γ-Lactam-containing peptidomimetics

Article abstract of DOI:10.1016/j.tet.2010.05.099

Protected diaminoalcohols obtained through allyl addition to α-amino acid-derived imines and subsequent hydroboration were used for the preparation of pyrrolidinones and pyrrolidines. Pyrrolidinones were synthesized with moderate yields by oxidation of the hydroxy function with tetrapropylammonium perruthenate/N-methylmorpholine-N-oxide and concomitant cyclization while pyrrolidines were synthesized in good yields by tosylation of the hydroxy group and subsequent intramolecular nucleophilic substitution. Thus accessible substrates were transferred into peptidomimetics by attachment of amino acid moieties at both termini using conventional peptide coupling strategies. Molecular mechanics optimizations suggest that these substrates preferentially adopt a turn conformation.

Full text of DOI:10.1016/j.tet.2010.05.099

Tetrahedron 66 (2010) 6174e6180
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
g
-Lactam-containing peptidomimetics
*
Mickael Virlouvet, Joachim Podlech
Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Protected diaminoalcohols obtained through allyl addition to
a-amino acid-derived imines and sub-
Received 17 February 2010
Received in revised form 10 May 2010
Accepted 26 May 2010
sequent hydroboration were used for the preparation of pyrrolidinones and pyrrolidines. Pyrrolidinones
were synthesized with moderate yields by oxidation of the hydroxy function with tetrapropylammonium
perruthenate/N-methylmorpholine-N-oxide and concomitant cyclization while pyrrolidines were syn-
thesized in good yields by tosylation of the hydroxy group and subsequent intramolecular nucleophilic
substitution. Thus accessible substrates were transferred into peptidomimetics by attachment of amino
acid moieties at both termini using conventional peptide coupling strategies. Molecular mechanics op-
timizations suggest that these substrates preferentially adopt a turn conformation.
Available online 4 June 2010
Keywords:
Amino acids
Pyrrolidinones
Pyrrolidines
Ó 2010 Elsevier Ltd. All rights reserved.
Peptidomimetics
Peptide coupling
1. Introduction
previously.8 Their synthesis comprises allyl addition to
a-amino
acid-derived imines and hydroboration using 9-borabicyclo[3.3.1]
nonane (9-BBN) followed by oxidative work-up (Scheme 1).
Peptides showing a turn conformation1 are of major relevance
since, in most cases, these turn regions are responsible for the
biological activity of the respective peptide. Well known repre-
sentatives showing a turn conformation are, inter alia, somato-
statin2 and oxytocin.3 Substrates containing rigid frameworks, i.e.,
turn mimics, can be prepared by replacement of the turn region
with other, mostly cyclic templates.4 Among other heterocyclic
scaffolds, lactams have successfully been used as turn-inducing
moieties.5 In our ongoing research on the preparation of peptido-
mimetics,6 we recently prepared amino acid-derived
suitable as scaffolds for
-turn mimetics.7 In this paper we present
the utilization of -lactams and similar compounds as building
b-lactams
b
g
blocks for the synthesis of peptidomimetics.
2. Synthesis of pyrrolidines and pyrrolidinones
Scheme 1. Synthesis of a-amino acid-derived diaminoalcohols.
a-Amino acid-derived pyrrolidinones and pyrrolidines suitable
for the synthesis of peptidomimetics were prepared starting with
Oxidation of the alcohol function was necessary for the pyrro-
lidinone synthesis. The tested methods are summarized in Table 1.
Neither DesseMartin’s periodinane (DMP, entry 1), which was
reported to be a suitable oxidation agent for the oxidation of al-
cohols to aldehydes and furthermore for the oxidation of lactols to
lactones,9 nor 2-iodoxybenzoic acid (IBX, entry 2)10 or 2,2,6,6-tet-
ramethylpiperidinyloxyl (TEMPO)/NaOCl (entry 3)11 did yield the
respective aldehydes or pyrrolidinones when alcohol 1 was used as
substrate. Direct oxidation to the pyrrolidinone was furthermore
diaminoalcohols 1e9 whose preparation has been published by us
Abbreviations: DMAP, 4-dimethylaminopyridine; HATU, 2-(1H-7-azabenzo-
triazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate; NMO, N-methyl-
morpholin-N-oxid; TBS, tert-butyldimethylsilyl; TBDPS, tert-butyldiphenylsilyl;
Tos, 4-toluenesulfonyl; TPAP, tetrapropylammonium perruthenate.
* Corresponding author. Tel.: þ49 721 608 3209; fax: þ49 721 608 7652; e-mail
address: joachim.podlech@kit.edu (J. Podlech).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.099

M. Virlouvet, J. Podlech / Tetrahedron 66 (2010) 6174e6180
6175
not achieved with pyridinium dichromate (PDC),12 with TEMPO/
PhI(OAc)213 or with Jones’ reagent14 (CrO3, H2SO4, acetone; entries
15
4e6). While utilization of RuCl3/NaIO4 (entry 7) led to the for-
mation of pyrrolidinone 10 with 39% yield, a similar yield (35%) was
achieved with catalytic amounts of tetrapropylammonium per-
ruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) as co-
oxidant (entry 8).16 The latter conditions in due course turned out
to give best results and were successfully applied to the preparation
of the pyrrolidinones 10e16 (Table 2).
Table 1
Conditions used in pyrrolidinone synthesis
Z
Z
oxidation reagent
conditions
N
H
OH
Ph
N
H
N
HN
Figure 1. Conversion of d
-lactam 17 as monitored by 1H NMR spectroscopy.
Ph
O
1
10
OTBS
TBSO
Preparation of pyrrolidines 18e21 was possible by slight varia-
tion of a method published by Alexakis et. al.18 The hydroxy function
in compounds 3 and 7e9 was converted with p-toluenesulfonyl
chloride, triethylamine, and a catalytic amount of p-dimethylami-
nopyridine (DMAP) into a good leaving group. The subsequent
spontaneous ring closure led to pyrrolidines 18e21 with good yields
(Table 3).
#
Reagent (equiv)
Conditions
Yield [%]
1
2
3
4
5
6
7
8
DMP (2.5)
IBX (1.1)
TEMPO/NaOCl (0.2/1.1)
PDC (2)
TEMPO/PhI(OAc)2 (0.1/2.2)
Jones’ reagent (4)
RuCl3/NaIO4 (0.03/4.1)
TPAP/NMO (0.1/3)
CH2Cl2, rt
d
d
d
d
d
d
39
35
AcOEt, reflux
toluene/AcOEt/H2O (6:6:1), 0 ꢀ
C
CH2Cl2, 0 ꢀC to rt
CH2Cl2, rt
acetone, 0 ꢀ
CCl4/CH3CN/H2O (1:1:1.5), 0 ꢀ
CH2Cl2, 0 ꢀC to rt
C
C
Table 3
Synthesis of pyrrolidines
Table 2
Synthesis of pyrrolidinones
TsCl, Et3N
Z
Z
*
*
DMAP
N
H
OH
N
H
R1
R1
HN
R1
X
N
R1
Z
Z
*
TPAP/NMO
*
N
H
OH
N
H
R2O
X
R2
X
N
R2O
HN
R2
O
R1
X
R2
Product
Yield [%]
R3O
#
Alcohol
Config.
X
R3O
1
2
3
4
3
8
7
9
S
S
S
R
Me
iBu
Bn
iPr
H,H
O
O
TBDPS
tBu
18
19
20
21
88
78
80
71
Alcohol
Config.
R1
iBu
R2
X
R3
Product
Yield [%]
tBu
O
tBu
1
2
3
4
5
6
7
S
S
S
S
R
R
S
Bn
H,H
H,H
H,H
O
O
O
TBS
TBS
TBDPS
tBu
10
11
12
13
14
15
16
35
32
43
38
25
44
52
iPr
iPr
Me
iPr
iPr
iPr
Me
Me
iBu
Bn
tBu
3. Synthesis of peptidomimetics
iBu
Bn
tBu
O
tBu
Thus the obtained pyrrolidinones and pyrrolidines were avail-
able for the preparation of peptidomimetics. For this purpose, fur-
ther a-amino acids were supposed to be attached at the termini
The moderate yields are most probably due to side reactions
evolving from possible iminium intermediates17 and due to for-
with conventional peptide coupling strategies. Silyloxy-derivatives
10e12 and 18 had to be transferred into the corresponding car-
boxylic acids. Desilylation was cleanly achieved with good yields
with either catalytic amounts of sulfuric acid in methanol (TBS
derivatives, Scheme 3)19 or with tetrabutylammonium fluoride
(TBAF) in tetrahydrofuran (TBDPS derivative).19,20
Oxidation of the obtained alcohol 23 to carboxylic acid 24 was not
achieved with catalytic amounts of ruthenium trichloride and so-
dium periodate as co-oxidant (Scheme 4).21 While a consumption of
the alcohol was observed, no defined product could be identified in
the reaction mixture. A two-step protocol with oxidation to an al-
dehyde with subsequent oxidation into the carboxylic acid similarly
failed, since formation of the aldehyde was neither achieved with
tetrapropylammonium perruthenate/N-methylmorpholine-N-oxide
(TPAP/NMO) nor with DesseMartin’s periodinane. Consequently
a use of these intermediates was not further considered in the
preparation of peptidomimetics.
mation of a side product (e.g., 17), which was obtained in changing
yields. This d-lactam 17, which was initially obtained, did not turn
out to be stable with respect to a conversion into the desired solid
15 within some months (Scheme 2). Figure 1 depicts the complete
conversion of
months.
d-lactam 17 over a period of approximately three
Scheme 2. Conversion of d-lactam 17 into g-lactam 15.

6176
M. Virlouvet, J. Podlech / Tetrahedron 66 (2010) 6174e6180
Scheme 3. Deprotection of silyl protection groups.
Scheme 4. Attempts to achieve oxidation of alcohol 23.
Scheme 5. Synthesis of peptidomimetics.
To obtain pseudo-tetrapeptides from pyrrolidinones 13e16 and
pyrrolidines 19e21 two strategies are possible. Route A comprises
the cleavage of the tert-butyl ester with coupling of a further amino
acid,22 deprotection of the N-terminal protection group and again
attachment of a further amino acid. Route B consists of the same
steps in reversed order (Scheme 5).
peptidomimetics 27 and 28 adopt a turn-conformation stabilized
by hydrogen bonds between the incoming and the leaving strand
(Fig. 3). The obtained structures do not allow a classification into
Both routes were tested in the synthesis of pseudo-tetrapeptides
26e28 (Fig. 2). Route A was used for the preparation of 26 and route
B was used for the synthesis of 28. Compound 27 was prepared via
both routes. Route A turned out to afford the desired compounds in
significantly better yields than route B, possibly due the formation
of a side product 29 formed during N-terminal deprotection in
route B. This side product is an analog of a diketopiperazide; its
formation should be favored by the proline-like scaffold, which is
known to enforce a cyclization.23 When pyrrolidinone 14 was
reacted according to route B, this side product was obtained
quantitatively (Scheme 6), despite the fact that a tert-butyl ester
should prevent a lactam formation. This gives clear evidence that
these compounds tend to form a turn structure, thus favoring this
cyclization (vide infra).
pseudo-Tetrapeptides 26e28 were obtained as foamy solids,
which could not be transferred into crystals suitable for X-ray
crystallographic analysis. Interpretation of NOESY and ROESY
spectra was not possible due to a severe overlap of signals. Con-
sequently a comprehensive investigation on the preferred confor-
mations in these compounds was not possible. Nevertheless,
molecular mechanics optimizations (MM2)24 gave evidence
that both the pyrrolidinone- and the pyrrolidine-derived
Figure 2. Synthesized pseudo-tetrapeptides.

M. Virlouvet, J. Podlech / Tetrahedron 66 (2010) 6174e6180
6177
were performed on a Heraeus, CHNeO-rapid or on an elementar
vario MICRO. Electrical ionization and high resolution mass spectra
were recorded on a Finnigan MAT-90. Optical rotations were
recorded on a Perkin Elmer 241 polarimeter (using the sodium D
line, 589 nm) and specific optical rotations [a] are given in units of
10ꢁ1$deg$cm2$gꢁ1. Detailed spectroscopic data are given as sup-
plementary data.
4.2. Synthesis of pyrrolidinones
Scheme 6. Side reaction during hydrogenolysis.
4.2.1. (2S,10S,200S)-5-(1-Benzyloxycarbonylamino-3-methyl-butyl)-1-
(1-tert-butyldimethylsilyloxy-3-phenyl-propan-2-yl)pyrrolidin-2-one
(10). TPAP (73 mg, 0.02 mmol) was added to a suspension of al-
cohol 1 (1.15 g, 2.07 mmol), NMO (837 mg, 6.20 mmol), and MS 4 Å
(1.00 g) in CH2Cl2 (5 mL). The mixture was stirred for 3 h at rt
(monitoring with TLC), filtered (Celite), concentrated, and purified
by chromatography (silica gel, 200 mmꢂ25 mm Ø, hexanes/EtOAc
3:1) to yield pyrrolidinone 10 (397 mg, 0.72 mmol, 35%) as a color-
less solid.
4.2.2. (5S,10S,200S)-5-(1-Benzyloxycarbonylamino-3-methyl-pro-
pyl)-1-(1-tert-butyldimethylsilyloxy-propan-2-yl)pyrrolidin-2-one
(11). TPAP (118 mg, 0.33 mmol) was added to a suspension of al-
cohol 2 (1.56 g, 3.34 mmol), NMO (1.35 g, 10.0 mmol), and MS 4 Å
(1.67 g) in CH2Cl2 (5 mL). The mixture was stirred for 3 h at rt
(monitoring with TLC), filtered (Celite), concentrated, and purified
by chromatography (silica gel, 200 mmꢂ25 mm Ø, hexanes/EtOAc
2:1/1:1) to yield pyrrolidinone 11 (500 mg, 1.08 mmol, 32%) as
a yellow oil.
Figure 3. Peptides containing the core of 27 (left) and 28 (right) optimized using
a MM2 force field (non-polar hydrogen atoms and side chains are omitted here for
clarity but were considered during optimizations).24
4.2.3. (5S,10S,100S)-5-(1-Benzyloxycarbonylamino-2-methyl-pro-
pyl)-1-(1-tert-butyldiphenylsilyloxy-propan-2-yl)pyrrolidin-2-one
(12). TPAP (52 mg, 0.15 mmol) was added to a suspension of al-
cohol 3 (868 mg, 1.47 mmol), NMO (596 mg, 4.40 mmol), and MS
4 Å (750 mg) in CH2Cl2 (5 mL). The mixture was stirred for 3 h at
rt (monitoring with TLC), filtered (Celite), concentrated, and
purified by chromatography (silica gel, 200 mmꢂ30 mm Ø, hex-
anes/EtOAc 4:1/2:1) to yield pyrrolidinone 12 (501 mg,
0.85 mmol, 43%) as a yellow oil.
given turn types.1 Compounds 27 and 28 uncommonly show hy-
drogen bonds in the turn region between the NeH of the incoming
strand with the C]O group of the leaving strand. Most published
turn mimics shown hydrogen bonds vice versa from NeH of the
leaving strand to a C]O of the incoming strand. Compound 27 is
additionally stabilized by a further hydrogen bond with participa-
tion of the pyrrolidinone carbonyl group leading to a somewhat
more open angle between incoming and leaving peptide strands.
4.2.4. tert-Butyl (2S,20S,100S)-2-[2-(1-benzyloxycarbonylamino-ethyl)-
5-oxo-pyrrolidin-1-yl]-4-methyl-pentanoate
(13). TPAP
(5 mg,
14 mol) was added to suspension of alcohol
m
a
4
(120 mg,
0.27 mmol), NMO (89 mg, 0.66 mmol), and MS 4 Å (137 mg) in
CH2Cl2 (5 mL). The mixture was stirred for 3 h at rt (monitoring with
TLC), filtered (Celite), concentrated, and purified by chromatography
(silica gel, 150 mmꢂ15 mm Ø, hexanes/EtOAc 2:1/1:1) to yield
pyrrolidinone 13 (45 mg, 0.10 mmol, 38%) as a yellow oil.
4. Experimental section
4.1. General remarks
Compounds 1e9 were prepared as described previously.8 Tet-
rahydrofuran (THF) was distilled from sodium benzophenone ketyl
radical and CH2Cl2 was distilled from CaH2. All moisture-sensitive
reactions were carried out under oxygen-free argon or N2 using
oven-dried glassware and a vacuum line. Flash column chroma-
tography25 was carried out using Merck silica gel 60
(230e400 mesh) and thin layer chromatography (TLC) was carried
out using commercially available Merck F254 pre-coated sheets.
HPLC analyses were carried out with a Merck-Hitachi LaChrom
D7000 apparatus with a L7100 mixer and diode-array detection
4.2.5. tert-Butyl
(2S,20R,100S)-2-[2-(1-benzyloxycarbonylamino-2-
methyl-propyl)-5-oxo-pyrrolidin-1-yl]-3-phenyl-propanoate (14). TPAP
(37 mg, 0.11 mmol) was added to a suspension of alcohol 5 (519 mg,
1.05 mmol), NMO (300 mg, 2.52 mmol), and MS 4 Å (500 mg) in
CH2Cl2 (5 mL). The mixture was stirred for 3 h at rt (monitoring with
TLC), filtered (Celite), concentrated, and purified by chromatography
(silica gel, 200 mmꢂ25 mm Ø, hexanes/EtOAc 2:1/1:1) to yield
pyrrolidinone 14 (129 mg, 0.26 mmol, 25%) as a yellow solid.
(L7455) on a LiChrospher Si 60, 5
m
m, Merck (flow: 1e1.5 ml/min)
4.2.6. tert-Butyl
(2S,20R,100S)-2-[2-(1-benzyloxycarbonylamino-2-
chromatographic column. 1H and 13C NMR spectra were recorded
on a Bruker Cryospek WM-250, an AM-400 or a DRX 500. Chemical
shifts are given in parts per million downfield of tetramethylsilane.
13C NMR spectra were recorded with broad band proton decoupling
and were assigned using DEPT 135 and DEPT 90 experiments.
Melting points were measured on a Büchi apparatus. IR spectra
were recorded on a Bruker IFS-88 spectrometer. Elemental analyses
methyl-propyl)-5-oxo-pyrrolidin-1-yl]-4-methyl-pentanoate (15). TPAP
(408 mg, 1.16 mmol) was added to a suspension of alcohol 6 (5.39 g,
11.6 mmol), NMO (3.76 g, 27.8 mmol), and molecular sieves (4 Å,
5.80 g) in CH2Cl2 (30 mL). The mixture was heated to reflux for 2 h
(monitoring with TLC), cooled, filtered (Celite), concentrated, and
purified by chromatography (silica gel, 200 mmꢂ45 mm Ø, hexanes/
EtOAc 2:1/1:1) to yield pyrrolidinone 15 (2.36 g, 5.13 mmol, 44%) as

6178
M. Virlouvet, J. Podlech / Tetrahedron 66 (2010) 6174e6180
a yellow solid and side product 17 (600 mg, 1.30 mmol, 11%) as
a yellow oil.
H2SO4 (two drops) was added at room temperature to a solution of O-
TBS-protected alcohol 10 (316 mg, 0.57 mmol) in MeOH (5 mL). After
stirring for 15 h the mixture was concentrated, digerated with Et2O
(10 mL), washed with H2O (3ꢂ3 mL), dried (Na2SO4), concentrated,
and purified by chromatography (silica gel, 200 mmꢂ25 mm Ø,
CH2Cl2/MeOH 20:1) to yield alcohol 22 (296 mg, 0.85 mmol, 77%) as
a colorless solid.
4.2.7. tert-Butyl
(2S,20S,100S)-2-[2-(1-benzyloxycarbonylamino-2-
methyl-propyl)-5-oxo-pyrrolidin-1-yl]-3-phenyl-propanoate (16). TPAP
(141 mg, 0.40 mmol) was added to a suspension of alcohol 7 (2.00 g,
4.00 mmol), NMO (1.30 g, 9.60 mmol), and molecular sieves (4 Å,
2.00 g) in CH2Cl2 (10 mL). The mixture was heated to reflux for 2 h
(monitoring with TLC), cooled, filtered (Celite), concentrated, and
purified by chromatography (silica gel, 200 mmꢂ45 mm Ø, hexanes/
EtOAc 4:1/2:1) to yield pyrrolidinone 16 (1.03 g, 2.08 mmol, 52%) as
a yellow oil.
4.4.2. (5S,10S,200S)-5-(1-Benzyloxycarbonylamino-2-methyl-propyl)-
1-(1-hydroxy-propan-2-yl)pyrrolidin-2-one (23). Method (1) Con-
centrated H2SO4 (two drops) was added at room temperature to
a solution of O-TBS-protected alcohol 11 (429 mg, 0.93 mmol) in
MeOH (5 mL). After stirring for 15 h the mixture was concentrated,
digerated with Et2O (10 mL), washed with H2O (3ꢂ3 mL), dried
(Na2SO4), concentrated, and purified by chromatography (silica gel,
200 mmꢂ25 mm Ø, CH2Cl2/MeOH 20:1) to yield alcohol 23
(192 mg, 0.44 mmol, 92%) as a yellow oil.
Method (2) TBAF (1.04 g, 3.30 mmol) was added portionwise at
0 ꢀC to a solution of O-TBDPS-protected alcohol 12 (242 mg,
0.41 mmol) in THF (3 mL) and the mixture was stirred for 15 h at
room temperature, concentrated, and purified by chromatography
(silica gel, 200 mmꢂ25 mm Ø, CH2Cl2/acetone 10:1/5:1) to yield
alcohol 23 (134 mg, 0.38 mmol, 94%) as a yellow oil.
4.3. Synthesis of pyrrolidines
4.3.1. (2S,10S,200S)-2-[1-(Benzyloxycarbonylamino)-2-methyl-pro-
pyl]-1-(tert-butyldiphenylsilyloxy-prop-2-yl)pyrrolidine (18). TosCl
(200 mg, 1.05 mmol) was added at rt to a solution of alcohol 3
(591 mg, 1.00 mmol), Et3N (152 mL, 1.10 mmol), and a catalytic
amount of DMAP in CH2Cl2 (10 mL). The reaction was stopped after
stirring for 18 h by addition of saturated aqueous NaHCO3 solution
(5 mL). The aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL) and
the combined organic layers were dried (Na2SO4), concentrated,
and purified by chromatography (silica gel, 200 mmꢂ30 mm Ø,
hexanes/EtOAc 3:1) to yield pyrrolidine 18 (506 mg, 0.88 mmol,
88%) as a yellowish oil.
4.4.3. (1S,4S,8bS)-4-Benzyl-tetrahydro-1-isopropylpyrrolo[1,2-a]pyr-
azine-3,6(4H,7H)-dione (29). A suspension of Z-protected substrate
14 (944 mg, 1.91 mmol) and Pd/C (5%, 407 mg, 0.19 mmol) in an-
hydrous MeOH (10 mL) was stirred for 5 h under a hydrogen at-
mosphere. The mixture was filtrated (Celite) after complete
consumption (monitoring with TLC) and the filtrate was concen-
trated to yield heterocycle 29 (547 mg, quant.) as a yellow solid.
4.3.2. tert-Butyl
methyl-propyl)-pyrrolidin-1-yl]-4-methyl-pentanoate
(2S,20S,100S)-2-[2-(1-benzyloxycarbonylamino-2-
(19). TosCl
(2.22 g, 11.7 mmol) was added at room temperature to a solution of
alcohol 8 (5.16 g, 11.1 mmol), Et3N (1.85 mL, 13.3 mmol), and DMAP
(136 mg, 1.1 mmol) in CH2Cl2 (70 mL). After stirring for 15 h satu-
rated aqueous NaHCO3 solution (50 mL) was added, the aqueous
layer was extracted with CH2Cl2 (3ꢂ50 mL) and the combined or-
ganic layers were dried (Na2SO4), concentrated, and purified by
chromatography (silica gel, 200 mmꢂ45 mm Ø, hexanes/EtOAc 7:1)
to yield pyrrolidine 19 (3.89 g, 8.70 mmol, 78%) as a yellowish oil.
4.4.4. tert-Butyl (2S,20S,200R,1000S)-2-{2-[2-(1-benzyloxycarbonylamino-
2-methyl-propyl)-5-oxo-pyrrolidin-1-yl]-4-methyl-pentanoylamino}-
propanoate (30). TFA/H2O (9:1, 1.1 mL) was added to tert-butyl ester
15 (465 mg, 1.00 mmol), the mixture was concentrated and the
resulting carboxylic acid was used without further purification.
Collidine (662 m
L, 5.00 mmol) was added at 0 ꢀC to a solution of the
4.3.3. tert-Butyl
methyl-propyl)pyrrolidin-1-yl]-3-phenylpropanoate
(400 mg, 2.10 mmol) was added at rt to a solution of alcohol 7
(997 mg, 2.00 mmol), Et3N (334 L, 2.40 mmol), and a catalytic
(2S,20S,100S)-2-[2-(1-benzyloxycarbonylamino-2-
(20). TosCl
carboxylic acid (404 mg, 1.00 mmol), HATU (951 mg, 2.50 mmol),
and HeAlaeOtBu (363 mg, 2.50 mmol) in DMF (5 mL). The mixture
was stirred for 16 h, poured into H2O (500 mL), and extracted with
Et2O (4ꢂ25 mL). The combined organic layers were washed with
H2O (2ꢂ30 mL) and brine (30 mL), dried (Na2SO4), concentrated, and
purified (silica gel, 200 mmꢂ25 mm Ø, CH2Cl2/acetone 10:1) to yield
product 30 (406 mg, 0.76 mmol, 76%) as a colorless foam.
m
amount of DMAP in CH2Cl2 (15 mL). The reaction was stopped after
stirring for 18 h by addition of saturated aqueous NaHCO3 solution
(5 mL). The aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL) and
the combined organic layers were dried (Na2SO4), concentrated,
and purified by chromatography (silica gel, 200 mmꢂ30 mm Ø,
hexanes/EtOAc 6:1/4:1) to yield pyrrolidine 20 (766 mg,
1.59 mmol, 80%) as a yellowish oil.
4.4.5. tert-Butyl (2S,20S,200R)-2-{2-[2-(1-amino-2-methyl-propyl)-5-
oxo-pyrrolidin-1-yl]-4-methyl-pentanoylamino}-propanoate (31). A
suspension of carbamate 30 (319 mg, 0.60 mmol) and Pd/C (5%,
128 mg, 0.06 mmol) in anhydrous MeOH (5 mL) was stirred under
a hydrogen atmosphere until completion of the hydrogenolysis
(monitoring with TLC). The mixture was filtered (Celite), concen-
trated, and used for the peptide coupling without further purifi-
cation as a colorless oil (240 mg, 0.60 mmol, quant.).
4.3.4. tert-Butyl
(2S,20R,100S)-2-[2-(1-benzyloxycarbonylamino-
2-methyl-propyl)pyrrolidin-1-yl]-3-methyl-butanoate (21). TosCl
(264 mg, 1.38 mmol) was added at rt to a solution of alcohol 9
(594 mg, 1.32 mmol), Et3N (220 mL, 1.58 mmol), and a catalytic
amount of DMAP in CH2Cl2 (10 mL). The reaction was stopped after
stirring for 18 h by addition of saturated aqueous NaHCO3 solution
(5 mL). The aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL) and
the combined organic layers were dried (Na2SO4), concentrated,
and purified by chromatography (silica gel, 200 mmꢂ25 mm Ø,
hexanes/EtOAc 6:1) to yield pyrrolidine 21 (406 mg, 0.94 mmol,
71%) as a yellowish oil.
4.4.6. tert-Butyl (2S,20S,200R,1000S,20000S)-2-[2-(2-{1-[2-(9H-fluoren-9-
ylmethoxycarbonylamino)-3-phenyl-propionylamino]-2-methyl-pro-
pyl}-5-oxo-pyrrolidin-1-yl)-4-methyl-pentanoylamino]-propanoate
(27). Collidine (224 m
L, 205 mg, 1.69 mmol) was added at 0 ꢀC to
a solution of amine 31 (239 mg, 0.60 mmol), HATU (321 mg,
0.85 mmol), and FmocePheeOH (327 mg, 0.85 mmol) in DMF
(5 mL). The mixture was stirred for 16 h, poured into H2O (500 mL),
and extracted with Et2O (4ꢂ25 mL). The combined organic layers
were washed with H2O (2ꢂ30 mL) and brine (30 mL), dried
(Na2SO4), concentrated, and purified by chromatography (silica gel,
4.4. Synthesis of pyrrolidinone-derived peptidomimetics
4.4.1. (5S,10S,200S)-5-(1-Benzyloxycarbonylamino-3-methyl-butyl)-1-
(1-hydroxy-3-phenyl-propan-2-yl)pyrrolidin-2-one (22). Concentrated

M. Virlouvet, J. Podlech / Tetrahedron 66 (2010) 6174e6180
6179
150 mmꢂ20 mm Ø, CH2Cl2/acetone 10:1) to yield product 27
propyl}-pyrrolidin-1-yl)-4-methyl-pentanoylamino]-propanoate
(28). TFA/H2O (9:1, 2.2 mL) was added to tert-butyl ester 35
(261 mg, 0.38 mmol), the mixture was concentrated and the
resulting carboxylic acid was used without further purification.
(293 mg, 0.38 mmol, 68%) as a colorless foam.
4.4.7. tert-Butyl (2S,20S,200R,1000S)-2-(2-{2-[1-(benzyloxycarbonylamino)-
2-methyl-propyl]-5-oxo-pyrrolidin-1-yl}-4-methylpentanamido)-3-phe-
nylpropanoate (32). TFA/H2O (9:1, 1.1 mL) was added to tert-butyl ester
15 (170 mg, 1.00 mmol), the mixture was concentrated and the
resulting carboxylic acid was used without further purification. Colli-
Collidine (185 m
L, 170 mg, 1.40 mmol) was added at 0 ꢀC to a solu-
tion of the carboxylic acid (173 mg, 0.28 mmol), HATU (126 mg,
0.33 mmol), and HeAlaeOtBu (40 mg, 0.33 mmol) in DMF (5 mL).
The mixture was stirred for 16 h, poured into H2O (500 mL), and
extracted with Et2O (4ꢂ25 mL). The combined organic layers were
washed with H2O (2ꢂ30 mL) and brine (30 mL), dried (Na2SO4),
concentrated, and purified (silica gel, 200 mmꢂ25 mm Ø, CH2Cl2/
acetone 10:1) to yield product 28 (102 mg, 0.14 mmol, 49%) as
a colorless foam.
dine (662 m
L, 5.00 mmol) was added at 0 ꢀC to a solution of the car-
boxylic acid (404 mg, 1.00 mmol), HATU (951 mg, 2.50 mmol), and
HePheeOtBu (553 mg, 2.50 mmol) in DMF (5 mL). The mixture was
stirred for 16 h, poured into H2O (500 mL), and extracted with Et2O
(4ꢂ25 mL). The combined organic layers were washed with H2O
(2ꢂ30 mL) and brine (30 mL), dried (Na2SO4), concentrated, and pu-
rified (silica gel, 200 mmꢂ25 mm Ø, CH2Cl2/acetone 10:1) to yield
product 32 (474 mg, 0.78 mmol, 78%) as a colorless foam.
Supplementary data
Supplementary data for this article can be found in the online
version, at doi:10.1016/j.tet.2010.05.099. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
4.4.8. tert-Butyl (2S,20S,200R)-2-{2-[2-(1-amino-2-methyl-propyl)-5-
oxo-pyrrolidin-1-yl]-4-methyl-pentanoylamido}-3-phenyl-prop-
anoate (33). A suspension of carbamate 32 (395 mg, 0.65 mmol)
and Pd/C (5%, 138 mg, 65 mmol) in anhydrous MeOH (5 mL) was
stirred under a hydrogen atmosphere until completion of the
hydrogenolysis (5 h, monitoring with TLC). The mixture was fil-
tered (Celite), concentrated, and used for the peptide coupling
without further purification as a colorless oil (308 mg, 0.65 mmol,
quant.).
References and notes
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G. D.; Gierasch, L. M.; Smith, J. A. In Advances in Protein Chemistry; Anfinsen, C.
B., Edsall, J. T., Richards, F. M., Eds.; Academic: Orlando, 1985; Vol. 37, 1e109; (d)
Houben-Weyl, Synthesis of Peptides and Peptidomimetics, E22; Goodman, M.,
Felix, A., Moroder, L., Toniolo, C., Eds.; Thieme: Stuttgart, 2001.
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Arison, B. H.; Homnick, C.; Randall, W. C.; Glitzer, M. S.; Saperstein, R.;
Hirschmann, R. Nature 1981, 292, 55e58; (c) Rivier, J.; Spiess, J.; Thorner, M.;
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3. Urry, D. W.; Walter, R. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 956e958.
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Science 1980, 210, 656e658; (b) Ball, J. B.; Alewood, P. F. J. Mol. Recognit. 1990, 3,
55e64; (c) Kahn, M.; Eguchi, M. In Houben-Weyl, Synthesis of Peptides and
Peptidomimetics, E22; Goodman, M., Felix, A., Moroder, L., Toniolo, C., Eds.;
Thieme: Stuttgart, 2001; pp 695e740; (d) See as well: Müller, G.; Hessler, G.;
Decornez, H. Y. Angew. Chem., Int. Ed. 2000, 39, 894e896.
4.4.9. tert-Butyl (2S,20S,200R,1000S,20000S)-2-[2-(2-{1-[3-tert-butoxy-2-
(9H-fluoren-9-ylmethoxycarbonylamino)-propionylamino]-2-
methyl-propyl}-5-oxo-pyrrolidin-1-yl)-4-methyl-pentanoylamino]-
3-phenyl-propanoate (26). Collidine (242 mL, 221 mg, 1.82 mmol)
was added at 0 ꢀC to a solution of amine 33 (288 mg, 0.61 mmol),
HATU (347 mg, 0.91 mmol), and FmoceSer(OtBu)eOH (350 mg,
0.91 mmol) in DMF (5 mL). The mixture was stirred for 16 h, poured
into H2O (500 mL), and extracted with Et2O (4ꢂ25 mL). The com-
bined organic layers were washed with H2O (2ꢂ30 mL) and brine
(30 mL), dried (Na2SO4), concentrated, and purified by chroma-
tography (silica gel, 150 mmꢂ20 mm Ø, CH2Cl2/acetone 10:1) to
yield product 26 (292 mg, 0.35 mmol, 57%) as a colorless foam.
5. Reviews: (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
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b-, g- and d-lactam scaffolds; (c) Yu, K.-L.;
Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1988,
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(2S,20S)-2-[2-(1-amino-2-methyl-propyl)-pyrroli-
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Gmeiner, P. Heterocycles 1999, 51, 1389e1400; (f) Hoffmann, T.; Lanig, H.;
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din-1-yl]-4-methyl-pentanoate (34). A suspension of carbamate 19
(670 mg, 1.50 mmol) and Pd/C (5%, 319 mg, 0.15 mmol) in anhy-
drous MeOH (5 mL) was stirred under a hydrogen atmosphere until
completion of the hydrogenolysis (5 h, monitoring with TLC). The
mixture was filtered (Celite), concentrated, and used for the pep-
tide coupling without further purification as a colorless oil (450 mg,
1.44 mmol, 96%).
4.5.2. tert-Butyl
thoxycarbonylamino)-3-phenyl-propionylamino]-2-methyl-propyl}-
pyrrolidin-1-yl)-4-methyl-pentanoate (35). Collidine (270 L,
(2S,20S,100S,2000S)-2-(2-{1-[2-(9H-fluoren-9-ylme-
m
251 mg, 2.07 mmol) was added at 0 ꢀC to a solution of amine 34
(341 mg, 1.09 mmol), HATU (548 mg, 1.44 mmol), and FmocePhe-
eOH (511 mg, 1.44 mmol) in DMF (5 mL). The mixture was stirred
for 16 h, poured into H2O (500 mL), and extracted with Et2O
(4ꢂ25 mL). The combined organic layers were washed with H2O
(2ꢂ30 mL) and brine (30 mL), dried (Na2SO4), concentrated, and
purified by chromatography (silica gel, 200 mmꢂ25 mm Ø, CH2Cl2/
acetone 10:1) to yield product 35 (467 mg, 0.68 mmol, 63%) as
a colorless foam.
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