Cyclic endiamino peptides: A new synthesis of imidazopyrazines

Article abstract of DOI:10.1002/ejoc.200900008

By applying the cyclic endiamino cyclisation methodology to linear tripeptides embodying a β-turn-directing amino acid, the imidazopyrazine ring system was afforded. A mechanism involving the originally desired nine-membered cyclic encliamine is suggested

Full text of DOI:10.1002/ejoc.200900008

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900008
Cyclic Endiamino Peptides: A New Synthesis of Imidazopyrazines
Yael Kogon,[a] Lee Goren,[a] Doron Pappo,[a] Amira Rudi,[a] and Yoel Kashman*[a]
Keywords: Cyclization / Peptides / Nitrogen heterocycles / Enols
By applying the cyclic endiamino cyclisation methodology to
linear tripeptides embodying a β-turn-directing amino acid,
the imidazopyrazine ring system was afforded. A mechanism
involving the originally desired nine-membered cyclic endi-
amine is suggested.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Following the discovery of callynormine A, a natural en-
diamino peptide, in which the lactone group of depsipep-
tides is replaced by an endiamino functionality,[1] we syn-
thesized several cyclic endiamino peptides. Herewith we
present the investigation of the scope of cyclisation of small
oligopeptides to endiamino peptides.[2] As could be ex-
pected,[3] oligotri- and oligotetrapeptides gave upon cycli-
sation, between the N-terminal and an enol-tosylate[2]
group on the C-terminus, mainly dimeric compounds.[3] The
hexapeptide was the first compound not to dimerize but
rather to afford the monomeric cyclic hexapeptide.[4] To fav-
our monomeric over dimeric cyclisations of the latter small
peptides, β-turn-directing acids were inserted into the oligo-
peptide. Namely, proline and N-methylleucine, both pos-
sessing high β-turn values,[5]were inserted into a tripeptide.
Scheme 1. Cyclisation of BocPheProSerOMe enol-tosylate 2.
Results and Discussion
The first cyclisation, starting from tripeptide 1, which
was oxidised to enol-tosylate 2, afforded major compound
3a (24% yield, the serine residue was oxidised to formyl
glycine, FGly); however, this was not the expected product
(Scheme 1).[6] The MS showed, instead of the anticipated
monomer peak, one that fits [M – H2O].[7] Also unexpected
in the NMR spectra were two, instead of three, amide CO
group resonances (162.9 and 163.0 ppm) and the appear-
ance of a nonanticipated singlet at 143.6 ppm.[8] Compre-
hensive analysis of the 1D and 2D data (Figure 1) suggested
a substituted imidazopyrrolopyrazine structure for com-
pound 3a.
Figure 1. Selected COSY and 13CH-HMBC correlations for com-
pound 3a.
A suggested mechanism for obtaining the imidazopyr-
rolopyrazine ring system is depicted in Scheme 2. It is sug-
gested that cyclisation of the tripeptide to afford the ex-
pected cyclic endiamino peptide does indeed take place ini-
tially (a–c, Scheme 2). However, the high ring-strain of the
nine-membered cyclic peptide triggers a trans annular nu-
cleophilic attack; that is, the endiamino amine group, the
best nucleophile in the nine-membered ring, attacks the
proline amide carbonyl group to afford azacyclol d, which
[a] School of Chemistry, Tel-Aviv University,
Tel-Aviv 69978, Israel
Fax: +972-3-6409293
E-mail: kashman@post.tau.ac.il
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1852–1854

Cyclic Endiamino Peptides: A New Synthesis of Imidazopyrazines
after dehydration affords imidazopyrrolopyrazine 3a.[9,10] In was found to be identical to 3b, thus establishing the epi-
addition, it was found that compound 3a isomerises slowly merisation site. In addition, dimer 5 was obtained in the
in MeOH (50 °C) to a 2:1 mixture of compounds 3a/3b.
latter reaction.
The 15NH-HMBC experiment showed four informative
correlations for three nitrogen atoms of compound 3b (Fig-
ure 2).
Figure 2. Selected HN correlations for compound 3b.
The third examined cyclisation was that of BocPheN-
Me-LeuSerOMe enol-tosylate 6,[12] embodying the β-turn
inducing N–Me–Leu. Indeed, desired imidazopyrazine 8 ac-
companied by dimeric endiamine 9[13] were obtained. Cycli-
sation of the non-methylated counterpart tripeptide, Boc-
PheLeuSerOMe enol-tosylate 7, in contrast, led as expected
to dimeric product 10 (Scheme 4).
Conclusions
Scheme 2. Proposed mechanism for the formation of imidazopyr-
rolopyrazine via enol-tosylate.
In summary, the linear enol-tosylate tripeptide embody-
In order to clarify the isomerisation spot, we next ing a β-turn-inducing amino acid cyclised to afford a cyclic
cyclised diastereoisomer tripeptide 4 containing a -Pro in- nine-membered endiamino peptide, which collapses to the
stead of the -Pro residue in 3a (Scheme 3). The product imidazopyrazine.
Scheme 3. Cyclisation of BocPhe--ProSerOMe enol-tosylate 4.[11]
Scheme 4. Cyclisation of enol-tosylates 6 and 7.
Eur. J. Org. Chem. 2009, 1852–1854
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1853

Y. Kogon, L. Goren, D. Pappo, A. Rudi, Y. Kashman
SHORT COMMUNICATION
(dd, J = 12.4 Hz, 1 H), 3.52 (s, 3 H), 3.46 (m, 1 H), 2.94 (br. d, J
= 8 Hz, 2 H), 2.77 (m, 1 H), 1.86 (m, 1 H), 1.83 (m, 1 H), 1.70
(quint., J = 8 Hz, 1 H), 1.37 (m, 1 H) ppm. 13C NMR (125 MHz,
DMSO): δ = 170.8 (s), 169.1 (s), 166.5 (s), 145.2 (s), 136.6 (s), 130.0
(d), 128.6 (d), 127.2 (d), 96.1 (s), 60.1 (d), 60.0 (d), 50.7 (q), 47.2
(t), 43.0 (t), 28.8 (t), 25.0 (t) ppm. HRMS (MALDI-TOF): calcd.
for C36H42N6NaO8 [M + Na+] 709.2943; found 709.2956.
Experimental Section
General Experimental Procedures: Optical rotations were obtained
with a Jasco P-1010 polarimeter. IR spectra were obtained with a
Bruker FTIR Vector 22 spectrometer. 1H and 13C NMR spectra
were recorded with Bruker Avance-500 and Avance-400 spectrome-
ters.1H, 13C, COSY, HSQC, NOESY and HMBC were recorded by
using standard Bruker pulse sequences. MS (FAB) measurements
were recorded with a Fisons, Autospec Q instrument. MALDI
(HRMS) measurements were recorded with an Applied Biosystem
Voyager DE-STR MALDI TOF instrument.
8: Yellow oil. Yield: 3 mg (4%). [α]2D6 = +55 (c = 0.5, MeOH). IR
(KBr): ν = 2926, 1734, 1684, 1653, 1647, 1207 cm–1. 1H NMR
˜
(500 MHz, DMSO): δ = 7.29 (s, 1 H), 7.22–7.24 (m, 3 H), 6.92 (m,
2 H), 4.95 (t, J = 5 Hz, 1 H), 4.38 (dd, J = 8.4 Hz, 1 H), 3.87 (s, 3
H), 3.37 (qd, J = 14.6 Hz, 2 H), 3.02 (s, 3 H), 1.81 (m, 1 H), 1.08
(m, 1 H), 0.88 (d, J = 7 Hz, 3 H), 0.72 (d, J = 7 Hz, 3 H), 0.43 (m,
1 H) ppm. 13C NMR (125 MHz, DMSO): δ = 164.4 (s), 164.4 (s),
143.6 (s), 134.5 (s), 133.9 (s), 129.6 (d), 128.9 (d), 127.8 (d), 122.8
(d), 60.1 (d), 56.3 (d), 51.7 (q), 44.2 (t), 40.5 (t), 34.1 (q), 23.8 (q),
22.9 (q), 21.7 (q) ppm. MS (FAB): m/z (%) = 378 (40) [M + Na+].
General Procedure for the Oxidation of the “Serine Peptide”: A
solution of the “serine peptide” (1 mmol) in DMF (5 mL) was
added to a mixture of p-toluenesulfonyl chloride (5 mmol) in
DMSO/DMF (1:1, 5 mL) at –5 °C under an argon atmosphere. Af-
ter stirring for 5 min at the same temperature, TEA (15 mmol) was
added, and the mixture was warmed up to room temperature over
1 h. The reaction was quenched by the addition of ice-cold water
(50 mL), and the aqueous solution was extracted with ethyl acetate
(3ϫ30 mL). The combined organic layer was washed with brine
(50 mL), dried with Na2SO4, and filtered, and the solvents were
evaporated in vacuo. The residue was purified by VLC to afford
the enol-tosylate of the FGly (formyl glycine) peptide.
9: Yellow oil. Yield: 6 mg (4%). [α]2D6 = –193 (c = 0.5, MeOH). IR
(KBr): ν = 3279, 2952, 1652, 1559, 1383 cm–1. 1H NMR (500 MHz,
˜
DMSO): δ = 7.22–7.24 (m, 3 H), 7.20 (d, J = 14 Hz, 1 H), 6.92 (m,
2 H), 6.66 (br. s, 1 H), 6.37 (dd, J = 9.14 Hz, 1 H), 4.31 (dt, J =
9.6 Hz, 1 H), 3.62 (s, 3 H), 3.50 (dd, J = 5.9 Hz, 1 H), 3.27 (dd, J
= 13.6 Hz, 1 H), 3.07 (dd, J = 13.6 Hz, 1 H), 2.96 (s, 3 H), 1.91
(m, 1 H), 1.28 (m, 2 H), 0.87 (d, J = 4 Hz, 3 H), 0.86 (d, J = 4 Hz,
3 H) ppm. 13C NMR (125 MHz, DMSO): δ = 172.3 (s), 168.4 (s),
167.6 (s), 144.4 (d), 136.8 (s), 130.3 (d), 129.5 (d), 127.9 (d), 96.8
(s), 65.0 (d), 61.4 (d), 51.8 (q), 42.1 (t), 39.7 (q), 38.2 (t), 25.6 (d),
24.1 (q), 22.6 (q) ppm. MS (FAB): m/z (%) = 747 (55) [M + H+].
General Procedure for the Preparation of “Imidazopyrazines”: The
“enol-tosylate FGly tripeptide” (0.1 mmol) was dissolved in an ice-
cold mixture of TFA/DCM (1:10, 4 mL) and stirred at room tem-
perature for 3 h. The solvent was then evaporated, and the residue
was dissolved in CH3CN (50 mL), basified with TEA (0.3 mmol)
and stirred at room temperature. After 18 h, CH3COOH (10%,
0.3 mL) was added, and the solvents were evaporated. The residue
was purified by sephadex LH20 chromatography and HPLC (Hiber
prepacked column 250–25 lichrospher 60 RP –select B 5 µm).
[1] N. Berer, A. Rudi, I. Goldberg, Y. Benayahu, Y. Kashman, Org.
Lett. 2004, 6, 2543–2545.
[2] T. Nakazawa, T. Suzuki, M. Ishii, Tetrahedron Lett. 1997, 38,
8951–8954.
3a: Yellow oil. Yield: 8 mg (14%). [α]2D6 = –44 (c = 0.5,MeOH). IR
[3] D. Pappo, M. Vartanian, S. Lang, Y. Kashman, J. Am. Chem.
Soc. 2005, 127, 7682–7683.
(KBr): ν = 2948, 1734, 1681, 1495, 1212 cm–1. 1H NMR (500 MHz,
˜
[4] D. Pappo, Y. Kashman, Org. Lett. 2006, 8, 1177–1179.
[5] G. Deléage, B. Roux, Protein Eng. 1987, 1, 289–294.
[6] All tripeptides were synthesized by the well-established meth-
odology for oligopeptides. The serine alcohol was oxidized and
trapped to the appropriate enol-tosylate by Nakazawa oxi-
dation.[2] Cyclisation conditions: serine peptide (1.6 m),
CH3CN (50 mL), TEA (3 equiv.).
[7] Compound 3 (a or b): HRMS (MALDI-TOF): calcd. for
C18H19N3NaO3 [M + Na+] 348.1318; found 348.1288.
[8] Data recorded in CDCl3 with Bruker Avance 500 and 400 MHz
instruments (100 MHz for 13C).
[9] S. Bajusz, E. Szell, D. Bagdy, E. Barabas, G. Horvath, M. Di-
oszegi, Z. Fittler, G. Szabo, A. Juhasz, E. Tomori, G. Szilagyi,
J. Med. Chem. 1990, 33, 1729–1735.
[10] G. Lucente, P. Francesco, A. Romeo, G. Zanotti, J. Chem. Soc.
Perkin Trans. 1 1983, 1127–1130.
DMSO): δ = 8.10 (s, 1 H), 7.16 (m, 3 H), 6.83 (m, 2 H), 5.23 (dd,
J = 4.2 Hz, 1 H), 4.45 (m, 1 H), 3.75 (s, 3 H), 3.55 (m, 2 H), 3.50
(m, 2 H), 2.18 (dquint., J = 2.6 Hz, 1 H), 1.80 (m, 1 H), 1.72 (m,
1 H), 0.74 (m, 1 H) ppm. 13C NMR (125 MHz, DMSO): δ = 163.0
(s), 162.9 (s), 143.6 (s), 135.6 (s), 132.5 (s), 129.1 (d), 128.4 (d),
127.1 (d), 124.1 (d), 58.8 (d), 54.7 (d), 51.4 (q), 44.7 (t), 37.5 (t),
30.6 (t), 21.7 (t) ppm. HRMS (MALDI-TOF): calcd. for
C18H19N3NaO3 [M + Na+] 348.1318; found 348.1288.
3b: Yellow oil. Yield: 8 mg (24%). [α]2D6 = +107 (c = 0.5,MeOH).
IR (KBr): ν = 2952, 1723, 1683, 1495, 1292, 1210 cm–1. H NMR
1
˜
(500 MHz, DMSO): δ = 7.81 (s, 1 H), 7.13–7.29 (m, 3 H), 6.81 (dd,
J = 2.6 Hz, 2 H), 5.16 (t, J = 5 Hz, 1 H), 3.74 (s, 3 H), 3.42 (dt, J
= 8.12 Hz, 1 H), 3.33 (m, 1 H), 3.28 (m, 1 H), 3.25 (m, 2 H), 2.28
(quint., J = 6 Hz, 1 H), 1.92 (m, 1 H), 1.66 (m, 2 H) ppm. 13C
NMR (125 MHz, DMSO): δ = 163.7 (s), 162.9 (s), 144.9 (s), 135.1
(s), 132.6 (s), 129.6 (d), 128.8 (d), 127.8 (d), 124.8 (d), 60.7 (d), 53.9
(s), 51.5 (q), 45.0 (t), 39.3 (t), 30.5 (t), 22.2 (t) ppm. HRMS
(MALDI-TOF): calcd. for C18H20N3O3 [M + H+] 326.1426; found
326.1498.
[11] The structure of compound 5 was established by 1D and 2D
NMR spectroscopic data. HRMS (MALDI-TOF): calcd. for
C36H42N6NaO8 [M + Na+] 709.2943; found 709.2956.
[12] The structure of compound 6 was established by 1D and 2D
NMR spectroscopic data. HRMS (MALDI-TOF): calcd. for
C25H39N3O7 [M+] 494.2860; found 494.2873.
[13] Compound 8: MS (FAB): m/z = 355.2 [M+] for C20H25N3O3.
5: Yellow oil. Yield: 9 mg (16%). [α]2D6 = –184 (c = 0.5,MeOH). IR
Compound 9: MS (FAB): m/z
C40H55N6O8.
=
747.2 [M + H+] for
(KBr): ν = 2957, 3227, 1669, 1559, 1496 cm–1. 1H NMR (500 MHz,
˜
DMSO): δ = 8.57 (br. s, 1 H), 7.40 (d, J = 14 Hz, 1 H), 7.27–7.35
(m, 5 H), 6.42 (dd, J = 12.8 Hz, 1 H), 4.58 (q, J = 8 Hz, 1 H), 4.08
Received: January 7, 2009
Published Online: March 12, 2009
1854
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1852–1854