Synthesis of 3-oxo-2,3-dihydropyrrole amino acids as chiral dipeptidomimics

Article abstract of DOI:10.1055/s-2006-942497

We describe the synthesis of a novel chiral dipeptide β-sheet mimic based on aminomethyl-3-oxo-2,3-dihydropyrrole carboxylic acids. The synthesis uses a palladium-catalyzed allylation with the chiral Trost ligand as a key step for the construction of a qu

Full text of DOI:10.1055/s-2006-942497

PAPER
A
Synthesis of 3-Oxo-2,3-dihydropyrrole Amino Acids as Chiral
Dipeptidomimics
C
hira
l
dipeptid
r
e
mimicantik Maity, Burkhard König*
Institut für Organische Chemie, Universität Regensburg, 93040 Regensburg, Germany
Fax +49(941)9431717; E-mail: Burkhard.koenig@chemie.uni-regensburg.de
Received 20 April 2006
First, we prepared 3-hydroxypyrrole amino acids (HO-
PAS) 7 as the starting materials for the asymmetric syn-
thesis of chiral 3-oxo-2,3-dihydropyrrole amino acids
such as 8 (Scheme 1). The hydroxyl group of pyrrole 38
Abstract: We describe the synthesis of a novel chiral dipeptide b-
sheet mimic based on aminomethyl-3-oxo-2,3-dihydropyrrole car-
boxylic acids. The synthesis uses a palladium-catalyzed allylation
with the chiral Trost ligand as a key step for the construction of a
quaternary chiral center. This allows the enantioselective conver- was benzyl protected, formylated at the 5-position, con-
sion of 2-carboxy-3-hydroxy-pyrrole into 3-oxo-2,3-dihydropyr-
role-2-allyl-2-carboxylate. The allyl group is subsequently
converted into an aldehyde or ester group. Peptide coupling of the
3-oxo-2,3-dihydropyrrole amino acid leads to more extended sys-
tems with partially constrained dipeptide units.
verted into Boc-protected amino ester 6, and debenzylated
to give 7.
OBn
OBn
OH
b)
a)
OEt
OEt
Key words: pyrroles, 3-oxo-2,3-dihydropyrrole, allylations, amino
acids, catalysis, palladium
OEt
54%
92%
N
H
N
H
N
H
O
O
O
O
3
4
5
A peptidomimic imitates peptide structures by controlled
spatial disposition of functional groups and by exhibiting
a generally analogous structure. Previously reported pep-
tide mimics based on oligo-3-oxo-2,3-dihydropyrroles
have been used as a protease inhibitor and ligand for hor-
mone and protein receptors.1 Their chiral sequence can
adopt the bioactive conformation of peptide ligands while
exhibiting good pharmacokinetic properties.2 Smith and
Hirschmann3 first prepared 2,5-linked 3-oxo-2,3-dihydro-
OBn
O
OH
O
e)
c), d)
59%
OEt
BocHN
OEt
BocHN
100%
N
N
H
H
6
7
Scheme 1 Synthesis of HOPAS 7. Reagents and conditions: a)
BnCl, K2CO3, in DMF, 85 °C, 16 h; b) POCl3, DMF, DCE, reflux,
pyrroles 1 starting from chiral natural amino acids 2.5 h; c) NH2Boc, HCOOH, p-TsONa, THF–H2O, r.t., 3 d; d) NaBH4,
(Figure 1). Seebach et al.4 have prepared a-substituted
proline derivatives while retaining the chirality, which
THF, r.t., 2 h; e) Pd/C, H2, MeOH, r.t., 1 d.
was further developed into b-turn peptide mimics 2 by
Gmeiner et al.5 We have recently reported methoxypyr-
role amino acids (MOPAS), which mimic the structure of
a H2N-Gly-D-Ala-OEt unit with b-sheet conformation.6
Extending this, we report here the synthesis of 2-allyl-2,3-
dihydro-3-oxopyrrole amino acids by stereoselective
chiral allylation using the Trost ligand7 as the chiral con-
trol element.
The basic hydrolysis of 2-ethyl-3-hydroxypyrrole carbox-
ylates is known to be difficult. In basic media the com-
pound exists in its two tautomeric forms (Figure 2).9
Using this property we intended to introduce an allyl
group at C-2 in a stereoselective manner via Pd-catalyzed
allylation using the chiral Trost ligand.10,11 The allylated
3-oxo-2,3-dihydropyrrole amino acid 8 was obtained, but
the yield (35%) and the enantiomeric excess (28%) of the
reaction were unsatisfactory (Scheme 2).
O
During the alkylation reaction the thermodynamically un-
favorable loss of aromaticity occurs, which may explain
the difficulties. Introduction of an electron-withdrawing
group onto the pyrrole nitrogen, which reduces the avail-
ability of the lone pair,12 may improve the situation.
H
N
O
R
O
R
N
H
H
R
N
N
O
N
O
O
N
R
O
O
H
H
H
R
O
2
1
Figure 1 Structures of 2,5-linked 3-oxo-2,3-dihydropyrroles 1 and
b-turn peptide mimics 2.
OH
O
H
OEt
OEt
N
N
H
H
O
O
SYNTHESIS 2006, No. x, pp 000A–000F
x
x
.xx.
2
0
0
6
Advanced online publication: xx.xx.2006
DOI: 10.1055/s-2006-942497; Art ID: Z08406SS
Figure 2 Tautomers of 2-ethyl-3-hydroxypyrrolecarboxylate.
© Georg Thieme Verlag Stuttgart · New York

B
P. Maity, B. König
PAPER
Table 1 Yield and Optical Purity of Compound 12 under Different
Reaction Conditions
OAc
KOtBu, r.t.,
MeCN, Pd (II),
Trost ligand
O
Base
Solvent
MeCN
MeCN
THF
Time (h) Temp (°C) Yield (%) ee (%)a
BocHN
OEt
7
t-BuOK
t-BuOK
NaH
2
0
–22
r.t.
83
87
90
68
71
17
31
9
N
H
35%
O
2.5
0.16
6
8
Scheme 2 Synthesis of allylated 3-oxo-2,3-dihydropyrrole amino
acid 8.
NaH
THF
–15 to 0 95
–78 80
n-BuLi
THF
1.5
Therefore, N-Boc protected pyrrole 10 was prepared start-
ing from 5 (Scheme 3). The H NMR spectrum of 3-hy-
a Optical purity was determined by chiral HPLC analysis.
1
droxypyrrole 11 in CDCl3 reveals the presence of the keto
tautomer as the only isomer, which indicates the reduced
heteroaromatic character of the pyrrole ring.
To demonstrate the ability of compound 12 to be incorpo-
rated into peptide chains, the Boc protecting group of the
primary amine was removed selectively using HCl in
Et2O. The amine was coupled using standard peptide cou-
pling conditions with Boc-Phe-OH giving tripeptide 13 in
58% yield (Scheme 4). The allyl group of 12 allows the
introduction of additional functional groups if desired;
conversion to aldehyde 14 was effected using K2OsO4 and
NaIO4 in THF and H2O.13 The aldehyde was converted
into the corresponding acid 15 using NaClO2, NaH2PO4,
and H2O2 in MeCN and H2O.14 Compound 15 resembles
the structure of a partially constrained dipeptide of glycine
and a b-amino acid. Acid 15 was coupled using standard
peptide coupling conditions with Boc-deprotected com-
pound 12 to give the tetrapeptide structure 1615 in 30%
yield (Scheme 5).
OBn
a)
b),c)
55%
OEt
5
100%
N
O
O
Boc
9
OBn
O
O
H
OEt
BocHN
d)
75%
BocHN
OEt
N
N
O
Boc
Boc
11
10
KOtBu,
MeCN,
O
Pd(II),
Trost ligand
BocHN
OEt
O
N
Boc
12
O
OAc
a), b)
H
OEt
12
N
58%
N
BocHN
O
O
Boc
O
Scheme 3 Synthesis of Boc-protected pyrrole 10 and its asymmetric
allylic alkylation to 3-oxo-2,3-dihydropyrrole amino acid 12.
Reagents and conditions: a) Boc2O, DMAP, CH2Cl2, r.t., 2 h; b)
NH2Boc, HCOOH, p-TsONa, THF–H2O, r.t., 2 d; c) NaBH4, THF,
r.t., 2 h; d) Pd/C, H2, MeOH–CHCl3 (8:1).
13
O
c)
BocHN
12
H
OEt
62%
N
Boc
The reaction of 3-oxo-2,3-dihydropyrrole 11 with allyl
acetate in the presence allyl palladium(II) chloride as cat-
alyst and the chiral Trost ligand gave the desired com-
pound in good yield (Table 1). An ee of 68% was
observed at 0 °C with t-BuOK as base in MeCN. A de-
crease of the reaction temperature to –35 °C increased the
optical purity of the isolated product to 71% ee with a
chemical yield of 87%. Compound 12 was fully character-
ized by spectroscopic methods. The transition state model
for the formation of the quaternary centre predicts an ‘R’
configuration if the R,R stereoisomer of the Trost ligand is
used.12 This is supported by the optical rotation of 12,
[a]D +143.8, which corresponds to [a]D +22.0 reported for
the structurally related compound (R)-2,4-dibenzyl-2-(3-
methylbut-2-enyl)-1,2-dihydropyrrole-3-one.1
O
14
O
O
d)
OH
BocHN
85%
OEt
N
Boc
O
15
Scheme 4 Synthesis of tripeptide 13. Reagents and conditions: a)
HCl, Et2O; b) EDC, HOBt, DIPEA CH2Cl2, r.t.; c) K2OsO4, NaIO4,
THF–H2O; d) NaClO2, NaH2PO4, H2O2, MeCN–H2O (4:1), r.t.
Synthesis 2006, No. x, A–F © Thieme Stuttgart · New York

PAPER
Chiral Dipeptide Mimic
C
Ethyl 3-Benzyloxy-5-formyl-4-methyl-1H-pyrrole-2-carboxyl-
ate (5)
O
O
H
N
a), b) + 15
30%
BocNH
A solution of compound 4 (7.43 g, 28.7 mmol) in DCE (75 mL) was
added dropwise to an ice-cold solution of DMF (2.3 g, 31.5 mmol)
in DCE (75 mL) containing POCl3 (4.83 g, 31.5 mmol). After stir-
ring at r.t. for 1 h the mixture was heated to reflux for 2 h, then
cooled to r.t. EtOAc (50 mL) and H2O (100 mL) were added and the
organic layer was separated. The aqueous layer was washed with
EtOAc (2 × 100 mL), the combined organic layers were washed
with a 10% aq solution of NaCO3 (5 × 150 mL), and dried over
MgSO4. The solvent was evaporated to give 7.85 g of the crude
product, which was purified by CC (PE–EtOAc, 70: 30).
12
N
R
N
R
O
Boc
Boc
R = CO2Et
16
Scheme 5 Synthesis of compound 16. Reagents and conditions: a)
HCl, Et2O; b) EDC, HOBt, DIPEA, CH2Cl2, r.t.
We have used the enantioselective Pd-catalyzed allylic
alkylation with the Trost ligand to convert N-Boc protect-
ed 3-hydroxypyrrole 11 into 3-oxo-2,3-dihydropyrrole
amino acid 12 breaking the heteroaromatic p-system.
Yield: 7.60 g (92%); mp 81–83 °C; Rf 0.43.
IR (KBr): 3258, 2938, 2817, 169, 1672, 1555, 1507, 1487, 1377,
With t-BuOK as base and at low reaction temperatures an 1280 cm–1.
1H NMR: d = 1.38 (t, J = 7.14 Hz, 3 H), 2.12 (s, 3 H), 4.38 (q,
J = 7.14 Hz, 2 H), 5.06 (s, 2 H), 7.30–7.47 (m, 5 H), 9.25 (br s, 1 H),
9.71 (br s, 1 H).
13C NMR: d = 6.8 (+), 14.4 (+), 61.2 (–), 77.1 (–), 117.8 (Cquat),
123.1 (Cquat), 127.7 (Cquat), 128.3 (+), 128.5 (+), 128.5 (+), 137.0
(Cquat), 148.7 (Cquat), 159.6 (Cquat), 179.1 (+).
ee of 71% with a chemical yield of 87% was obtained. 3-
Oxo-2,3-dihydropyrrole amino acid 12 resembles the
structure of a partially constrained dipeptide, which may
find use in the synthesis of more extended peptide mimics.
Melting points are uncorrected. Specific rotations were measured
on a polarimeter using a 10 cm cell. NMR spectra were recorded in
CDCl3 at 300 MHz (1H) or 75 MHz (13C) unless stated otherwise.
Structural assignments are based on DEPT and COSY experiments
where applicable. The multiplicity of the carbon atoms is given as
(+) = CH3 or CH, (–) = CH2 and (Cquat) for quaternary carbon at-
oms. Analytical TLC plates (silica gel 60 F254) and silica gel 60 (70–
230 or 230–400 mesh) for column chromatography (CC) were pur-
chased from Merck. Spots were visualized by UV light and/or stain-
ing with phosphomolybdate or ninhydrine in EtOH. DMF, MeCN,
THF, and Et2O were dried by standard procedures and stored over
molecular sieves or Na. PE had a boiling range of 70–90 °C. All
other solvents and chemicals were of reagent grade and used with-
out further purification. The Trost ligand was prepared as described
in the literature.7,16
MS (70 eV): m/z (%) = 287 (22) [M+], 91 (100) [C7H7 ].
+
Anal. Calcd for C16H17NO4 (287.32): C, 66.89; H, 5.96; N, 4.88.
Found: C, 66.79; H, 5.95; N, 4.87.
Ethyl 3-Benzyloxy-5-(tert-butoxycarbonylaminomethyl)-4-
methyl-1H-pyrrole-2-carboxylate (6)
A mixture of NH2Boc (554 mg, 4.73 mmol), THF (1.9 mL), H2O (2
mL), sodium p-toluene sulfinate (843 mg, 4.73 mmol), aldehyde 5
(1 g, 4.73 mmol), and HCOOH (1.18 mL) was stirred until the mix-
ture became homogeneous and stirring was continued for 6 d at r.t.
The solid product was suction filtered, washed successively with
H2O and PE, then dried over P2O5 to give 2.02 g of the tosylated in-
termediate, which was used in the next step without further purifi-
cation. The intermediate (522 mg) was added portionwise to a
suspension of NaBH4 (72 mg, 1.92 mmol) in THF (5 mL), while the
mixture was ice cooled. Stirring was continued for 15 min with ice
cooling and then at r.t. for 2 h. The mixture was ice cooled again,
quenched with a sat. solution of aq NH4Cl (1 mL), and stirring was
continued for 30 min. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (15 mL), the combined
layers were dried over MgSO4, and concentrated. The crude product
was purified by CC (CHCl3–acetone, 95:5→90:10) to give 232 mg
(59%) of compound 6.
Ethyl 3-Benzyloxy-4-methyl-1H-pyrrole-2-carboxylate (4)
To a stirred solution of hydroxypyrrole 3 (12 g, 70.9 mmol) in an-
hyd DMF, K2CO3 (9.8 g, 71 mmol) was added followed by BnCl
(8.98 g, 70.9 mmol). The suspension was stirred for 14 h at 70 °C
and then for 4 h at 110 °C. Then BnCl (820 mg, 6.47 mmol) was
added and the solution was heated for 1 h at the same temperature.
The reaction mixture was allowed to cool to r.t. and poured into H2O
(1 L). The aqueous layer was extracted with EtOAc (3 × 150 mL).
The combined organic layers were washed with a 10% aq solution
of Na2CO3 (100 mL), H2O (2 × 100 mL), and dried over MgSO4.
The solvent was removed in vacuo to give an oily product, which
was solidified by addition of PE. The solid was recrystallized from
MeOH.
Yield: 232 mg (59%); mp 112.5–113 °C; Rf 0.68 (CHCl3–acetone,
90:10).
IR (KBr): 3357, 3282, 2980, 2934, 1687, 1665, 1531, 1461, 1294,
1171, 1027 cm–1.
1H NMR: d = 1.34 (t, J = 7.14 Hz, 3 H), 1.46 (s, 9 H), 1.86 (s, 3 H),
4.16 (m, 2 H), 4.32 (q, J = 7.14 Hz, 2 H), 4.98 (br s, 1 H), 5.04 (s, 2
H), 7.27–7.49 (m, 5 H), 9.08 (br s, 1 H).
13C NMR: d = 7.2 (+), 14.5 (+), 28.4 (+), 35.9 (–), 60.1 (–), 76.7
(–), 80.1 (Cquat), 110.4 (Cquat), 110.7 (Cquat), 127.9 (+), 128.2 (+),
128.3 (+), 129.5 (Cquat), 137.8 (Cquat), 149.7 (Cquat), 156.6 (Cquat),
160.4 (Cquat).
Yield: 9.93 g (54%); mp 78–83 °C.
IR (KBr): 3298, 2974, 2862, 1660, 1466, 1411, 1288 cm–1.
1H NMR: d = 1.35 (t, J = 7.14 Hz, 3 H), 1.91 (s, 3 H), 4.35 (q,
J = 7.14 Hz, 2 H), 5.07 (s, 2 H), 6.57 (m, 1 H), 7.27–7.50 (m, 5 H),
8.45 (br s, 1 H).
13C NMR: d = 8.3 (+), 14.3 (+), 59.0 (–), 75.4 (–), 110.5 (Cquat),
111.4 (Cquat), 120.3 (+), 127.7 (+), 128.0 (+), 128.0 (+), 137.7
(Cquat), 149.1 (Cquat), 159.6 (Cquat).
Anal. Calcd for C21H28N2O5 (388.47): C, 64.93; H, 7.27; N, 7.21.
Found: C, 64.74; H, 7.64; N, 7.00.
MS (70 eV): m/z (%) = 259 (48) [M+], 186 (14) [M+ – C3H5O2], 91
+
(100) [C7H7 ].
Ethyl 5-(tert-Butoxycarbonylaminomethyl)-3-hydroxy-4-meth-
yl-1H-pyrrole-2-carboxylate (7)
To a solution of compound 6 (100 mg, 257 mmol) in EtOAc (3 mL),
10% Pd/C (10 mg) was added and the mixture was transferred to an
autoclave. The mixture was stirred for 48 h under H2 (10 bar) at r.t.
Anal. Calcd for C15H17NO3 (259.31): C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.26; H, 6.27; N, 5.34.
Synthesis 2006, No. x, A–F © Thieme Stuttgart · New York

D
P. Maity, B. König
PAPER
The solution was filtered through celite and the solvent was evapo-
rated in vacuo.
13C NMR: d = 8.3 (+), 14.2 (+), 27.5 (+), 61.6 (–), 77.4 (–), 86.4
(Cquat), 118.9 (Cquat), 125.1 (Cquat), 128.3 (+), 128.4 (+), 128.6 (+),
136.60 (+), 148.23 (Cquat), 148.81 (Cquat), 160.05 (Cquat), 181.55
(Cquat).
Yield: 76.7 mg (257 mmol, quantitative); mp 102–103 °C.
IR (KBr): 3354, 3281, 2972, 2929, 1675, 1536, 1482, 1293, 1247
cm–1.
1H NMR: d = 1.34 (t, 3J = 7.14 Hz, 3 H), 1.46 (s, 9 H), 1.94 (s, 3 H),
4.15 (m, 2 H), 4.31 (q, 3J = 7.14 Hz, 2 H), 4.89 (br s, 1 H), 7.69 (br
s, 1 H), 8.47 (br s, 1 H).
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 388.2
(95) [M + H+], 288.1 (100) [M + H+ – C4H8].
Anal. Calcd for C21H25NO6 (387.44): C, 65.10; H, 6.50; N, 3.62.
Found: C, 64.92; H, 6.57; N, 3.52.
13C NMR: d = 6.5 (+), 14.6 (+), 28.3 (+), 59.9 (–), 77.2 (Cquat), 80.3
(Cquat), 104.2 (Cquat), 104.6 (Cquat), 131.2 (Cquat), 152.7 (Cquat), 156.7
(Cquat).
1-tert-Butyl-2-ethyl-3-benzyloxy-5-(tert-butoxycarbonylamino-
methyl)-4-methylpyrrole-1,2-dicarboxylate (10)
A mixture of NH2Boc (302 mg, 2.58 mmol), THF (1.9 mL), H2O (2
mL), sodium p-toluene sulfinate (459.8 mg, 2.58 mmol), aldehyde
9 (1 g, 4.73 mmol), and HCOOH (1.18 mL) was stirred until a ho-
mogeneous mixture was obtained, then stirring was continued for 2
d at r.t. The solid product was removed by suction filtration, washed
successively with H2O, PE, and dried over P2O5 to give 1.50 g of 1-
tert-butyl-2-ethyl-3-benzyloxy-5-[tert-butoxycarbonylamino(tolu-
ene-4-sulfinyloxy)methyl]-4-methyl-pyrrole-1,2-dicarboxylate,
which was used in the next step without further purification.
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 299
(100) [M + H+], 243 (13) [M + H+ – C4H8].
Anal. Calcd for C14H22N2O5 (298.34): C, 56.36; H, 7.43; N, 9.39.
Found: C, 56.17; H, 7.78; N, 9.06.
Ethyl 2-Allyl-5-(tert-butoxycarbonylaminomethyl)-4-methyl-3-
oxo-2,3-dihydro-1H-pyrrole-2-carboxylate (8)
To a flask containing a solution of compound 7 (2 g, 6.5 mmol) in
anhyd MeCN (25 mL), t-BuOK (0.73 g, 6.5 mmol) was added under
nitrogen. The mixture was stirred for 15 min at 0 °C. Meanwhile,
the palladium complex (h3-C3H5PdCl)2 (36.5 mg, 100 mmol) and
(R,R)-Trost ligand (69.2 mg, 100 mmol) were dissolved in anhyd
MeCN and stirred for 15 min at r.t. before allyl acetate (2.10 mL,
19.54 mmol) was added and stirring was continued at r.t. for an ad-
ditional 5 min. The catalyst solution was cooled to 0 °C, then trans-
ferred via syringe into the enolate solution at 0 °C. The mixture was
stirred for 1 d. The reaction was quenched with a sat. aq solution of
NH4Cl (10 mL), stirred vigorously for 10 min, and then H2O (20
mL) was added to dissolve the precipitate. The solution was extract-
ed with Et2O (3 × 30 mL), the organic phase was dried over MgSO4,
and the solvent removed in vacuo. The crude product was purified
by CC (PE–EtOAc; 1:1).
To a suspension of NaBH4 (72 mg, 1.92 mmol) in THF (5 mL), 1-
tert-butyl-2-ethyl-3-benzyloxy-5-[tert-butoxycarbonylamino(tolu-
ene-4-sulfinyloxy)methyl]-4-methyl-pyrrole-1,2-dicarboxylate
(522 mg) was added portionwise while the mixture was ice cooled.
Stirring was continued for 15 min with ice cooling and then the mix-
ture was stirred for 2 h at r.t. The mixture was ice cooled again,
quenched with a sat. aq solution of NH4Cl (1 mL) and stirred for 30
min. The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (15 mL). The combined layers were dried over
MgSO4 and concentrated. The crude product was purified by CC
(EtOAc–PE, 1:4) and then recrystallized from Et2O.
Yield: 232 mg (55%); Rf 0.59; mp 103–105 °C.
IR (KBr): 3448, 3245, 3035, 2977, 2933, 2875, 2200, 1739, 1714,
1603, 1500, 1462, 1432, 1389, 1336, 1302, 1238 cm–1.
1H NMR: d = 1.34 (t, J = 7.14 Hz, 3 H), 1.47 (s, 9 H), 1.63 (s, 9 H),
2.06 (s, 3 H), 4.25 (m, 4 H), 5.05 (s, 2 H), 5.51 (br s, 1 H), 7.27–7.49
(m, 5 H).
13C NMR: d = 7.6 (+), 14.6 (+), 15.3 (+), 27.6 (+), 28.4 (+), 35.1
(–), 60.8 (–), 60.8 (+), 77.1 (–), 85.3 (Cquat), 114.1 (Cquat), 115.3
(Cquat), 128.1 (+), 128.1 (+), 128.4 (+), 132.1 (+), 137.6 (+), 149.6
(Cquat), 151.6 (Cquat), 155.6 (Cquat), 160.7 (Cquat).
Yield: 768 mg (35%); colorless oil; Rf 0.32.
IR (NaCl): 3327, 2983, 2933, 1772, 1729 cm–1.
1H NMR: d = 1.27 (m, 3 H), 1.46 (s, 9 H), 1.66 (s, 3 H), 2.43 (m, 1
H), 2.93 (m, 1 H), 4.16 (m, 1 H), 4.19 (m, 2 H), 4.24 (m, 1 H), 4.98
(m, 1 H), 5.10 (m, 1 H), 5.15 (m, 1 H), 5.67 (m, 1 H), 5.81 (m, 1 H).
13C NMR: d = 6.0 (+), 14.2 (+), 28.3 (+), 38.0 (–), 39.9 (–), 62.4
(–), 72.6 (Cquat), 105.5 (Cquat), 119.8 (–), 131.6 (+), 156.4 (Cquat),
167.4 (Cquat), 173.7 (Cquat), 196.1 (Cquat).
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 489.3
(100) [M + H+], 433.1 (10) [M + H+ – C4H8], 389.2 (20) [M + H+ –
2C4H8].
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 339.1
(100) [M + H+], 283.0 (15) [M + H+ – C4H8].
Anal. Calcd for C26H36N2O7 (488.59): C, 63.92; H, 7.43; N, 5.73.
Found: C, 63.83; H, 7.71; N, 5.64.
1-tert-Butyl-2-ethyl-3-benzyloxy-5-formyl-4-methylpyrrole-
1,2-dicarboxylate (9)
To a solution of compound 5 (5 g, 17.42 mmol) in anhyd CH2Cl2
(100 mL) at r.t., DMAP (2.2 g, 18.0 mmol) was added and the mix-
ture was stirred for 10 min under nitrogen. (Boc)2O (3.93 g, 18.0
mmol) was added and the resulting mixture was stirred for 30 min.
The solution was washed with H2O (4 × 100 mL) and dried over
MgSO4. The solvent was evaporated in vacuo and the crude product
was purified by CC (PE–EtOAc, 2:1).
1-tert-Butyl-2-ethyl-5-(tert-butoxycarbonylaminomethyl)-4-
methyl-3-oxo-2,3-dihydropyrrole-1,2-dicarboxylate (11)
Compound 10 (2 g, 4.1 mmol) was dissolved in CHCl3 (2 mL) and
MeOH (10 mL), 10% Pd/C (200 mg) was added and the mixture
was transferred to an autoclave. The mixture was stirred for 2 h un-
der H2 (8 bar) at r.t. The solution was filtered through celite and the
solvent was evaporated in vacuo to give the crude product, which
was purified by CC (PE–EtOAc, 4:1). The product decomposed at
r.t. and therefore was stored in a refrigerator.
Yield: 6.7 g (quantitative yield); colorless oil; Rf 0.60 (EtOAc–PE,
1:4).
Yield: 1.2 g (75%); colorless oil; Rf 0.32.
IR (NaCl): 3444, 3145, 3005, 2977, 2933, 2875, 2200, 1729, 1754,
1603, 1500, 1462, 1432, 1389 cm–1.
1H NMR: d = 1.35 (t, J = 7.14 Hz, 3 H), 1.69 (s, 9 H), 2.20 (s, 3 H,),
4.35 (q, J = 7.14 Hz, 2 H), 5.00 (s, 2 H), 7.27–7.50 (m, 5 H), 10.05
(s, 1 H).
IR (NaCl): 3453, 3412, 3101, 2973, 2943, 1763, 1724, 1698, 1623,
1489, 1367 cm–1.
1H NMR: d = 1.34 (t, 3J = 7.14 Hz, 3 H), 1.43 (s, 9 H), 1.53 (s, 9 H),
1.86 (s, 3 H), 4.31 (q, 3J = 7.14 Hz, 2 H), 4.54 (m, 2 H), 4.79 (s, 1
H), 5.56 (br s, 1 H).
Synthesis 2006, No. x, A–F © Thieme Stuttgart · New York

PAPER
Chiral Dipeptide Mimic
E
13C NMR: d = 6.6 (+), 14.2 (+), 28.0 (+), 28.4 (+), 36.5 (–), 62.0
(–), 67.0 (+), 79.3 (Cquat), 83.7 (Cquat), 117.7 (Cquat), 149.2 (Cquat),
155.5 (Cquat), 164.1 (Cquat), 165.5 (Cquat), 192.3 (Cquat).
4.51 (m, 2 H), 4.61–4.72 (m, 1 H), 4.75–5.10 (m, 3 H), 5.16–5.27
(m, 1 H), 6.90 (br s, 1 H), 7.13–7.37 (m, 5 H).
13C NMR: d = 6.6 (+), 14.1 (+), 28.1 (+), 28.2 (+), 35.3 (–), 38.3
(–), 38.8 (–), 55.5 (+), 62.4 (–), 73.7 (Cquat), 84.0 (Cquat), 83.7 (Cquat),
117.7 (Cquat), 119.9 (–), 120.0 (+), 128.6 (+), 129.4 (+), 129.8 (+),
136.4 (Cquat), 149.2 (Cquat), 164.7 (Cquat), 165.5 (Cquat), 170.7(Cquat),
195.6 (Cquat).
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 399
(100) [M + H+], 343.1 (17) [M + H+ – C4H8].
Anal. Calcd for C19H30N2O7 (398.46): C, 57.27; H, 7.59; N, 7.03.
Found: C, 55.28; H, 7.31; N, 6.65.
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 586.5
+
1-tert-Butyl-2-ethyl-2-allyl-5-(tert-butoxycarbonylaminometh-
yl)-4-methyl-3-oxo-2,3-dihydropyrrole-1,2-dicarboxylate (12)
To a flask containing a solution of compound 11 (0.3 g, 0.8 mmol)
in anhyd MeCN (15 mL), t-BuOK (0.09 g, 0.8 mmol) was added un-
der nitrogen. The mixture was stirred for 15 min at –22 °C. Mean-
while the palladium catalyst (h3-C3H5PdCl)2 (27.6 mg, 75 mmol)
and (R,R)-Trost ligand (52.2 mg, 75 mmol) were dissolved in anhyd
MeCN (5 mL) and stirred for 15 min at r.t. before allyl acetate (0.4
mL, 3.8 mmol) was added. Stirring was continued at r.t. for an ad-
ditional 5 min. The catalyst solution was cooled to –22 °C before the
enolate solution was transferred via syringe at –22 °C. The resulting
mixture was stirred for 2.5 h at –22 °C. The reaction was quenched
with a sat. aq solution of NH4Cl (5 mL) and the mixture was stirred
vigorously for 10 min. H2O (10 mL) was then added to dissolve the
precipitate. The solution was extracted with Et2O (3 × 15 mL) and
the organic phase was dried over MgSO4. The solvent was removed
in vacuo to give the crude product, which was purified by CC (PE–
EtOAc; 1:4).
(100) [M + H+], 530.5 (21) [M + H+ – C4H8], 630.6 (25) [M + NH4 ].
Anal. Calcd for C31H43N3O8 (585.70): C, 63.57; H 7.40; N, 7.17.
Found: C, 63.80; H, 7.21; N, 7.54.
1-tert-Butyl-2-ethyl-5-(tert-butoxycarbonylaminomethyl)-4-
methyl-3-oxo-2-(2-oxoethyl)-2,3-dihydropyrrole-1,2-dicarbox-
ylate (14)
Compound 12 (200 mg, 0.46 mmol) was dissolved in THF–H2O
(4:1, 12 mL). This solution was stirred under nitrogen, and
K2OsO4⋅2H2O (20 mg) was added, which turned the reaction dark
brown. After 5 min NaIO4 (312 mg) was added in three batches over
a 10 min period. The reaction turned light green and stirring was
continued for 5 h. The reaction was diluted with Et2O (10 mL) and
H2O (5 mL). The aqueous layer was extracted with Et2O (2 × 12
mL), the combined ethereal layers were washed with brine (5 mL),
and dried over MgSO4. The solvent was removed in vacuo and the
crude product was purified by CC (EtOAc–PE, 1:3).
Yield: 150 mg (75%); colorless oil; Rf 0.4; [a]D +17.7 (c 0.007,
Yield: 305 mg (87%); colorless oil; Rf 0.37; [a]D +143.8 (c 0.2,
CHCl3).
CHCl3).
IR (NaCl): 3453, 2980, 2930, 2728, 2199, 2097, 1789, 1698, 1622,
1492, 1365, 1284, 1247, 1167 cm–1.
1H NMR: d = 1.27 (t, 3J = 7.14 Hz, 3 H), 1.43 (s, 9 H), 1.47 (s, 9 H),
1.90 (s, 3 H), 3.20–3.42 (m, 2 H), 4.15–4.23 (q, 3J = 7.14 Hz, 2 H),
4.45–4.51 (d, 2 H), 5.40–5.55 (br s, 1 H), 9.55 (s, 1 H).
13C NMR: d = 6.0 (+), 14.2 (+), 28.3 (+), 38.0 (–), 39.9 (–), 62.4
(–), 72.6 (Cquat), 105.5 (Cquat), 119.8 (–), 131.6 (+), 156.4 (Cquat),
167.4 (Cquat), 173.7 (Cquat), 196.1 (Cquat).
IR (NaCl): 3454, 3402, 3081, 2980, 2933, 1753, 1716, 1698, 1622,
1489, 1367, 1285, 1246, 1166, 1115, 1068 cm–1.
1H NMR: d = 1.27 (m, 3J = 7.14 Hz, 3 H), 1.43 (s, 9 H), 1.49 (s, 9
H), 1.66 (s, 3 H), 3.05 (d, 2 H), 4.16 (q, 3J = 7.14 Hz, 2 H), 4.36–
4.54 (m, 2 H), 4.96–5.10 (m, 2 H), 5.23–5.37 (m, 1 H), 5.50–5.60
(br s, 1 H).
13C NMR: d = 6.0 (+), 14.2 (+), 28.3 (+), 38.0 (–), 39.9 (–), 62.4
(–), 72.6 (Cquat), 105.5 (Cquat), 119.8 (–), 131.6 (+), 156.4 (Cquat),
167.4 (Cquat), 173.7 (Cquat), 196.1 (Cquat).
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 441.2
(100) [M + H+], 385.1 (30) [M + H+ – C4H8], 285.0 (30) [M + H+
– 2 C4H8 – CO2].
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 339.1
(100) [M + H+], 283.0 (15) [M + H+ – C4H8].
Anal. Calcd for C21H32N2O8 (440.50): C, 57.26; H, 7.32; N, 6.36.
Found: C, 57.28; H, 7.51; N, 6.65
Anal. Calcd for C22H34N2O7 (438.53): C, 60.26; H, 7.82; N, 6.39.
Found: C, 59.71; H, 7.64; N, 6.09.
1-tert-Butyl-2-ethyl-5-(tert-butoxycarbonylaminomethyl)-2-
carboxyethyl-4-methyl-3-oxo-2,3-dihydropyrrole-1,2-dicar-
boxylate (15)
Aldehyde 14 (40 mg, 0.09 mmol) and NaH2PO4⋅H2O (21 mg, 0.17
mmol) were dissolved in MeCN–H2O (4:1, 2.5 mL). H2O2 (1.5 mL)
and NaClO2 (32 mg, 0.35 mmol) were added and the resulting mix-
ture was stirred for another 30 min. H2O (1 mL) was added and the
aqueous layer was extracted with EtOAc (3 × 1 mL). The combined
organic layers were washed with brine (1 mL), dried over MgSO4,
and concentrated.
1-tert-Butyl-2-ethyl-2-allyl-5-[(2-tert-butoxycarbonylamino-3-
phenylpropinoylamino)methyl]-4-methyl-3-oxo-2,3-dihydro-
pyrrole-1,2-dicarboxylate (13)
Compound 12 (100 mg, 0.25 mmol) was dissolved in CH2Cl2 (4
mL), a solution of Et2O saturated with HCl (4 mL) was added and
the resulting mixture was stirred at r.t. overnight. The resulting am-
monium salt (90 mg, 0.24 mmol) was dissolved in a solution of N-
Boc-phenylalanine (82.7 mg, 0.312 mmol), EDC (60 mL, 0.312
mmol), HOBt (42.1 mg, 0.312 mg), and DIPEA (0.09 mL, 0.528
mmol) in CH2Cl2 (5 mL) and the resulting solution was stirred for 4
h at r.t. Then the reaction mixture was washed with H2O (2 × 5 mL),
a 5% aq solution of KHSO4 (5 mL), and a sat. aq solution of
NaHCO3 (2 mL). The resulting solution was dried over MgSO4 and
the solvent was evaporated.
Yield: 35 mg (85%); Rf 0.12 (EtOAc–PE, 1:1); [a]D +15.4 (c 0.015,
CHCl3).
IR (NaCl): 3435, 2982, 2913, 2728, 2200, 2097, 1698, 1650, 1622,
1492, 1365, 1284, 1247, 1167 cm–1.
Yield: 52%; white solid; mp 58–60 °C; [a]D –110.3 (c 0.007,
1H NMR: d = 1.27 (t, 3J = 7.14 Hz, 3 H), 1.43 (s, 9 H), 1.47 (s, 9 H),
1.90 (s, 3 H), 3.20–3.42 (m, 2 H), 4.15–4.23 (q, 3J = 7.14 Hz, 2 H),
4.45–4.51 (d, 2 H), 5.40–5.55 (br s, 1 H), 9.55 (s, 1 H).
13C NMR: d = 6.0 (+), 14.2 (+), 28.3 (+), 38.0 (–), 39.9 (–), 62.4
(–), 72.6 (Cquat), 105.5 (Cquat), 119.8 (–), 131.6 (+), 156.4 (Cquat),
167.4 (Cquat), 173.7 (Cquat), 196.1 (Cquat).
CHCl3).
IR (KBr): 3424, 3365, 2978, 2933, 2872, 2362, 2199, 1944, 1753,
1702, 1620, 1498, 1454, 1367, 1280 cm–1.
1H NMR: d = 1.25 (t, 3J = 7.14 Hz, 3 H), 1.43 (s, 9 H), 1.53 (s, 9 H),
1.86 (s, 3 H), 2.85–3.14 (m, 4 H), 4.19 (q, 3J = 7.14 Hz, 2 H), 4.29–
Synthesis 2006, No. x, A–F © Thieme Stuttgart · New York

F
P. Maity, B. König
PAPER
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 457.3
L.; Hirschmann, R.; Holloway, M. K. Biopolymers 1995, 37,
2953.
(100) [M + H+], 474.3 (75) [M + NH4 ].
+
(2) Smith, A. B. III; Hirschmann, R.; Pasternak, A.; Guzman,
M. C.; Yokoyama, A.; Sprengeler, P. A.; Darke, P. L.;
Emini, E. A.; Schleif, W. A. J. Am. Chem. Soc. 1995, 117,
11113.
(3) Smith, A. B. III; Guzman, M. C.; Sprengeler, P. A.; Keenan,
T. P.; Holocomb, R. C.; Wood, J. L.; Carroll, P. J.;
Hirschmann, R. J. Am. Chem. Soc. 1994, 116, 9947.
(4) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390.
(5) Bittermann, H.; Gmeiner, P. J. Org. Chem. 2006, 71, 97.
(6) (a) Bonauer, C.; Zabel, M.; König, B. Org. Lett. 2004, 6,
1349. (b) Kruppa, M.; Bonauer, C.; Michlová, V.; König, B.
J. Org. Chem. 2005, 70, 5305. (c) Bonauer, C.; König, B.
Synthesis 2005, 2367.
(7) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem.
Soc. 1992, 114, 9327.
(8) The compound was prepared according to: Bonauer, C.
Dissertation; Universität Regensburg: Germany, 2004.
(9) Momose, T.; Tanaka, T.; Yokota, T.; Nagamoto, N.;
Yamada, K. Chem. Pharm. Bull. 1978, 26, 3521.
(10) Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174.
(11) For examples of non-enantioselective stoichiometric related
reactions, see: (a) Beyer, M.; Ghaffari-Tabrizi, R.; Jung, M.;
Margaretha, P. Helv. Chim. Acta 1984, 67, 1535.
(b) Plieninger, H.; Herzog, H. Monatsh. Chem. 1967, 98,
807.
(12) (a) Drew, M. G. B.; George, A. V.; Isaacs, N. S.; Rzepa, H.
S. J. Chem. Soc., Perkin Trans. 1 1985, 1277. (b) Bennes,
R.; Babiloni, M. S.; Hayes, W.; Philip, D. Tetrahedron Lett.
2001, 42, 2377. (c) Chen, Z.; Trudell, M. L. Chem. Rev.
1996, 96, 1179.
HRMS: m/z calcd for C21H33N2O9 [M + H+], 457.2186; found:
457.2188 0.42.
Compound 16
Compound 12 (28 mg, 0.06 mmol) was dissolved in CH2Cl2 (2 mL),
a solution of Et2O saturated with HCl (2 mL) was added and the re-
action mixture was stirred at r.t. overnight. The resulting ammoni-
um salt (24 mg, 0.06 mmol) was dissolved in a solution of
compound 15 (30 mg, 0.065 mmol), EDC (0.01 mL, 0.065 mmol),
HOBt (10.0 mg, 0.065 mmol), and DIPEA (0.03 mL, 0.15 mmol) in
CH2Cl2 (2 mL) and the resulting solution was stirred for 4 h at r.t.
The reaction mixture was washed with H2O (2 × 1 mL), a 5% aq so-
lution of KHSO4 (1 mL), and a sat. aq solution of NaHCO3 (1 mL).
The resulting solution was dried over MgSO4, the solvent was evap-
orated, and the crude product was purified by CC (EtOAc–PE, 1:3).
Yield: 12 mg (30%); colorless oil; Rf 0.15.
1H NMR: d = 1.26 (m, 6 H), 1.45 (s, 9 H), 1.51 (s, 9 H), 1.54 (s, 9
H), 1.80 (s, 3 H), 1.90 (s, 3 H), 3.05 (m, 2 H), 3.20 (m, 2 H), 4.18
(m, 4 H), 4.30 (dd, 3J = 5.88 Hz, 2J = 14.75 Hz, 1 H, CHH), 4.48 (m,
2 H), 4.58 (dd, 3J = 5.88 Hz, 2J = 14.75 Hz, 1 H, CHH), 5.05–5.07
(m, 2 H), 5.23–5.26 (m, 1 H), 5.58 (br s, 1 H), 6.60 (br s, 1 H).
13C NMR: d = 6.5 (+), 6.7 (+), 14.3 (+), 14.2 (+), 28.3 (+), 28.4 (+),
29.0 (+), 34.9 (–), 36.7 (–), 38.2 (–), 40.6 (–), 62.2 (–), 62.6 (–), 71.8
(Cquat), 73.8 (Cquat), 79.5 (Cquat), 84.0 (Cquat), 117.5 (Cquat), 119.9
(–), 120.2 (Cquat), 129.5 (+), 129.7 (+), 148.9 (Cquat), 149.3 (Cquat),
155.5 (Cquat), 164.7 (Cquat), 165.3 (Cquat), 165.4 (Cquat), 166.0 (Cquat),
166.4 (Cquat), 195.0 (Cquat), 195.5 (Cquat).
MS [ESI, CH2Cl2–MeOH–NH4Ac (10 mmol/L)]: m/z (%) = 777.6
+
(100) [M + H+], 794 (20) [M + NH4 ].
(13) Genin, M. L.; Johnson, R. L. J. Am. Chem. Soc. 1992, 114,
8778.
Acknowledgment
(14) Zhang, R.; Mamai, A.; Madalengoitia, J. S. J. Org. Chem.
1999, 64, 547.
We acknowledge financial support from the University of Regens-
burg, GRK 760 and the Fonds der Chemischen Industrie.
(15) The 1H NMR coupling constant (3J) between NH of the
peptide bond and the a-CH shows a value of 5.9 Hz which
indicates free rotation of the 3-oxo-2,3-dihydropyrrole
moieties around the connecting single bond.
References
(16) (a) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew.
Chem. Int Ed. 2002, 41, 3429. (b) Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc. 1999, 121, 4545.
(1) Smith, A. B. III; Akaishi, R.; Jones, D. R.; Keenan, T. P.;
Guzman, M. C.; Holcomb, R. C.; Hirschmann, R.; Wood, J.
Synthesis 2006, No. x, A–F © Thieme Stuttgart · New York