

1 H, mЈ-C₆H₄CON), 7.26 (ddd, J = 7.7, 7.7, 1.4 Hz, 1 H, m-

C₆H₄COO), 7.16 (ddd, J = 7.7, 7.7, 1.4 Hz, 1 H, p-C₆H₄CON),

7.01 (dd, J = 7.7, 1.4 Hz, 1 H, o-C₆H₄CON), 6.94 (ddd, J = 7.7,

7.7, 1.4 Hz,

1

H, m-C₆H₄CON), 5.22–4.88 (br. s,

1 H,

CONCHHAr), 4.88–4.48 (br. s, 1 H, CONCHHAr), 3.82–3.52

(br. s, 2 H, HNCH₂Ar), 1.54 [s, 9 H, CONC(CH₃)₃], 1.49 (s, 9 H,

OtBu), 1.18 [s, 9 H, HNC(CH₃)₃] ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 173.4 (C_q, CON), 166.0 (C_q, COO), 141.6 (C_q, oЈ-

C₆H₄COO), 138.4 (C_q, ipso-C₆H₄CON), 137.1 (C_q, oЈ-C₆H₄CON),

131.3 (CH, p-C₆H₄COO), 130.7 (CH, o-C₆H₄COO), 129.8 (CH,

mЈ-C₆H₄CON), 129.2 (C_q, ipso-C₆H₄COO), 128.4 (CH, p-

C₆H₄CON), 127.2 (CH, mЈ-C₆H₄COO), 126.4 (CH, m-C₆H₄COO),

126.2 (CH, m-C₆H₄CON), 124.2 (CH, o-C₆H₄CON), 81.3 (C_q,

OtBu), 58.1 [C_q, CONC(CH₃)₃], 50.7 [C_q, HNC(CH₃)₃], 49.5 (CH₂,

CONCH₂Ar), 44.7 (CH₂, HNCH₂Ar), 29.1 [3ϫ CH₃, HNC-

(CH₃)₃], 28.5 [3ϫ CH₃, CONC(CH₃)₃], 28.1 (3ϫ CH₃, OtBu) ppm.

HRMS (TOF MS, ES⁺): m/z calcd. for C₂₈H₄₁N₂O₃[M + H]⁺

453.3112; found 453.3107.

Solid-phase Synthesis

General Procedure for Attachment to Rink Amide Resin: Rink

amide resin (162 mg, 0.74 mmolg^–1; thus 0.120 mmol) was washed

with CH₂Cl₂(2ϫ 2 mL) and NMP (5ϫ 2 mL). Piperidine/NMP,

Arylopeptoid Trimer 4c: Treatment of 3c (408 mg, 0.90 mmol) by

Method C with tert-butylamine yielded 4c (449 mg, 78%, Ͼ99%

3584

www.eurjoc.org

Eur. J. Org. Chem. 2013, 3574–3589

Synthesis and Study of ortho-Arylopeptoids

1:4 (1.0 mL) was added and the resin was agitated for 2 min and

drained. Further piperidine/NMP, 1:4 (1.0 mL) was added and the

resin was agitated for 15 min, drained and washed with NMP (3ϫ

2 mL) and CH₂Cl₂(3ϫ 2 mL). To a solution of 2-(chloromethyl)

benzoyl chloride (71 mg, 0.38 mmol) in CH₂Cl₂(0.76 mL) at room

temp. was added DIPEA (0.132 mL, 0.76 mmol). The mixture was

added to the resin and the resulting mixture was agitated for 20 min

at room temp. The resin was drained and washed with CH₂Cl₂(3ϫ

2 mL) and DMSO (3ϫ 2 mL).

General Procedure for Cleavage from Rink Amide Resin: The resin

was cleaved in TFA/water, 95:5 (2 mL) with agitation for 2 h (2ϫ

10 min for 7g). The resin was drained and washed with TFA (2 mL)

and CH₂Cl₂(5ϫ 2 mL). The solvents were evaporated under re-

duced pressure and the residue was evaporated with CH₂Cl₂(3ϫ

5 mL) giving the crude product, which was purified by preparative

HPLC (see the Supporting Information for details).

General Procedure for Cleavage from Rink Acid Resin: The resin

was cleaved in HFIP/CH₂Cl₂, 1:4 (2 mL) with agitation for 1 h. The

resin was drained and washed with CH₂Cl₂(5ϫ 2 mL). The sol-

vents were evaporated under reduced pressure and the residue was

evaporated with CH₂Cl₂(3ϫ 5 mL), giving the crude product,

which was purified by preparative HPLC (see the Supporting Infor-

mation for details).

General Procedure for Attachment to Rink Acid Resin: Rink acid

resin (218 mg, 0.55 mmolg^–1; thus 0.120 mmol) was washed with

CH₂Cl₂(2ϫ 2 mL). The resin was swelled in CH₂Cl₂(2 mL) for

5 min and drained. To a solution of DMAP (45.6 mg, 0.38 mmol)

in CH₂Cl₂(0.76 mL) at room temp. was added 2-(chloromethyl)-

benzoyl chloride (71 mg, 0.38 mmol) and then DIPEA (0.132 mL,

0.76 mmol). The mixture was added to the resin and the resulting

mixture was agitated for 20 min at room temp. The resin was

drained and washed with CH₂Cl₂(3ϫ 2 mL) and DMSO (3ϫ

2 mL).

Arylopeptoid Hexamer 6b: Synthesized on Rink acid resin using

Method D, performing the substitution steps at room temp.

(142 mg crude, 101%, 93% crude purity). Data for 6b: Colorless

foam (136 mg, 97%, Ͼ99% purity); m.p. 165–168 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 9.98–9.52 (br. s, 1 H, COOH), 7.94–7.00

(m, 29 H), 5.24–4.30 (br. m, 12 H, 6ϫ CONCH₂Ar), 4.30–4.00

[br. m, 6 H, 6ϫ CONCH(CH₃)₂], 1.48–0.65 (m, 36 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 172.0, 171.8, 171.6 (7ϫ C_q), 136.5,

136.3, 135.8, 134.8, 134.6, 134.3 (13ϫ C_q), 131.9, 131.0, 129.6,

129.3, 128.6, 127.3, 127.0, 126.7, 126.1, 125.3 (29ϫ CH), 51.4, 51.2

[6ϫ CH, 6ϫCONCH(CH₃)₂], 42.2, 41.6, 41.2, 40.7 (6ϫ CH₂, 6ϫ

CONCH₂Ar), 21.6, 21.2, 20.9 (12ϫ CH₃) ppm. HRMS (TOF MS,

ES⁺): m/z calcd. for C₇₃H₈₅N₆O₈[M + 2 H]²⁺587.3248; found

587.3246.

Methods D and E. General Procedure for Acylation Step (except

for tert-butyl side chain): To a solution of 2-(chloromethyl)benzoyl

chloride (71 mg, 0.38 mmol) in CH₂Cl₂(0.76 mL) at room temp.,

was added DIPEA (0.132 mL, 0.76 mmol). The mixture was added

to the resin and the resulting mixture was agitated for 20 min at

room temp. The resin was drained and washed with CH₂Cl₂(3ϫ

2 mL) and DMSO (3ϫ 2 mL).

Method F. General Procedure for Acylation Step (only for tert-butyl

side chain): To a solution of 2-(chloromethyl)benzoyl chloride

(143 mg, 0.76 mmol) in CH₂Cl₂(0.76 mL) at room temp., was

added DIPEA (0.264 mL, 1.52 mmol). The mixture was added to

the resin and the resulting mixture was agitated for 180 min at

room temp. The resin was drained and washed with CH₂Cl₂(3ϫ

2 mL) and DMSO (3ϫ 2 mL).

Arylopeptoid Hexamer 6c: Synthesized on Rink acid resin using

Method F (81 mg crude, 54%, 23% crude purity). Data for 6c: Col-

1

orless foam (9 mg, 7%, Ͼ99% purity); m.p. 154–157 °C (dec.). H

NMR (300 MHz, CDCl₃): δ = 8.02–6.88 (m, 30 H), 4.94–4.20 (m,

12 H, 6ϫ CONCH₂Ar), 1.80–1.10 (s, 54 H, 6ϫ CONtBu) ppm.

Insufficient amounts of material to obtain satisfactory ¹³C NMR

spectra. HRMS (TOF MS, ES⁺): m/z calcd. for C₇₉H₉₈N₆O₈[M +

2H]²⁺629.3718; found 629.3713.

Methods D and F. General Procedure for Substitution Step (except

for phenyl side chain): A solution of the primary amine (20 equiv.,

2 m) in DMSO (1.3 mL) was added to the resin and the mixture

was agitated at 50 °C for 1 h. The resin was drained and washed

with DMSO (3ϫ 2 mL) and CH₂Cl₂(3ϫ 2 mL).

Arylopeptoid Hexamer 6e: Synthesized on Rink acid resin using

Method D, performing the substitution steps at room temp. (31 mg

crude, 20%, 76% crude purity). Data for 6e: Colorless foam iso-

lated as the corresponding TFA-salt (28 mg, 10%, Ͼ99% purity);

m.p. 98–101 °C. ¹H NMR (300 MHz, [D₃]MeCN): δ = 8.04–7.86

(m, 1 H), 7.82–6.74 (m, 28 H), 5.50–2.50 (m, 91 H) ppm. Insuf-

ficient amounts of material to obtain satisfactory ¹³C NMR spec-

tra. HRMS (TOF MS, ES⁺): m/z calcd. for C₉₁H₁₁₈N₁₂O₁₄[M +

4H]⁴⁺400.7217; found 400.7221.

Method E. General Procedure for Substitution Step (only for phenyl

side chain): A solution of the primary amine (20 equiv., 4 m) in

DMSO (0.65 mL) was added to the resin and the mixture was agi-

tated at 50 °C for 3 h. The resin was drained and washed with

DMSO (3ϫ 2 mL) and CH₂Cl₂(3ϫ 2 mL).

Methods D and E; General Procedure for Capping Step (except for

tert-butyl side chain): To a solution of benzoyl chloride or 2-meth-

ylbenzoyl chloride (0.38 mmol) in CH₂Cl₂(0.76 mL) at room

temp., was added DIPEA (0.132 mL, 0.76 mmol). The solution was

added to the resin and the resulting mixture was agitated for 20 min

at room temp. The resin was drained and washed with CH₂Cl₂/

DIPEA, 4:1 (3ϫ 1 mL, only for arylopeptoids that contain side

chains with basic functionalities), CH₂Cl₂(3ϫ 2 mL), NMP (3ϫ

2 mL, only Rink amide), and CH₂Cl₂(3ϫ 2 mL).

Arylopeptoid Hexamer 6f: Synthesized on Rink acid resin using

Method D, performing the substitution steps at room temp.

(150 mg crude, 86%, 36% crude purity). Data for 6f: Pale-yellowish

foam isolated as the corresponding TFA-salt (58 mg, 23%, Ͼ99%

purity); m.p. 63–66 °C. ¹H NMR (300 MHz, [D₃]MeCN): δ = 8.92–

6.60 (m, 60 H), 5.18–3.88 (m, 24 H) ppm. ¹³C NMR (75 MHz,

[D₃]MeCN): δ = 172.2, 171.9 (6ϫ C_q), 168.5 (C_q), 161.1 (q, J =

36.5 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 146.7, 146.5, 146.1, 142.6 (18ϫ

CH), 139.1, 138.9, 138.1, 137.6, 136.4, 135.4, 135.2, 134.2 (19ϫ

C_q), 131.9, 131.0, 129.6, 129.2, 129.0, 128.6, 127.6 (35ϫ CH), 117.2

(q, J = 289.2 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 53.1, 52.8, 52.1,

51.6, 47.2, 46.6 (2ϫ 6CH₂, 6ϫ CONCH₂Ar and 6ϫ

CONCH₂Pyr) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₉₁H₈₁N₁₂O₈[M + 3H]³⁺489.8761; found 489.8761.

Method F. General Procedure for Capping Step (only for tert-butyl

side chain): To a solution of benzoyl chloride or 2-methylbenzoyl

chloride (0.76 mmol) in CH₂Cl₂(0.76 mL) at room temp., was

added DIPEA (0.264 mL, 1.52 mmol). The solution was added to

the resin and the resulting mixture was agitated for 180 min at

room temp. The resin was drained and washed with CH₂Cl₂/

DIPEA, 4:1 (3ϫ 1 mL, only for arylopeptoids that contain side

chains with basic functionalities), CH₂Cl₂(3ϫ 2 mL), NMP (3ϫ

2 mL, only Rink amide), and CH₂Cl₂(3ϫ 2 mL).

Arylopeptoid Hexamer 6g: Synthesized on Rink acid resin using

Method D (170 mg crude, 92%, 98% crude purity). Due to poor

Eur. J. Org. Chem. 2013, 3574–3589

www.eurjoc.org

3585

T. Hjelmgaard, J. Nielsen

FULL PAPER

solubility, the crude product was purified as follows: The crude

product was taken up in CH₂Cl₂(10 mL) and the mixture was

washed with 1 M HCl (10 mL). The aqueous layer was extracted

with CH₂Cl₂(10 mL) and the combined organic layers were con-

centrated and dried in vacuo, giving 6g (174 mg, 94%, 98% purity)

Colorless foam isolated as the corresponding TFA-salt (173 mg,

63%, Ͼ99% purity); m.p. 78–81 °C. ¹H NMR (300 MHz, [D₃]-

MeCN): δ = 7.74–6.15 (m, 37 H), 5.40–5.52 (m, 84 H) ppm. ¹³C

NMR (75 MHz, [D₃]MeCN): δ = 172.9, 172.7, 172.3 (7ϫ C_q),

160.9 (q, J = 36.1 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 136.0, 135.9, 135.6,

135.2, 134.5, 134.4, 133.9, 133.3, 133.1 (13ϫ C_q), 131.8, 131.6,

131.4, 130.0, 129.6, 129.3, 129.1, 128.7, 128.1, 127.9, 127.3, 127.2

1

as a colorless foam; m.p. Ͼ 250 °C. H NMR (300 MHz, CDCl₃):

δ = 6.80–6.70 (m, 60 H), 5.50–3.90 (m, 18 H, 6ϫ CONCHCH₃

and 6ϫ CONCH₂Ar), 1.85–1.10 (m, 18 H, 6ϫ (29ϫ CH), 117.2 (q, J = 290.7 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 64.5,

CONCHCH₃) ppm. Not sufficiently soluble to obtain satisfactory

¹³C NMR spectra. HRMS (TOF MS, ES⁺): m/z calcd. for

C₁₀₃H₉₈N₆O₈[M + 2H]²⁺773.3718; found 773.3724.

64.3 (12ϫ CH₂), 56.2, 56.1, 55.9, 55.8, 55.3, 55.1, 54.3, 54.3, 53.1,

52.6, 52.4, 52.1, 51.7, 51.3 (24ϫ CH₂), 40.7, 40.5, 40.4, 40.0 (6ϫ

CH₂) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for C₉₁H₁₁₉N₁₃O₁₃

[M + 4H]⁴⁺400.4763; found 400.4771.

Arylopeptoid Hexamer 6h: Synthesized on Rink acid resin using

Method E (11 mg crude, 7%, 91% crude purity). Data for 6h: Col-

Arylopeptoid Hexamer 7f: Synthesized on Rink amide resin using

Method D (273 mg crude, 106%, 28% crude purity). Data for 7f:

Pale-yellowish foam isolated as the corresponding TFA-salt (52 mg,

1

orless solid (9 mg, 5%, Ͼ99% purity); m.p. 168–171 °C. H NMR

(300 MHz, CDCl₃): δ = 7.79–6.72 (m, 60 H), 5.62–5.10 (m, 12 H,

6ϫ CONCH₂Ar) ppm. Insufficient amounts of material to obtain 20%, Ͼ99% purity); m.p. 72–75 °C. ¹H NMR (300 MHz, [D₃]-

satisfactory ¹³C NMR spectra. HRMS (TOF MS, ES⁺): m/z calcd.

MeCN): δ = 8.98–8.02 (m, 18 H), 7.94–7.62 (m, 8 H), 7.60–7.03

(m, 27 H), 6.02–6.40 (m, 8 H, 6ϫ CF₃COOH and CONH₂), 5.10–

3.90 (m, 24 H, 6ϫ CONCH₂Ar and 6ϫ CONCH₂Pyr) ppm. ¹³C

NMR (75 MHz, [D₃]MeCN): δ = 172.1, 172.0, 171.7 (7ϫ C_q),

161.1 (q, J = 36.2 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 146.7, 146.5, 146.1,

142.5, 141.2, 141.0 (18ϫ CH), 139.1, 136.4, 135.9, 135.4, 135.1,

134.9 (19ϫ C_q), 131.5, 131.4, 131.0, 130.7, 130.4, 130.1, 129.6,

129.4, 129.1, 128.9, 128.6, 128.1, 127.9, 127.6, 127.5, 127.0 (35ϫ

CH), 117.2 (q, J = 290.0 Hz, 6ϫ C_q, 6ϫ CF₃COOH), 52.2, 52.0,

46.9, 46.7, 46.6 (2ϫ 6CH₂, 6ϫ CONCH₂Ar and 6ϫ

CONCH₂Pyr) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₉₁H₈₂N₁₃O₇[M + 3H]³⁺489.5481; found 489.5485.

for C₉₁H₇₄N₆O₈[M + 2H]²⁺689.2779; found 689.2779.

Arylopeptoid Hexamer 7a: Synthesized on Rink amide resin using

Method D (172 mg crude, 132%, 91% crude purity). Data for 7a:

Colorless foam (106 mg, 81%, Ͼ99% purity); m.p. 95–98 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 7.80–7.00 (m, 29 H), 6.62–6.08 (m,

2 H, CONH₂), 5.42–2.54 (m, 24 H, 6ϫ CONCH₂Ar and 6ϫ

CONCH₂CH₃), 1.32–0.52 (m, 18 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 172.4, 172.3, 171.4, 171.3, 171.1, 171.0, 170.6, 170.5,

170.4 (7ϫ C_q), 136.0, 135.8, 135.7, 135.6, 134.7, 134.2, 134.1, 133.9,

133.4, 133.3 (13ϫ C_q), 130.9, 130.7, 130.7, 129.6, 129.5, 128.5,

128.1, 127.9, 127.7, 127.5, 127.3, 126.3, 126.0, 125.8, 125.7 (29ϫ

CH), 48.9, 45.8, 45.4, 44.3, 44.0, 43.7, 43.6, 40.3 (12ϫ CH₂, 6ϫ

Arylopeptoid Hexamer 7g: Synthesized on Rink amide resin using

CONCH₂Ar and 6ϫ CONCH₂CH₃), 14.0, 13.7, 13.4, 12.5, 12.4, Method D (192 mg crude, 104%, 80% crude purity), performing

12.2 (6ϫ CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

the final cleavage in 2ϫ 10 min. Data for 7g: Colorless foam

(43 mg, 23%, Ͼ99% purity); m.p. Ͼ 250 °C. H NMR (300 MHz,

1

C₆₇H₇₅N₇O₇[M + 2H]²⁺544.7859; found 544.7851.

CDCl₃): δ = 7.98–6.70 (m, 59 H), 6.45–5.90 (br. m, 3.14 H, CONH₂

and 1.14ϫ CONCHCH₃), 5.42–3.88 (br. m, 16.86 H, 4.86ϫ

CONCHCH₃and 6ϫ CONCH₂Ar), 1.74–1.20 (m, 18 H, 6ϫ

CONCHCH₃) ppm. Not sufficiently soluble to obtain satisfactory

¹³C NMR spectra. HRMS (TOF MS, ES⁺): m/z calcd. for

Arylopeptoid Hexamer 7b: Synthesized on Rink amide resin using

Method D (135 mg crude, 141%, 99% crude purity). Data for 7b:

Colorless foam (135 mg, 96%, Ͼ99% purity); m.p. 140–143 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 8.20–8.00 (br. s, 1 H, CONHH),

7.72–7.00 (m, 29 H), 6.80–6.62 (br. s, 1 H, CONHH), 5.24–3.96 [m,

18 H, 6ϫ CONCH₂Ar and 6ϫ CONCH(CH₃)₂], 1.42–0.90 (m, 36

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 173.0, 172.5, 172.2,

171.7 (7ϫ C_q), 136.5, 136.2, 135.6, 134.7, 134.4 (13ϫ C_q), 130.5,

130.4, 129.5, 129.2, 129.0, 128.6, 128.2, 127.3, 127.1, 126.7, 126.1,

125.4 (29ϫ CH), 51.3, 51.1 [6ϫ CH, 6ϫ CONCH(CH₃)₂], 41.7,

C

₁₀₃H₉₉N₇O₇[M + 2H]²⁺772.8803; found 772.8801.

Arylopeptoid Hexamer 7h: Synthesized on Rink amide resin using

Method E (175 mg crude, 106%, 50% crude purity). Data for 7h:

1

Colorless solid (57 mg, 35%, Ͼ99% purity); m.p. 156–159 °C. H

NMR (300 MHz, CDCl₃): δ = 7.48–6.76 (m, 59 H), 6.36–6.10

41.2, 40.8 (6ϫ CH₂, 6ϫ CONCH₂Ar), 21.7, 21.6, 21.5, 21.3, 20.9, (br. m, 2 H, CONH₂), 5.47–5.12 (m, 12 H, 6ϫ CONCH₂Ar) ppm.

20.9 (12ϫ CH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 170.9, 170.1 (7ϫ C_q),

143.5, 142.7, 142.4, 142.1, 135.8, 135.5, 135.4, 135.3, 135.1, 134.9

(19ϫ C_q), 130.5, 129.7, 129.1, 129.0, 128.9, 128.9, 128.8, 128.8,

128.7, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5, 126.8, 126.5, 126.3

(59ϫ CH), 51.9, 50.9, 50.8 (6ϫ CH₂, 6ϫ CONCH₂Ar) ppm.

HRMS (TOF MS, ES⁺): m/z calcd. for C₉₁H₇₅N₇O₇[M + 2H]²⁺

688.7859; found 688.7850.

C₇₃H₈₆N₇O₇[M + 2H]²⁺586.8328; found 586.8331.

Arylopeptoid Hexamer 7d: Synthesized on Rink amide resin using

Method D (241 mg crude, 117%, 92% crude purity). Data for 7d:

Colorless foam (157 mg, 76%, Ͼ99% purity); m.p. 60–63 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 7.78–6.86 (m, 59 H), 6.45–5.74 (m,

2 H, CONH₂), 5.40–2.14 (m, 36 H), 1.82–0.94 (m, 24 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 172.4, 172.4, 171.3, 171.2, 171.0,

170.9, 170.6, 170.5 (7ϫ C_q), 142.2, 142.1, 142.1, 142.0, 141.9, 141.6,

141.5, 141.4, 136.1, 136.0, 135.7, 135.6, 135.6, 134.9, 134.7, 134.5,

134.1, 133.8, 133.4 (19ϫ C_q), 130.7, 130.6, 130.5, 129.5, 128.4,

128.3, 128.2, 127.5, 127.4, 127.3, 126.5, 126.2, 125.9, 125.8, 125.7

(59ϫ CH), 50.8, 50.7, 49.8, 49.7, 49.4, 46.5, 45.4, 45.3, 45.0, 44.9,

Arylopeptoid Hexamer 7i: Synthesized on Rink amide resin using

Method F. Purification of the crude product (111 mg crude, 101%,

48% crude purity) was hindered due to poor solubility in HPLC

solvents and other useful organic and inorganic solvents. Major

peak in analytical HPLC of the crude product corresponded to the

desired product as established by LC-MS and HRMS: HRMS

44.8, 44.3 (12ϫ CH₂, 6ϫ CONCH₂Ar and 6ϫ CONCH₂CH₂), (TOF MS, ES⁺): m/z calcd. for C₅₅H₅₀N₇O₇[M + H]⁺920.3766;

35.5, 35.0, 34.9, 34.8 (6ϫ CH₂), 29.0, 28.9, 28.8, 28.2, 28.1, 28.0,

27.8, 27.5, 27.1, 27.0 (12ϫ CH₂) ppm. HRMS (TOF MS, ES⁺):

m/z calcd. for C₁₁₅H₁₂₃N₇O₇[M + 2H]²⁺856.9737; found 856.9736.

found 920.3769.

Arylopeptoid Model Monomer 8b: Synthesized on Rink acid resin

using Method D (52 mg crude, 70%, 84% crude purity) at twice

the scale described in the general methods. Data for 8b: Colorless

foam (42 mg, 56%, Ͼ99% purity); m.p. 178–181 °C. ¹H NMR

Arylopeptoid Hexamer 7e: Synthesized on Rink amide resin using

Method D (294 mg crude, 107%, 84% crude purity). Data for 7e:

3586

www.eurjoc.org

Eur. J. Org. Chem. 2013, 3574–3589

Synthesis and Study of ortho-Arylopeptoids

(300 MHz, CDCl₃): δ = 11.25–10.85 (br. s, 1 H, COOH), 8.01 (dd, J = 6.8 Hz, 0.25 H, CONCHCH₃, minor), 5.16–4.98 (m, 1.50 H,

J = 7.6, 1.0 Hz, 0.80 H, o-C₆H₄COO, major), 7.97 (d, 0.20 H, o- CONCHCH₃, minor and CONCHHAr, major), 4.98–4.62 (m, 1.25

C₆H₄COO, minor), 7.62–7.49 (m, 2 H, p/mЈ-C₆H₄COO), 7.40–7.21 H, CONCHHAr, major and CONCH₂Ar, minor), 2.47, 2.38, 2.24

(m, 4.20 H, m-C₆H₄COO and C₆H₄CON, major), 7.20–7.09 (m, (3ϫ s, 3 H, CH₃Ar), 1.66–1.52 (m, 3 H, CONCHCH₃) ppm. ¹³C

0.40 H, C₆H₄CON, minor), 7.09–7.02 (m, 0.20 H, C₆H₄CON,

minor), 6.99–6.90 (m, 0.20 H, C₆H₄CON, minor), 5.09 (d, J = (0.25ϫ C_q, CON, minor), 171.5 (0.75ϫ C_q, COO, major), 171.0

16.7 Hz, 0.80 H, CONCHHAr, major), 4.99 (d, J = 16.7 Hz, 0.80 (0.25ϫ C_q, COO, minor), 141.0, 140.2, 139.3, 138.6, 136.0, 135.6,

H, CONCHHAr, major), 4.92–4.67 [m, 0.60 H, CONCH(CH₃)₂, 135.3, 134.3, 133.8, 129.6 (5ϫ C_q), 132.3, 132.1, 131.5, 131.2, 130.9,

NMR (75 MHz, CDCl₃): δ = 173.3 (0.75ϫ C_q, CON, major), 173.3

minor and CONCH₂Ar, minor], 4.06–3.90 [m, 0.80 H,

CONCH(CH₃)₂, major], 2.40 (s, 2.40 H, CH₃Ar, major), 2.33 (s,

130.3, 129.4, 129.4, 129.3, 128.8, 128.7, 128.4, 128.1, 128.1, 127.9,

127.8, 127.6, 127.3, 127.2, 127.0, 126.9, 126.6, 126.2, 125.9, 125.7,

0.60 H, CH₃Ar, minor), 1.34–1.22 [m, 1.20 H, CONCH(CH₃)₂, 125.5 (13ϫ CH), 58.1, 57.8 (0.75ϫ CH, CONCHCH₃, major), 53.2

minor], 1.21–1.10 [m, 4.80 H, CONCH(CH₃)₂, major] ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 173.8 (0.20ϫ C_q, CON, minor), 173.2

(0.80ϫ C_q, CON, major), 171.7 (0.80ϫ C_q, COO, major), 171.0

(0.25ϫ CH, CONCHCH₃, minor), 46.3, 43.5 (CH₂, CONCH₂Ar),

19.5, 19.0 (CH₃, CH₃Ar), 18.3, 17.6 (CH₃, CONCHCH₃) ppm.

HRMS (TOF MS ES⁺): m/z calcd. for C₂₄H₂₄NO₃[M + H]⁺

(0.20ϫ C_q, COO, minor), 141.3 (0.20ϫ C_q, oЈ-C₆H₄COO, minor), 374.1751; found 374.1754.

139.5 (0.80ϫ C_q, oЈ-C₆H₄COO, major), 135.9 (0.20ϫ C_q,

Arylopeptoid Model Monomer 8h: Synthesized on Rink acid resin

C₆H₄CON, minor), 135.7 (0.80ϫ C_q, C₆H₄CON, major), 134.2

(0.80ϫ C_q, C₆H₄CON, major), 133.6 (0.20ϫ C_q, C₆H₄CON,

minor), 132.8 (0.20ϫ CH, p-C₆H₄COO, minor), 132.6 (0.80ϫ CH,

p-C₆H₄COO, major), 131.9 (0.20ϫ CH, o-C₆H₄COO, minor),

131.4 (0.20ϫ CH, o-C₆H₄COO, minor), 130.7 (0.80ϫ CH,

C₆H₄CON, major), 130.3 (0.20ϫ CH, C₆H₄CON, minor), 129.2

(0.80ϫ CH, C₆H₄CON, major), 128.9 (0.20ϫ CH, C₆H₄CON,

minor), 128.8 (0.80ϫ C_q, ipso-C₆H₄COO, major), 127.6 (0.20ϫ

CH, mЈ-C₆H₄COO, minor), 127.2 (0.80ϫ CH, mЈ-C₆H₄COO,

major), 127.0 (CH, m-C₆H₄COO), 126.7 (0.20ϫ C_q, ipso-

C₆H₄COO, minor), 125.9 (0.80ϫ CH, C₆H₄CON, major), 125.5

(0.20ϫ CH, C₆H₄CON, minor), 125.3 (0.80ϫ CH, C₆H₄CON,

major), 125.1 (0.20ϫ CH, C₆H₄CON, minor), 51.2 [0.80ϫ CH,

CONCH(CH₃)₂, major], 47.6 [0.20ϫ CH, CONCH(CH₃)₂, minor],

46.7 (0.20ϫ CH₂, CONCH₂Ar, minor), 42.2 (0.80ϫ CH₂, CON-

CH₂Ar, major), 21.5, 21.1 [0.80ϫ CH₃, CONCH(CH₃)₂, major],

20.2 [0.20ϫ CH₃, CONCH(CH₃)₂, minor], 19.3 (0.80ϫ CH₃,

CH₃Ar, major), 18.9 (0.20ϫ CH₃, CH₃Ar, minor) ppm. HRMS

(TOF MS, ES⁺): m/z calcd. for C₁₉H₂₂NO₃[M + H]⁺312.1600;

found 312.1600.

using Method E (40 mg crude, 48%, 99% crude purity) at twice the

scale described in the general methods. Data for 8h: Colorless foam

(33 mg, 40%, Ͼ99% purity); m.p. 175–178 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 10.40–9.90 (br. s, 1 H, COOH), 7.99 (dd,

J = 7.8, 1.3 Hz, 1 H, o-C₆H₄COO), 7.66 (dd, J = 7.7, 1.2 Hz, 1 H,

mЈ-C₆H₄COO), 7.57 (ddd, J = 7.8, 7.7, 1.3 Hz, 1 H, p-C₆H₄COO),

7.36 (ddd, J = 7.8, 7.8, 1.2 Hz, 1 H, m-C₆H₄COO), 7.15–6.90 (m,

9 H, C₆H₄CON and CONC₆H₅), 5.61 (s, 2 H, CONCH₂Ar), 2.39

(s, 3 H, CH₃Ar) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 171.8 (C_q,

CON), 171.7 (C_q, COO), 142.4 (C_q), 138.9 (C_q, oЈ-C₆H₄COO),

135.8 (C_q, oЈ-C₆H₄CON), 135.0 (C_q), 132.9 (CH, p-C₆H₄COO),

131.5 (CH, o-C₆H₄COO), 130.3 (CH), 128.9 (3ϫ CH), 128.6 (CH,

mЈ-C₆H₄COO), 127.5 (CH and C_q), 127.3 (CH), 127.2 (2ϫ CH),

127.0 (CH), 125.0 (CH), 51.4 (CH₂, CONCH₂Ar), 19.7 (CH₃,

CH₃Ar) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for C₂₂H₂₀NO₃

[M + H]⁺346.1438; found 346.1444.

Arylopeptoid Model Monomer 8i: Synthesized on Rink acid resin

using Method F at twice the scale described in the general methods

with tert-butylamine. The crude product (94 mg) carrying the tert-

butyl side chain was agitated in TFA/water, 95:5 (2 mL) for 2 h at

room temp. The solvents were evaporated under reduced pressure

and the residue was evaporated with CH₂Cl₂(3ϫ 5 mL), yielding

the crude product (85 mg crude, 132%, 98% crude purity), which

was purified by preparative HPLC. Data for 8i: Colorless foam

(48 mg, 74%, Ͼ99% purity); m.p. 168–171 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 8.68 (t, J = 6.0 Hz, CONH), 7.89 (dd,

J = 7.8, 1.3 Hz, 1 H, o-C₆H₄COO), 7.58 (m, 1 H, p-C₆H₄COO),

7.49 (dd, J = 7.7, 0.8 Hz, 1 H, mЈ-C₆H₄COO), 7.46–7.31 (m, 3 H,

C₆H₄CON and m-C₆H₄COO), 7.29–7.22 (m, 2 H, C₆H₄CON), 4.78

(d, J = 6.0 Hz, 2 H, CONCH₂Ar), 2.35 (s, 3 H, CH₃Ar) ppm. ¹³C

NMR (75 MHz, [D₆]DMSO): δ = 169.1 (C_q, CON), 168.3 (C_q,

COO), 140.4 (C_q, oЈ-C₆H₄COO), 136.8 (C_q), 135.2 (C_q), 131.9 (CH,

p-C₆H₄COO), 130.4 (CH), 130.3 (CH, o-C₆H₄COO), 129.3 (C_q,

ipso-C₆H₄COO), 129.3 (CH), 127.3 (CH, m-C₆H₄COO), 127.0

(CH), 126.6 (CH, mЈ-C₆H₄COO), 125.4 (CH), 41.0 (CH₂, CON-

CH₂Ar), 19.4 (CH₃, CH₃Ar) ppm. Similar NMR spectra were ob-

tained in [D₄]MeOH except for the disappearance of the amide

proton. HRMS (TOF MS, ES⁺): m/z calcd. for C₁₆H₁₆NO₃[M +

H]⁺270.1130; found 270.1138.

Arylopeptoid Model Monomer 8c: Synthesized on Rink acid resin

using Method F (91 mg crude, 117%, 86% crude purity) at twice

the scale described in the general methods. Data for 8c: Colorless

foam (60 mg, 77%, Ͼ99% purity); m.p. 205–208 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 11.00–10.40 (br. s, 1 H, COOH), 7.96 (dd,

J = 7.8, 1.3 Hz, 1 H, o-C₆H₄COO), 7.71 (d, J = 7.5 Hz, 1 H, mЈ-

C₆H₄COO), 7.62 (ddd, J = 7.9, 7.5, 1.3 Hz, 1 H, p-C₆H₄COO),

7.32 (ddd, J = 7.9, 7.7, 1.3 Hz, 1 H, m-C₆H₄COO), 7.14–7.03 (m,

3 H, o/p/mЈ-C₆H₄CON), 6.96–6.87 (m, 1 H, m-C₆H₄CON), 5.50–

4.91 (br. s,

1

H, CONCHHAr), 4.91–4.30 (br. s,

1

H,

CONCHHAr), 2.34 (s, 3 H, CH₃Ar), 1.55 (s, 9 H, CONtBu) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 174.0 (C_q, CON), 170.9 (C_q,

COO), 142.6 (C_q, oЈ-C₆H₄COO), 138.2 (C_q, ipso-C₆H₄CON), 133.2

(C_q, oЈ-C₆H₄CON), 132.7 (CH, p-C₆H₄COO), 132.0 (CH, o-

C₆H₄COO), 130.2 (CH, mЈ-C₆H₄CON), 128.3 (CH), 127.4 (CH,

mЈ-C₆H₄COO), 126.7 (CH, m-C₆H₄COO), 126.3 (C_q, ipso-

C₆H₄COO), 125.5 (CH, m-C₆H₄CON), 124.4 (CH), 58.6 (C_q,

CONtBu), 49.0 (CH₂, CONCH₂Ar), 28.6 (3ϫ CH₃, CONtBu),

18.9 (CH₃, CH₃Ar) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₂₀H₂₄NO₃[M + H]⁺326.1751; found 326.1751.

Arylopeptoid Model Monomer 8g: Synthesized on Rink acid resin

Arylopeptoid Monomer 9g: Synthesized on Rink acid resin using

using Method D (100 mg crude, 112%, 91% crude purity) at twice Method D (97 mg crude, 113%, 95% crude purity) at twice the

the scale described in the general methods. Data for 8g: Colorless

foam (82 mg, 92%, Ͼ99% purity); m.p. 61–64 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 11.20–10.75 (br. s, 1 H, COOH), 7.87 (dd, J

= 7.8, 0.8 Hz, 1 H, o-C₆H₄COO, major), 7.84 (d, 1 H, o-C₆H₄COO,

minor), 7.48–7.03 (m, 12.75 H), 6.99–6.90 (m, 0.25 H), 6.19 (q,

scale described in the general methods. Data for 9g: Colorless foam

(78 mg, 90%, Ͼ99% purity); m.p. 51–54 °C. H NMR (300 MHz,

CDCl₃): δ = 11.15–10.95 (br s, 1 H, COOH), 7.89 (dd, J = 7.6,

0.9 Hz, 1 H), 7.65–7.15 (m, 13 H), 6.24–5.88 (br. m, 0.23 H, 0.23ϫ

CONCHCH₃), 5.43–5.18 (br. m, 0.77 H, 0.77ϫ CONCHCH₃),

1

Eur. J. Org. Chem. 2013, 3574–3589

www.eurjoc.org

3587

T. Hjelmgaard, J. Nielsen

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5.14–4.54 (m, 2 H, CONCH₂Ar), 1.60 (d, J = 7.0 Hz, 3 H,

CONCHCH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 173.6 (C_q),

171.3 (C_q), 139.4 (C_q), 138.9 (C_q), 136.0 (C_q), 132.4 (CH), 131.1

(CH), 130.0, 128.7, 127.9, 127.3, 126.8, 126.4 (12ϫ CH), 57.9 (br.,

CH, CONCHCH₃), 43.7 (br., CH₂, CONCH₂Ar), 18.0 (br., CH₃,

CONCHCH₃) ppm. HRMS (TOF MS, ES⁺): m/z calcd. for

C₂₃H₂₂NO₃[M + H]⁺360.1594; found 360.1591.

Arylopeptoid Trimer 10g: Synthesized on Rink acid resin using

Method D (100 mg crude, 100%, 99% crude purity). Data for 10g:

1

Colorless foam (85 mg, 85%, Ͼ99% purity); m.p. 131–134 °C. H

NMR (300 MHz, CDCl₃): δ = 10.55–10.05 (br. s, 1 H, COOH),

7.87–6.58 (m, 32 H), 6.06–3.90 (m, 9 H, 3ϫ CONCHCH₃and

3ϫ CONCH₂Ar), 1.75–1.20 (m, 9 H, 3ϫ CONCHCH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 173.0, 172.6, 172.4, 172.1, 170.6,

169.5 (4ϫ C_q), 140.4, 140.0, 138.5, 136.4, 136.1, 135.5, 135.0, 134.5,

134.1, 133.7 (10ϫ C_q), 132.0, 131.7, 131.3, 130.9, 129.9, 129.4,

128.7, 128.4, 128.3, 127.9, 127.7, 127.5, 127.5, 127.3, 126.8, 126.6,

126.4, 126.1, 125.8 (32ϫ CH), 58.0, 57.7, 57.6 (3ϫ CH, 3ϫ

CONCHCH₃), 44.1, 44.0, 43.8, 42.9 (3ϫ CH₂, 3ϫ CONCH₂Ar),

20.0, 19.7, 17.7, 17.2 (3ϫ CH₃, 3ϫ CONCHCH₃) ppm. HRMS

(TOF MS, ES⁺): m/z calcd. for C₅₅H₅₂N₃O₅[M + H]⁺834.3907;

found 834.3815.

Supporting Information (see footnote on the first page of this arti-

cle): Methods used for analytical and preparative HPLC; details

concerning optimization of acylation and substitution steps using

HPLC; HPLC profiles and NMR spectra (proton and j-mod) of

synthesized ortho-arylopeptoids; NOESY spectra of model mono-

mers 8c, 8h, and 8i.

[4]

Acknowledgments

The authors gratefully thank Dr. Sophie Faure and Prof. Claude

Taillefumier [Institut de Chimie de Clermont-Ferrand (ICCF),

Université Blaise Pascal, Clermont-Ferrand, France] for inspira-

tional and helpful discussions. The authors likewise gratefully

thank the Carlsberg Foundation (grant 2011_01_0432, to T. H.),

the Villum Kann Rasmussen Foundation, the Lundbeck Founda-

tion, the Aase and Ejnar Daninielsens Foundation and the Augus-

tinus Foundation for supporting this research project.

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Received: March 15, 2013

Published Online: May 7, 2013

Eur. J. Org. Chem. 2013, 3574–3589

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3589

Article Doi

Aromatic oligoamides with a rare ortho-connectivity: Synthesis and study of ortho-arylopeptoids

DOI: 10.1002/ejoc.201300398

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