Synthesis and structure of chiral methoxypyrrole amino acids (MOPAS)

Article abstract of DOI:10.1055/s-2005-870023

A methoxypyrrole amino acid (MOPAS) resembling the structure of H ₂N-Val-Δ-Ala-OEt in β-sheet conformation has been prepared by a chiral auxiliary approach. The X-ray structure analysis confirms the absolute configuration of the dipeptide mimic

Full text of DOI:10.1055/s-2005-870023

PAPER
2367
Synthesis and Structure of Chiral Methoxypyrrole Amino Acids (MOPAS)
S
ynthesis and Str
h
ucture of Ch
r
iral Meth
i
oxypy
s
rrole Ami
t
no
A
cid
o
s
ph Bonauer, Burkhard König*
Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany
Fax +49(941)9434576; E-mail: Burkhard.koenig@chemie.uni-regensburg.de
Received 7 March 2005; revised 6 April 2005
Abstract: A methoxypyrrole amino acid (MOPAS) resembling the
structure of H2N-Val-D-Ala-OEt in b-sheet conformation has been
prepared by a chiral auxiliary approach. The X-ray structure analy-
sis confirms the absolute configuration of the dipeptide mimic.
Standard peptide coupling procedures allow coupling of the chiral
MOPAS with natural amino acids or their extension by additional
MOPAS units. A tight self-association of bis-MOPAS 13 in CDCl3
and the affinity to Ac-Ala-Ile-OMe dipeptides illustrates the ability
of the constrained dipeptide mimic MOPAS to interact with pep-
tides.
Key words: heterocycles, amino acids, peptides, chiral auxiliaries,
imines
Scheme 1 Synthesis of a chiral MOPAS 3 from a natural amino acid
derivative
Compounds with a molecular structure that mimic motifs
of natural peptides1 have found wide applications in me-
dicinal chemistry2 and protein recognition studies. Struc-
tures complementary to b-sheets are of particular interest,
because of their potential to intercept protein–protein in-
teractions,3 inhibit protein aggregation,4 or induce5 or
mimic peptide b-sheets.6 We have recently reported a het-
We changed the synthetic strategy to a chiral auxiliary ap-
proach and reacted aldehyde 4 as starting material with
chiral amines.12 The initial route using (R)-phenyl gly-
cineamide to form the Schiff base followed by addition of
an allyl zinc reagent13 gave only a disappointing 42%
yield in the addition reaction.
erocyclic dipeptide mimic based on methoxypyrrole ami- The use of amino alcohols as chiral auxiliaries and Grig-
no acids (MOPAS), which resembles the structure of a nard reagents for addition proved to be more efficient.
H2N-Gly-D-Ala-OEt unit in b-sheet conformation.7,8 We Phenylglycinol and valinol gave imine 9 in quantitative
now report the extension of the concept to a chiral dipep- yield. The compounds were characterized by X-ray struc-
tide mimic H2N-Val-D-Ala-OEt,9 which has been pre- ture analysis and chiral HPLC. Isopropyl magnesium
pared using a chiral auxiliary approach.
chloride undergoes clean addition in THF to compound 9-
Ph yielding 10-Ph in 77% isolated yield. Deprotection
with dihydrogen and Pd/C yields the target compound i-
Pr-MOPAS 11 nearly quantitatively.14
Our first attempts to prepare a chiral MOPAS unit used g-
amino-b-keto ester 110 as starting material. Condensation
with Gly gave amino ester 2, unfortunately this resulted in
only trace amounts of the desired cyclization product 3.11
Scheme 2 Synthesis of substituted MOPAS 7 via allyl-zinc bromide addition
SYNTHESIS 2005, No. 14, pp 2367–2372
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x
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Advanced online publication: 14.07.2005
DOI: 10.1055/s-2005-870023; Art ID: Z05005SS
© Georg Thieme Verlag Stuttgart · New York

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C. Bonauer, B. König
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analysis shows the expected S-configured i-Pr-MOPAS
group (see Figure 2). Coupling of 11 with previously pre-
pared 12 gave the constrained tetrapeptide mimic 13.
In chloroform compound 13 shows a strong self-associa-
tion of 5.2 3.7 × 103 L/mol.15 Titration of 13 with the
isomeric dipeptides Ac-Ala-Ile-OMe and Ac-Ile-Ala-
OMe16 was monitored by NMR and revealed a binding
constants of K11 = 293 35 L/mol.17
Scheme 3 Enantioselective synthesis of i-Pr-MOPAS 11, R = i-Pr,
Ph
Chiral HPLC analysis shows a diastereoselectivity of
> 99:1 for the addition reaction and high optical purity of
the final product. Figure 1 shows a likely mechanism of
the 1,2-addition reaction. The imine alcohol is deprotonat-
ed by the first equivalent of added Grignard reagent. A
six-membered chair-like conformation induced by coordi-
nation of the imine nitrogen lone pair to the magnesium
alcoholate guides the second i-PrMgCl in its diastereose-
lective addition to the C=N bond. The mechanism propos-
es the formation of (S)-i-Pr MOPAS from imines of S-
amino alcohols, which corresponds to the natural dipep-
tide sequence L-Val-D-Ala.
Figure 2 X-ray structure analysis of 14 confirming the proposed
stereochemistry
In summary, we have prepared the constrained chiral
dipeptide mimic 11, which resembles the structure of
H2N-Val-D-Ala-OEt in b-sheet conformation. A chiral
auxiliary controlled the stereochemistry during synthesis
and an X-ray structure analysis confirms the structure of
the final product. Standard peptide chemistry protocols al-
low coupling of 11 with natural amino acids or extension
by additional MOPAS units. The tight self-association ob-
served in chloroform for MOPAS 13 resembles a typical
Figure 1 Proposed mechanism of the nucleophilic 1,2-addition to peptide b-sheet property. The binding, although rather
imine 9-Ph
weak, to Ac-Ile-Ala-OMe dipeptides illustrates the ability
of i-Pr-MOPAS to interact with natural peptides. The con-
strained dipeptide mimic can replace amino acid residues
in peptides or proteins in the investigation of structure–
function relationships. The new MOPAS building block
Dipeptide 14 was prepared from 11 and L-Boc-Phe-OH
using standard peptide coupling conditions to confirm the
predicted absolute stereochemistry. The X-ray structure
Scheme 4 Synthesis of MOPAS dipeptides
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Synthesis and Structure of Chiral Methoxypyrrole Amino Acids
2369
IR (KBr): 3413 (m), 3294 (m), 2979 (m), 2933 (m), 2873 (sh), 1682
(s), 1564 (m), 1511 (m), 1473 (m), 1369 (w), 1275 (s), 1121 (w),
1028 (w) cm–1.
allows issues of stereochemistry and amino acid side
chain interactions in b-sheet recognition to be addressed.
1H NMR (300 MHz, CDCl3): d = 1.41 (t, 3J = 7.14 Hz, 3 H), 2.11
(s, 3 H), 3.86 (s, 3 H), 4.39 (q, J = 7.14 Hz, 2 H), 4.94 (s, 1 H),
NMR spectra: Bruker AC-250, Bruker Avance 300, and Bruker
ARX-400. All chemical shifts d (ppm) relative to TMS as internal
standard. All assignment are based on COSY, HMQC, and HSQC
spectra. Multiplicity of carbon resonances (+) = CH3 or CH; (–)
CH2; and Cquat = quaternary carbon atom. Mass spectrometry: Vari-
an CH-5 (EI), Finnigan MAT 95 (CI; FAB und FD) and Finnigan
MAT TSQ 7000 (ESI). IR: Bio-Rad FT-IR FTS 155. Optical rota-
tion: PE 241 Perkin-Elmer, Uvasol-grade solvents were used for
measurements in a 10 cm cuvette at a wavelength of 589 nm. Melt-
ing points are not corrected. All solvents for synthesis were purified
and dried before use by standard laboratory methods. Petroleum
ether (PE) with a boiling range 60–70 °C was used.
3
5.56 (br s, 1 H), 6.85 (br s, 1 H), 7.27–7.48 (m, 5 H), 8.14 (s, 1 H),
9.26 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 6.9 (+), 14.4 (+), 60.8 (–), 62.4
(+), 77.2 (+), 114.7 (Cquat), 118.0 (Cquat), 127.3 (+), 128.1 (+, 2 C),
128.8 (+, 2 C), 139.2 (Cquat), 150.7 (Cquat), 151.3 (+,), 160.5 (Cquat),
174.2 (Cquat, 2 C).
MS [ESI, CH2Cl2–MeOH, NH4Ac (10 mmol/L)]: m/z (%) = 343.9
(100) [M + H+], 365.9 (12) [M + Na+], 709.4 (13) [2 M + Na+].
Anal. Calcd for C18H21N3O4 (343.38): C, 62.96; H, 6.16; N, 12.29.
Found: C, 62.61; H, 5.92; N, 11.83.
Compounds R-6, 9-i-Pr, 9-Ph, and 14 were characterized by X-ray
structure analysis. All bond length and distances are typical. Depos-
ited data are available from the Cambridge Structural Database:
CCDC 267442–267445.
Ethyl 5-{1-[(Carbamoylphenylmethyl)amino]but-3-enyl}-3-
methoxy-4-methyl-1H-pyrrole-2-carboxylate (7)
To a suspension of granulated Zn (17.5 mg, 268 mmol) in anhyd
THF (2 mL) was added allylbromide (23.3 mL, 268 mmol) and the
mixture was stirred for 6 h until all Zn had dissolved. Subsequently,
this solution of allylzinc bromide was transferred into a solution of
6 (61.4 mg, 179 mmol, non-enantiomerically enriched) in THF (1
mL) at 0 °C and allowed to warm to r.t.; H2O (2 mL) and EtOAc (5
mL) were added, the mixture was filtered, and the organic phase ex-
tracted with EtOAc (2 × 5 mL). The combined organic phases were
dried over MgSO4, the solvent was removed under vacuum and the
crude product recrystallized from EtOAc–PE to give 3 (29.2 mg,
42%) as a colorless solid.
Ethyl (S)-4-tert-Butoxycarbonylamino-3-ethoxycarbonylmeth-
yliminopentanoate (2)
A mixture of keto ester (1; 1.27 g, 4.89 mmol) and glycine ethyl es-
ter (504 mg, 4.89 mmol) was stirred for 14 h at 40 °C. The reaction
mixture was dried under vacuum, the viscose residue was dissolved
in Et2O (20 mL), filtered, and the reaction product was precipitated,
by the addition of PE, as a colorless solid. Recrystallization from
PE–toluene gave 1.42 g (84%) of 2.
[a]D20 –5 (c 6.6, CHCl3).
1H NMR and 13C NMR spectra cannot be assigned. The compound
Mp 126–128 °C.
exists in solution as a mixture of tautomeric forms and E/Z-isomers.
MS (CI, NH3): m/z (%) = 345.3 (100) [M + H+].
IR (KBr): 3439 (m), 3319 (m), 3192 (m), 2983 (w), 2933 (w), 1675
(s), 1663 (s), 1513 (w), 1470 (m), 1447 (m), 1274 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 (dd, 3J = 7.11, 7.14 Hz, 3 H,
1-H), 1.89 (s, 3 H, 8-H), 2.44 (ddt, 3J = 7.07, 7.05, 1.15 Hz, 2 H, 11-
H), 2.58 (br s, 1 H), 3.83 (t, 3J = 7.05 Hz, 1 H, 10-H), 3.84 (s, 3 H,
6-H) 3.99 (s, 1 H, 14-H), 4.25 (dq, 2J = 10.75, 3J = 7.11 Hz, 1 H, 2-
Anal. Calcd for C16H28N2O6 (344.41): C, 55.80; H, 8.19; N, 8.13.
Found: C, 56.22; H, 8.12; N, 8.02.
Ethyl 5-(S)-1-tert-Butoxycarbonylaminoethyl-3-hydroxy-1H-
pyrrole-2-carboxylate (3)
2
3
H
a/b), 4.28 (dq, J = 10.75, J = 7.14 Hz, 1 H, 2-Hb/a), 5.10 (ddt,
3J = 10.11, 2J = 1.82, 4J = 1.15 Hz, 1 H, 13-HE), 5.11 (ddt,
3J = 17.04, 2J = 1.82, 4J = 1.15 Hz, 1 H, 13-HZ), 5.74 (ddt,
3J = 17.04, 10.11, 7.07 Hz, 1 H, 12-H), 5.92 (br s, 1 H), 6.29 (br
s, 1 H), 7.15–7.31 (m, 5 H, 16–20-H), 8.97 (br s, 1 H, 4-NH).
To a solution of NaOEt [prepared from Na (67 mg, 2.9 mmol), an-
hyd EtOH (5 mL) under N2] was added 3 (1 g). The reaction mixture
was refluxed for 2.5 h, the solvent was removed under vacuum, the
residue was dissolved in H2O (2 mL), and neutralized by the addi-
tion of 1 N HCl. Only a trace amount (13 mg) of the desired com-
pound was isolated.
13C NMR (75 MHz, CDCl3): d = 7.1 (+), 14.5 (+), 40.5 (–), 53.8
(+), 59.9 (–), 62.2 (+), 64.7 (+), 109.7 (Cquat), 110.5 (Cquat), 118.3
(–), 127.3 (+, 2 C), 128.2 (+), 128.9 (+, 2 C), 133.0 (Cquat), 134.2
(+), 139.0 (Cquat), 151.2 (Cquat), 160.4 (Cquat), 174.8 (Cquat).
MS (EI, 70 eV): m/z (%) = 298.2 (11) [M+·], 198.1 (97) [M+·
–
C4H8CO2], 125.0 (100) [M+· –C4H8CO2C2H5CO2].
HRMS: m/z calcd for C14H22N2O5 [M+·], 298.15287; found,
298.15280.
MS [ESI, CH2Cl2–MeOH, NH4Ac (10 mmol/L)]: m/z (%) = 408.0
(11) [M + Na+], 386.0 (29), [M + H+], 235.8 (100) [M + H+ –
C8H7N2O].
Schiff Bases from 4 and Chiral Primary Amines; General Pro-
cedure
Anal. Calcd for C15H17N1O3 (385.47): C, 65.44; H, 7.06; N, 10.90.
Found: C, 65.21; H, 6.98; N, 10.87.
To a solution of 4 (0.25 M) and amine (1 equiv) in CH2Cl2 was add-
ed MgSO4 (250 mg/mmol 4), and the reaction mixture was stirred
overnight. Evaporating the filtered solution under vacuum yielded
the crude product.
Ethly 4-Methyl-3-methoxy-5-[(L-valinolimino)methyl]-1H-pyr-
role-2-carboxylate (S-9-i-Pr)
Compound 4 (100 mg, 473 mmol) and L-valinol (48.8 mg, 473
mmol) were allowed to react according to the general procedure to
give S-9-i-Pr (138 mg, 99%).
Ethyl 4-Methyl-3-methoxy-5-[(D-phenylglycineamidim-
ino)methyl]-1H-pyrrole-2-carboxylate (R-6)
Compound 4 (100 mg, 473 mmol) and D-phenylglycine amide (71.1
mg, 473 mmol) were reacted according to the general procedure to
give R-6 (133 mg, 82%), which was recrystallized from acetone.
Mp 105.5–106 °C; [a]D20 +151 (c 2.85, CHCl3).
IR (KBr): 3196 (s), 3980 (s), 2867 (sh), 1715 (s), 1628 (s), 1566 (s),
1471 (s), 1380 (s), 1283 (s), 1111 (s) cm–1.
3
Mp (dec) > 158 °C; [a]D20 +187 (c 1.5, CHCl3).
1H NMR (300 MHz, DMSO-d6): d = 0.84 (d, J = 6.86 Hz, 3 H),
0.86 (d, 3J = 6.86 Hz, 3 H), 1.29 (t, 3J = 7.00 Hz, 3 H), 1.85 (dsept,
3J = 5.37, 6.86 Hz, 1 H), 2.12 (s, 3 H), 2.80 (ddd, J = 4.12, 8.10,
3
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C. Bonauer, B. König
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2
3
5.37 Hz, 1 H), 3.38 (dd, J = 10.57, J = 8.10 Hz, 1 H), 3.59 (dd,
18-C), 127.2 (2 C, 16-C, 20-C or 17-C, 19-C), 127.5 (2 C, 17-C, 19-
C or 16-C, 20-C), 135.3 (1 C, 9-C), 142.9 (1 C, 15-C), 150.3 (1 C,
5-C), 159.5 (1 C, 3-C).
2J = 10.57, J = 4.12, 1 H), 3.74 (s, 3 H), 4.25 (q, 3J = 7.00 Hz,
2 H), 4.46 (br s, 1 H), 8.15 (s, 1 H).
3
13C NMR (75 MHz, CDCl3): d = 5.6 (+), 13.5 (+), 17.9 (+), 18.5
(+), 29.7 (+), 59.3 (–), 61.2 (+), 63.5 (–), 76.2 (+), 77.7 (+), 112.9
(Cquat), 117.0 (Cquat), 124.6 (Cquat), 149.3 (Cquat), 150.7 (+), 158.9
(Cquat).
MS [ESI, CH2Cl2–MeOH, NH4Ac (10 mmol/L)]: m/z (%) = 375
(100) [M + H+], 238 (36) [M + H+ –C8H11NO].
HRMS: m/z calcd for C21H30N2O4, 374.2206 [M·+]; found,
374.2209.
MS (CI, NH3): m/z (%) = 297 (100) [M + H+].
Ethyl 5-[(S)-1-Amino-2-methylpropyl)]-3-methoxy-4-methyl-
1H-pyrrole-2-carboxylate [H-(S)-i-PrMOPAS-OEt (S-11)]
To a solution of S,S-10-Ph (645 mg, 1.72 mmol) in MeOH–H2O–
AcOH (10 mL; 20:2:1), Pd/C (10%, 60 mg) was added and the re-
action mixture was stirred for 48 h under H2 (1 MPa). The mixture
was filtered through celite, the solvent was removed under vacuum,
the residue was dissolved in EtOAc (50 mL), and extracted with aq
KHSO4 (5%; 5 × 10 mL). The pH of the combined aqueous phases
were adjusted to >12 by addition of 2 N NaOH and then extracted
with CH2Cl2 (2 × 20 mL). The combined organic phases were dried
over MgSO4 and the solvent was removed under vacuum to give S-
11 (433 mg, 99%) as a colorless oil.
Anal. Calcd for C15H24N2O4: C, 60.79; H, 8.16; N, 9.45.
Found: C, 60.70; H, 7.71; N, 9.33.
Ethyl 4-Methyl-3-methoxy-5-[(L-phenylglycinolimino)methyl]-
1H-pyrrole-2-carboxylate (S-9-Ph)
Compound 4 (1.03 g, 4.90 mmol) and L-phenylglycinole (672 mg,
4.90 mmol) were allowed to react according to the general proce-
dure to give S-9-Ph in quantitative yield.
Mp 88–90 °C; [a]D20 –129 (c 2.0, CHCl3).
IR (KBr): 3240 (s), 2980 (s), 2933 (s), 2870 (sh), 1710 (s), 1630 (s),
1564 (s), 1510 (s), 1474 (s), 1381 (s), 1163 (s), 1028 (s) cm–1.
[a]D20 +33 (c 3.7, CHCl3).
1H NMR (300 MHz, DMSO-d6): d = 1.30 (t, 3J = 7.14 Hz, 3 H),
2.19 (s, 3 H), 3.58 (m, 2 H), 7.75 (s, 3 H), 4.22 (m, 1 H), 4.26 (q,
3J = 7.14 Hz, 2 H), 4.88 (br s, 1 H), 7.16–7.52 (m, 5 H), 8.30 (s,
1 H), 11.49 (br s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 8.1 (+), 14.2 (+), 59.5 (–), 61.6
(+), 66.8 (–), 76.9 (+), 112.1 (Cquat), 113.7 (Cquat), 126.8 (+), 127.1
(+, 2 C), 127.8 (Cquat), 128.1 (+, 2 C), 141.7 (Cquat), 150.7 (Cquat),
152.5 (+), 159.3 (Cquat).
IR (neat): 3348 (s), 2964 (s), 2937 (sh), 2871 (sh), 1683 (s), 1513
(w), 1470 (s), 1274 (s) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.68 (d, J = 6.68 Hz, 3 H),
3
0.91 (d, 3J = 6.68 Hz, 3 H), 1.27 (t, 3J = 7.00 Hz, 3 H), 1.76 (dsept,
3J = 7.72, 6.68 Hz, 1 H), 1.84 (s, 3 H), 3.42 (d, J = 7.72 Hz, 1 H),
3.71 (s, 3 H), 4.20 (q, 3J = 7.00 Hz, 2 H), 10.56 (br s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 7.3 (+), 14.4 (+), 19.3 (+), 19.5
(+), 33.1 (+), 54.1 (+), 58.7 (–), 61.3 (+), 107.4 (Cquat), 108.0 (Cquat),
137.7 (Cquat), 150.6 (Cquat), 159.5 (Cquat).
MS (CI, NH3): m/z (%) = 331.2 (100) [M + H+], 211.1 (11) [144 +
H+].
HRMS: m/z calcd for C13H22N2O3 [M·+], 254.1630; found,
254.1633.
Anal. Calcd for C18H22N2O4 (330.39): C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.23; H, 6.52; N, 8.45.
Anal. Calcd for C13H22N2O3 (254.22): C, 61.39; H, 8.72; N, 11.01.
Found: C, 60.59; H, 8.32; N, 10.51.
Ethyl 5-{(S)-1-[(S)-2-Hydroxy-1-phenylethylamino]-2-methyl-
propyl}-3-methoxy-4-methyl-1H-pyrrole-2-carboxylate (S,S-
10-Ph)
Boc-MOPAS-(S)-i-PrMOPAS-OEt (S-13)
A solution of S-9-Ph (59.8 mg, 181 mmol) in THF (2 mL) was
cooled to –5 °C and i-PrMgCl (400 mL, 2 M in Et2O) was added via
cannula. The reaction mixture was stirred for 1.5 h at 0 to –5 °C (a
blue color slowly developed), and subsequently was allowed to
warm to r.t. and then stirred overnight. Aq NH4Cl (1 mL) and 1 N
HCl (1 mL) were added to quench the reaction. The solution was di-
luted with EtOAc (2 mL) and aq 1 N NaOH was added until
pH > 13. The organic phase was separated and the aqueous phase
was extracted with EtOAc (3 × 2 mL), the combined organic phases
were dried over MgSO4 and the solvent removed under vacuum to
give 69 mg of the crude product, which was purified by column
chromatography (SiO2, CHCl3–EtOAc, 80:20→50:50) to give S,S-
10-Ph (52.4 mg, 77%) as a colorless oil.
A solution of S-11 (100 mg, 393 mmol), Boc-MOPAS-OBt (158
mg, 393 mmol), and i-Pr2EtN (82.0 mL, 60.7 mg, 469 mmol) in
CH2Cl2 (5 mL) was stirred for 2 h at r.t. The solution was diluted
with CH2Cl2 (3 mL), extracted with aq KHSO4 (5 × 3 mL), aq
NaHCO3 (4 × 3 mL), and H2O (3 mL). The organic phase was dried
over MgSO4 and the solvent was removed under vacuum to yield
210 mg of the crude product, which was recrystallized from CHCl3–
PE (60:40) to give 176 mg (86%) of S-13 as a colorless solid.
Mp 91–93 °C; [a]D20 +34 (c 2.1, CHCl3).
IR (KBr): 3385 (s), 3296 (s), 2972 (m), 2933 (sh), 2875 (sh), 1663
(s), 1640 (s), 1532 (s), 1459 (m) cm–1.
1H NMR (600 MHz, CDCl3): d = 0.88 (m, 3 H), 1.42 (m, 3 H),
1.32–1.54 (m, 12 H), 2.10 (s, 3 H), 2.12–2.22 (m, 4 H), 3.82 (s,
3 H), 3.86 (s, 3 H), 4.28 (m, 2 H), 4.37 (m, 2 H), 5.54 (m, 1 H), 5.60
(m, 1 H), 7.56 (m, 1 H), 10.79 (br s, 1 H), 11.47 (br s, 1 H).
[a]D20 –71 (c 2.9, MeCN); Rf 0.46 (CHCl3–EtOAc, 50:50).
IR (neat): 3458 (s), 3323 (s), 2960 (s), 2933 (sh), 2871 (sh), 1675
(s), 1463 (s), 1270 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.64 (d, 3J = 6.50 Hz, 3 H, 12-
13C NMR (150 MHz, CDCl3): d = 7.8 (+), 8.1 (+), 14.4 (+), 19.8
(+), 20.0 (+), 28.4 (+), 34.0 (+), 35.5 (–), 53.4 (+), 60.4 (–), 61.4 (+),
62.4 (+), 79.2 (Cquat), 108.1 (Cquat), 108.7 (Cquat), 112.4 (Cquat), 128.4
(Cquat), 134.5 (Cquat), 146.9 (Cquat), 152.4 (Cquat), 155.6 (Cquat), 160.3
(Cquat), 162.3 (Cquat).
HRMS: m/z calcd for C26H40N4O7 [M+·], 520.2897; found,
520.2895.
H or 13-H), 1.02 (d, 6.50 Hz, 3 H, 13-H or 12-H), 1.26 (t, 3J = 7.15
3
Hz, 3 H, 1-H), 1.70 (s, 3 H, 8-H), 1.92 (dsept, J = 8.31, 6.50 Hz ,
1 H, 11-H), 2.56 (br s, 1 H, 10-NH or 21-OH), 3.37 (d, 3J = 8.31 Hz,
1 H, 10-H), 3.46 (m, 2 H, 21-H), 3.49 (m, 1 H, 14-H), 3.64 (s, 3 H,
3
6-H), 4.18 (q, J = 7.15 Hz, 2 H,), 4.59 (br s, 1 H, 21-OH or 10-
NH), 7.09–7.21 (m, 5 H, 16–20-H), 10.37 (br s, 1 H, 4-NH).
13C NMR (75 MHz, CDCl3): d = 7.1 (1 C, 8-C), 14.4 (1 C, 1-C),
19.3 (1 C, 12-C or 13-C), 20.4 (1 C, 13-C or 12-C), 32.8 (1 C, 11-
C), 58.7 (1 C, 2-C), 59.3 (1 C, 10-C), 61.2 (1 C, 6-C), 63.0 (1 C, 14-
C), 65.6 (1 C, 21-C), 108.4 (1 C, 4-C), 109.1 (1 C, 7-C), 126.4 (1 C,
Anal. Calcd for C26H40N4O7: C, 59.98; H, 7.74; N, 10.76.
Found: C, 59.31; H, 7.67; N, 10.45.
Synthesis 2005, No. 14, 2367–2372 © Thieme Stuttgart · New York

PAPER
Synthesis and Structure of Chiral Methoxypyrrole Amino Acids
2371
Boc-Phe-(S)-i-PrMOPAS-OEt (S,S-14)
(4) (a) Nowick, J. S.; Chung, D. M.; Maitra, K.; Maitra, S.;
Stigers, K. D.; Sun, Y. J. Am. Chem. Soc. 2000, 122, 7654.
(b) Boumendjel, A.; Roberts, J. C.; Hu, E.; Pallai, P. V. J.
Org. Chem. 1996, 61, 4434. (c) Michne, W. F.; Schroeder,
J. D. Int. J. Pept. Protein Res. 1996, 47, 2. (d) Roberts, J.
C.; Pallai, P. V.; Rebek, J. Jr. Tetrahedron Lett. 1995, 36,
691. (e) Rzepecki, P.; Gallmeier, H.-C.; Geib, N.;
Cernovska, K.; König, B.; Schrader, T. J. Org. Chem. 2004,
69, 5168. (f) Černovská, K.; Kemter, M.; Gallmeier, H.-C.;
Rzepecki, P.; Schrader, T.; König, B. Org. Biomol. Chem.
2004, 2, 1603.
(5) (a) Rzepecki, P.; Wehner, M.; Molt, O.; Zadmard, R.;
Harms, K.; Schrader, T. Synthesis 2003, 1815. (b) Kemp,
D. S.; Bowen, B. R.; Muendel, C. C. J. Org. Chem. 1990, 55,
4650. (c) Kemp, D. S. Trends Biotechnol. 1990, 8, 249.
(d) Kemp, D.; Bowen, B. R. Tetrahedron Lett. 1988, 29,
5077.
A mixture of S-11 (22.0 mg, 86.5 mmol), S-Boc-Phe-OH (22.9 mg,
86.5 mmol), HATU (32.9 mg, 86.5 mmol), HOAt (11.8 mg, 86.5
mmol), and i-Pr2NH (14.7 mL, 11.2 mg, 86.5 mmol) in CH2Cl2
(3 mL) was stirred for 6 h at r.t. The reaction mixture was diluted
with of CH2Cl2 (10 mL), washed with aq KHSO4 (5%, 5 × 10 mL),
aq NaHCO3 (0.5 M; 3 × 10 mL), the organic phase was dried over
MgSO4, and the solvent was removed under vacuum. The crude
product was recrystallized from EtOAc–PE to give S,S-14
(36.3 mg, 84%) as a colorless solid.
Mp 159.5–161 °C; [a]D20 –90 (c 2.2, MeCN).
1H NMR (300 MHz, CDCl3): d = 0.69 (m, 3 H), 0.84 (m, 3 H),
1.18–1.46 (m, 12 H), 1.88 (s, 3 H), 1.89–2.06 (m, 1 H), 2.97 (m,
2 H), 3.81 (s, 3 H), 4.15–4.39 (m, 3 H), 4.62 (m, 1 H), 5.29 (m,
1 H), 6.63 (m, 1 H), 6.96–7.17 (m, 5 H), 9.12 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 7.4 (+), 14.6 (+), 19.2 (+), 19.4
(+), 28.3 (+, 3 C), 32.4 (+), 38.1 (–), 52.6 (+), 56.5 (+), 60.1 (–), 62.2
(+), 80.3 (Cquat), 109.7 (Cquat), 110.2 (Cquat), 126.9 (+), 128.6 (+,
2 C), 129.1 (+, 2 C), 132.1 (Cquat), 136.4 (Cquat), 151.2 (Cquat), 155.7
(Cquat), 160.8 (Cquat), 171.0 (Cquat).
(6) The work on b-sheet recognition and peptidomimetics has
been extensively reviewed: (a) Glenn, M. P.; Fairlie, D. P.
Mini Rev. Med. Chem. 2002, 2, 433. (b) Peczuh, M. W.;
Hamilton, A. D. Chem. Rev. 2000, 100, 2479.
(7) (a) Bonauer, C.; Zabel, M.; König, B. Org. Lett. 2004, 6,
1349. (b) Recent related work: Chakraborty, T. K.; Mohan,
B. K.; Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett. 2003,
44, 471. (c) Rao, M. H. V. R.; Kumar, S. K.; Kunwar, A. C.
Tetrahedron Lett. 2003, 44, 7369. (d) Nowick, J. S.; Lam,
K. S.; Khasanova, T. V.; Kemnitzer, W. E.; Maitra, S.; Mee,
H. T.; Liu, R. J. Am. Chem. Soc. 2002, 124, 4972.
(e) Nowick, J. S.; Cary, J. M.; Tsai, J. H. J. Am. Chem. Soc.
2001, 123, 5176. (f) Nowick, J. S.; Chung, D. M.; Maitra,
K.; Maitra, S.; Stigers, K. D.; Sun, Y. J. Am. Chem. Soc.
2001, 123, 1545. (g) Nowick, J. S.; Chung, D. M.; Maitra,
K.; Maitra, S.; Stigers, K. D.; Sun, Y. J. Am. Chem. Soc.
2000, 122, 7654.
MS [ESI, CH2Cl2–MeOH, NH4Ac (10 mmol/L]: m/z (%) = 502
(100) [M + H+], 446 (12) [M + H+ –C4H8].
Anal. Calcd for C27H39N3O6 (501.62): C, 64.65; H, 7.84; N, 8.38.
Found: C, 64.39; H, 7.27; N, 8.12.
Acknowledgment
We thank the Fonds der Chemischen Industrie (fellowship for C.B.)
and the Graduiertenkolleg GRK 760 Medicinal Chemistry for sup-
port.
(8) (a) For a recent review on non-natural amino acids see:
Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K.
J. Chem. Sci. 2004, 116, 187. (b) For examples of other
non-natural heterocyclic amino acids see: König, B.; Rödel,
M. Chem. Commun. 1998, 605. (c) König, B.; Rödel, M.
Synth. Commun. 1998, 29, 943. (d) Miltschitzky, S.; König,
B. Synth. Commun. 2004, 34, 2077.
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Synthesis 2005, No. 14, 2367–2372 © Thieme Stuttgart · New York

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C. Bonauer, B. König
PAPER
(14) For a recent example of the method used on solid support
(10) Honore, T.; Hjeds, H.; Krogsgaard-Larsen, P.; Christiansen,
T. R. Eur. J. Med. Chem. 1978, 13, 429.
(11) A derivative of 1 bearing a methyl group in position 2 may
cyclize more easily. However, our attempts to transform this
compound into the Schiff base corresponding to compound
2 were not successful.
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chiral imines see: (a) Bloch, R. Chem. Rev. 1998, 98, 1407.
(b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997,
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see: Wu, G.; Cai, Z.-W.; Bednarz, M. S.; Kocy, O. R.; Gavai,
A. V.; Godfrey, J. D.; Washburn, W. N.; Poss, M. A.; Sher,
P. M. J. Comb. Chem. 2005, 7, 99.
(15) The self-association of 10 is one order of magnitude higher
if compared to a Boc-(MOPAS)2-OEt missing the isopropyl
substituent; see ref. 7a for data.
(16) For DNA binding properties of pyrrole amino acids see:
Chakraborty, T. K.; Mohan, B. K.; Gnanamani, M.; Maiti, S.
Tetrahedron Lett. 2005, 46, 647.
(13) (a) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron
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(17) The self-association of 10 and the dipeptides were included
in the binding model.
Synthesis 2005, No. 14, 2367–2372 © Thieme Stuttgart · New York