Bifunctional 2,5-diketopiperazines as efficient organocatalysts for the enantioselective conjugate addition of aldehydes to nitroolefins

Article abstract of DOI:10.1002/ejoc.201100794

Four peptidomimics (3-6) containing the cis-DKP-1 or trans-DKP-2 scaffolds and either L-Pro or D-Pro were synthesized. DKP-1 and DKP-2 are bifunctional diketopiperazines formally derived from the head-to-tail cyclization of L-aspartic acid and either (R)-

Full text of DOI:10.1002/ejoc.201100794

FULL PAPER
DOI: 10.1002/ejoc.201100794
Bifunctional 2,5-Diketopiperazines as Efficient Organocatalysts for the
Enantioselective Conjugate Addition of Aldehydes to Nitroolefins
Marco Durini,[a] Florian A. Sahr,[a] Michael Kuhn,[a] Monica Civera,[b] Cesare Gennari,*[b]
and Umberto Piarulli*[a]
Dedicated to Professor Gianfranco Scorrano on the occasion of his 72nd birthday
Keywords: Organocatalysis / Michael addition / Peptidomimetics / Diketopiperazines / Nitroolefins
Four peptidomimics (3–6) containing the cis-DKP-1 or trans-
DKP-2 scaffolds and either -Pro or -Pro were synthesized.
DKP-1 and DKP-2 are bifunctional diketopiperazines for-
mally derived from the head-to-tail cyclization of -aspartic
acid and either (R)- or (S)-2,3-diaminopropionic acid, which
feature aminomethyl and carboxymethyl side arms in the 3-
and 6-positions of the 2,5-piperazindione ring. Peptidomim-
ics (3–6) were tested as organocatalysts in the conjugate ad-
dition of several aldehydes to β-nitrostyrene and (E)-2-(furan-
2-yl)nitroethene with good to excellent diastereo- and
enantioselectivities. Monte Carlo/Energy Minimization (MC/
EM) conformational searches were performed on the four
catalysts and their enamine derivatives with propanal to ra-
tionalize the observed stereoselectivity.
L
D
L
cordingly, functionalized DKPs have been inserted as scaf-
folding elements in two-armed receptors capable of selective
recognition of small peptides and anions and in peptidomi-
metics mimicking protein secondary structures (e.g. β-turns,
β-hairpins, and α-helices).[13] In this field, our group re-
cently reported a new class of bifunctional DKPs (DKP-1
and DKP-2, Figure 1), formally derived from aspartic acid
and 2,3-diaminopropionic acid, bearing a carboxylic acid
and an amino functionality.[14] As a consequence of the ab-
solute configuration of the two α-amino acids forming the
cyclic dipeptide unit, the two reactive functionalities (amino
and carboxylic acid) are locked in a cis (DKP-1) or trans
configuration (DKP-2). In addition, this DKP scaffold, al-
though derived from α-amino acids, can be seen as a con-
formationally constrained dipeptide formed by two β-
amino acids (see Figure 1), in particular, a β2- and a β3-
amino acid (according to Seebach’s nomenclature).[15] The
bifunctional DKP-1, derived from l-aspartic acid and (S)-
Introduction
2,5-Diketopiperazines (DKPs) are cyclic dipeptides com-
posed of two α-amino acids, and their crystal structure was
first elucidated by R. B. Corey in 1938.[1] Once believed to
be merely protein artifacts or degradation products, they
have regained the interest of chemists and pharmacologists
thanks to their wide spectrum of biological properties[2] and
therapeutic applications, ranging from antibiotics[3,4] to
synthetic vaccines and anticancer agents.[5,6] From a struc-
tural and synthetic point of view, DKPs are simple hetero-
cyclic scaffolds in which diversity can be introduced at up
to four positions (N1, N4, C3, C6) and stereochemically
controlled at two (C3, C6), and they can be prepared from
readily available α-amino acids using conventional synthetic
procedures,[7,8] solid phase,[9,10] and microwave-assisted syn-
thesis.[11,12] An application of DKPs, which has gained im-
portance in the last decade, is their use as scaffolds capable
of inducing a well defined 3D structure. To that end, advan-
tage can be taken from the synthesis of symmetrical and
unsymmetrical DKPs bearing reactive functionalities (e.g.
NH2, COOH) in the lateral chains of the amino acids. Ac-
[a] Università degli Studi dell’Insubria, Dipartimento di Scienze
Chimiche e Ambientali,
Via Valleggio 11, 22100 Como, Italy
Fax: +39-031-238-6449
E-mail: umberto.piarulli@uninsubria.it
[b] Università degli Studi di Milano, Dipartimento di Chimica
Organica e Industriale, Centro Interdipartimentale C.I.S.I.,
Via G. Venezian 21, 20133 Milano, Italy
Fax: +39-02-5031-4072
Figure 1. Structure of bifunctional DKP-1 and DPK-2 highlighting
the conformationally constrained β2–β3 dipeptide sequence.
E-mail: cesare.gennari@unimi.it
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FULL PAPER
2,3-diaminopropionic acid, bears the amino and carboxylic
acid functionalities in a cis relationship and has been shown
to act as a reverse-turn inducer and promoter of antiparallel
β-sheets.[14a,16]
DKP scaffolds are also interesting candidates as organo-
catalysts and have been used in the asymmetric hydrocyan-
ation of aldehydes,[17,18a] and imines,[18b] although for the
latter case the results have been questioned.[18c] In this field,
small linear peptides, composed of two to ten amino acid
residues, have recently been investigated as chiral organoca-
talysts.[19] Thanks to their straightforward synthesis and
their modular nature, as well as their ability to adopt a well
defined 3D secondary structure suitable for the transfer of
stereochemical information, a number of catalysts have
been prepared and tested. In particular, peptides bearing
N-terminal proline residues have been shown to effectively
catalyze asymmetric aldol reactions and conjugate addition
of aldehydes to nitroolefins.[19] Especially worth mentioning
is the work of Wennemers and coworkers, who have iden-
tified highly enantioselective tripeptide catalysts from a li-
brary of 3375 tripeptides generated by the split–mix meth-
odology and screened by “catalyst–substrate coimmobiliza-
tion”.[20] The tripeptide Pro–Pro–AspNH2 emerged as a
very active and selective organocatalyst for the aldol ad-
dition of acetone to several aldehydes. The reasons for this
behavior were investigated and attributed to the turn-like
conformation that this tripeptide adopts in solution, bring-
ing the catalytically active secondary amine and carboxylic
acid groups in close proximity. This tripeptide was later
found to be a powerful catalyst in the conjugate addition
of aldehydes to nitroolefins.[21] A subsequent structure opti-
mization revealed that better results could be achieved using
the tripeptides d-Pro–Pro–AspNH2 and d-Pro–Pro–
GluNH2. An important feature of these catalysts is their
bifunctional nature with the secondary amine promoting
the formation of the enamine, and the carboxylic acid
group activating the nitroolefin moiety through Brönsted
acid catalysis.
Figure 2. Organocatalysts 3–6.
diates 7 and 8 were then Boc deprotected and coupled to
either l-Boc–Pro or d-Boc–Pro to give, after deallylation
and Boc removal, the four catalysts 3–6 (Scheme 1).
Scheme 1. Synthesis of the organocatalysts 3–6. a) Trifluoroacetic
acid (TFA), CH2Cl2; b) l-Boc–Pro or d-Boc–Pro (1.1 equiv.),
HATU or HBTU (1.3 equiv.), DIPEA or collidine (3.0 equiv.),
CH2Cl2 or CH3CN; c) Pd(PPh3)4 (0.05 equiv.), PPh3 (0.2 equiv.),
pyrrolidine (1.2 equiv.), CH2Cl2.
Prompted by these inspiring observations and by the bi-
functional nature and turn inducing ability of our DKPs,
The conjugate addition of aldehydes and ketones to ni-
we decided to explore DKP-containing peptidomimics as trooloefins has been studied using proline based organocat-
organocatalysts in the enantioselective conjugate addition alysts[23] as well as a number of other amine catalysts,[24]
of aldehydes to nitroolefins.
usually containing a pyrrolidine moiety[25] or a primary
amine.[26] In most cases bifunctional organocatalysts, also
containing a hydrogen-bond donor (e.g. carboxylic acid,
thiourea, hydroxy group, sulfonamide), were superior in
terms of reactivity and selectivity.
Results and Discussion
Herein we report the synthesis of four peptidomimics 3–
The enantioselective conjugate addition of n-butanal to
6 (Figure 2) containing the cis-DKP-1 or trans-DKP-2 scaf- β-nitrostyrene was chosen as a benchmark reaction to
fold and either l-Pro or d-Pro, and their screening as cata- screen catalysts 3–6. The reaction was performed at room
lysts in the conjugate addition of several aldehydes to β- temperature in a range of solvents (including CHCl3,
nitrostyrene and (E)-2-(furan-2-yl)nitroethene. The confor- CH2Cl2, THF, and iPrOH) and, as already noted by Wen-
mational preferences of the organocatalysts 3–6 were also nemers and coworkers,[21a] the best results were obtained in
investigated by computer modeling (vide infra).
a mixture of CHCl3 and iPrOH 9:1 using 5 mol-% of cata-
The synthesis of DKPs cis-Boc-DKP-1-OAllyl (7) and lyst. As 3–6 are stored after N-Boc deprotection as the cor-
trans-Boc-DKP-2-OAllyl (8) started from β-allyl-N-(tert- responding trifluoroacetate salts, one equivalent of N-meth-
butoxycarbonyl)-l-aspartate and either l- or d-N-benz- ylmorpholine (NMM) with respect to the catalyst (i.e.
ylserine methyl ester, as previously reported.[14,22] Interme- 5 mol-%) was added to free the amine. Good to excellent
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2,5-Diketopiperazines as Organocatalysts
results were obtained using catalysts 3–6 in the conjugate turing a covalently bound benzoic acid moiety, the carbox-
addition reaction (Table 1). In particular, 3 and 5 contain- ylic acid is already present in the catalyst, albeit without
ing l-proline and cis-DKP-1 or trans-DKP-2, respectively, any spatial preorganization. In both cases the reaction oc-
provided quantitative yields as well as excellent dia- curred in low yield and modest dr and ee (Table 1, Entries
stereomeric ratios (dr) and enantiomeric excesses (Table 1, 6–7), thus confirming the importance of suitable geometric
Entries 1 and 3). It is evident that the enantioface discrimi- requirements and conformational constraints for the
nation in the attack of the enamine to the nitroolefin is achievement of significant stereoselectivity. The key role of
determined by the absolute configuration of the proline res- the carboxylic acid in the activation and orientation of the
idue in the catalyst, whereas the DKP scaffolds tune the nitroolefin was established by the inferior results obtained
degree of selectivity. Proline itself, which has been widely with catalyst 15 (the allyl ester of 5, Figure 3), cf. Entry 8
used as an organocatalyst in numerous successful applica- and Entry 3 of Table 1. Thus, Entries 6–8 (Table 1) confirm
tions, has been reported to afford only moderate reactivity the importance of the bifunctional nature of catalysts 3–6,
and low diastereo- and enantioselectivity (Table 1, Entry with the secondary amine promoting the formation of the
5).[20a] To further prove the importance of a properly ori- enamine, and the carboxylic acid group activating the ni-
ented chiral bifunctional scaffold attached to the proline troolefin through hydrogen bonding (see below for a model
moiety (DKP in our case and a dipeptide in the case of the of a proposed transition structure).
catalyst developed by Wennemers and coworkers[21]), two
The substrate scope of catalysts 3–6 was then investigated
simple prolinamides, 14a and 14b (Figure 3), were prepared under the same reaction conditions, using several aliphatic
by condensation of proline with commercially available aldehydes with β-nitrostyrene (Table 2). In most cases, 5
amines, and tested in the conjugate addition reaction de- was the best performing catalyst in terms of enantio-
scribed above.
selectivity, whereas better diastereoselectivity was usually
obtained with 3.
Table 1. Conjugate addition of n-butanal to nitrostyrene catalyzed
by 3–6.[a]
Table 2. Scope of the conjugate addition of different aldehydes to
nitrostyrene catalyzed by 3–6.[a]
Entry Cat.
Yield
[%][b]
syn/anti[c]
ee [%][d]
(syn isomer) configuration
Absolute
Entry
R
Cat. Yield syn/anti[c]
ee [%][d]
(syn isomer) configuration
Absolute
[%][b]
1
2
3
4
5
6
7
8
3[e]
99
99
96
95
85
27
33
76
40:1
33:1
50:1
33:1
8:1
5:1
4:1
16:1
99
76
92
80
39
53
52
82
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
4[e]
3[e]
4[e]
5[e]
6[e]
3[e]
4[e]
5[e]
6[e]
3[e]
4[e]
5[e]
6[e]
3[e]
4[e]
5[e]
6[e]
99
98
99
99
81
77
40
40
99
98
99
95
99
97
94
94
11:1
13:1
20:1
25:1
99:1
50:1
99:1
99:1
20:1
20:1
8:1
83
66
94
82
88
78
92
80
97
91
98
95
92
83
98
85
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
5[e]
1
2
3
4
5
6
7
8
n-C3H7
n-C3H7
n-C3H7
n-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
n-C5H11
n-C5H11
n-C5H11
n-C5H11
CH2Ph
CH2Ph
CH2Ph
CH2Ph
6[e]
l-Pro[f]
14a[e,g]
14b[e]
15[e]
[a] Reaction conditions: n-butanal/β-nitrostyrene/cat. = 300:100:5,
solvent = CHCl3/iPrOH, 90:10, T = 20 °C. [b] Isolated yield. [c]
Determined by H NMR spectroscopy on the crude reaction mix-
ture. [d] Determined by HPLC equipped with a chiral column
(Daicel Chiralpak AD-H). [e] As the catalysts were stored as tri-
fluoroacetate salts, 5 mol-% of NMM was added. [f] Ref.[20a] [g]
5 mol-% of benzoic acid was added as a cocatalyst.
[f]
[f]
[f]
[f]
9
1
10
11
12
13
14
15
16
13:1
33:1
20:1
7:1
10:1
[a] Reaction conditions: aldehyde/β-nitrostyrene/cat. = 300:100:5,
solvent = CHCl3/iPrOH, 90:10, T = 20 °C, t = 24 h. [b] Isolated
1
yield. [c] Determined by H NMR spectroscopy on the crude reac-
tion mixture. [d] Determined by HPLC equipped with a chiral col-
umn (Daicel Chiralpak AD-H). [e] As the catalysts were stored as
trifluoroacetate salts, 5 mol-% of NMM was added. [f] t = 72 h.
Catalysts 4 and 6, derived from d-proline, gave the enan-
tiomeric products (2S,3R)-13. Remarkably, 4 and 6 parallel
Figure 3. Organocatalysts 14a, 14b, and 15.
Benzylprolinamide 14a reacted in the presence of an the behavior of 3 and 5 in terms of performance: catalyst 6
equimolar amount of benzoic acid as an additive (Table 1, gave better ee values than 4 and, conversely, 4 was often
Entry 6).[27] In the case of prolinamide 14b (Entry 7), fea- more diastereoselective than 6.
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The conjugate addition to (E)-2-(furan-2-yl)nitroethene formation of 5 features a kinked arrangement (Figure 4, a),
was also investigated, using the best performing catalysts 5 with the proline residue folding towards the DKP ring, and
and 6, yielding enantiomeric products, and the results are the proline N–H pointing to the C=O of the carboxylic acid
collected in Table 3. Good to excellent ee values and dia- forming an intramolecular hydrogen bond. A similar fold-
stereoselectivities were also obtained, albeit with moderate ing of the proline ring was revealed in the global minimum
conversions, which can be attributed to the lower reactivity of 3, where the carboxylic acid proton is intramolecularly
of the electron-rich heteroaromatic nitroolefin.
H-bonded to the proline nitrogen atom (Figure 4, b).
Table 3. Conjugate addition to (E)-2-(furan-2-yl)nitroethene cata-
lyzed by 5 and 6.[a]
Yield syn/anti[c]
ee [%][d]
(syn isomer)
Figure 4. Lowest energy conformations of 5 (a) and 3 (b).
Entry
R
Cat.
[%][b]
On the other hand, it can be envisaged that intramolecu-
lar H-bonds are less important once the enamine is formed
by reaction with the aldehyde. For this reason, we per-
formed a MC/EM conformational search also on the en-
amine intermediates of 3–6 with propanal. As expected, the
conformational equilibrium in the enamines is more com-
plex, featuring either folded or more extended (unfolded)
geometries. For the enamine of 5, a low-energy structure
was found that superimposes well to the kinked, global
minimum of the catalyst (cf. parts a in Figures 4 and 5). In
this conformation the re-face of the enamine is shielded by
the DKP ring and the N-bound benzyl group, leaving the
si-face exposed to the attack of the electrophilic nitroolefin.
The carboxylic acid (above the enamine plane in Figure 5,
a) is likely to act as a hydrogen-bond donor, activating the
acceptor (–NO2), and directing its approach from the less
hindered enamine si-face, thus leading to the expected
(2R,3S)-enantiomer (Figure 5, b).[31]
1
2
3
4
5
6
7
8
n-C2H5
n-C2H5
n-C3H7
n-C3H7
i-C3H7
i-C3H7
CH2Ph
CH2Ph
5[e]
6[e]
5[e]
6[e]
5[e]
6[e]
5[e]
6[e]
66
87
61
64
42
31
97
81
9:1
93
85
94
78
92
80
95
77
16:1
13:1
33:1
99:1
99:1
12:1
10:1
[a] Reaction conditions: n-butanal/β-nitrostyrene/cat. = 300:100:5,
solvent = CHCl3/iPrOH, 90:10, T = 20 °C, t = 24 h. [b] Isolated
yield. [c] Determined by H NMR spectroscopy on the crude reac-
tion mixture. [d] Determined by HPLC equipped with a chiral col-
umn (Daicel Chiralpak AD-H). [e] As the catalysts were stored as
trifluoroacetate salts, 5 mol-% of NMM was added.
1
Overall, the above results are puzzling if one considers
that organocatalysts 3 and 5, which possess different stere-
ostructures (Figure 2), yield conjugate addition products
with the same absolute configuration and similar enantio-
selectivity. As already noted by Wennemers and coworkers,
the absolute configuration of the final product is deter-
mined by the configuration of the terminal proline residue:
catalysts 3 and 5 bearing l-Pro gave (R,S)-13, whereas 4
and 6 with d-Pro afforded (S,R)-13. On the other hand, the
similar level of enantioselectivity of catalysts 3 and 5 bear-
ing cis-DKP-1 and trans-DKP-2, respectively, is rather
counterintuitive. In fact, the relative stereochemistry of the
DKP units of 3 and 5 should confer different spatial prop-
erties to their peptidomimics (i.e. cis-DKP-1 has hairpin in-
ducing ability,[14a] whereas trans-DKP-2 usually favors the
formation of unfolded structures).[14b]
To shed light on the activity and selectivity of catalysts
3–6, we decided to undertake a conformational analysis of
these peptidomimics by means of computational studies.
The molecules were subjected to an extensive, uncon-
strained Monte Carlo/Energy Minimization (MC/EM) con-
formational search[28] by molecular mechanics methods,
using the OPLSA-AA force field[29] and the implicit CHCl3
GB/SA solvent model.[30]
Figure 5. (a) Enamine intermediate of catalyst 5 with propanal: low
energy conformation featuring si-face attack; (b) Proposed transi-
tion-structure model for the reaction of the propanal enamine of 5
with β-nitrostyrene, leading to (2R,3S)-2-methyl-4-nitro-3-phen-
ylbutanal.
Conclusions
Limiting our discussion to a few selected cases, an inter-
A new class of peptidomimetic organocatalysts was pre-
esting comparison is between 5 (l-proline and trans-DKP- pared starting from two bifunctional diketopiperazines for-
2) and 3 (l-proline and cis-DKP-1). The lowest energy con- mally derived from the head-to-tail cyclization of l-aspartic
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2,5-Diketopiperazines as Organocatalysts
Materials: Commercially available reagents were used as received.
Allyl [(3S,6S)-4-benzyl-3-(tert-butoxycarbonylaminomethyl)-2,5-
dioxopiperazin-5-yl]acetate[14] (7), allyl [(3R,6S)-4-benzyl-3-(tert-
butoxycarbonylaminomethyl)-2,5-dioxopiperazin-5-yl]acetate[14]
(8), and (S)-benzylprolinamide (14a)[33] were prepared according to
literature procedures.
acid and either (R)- or (S)-2,3-diaminopropionic acid, fea-
turing aminomethyl and carboxymethyl side arms in the 3-
and 6-positions of the 2,5-piperazindione ring. The ter-
minal amino group of the DKP scaffold was coupled to a
l- or d-proline residue giving rise to four organocatalysts
3–6. These were tested in the conjugate addition reaction of
several aldehydes to β-nitrostyrene and (E)-2-(furan-2-yl)-
nitroethene with good to excellent diastereo- and enantio-
selectivities, particularly for catalysts 3 and 5. The absolute
configuration of the conjugate addition products depended
on the configuration of the terminal proline residue: cata-
lysts 3 and 5 bearing l-Pro gave (2R,3S)-13, whereas cata-
lysts 4 and 6 with d-Pro afforded (2S,3R)-13. To rationalize
the stereoselectivity of these catalysts, a Monte Carlo/En-
ergy Minimization conformational search by molecular me-
chanics methods was undertaken on the four catalysts and
their enamine derivatives with propanal. The four catalysts
showed a folded arrangement with the COOH group
pointing towards the proline nitrogen atom, whereas the en-
amine derivatives revealed conformations where one face of
the enamine moiety is shielded by the DKP ring and the
Spectroscopic and analytical data for the following products were
determined in agreement with those described in the literature: 2-
ethyl-4-nitro-3-phenylbutanal[21c] (13a), 4-nitro-3-phenyl-2-pro-
pylbutanal[21c] (13b), 4-nitro-2-pentyl-3-phenylbutanal[21c] (13c), 2-
isopropyl-4-nitro-3-phenylbutanal[21c] (13d), 2-benzyl-4-nitro-3-
phenylbutanal[21c] (13e), 2-ethyl-3-(furan-2-yl)-4-nitrobutanal[27a]
(16a), and 3-(furan-2-yl)-4-nitro-2-propylbutanal[27b] (16b).
tert-Butyl (2S)-2-[({3S,6S}-6-{2-(Allyloxy)-2-oxoethyl}-4-benzyl-
2,5-dioxopiperazin-3-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
(9): TFA (5 mL) was added dropwise at 0 °C to a solution of 7
(170 mg, 0.394 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) and the reac-
tion mixture was stirred at the same temperature for 3 h. Volatiles
were evaporated under reduced pressure and the residue was
treated with Et2O to cause the precipitation of the TFA salt, which
was isolated by decantation. l-Boc-Proline (93 mg, 0.432 mmol,
1.1 equiv.) was dissolved in acetonitrile (4 mL), and HATU
carboxylic acid is likely to act as a hydrogen-bond donor, (194 mg, 0.510 mmol, 1.3 equiv.) and DIPEA (169 μL, 0.985 mmol,
2.5 equiv.) were added at 0 °C under N2. The solution was stirred
for 30 min before the TFA salt was added, and the mixture was
stirred for 1 h at 0 °C, and overnight at room temperature. The
reaction mixture was poured into EtOAc (40 mL) and washed with
1 m KHSO4 solution (2 ϫ 5 mL), satd. NaHCO3 solution (2 ϫ
5 mL), and brine (1ϫ 5 mL). The organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography using 2%
MeOH in CH2Cl2 to yield 9 as a white solid (164 mg, 0.311 mmol,
79%). Rf = 0.28 (ethyl acetate); m.p. 61–62 °C. [α]2D0 = +6.6 (c =
0.1, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.45 (s, 9
H), 1.63 (br., 4 H), 1.87 (br. s, 2 H), 2.82 (m, 1 H), 3.43 (br., 1 H),
3.58 (m, 1 H), 3.79–3.96 (br., 2 H), 4.17 (d, J = 15.0 Hz, 1 H), 4.25
(br. s, 1 H), 4.47 (m, J = 10.4, 2.6 Hz, 1 H), 4.66 (m, 2 H), 5.29
(dd, J = 10.3, 1.2 Hz, 1 H), 5.35 (dd, J = 17.2, 1.2 Hz, 1 H), 5.46
(d, J = 15.0 Hz, 1 H), 5.91 (m, 1 H), 6.61 (br., 1 H), 7.31 (m, 5 H)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.5, 28.3, 39.5,
40.1, 43.8, 47.1, 52.0, 55.8, 57.8, 66.1, 80.6, 119.2, 128.1, 128.6,
activating the nitroolefin acceptor (–NO2) and directing its
approach from the less hindered enamine face.
Experimental Section
General Remarks: All reactions were carried out in flame-dried
glassware with magnetic stirring under a nitrogen atmosphere, un-
less otherwise stated. Dry solvents (over molecular sieves in bottles
with crown caps) were purchased from Sigma–Aldrich and stored
under nitrogen. The reactions were monitored by analytical TLC
using silica gel 60 F254 precoated glass plates (0.25 mm thickness).
Visualization was accomplished by irradiation with a UV lamp
and/or staining with a potassium permanganate alkaline solution.
Flash column chromatography was performed using silica gel 60 Å,
particle size 40–64 μm, following the procedure reported by Still
and coworkers.[32] 1H NMR spectra were recorded with a spectrom-
eter operating at 400.13 MHz. Chemical shifts are reported in ppm
with the solvent reference relative to tetramethylsilane (TMS) em-
ployed as the internal standard (CDCl3 δ = 7.26 ppm). The follow-
ing abbreviations are used to describe spin multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br. = broad
signal, dd = doublet of doublets. 13C NMR spectra were recorded
with a 400 MHz spectrometer operating at 100.56 MHz with com-
plete proton decoupling. Chemical shifts are reported in ppm rela-
tive to TMS with the respective solvent resonance as the internal
standard (CDCl3, δ = 77.23 ppm). Infrared spectra were recorded
with a standard FTIR spectrometer. Optical rotation values were
measured with an automatic polarimeter with a 1-dm cell at the
sodium D line (λ = 589 nm). HPLC was performed with an instru-
ment equipped with a diode array detector using a chiral column.
HRMS were measured with a Fourier Transform Ion Cyclotron
Resonance (FT-ICR) Mass Spectrometer APEX II & Xmass soft-
ware (Bruker Daltonics)–4.7 T Magnet (Magnex) equipped with
ESI source, available at CIGA (Centro Interdipartimentale Grandi
Apparecchiature), c/o Università degli Studi di Milano. MS were
acquired either with a Thermo-Finnigan LCQ Advantage mass
spectrometer (ESI ion source) or a VG Autospec M246 spectrome-
ter (FAB ion source). Elemental analyses were performed with a
Perkin–Elmer Series II CHNS/O Analyzer 2000.
129.0, 131.3, 135.2, 164.4 ppm. IR: ν = 1734, 1662, 1307, 1162,
˜
1124, 970, 842, 723 cm–1. C27H36N4O7 (528.60): calcd. C 61.35, H
6.86, N 10.60; found C 61.03, H 7.18, N 10.22.
tert-Butyl (2R)-2-[({3S,6S}-6-{2-(Allyloxy)-2-oxoethyl}-4-benzyl-
2,5-dioxopiperazin-3-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
(10): TFA (5 mL) was added dropwise at 0 °C to a solution of 7
(170 mg, 0.394 mmol, 1.0 equiv.) in CH2Cl2 (5 mL). The resulting
solution was stirred at the same temperature for 3 h. Volatiles were
removed under reduced pressure and the residue was treated with
Et2O to cause the precipitation of the TFA salt, which was isolated
by decantation. d-Boc-Proline (93 mg, 0.432 mmol, 1.1 equiv.) was
dissolved in CH2Cl2 (4 mL), and HATU (194 mg, 0.510 mmol,
1.3 equiv.) and DIPEA (169 μL, 0.985 mmol, 2.5 equiv.) were
added at 0 °C under N2. The solution was stirred for 30 min before
the TFA salt was added, and the mixture was stirred for 1 h at
0 °C and overnight at room temperature. The reaction mixture was
poured into EtOAc (40 mL) and washed with 1 m KHSO4 solution
(2ϫ 5 mL), satd. NaHCO3 solution (2ϫ 5 mL), and brine (1ϫ
5 mL). The organic layer was dried with Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography using 2% MeOH in CH2Cl2 to yield 10
Eur. J. Org. Chem. 2011, 5599–5607
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5603

C. Gennari, U. Piarulli et al.
FULL PAPER
as a white solid (183 mg, 0.346 mmol, 88%). Rf = 0.28 (ethyl acet-
MeOH in CH2Cl2 to yield 12 as a pale yellow solid (734 mg,
ate); m.p. 63–64 °C. [α]2D0 = +29.90 (c = 0.1, CHCl3). 1H NMR
1.39 mmol, 100%). Rf = 0.26 (ethyl acetate); m.p. 59–60 °C. [α]D20
=
1
(400 MHz, CDCl3, 25 °C): δ = 1.44 (s, 9 H), 1.62–1.99 (br., 4 H), +18.20 (c = 0.1, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ =
3.21–3.67 (br., 4 H), 3.84 (br., 1 H), 3.92 (br., 1 H), 4.13 (d, J =
1.46 (s, 9 H), 1.86 (br., 2 H), 2.34 (br., 1 H), 2.60 (s, 1 H), 2.79 (m,
14.5 Hz, 1 H), 4.28 (br., 1 H), 4.48 (d, J = 10.7 Hz, 1 H), 4.58–4.70 1 H) 3.26 (dd, J = 17.52, 1.52 Hz, 1 H), 3.31 3.52 (br., 3 H), 3.86
(m, 2 H), 5.27 (d, J = 10.5 Hz, 1 H), 5.34 (dd, J = 17.2, 1.3 Hz, 1
H), 5.53 (br. 1 H), 5.91 (m, 1 H), 6.79 (br. s, 1 H), 7.28–7.34 (m, 5
H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.5, 28.3,
(br., 1 H), 4.05–4.75 (br., 3 H), 4.61–4.80 (m, 3 H), 5.28 (m, 2 H),
5.50 (m, 1 H), 5.89 (m, 1 H), 6.72 (br., 1 H), 7.18 (br., 1 H), 7.25–
7.41 (m, 5 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ =
29.6, 39.4, 43.6, 46.8, 47.2, 52.0, 55.7, 60.1, 66.0, 80.6, 119.1, 128.1, 24.5, 28.4, 28.5, 37.7, 38.6, 39.2, 47.0, 47.3, 50.8, 58.6, 60.3, 65.8,
128.6, 129.0, 131.4, 135.1, 164.5, 165.5, 171.2, 173.0 ppm. IR: ν =
80.6, 119.0, 128.0, 128.3, 128.6, 131.4, 135.4, 165.0, 166.6, 170.7,
˜
1740, 1667, 1533, 1251, 1164, 1127, 970, 849, 723 cm– 1
.
173.1 ppm. IR: ν = 1733, 1668, 1164, 1126, 723 cm–1. C H N O
˜
27 36
4
7
C27H36N4O7 (528.60): calcd. C 61.35, H 6.86, N 10.60; found C
61.21, H 7.14, N 10.25.
(528.60): calcd. C 61.35, H 6.86, N 10.60; found C 61.24, H 7.10,
N 10.74.
tert-Butyl (2S)-2-[({3R,6S}-6-{2-(Allyloxy)-2-oxoethyl}-4-benzyl-
2,5-dioxopiperazin-3-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
(11): To a solution of 8 (650 mg, 1.50 mmol, 1.0 equiv.) in CH2Cl2
(19.2 mL) was added TFA (19.2 mL) dropwise at 0 °C, and the re-
sulting solution was stirred at the same temperature for 2 h. Vola-
tiles were evaporated under reduced pressure and the residue was
treated with Et2O to cause the precipitation of the TFA salt, which
was isolated by decantation. l-Boc-Proline (355 mg, 1.65 mmol,
1.1 equiv.) was dissolved in acetonitrile (15 mL), and HBTU
(740 mg, 1.95 mmol, 1.3 equiv.) and collidine (0.60 mL, 4.50 mmol,
3.0 equiv.) were added at 0 °C under N2. The solution was stirred
for 30 min before the TFA salt was added and the mixture was
stirred for 1 h at 0 °C and at room temperature overnight. The reac-
tion mixture was poured into EtOAc (150 mL) and washed with
1 m KHSO4 solution (2ϫ 20 mL), satd. NaHCO3 solution (2ϫ
20 mL), and brine (1ϫ 20 mL). The organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography using 2 %
MeOH in CH2Cl2 to yield 11 as a pale yellow solid (793 mg,
6-[(3S,6S)-4-Benzyl-3-({(2S)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxamido}methyl)-2,5-dioxopiperazin-6-yl]acetic Acid: To a solu-
tion of 9 (75 mg, 0.142 mmol, 1.0 equiv.) in CH2Cl2 (1.2 mL) at
0 °C were added pyrrolidine (15 μL, 0.170 mmol, 1.2 equiv.), tri-
phenylphosphane (6.7 mg, 0.025 mmol, 0.18 equiv.), and tetrakis-
(triphenylphosphane)palladium(0) (6.6 mg, 0.0057 mmol,
0.04 equiv.). The mixture was stirred for 15 min at 0 °C and 2 h at
room temperature, then poured into EtOAc (20 mL) and extracted
into satd. NaHCO3 solution (3ϫ 3 mL). The organic layers were
discarded and the combined aqueous phases were acidified to pH
2 with 1 m KHSO4 solution. The acidified aqueous solution was
extracted into CH2Cl2 (3ϫ 5 mL), and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with 10% MeOH in CH2Cl2 to yield the product as a white
solid (56 mg. 0.115 mmol, 81%). Rf = 0.30 (CH2Cl2/MeOH 9:1);
m.p. 128–129 °C. [α]D20 = +57.40 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.41–1.48 (br., 9 H), 1.83, 2.34 (br.,
4 H), 2.93–3.01 (br., 1 H), 3.10–3.20 (br., 1 H), 3.32–3.63 (br., 4
H), 3.81–3.99 (br., 2 H), 4.24–4.50 (br., 2 H), 5.51 (m, 1 H), 7.28–
7.37 (br., 5 H), 7.50 (br., 1 H) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 24.4, 28.4, 29.9, 39.8, 40.5, 46.8, 47.2, 52.1, 57.6, 59.8,
1.50 mmol, 100%). Rf = 0.26 (ethyl acetate); m.p. 57–58 °C. [α]D20
=
–3.7 (c = 0.1, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
1.47 (s, 9 H), 1.88 (br., 2 H), 2.08 (br., 1 H), 2.81 (br., 2 H), 3.22
(dd, J = 17.57, 3.12 Hz, 1 H), 3.33 (br., 1 H), 3.41 (br., 1 H), 3.58
(br., 1 H), 3.88 (br., 1 H), 3.95 (br., 1 H), 4.21 (d, J = 15.17 Hz, 1
H), 4.30 (br., 1 H), 4.55–4.63 (m, 3 H), 5.28 (ddd, J = 30.17, 17.20,
1.16 Hz, 2 H), 5.43 (d, J = 15.16 Hz, 1 H), 5.89 (m, 1 H), 6.97
(broad s, 1 H), 7.27–7.35 (m, 5 H), 7.51 (br. m, 1 H) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.5, 28.4, 28.6, 37.5, 39.2,
47.0, 47.4, 50.6, 59.0, 59.8, 65.8, 80.6, 118.9, 127.9, 128.4, 128.9,
128.1, 128.5, 129.0, 135.0, 155.1, 164.8, 173.3 ppm. IR: ν = 2725,
˜
2676, 1738, 1666, 1252, 1162, 1126, 969, 849, 724 cm– 1
.
C24H33N4O7 (489.55): calcd. C 59.00, H 6.60, N 11.47; found C
58.97, H 6.55, N 11.64.
6-[(3S,6S)-4-Benzyl-3-({(2S)-1-pyrrolidine-2-carboxamido}methyl)-
2,5-dioxopiperazin-6-yl]acetic Acid, Trifluoroacetate Salt (3·TFA):
The Boc derivative from the previous reaction was dissolved in
CH2Cl2 (1.5 mL), TFA (1.5 mL) was added dropwise at 0 °C, and
the mixture stirred at the same temperature for 2 h. The solution
was evaporated under reduced pressure and the residue was treated
with Et2O to cause the precipitation of the TFA salt, which was
isolated by decantation.
131.4, 135.6, 164.8, 167.0, 170.6, 173.85 ppm. IR: ν = 2360, 1736,
˜
1686, 1532, 1166, 843, 723 cm–1. C27H36N4O7 (528.60): calcd. C
61.35, H 6.86, N 10.60; found C 60.99, H 6.93, N 10.40.
tert-Butyl (2R)-2-[({3R,6S}-6-{2-(Allyloxy)-2-oxoethyl}-4-benzyl-
2,5-dioxopiperazin-3-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
(12): Compound 8 (600 mg, 1.39 mmol, 1.0 equiv.) was dissolved
in CH2Cl2 (18 mL), and TFA (18 mL) was added dropwise at 0 °C.
The reaction mixture was stirred at the same temperature for 2 h.
The solution was evaporated under reduced pressure and the resi-
due was treated with Et2O to cause precipitation of the TFA salt,
which was isolated by decantation. d-Boc-Proline (329 mg,
1.53 mmol, 1.1 equiv.) was dissolved in acetonitrile (14 mL), and
HBTU (685 mg, 1.80 mmol, 1.3 equiv.) and collidine (0.55 mL,
4.17 mmol, 3.0 equiv.) were added at 0 °C under N2. The solution
was stirred for 30 min before the TFA salt was added and the mix-
ture was stirred for 1 h at 0 °C and overnight at room temperature.
The reaction mixture was poured into EtOAc (150 mL) and washed
with 1 m KHSO4 solution (2ϫ 20 mL), 5% NaHCO3 solution (2ϫ
20 mL), and brine (1ϫ 20 mL). The organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography using 2 %
6-[(3S,6S)-4-Benzyl-3-({(2R)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxamido}methyl)-2,5-dioxopiperazin-6-yl]acetic Acid: To a solu-
tion of 10 (75 mg, 0.142 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) at 0 °C
were added pyrrolidine (15 μL, 0.170 mmol, 1.2 equiv.), tri-
phenylphosphane (6.7 mg, 0.025 mmol, 0.18 equiv.), and tetrakis-
(triphenylphosphane)palladium(0) (6.6 mg, 0.0057 mmol,
0.04 equiv.). The mixture was stirred for 15 min at 0 °C and 2 h at
room temperature, poured into EtOAc (20 mL), and extracted into
satd. NaHCO3 solution (3ϫ 3 mL). The organic layers were dis-
carded and the combined aqueous phases were acidified to pH 2
with 1 m KHSO4 solution. The acidified aqueous solution was ex-
tracted into CH2Cl2 (3ϫ 5 mL) and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with 10% MeOH in CH2Cl2 to yield the product as a white
5604
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5599–5607

2,5-Diketopiperazines as Organocatalysts
solid (59.0 mg, 0.120 mmol, 85%). Rf = 0.30 (CH2Cl2/MeOH 9:1);
m.p. 131–132 °C. [α]D20 = +107.60 (c = 0.2, CHCl3). 1H NMR
(3ϫ 10 mL). The organic layers were discarded and the combined
aqueous phases were acidified to pH 2 with 1 m KHSO4 solution.
(400 MHz, CDCl3, 25 °C): δ = 1.44 (s, 9 H), 1.70 (br., 1 H), 1.86 The acidified aqueous solution was extracted into CH2Cl2 (3ϫ
(br., 1 H), 2.06 (br., 2 H), 2.90 (dd, J = 17.7, 3.2 Hz, 1 H), 3.27 15 mL) and the combined organic layers were dried with Na2SO4,
(dd, J = 17.7, 4.1 Hz, 1 H) 3.33–3.57 (br., 4 H), 3.76–3.86 (m, 2 filtered, and concentrated under reduced pressure. The crude prod-
H), 4.30–4.40 (m, 3 H), 5.66 (d, J = 15.3 Hz, 1 H), 7.18 (d, J = uct was purified by flash chromatography eluting with 10% MeOH
8.7 Hz, 1 H), 7.28–7.38 (m, 5 H), 8.95 (s, 1 H) ppm. 13C NMR in CH2Cl2 to yield the product as a white solid (620 mg, 1.27 mg,
(100.6 MHz, CDCl3, 25 °C): δ = 24.5, 28.4, 30.3, 35.3, 38.2, 45.6,
91%). Rf = 0.31 (CH2Cl2/MeOH 9:1); m.p. 111–112 °C. [α]D20
=
1
47.4, 51.2, 56.4, 60.1, 81.2, 128.2, 128.6, 129.0, 134.6, 154.9, 165.0,
+5.50 (c = 0.2, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ =
1.44 (s, 9 H), 1.75–2.15 (br., 4 H), 2.70 (m, 1 H), 3.35–3.55 (br., 3
H), 3.67 (br., 1 H), 3.82 (br., 1 H), 3.90 (br. s, 1 H), 4.07 (d, J =
14.4 Hz, 1 H), 4.35 (br., 1 H), 4.53 (d, J = 9.7 Hz, 1 H), 5.48 (d, J
= 14.4 Hz, 1 H), 7.25–7.45 (m, 5 H), 7.57 (broad s, 1 H), 8.30 (s, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.7, 28.4,
29.3, 37.6, 40.0, 47.1, 47.2, 50.9, 58.4, 59.8, 81.2, 128.1, 128.4,
167.3, 173.0, 173.1 ppm. IR: ν = 2726, 1656, 1165, 1123, 723 cm–1.
˜
C24H33N4O7 (489.55): calcd. C 59.00, H 6.60, N 11.47; found C
55.91, H 6.54, N 11.58.
6-[(3S,6S)-4-Benzyl-3-({(2R)-1-pyrrolidine-2-carboxamido}meth-
yl)-2,5-dioxopiperazin-6-yl]acetic Acid, Trifluoroacetate Salt
(4·TFA): The Boc derivative from the previous reaction was dis-
solved in CH2Cl2 (1.6 mL), TFA (1.6 mL) was added dropwise at
0 °C, and the mixture stirred at the same temperature for 2 h. The
solution was evaporated under reduced pressure and the residue
was treated with Et2O to cause the precipitation of the TFA salt,
which was isolated by decantation.
128.9, 135.3, 155.7, 165.3, 168.6, 173.7, 174.3 ppm. IR: ν = 1734,
˜
1675, 1163, 1124, 723 cm–1. C24H33N4O7 (489.55): calcd. C 59.00,
H 6.60, N 11.47; found C 59.13, H 6.75, N 11.61.
6-[(3R,6S)-4-Benzyl-3-({(2R)-1-pyrrolidine-2-carboxamido}meth-
yl)-2,5-dioxopiperazin-6-yl]acetic Acid, Trifluoroacetate Salt
(6·TFA): The Boc-protected derivative from the previous reaction
was dissolved in CH2Cl2 (16.5 mL), TFA (16.5 mL) was added
dropwise at 0 °C, and the mixture stirred at the same temperature
for 2 h. The solution was evaporated under reduced pressure and
the residue was treated with Et2O to cause the precipitation of the
TFA salt, which was isolated by decantation.
6-[(3R,6S)-4-Benzyl-3-({(2S)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxamido}methyl)-2,5-dioxopiperazin-6-yl]acetic Acid: To a solu-
tion of 11 (793 mg, 1.50 mmol, 1.0 equiv.) in CH2Cl2 (15 mL) at
0 °C were added pyrrolidine (0.149 mL, 1.80 mmol, 1.2 equiv.), tri-
phenylphosphane (77 mg, 0.3 mmol, 0.2 equiv.), and tetrakis(tri-
phenylphosphane)palladium(0) (87 mg, 0.075 mmol, 0.05 equiv.).
The mixture was stirred for 15 min at 0 °C and 2 h at room tem-
perature, poured into EtOAc (60 mL), and extracted into satd.
NaHCO3 solution (3ϫ 10 mL). The organic layers were discarded
and the combined aqueous phases were acidified to pH 2 with 1 m
KHSO4 solution. The acidified aqueous solution was extracted into
CH2Cl2 (3ϫ 15 mL) and the combined organic layers were dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography eluting
with 10% MeOH in CH2Cl2 to yield the product as a white solid
(687 mg, 1.40 mg, 94%). Rf = 0.31 (CH2Cl2/MeOH 9:1); m.p. 117–
118 °C. [α]2D0 = –50.16 (c = 0.2, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.33–1.45 (br., 9 H), 1.75–2.40 (br., 4 H), 2.67
(dd, J = 18.0, 10.4 Hz, 1 H), 3.27–3.96 (br., 6 H), 4.16–4.70 (br.,
3 H), 4.33–4.60 (br., 1 H), 7.23–7.34 (br., 5 H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 24.4, 28.4, 29.1, 31.2, 38.0, 39.3,
47.3, 50.9, 59.1, 59.9, 80.9, 135.6, 155.8, 164.9, 165.3, 168.3, 168.7,
4-[{(2S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamido}-
methyl]benzoic Acid: Boc-l-Proline (50 mg, 0.23 mmol, 1.0 equiv.)
was dissolved in CH2Cl2 (2.5 mL), and HATU (88 mg, 0.23 mmol,
1.0 equiv.) and collidine (73 μL, 0.55 mmol, 2.5 equiv.) were added
at 0 °C under N2. The solution was stirred for 30 min before 4-
(aminomethyl)benzoic acid (35 mg, 0.23 mmol, 1.0 equiv.) was
added, and the mixture stirred for 1 h at 0 °C and overnight at
room temperature. The reaction mixture was poured into EtOAc
(25 mL) and washed with 1 m KHSO4 solution (3ϫ15 mL) and
brine (1ϫ20 mL). The organic layer was dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography using 8% MeOH in CH2Cl2
to yield the product as a white-yellow solid (52 mg, 0.15 mmol,
65%). Rf = 0.33 (CH2Cl2/MeOH 9:1); m.p. 177–178 °C. [α]D20
=
1
–73.43 (c = 0.1, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ =
1.43 (s, 9 H), 1.82–2.42 (br., 4 H), 3.30–3.55 (br., 2 H), 4.32–4.74
(br., 3 H), 7.30–7.34 (br., 2 H), 7.88–7.93 (br., 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 23.7, 24.7, 28.4, 43.1, 47.2, 60.0,
173.9 ppm. IR: ν = 1737, 1652, 1159, 1072, 723 cm–1. C H N O
˜
24 33
4
7
(489.55): calcd. C 59.00, H 6.60, N 11.47; found C 59.21, H 6.70,
N 11.80.
80.8, 127.3, 128.7, 130.3, 143.9, 155.9, 169.8, 172.5 ppm. IR: ν =
˜
1716, 1649, 1562, 1259, 1162, 1022, 923 cm–1. C18H24N2O5
(348.40): calcd. C 62.05, H 6.94, N 8.04; found C 61.97, H 6.71, N
7.99.
6-[(3R,6S)-4-Benzyl-3-({(2S)-1-pyrrolidine-2-carboxamido}meth-
yl)-2,5-dioxopiperazin-6-yl]acetic Acid, Trifluoroacetate Salt
(5·TFA): The Boc derivative from the previous reaction was dis-
solved in CH2Cl2 (18.2 mL), TFA (18.2 mL) was added dropwise
at 0 °C, and the mixture stirred at the same temperature for 2 h.
The solution was evaporated under reduced pressure and the resi-
due was treated with Et2O to cause the precipitation of the TFA
salt, which was isolated by decantation.
4-{[(2S)-Pyrrolidine-2-carboxamido]methyl}benzoic Acid, Trifluo-
roacetate Salt (14b·TFA): The compound from the previous reac-
tion was dissolved in CH2Cl2 (1.9 mL), TFA (1.9 mL) was added
dropwise at 0 °C, and the mixture stirred at the same temperature
for 2 h. The solution was evaporated under reduced pressure and
the residue was treated with Et2O to cause the precipitation of the
TFA salt, which was isolated by decantation.
6-[(3R,6S)-4-Benzyl-3-({(2R)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxamido}methyl)-2,5-dioxopiperazin-6-yl]acetic Acid: Com-
pound 12 (734 mg, 1.39 mmol, 1.0 equiv.) was dissolved in CH2Cl2
(14 mL), and the solution was cooled to 0 °C. Pyrrolidine
(2S)-2-[({3R,6S}-6-{2-(Allyloxy)-2-oxoethyl}-4-benzyl-2,5-dioxo-
(0.138 mL,1.67 mmol, 1.2 equiv.), triphenylphosphane (73 mg, piperazin-3-yl)methylcarbamoyl]pyrrolidine, Trifluoroacetate Salt
0.278 mmol, 0.2 equiv.), and tetrakis(triphenylphosphane)palla- (15·TFA): To a solution of 11 (30 mg, 0.06 mmol, 1.0 equiv.) in
dium(0) (80 mg, 0.0685 mmol, 0.05 equiv.) were added, the mixture CH2Cl2 (0.5 mL) was added TFA (0.5 mL) dropwise at 0 °C, and
was stirred for 15 min at 0 °C and 2 h at room temperature, poured
into EtOAc (60 mL), and extracted into satd. NaHCO3 solution
the resulting solution was stirred at the same temperature for 2 h.
Volatiles were evaporated under reduced pressure and the residue
Eur. J. Org. Chem. 2011, 5599–5607
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Gennari, U. Piarulli et al.
FULL PAPER
was treated with Et2O to cause the precipitation of the TFA salt,
which was isolated by decantation.
sche Forschungsgemeinschaft (Graduiertenkolleg 760 Medizinische
Chemie). We also gratefully acknowledge Ministero dell’Università
e della Ricerca (PRIN prot. 2008J4YNJY) for financial support
and CILEA for computing facilities. M. Civera thanks Ministero
dell’Università e della Ricerca (MIUR) (FIRB “Futuro in Ricerca”
RBFR088ITV) for a postdoctoral fellowship and financial support.
The authors would like to thank Dr. Laura Belvisi (University of
Milano) for helpful discussions.
General Procedure for 1,4-Addition Reactions: To a solution of the
catalyst (5.6 mg, 0.011 mmol, 0.05 equiv.) in solvent (500 μL,
CHCl3/iPrOH, 9:1) was added NMM (1.23 μL, 0.011 mmol,
0.05 equiv.), and the solution was stirred for 10 min. The nitroolefin
(1 equiv.) and the aldehyde (3 equiv.) were added and the mixture
was stirred for 24 h at 20 °C. The reaction mixture was purified by
flash chromatography on silica gel eluting with a mixture of n-
hexane and EtOAc.
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3-(Furan-2-yl)-2-isopropyl-4-nitrobutanal (16c): Synthesized from 2-
(2-nitrovinyl)furan and isobutanal according to the general pro-
cedure. The product was purified by flash chromatography (hexane/
1
EtOAc, 9:1). Rf = 0.31 (hexane/EtOAc, 6:1). H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.89 (d, J = 6.9 Hz, 3 H), 1.16 (d, J = 7.2 Hz,
3 H), 1.75 (m, 1 H), 2.86 (ddd, J = 9.9, 4.8, 1.8 Hz, 1 H), 4.05 (m,
1 H), 4.58–4-68 (m, 2 H), 6.22 (dd, J = 3.2, 0.5 Hz, 1 H), 6.31 (dd,
J = 3.2, 1.9 Hz, 1 H), 7.37 (dd, J = 1.9, 0.5 Hz, 1 H) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 17.8, 21.2, 28.0, 35.9, 57.3,
76.6, 109.0, 110.4, 142.6, 150.3, 203.4 ppm. IR: ν = 2725, 1715,
˜
1557, 1151, 1015, 731 cm– 1 . HRMS (ESI+): calcd. for
C11H15NO4Na [M + Na]+ 248.08958; found 248.08933.
The enantiomeric excess was determined by HPLC using a Chiracel
AD-H column (n-hexane/iPrOH, 99:1, 25 °C) at 0.6 mL/min, UV
detection at 212 nm: tR1 (syn) = 27.5 min, tR2 (syn) = 32.0 min.
2-Benzyl-3-(furan-2-yl)-4-nitrobutanal (16d): Synthesized from 2-(2-
nitrovinyl)furan and hydrocinnamaldehyde according to the general
procedure. The product was purified by flash chromatography (hex-
ane/EtOAc, 9:1). Rf = 0.25 (hexane/EtOAc, 6:1). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.76 (dd, J = 14.4, 5.6 Hz, 1 H),
2.90 (dd, J = 14.4, 8.8 Hz, 1 H), 3.18 (dddd, J = 8.8, 7.2, 5.6,
1.6 Hz, 1 H), 4.08 (ddd, J = 8.8, 7.2, 5.2 Hz, 1 H), 4.63, (dd, J =
12.8, 5.2 Hz, 1 H), 4.70 (dd, J = 12.8, 8.8 Hz, 1 H), 6.23 (m, 1 H),
6.35, (dd, J = 3.2, 2.0 Hz, 1 H), 7.12 (m, 2 H), 7.24–7.34 (m, 3 H),
7.41 (dd, J = 2.0, 0.8 Hz), 9.73 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 33.4, 37.2, 53.8, 75.8, 109.1, 110.6,
127.0, 128.4, 128.9, 137.3, 142.8, 149.9, 202.0 ppm. IR: ν = 2728,
˜
1725, 1554, 1496, 1144, 1074, 1017, 969, 918, 738, 701 cm–1. HRMS
(ESI+): calcd. for C15H15NO4Na [M + Na]+ 296.08988; found
296.08933.
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AD-H column (n-hexane/iPrOH, 99:1, 25 °C) at 0.6 mL/min, UV
detection at 212 nm: tR1 (syn) = 42.1 min, tR2 (syn) = 46.7.
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Acknowledgments
We thank the European Commission (Marie Curie Early Stage Re-
search Training Fellowship “Foldamers” MEST-CT-2004-515968)
for financial support. This work was also supported by the Deut-
5606
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: June 3, 2011
Published Online: August 23, 2011
Eur. J. Org. Chem. 2011, 5599–5607
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5607