Preparation of 'carba' dipeptides bearing a basic side-chain at the C-terminus: Synthesis of enantiopure Boc-D-Phe-Ψ[CH2CH2]-L-Arg(NO2)-OH and Boc-D-Phe-Ψ[CH2CH2]-D-Arg(NO2)OH

Article abstract of DOI:10.1016/S0040-4039(01)01183-2

A new approach to synthesize 'carba' Ψ[CH₂CH₂] dipeptides, e.g. Boc-D-Phe-Ψ[CH₂CH₂]-L-Arg(NO₂)-OH and Boc-D-Phe-Ψ[CH₂CH₂]-D-Arg(NO₂)-OH, is described.

Full text of DOI:10.1016/S0040-4039(01)01183-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6015–6018
Preparation of ‘carba’ dipeptides bearing a basic side-chain at
the C-terminus: synthesis of enantiopure
Boc-
D
Boc-
-Phe-C[CH2CH2]-
L
-Arg(NO2)-OH and
D
-Phe-C[CH2CH2]-
D
-Arg(NO2)-OH
Andrew S. Kende,a,* Han-Qing Dong,a Adam W. Mazurb and Frank H. Ebetinob
aChemistry Department, University of Rochester, Rochester, NY 14627-0216, USA
bProcter & Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040-8006, USA
Received 23 May 2001; accepted 26 June 2001
Abstract—A new approach to synthesize ‘carba’ C[CH2CH2] dipeptides, e.g. Boc-
D
-Phe-C[CH2CH2]-L-Arg(NO2)-OH and
Boc- -Phe-C[CH2CH2]- -Arg(NO2)-OH, is described. © 2001 Elsevier Science Ltd. All rights reserved.
D
D
Peptidomimetic research is an increasingly important
feature of drug design, given the wealth of therapeuti-
cally useful natural peptide leads currently available.
Work continues in the field to develop diverse non-pep-
tidic scaffolds1 to restrict conformational freedom of
short peptides or offer 3-dimensional mimicry of pep-
tide motifs such as b-turns, g-turns2 and helices.2,3 An
important aspect of this research is the design and
synthesis of novel isosteric dipeptide mimetics as build-
ing blocks for longer peptides. This term describes
structures which retain a 1,4-relationship between cen-
ters corresponding to the a-carbons in a dipeptide,
while the amide bond is replaced with a different func-
tionality. These structures vary in properties and
degrees of conformational constraint, as in the Phe-Gly
analogs recently reported by Gillespie.4 Kaltenbronn5
described synthesis of renin inhibitors containing any of
13 peptide bond isosteres. The chemical and enzymatic
reactivities of such pseudopeptide linkages as
C[CH2CH2] and C[CHꢀCH] are generally lower than
those of the typical peptide bond and they generally do
not form a hydrogen bond under physiological condi-
tions. Hydrogen bonding in the peptide backbone has
been implicated in inhibiting peptide transport through
the intestinal wall.6 Consequently, certain isosteric
replacements of the amide bond may also facilitate oral
bioavailability.
The synthesis of certain C[CH2CH2] dipeptides, in
which CH2CH2 replaces the amide bond, has been
reported by Martinez7 and by Wilson.8 Typically the
CH2CH2 unit in these syntheses was constructed by
Horner–Wadsworth–Emmons or Wittig olefination of
an enantiopure aldehyde, followed by reduction of the
internal ethylene to an ethane segment. These sequences
generally lead to a protected d-amino ester, which may
be cyclized to a pair of diastereomeric piperidones.
Chromatographic separation of these epimers, followed
by ring cleavage, leads to the free pseudo dipeptides.
More recently, Guichard9 has disclosed the stereoselec-
tive synthesis of pseudo dipeptides bearing aliphatic or
aralkyl side-chains by direct C(2)-alkylation of a pre-
formed N-Boc-piperidone with reactive primary
halides.
Scheme 1.
Keywords: ‘carba’ dipeptide; arginine; guanidination.
* Corresponding author. Fax: 716-473-6889; e-mail: kende@chem.rochester.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01183-2

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A. S. Kende et al. / Tetrahedron Letters 42 (2001) 6015–6018
We have independently explored the synthesis of novel
C[CH2CH2] dipeptides bearing a guanidine side-chain,
in which there are orthogonally protected guanidine
and N-terminal NH2 groups, allowing convenient syn-
thesis of longer peptides. Specifically, we illustrate a
useful strategy for the synthesis of a,d-disubstituted
d-amino acids containing a pendant guanidine unit.
ment of 5 with excessive 1N aqueous lithium hydroxide
in methanol at room temperature resulted in the
hydrolysis of one methyl ester; the second methyl ester
was readily hydrolyzed when the reaction temperature
was raised to reflux. The crude diacid was heated in
toluene for 7 h to give an unseparable 1:1 diasteromeric
mixture 613 in 86% overall yield, as shown in Scheme 2.
Our sequence utilizes
a new ‘carba’ C[CH2CH2]
replacement method to achieve this goal, and permits
the rigorous identification of stereochemically pure iso-
mers for basic researchers to scan for 3-D requirements
in any given dipeptide pharmacophore. This work has
The diastereomeric mixture 6 was subjected to acetyl
chloride in methanol;14 esterification and deprotection
of N-Boc resulted in 7. Cyclization of 7 occurred in
refluxing pyridine to give lactams 8a and 8b,15 which
could be separated by flash chromatography, in 40 and
36% yield, respectively. Hydrolysis of the lactams 8a
and 8b in refluxing aqueous HCl solution destroyed the
azido group, while an alternative way via the Boc-pro-
tected lactams 9a and 9b proceeded smoothly with
LiOOH in THF/H2O to produce the optically pure
d-azido acids 10a and 10b without epimerization at
resulted in the first synthesis of pure Boc-
C[CH2CH2]- -Arg(NO2)-OH and Boc- -Phe-C[CH2-
CH2]- -Arg(NO2)-OH. Our synthetic strategy for such
‘carba’ peptides is shown in Scheme 1.
D-Phe-
L
D
D
Starting from Boc-D-phenylalanine, homologation with
the classical Arndt–Eistert procedure afforded ester 1,10
which could be reduced by sodium borohydride to give
alcohol 2 in quantitative yield. Bromination of 2 with
carbon tetrabromide and triphenylphosphine, followed
by alkylation with dimethyl malonate, produced 4.11
The requirement of a guanidine residue led us to choose
the azido group as a potential amine. This side-chain,
3-azido-propyl, was successfully introduced using 1-
azido-3-iodopropane12 as the alkylating reagent. Treat-
1
a-position as shown in their H and 13C NMR spec-
tra.16 The structure of the compounds in series a and b
was unambiguously assigned by X-ray crystallography
of the derivative from 9a as shown in Scheme 3.
With both optically pure d-azido acids 10a and 10b in
hand, hydrogenation with 5% Pd-C and subsequent
guanidination17 using 3,5-dimethyl-N-nitro-1H-pyra-
Scheme 2. Reagents and conditions: (a) (i) ClCO2Et, Et3N, THF, then CH2N2, 93%, (ii) PhCOOAg, MeOH, 100%; (b) NaBH4,
THF/MeOH (20/1), 100%; (c) CBr4, Ph3P, CH2Cl2, 84%; (d) MeONa, CH2(COOMe)2, DME, 86%; (e) MeONa, I(CH2)3N3,
DME, 90%; (f) (i) 1N aq. LiOH, MeOH, reflux, (ii) toluene, reflux, 86% (from 5); (g) AcCl, MeOH; (h) pyridine, reflux, 40% for
8a, 36% for 8b (from 6); (i) Boc2O, DMAP, MeCN, 80%; (j) 1N LiOH, H2O2, THF/H2O (4:1), then Na2SO3, 98%.

A. S. Kende et al. / Tetrahedron Letters 42 (2001) 6015–6018
6017
Scheme 3.
Scheme 4. Reagents and conditions: (a) 5% Pd–C, H2, MeOH; (b) 3,5-dimethyl-N-nitro-1H-pyrazole-1-carboximidamide, Et3N,
MeOH, 55–60% (two steps).
zole-1-carboximidamide afforded Boc-
CH2]- -Arg(NO2)-OH (11a) and
C[CH2CH2]-
-Arg(NO2)-OH (11b),18,19 respectively.
D
-Phe-C[CH2-
Lett. 1990, 31, 5153; (b) Rodriguez, M.; Heitz, A.; Mar-
tinez, J. Tetrahedron Lett. 1990, 31, 7319.
8. Attwood, M. R.; Conway, E. A.; Dunsdon, R. M.;
Greening, J. R.; Handa, B. K.; Jones, P. S.; Jordan, S. C.;
Keech, E.; Wilson, F. X. Bioorg. Med. Chem. Lett. 1997,
7, 429.
9. Casimir, J. R.; Didierjean, C.; Aubry, A.; Rodriguez, M.;
Briand, J.-P.; Guichard, G. Org. Lett. 2000, 2, 895.
10. Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217.
11. Compound 4: [h]D=−3.9 (c=1.14, MeOH); mp 73–74°C;
1H NMR (CDCl3, 400 MHz): l 1.33–1.55 (m, 2H), 1.42
(s, 9H), 1.91–2.03 (m, 2H), 2.73 (dd, J=13.3, 6.9 Hz,
1H), 2.82 (m, 1H), 3.39 (t, J=7.4 Hz, 1H), 3.71 (s, 3H),
3.73 (s, 3H), 3.84 (m, 1H), 4.38 (br d, J=8.0 Hz, 1H),
7.17–7.32 (m, 5H) ppm; 13C NMR (CDCl3, 100 MHz): l:
25.3 (t), 28.3 (q), 31.4 (t), 41.3 (t), 51.1 (d), 52.41 (q),
52.44 (q), 79.1 (s), 126.3 (d), 128.3 (d), 129.4 (d), 137.8
(s), 155.4 (s), 169.6 (s) ppm. Anal. calcd for C20H29NO6:
C, 63.31; H, 7.70; N, 3.69. Found: C, 63.04; H, 7.87; N,
3.64%.
L
Boc- -Phe-
D
D
(Scheme 4). These two convenient building blocks are
now being utilized within peptidomimetic strategies in
our laboratory in effort to scan for effective three-
dimensional requirements of active peptide leads.
Unlike earlier Wittig methodology, our route to ‘carba’
C[CH2CH2] dipeptides proceeds through the ‘modular’
malonate intermediate 4, which can be readily alkylated
by a diverse range of electrophiles.
References
1. Obrecht, D.; Altorfer, M.; Robinson, J. A. Adv. Med.
Chem. 1999, 4, 1–68.
2. Etzkorn, F. A.; Travins, J. M.; Hart, S. A. Advances in
Amino Acid Mimetics and Peptidomimetics; 1999; pp.
125–163.
3. Andrews, M. J. I.; Tabor, A. B. Tetrahedron 1999, 55,
11711.
4. Gillespie, P.; Cicariello, J.; Olson, G. L. Biopolymers
1997, 43, 191.
5. Kaltenbronn, J. S.; Hudspeth, J. P.; Lunney, E. A.;
Michniewicz, B. M.; Nicolaides, E. D.; Repine, J. T.;
Roark, W. H.; Stier, M. A.; Tinney, F. J.; Woo, P. K.
W.; Essenburg, A. D. J. Med. Chem. 1990, 33, 838.
6. Conradi, R. A.; Hilgers, A. R.; Ho, N. F.; Burton, P. S.
Pharm. Res. 1992, 9, 435.
12. Lebreton, L.; Jost, E.; Carboni, B.; Annat, J.; Vaultier,
M.; Dutartre, P.; Renaut, P. J. Med. Chem. 1999, 42,
4749.
13. Compound 6: 1H NMR (CD3OD, 400 MHz): l 1.20–1.66
(m, 8H), 1.39 (s, 9H), 2.31–2.38 (m, 1H), 2.71 (m, 2H),
3.29 (m, 2H), 3.70 (m, 1H), 7.16–7.28 (m, 5H) ppm.
14. Nudelman, A.; Bechor, Y.; Falb, E.; Fischer, B.; Wexler,
B. A.; Nudelman, A. Synth. Commun. 1998, 28, 471.
15. Compound 8a (less polar): [h]D=+33.2 (c=0.74, CHCl3);
1
mp 57–58°C; H NMR (CDCl3, 400 MHz): l 1.46–1.68
7. (a) Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron
(m, 5H), 1.98–2.03 (m, 3H), 2.25 (m, 1H), 2.62, 2.87

6018
A. S. Kende et al. / Tetrahedron Letters 42 (2001) 6015–6018
(ABX, JAB=13.5 Hz, JAX=8.7 Hz, JBX=5.2 Hz, 2H),
7.16–7.33 (m, 5H) ppm; 13C NMR (CD3OD, 100 MHz):
l 26.3 (t), 27.4 (q), 28.5 (t), 28.8 (t), 31.8 (t), 41.1 (t), 44.7
(d), 50.8 (t), 52.0 (d), 78.3 (s), 125.7 (d), 127.8 (d), 129.0
(d), 138.7 (s), 156.6 (s), 178.1 (s) ppm. HRMS (M+H)
calcd: 391.2345; found: 391.2364.
3.29 (t, J=6.7 Hz, 2H), 3.60 (m, 1H), 5.71 (br, 1H),
7.18–7.36 (m, 5H) ppm; 13C NMR (CDCl3, 100 MHz): l
26.1 (t), 26.3 (t), 28.4 (t), 29.1 (t), 40.7 (d), 43.5 (t), 51.5
(t), 54.6 (d), 127.0 (d), 128.9 (d), 129.1 (d), 136.6 (s), 173.9
(s) ppm. Anal. calcd for C15H20N4O: C, 66.15; H, 7.40;
N, 20.57. Found: C, 66.00; H, 7.54; N, 20.42%. Com-
pound 8b (more polar): a colorless oil, [h]D=+86.7 (c=
17. Golding, B. T.; Mitchinson, A.; Clegg, W.; Elsegood, M.
R. J.; Griffin, R. J. J. Chem. Soc., Perkin Trans. 1 1999,
349.
1
0.81, CHCl3); H NMR (CDCl3, 400 MHz): l 1.50–1.75
18. Compound 11a: [h]D=−5.6 (c=0.45, MeOH), mp 75–
77°C, 1H NMR (CD3OD, 400 MHz): l 1.38 (s, 9H),
1.43–1.72 (m, 8H), 2.38 (m, 1H), 2.71 (d, J=7.0 Hz, 2H),
3.24 (t, J=6.3 Hz, 2H), 3.75 (m, 1H), 7.16–7.28 (m, 5H)
ppm; 13C NMR (CD3OD, 100 MHz): l 27.3 (q), 28.4 (t),
29.1 (t), 31.9 (t), 40.6 (t), 41.4 (t), 44.5 (d), 51.6 (d), 78.3
(s), 125.7 (d), 127.8 (d), 129.0 (d), 138.7 (s), 156.7 (s),
159.5 (s), 178.3 (s) ppm. HRMS (M+Na): calcd 474.2329;
found: 474.2341. Compound 11b: [h]D=−1.3 (c=0.38,
(m, 5H), 1.82–1.88 (m, 3H), 2.31 (m, 1H), 2.68, 2.84
(ABX, JAB=13.4 Hz, JAX=8.4 Hz, JBX=5.7 Hz, 2H),
3.32 (m, 2H), 3.62 (m, 1H), 5.86 (br, 1H), 7.17–7.35 (m,
5H) ppm; 13C NMR (CDCl3, 100 MHz): l 23.7 (t), 25.3
(t), 26.8 (t), 29.1 (t), 40.0 (d), 43.1 (t), 51.4 (t), 53.8 (d),
126.9 (d), 128.8 (d), 129.2 (d), 136.9 (s), 174.5 (s) ppm.
Anal. calcd for C15H20N4O: C, 66.15; H, 7.40; N, 20.57.
Found: C, 66.05; H, 7.61; N, 20.19%.
16. Compound 10a: a colorless oil, [h]D=−3.4 (c=1.73,
CHCl3); 1H NMR (CD3OD, 400 MHz): l 1.38 (s, 9H),
1.48–1.69 (m, 8H), 2.37 (m, 1H), 2.71 (d, J=7.0 Hz, 2H),
3.29 (t, J=6.2 Hz, 2H), 3.74 (m, 1H), 7.16–7.33 (m, 5H)
ppm; 13C NMR (CD3OD, 100 MHz): l 26.4 (t), 27.3 (q),
28.4 (t), 29.2 (t), 31.8 (t), 41.4 (t), 44.4 (d), 50.8 (t), 51.5
(d), 78.3 (s), 125.7 (d), 127.8 (d), 129.0 (d), 138.7 (s),
156.7 (s), 178.1 (s) ppm. HRMS (M+H): calcd 391.2345;
found: 391.2354. Compound 10b: a colorless oil, [h]D=
1
MeOH), mp 80–82°C, H NMR (CD3OD, 400 MHz): l
1.38 (s, 9H), 1.54–1.61 (m, 8H), 2.33 (m, 1H), 2.72 (d,
J=7.6 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 3.68 (m, 1H),
7.16–7.28 (m, 5H) ppm; 13C NMR (CD3OD, 100 MHz):
l 27.4 (q), 28.6 (t), 28.7 (t), 31.9 (t), 40.6 (t), 41.1 (t), 44.8
(d), 52.0 (d), 78.3 (s), 125.7 (d), 127.8 (d), 129.0 (d), 138.7
(s), 156.7 (s), 159.5 (s), 178.3 (s) ppm. HRMS (M+Na):
calcd 474.2329; found: 474.2338.
1
19. For an alternative strategy toward a Phe-Arg hydroxy-
ethylene isostere, see: Brewer, M.; Rich, D. H. Org. Lett.
2001, 3, 945.
−0.5 (c=1.48, CHCl3), H NMR (CD3OD, 400 MHz): l
1.39 (s, 9H), 1.51–1.63 (m, 8H), 2.30 (m, 1H), 2.72 (d,
J=7.0 Hz, 2H), 3.28 (t, J=6.1 Hz, 2H), 3.69 (m, 1H),
.