Synthesis of quaternary α-amino acid-based arginase inhibitors via the Ugi reaction

Article abstract of DOI:10.1016/j.bmcl.2013.06.092

The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.

Full text of DOI:10.1016/j.bmcl.2013.06.092

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4837–4841
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of quaternary
the Ugi reaction
a-amino acid-based arginase inhibitors via
a
a
a
a
Adam Golebiowski a, , Darren Whitehouse , R. Paul Beckett , Michael Van Zandt , Min Koo Ji ,
Todd R. Ryder a, Erik Jagdmann a, Monica Andreoli a, Yung Lee a, Ryan Sheeler a, Bruce Conway a,
Jacek Olczak b, Marzena Mazur b, Wojciech Czestkowski b, Wieslawa Piotrowska b,
⇑
Alexandra Cousido-Siah c, Francesc X. Ruiz c, Andre Mitschler c, Alberto Podjarny c, Hagen Schroeter d
a Institutes for Pharmaceutical Discovery, 23 Business Park Drive, Branford, CT, United States
b TriMen Chemicals S.A., Al. Pilsudskiego 141, Lodz 92-318, Poland
c Department of Integrative Biology, IGBMC, CNRS, INSERM, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France
d Mars Incorporated, 6885 Elm Street, McLean, VA 22101, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to
decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid
(ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is
linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved
by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in
activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen
atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here
enabled the design of novel arginase inhibitors with improved potency and markedly different physico-
chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhib-
itor reported to date.
Received 18 May 2013
Revised 22 June 2013
Accepted 27 June 2013
Available online 8 July 2013
Keywords:
Arginase inhibitor
Ugi reaction
Metalloenzyme
Boronic acid
ABH
Ó 2013 Elsevier Ltd. All rights reserved.
Inhibition of human arginases has been proposed as a potential
therapy for various diseases.1 While there is great interest in
studying this enzymatic target, the small molecule inhibitors re-
ported in the literature to date, are only moderately active, for
example, (S)-2-amino-6-boronohexanoic acid (ABH).2 Recently,
we reported the structure-based design and synthesis of a novel
series of arginase inhibitors based on alpha substitution of ABH.3
Compounds with a tertiary amine linked via a two carbon chain
to the alpha amino acid center (e.g., 13a) show improved (ca. five-
fold) inhibitory potency for both enzyme isoforms, arginase I (Arg
I) and arginase II (Arg II), due to increased hydrogen bonding of the
side chain nitrogen to the Asp200 of the Arg II enzyme (Asp181 in
Arg I). To develop this series further, we designed a series of alpha
linked piperidines 2 (as well as other ring systems), that allowed us
to position the side chain basic nitrogen atom in a similar region of
space while modulating the physicochemical properties of the
molecule. (Fig. 1)
logs of type 1, by ourselves3 and others.6 However, all of these
routes proved to be very low yielding when applied to the synthe-
sis of the desired cyclic amine analogs 2, very forceful reaction con-
ditions. This difference in reactivity could be explained by the
increased steric hindrance at the alpha carbon atom. As a result,
we turned our attention instead to multi-component reactions,
and used ketone 5 as a model substrate.
The Ugi reaction has been widely applied to produce amino acid
type products,7 but very few reports describe the synthesis of qua-
ternary amino acids, that is, where the carbonyl component of the
reaction is a ketone, not an aldehyde. Furthermore, the reported
examples were usually carried out with simple symmetrical keto-
nes8a–c (e.g., acetone, cyclopentanone). These reactions were
R
N
N
There are several well-documented approaches to the synthesis
of quaternary amino acids4 including the method of O’Donnell,5
which has been successfully adapted to the synthesis of ABH ana-
NH2
NH2
NH2
OH
OH
OH
HO2C
B
HO2C
B
HO2C
B
OH
OH
OH
ABH
1
2
⇑
Figure 1. Development of 2-substituted-2-amino-6-boronohexanoic acids as argi-
nase inhibitors.
Corresponding author. Tel.: +1 203 315 5947; fax: +1 203 315 4002.
E-mail address: golebiowski.a@gmail.com (A. Golebiowski).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.092

4838
A. Golebiowski et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4837–4841
extremely slow (2–3 weeks) and yields were generally low, espe-
cially for alicyclic ketones8d with a few exceptions.8e,8f
the synthesis of tropane ring analogs. In this particular case it is
noteworthy that ketone 9, and subsequently Ugi product 10, are
both thermodynamically preferred (the use of the trans isomer of
9 as substrate for the Ugi reaction still led to the same relative ste-
reochemistry, exclusively, in product 10). All products (2a–k and
11a–e) were deprotected by heating in 6 N HCl (all final products
were very stable in acidic conditions), and were purified by
water/dichloromethane extraction (to remove pinacol), followed
by reverse phase HPLC and lyophilization.
Compounds were tested for inhibition of human Arg I and Arg II
using a colorimetric assay that has been previously reported.3a
The inhibitory potency of the simple piperidine analog 2a
showed a clear improvement over ABH, similar to our previously
reported compound 1. This improvement in potency can be ratio-
nalized, as described previously,3a by X-ray crystallography, which
shows a water-mediated contact between the basic nitrogen and
the carboxylic acid side chain of Asp200 and Asp202, which are sit-
uated at the opening of the active site pocket of arginase II (Asp181
and Asp183 in arginase I).
N-Alkylation of the piperidine nitrogen atom (2b–2f) led to fur-
ther increases in potency, which did not vary significantly as the
basic side chain substituent is directed away from the active site
pocket towards solvent (see Fig. 2) and its main impact is on the
polarity and physicochemical profile of the inhibitors.
Formation of sulfonamide 2i, as well as amides (data not
shown), led to a drastic reduction in inhibitory activity, but urea
and thiourea analogs 2j and 2k, are still able to interact with
Asp200 (see Fig. 4; Supplementary data), and therefore retained
good in vitro inhibitory activity and were less polar than the N-al-
kyl analogs (Table 1).
We chose to evaluate the Ugi reaction of ketone 5 (prepared
from the alkylation of the corresponding Weinreb amide 4 with
but-3-en-1-ylmagnesium bromide) and tert-butyl isocyanide un-
der several reaction conditions. To our delight, we found that when
ammonium acetate was used as both the amine and acid compo-
nents, and trifluoroethanol was used as solvent in place of metha-
nol to suppress the competing Passerini reaction8e,f,9 the desired
Ugi-product 6 was produced in high yield (typically 80–90%).10
Hydroboration11 of the Ugi product cleanly afforded the com-
mon intermediate 7. Acidic deprotection gave inhibitor 2a, while
selective deprotection of the piperidine nitrogen, followed by
reductive amination and subsequent acidic deprotection gave
products 2b–h. Compounds 2i–k were made by selective sulfony-
lation, carbamoylation and thiocarbamoylation, respectively, of
diamino acid 2a (Scheme 1).
Other amino acids with more complex and sterically demand-
ing piperidine ring systems linked to the alpha carbon atom, were
prepared in a similar fashion. As an example, Scheme 2 illustrates
Boc
N
Boc
N
Boc
N
Boc
N
b
AcHN
a
c
t-BuHN
O
O
N
O
OMe
O
O
d
6
5
3
4
O
O
Boc
N
S
NH
AcHN
O
N
R
H2N
O
g
h
H2N
O
t-BuHN
O
B
HO
Detailed analysis of the crystallographic interactions of inhibi-
tor 2d with Arg II (PDB 4IXU), specifically the interaction of the ba-
sic piperidine nitrogen atom with Asp202 and Asp200, encouraged
us to design new analogs in an effort to improve this contact fur-
ther. In one approach, we discovered that substitution of the piper-
HO
B(OH)2
O
B(OH)2
2i
2a
7
i
e,f,g
j
O
S
idine ring system with
improvements in enzyme inhibitory activity (Table 2).
This was rationalized by comparison of the Arg II inhibitor com-
plex of 11d (PDB 4IXV) with that of 2d. In the case of compound 2d
a tropane led to further 10-fold
R
R
N
R
N
N
H
N
N
H
H2N
O
H2N
O
H2N
HO
HO
HO
B(OH)2
B(OH)2
B(OH)2
O
2j
2k
2b-h
Scheme 1. Synthesis of inhibitors 2a–k. Reagents and conditions: (a) MeNH(OMe),
i-PrMgBr, THF, 0 °C (98%); (b) But-3-en-1-ylmagnesium bromide, THF, 0 °C (91%);
(c) NH4OAc 3 equiv, t-But-NC, CF3CH2OH, rt, 3 days (83%); (d) Pinacolborane,
chloro-1,5-cyclooctadiene iridium (I) dimer, dppe, THF (95%); (e) 2 N HCl, dioxane,
rt 2 h (96%); (f) RCHO, 1,2-DCE, NaBH(OAc)3, rt, 16 h (70–90% yield); (g) 6 N HCl,
95 °C, 16 h (80–90% yield); (h) TosCl, Py, DMF; (i) p-Cl–PhNCO, Et3N, DMF; (j) p-Cl–
BnNCS, Et3N, DMF.
NH
HO2C
H2N
OH
B
OH
CONH-t-But
O
d,g
H
N
CO2H
Ac
a,b
11a
c
d,e,f,g
N
Boc
N
Boc
N
R
N
Boc
HO2C
H2N
OH
B
8
9
10
OH
11b-e
Scheme 2. Synthesis of inhibitors 11a–e. Reagents and conditions: (a) MeN-
H(OMe), EDC, HOBt, DMAP, DCM, RT (86%); (b) But-3-en-1-ylmagnesium bromide,
THF, 0 °C (96%); (c) NH4OAc 3 equiv, t-But-NC, CF3CH2OH, rt, 7 days (70%); (d)
Pinacolborane, chloro-1,5-cyclooctadiene iridium (I) dimer, dppe, THF (74%); (e) 4 N
HCl–dioxane, rt, 3 h; (f) RCHO, 1,2-DCE, NaBH(OAc)3, rt, 16 h (70–80% yield from
10); (g) 6 N HCl, 95 °C, 16 h (75–86% yield).
Figure 2. X-ray structure of compound 2d in human Arg II.

A. Golebiowski et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4837–4841
4839
Table 1
SAR for
a
,
a
disubstituted ABH analogs 2a
R
N
NH2
OH
HO2C
B
OH
2
Entry
ABH
R
Arg I IC50 (nM)
1470
Arg II IC50 (nM)
2150
mlogD/clogDb
NT/À2.5
1
2a
320
380
620
640
NT/À2.9
H
À2.8/À5.2
2b
180
230
À1.1/À3.3
2c
200
190
230
240
À0.4/À2.5
0.3/À1.7
2d
Cl
Cl
2e
2f
200
210
290
330
1.5/À1.0
NT/À1.1
Cl
Cl
Cl
Cl
2g
100c
50
1.2/À1.2
Cl
2h
2i
120
70
NT/À2.3
NT/À0.7
CF3
O
O
S
O
S
6650
4650
Cl
2j
720
330
1100
1120
0.5/À0.3
N
H
N
H
2k
NT/0.1
Cl
a
All compounds were tested as their racemates (n P 2).
Ref. 12.
b
(Fig. 2), X-ray structure obtained at 2.3 Å resolution on a laboratory
X-ray source, show that the piperidine ring adopts a chair confor-
mation and the contact of the N-atom with Asp202 and Asp200 is
through water W314 (H-bonds of 2.9, 3.6 and 3.1 Å). In contrast,
for 11d (Fig. 3, see also Fig. 5, Supplementary data) X-ray structure
obtained at 1.9 Å resolution on the X06DA beamline at the Swiss
Light Source, (Switzerland) show that the two carbon bridge of
the tropane locks the corresponding piperidine ring in a boat con-
formation allowing the N-atom of 11d to make a direct contact
with the Asp202 side chain (3.3 Å) in addition to the interaction
with Asp200 through water W426 (3.7 and 2.6 Å). Therefore, com-
pound 11d has two advantages which explain its higher potency:
fixation of the geometry of the ring so side chain nitrogen atom
has the right position (entropy gain) and direct contact with
Asp202 instead of water mediated contact (Fig. 3). X-ray method-
ology was done as reported,3a and the data collection and refine-
ment statistics are included in the Supplementary material. This
substantial improvement of in vitro activity, is accompanied by a
decrease in measured polarity (2e mlogD = 1.5; 11d mlogD =
2.4).12
Rat pharmacokinetics of compounds 2e and 11d are compared
in Table 3. Following intravenous administration in rats, com-
pounds in this series generally exhibited low to moderate clear-
ances, high volumes of distribution, and moderate to adequate
half lives. Bioavailability for oral dosing was poor for all tested ana-
logs in the series, typically <5%. Intraperitoneal dosing resulted in
higher bioavailabilities (>50%), allowing ease in multiple dose test-
ing in rodent disease efficacy models. The more polar compounds
were primarily excreted via renal elimination, with an increased
hepatic clearance component as polarity decreased, resulting in
the increased clearance of example 11d over that of example 2e.
In conclusion, we have developed a practical route to the syn-
thesis of complex quaternary amino acids, via the Ugi reaction of
ketones and applied it to synthesis of several series of novel boro-
nic acid arginase inhibitors related structurally to ABH. Clearly,
however, the scope of this reaction remains largely unexplored

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A. Golebiowski et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4837–4841
Table 2
SAR for
a
,a
disubstituted ABH analogsa
R
N
HO2C
H2N
OH
B
OH
11
Entry
ABH
1
R
Arg I IC50 (nM)
Arg II IC50 (nM)
mlogD /clogDb
NT/À2.5
NT/À2.9
1470
320
80
2150
620
85
11a
H
NT/À4.9
11b
11c
24
17
47
30
NT/À1.9
NT/À0.6
Cl
Cl
11d
11e
21
22
23
33
2.4/0.2
Cl
F
NT/À0.7
F
a
All compounds were tested as their racemates (n P 2).
Ref. 12.
b
and it may have a much broader synthetic potential. While a
marked improvement in in vitro activity over ABH has been
achieved, the optimization of pharmacokinetic parameters to sup-
port the development of orally active compounds remains a signif-
icant challenge. Our studies to further develop structure activity
relationships and improve understanding of parameters control-
ling pharmacokinetic profile for this compounds class, will be the
subject of future publications.
Acknowledgments
This work was funded by Mars Incorporated. Infrastructures
used in this research were supported by the Centre National de
la Recherche Scientifique (CNRS), the Institut National de la Santé
et de la Recherche Médicale, the Hôpital Universitaire de Stras-
bourg (H.U.S) and the Université de Strasbourg. We thank the
IGBMC Structural genomics platform. The crystallographic experi-
ments were performed on the laboratory source and on the X06DA
beamline at the Swiss Light Source, Paul Scherrer Institut, Villigen,
Switzerland. We thank in particular Vincent Olieric and Chitra
Rajendran for their help in data collection.
Figure 3. Contacts of 2d (magenta carbons) superposed with 11d (pink carbons, red
water) with Asp202 (same position for 2d and 11d)
Supplementary data
Table 3
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.06.
092.
Rat pharmacokinetics of selected compounds following intravenous bolus and oral
administration
Compound
2e
11d
IV AUC,n0-inf (kg*h/L)
IV AUC,n0-t (kg*h/L)
C0,n (mg/L)
2.12
2.05
4.72
7.83
7.87
1.51
2.14
4.8%
0.994
0.951
4.77
References and notes
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(s, NH, 1H), 4.97 (m, 2H), 4.12 (m, 2H), 2.96 (ddd, J1 = 16.5 Hz, J2 = 11.5 Hz,
J3 = 5.5 Hz, 1H), 2.62 (m, 2H), 2.35 (tt, J1 = 12.5 Hz, J2 = J3 = 3 Hz, 1H), 2.10–1.96
(m, 1H), 2.00 (s, 3H), 1.86–1.64 (m, 3H), 1.48 (m, 1H), 1.43 (s, 9H), 1.36 (s, 9H),
1.28–1.20 (m, 1H), 1.10 (m, 1H).
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