Ketopiperazines: Conformationally constrained peptidomimetic of arginine amides

Article abstract of DOI:10.1080/00397910500383550

We have synthesized guanidine-containing ketopiperazines designed to be conformational mimics of peptidomimetic arginine amides. D-Allylglycine was converted by an efficient approach to give enantiopure ketopiperazines in which the trans stereochemistry o

Full text of DOI:10.1080/00397910500383550

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Ketopiperazines: Conformationally
Constrained Peptidomimetic of Arginine
Amides
Zecheng Chen a , Andrew S. Kende a , Anny‐Odile Colson b , Jose L.
Mendezandino b , Frank H. Ebetino b , Rod D. Bush b & X. Eric Hu b
a Department of Chemistry, University of Rochester, Rochester, New York,
USA
b Health Care Rearch Center, Procter & Gamble Pharmaceuticals, Mason,
Ohio, USA
Version of record first published: 19 Aug 2006.
To cite this article: Zecheng Chen , Andrew S. Kende , Anny‐Odile Colson , Jose L. Mendezandino , Frank H.
Ebetino , Rod D. Bush & X. Eric Hu (2006): Ketopiperazines: Conformationally Constrained Peptidomimetic of
Arginine Amides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:4, 473-479
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Synthetic Communicationsw, 36: 473–479, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500383550
Ketopiperazines: Conformationally
Constrained Peptidomimetic of
Arginine Amides
Zecheng Chen and Andrew S. Kende
Department of Chemistry, University of Rochester,
Rochester, New York, USA
Anny-Odile Colson, Jose L. Mendezandino, Frank H. Ebetino,
Rod D. Bush, and X. Eric Hu
Health Care Rearch Center, Procter & Gamble Pharmaceuticals,
Mason, Ohio, USA
Abstract: We have synthesized guanidine-containing ketopiperazines designed to be
conformational mimics of peptidomimetic arginine amides. D-Allylglycine was
converted by an efficient approach to give enantiopure ketopiperazines in which the
trans stereochemistry of the C-substituents resulted from stereospecific enolate
alkylation.
Keywords: Arginine, ketopiperazines, peptidomimetics
INTRODUCTION
It has long been recognized that biologically active peptides possess signifi-
cant potential for drug development.[1] However, major limitations in
developing peptide drugs arise from their susceptibility to protease degra-
dation, poor transportability through cell membranes, and their high
Received in USA August 15, 2005
Address correspondence to Zecheng Chen (current address), Wyeth Research,
401 N. Middletown Road, Pearl River, New York 10965, USA. E-mail: Chenz1@
wyeth.com
473

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Z. Chen et al.
hydrophilicity leading to rapid clearance from plasma.[2,3] We have been
involved in research to identify effective peptidomimetics that overcome
these drawbacks yet maintain their conformational properties, which may
lead to therapeutic utility.
One such approach has been to test the hypothesis that an arginine peptide
conformation A can be maintained by constraining the amide groups within a
piperazine ring, as shown in B (Figure 1).
To help design these mimics, a conformational analysis was performed
on the arginine scaffold using a Monte Carlo approach with the Merck
Molecular Force Field (MMFF) force field implemented in Spartan.[4]
This search generated seven low-energy conformations, which were further
treated using ab initio quantum mechanical calculations to determine
the equilibrium geometry. Target compound 1 was also subjected to a
Monte Carlo search in which 25 low-energy conformers were found to exist
with strain energies within 10 kcal/mol of the minimum energy. These 25
conformers were entered into a database that was subsequently flexibly
superimposed using FlexS[5,6] onto the seven conformers obtained for the
arginine scaffold. The result indicates that the proposed scaffold allows
three substituents to maintain a spatial orientation similar to that found in
the unconstrained arginine scaffold. On this basis we initiated our synthetic
efforts toward such a peptidomimetic scaffold of arginine.
Figure 1. Ketopiperazine—a constrained argine mimic.

Ketopiperazines
475
RESULT AND DISCUSSION
Our synthesis of ketopiperazines is outlined in Scheme 1. Commercially
available D-allylglycine was protected as an N-Boc derivative, which was sub-
sequently converted to the corresponding aldehyde 2 by LiAlH4 reduction of
the Weinreb amide.[7] Following the procedure of Dinsmore et al.,[8] the
aldehyde 2 was reductively aminated with 3,4-difluorobenzylamine to give
secondary amines 3 in excellent yield. Key intermediate ketopiperazine ring
compound 4 was produced by chloroacetylation, followed by base-mediated
Scheme 1. Reagents and conditions: (a) Boc2O, Et3N, MeOH, rt, 79%; (b) ClCO2CH3,
NMM, MeNH(OMe), CH2Cl2-THF; (c) LiAlH4, Et2O, 245 to 258C, 2 h, 65% for two
˚
steps; (d) NaBH(OAc)3, 4A MS, ClCH2CH2Cl, rt, 24 h, 90%; (e) ClCH2COCl,
NaHCO3, EtOAc-H2O, 08C, 30 min; (f) Cs2CO3, DMF, 658C, 2 h, 93%; (g) LiHMDS,
THF, 2788C, 2 h, 69%; (h) 9-BBN, THF, rt, 3 h, then H2O2/NaOH, 78%; (i) PPh3,
DIAD, THF, rt, 2 h, 90%; (j) CF3COOH, CH2Cl2, 100%.

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Z. Chen et al.
cyclization in high yield.[8] In the chloroacetylation step, it was essential to
completely remove excess chloroacetyl chloride by repeated washes of the
reaction mixture with aqueous NaHCO3 to avoid by-product formation in
the cyclization step. Alkylation of compound 4 with 2-(bromomethyl)-
naphthalene using LiHMDS at 2788C gave the disubstituted products 5
with high trans diastereoselectivity.[8]
To introduce elements of the guanidine side chain, hydroboration–
oxidation of the allyl terminus in 5 afforded alcohol 6 in good yield.[9]
Mitsunobu reaction of 6 with N,N0-Bis-Boc-guanidine provided the corre-
sponding guanidine 7 in high yield.[10] Treatment of 7 with TFA resulted in
Boc deprotection in quantitative yield. Thus, the synthesis of target
compound 1 was achieved in 23% overall yield from D-allylglycine.
In conclusion, a ketopiperazine scaffold for arginine peptidomimetics
was designed based on computer modeling using conformation analysis and
synthesized starting from optically active allylglycine in an efficient
manner. The synthetic approach we have established should have potential
for the generation of analogs with substituent variations around the ketopiper-
azine ring, which are useful in pharmaceutical research.
EXPERIMENTAL
1
All melting points are uncorrected. H NMR spectra were determined in the
solvent indicated at 400 MHz. Mass spectra were recorded by using APCI
or API-ES mode. Flash chromatography was performed with 40–63-mm
silica gel.
f1-[(3,4-Difluorobenzylamino)-methyl]-but-3-enylg-carbamic Acid
tert-Butyl Ester (3)
To a solution of aldehyde 2 (342 mg, 1.72 mmol, prepared by the reported
procedure[7]) and 3,4-difluorobenzylamine (224 mg, 1.89 mmol) in 4 mL of
1,2-dichloroethane at 08C was added 4A molecular sieves (0.45 g), followed
by addition of sodium triacetoxyborohydride (537 mg, 2.41 mmol). The
reaction mixture was then stirred at room temperature for 14 h. The mixture
was diluted with EtOAc and washed with aqueous sodium bicarbonate
solution and brine, and then dried over MgSO4. The solvent was removed
under the reduced pressure, and the residue was purified by flash chromato-
graphy to give the pure product 3 as colorless oil (505 mg, 90%).
MS (API-ES, positive): m/z 327.2 [M þ H]; 1H NMR (400 MHz,
CDCl3): d 7.20–7.15 (m, 1H), 7.11–7.03 (m, 2H), 5.81–5.71 (m, 1H), 5.10
(d, J ¼ 18.7 Hz, 1H), 5.08 (d, J ¼ 9.9 Hz, 1H), 4.64 (br, 1H), 3.78, 3.72
(AB, J ¼ 13.5 Hz, 2H), 3.80–3.71 (m, 1H), 2.70–2.61 (m, 2H), 2.28–2.23
(m, 2H), 1.45 (s, 9H).

Ketopiperazines
477
2-Allyl-4-(3,4-difluorobenzyl)-5-oxo-piperazine-1-carboxylic Acid
tert-Butyl Ester (4)
Chloroacetylchloride (80 mg, 1.0 mmol) and saturated aqueous sodium bicar-
bonate solution (1 mL) were added to a solution of 3 (163 mg, 0.5 mmol) in
EtOAc (1 mL) at 08C. The resulting mixture was stirred at this temperature
for 20 min and diluted with EtOAc (20 mL). The organic layer was washed
with water and aqueous sodium bicarbonate, and then dried over MgSO4.
The solvent was removed under reduced pressure, and the residue was dried
in vacuum to give colorless oil (202 mg, 100%), which is directly used in
the next step without further purification.
Cs2CO3 (326 mg, 1.0 mmol) was added to this intermediate solution in
dry DMF (2 mL). The resulting mixture was gently heated to 658C and
stirred at this temperature for 2 h. The mixture was cooled to room temperature
and diluted with a mixed solvent EtOAc–hexanes (90 : 10). The mixture was
washed with water and brine, and then dried over Na2SO4. The solvent was
removed in vacuum, and the residue was purified by flash chromatography
to give compound 4 as colorless oil (170 mg, 93%).
MS (API-ES, positive): m/z 389.2 [M þ Na]; 1H NMR (400 MHz,
CDCl3): d 7.17–7.10 (m, 2H), 7.04–7.01 (m, 1H), 5.65–5.56 (m, 1H), 5.01
(d, J ¼ 10.1 Hz, 1H), 4.87 (d, J ¼ 16.9 Hz, 1H), 4.75 (d, J ¼ 14.5 Hz, 1H),
4.41–4.31 (m, 3H), 3.82 (d, J ¼ 18.8 Hz, 1H), 3.50 (dd, J ¼ 4.5 Hz,
12.3 Hz, 1H), 3.07 (d, J ¼ 12.2 Hz, 1H), 2.33–2.26 (m, 1H), 2.16–2.05
(m, 1H), 1.46 (s, 9H). 13C NMR (400 MHz, CDCl3): d 28.6 (3C), 34.8,
45.2, 48.3, 49.6 (2C), 81.2, 117.8, 118.0, 118.8, 124.9, 125.0, 133.8, 148.8,
152.3, 154.0, 166.0. HRMS: calcd. for C15H17F2N2O3 [M þ H-tBu] m/z
311.1207; found 311.1216.
6-Allyl-4-(3,4-difluorobenzyl)-2-naphthalen-2-ylmethyl-3-oxo-
piperazine-1-carboxylic Acid tert-Butyl Ester (5)
Lithium bis(trimethylsilyl)amide (1M in THF, 0.51 mL, 0.51 mmol) was added
dropwise to a solution of 4 (170 mg, 0.46 mmol) in THF (1 mL) at 2788C. The
mixture was stirred under argon at 2788C for 20 min, and then a solution of
2-(bromomethyl)-naphthalene (122 mg, 0.55 mmol) in THF (1 mL) was
added dropwise. The mixture was stirred at 2788C for 2 h and then
quenched by addition of saturated ammonium chloride aqueous solution
(2 mL). The mixture was allowed to warm to room temperature and partitioned
with EtOAc and saturated aqueous sodium bicarbonate solution. The organic
layer was separated and washed with brine, and then dried over MgSO4. The
solvent was removed in vacuum, and the residue was purified by flash chrom-
atography to give the pure compound 5 as white solid (161 mg, 69%).
1
Mp: 112–1138C. MS (API-ES, positive): m/z 507.2 [M þ H]; H NMR
(400 MHz, CDCl3): d 7.83–7.80 (m, 1H), 7.73–7.68 (m, 2H), 7.51–7.47

478
Z. Chen et al.
(m, 3H), 7.18 (d, J ¼ 8.0 Hz, 1H), 7.04–6.98 (m, 2H), 6.84 (br, 1H),
5.37–5.32 (m, 1H), 4.87 (d, J ¼ 10.1 Hz, 1H), 4.69 (dd, J ¼ 3.0 Hz, 5.5 Hz,
1H), 4.59 (d, J ¼ 16.9 Hz, 1H), 4.48 (br, 1H), 4.17–4.10 (m, 1H),
3.81–3.57 (m, 2H), 3.31 (dd, J ¼ 3.0 Hz, 13.6 Hz, 1H), 2.58–2.48 (m, 1H),
2.32–2.19 (m, 1H), 1.92–1.84 (m, 2H), 1.59 (s, 9H). 13C NMR (400 MHz,
CDCl3): d 28.8 (3C), 35.8, 39.9, 45.1, 49.9, 50.8, 59.2, 81.4, 117.5, 117.8,
118.3, 118.5, 125.5, 126.1, 126.5, 127.9, 128.0, 128.7, 129.0, 132.7, 133.4,
133.5, 133.6, 134.2, 148.8, 152.1, 154.1, 169.0. HRMS: calcd. for
C30H33F2N2O3 [M þ H] m/z 507.2459; found 507.2477.
4-(3,4-Difluorobenzyl)-6-(3-hydroxy-propyl)-2-naphthalen-2-
ylmethyl-3-oxo-piperazine-1-carboxylic Acid tert-Butyl Ester (6)
A solution of compound 5 (320 mg, 0.64 mmol) in THF (4 mL) was added
dropwise to a 9-BBN solution (0.5M in THF, 1.5 mL, 0.77 mmol) at 08C.
The mixture was stirred at room temperature for 3 h and then cooled to 08C
again. An aqueous solution of 3M NaOH (4.8 mL) was added, followed by
dropwise addition a solution of H2O2 (30%, 4.8 mL). The resulting mixture
was stirred at room temperature overnight. The mixture was extracted with
EtOAc. The combined extacts were washed with water and brine, and then
dried over MgSO4. The solvent was removed in vacuum, and the residue
was purified by flash chromatography to give the pure compound 6 as white
foam (261 mg, 78%).
1
Mp: 135–1378C. MS (API-ES, positive): m/z 525.2 [M þ H]; H NMR
(400 MHz, CDCl3): d 7.83–7.81 (m, 1H), 7.75–7.70 (m, 2H), 7.52–7.47
(m, 3H), 7.18 (dd, J ¼ 1.3 Hz, 8.3 Hz, 1H), 7.04–6.98 (m, 2H), 6.83 (br,
1H), 4.75 (d, J ¼ 13.7 Hz, 1H), 4.66 (dd, J ¼ 3.2 Hz, 5.5 Hz, 1H), 3.86
(d, J ¼ 14.3 Hz, 1H), 3.88–3.57 (m, 2H), 3.43 (br, 2H), 3.30 (dd,
J ¼ 3.0 Hz, 13.6 Hz, 1H), 2.51–2.47 (m, H), 1.94–1.86 (m, 1H), 1.57
(s, 9H), 1.52–1.48 (m, 2H), 1.07–0.93 (m, 2H). 13C NMR (400 MHz,
CDCl3): d 26.6, 28.0, 28.8 (3C), 38.7, 45.1, 49.7, 50.3, 59.2, 62.1, 81.6,
117.6, 117.8, 118.2, 118.4, 125.4, 126.1, 126.5, 127.9, 128.0, 128.6, 129.0,
132.8, 133.6, 134.5, 149.0, 152.1, 154.5, 169.0. HRMS: calcd. for
C30H35F2N2O4 [M þ H] m/z 525.2565; found 525.2587.
Mitsunobu Reaction of Compound 6 with N,N0-Bis-Boc-guanidine
Triphenylphosphine (173 mg, 0.66 mmol) and 1,3-bis(tert-butoxycarbonyl)-
guanidine (257 mg, 0.99 mmol) were added to a solution of compound 6
(173 mg, 0.33 mmol) in THF (4 mL) at 08C, followed by dropwise addition
of diisopropyl azodicarboxylate (133 mg, 0.66 mmol). The resulting mixture
was stirred at room temperature for 2 h. Then the mixture was diluted with
EtOAc, washed with water and brine, and then dried over MgSO4. The

Ketopiperazines
479
solvent was removed in vacuum, and the residue was purified by flash chrom-
atography to give the pure compound 7 as white foam (227 mg, 90%).
1
Mp: 102–1038C. MS (API-ES, positive): m/z 766.4 [M þ H]; H NMR
(400 MHz, CDCl3): d 9.29 (br, 1H), 9.12 (br, 1H), 7.81–7.79 (m, 1H), 7.73–
7.69 (m, 2H), 7.53–7.46 (m, 3H), 7.20 (d, J ¼ 8.2 Hz, 1H), 7.15–7.05
(m, 1H), 6.98 (dd, J ¼ 6.0 Hz, 16.0 Hz, 1H), 6.87 (br, 1H), 4.65 (dd,
J ¼ 3.2 Hz, 5.6 Hz, 1H), 4.67–4.64 (m, 1H), 4.00–3.51 (m, 5H), 3.31 (dd,
J ¼ 3.0 Hz, 13.5 Hz, 1H), 3.05–2.80 (m, 1H), 2.09–1.95 (m, 1H), 1.60–
1.10 (m, 4H), 1.57 (s, 9H), 1.48 (s, 9H), 1.30 (s, 9H). HRMS: calcd. for
C41H54F2N5O7 [M þ H] m/z 766.3991; found 766.3961.
N-f3-(3,4-Difluorobenzyl)-6-naphthalen-2-ylmethyl-5-oxo-
piperazin-2-yl]-propylg-guanidine (1)
Trifluoroacetic acid (1 mL) was added dropwise to a solution of compound 7
(50 mg, 0.065 mmol) in CH2Cl2 (1 mL) at 08C. The mixture was stirred at
room temperature for 2 h. The mixture was concentrated under reduced
pressure, and the residue was treated with dried toluene. Removal of
solvent provided compound 1 as white foam (TFA salt: 45 mg, 100%).
1
Mp: 185–186 8C. MS (API-ES, positive): m/z 466.2 [M þ H]; H NMR
(400 MHz, CD3OD): d 7.86–7.80 (m, 4H), 7.50–7.46 (m, 3H), 7.26–7.19
(m, 2H), 7.11 (br, 1H), 4.70, 4.54 (AB, J ¼ 14.7Hz, 2H), 4.06 (br, 1H), 3.40
(d, J ¼ 5.4 Hz, 2H), 3.29 (d, J ¼ 10.7Hz, 1H), 3.14 (d, J ¼ 12.2Hz, 1H),
3.16–3.07 (m, 3H), 1.57–1.26 (m, 5H). 13C NMR (400MHz, CDCl3): d 27.7,
29.8, 39.4, 43.8, 50.8, 51.6, 53.5, 59.6, 120.6, 120.9, 121.0, 121.3, 127.9,
130.0, 130.5, 131.1, 131.2, 132.4, 132.6, 135.8, 136.3, 137.0, 152.0, 155.5,
160.7, 168.0. HRMS: C26H30F2N5O [M þ H] m/z 466.2418; found 466.2423.
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