Split-Ugi Reaction with Chiral Compounds: Synthesis of Piperazine- and Bispidine-Based Peptidomimetics

Article abstract of DOI:10.1002/hlca.201500505

A simple, one-step, stereoconservative synthesis of diamine-based peptidomimetics is described, by split-Ugi multicomponent reaction, involving chiral N-protected amino acids and α-substituted isocyanoacetate. In particular, piperazine and bispidine (3,7-diazabicyclo[3.3.1]nonane) are exploited as diamine components, bispidine being the first example of a sterically demanding bicyclic system employed in a split-Ugi reaction.

Full text of DOI:10.1002/hlca.201500505

Helv. Chim. Acta 2016, 99, 315 – 320
315
FULL PAPER
Split-Ugi Reaction with Chiral Compounds: Synthesis of Piperazine- and Bispidine-
Based Peptidomimetics
by Mattia Stucchi* and Giordano Lesma
ꢀ
Dipartimento di Chimica, Universita degli Studi di Milano, via Golgi 19, IT-20133 Milan (phone: +39-02-50314077,
e-mail: mattia.stucchi@unimi.it)
A
simple, one-step, stereoconservative synthesis of diamine-based peptidomimetics is described, by split-Ugi
multicomponent reaction, involving chiral N-protected amino acids and a-substituted isocyanoacetate. In particular, piperazine
and bispidine (3,7-diazabicyclo[3.3.1]nonane) are exploited as diamine components, bispidine being the first example of a
sterically demanding bicyclic system employed in a split-Ugi reaction.
Keywords: Split-Ugi reaction, Multicomponent reaction, Peptidomimetics, Chiral a-substituted isocyanoacetates, Bispidine.
priate conformationally constrained cyclic symmetric
secondary diamine, it would be possible to induce a well-
Introduction
The split-Ugi reaction is an isocyanide-based multicompo- defined secondary structure on the resulting pep-
nent reaction (IMCR), developed by Giovenzana et al. tidomimetic (Scheme 1), opening the way to possible mod-
in 2006 [1]. It resembles the Ugi four-component reaction
(U-4CR) [2], but instead of a primary amine, a symmetric
secondary diamine is used, allowing to generate a molecu-
lar scaffold in which one N-atom is acylated and the other
one is alkylated in one step without the necessity of pro-
tecting groups. The key step of the mechanism is the final
‘remote’ Mumm rearrangement, which occurs thanks to
ulation of specific protein–protein interactions (PPIs) [6].
PPIs determine the biological role of the relative pro-
teins, and only in the last decade have begun to gain
attention as viable targets for therapeutic intervention [7].
Only a few studies have been published on the applica-
tion of diamine-based conformationally constrained pep-
tidomimetics for regulating PPIs [8 – 10]. We believe that
the second N-atom, achieving in this way the observed such a unexplored class of potential PPI modulators is vir-
regiochemical desymmetrization of the diamine core in
only one step.
Although different cyclic and linear symmetrical sec-
tually accessible via the split-Ugi reaction in a straightfor-
ward manner. Therefore, relying on our previous
experience with the use of chiral compounds in the U-
ondary diamines proved to be suitable substrates [1][3], no 4CR [11], and our recent effort in expanding the scope of
examples are reported for sterically demanding, more con-
strained, and rigid bicyclic systems. Furthermore, to the
best of our knowledge, no efforts have been made for the
the split-Ugi protocol [12], we decided to develop a syn-
thetic route for obtaining diamine-based peptidomimetics
in a one-step process. We chose the symmetric secondary
introduction of enantiopure chiral compounds, although diamines among those reported to induce a certain con-
they have been extensively employed in the related U-4CR
[4], in particular, for the synthesis of peptidomimetics [5].
In principle, by simply using N-protected natural amino
formation or to increase the activity of the related pep-
tidomimetic.
In particular, bispidine (3,7-diazabicyclo[3.3.1]nonane;
acids and enantiopure a-substituted isocyanoacetates and 2b) was reported to act as secondary structure nucleator
relying on the split-Ugi reaction, diamine-based pep- by Haridas and co-workers [13]. Indeed, when both
tidomimetics could be accessible. By choosing the appro-
N-atoms of the bispidine core are alkylated, an open-turn
Scheme 1. Synthetic approach toward diamine-based peptidomimetics by means of split-Ugi reaction. PG, protecting group.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
DOI: 10.1002/hlca.201500505

316
Helv. Chim. Acta 2016, 99, 315 – 320
is observed, while when both N-atoms are acylated, a cyanoacetate in U-4CR. Therefore, we the adapted their
b-sheet conformation is induced. A helical conformation procedure to the split-Ugi protocol by adding N-Boc
can be obtained if one N-atom is alkylated and the other
one acylated [8]. Helix is one of the most common pep-
tide secondary structures and a major recognition motif
of PPIs, currently a compelling therapeutic target for
small molecules-based drug discovery [14].
On the other side, targeting the specific PPI VLA-4-
mediated MOLT-4 adhesion, Dutta and co-workers
reported cyclic peptides containing the Ile-Leu-Asp-Val
L-alanine (1a) from the beginning, in order to quench the
basicity of the second N-atom of piperazine (2a), and by
increasing the temperature, in order to depolymerize
paraformaldehyde. The subsequent addition of iso-
cyanides 3a – 3d, at room temperature, smoothly afforded
the desired split-Ugi adducts 4a – 4d (Table 1).
The steric hindrance of the isocyanide moiety did not
affect the reaction kinetics, with bulky isocyanides 3a
sequence, suitable as lead compounds for the develop- and 3b affording the desired products in moderate to
ment of new treatments for several inflammatory and good yields. By using commercially available methyl
autoimmune diseases. Among these cyclic peptides, the isocyanoacetate (3c), the first piperazine-based pep-
piperazine-based ones show promising results both tidomimetic 4c was synthesized in good yields, bearing
in vitro and in vivo, indicating the presence of the piper-
azine moiety as crucial for their activity [9].
L-Ala and Gly amino acids. As expected, we did not
observe any appreciable loss of optical purity using
methyl (2S)-2-isocyanopropanoate (3d), prepared as pure
enantiomer by a two-step protocol starting from commer-
cially available L-alanine methyl ester hydrochloride [16].
Indeed, the piperazine-based peptidomimetic 4d was
By employing chiral compounds, such as N-protected
L-Ala and methyl (2S)-2-isocyanopropanoate, in combina-
tion with formaldehyde, we demonstrated the configura-
tional stability of the chiral isocyanoacetate in the split-
Ugi reaction. Using piperazine (2a) or, alternatively, bis- smoothly obtained in good yield and as single
1
pidine (2b) as diamine substrate, we achieved the synthe-
sis of relevant diamine-based peptidomimetics.
diastereoisomer, as observed by H- and 13C-NMR.
As far as we know, bicyclic symmetric secondary
diamines were never reported as substrates in the split-
Ugi reaction and, in particular, the constrained bispidine
(2b) was supposed to be a challenging and less reactive
Results and Discussion
Firstly, we evaluated the compatibility of a N-protected substrate in comparison to piperazine (2a). Firstly, we
amino acid under split-Ugi reaction conditions by using applied to 2b the same reaction conditions as described
commercially available N-Boc L-alanine as carboxylic acid
above, by selecting benzoic acid (1b) and 1-(isocyano-
in combination with the well-studied piperazine (2a) as methyl)-4-methoxybenzene (3e) as non-chiral compounds.
secondary diamine. Among the different carbonyl sources, In this case, the desired split-Ugi adduct 5a was isolated
we selected the simplest not prochiral one, formaldehyde, in low yield, while 1,3-diazaadamantane (1,3-diazatricyclo
in its easy-to-handle polymeric form paraformaldehyde.
[3.3.1.13,7]decane; 6) proved to be the major product, as
Despite the expected configurational instability of chi- observed by the 1H-NMR of the crude reaction mixture
ral a-substituted isocyanoacetates, Carney and co-workers (Scheme 2). Due to prolonged reaction time, we hypothe-
[15] reported that a precondensation time of 2 h between
sized 1,3-diazaadamantane (6) to be an unreactive bypro-
the amine and the C=O moiety, followed by the sequen- duct, and not a suitable electrophilic intermediate. To
tial addition of carboxylic acid and isocyanoacetate,
would allow to preserve the optical purity of the iso-
demonstrate its role, we synthesized 6 by treating bis-
pidine (2b) with paraformaldehyde under acidic anhy-
Table 1. One-step synthesis of piperazine-based peptidomimetics 4a – 4d via split-Ugi reaction employing chiral compoundsa)
Entry
R
Product
Yield [%]b)
1
2
3
3a
3b
3c
tBu
4a
4b
4c
51
72
79
Me3CC(Me)2CH2–
MeOOCCH2–
4
3d
4d
66
a) Reagents and conditions: 1. 1a (0.8 mmol), 2a (0.87 mmol), paraformaldehyde (0.95 mmol), MeOH (2 ml), reflux, 2 h; 2. R–NꢀC
t
(3; 0.95 mmol), r.t., 24 h. Boc, BuOC=O. b) Yield of isolated product.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com

Helv. Chim. Acta 2016, 99, 315 – 320
317
Scheme 2. Split-Ugi reaction involving bispidine (2b) with the formation of the desired product 5a in combination with 1,3-diazaadamantane (6).
a) 1. 1b (0.8 mmol), 2b (0.87 mmol), paraformaldehyde (0.95 mmol), MeOH (2 ml), reflux, 2 h; 2. 3e (0.95 mmol), r.t., 24 h. b) 1b (0.8 mmol), 6
(0.87 mmol), 3e (0.95 mmol), MeOH, r.t., 24 h.
drous conditions at high temperature [17]. After mixing it
amount of H2O, which reduce the kinetic of the
with benzoic acid (1a) and 1-(isocyanomethyl)-4-methoxy- intramolecular formation of 6, favoring the formation of
benzene (3e), we could recover only starting materials, the thermodynamic split-Ugi product. Under these milder
even after prolonged reaction times (Scheme 2). There- conditions, complete conversion was achieved, although
fore, we concluded that 1,3-diazaadamantane (6) is an the desired split-Ugi adducts were isolated in moderate to
unreactive byproduct, whose formation is facilitated by
the high temperature of the previously optimized condi-
tions.
good yields, due to the formation of typical U-4CR
byproducts, like the Passerini adduct and the formamide
derived from hydration of the isocyanide.
At room temperature, by replacing paraformaldehyde
with a highly reactive carbonyl source, such as aqueous
The reaction proceeded smoothly with carboxylic
acids 1b and 1c, allowing the formation of desired prod-
formaldehyde, product yields increase drastically ucts 5a and 5b in good yields, without any relevant
(Table 2), avoiding the formation of 1,3-diazaadamantane influence of electronic properties, steric hindrance, and
(6). This result can be explained by taking into account
the double effect of a lower temperature and of a little
acidity of the carboxylic acid (Table 2). Although benzyl
isocyanide 3e can be used with good results, aromatic iso-
Table 2. One-pot synthesis of bispidine-containing split-Ugi adducts 5a and 5b, and bispidine-based peptidomimetics 5c – 5ea)
Entry
R1
R2
Product
Yield [%]b)
1
2
1b
1c
Bz
Ac
3e
3e
4-MeO–C6H4–CH2–
4-MeO–C6H4–CH2–
5a
5b
60
62
3
4
5
1a
1d
1e
Boc–L-Ala–
Cbz–L-Ala–
Fmoc–L-Ala–
3d
3d
3d
5c
5d
5e
39
38
40
a) Reagents and conditions: 1 (0.95 mmol), 2b (0.8 mmol), aqueous HCHO (1.6 mmol), R2–NꢀC (3; 0.95 mmol), MeOH (1.6 ml), r.t., 24 h.
t
Boc, BuOC=O; Cbz, BnOC=O; Fmoc, (9H-fluoren-9-ylmethoxy)carbonyl. b) Yield of isolated product.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com

318
Helv. Chim. Acta 2016, 99, 315 – 320
cyanides 1-bromo-4-isocyanobenzene and 1-isocyano-4-
methoxybenzene afforded only complex mixtures, with no
significant formation of the expected split-Ugi adducts.
We also explored the use of differently N-protected L-
alanines (1a, 1d, and 1e) in combination with the chiral
a-isocyanoacetate 3d, obtaining bispidine-based pep-
tidomimetics 5c – 5e in moderate yields. 1H- and 13C-
NMR spectra showed no evidence of loss of optical
purity, and no N-deprotection was observed, even when
the labile (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc)
functional group was employed (Table 2).
Typical Synthesis Procedure for Piperazine-Peptido-
mimetics Exemplified with 4a. To a soln. of piperazine
(2a; 0.068 g, 0.793 mmol) in anhyd. MeOH (2 ml) under
N2 were added N-Boc-L-alanine (0.165 g, 0.872 mmol)
and HCHO (0.029 g, 0.952 mmol). The soln. was heated
under reflux and stirred for 2 h. After cooling to room
temperature, tBuNꢀC (3a; 0.108 ml, 0.952 mmol) was
added and stirring was continued for 48 h. The solvent
was evaporated in vacuo and the crude mixture was puri-
fied by FC (SiO2; AcOEt) to afford pure product 4a.
tert-Butyl [(2S)-1-{4-[2-(tert-Butylamino)-2-oxoethyl]
piperazin-1-yl}-1-oxopropan-2-yl]carbamate (4a). Yield:
30
Conclusions
0.136 g (51%). White solid. ½aꢁD = +8.3 (c = 1.0, CHCl3).
1H-NMR (400 MHz, CDCl3): 6.87 (s, 1 H); 5.49 (d, J = 7.8,
1 H); 4.65 – 4.60 (m, 1 H); 3.70 – 3.45 (m, 4 H); 2.95 (s, 2
H); 2.64 – 2.49 (m, 4 H); 1.46 (s, 9 H); 1.39 (s, 9 H); 1.32 (d,
J = 6.9, 3 H). 13C-NMR (100 MHz, CDCl3): 171.3; 168.4;
155.1; 79.6; 62.1; 53.3; 53.0; 50.7; 46.0; 45.4; 42.0; 28.8 (3 C);
28.4 (3 C); 19.38. HR-ESI-MS: 371.2661 ([M + H]+,
C18H35N4Oþ4 ; calc. 371.2653).
We reported an easier access to biologically relevant
cyclic secondary diamine-based peptidomimetics by a
split-Ugi reaction involving chiral compounds, such as N-
protected amino acids and a-substituted isocyanoacetates.
The regiochemical desymmetrization of the diamine is
achieved in a one-step process, without expensive cou-
pling agents and protection/deprotection steps. In particu-
lar, piperazine (2a) reacts smoothly, giving desired optical
pure compounds in good yields. We also reported the first
example of a split-Ugi reaction using a bicyclic secondary
diamine, namely bispidine (2b), which reacts under mild
conditions with moderate to good yields. In particular,
bispidine-based peptidomimetics were synthesized as
a-helix nucleators, bearing different N-protecting groups,
which make them suitable for incorporation into peptide
sequences. Further studies on different symmetric sec-
ondary diamines are underway, in order to expand the
range of secondary peptidomimetic structure potentially
achieved by this method.
tert-Butyl [(2S)-1-Oxo-1-(4-{2-oxo-2-[(2,2,3,3-tetra-
methylbutyl)amino]ethyl}piperazin-1-yl)propan-2-
yl]carbamate (4b). Yield: 0.243 g (72%). White solid.
30
½aꢁD = +7.19 (c = 0.9, CHCl3). 1H-NMR (400 MHz,
CDCl3): 7.02 (s, 1 H); 5.49 (d, J = 7.5, 1 H); 4.62 (m, 1
H); 3.82 – 3.43 (m, 4 H); 2.94 (s, 2 H); 2.54 (m, 4 H);
1.72 (s, 2 H); 1.45 (s, 15 H); 1.31 (d, J = 6.8, 3 H); 1.04
(s, 9 H). 13C-NMR (100 MHz, CDCl3): 171.9; 168.9;
155.7; 80.3; 63.1; 55.4; 54.1; 53.7; 53.4; 46.7; 46.0; 42.7 (2
C); 32.2 (3 C); 29.5 (2 C); 29.0 (3 C); 20.1. HR-ESI-
MS: 427.3271 ([M + H]+, C22H43N4O4þ; calc. 427.3279).
Methyl N-({4-[N-(tert-Butoxycarbonyl)-L-alanyl]
piperazin-1-yl}acetyl)glycinate (4c). Yield: 0.242 g
30
(79%). Yellowish oil. ½aꢁD = +5.2 (c = 0.3, CHCl3). 1H-
Experimental Part
NMR (400 MHz, CDCl3): 7.54 (br. m, 1 H); 5.48 (d,
J = 7.7, 1 H); 4.59 (m, 1 H); 4.08 (d, J = 5.7, 2 H);
3.75 (s, 3 H); 3.74 – 3.43 (m, 4 H); 3.09 (s, 2 H); 2.58
(m, 4 H); 1.42 (s, 9 H); 1.29 (d, J = 6.9, 3 H). 13C-
NMR (100 MHz, CDCl3): 171.8; 170.6; 169.7; 155.5;
80.2; 60.8; 53.4; 53.2; 52.9; 46.4; 45.0; 41.2; 40.8; 28.8
(3 C); 19.6. HR-ESI-MS: 409.2071 ([M + Na]+, C17H30
N4NaOþ6 ; calc. 409.2058).
General
All commercial materials (Sigma-Aldrich, Milan, Italy)
were used without further purification. All solvents were
of reagent or HPLC grade. Compound 2b was synthesized
via a slightly modified reported procedure [18] and stored
as perchlorate salt. All reactions were carried out under
N2 atmosphere unless otherwise noted. All reactions were
monitored by thin-layer chromatography (TLC). TLC: pre-
coated silica gel 60 F254 (SiO2); visualized under UV light
or by treatment with 1% aq. KMnO4 soln. Flash column
chromatography (FC): SiO2 60 (230 – 400 mesh). UV/VIS
spectra: JASCO V-650 spectrophotometer (JASCO, Cre-
mella, Italy); kmax (log e) in nm. CD Spectra: JASCO J-715
spectropolarimeter; kmax (De) in nm. 1H- and 13C-NMR
spectra: Bruker AC 300, (300 and 75 MHz, resp.) and Bru-
ker Avance I400 (400 and 100 MHz, resp.) spectrometers;
d in ppm rel. to residual solvent, J in Hz. 13C-NMR spectra
were recorded using the APT pulse sequence. HR-ESI-
MS: Waters Q-Tof Micro instrument; in m/z.
Methyl N-({4-[N-(tert-Butoxycarbonyl)-L-alanyl]
piperazin-1-yl}acetyl)-L-alaninate (4d). Yield: 0.210 g
30
(66%). Yellowish oil. ½aꢁD = +4.1 (c = 0.6, CHCl3). 1H-
NMR (400 MHz, (D6)DMSO, 80°): 7.57 (br. m, 1 H); 5.51
(d, J = 7.7, 1 H); 4.63 (m, 2 H); 3.77 (s, 3 H); 3.76 – 3.49
(m, 4 H); 3.13 (d, J = 16.2, 1 H); 3.03 (d, J = 16.2, 1 H);
2.78 – 2.47 (m, 4 H); 1.47 – 1.42 (m, 12 H); 1.31 (d, J = 6.9,
3 H). 13C-NMR (100 MHz, (D6)DMSO, 80°): 174.0; 171.9;
169.8; 155.7; 80.3; 61.9; 54.0; 53.6; 53.2; 48.1; 46.7; 46.0; 42.7;
29.0 (3 C); 20.0; 19.1. HR-ESI-MS: 423.2209 ([M + Na]+,
C18H32N4NaOþ6 ; calc. 423.2214).
Typical Synthesis Procedure for Bispidine-Peptidomi-
metics Exemplified with 5a. To a soln. of bispidine (2b;
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com

Helv. Chim. Acta 2016, 99, 315 – 320
319
0.100 g, 0.792 mmol) in MeOH (1.6 ml) were added ben-
zoic acid (0.116 g, 0.950 mmol) and aq. 37 wt% HCHO
soln. (0.118 ml, 1.584 mmol). After 2 h, 1-isocyano-4-
methoxybenzene (3e; 0.140 g, 0.950 mmol) was added and
H); 4.87 – 4.75 (m, 2 H); 4.39 – 3.95 (m, 1 H); 3.75 – 3.72
(m, 3 H); 3.55 – 2.77 (m, 3 H); 2.82 – 2.45 (m, 2 H); 2.45 (d,
J = 16.1, 1 H); 2.28 – 2.07 (m, 2 H); 2.07 – 1.60 (m, 4 H);
1.58 – 1.44 (m, 3 H); 1.36 – 1.29 (m, 3 H). 13C-NMR
stirring was continued for 48 h. The solvent was evapo- (100 MHz, CDCl3): 174.2 – 172.0 (2 C); 169.4; 155.9; 136.5;
rated in vacuo and the crude mixture was purified by FC 128.5 – 128.1 (2 C); 66.6; 62.7; 59.0 – 58.3 (2 C); 52.4 – 52.1
(SiO2; AcOEt) to afford the pure product 5a.
(2 C); 50.3; 47.2; 46.2 – 46.0 (2 C); 45.8; 32.1; 28.9 (2 C);
2-(7-Benzoyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(4- 18.7; 17.4. HR-ESI-MS: 475.2562 ([M + H]+, C24H35N4O6þ;
methoxybenzyl)acetamide (5a). Yield: 0.194 g (60%). calc. 475.2551).
Yellowish solid. 1H-NMR (300 MHz, CDCl3, rotameric Methyl N-[(7-{N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-
mixture): 8.70 (m, 0.5 H); 8.33 (m, 0.5 H); 7.67 – 7.24 L-alanyl}-3,7-diazabicyclo[3.3.1]nonan-3-yl)acetyl]-L-
30
(m, 5 H); 7.17 (d, J = 8.7, 2 H); 6.87 – 6.71 (m, 2 H); alaninate (5e). Yield: 0.178 g (40%). White solid. ½aꢁD
=
1
4.94 (br. d, J = 13.7, 1 H); 4.45 (br. t, J = 6.4, 1 H); 4.33 ꢂ6.8 (c = 1.0, CHCl3). H-NMR (400 MHz, CDCl3, rota-
(br. d, J = 5.5, 2 H); 3.81 – 3.50 (m, 6 H); 3.40 (m, 1 meric mixture): 7.77 (br. d, J = 6.9, 2 H); 7.69 (br. d,
H); 3.25 (br. d, J = 11.2, 1 H); 3.15 (m, 1 H); 2.99 (d, J = 9.4, 1 H); 7.65 – 7.58 (m, 2 H); 7.41 (br. d, J = 7.3, 2
J = 12.0, 1 H); 2.65 (m, 1 H); 2.48 – 1.57 (m, 4 H). 13C- H); 7.37 – 7.29 (m, 2 H); 6.98 (br. d, J = 9.5, 1 H); 4.97
NMR (75 MHz, CDCl3): 172.2; 169.6; 158.5; 136.6;
131.9; 129.8 (2 C); 129.5; 128.5 (2 C); 126.8 (2 C); 113.6
(2 C); 63.3; 58.7 (2 C); 55.2; 53.4; 46.0; 42.2; 32.2; 29.7;
(m, 1 H); 4.92 – 4.78 (m, 1.5 H); 4.71 (m, 0.5 H);
4.54 – 4.30 (m, 2 H); 4.30 – 4.13 (m, 1.5 H); 4.13 – 3.93
(m, 0.5 H); 3.84 – 3.69 (m, 3 H); 3.58 – 3.35 (m, 1.5 H);
28.8. HR-ESI-MS: 408.2286 ([M + H]+, C24H30N3O3þ, 3.20 – 3.03 (m, 1.5 H); 3.01 – 2.93 (m, 1.5 H); 2.92 – 2.82
calc. 408.2282).
(m, 1 H); 2.66 – 2.42 (m, 1.5 H); 2.39 (br. d, J = 11.2, 1
2-(7-Acetyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(4- H); 2.10 – 1.92 (m, 2 H); 1.90 – 1.65 (m, 2 H); 1.62 – 1.44
methoxybenzyl)acetamide (5b). Yield: 0.164 g (62%).
(m, 3 H); 1.44 – 1.34 (m, 3 H). 13C-NMR (100 MHz,
CDCl3): 174.2 – 171.0 (2 C); 169.4; 155.9; 143.9 (2 C);
Yellowish solid. 1H-NMR (400 MHz, CDCl3): 7.74 (br.
m, 1 H); 7.36 (d, J = 8.2, 2 H); 6.86 (d, J = 8.2, 2 H); 141.2 (2 C); 127.7 (2 C); 127.2 – 127.0 (2 C); 125.2 (2 C);
4.75 (br. d, J = 12.9, 1 H); 4.47 (br. dd, J = 14.0, 6.7, 1 119.9 (2 C); 67.1; 62.6; 58.6 – 58.1 (2 C); 52.3; 50.2;
H); 4.29 (br. dd, J = 14.0, 5.2, 1 H); 3.86 (br. d, 47.4 – 47.0 (2 C); 46.3; 46.0; 32.2; 29.0 – 28.5 (2 C); 18.8;
J = 11.7, 1 H); 3.80 (s, 3 H); 3.40 (br. d, J = 12.6, 1 H); 17.5. HR-ESI-MS: 563.2868 ([M + H]+, C31H39N4O6þ; calc.
3.15 – 2.97 (br. m, 2 H); 2.93 (br. d, J = 9.5, 1 H); 2.83 563.2864).
(br. d, J = 13.1, 1 H); 2.70 (br. d, J = 15.8, 1 H); 2.55
(br. d, J = 8.5,
1 H); 2.20 (br. d, J = 9.5, 1 H);
REFERENCES
2.05 – 1.85 (br. m, 5 H); 1.83 – 1.63 (br. m, 2 H). 13C-
NMR (100 MHz, CDCl3): 172.0; 169.5; 158.6; 131.6;
129.5 (2 C); 113.7 (2 C); 61.6; 59.2; 58.7; 51.3; 45.8 (2
C); 42.2; 29.7; 28.8 (2 C); 22.1. HR-ESI-MS: 368.1954
([M + Na]+, C19H27N3NaOþ3 , calc. 368.1945).
[1] G. B. Giovenzana, G. C. Tron, S. Di Paola, I. G. Menegotto,
T. Pirali, Angew. Chem. 2006, 118, 1117; G. B. Giovenzana,
G. C. Tron, S. Di Paola, I. G. Menegotto, T. Pirali, Angew.
Chem., Int. Ed. 2006, 45, 1099.
[2] I. Ugi, Angew. Chem. 1962, 74, 9; I. Ugi, Angew. Chem., Int.
Ed. 1962, 1, 8.
Methyl N-({7-[N-(tert-Butoxycarbonyl)-L-alanyl]-3,
7-diazabicyclo[3.3.1]nonan-3-yl}acetyl)-L-alaninate
[3] T. Pirali, G. Callipari, E. Ercolano, A. A. Genazzani, G. B.
Giovenzana, G. C. Tron, Org. Lett. 2008, 10, 4199; G. Piersanti,
F. Remi, V. Fusi, M. Formica, L. Giorgi, G. Zappia, Org. Lett.
30
(5c). Yield: 0.136 g (39%). White solid. ½aꢁD = ꢂ17.6 (c =
1
0.95, CHCl3). H-NMR (400 MHz, CDCl3, rotameric mix-
ꢁ
ꢁ
_
2009, 11, 417; M. Sienczyk, D. Podgorski, A. Błazejewska,
J. Kulbacka, J. Saczko, J. Oleksyszyn, Bioorg. Med. Chem.
2011, 19, 1277; F. La Spisa, A. Feo, R. Mossetti, G. C. Tron,
Org. Lett. 2012, 14, 6044.
ture): 7.75 (m, 0.5 H); 7.6 (br. d, J = 9.5, 1 H); 6.3 (m, 0.5
H); 5.11 – 4.73 (m, 2 H); 4.7 – 4.5 (m, 1 H); 4.4 (br. d,
J = 10.3, 0.75 H); 4.20 – 4.07 (m, 0.25 H); 3.8 – 3.7 (m, 3
H); 3.5 – 3.3 (m, 1 H); 3.2 – 3.0 (m, 1 H); 3.0 – 2.8 (m, 1
H); 2.7 – 2.5 (m, 1 H); 2.5 – 2.35 (m, 1 H); 2.2 – 2.1 (m, 1
H); 2.0 – 1.9 (m, 2 H); 1.9 – 1.7 (m, 2 H); 1.6 – 1.3 (m, 15
H). 13C-NMR (100 MHz, CDCl3): 174.5 – 173.2 (2 C);
171.2; 156.0; 80.1; 63.9 – 62.6; 59.0 – 58.3 (2 C); 53.0 – 52.6;
51.0 – 50.7; 48.4 – 47.8; 47.2 – 46.6; 45.8; 34.5 – 32.0;
29.5 – 28.7 (5 C); 19.2 – 17.5 (2 C). HR-ESI-MS: 463.2516
([M + Na]+, C21H36N4NaOþ6 ; calc. 463.2527).
€
[4] A. Domling, Chem. Rev. (Washington, DC, U.S.) 2006, 106, 17;
_
S. Berłozecki, W. Szymanski, R. Ostaszewski, Synth. Commun.
2008, 38, 2714; S. Berłozecki, W. Szymanski, R. Ostaszewski,
ꢁ
_
ꢁ
Tetrahedron 2008, 64, 9780; K. Perez-Labrada, I. Brouard, I.
ꢁ
Mendez, C. S. Perez, J. A. Gavın, D. G. Rivera, Eur. J. Org.
Chem. 2014, 3671.
ꢁ
ꢁ
[5] D. G. Rivera, O. E. Vercillo, L. A. Wessjohann, Org. Biomol.
Chem. 2008, 6, 1787; D. G. Rivera, L. A. Wessjohann, J. Am.
Chem. Soc. 2009, 131, 3721; S. Gunawan, C. Hulme, Org. Bio-
mol. Chem. 2013, 11, 6036.
Methyl N-[(7-{N-[(Benzyloxy)carbonyl]-L-alanyl}-
3,7-diazabicyclo[3.3.1]nonan-3-yl)acetyl]-L-alaninate
[6] J. Vagner, H. Qu, V. J. Hruby, Curr. Opin. Chem. Biol. 2008, 12,
292; O. N. Akram, D. J. DeGraff, J. H. Sheehan, W. D. Tilley, R.
J. Matusik, J.-M. Ahn, G. V. Raj, Mol. Cancer Res. 2014, 12, 967.
[7] A. L. Garner, K. D. Janda, Curr. Top. Med. Chem. (Sharjah,
United Arab Emirates) 2011, 11, 258; B. O. Villoutreix, M. A.
30
(5d). Yield: 0.143 g (38%). White solid. ½aꢁD = ꢂ10.2 (c =
0.8, CHCl3). 1H-NMR (400 MHz, CDCl3, rotameric
mixture): 7.61 (br. d, J = 9.0, 1 H); 7.45 – 7.23 (m, 5 H);
6.78 (br. d, J = 9.3, 1 H); 5.20 – 4.98 (m, 2 H); 4.91 (m, 1
ꢁ
Kuenemann, J.-L. Poyet, H. Bruzzoni-Giovanelli, C. Labbe, D.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com

320
Helv. Chim. Acta 2016, 99, 315 – 320
Lagorce, O. Sperandio, M. A. Miteva, Mol. Inf. 2014, 33, 414;
T. L. Nero, C. J. Morton, J. K. Holien, J. Wielens, M. W. Par-
ker, Nat. Rev. Cancer 2014, 14, 248.
[13] V. Haridas, S. Sadanandan, Y. K. Sharma, S. Chinthalapalli,
A. Shandilya, Tetrahedron Lett. 2012, 53, 623.
[14] C. G. Cummings, A. D. Hamilton, Curr. Opin. Chem. Biol.
2010, 14, 341.
[8] V. Haridas, S. Sadanandan, M. V. S. Gopalakrishna, M. B.
Bijesh, R. P. Verma, S. Chinthalapalli, A. Shandilya, Chem.
Commun. (Cambridge, U.K.) 2013, 49, 10980.
[15] D. W. Carney, J. V. Truong, J. K. Sello, J. Org. Chem. 2011, 76,
10279.
[9] A. S. Dutta, M. Crowther, J. J. Gormley, L. Hassall, C. F. Hay-
ward, P. R. Gellert, R. S. Kittlety, P. J. Alcock, A. Jamieson, J.
M. Moores, A. Rees, L. J. Wood, C. F. Reilly, D. Haworth,
J. Pept. Sci. 2000, 6, 321.
[10] P. Restorp, J. Rebek Jr., Bioorg. Med. Chem. Lett. 2008, 18,
5909.
[16] G. Skorna, I. Ugi, Angew. Chem. 1977, 89, 267; G. Skorna, I.
Ugi, Angew. Chem., Int. Ed. 1977, 16, 259; R. Urban, D. Mar-
quarding, P. Seidel, I. Ugi, A. Weinelt, Chem. Ber. 1977, 110,
2012; J. Zhu, X. Wu, S. J. Danishefsky, Tetrahedron Lett. 2009,
50, 577.
[17] E. E. Smissman, J. A. Weis, J. Heterocycl. Chem. 1968, 5, 405.
[18] J. Spieler, O. Huttenloch, H. Waldmann, Eur. J. Org. Chem.
2000, 391.
[11] M. Stucchi, S. Cairati, R. Cetin-Atalay, M. S. Christodoulou, G.
Grazioso, G. Pescitelli, A. Silvani, D. C. Yildirim, G. Lesma,
Org. Biomol. Chem. 2015, 13, 4993.
[12] M. Stucchi, P. Gmeiner, H. Huebner, G. Rainoldi, A. Sacchetti,
A. Silvani, G. Lesma, ACS Med. Chem. Lett. 2015, 6, 882.
Received November 25, 2015
Accepted December 23, 2015
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com