Proline-like β-turn mimics accessed via Ugi reaction involving monoprotected hydrazines

Article abstract of DOI:10.1016/j.tetlet.2009.12.141

A four-center, three-component Ugi-type reaction of a variety of keto acids, Boc- or Cbz-protected hydrazine, and isocyanides offers a simple and high yielding access to cyclic products containing an N-aminolactam unit. The latter are shown to form consistently an intramolecular hydrogen bond leading to a β-turn-like secondary structure. The possibility of integrating such N-aminolactam units (without disruption of the folded structure) into pseudotripeptide fragments is demonstrated.

Full text of DOI:10.1016/j.tetlet.2009.12.141

Tetrahedron Letters 51 (2010) 1367–1370
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Proline-like b-turn mimics accessed via Ugi reaction involving
monoprotected hydrazines
b
b
b
b
Mikhail Krasavin a,b, , Vladislav Parchinsky , Alexei Shumsky , Igor Konstantinov , Anton Vantskul
*
a Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University 150000, Russia
b Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg. 141400, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A four-center, three-component Ugi-type reaction of a variety of keto acids, Boc- or Cbz-protected
hydrazine, and isocyanides offers a simple and high yielding access to cyclic products containing an N-
aminolactam unit. The latter are shown to form consistently an intramolecular hydrogen bond leading
to a b-turn-like secondary structure. The possibility of integrating such N-aminolactam units (without
disruption of the folded structure) into pseudotripeptide fragments is demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 November 2009
Revised 16 December 2009
Accepted 23 December 2009
Available online 7 January 2010
Keywords:
Isocyanide-based multicomponent
reactions
Ugi reaction
Bifunctional reagents
Hydrazine
b-Turn mimics
Secondary structure by NMR
Pseudopeptides
The successful use of keto (as well as aldehydo) carboxylic acids
as bifunctional inputs for isocyanide-based multicomponent reac-
tions (IMCR) was demonstrated by Harriman1 and Ugi.2 This four-
center, three-component process was found to provide a simple
and efficient (as well as atom-economical) entry into novel dipep-
toid lactam structures. The strategy has been widely exploited to
give rise to a large variety of novel small- and medium-size lac-
tam-type heterocyclic scaffolds3 and validated, in general, the
use of bifunctional reagents in IMCR as a source of significant prod-
uct diversity.4
Replacement of the amine component in the Ugi reaction with
various surrogates has had a number of successful outcomes, as
documented in the literature. For example, the use of hydrazine
(as N-acylhydrazine, N,N-dialkylhydrazine, or even a symmetrical
hydrazone) in IMCR was described in the earlier work of Ugi5
and others.6 O-Protected and unprotected hydroxylamines7 were
also found to be good partners for Ugi-type IMCR while N-ben-
tive peptidomimetics,10 short hydrazinopeptides are known to
adopt a b-turn-like secondary structure known as a ‘hydrazino
turn’ (due to an intramolecular bifurcated hydrogen bond involv-
ing the sp3-hybridized nitrogen atom of the hydrazine motif).11
In this work, we have investigated the possibility of a new IMCR
design using various aliphatic keto carboxylic acids in combination
with a Boc- or Cbz-protected hydrazine as a surrogate for the
O
OH
R1
R1
NH2
X
H
O
O
N
O
N+
H
O
O
X
N
H
O
O
N+
C
O
R2
R1 = t-Bu, Bn
zylhydroxylamine additionally provided
a reactive N-hydroxy
group as the site for acyl migration.8 We recently developed a
modified protocol to prepare a variety of hydrazinopeptide-like
units via the Ugi reaction involving N-acyl- and alkoxyacyl-hydra-
zines.9 Besides their general appeal as hydrolytically more stable
pseudopeptide ‘inserts’ for the development of new biologically ac-
O
O
O
O
R1
H
X
N
R1
H
N
O
N
X
N
R2
H
H
O
N
N
R2
O
1
H+
* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
Scheme 1. A new IMCR design toward susbstituted N-aminolactams 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.141

1368
M. Krasavin et al. / Tetrahedron Letters 51 (2010) 1367–1370
amine component, which was expected to yield substituted N-
aminolactams 1 (Scheme 1). Such a design was primarily inspired
by: (i) a successful (but low-yielding) five-center, three-compo-
nent (hence ring-forming) reaction of 4-acetylbutyric acid, N-ben-
the keto acid and the hydrazine in order to go to completion (with
respect to isocyanide) for reasons that so far remain unclear.
Using the optimized reaction protocol we prepared analogous
N-aminolactams 1b–v using Boc- and Cbz-hydrazine, various iso-
cyanides and the known or commercially available keto acids 2a,
2b, 2c,15 2e,3c and the newly synthesized 2d (Scheme 2). The prod-
ucts 1 were isolated by column chromatography in good to excel-
lent yields (Table 2) and their identity and purity was established
by NMR spectroscopy, mass spectrometry, and elemental analyses
(see Supplementary data).
zylhydroxylamine, and ethyl isocyanoacetate,8 and (ii)
a
surprisingly efficient four-center, three-component reaction of
substituted a-hydrazino acids with aldehydes and isocyanides re-
ported to yield strained aza-b-lactams.12
In a trial experiment, equimolar amounts of levulinic acid, Boc-
hydrazine, and 4-methoxybenzylisocyanide in methanol were stir-
red at room temperature. Although the reaction was markedly
slow and proceeded to only a limited conversion over 72 h at room
temperature, the expected product 1a was isolated by chromatog-
raphy in low yield (<25%). A single crystal of this compound was
obtained and the X-ray crystallographic analysis not only con-
firmed the identity of this new type of N-aminolactam, but also re-
vealed the presence of a pronounced hydrogen bond between the
carbonyl oxygen atom of the Boc group and the exocyclic second-
ary amide side-chain (Fig. 1).13 This feature, in our view, makes 1a
(as well as its subsequently prepared analogs) similar to proline,
not only from the viewpoint of shape and chemical structure, but
also in terms of its potential ability to mimic b-turns when intro-
duced into a polypeptide chain—a secondary structure bias typi-
cally associated with proline in natural polypeptides. Prompted
by this exciting finding we proceeded to optimize the reaction to-
ward 1a. As is evident from the results presented in Table 1, the
reaction outcome was more favorable in aqueous methanol when
equimolar ammonium chloride was employed as a mildly acidic
promoter.14 The reaction also required excess amounts of both
We have also demonstrated that the synthesized N-aminolac-
tams could be elaborated into useful proline-like building blocks
as well as incorporated into short peptide structures. As shown
in Scheme 3, compounds 1e and 1f were hydrolyzed by aqueous
KOH in methanol into the respective ‘glycine-WPro’ carboxylic
acids 3a and 3b, without disruption of the lactam ring or the exo-
cyclic amide bond; likewise, the N-Boc group was easily removed
from the N-terminus of the N-aminolactam which was then acyl-
ated with Boc-protected glycine, as illustrated by the conversion
of 1g into the ‘BnNHGly-WPro-GlyBoc’ tripeptoid 4.
Finally, we were curious to see if the intramolecular hydrogen
bonding pattern (leading to a b-turn-like secondary structure) that
we initially observed by X-ray analysis for 1a (vide supra) contin-
ued to persist in the newly synthesized compounds and, especially,
in the more complex ‘tripeptide’ 4. While obtaining X-ray struc-
tures for the crystalline compounds 1 could, in principle, provide
an insight on how consistent is this H-bonding pattern for these
compounds in the solid state, it would not determine if the same
was true in solution. Fortunately, by recording 1H NMR spectra of
Figure 1. b-Turn-like hydrogen bonding pattern in 1a as evidenced by X-ray analysis.
Table 1
Optimization results for model compound 1a
O
O
OH
NH2
O
O
N
O
N
O
NH
O
H
H
N
N
O
+
O
H
O
OH
N
O
O
O
N+
1a
C
Entry
Keto acid (equiv)
BocNHNH2 (equiv)
Isocyanide (equiv)
Solvent
Acid catalyst
Time (h)
Isolated yield (%)
1
2
3
4
5
1
1
2
1
2
1
1
1
2
2
1
1
1
1
1
MeOH
—
72
72
36
36
24
18
34
71
54
84
MeOH/H2O (3:1)
MeOH/H2O (3:1)
MeOH/H2O (3:1)
MeOH/H2O (3:1)
NH4Cl (1 equiv)
NH4Cl (1 equiv)
NH4Cl (1 equiv)
NH4Cl (1 equiv)

M. Krasavin et al. / Tetrahedron Letters 51 (2010) 1367–1370
1369
the compounds in chloroform-d and in DMSO-d6 and observing the
resulting changes in the chemical shift of the protons ‘suspected’ of
participation in intramolecular hydrogen bonding versus those
protons that do not, it was possible to ascertain the existence of
intramolecular hydrogen bonds in solution.16 Indeed, DMSO-d6 as
a solvent capable of hydrogen bonding with the solute, led to a
downfield shift (compared to CDCl3) of both heteroatom-bound
protons in model compound 5 where no intramolecular H-bond
is possible. However, in the ‘tripeptide’ 4, a similar downfield shift
was not observed for the amide proton proximal to the lactam ring,
which is consistent with the expected intramolecular hydrogen
bonding. Likewise, for selected N-aminolactams 1a, 1b, 1k, 1l, 1s,
and 1v, the same amide proton appears almost insensitive to the
solvent change, which also confirms its intramolecular H-bonded
character (Table 3).
OH
O
R1NHNH2
R2NC
R1
O
H
N
O
O
N
X
X
NH4Cl, aq. MeOH
rt, 18-24 h
H
N
R2
O
2a, X = direct bond
2b, X = CH2
2c, X = S
2d, X = O
2e, X = NSO2Me
1a-v
Scheme 2. Preparation of N-aminolactams 1a–v.
In conclusion, we have developed an efficient method to pre-
pare a novel racemic proline-like N-aminolactams 1 which exist
in a folded, b-turn-like conformation, both in solid state and in
solution, as demonstrated by X-ray and 1H NMR analyses. These
structures can be elaborated into ‘dipeptide’ acid building blocks
and incorporated into a ‘tripeptide’ structure and thus holds poten-
tial as key elements for the design of mimetic analogs of bioactive
peptides. Efforts are currently underway in our laboratories to pre-
pare non-racemic versions of these useful structural motifs. The re-
sults of these studies will be reported in due course.
Table 2
N-Aminolactams 1a–v prepared in this work
Product
X
R1
R2
Isolated yield (%)
1a
1b
1c
1d
1e
1f
Direct bond
Direct bond
Direct bond
Direct bond
Direct bond
Direct bond
Direct bond
Direct bond
t-BuO
t-BuO
t-BuO
BnO
4-MeOC6H4CH2
4-FC6H4CH2
MeOCH2CH2CH2
4-FC6H4CH2
EtOOCCH2
EtOOCCH2
PhCH2NHCOCH2
t-Bu
84
86
69
75
69
65
71
92
BnO
t-BuO
t-BuO
t-BuO
1g
1h
Typical procedure: Synthesis of N-aminolactams 1: The syntheses
reported herein have been performed on 1–3 mmol scale. Equimo-
lar amounts of keto acid 2 and monoprotected hydrazine were dis-
solved in MeOH (6 mL). Solid NH4Cl (0.5 equiv) was added
followed by water (2 mL). Once a clear solution had formed, the
isocyanide (0.5 equiv) was added and the reaction mixture was
stirred under an argon atmosphere at rt for 18–24 h. It was then
partitioned between EtOAc (25 mL) and H2O (25 mL). The organic
layer was separated and the aqueous layer was back-extracted
with an equal volume of EtOAc. The combined organic extracts
were dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The N-aminolactams 1 were isolated by chromatography
(SiO2) using EtOAc–hexane mixtures as eluents.
O
*
*
1i
Direct bond
t-BuO
77
O
1j
1k
Direct bond
CH2
t-BuO
t-BuO
Cycloheptyl
4-FC6H4CH2
67
91
O
1l
CH2
t-BuO
92
O
1m
1n
1o
CH2
CH2
S
t-BuO
t-BuO
t-BuO
Cycloheptyl
t-Bu
4-FC6H4CH2
76
89
73
O
*
1p
S
t-BuO
79
O
1q
1r
1s
1t
1u
1v
S
S
O
O
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
Cycloheptyl
t-Bu
4-FC6H4CH2
Cycloheptyl
Cycloheptyl
4-FC6H4CH2
67
94
84
68
72
78
Compound 1a: White solid, mp = 189–191 °C. 1H NMR
(300 MHz, CDCl3) d 8.74 (br s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.07
(s, 1H), 6.77 (d, J = 8.4 Hz, 2H), 4.36 (dd, J = 14.4, 6.1 Hz, 1H), 4.21
(dd, J = 14.0, 4.5 Hz, 1H), 3.73 (s, 3H), 2.22–2.43 (m, 3H), 1.93–
2.04 (m, 1H), 1.48 (s, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3)
MeSO2N
MeSO2N
O
O
H
N
H
aq. KOH (1 equiv)
N
N
N
O
O
R
R
MeOH, rt, 16 h
H
N
O
H
O
HO
O
O
O
N
O
O
1e, R = Bn
1f, R = t-Bu
3a, R = Bn, 89%
3b, R = t-Bu, 72%
O
O
1) HCl/dioxane (4 equiv.), rt
2) BocGly, CDI, py/CH2Cl2, rt
H
N
H
O
N
N
N
O
56%
N
O
H
N
O
H
H
O
HN
O
HN
O
N
O
O
4
1g
Scheme 3. Preparation of the N-protected ‘dipeptides’ 3a,b, and the protected ‘tripeptide’ 4.

1370
M. Krasavin et al. / Tetrahedron Letters 51 (2010) 1367–1370
Table 3
Downfield shift (
D
, ppm) of various N–H signals in 1H NMR spectra on changing the solvent from chloroform-d to DMSO-d6
O
O
H2
O
H2
N
O
O
R1
N
H4
N
N
N
O
N
O
H1
3
O
N
X
H
H1
N
N
N
H1
O
O
O
4
R2
O
5
1
H3
N
Compound
D
(Y1)
D
(Y2)
D
(Y3)
D
(Y4)
1a
1b
1k
1l
1s
1v
4
1.7
2.2
1.9
2.0
2.0
2.0
0.9
—
—
—
—
—
—
—
—
—
—
—
—
—
0.2
0.1
0.0
0.1
0.2
0.0
(Broad)
1.1
1.1
—
0.0
1.1
5
A. P.; Loseva, M. V.; Vvedensky, V. Y.; Putsykina, E. B.; Tkachenko, S. E.;
Kravchenko, D. V.; Khvat, A.; Krasavin, M.; Ivachtchenko, A. V. J. Org. Chem.
2006, 71, 2811–2819.
d 174.0, 172.8, 158.6, 156.7, 130.3, 128.9, 113.7, 82.6, 67.1, 55.1,
42.8, 31.6, 27.8, 26.8, 21.6. LC–MS (M+H) m/z = 378. Anal. Calcd
for C19H27N3O5: C, 60.46; H, 7.21; N, 11.13. Found: C, 60.53; H,
7.28; N, 11.15.
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13. Crystallographic data (excluding structure factors) for the structure 1a in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 754888. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
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Acknowledgments
This research was supported by the Federal Agency for Science
and Innovation (Russian Federation Government Contract
02.740.11.0092). Dr. Alexander Manaev of Chemical Diversity Re-
search Institute is acknowledged for his help in obtaining X-ray
crystallography data.
Supplementary data
Characterization data and preparative procedures for the newly
synthesized compounds (1a–v, 2d, 3a–b, 4 and 5) and X-ray crys-
tallographic file (CIF) for compound 1a are available. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.12.141.
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