Synthesis of a cyclic pseudo 310 helical structure from a β-amino acid-L-proline derived tripeptide via a ring closing metathesis reaction

Article abstract of DOI:10.1016/S0040-4039(02)01239-X

The combination of homo-phenylglycine (Hpg) and proline leads to the formation of a β-turn mimic, which can be transformed into a cyclic peptide using a ring closing metathesis reaction. The presence of the pentenoyl and allyl groups at the terminus of th

Full text of DOI:10.1016/S0040-4039(02)01239-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6479–6483
Synthesis of a cyclic pseudo 310 helical structure from a b-amino
acid-
L
-proline derived tripeptide via a ring closing
metathesis reaction
Biswadip Banerji,a B. Mallesham,b S. Kiran Kumar,c A. C. Kunwarc and Javed Iqbala,b,
*
aDepartment of Chemistry, Indian Institute of Technology, Kanpur 208016, India
bDr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
cIndian Institute of Chemical Technology, Hyderabad 500007, India
Received 2 May 2002; revised 15 June 2002; accepted 24 June 2002
Abstract—The combination of homo-phenylglycine (Hpg) and proline leads to the formation of a b-turn mimic, which can be
transformed into a cyclic peptide using a ring closing metathesis reaction. The presence of the pentenoyl and allyl groups at the
terminus of the peptide leads to the concomitant formation of a linker surrogate fourth amino acid (6-amino-4-hexenoic acid;
Aha) during the cyclization. The cyclic peptide is unique in having a pseudo 310 helical structure. © 2002 Elsevier Science Ltd.
All rights reserved.
One of the major drawbacks associated with small
peptides as ideal drugs is their poor bioavailability due
to rapid proteolytic degradation. Thus, the design and
synthesis of small peptidomimetic1 libraries with non-
proteinogenic amino acids have gained tremendous
importance in the field of bioorganic chemistry. b-
Amino acids2 are emerging as an attractive alternative
to proteinogenic amino acids mainly due to their stabil-
ity towards proteolytic degradation by endopeptidases.
They are also attracting attention because of their
abundant presence in various natural products and turn
inducing properties in short chain peptides.
R
R
O
O
R
Phe-Pro bond
cleaved by
HIV protease
O
O
N
H
O
N
H
O
N
H
N
N
N
N
H
O
O
N
a
O
b
c
H
N
H
O
H
O
NH
Ph
Ph
N
HN
Ph
a
b
β-Turn
O
I
IIb
β-amino acid
IIa
c
R
O
O
N
H
N
N
O
H
O
Ph
HN
IIc
Scheme 1. Conformational mimics of PheꢀPro bond.
* Corresponding author. Present address: Director, Regional Research Laboratory, Trivandrum 695019, India; e-mail: javediqbaldrf@hotmail.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01239-X

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B. Banerji et al. / Tetrahedron Letters 43 (2002) 6479–6483
In an ongoing project in our laboratory3 on the discov-
ery of new chemical entities inhibiting HIV-I protease,4
we have undertaken the synthesis of small cyclic pep-
tides based upon the structural mimicry of the ‘Phe-
Pro’ bond present in the ‘gag-pol’ polyprotein. It is
known that HIV protease is very specific cleaving the
peptide bond between phenylalanine and proline. So
the design of a molecule, mimicking the stereoelectronic
environment of this scissile bond may lead to potent
inhibitors based on structural mimicry. In an attempt
to access a conformational mimic of the ‘PheꢀPro’
bond, we initiated a program where aziridine peptide
(I) was conceptualized to function as the surrogate of
the ‘bioactive’ conformation during the cleavage by
protease (Scheme 1). Conceivably, the breaking of the
aziridine bond ‘a’ may lead to a b-turn5 mimic (IIa) of
the natural PheꢀPro analogue whereas that of ‘b’ may
The b-amino acid required for the synthesis of the
acyclic peptide precursor was synthesized by a multi-
component coupling procedure previously developed in
our laboratory8 from benzaldehyde, ethyl acetoacetate
and acetyl chloride using catalytic anhydrous cobalt(II)
chloride in acetonitrile. On the other hand N-Boc-
Pro- -LeuOMe 1 was hydrolyzed (LiOH–MeOH) and
the resulting carboxylic acid was coupled with allyl-
amine (iBuOCOCl–Et3N) to give N-Boc-
-Pro- -Leu
L-
L
L
L
allyl amide 2 in 65% yield (Scheme 2). The peptide 2
was treated with CF3CO2H and the resulting product
was then coupled with the racemic acylated b-amino
acid (rac-8) by a standard amide (Et3N-HOBT-EDC)
coupling procedure9 to afford the tripeptide 3 as the
major diastereomer (65%, lower Rf value in TLC). The
other diastereomer corresponding to 3 was obtained as
the minor component (35%) and had a higher Rf value
on TLC. The presence of an unequal mixture of 3 may
be due to the difference in reactivity of the
diastereomers during the amide coupling reaction. Deu-
terium exchange studies10 on compound 3 suggested no
deuterium exchange for the allyl-NHa over a period of
5 hours on addition of CD3OD in CDCl3 solvent. This
observation strongly supports the existence of an
intramolecular hydrogen bond indicating that the
molecule may be preorganized by a b-turn formed
between the b-Phe carbonyl and the NHa of the allyl
amide. A similar b-turn has been observed in small
afford a homo-phenylglycine (Hpg)-L-proline contain-
ing b-turn mimic (IIb). On the other hand, the removal
of the aziridine a-proton may lead to the dehy-
drophenylalanine- -proline derived b-turn mimic (IIc).
L
Recently, Sung et al.6 have shown that short peptides
with an induced b-turn can inhibit HIV replication.
We reasoned here that the synthesis of cyclic b-turn
mimics possessing a b-amino acid may lead to the
development of small potent HIV-protease inhibitors
characterized by high selectivity, bioavailability and
resistance to proteolytic degradation. Thus, with appro-
priate terminal double bonds, these acyclic b-turn con-
taining structures can also be cyclized using ring closing
metathesis (RCM) leading to cyclic b-turn mimics. In
this paper, we report the synthesis of a cyclic b-turn
peptides having
-proline in the i+1 or i+2 positions.11
L
We demonstrated earlier that the tripeptides similar to
3 (with double bonds at both termini) generally preor-
ganize themselves leading to a b-turn and have a strong
propensity to undergo cyclization when subjected to a
RCM reaction.3 In view of these observations we sub-
jected 3 to RCM reaction conditions (0.01 M solution
in CH2Cl2) in the presence of Cl2[(Cy)3P]2RuꢁCHPh (10
mol%) to give the corresponding cyclic peptide 4 mainly
as the E-isomer in good yield (Scheme 2). It is interest-
mimic derived from a Hpg-L-proline derived tripeptide
through the RCM protocol.7 It is noteworthy that such
cyclization leads to the concomitant formation of 6-
amino-hex-4-enoic acid (Aha) as the surrogate for the
fourth amino acid in 4.
O
O
i) LiOH-MeOH-H2O / 25oC,1 h
O
HN
HN
CO2Me
ii) iBuOOCCl / Et3N / 0o-25oC
N
HN
N
BOC
BOC
iii) allylamine / Et3N
65%
2
1
i) CF3CO2H
ii) Et3N, EDC,
HOBT, CH2Cl2
CHCl3, 25oC
75%
rac-8
O
HN
O
N
O
Cl2(Cy3P)2Ru=CHPh
N
H
N
O
N
O
H
(10 mol %)
O
N
Ha
H
S
65%
NH
S
Ph
N
Ph
O
O
3 Major diastereomer
(lower Rf spot on TLC)
4
Scheme 2. Synthesis of cyclic b-turn mimic 4 by RCM.

B. Banerji et al. / Tetrahedron Letters 43 (2002) 6479–6483
6481
Table 1. 1H chemical shifts (l in ppm), coupling constants (J in Hz) of 4 in CDCl3 at 500 MHz
Protons
NH
Hpg
Pro
Leu
Aha
7.79 (d, JNHꢀbH=8.4)
–
5.70 (d, JNHꢀaH=9.8)
7.15 (dd, JNHꢀaH=2.5,
J
NHꢀa%H=7.3)
CaH
3.00 (t, JbHꢀaH=3.8,
JaHꢀa%H=15.4)
2.83 (dd, JbHꢀa%H=3.8)
5.52 (dt, JNHꢀbH=8.4)
–
–
–
–
–
4.15 (dd, JaHꢀbH=5.3,
JaHꢀb%H=8.6)
–
2.17 (m)
1.94 (m)
1.77 (m)
1.87 (m)
3.56 (dt, J=6.0, 9.5)
3.17 (dt, J=7.4, 9.5)
4.49 (dt, JaHꢀbH=3.5,
JaHꢀb%H=9.8)
–
2.00 (m)
1.55 (m)
1.55 (m)
–
4.10 (dt, J=7.3, 14.8)
Ca%H
CbH
CbH
CgH
Cg%H
CdH
Cd%H
3.62 (ddd, J=2.5, 6.6, 14.8)
–
–
–
–
–
–
0.93 (d, JgHꢀCH =6.4)
3
0.90 (d, JgHꢀCH =6.4)
3
Others: 5.75 (dt, J=5.7, 15.4, olefin-CH), 5.70 (dt, J=6.4, 15.4, olefin-CH), 2.43–2.49 (m, 4H, 2CH2), 7.22–7.40 (phenyls)
ing to note that 4 is a 17-membered macrocyclic peptide
with one b-amino acid and the cyclization results in the
synthesis of an unsaturated amino acid spacer, Aha. As
described below, the cyclic peptide exhibits a unique
pseudo 310 helical structure as revealed by NMR
studies.
hydrolysis (LiOH–THF–H2O) followed by a mixed
anhydride protocol using isobutyl chloroformate and
diazomethane in dichloromethane solvent. A general
Arndt–Eistert homologation13 on 6 using Ag(OAc)/
Et3N gave the b-amino ester 7 which was hydrolyzed
(LiOH–THF–H2O) to afford the corresponding b-
amino acid 8 without any racemization. Coupling of
1
The data from the solution H NMR (500 MHz) spec-
the pure acid 8 with L-proline-L-leucine allyl amide by
tra of compound 4 are presented in Table 1. Solvent
titration studies showed that the variation for the amide
chemical shift for the Hpg (<0.31 ppm) and the Aha
(<0.07 ppm) residues is very small when up to 33% v/v
DMSO-d6 was added to the chloroform solution, which
indicates their participation in intramolecular hydrogen
bonding. The appearance of the Hpg NHf (7.79 ppm)
as well as the Aha NHc (7.15 ppm) at low field in the
proton spectrum further confirms the presence of H-
bonding. In CDCl3 solution, only one isomer with a
trans amide bond preceding the proline was observed.
The observation of a NOE cross peak between Prod
Hd-Hpg CaHe in the NOESY spectrum strongly sup-
ports the presence of the trans imide bond geometry in
4. Restricted conformational mobility at the proline
backbone (ƒ=−60) may result in reverse turns. Usually
proline takes an i+1 position in such b-turns, however,
the presence of NOE cross peaks between Aha NHc–
Leu NHb, Aha NHc–Pro CaHa, Aha NHc–Leu CaHg
and Leu NHb–Pro CaHa in the NOESY spectrum cou-
pled with the Aha NHc hydrogen bonding implies the
presence of a b-turn involving the Pro–Leu residues as
shown in Fig. 1. The observation of a strong NOE
cross peak of Leu NHb–ProCaHa compared with Leu
NHb–Leu CaHg in the NOESY spectrum, indicates that
it is a type-II b-turn.12 Such a turn brings the proline
carbonyl and the Hpg NHf in proximity which results
in the subsequent formation of a hydrogen bond
between them leading to a 9-membered turn structure.
the EDC-HOBT method yielded the pure diastereomer
3.
HPLC studies and optical rotation indicated that the
absolute configuration of the b-amino acid residue in
the compound obtained by homologation ([h]D −12.2)
as described in Scheme 3 is identical to the diastereomer
3 ([h]D −16.6) obtained by the procedure described in
Scheme 2. Therefore the major diastereomer, 3 was
assigned the ‘S’ absolute stereochemistry at the asym-
metric center in the b-amino acid residue. Similarly the
‘R’ assignment was made for the minor diastereomer
(higher Rf value in TLC) and the corresponding cyclic
peptide (i.e. 4) also.
In conclusion, this paper describes the synthesis of a
novel b-and v-aminoacid containing cyclic peptide hav-
ing two consecutive intramolecular 9- and 10-mem-
bered hydrogen bonds. This is the first example of a
small cyclic peptide having a pseudo 310 helical
structure.
1
The H NMR studies clearly support the presence of
two consecutive 9- and 10-membered turns, which sug-
gests that the cyclic peptide 4 is organized in a pseudo
310 helical structure.
The absolute stereochemistry of the stereogenic center
in the b-amino acid in 3 and 4 was proved by chemical
correlation studies starting from
L
-phenylglycine. The
Figure 1. Important NOE interactions and hydrogen bonding
pattern of compound 4.
corresponding diazoketone 6 was made from 5 by base

6482
B. Banerji et al. / Tetrahedron Letters 43 (2002) 6479–6483
O
O
Ph
N2
Ph
Ph
OMe
(iii)
(i) , (ii)
58%
CO2Me
NH
O
NH
NH
O
O
55%
7
5
6
85%
(iv)
Ph
CO2H
(v)
72%
NH
3
O
8
Scheme 3. Assignment of the absolute configuration of the b-amino acid residue in 4. (i) LiOH, THF:H2O, rt; (ii) isobutyl
chloroformate, Et3N, CH2N2 (excess) in CH2Cl2; (iii) Ag(OAc), Et3N, MeOH, rt; (iv) LiOH, THF:H2O, (v) Et3N, EDC, HOBT,
N-allyl-
L
-leucine-
L
-proline: TFA, Et3N, CH2Cl2.
Acknowledgements
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We thank the DST, New Delhi for the financial support
of this work.
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in the following manner:

B. Banerji et al. / Tetrahedron Letters 43 (2002) 6479–6483
6483
LiOH.H2O,
MeOH:H2O
NHAc
NHAc
COOH
O
CoCl2
COOEt
Ph
Ph
PhCHO +
+ CH3COCl
CO2Et
CH3CN
6 days
45%
Reflux ,11 h
COCH3
21%
6N.HCl
reflux,13 h
67%
O
O
NH2.HCl
COOH
NH
Cl
COOH
Ph
Ph
K2CO3, Acetone,
0o-25oC, 15 h
rac-8
59%
9. Standard procedure for amide coupling: To an ice-cold
stirred solution of the acid (rac-8) (247 mg, 1 equiv., 1
mmol) in dry dichloromethane (5 mL) was added EDC
(191 mg, 1 equiv., 1 mmol) followed by HOBT (135 mg,
1 equiv., 1 mmol). The resulting mixture was stirred
vigorously for 30 min and then proline–leucine allyl
amide (267 mg, 1 equiv., 1 mmol) was added to it
followed by 1 equiv. of triethylamine and the mixture
stirred for 5 h, then washed thoroughly with saturated
citric acid solution and water (10 mL×3). Drying and
concentration in vacuo yielded the crude peptide as a
diastereomeric mixture (3:2). Preparative HPLC
(MeOH:water:acetonitrile) afforded the desired amide 3
in 75% yield as a white solid. General procedure for
RCM: To a stirred solution of Grubbs’ ruthenium cata-
lyst (10 mol%) in dry dichloromethane (60 mL) under
nitrogen was added the di-allylated peptide 3 (1 mmol)
dissolved in dry dichloromethane (40 mL) slowly over a
period of 30 min and the mixture refluxed. After 12 h,
further catalyst (10 mol%) was added to the reaction
mixture and the refluxing continued for another 12 h.
After this time, the reaction was exposed to air and
directly subjected to column chromatography (silica gel;
CHCl3:CH3OH) to afford the corresponding cyclic
product 4 mainly as the E isomer in 65% yield. Spectral
data for selected compounds: rac-8 IR (neat): 3298, 3069,
2.30 (bs, 4H); MS m/z (iso-butane): 248 (M+1, 100%),
204, 164, 149, 106, 100; 3: [h]D −16.6; IR (CHCl3): 3304,
3067, 1728, 1652, 1544 cm−1 1H NMR (200 MHz,
;
CDCl3) l: 7.41–7.17 (m, 7H), 6.84 (bs, 1H), 5.88–5.66 (m,
2H), 5.40–5.24 (m, 1H), 5.13–4.95 (m, 4H), 4.54–4.34 (m,
2H), 3.85 (m, 2H), 3.58 (m, 2H), 3.08–2.93 (m, 2H), 2.34
(bs, 4H), 2.10–1.40 (m, 7H), 0.95 (d, 3H, J=6 Hz), 0.89
(d, 3H, J=6 Hz); CI MS m/z (iso-butane): 497 (M+1),
440, 412, 327, 268, 230 (100%), 181, 131, 106. 4: IR
(CHCl3): 3318, 1645, 1517, 1449 cm−1; MS m/z (iso-
butane): 491 (M+Na)+, 469 (M+1); 7: [h]D +22.8; IR
(CHCl3): 3291, 3065, 1740, 1648, 1544 cm−1 1H NMR
;
(200 MHz, CDCl3) l: 7.36 (m, 5H), 6.65 (d, 1H, J=8
Hz), 5.88–5.71 (m, 1H), 5.48–5.38 (m, 1H), 5.06 (d, 1H,
J=16 Hz), 4.99 (d, 1H, J=9 Hz), 3.60 (s, 3H), 2.93 (dd,
1H, J=6 Hz, J=5.8 Hz), 2.80 (dd, 1H, J=6 Hz, J=5.8
Hz), 2.4–2.2 (bs, 4H); CI MS m/z (iso-butane): 262 (M+1,
100%), 230, 178, 100.
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Asymmetry 1994, 5, 195.
1718, 1641, 1545, 1386 cm−1 1H NMR (200 MHz,
;
CDCl3) l: 7.28 (m, 5H), 6.68 (bs, 1H), 5.85–5.63 (m, 1H),
5.44–5.4 (m, 1H), 5.03 (d, 1H, J=14 Hz), 4.97 (d, 1H,
J=10 Hz), 2.89 (d, 1H, J=6 Hz); 2.86 (d, 1H, J=8 Hz);