Direct Synthesis of Cyanopyrrolidinyl β-Amino Alcohols for the Development of Diabetes Therapeutics

Article abstract of DOI:10.1002/ejoc.201600969

Cyanopyrrolidinyl β-amino alcohols are novel scaffolds with potential for a wide array of pharmacological properties. We have discovered that we can selectively access these scaffolds from simple and inexpensive commercially available chemicals in few synthetic steps with minimal purification. We have produced a 36-compound library of these scaffolds and tested them as dipeptidyl peptidase IV (DPP4) inhibitors. These novel inhibitors are useful in the treatment of diabetes and inflammatory disorders.

Full text of DOI:10.1002/ejoc.201600969

A Journal of
Accepted Article
Title: Direct Synthesis of Cyanopyrrolidinyl -Amino Alcohols for the Development of
Novel Diabetes Therapeutics
Authors: Joseph R Lizza; Savan V Patel; Catherine F Yang; Gustavo Moura-Letts
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600969
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600969
Supported by

European Journal of Organic Chemistry
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Direct Synthesis of Cyanopyrrolidinyl β-Amino Alcohols for the
Development of Novel Diabetes Therapeutics
Joseph R. Lizza, Savan V. Patel, Catherine F. Yang and Gustavo Moura-Letts*
Abstract: Cyanopyrrolidinyl β-amino alcohols are novel scaffolds
kidney, epithelial cells, endothelial cells, the prostate, the brain,
with potential for a wide array of pharmacological properties. We
and the liver. DPP4 activity has also been discovered in serum,
have discovered that we can selectively access these scaffolds from
simple and inexpensive commercially available chemicals in few
synthetic steps with minimal purification. We have produced a 36-
compound library of these scaffolds and tested them as dipeptidyl
peptidase IV (DPP4) inhibitors. These novel inhibitors are useful in
the treatment of diabetes and inflammatory disorders.
8
urine, seminal plasma, and amniotic fluid. DPP4 activity and
expression was found to be elevated in prostate, colon, and lung
cancer, and elevated DPP4 has also been found in patients with
9
benign prostate hyperplasia. DPP4 also is being explored for its
role in type II diabetes because the glucagon-like peptide (GLP-
1) can be a substrate for DPP4 cleavage, and some DPP4
inhibitors have exhibited effectiveness in animal models of
1
0
diabetes. Inhibition of DPP4 has been shown to increase
release of TGF-β, a protein having neuroprotective properties.
DPP4 inhibition itself has been implicated in cellular
Introduction
1
1
mechanisms connected to neurodegeneration. It follows from
the above that inhibitors of DPP4 may be useful as therapeutics
Diabetes is a rapidly growing disease that affects millions of
people worldwide. 29.1 million children and adults in the United
States have diabetes. Recently DDP4 inhibitors have emerged
as a new class of therapeutic agents for treating diabetes, as
1
12
2
in the treatment of a range of medical conditions.
3
Cyanopyrrolidines are molecular scaffolds that are highly
evidenced by the FDA approval of sitagliptin for use as a
monotherapy, and in combination with other antidiabetic agents.
1
3
4
recurrent among natural products and commercial drugs. The
scaffold has shown affinity to dipeptidyl peptidases as a proline
mimetic group and it has been hypothesized that the activity
arises from a transient covalent interaction of the nitrile with
Several other DPP4 inhibitors such as vildagliptin, saxagliptin,
SYR-322 are either awaiting regulatory approval, or are in
5
human clinical trials. Compared to other existing antidiabetic
1
4
S630 that triggers a slow dissociation from the enzyme. Thus,
most of the most potent DPP4 inhibitors contain this scaffold
agents, DPP4 inhibitors have the benefit of not triggering
hypoglycemic episodes, not causing body-weight gain, and
potentially modifying disease progression by restoring β-cell
(
vinagliptin, saxagliptin, vildagliptin). Cyanopyrrolidines can be
6
easily obtained from naturally available proline and many
synthetic approaches are available. However, despite the
function of the pancreas.
DPP4 is a membrane-anchored aminopeptidase involved in the
release of N-terminal dipeptides from proteins and other
peptides. Physiological roles for DPP4 would be the activation,
inactivation, or degradation of its substrates through the specific
release of a proline-containing dipeptide from the N-terminal
15
diversity of methods many lack scalability and reproducibility.
β-Amino alcohols are an important class of compounds in
medicinal chemistry and drug discovery due to their high
1
6
occurrence in commercially available drugs.
They often
behave as β-adrenergic blockers, widely used in the
management of cardiovascular disorders, including hypertension,
anginapectoris, cardiac arrhythmias, and other disorders related
[
a]
Dr. Gustavo Moura-Letts*
Department of Chemistry and Biochemistry
Rowan University
1
7
to the sympathetic nervous system. Amino alcohols have also
been used as protein kinase C inhibitors, glycosidase inhibitor
201 Mullica Hill Rd., Glassboro, NJ, 08028, USA
E-mail: moura-letts@rowan.edu. www.gmlresearchgroup.com
18
and antimalarial agents.
Among commercial drugs, this
Supporting information for this article is given via a link at the end of
the document.
scaffold is present in Oxycontin, Coreg, and Toprol-XL. Other
pharmaceutical drugs such as Zyvox and Skelaxin feature
oxazolidones that can be formed through amino alcohol
precursors. Moreover, these can be used as chemical synthons
for the synthesis of more complex heterocyclic scaffolds. Thus,
7
region of the substrate peptide. DPP4 has been found in the
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European Journal of Organic Chemistry
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we envision developing a novel family of inhibitors that shares
the cyanopyrrolidine and β-amino alcohol scaffolds towards
more potent and selective diabetes therapeutics.
synthesis of similar cyanopyrrolidines, we were interested in
developing a more productive protocol for its synthesis. Starting
from L-proline we were able to obtain cyanopyrrolidinyl amine in
55% yield in three synthetic steps (Scheme 2). The initial N-
acetylation product was carefully triturated and the resulting acid
converted to the amide in very high yield and in 99% purity.
Amide to nitrile transformations has been widely studied and
many protocols are available in the literature. Despite their
popularity, we found only TFAA mediated elimination followed by
aminolysis in cold ammonium hydroxide provided the desired
cyanopyrrolidinyl amine in 78% yield and 55% yield over 3 steps.
The synthetic sequence for the desired scaffold proved to be
successful in small and large scale without the need for
2
6
cumbersome purifications.
The successful implementation of a synthetic route for the
desired amine turned our attention towards understanding the
reaction properties of epoxide opening reactions with
unhindered primary amines. The widely reported issues with
selectivity for this reaction prompted us to study a wide array of
solvents.
Figure 1. Representative examples of epoxide opening reactions
Despite the ease for the synthesis of cyanopyrrolidines, β-amino
alcohols selective synthesis remains challenging in the synthetic
community and a long list of methods and syntheses containing
1
9
this scaffold has been reported in the literature. While these
methods are effective, the epoxide opening with unhindered
primary amines introduces a large number of issues with the
20
chemo- and regioselectivity of this reaction (Figure 1).
Jamison reported that double alkylation for this approach lowers
the productivity and ease of isolation for unbranched primary
2
1
amines. On the other hand, multiple reports demonstrated that
secondary amines and anilines are kinetically favored for
2
2
monoalkylation.
This reactive pattern often displays poor
Scheme 2. Cyanopyrrolidinyl amine synthesis
regioselectivity for the least substituted side of the epoxide,
significantly decreasing its presence among similar promoters.
23
We began this portion of the study by assessing the reaction
outcomes between phenylgylcidylether and allylamine as proof
of principle substrates (Table 1). We found that in nonpolar and
polar aprotic solvents at room temperature and after 24h we
were obtaining 4:1 mixtures of 1a and 1b with very low
conversion (Entries 1-4). Polar protic solvents have shown to
accelerate this reaction through Brønsted acid activation of the
epoxide. We found a drastic increase in conversion with 3:1
Along those lines, a wide array of reports which attempt to
extrapolate the narrow success of epoxide opening with anilines
2
4
to primary amines, albeit with a clear lack of scope. Thus, there
is a clear void for more efficient reaction conditions for the
chemo- and regioselective epoxide opening with unhindered
primary amines.
1a/1b ratio of products for ethanol (Entry 5) and complete
conversion in 2:3 1a/1b ratios for H O (Entry 6). Epoxide
2
opening under neat conditions proved to increase the selectivity
to 3:1 for the monoalkylated product (Entry 7). Highly polar
solvents should promote the kinetically favored monoalkylation
and we found that in ACN and DMF only 1a was formed, with
very low conversions (Entries 8 and 9). Providing energy to the
reaction proved to increase conversion (Entries 10-12, 27, 31
and 40% yield respectively) along with complete selectivity for
the monoalkylated product 1a. However, at higher temperatures
the conversion remained moderate with relative loss of
selectivity (Entries 13-15). The desired balance between
conversion and selectivity arrived when using DMF with high
Scheme 1. Inhibitor design
Results and Discussion
Our laboratory is focused on developing novel synthetic
methods for the synthesis of pharmacologically relevant
25
molecular scaffolds.
Thus, we envision constructing the
proposed inhibitor scaffold by the selective monoalkylation of
glycidyl ethers and cyanopyrrolidinyl amines (Scheme 1). We
then turned our attention to the synthesis of cyanopyrrolidinyl
amine substrate. Despite many available methods for the
excess of H O. We anticipated an environment that would favor
2
the kinetic product with efficient activation of the epoxide and we
found that indeed when using 50 equiv. of H O at room
2
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European Journal of Organic Chemistry
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temperature we obtained 31% conversion and >95% selectivity
The success with styrene oxide electrophiles across the amine
nucleophiles served as a proof of principle for this study. We
then turned our attention to phenylgylcidylethers and we found
that the respective cyanopyrrolidine aminoalcohols were
obtained in great yields and as single isomers (Entry 5). The
resulting amino alcohols are obtained as mixtures of
diastereomers at the alcohol and cyano centers, but due to their
remote relationship, they are seen as one isomer by NMR.
for 1a. Increasing the reaction temperature proved to be quite
o
efficient and at 60 C we obtained 98% conversion with 94% of
1
a and 5% of 1b. Later we found that adding H
2
O after a few
hours of reaction at 60 C provides 1a in 96% yield with <2% of
b. Based on the results obtained on entry 6, we found that
o
1
under substoichiometric amounts of amine we could achieve
complete selectivity for 1b (Entry 20).
Having found a highly selective set of conditions for this reaction, Despite the remoteness between the chiral centers on the
we were interested in addressing which diversity points would
better address the pharmacological properties of the targeted
scaffold. Several studies have demonstrated that DPP4
inhibitors require a hindered primary or secondary amine to
avoid intramolecular cyclization of the cis-amide rotamer onto
proposed target, we anticipated that we might need to construct
this scaffold as a single diastereomer to validate the effect of the
remote chiral center.
Thus, we reacted (S)-phenylglycidylether with our amine series
to find the expected products in very good yields as well (Entry
6). We also envisioned that steric bulk around the phenyl group
on the epoxide would enhance the scaffold activity. We were
27
the pending nitrile. We propose to circumvent the potential
structural weaknesses of this molecular framework by
constructing a double alkylated scaffold and a descyano scaffold. able to successfully obtain o-tolyl, benzyl and p-methoxyphenyl
Thus, we aim to construct series aa (monoalkylated), ba
double-alkylated) and ab/bb (descyano) based on the structure-
activity relationships established for known DPP4 inhibitors
Table 2).
cyanopyrrolidinyl amino alcohol scaffolds with equally successful
yields (Entries 7-9). Another structural feature that has proven to
improve DPP4 inhibition rests on the fluorine substitution pattern
around the aromatic ring on the proposed scaffolds. Thus, our
next diversification goal was to introduce a large array of
substitution patterns around the phenyl group. However, due to
the lack of commercially available phenylglycidylethers and the
much larger availability of substituted phenols, we opted to
synthesize them via the alkylation of substituted phenols with
epichlorohydrin. With these electrophiles in hand we were able
to make a large array of phenyl substituted cyanopyrrolidinyl
amino alcohol scaffolds in very good yields and selectivities
(
(
Table 1. Reaction discovery and optimization
(
Entries 10-12). We also wanted to expand the structural profile
of the scaffold and synthesized napthyl, benzyl and furfuryl
cyanopyrrolidinyl amino alcohols in equally high yields (Entries
13, 14 and 15). With the library of scaffolds in hand, we were
ready to assess their pharmacological profile as DPP4 inhibitors.
The dual pharmacophoric character of our scaffold library would
warrant the assay against multiple lines of enzymes or cell to
address their potential inhibitory properties. Due to the
importance of DPP4 inhibition, we proposed to assay against
this enzyme as a proof of principle for the pharmacological
power of these molecules. Moreover, it has been proposed that
early preclinical assessment of potential therapeutic candidates
for off-target DPP inhibition to be highly complementary, with
selection and further diversification of agents that have
2
8
fundamentally no DPP8 and 9 inhibition. Inhibitory potency of
the synthesized compounds was measured by monitoring the
hydrolytic reaction of Gly-Pro-7-amidomethylcoumarin (Gly-Pro-
AMC) by human DPP4. Compounds were incubated with human
recombinant DPP4 under steady state conditions to detect the
cleavage of the substrate, Gly-Pro-AMC. The DPP4 inhibitory
activity for compounds 1-15 is summarized in Table 3.
We chose to begin with styrene oxides as a suitable electrophile
to obtain the cyanopyrrolidine aminoalcohol scaffold. We found
that under the optimized conditions (Entry 19, Table 1), we
obtained product 1aa and 1ab (Entry 1) with very high yields and
complete chemoselectivity. On the other hand, under the
optimized conditions for double alkylation (Entry 20, Table 1), we
obtained product 1ba and 1bb with very high yields and equal
selectivity (Entry 1). Similar results were found for substituted
styrene oxides, providing the respective scaffolds (Entries 2-4).
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Table 2. Reaction scope and library synthesis
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We anticipated that series aa would establish the baseline
activity for these inhibitors. Thus, aromatic cyanopyrrolidinyl
amino alcohols demonstrated to have significant potency (IC50
under 0.2 uM). We observed that analogue 1aa (42 nM), had
significant more inhibition against DPP4 than the other
substituted aromatic analogues (2aa, 3aa and 4aa). Moreover,
from those the p-fluorophenyl analogue surprisingly displayed
much lower inhibition. The introduction of phenoxy ethers is
known to enhance activity among several β-adrenergic blockers.
Consequently, we found that phenoxy (5aa, 6aa), o-
methylphenoxy (7aa), benzyloxy (8aa) and p-methoxy (9aa) had
similar inhibitory properties as to the previous analogues but
failed to improve 1aa activity. The scaffold remote relationship
between its chiral centers suggested that, as a mixture of
diastereomers the scaffold inhibition would be potentially
Table 3. DPP4 inhibitor activity
2
9
comparable. We corroborated this hypothesis as we found that
enantiopure amino alcohol 6aa inhibitory properties were very
similar to 5aa (mixture of diastereomers).
Based on the structure activity relationship (SAR) data found so
far, we envisioned that introducing fluorine atoms on the
phenoxy group might further increase the inhibitory properties.
We found that p-fluorophenoxy 10aa had comparable activity.
Moreover, 4,5-difluorophenoxy 11aa proved to be more active
(
analogues to SAR from reported studies), but 4,5,6-
trifluorophenoxy 12aa proved to decreased the inhibitory activity
10aa = 112 nM, 11aa = 78 nM, 12aa = 141 nM). Further
(
assessment of the SAR demonstrated that naphthyl
cyanopyrrolidinyl amino alcohol 13aa is comparably active (101
nM). Interestingly, removing the oxygen from the benzyloxy
analogue (14aa) fully drops DPP4 activity. Low activity from
heterocyclic analogue 15aa further proved the need for a more
lipophilic side chain.
Conclusions
In summary we have developed a novel synthetic approach for
the efficient and selective synthesis of cyanopyrrolidinyl amino
alcohols from easily accessible starting materials. This synthetic
method allows for the selective epoxide opening with unhindered
amines for either the monoalkylated or the double alkylated
amino alcohol. The reaction sequence has proven to be
scalable towards the synthesis of multigram amounts of
inhibitors. The biochemical studies on these analogues have
shown that the proposed scaffold is highly potent against DPP4
and opens the door for the development of a second-generation
library of cyanopyrrolidinyl amino alcohols as competitive
inhibitors. Moreover, these scaffolds can be easily obtained and
diversified compared to the current synthetic approaches for
DPP4 inhibitors. We are in the process of determining the
extended selectivity of the scaffold against other dipeptidyl
dipeptidases (DPP8 and DPP9) and further testing their in vivo
DPP4 inhibition properties.
Series ba biochemical inhibitory assays results are summarized
on Table 3. Analogue 4ba show significant activity (130 nM),
slightly higher than the monoalkylated analogue 4aa (160 nM).
However, we found that the remaining analogues had
significantly lower inhibitory activity. Moreover, Series ab/bb also
failed at providing significant activity against DPP4. The SAR
data from this preliminary biochemical study shows that
analogue 1aa is the most active (42 nM), and analogues that
introduce complexity around the phenyl ring have comparable
inhibitory properties. It has been demonstrated that the
monoalkylated scaffold is by far the most active scaffold. Despite
reported evidence of a potential decomposition pathway through
an acid-catalyzed intramolecular cyclization, stability studies
displayed complete structural stability for the inhibitor against
30
analogous conditions. This study also has shown that fluorine
incorporation can improve activity, but does not play a significant
role as seen in other DPP4 inhibitors.
Experimental Section
General Method A: Synthesis of mono-alkylated amino
alcohols: In a 20 mL vial at rt, epoxide (1.0 mmol, 1.0 equiv)
and amine (1.5 mmol, 1.5 equiv) were added to 6.7 mL of DMF.
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European Journal of Organic Chemistry
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The reaction was stirred at 60°C for 12 h at which point the rxn
mixture received deionized water (50 equiv). The reaction was
allowed to stir a 60°C for an additional 12 h. The resulting crude
was stripped of solvent and the residue loaded directly onto a
silica gel column.
140.8, 133.0, 128.4, 127.2, 118.1, 71.3, 57.3, 51.0, 46.4, 45.3,
+
29.8, 25.0 ppm. ESI-MS m/z (rel int): (pos) 308.1 ([M+H] , 100);
–
(neg) 306.1 ([MH] , 100). HRMS (ESI): Calculated for:
+
C
15
H19ClN
3
O
2
:
308.11603, found: 308.11633. Absolute
difference (ppm): 0.93.
General Method B: Synthesis of double-alkylated amino
alcohols: In a 20 mL vial at rt, epoxide (2.0 mmol, 2.0 equiv)
and amine (1.0 mmol, 1.0 equiv) were added to 5 mL of
deionized water. The reaction was stirred at rt for 12 h. The
resulting crude was stripped of water and the residue loaded
directly onto a silica gel column.
(2S)-1-((2-(4-bromophenyl)-2-hydroxyethyl)glycyl)pyrrolidine
-2-carbonitrile (4aa): Method A. 2-(4-bromophenyl)oxirane (150
mg, 0.75 mmol) and amine a (173 mg, 1.13 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl
3
)
produced amino alcohol 4aa (226 mg, 85%) as a clear oil. TLC:
-
1
R
f
0.25 (1:9 MeOH/CHCl
3
). IR (thin film) 3321, 2240, 1658 cm .
1
H-NMR (400 MHz, CDCl 7.49 (d, J= 6.2 Hz, 2H), 7.23 (d,
3
(
2S)-1-((2-hydroxy-2-phenylethyl)glycyl)pyrrolidine-2-
J= 6.2 Hz, 2H), 4.75 (dd, J = 7.1, 6.8 Hz, 1H), 4.71 (dd, J = 7.2,
7.1 Hz, 1H), 3.55-3.49 (m, 1H), 3.45 (s, 2H), 3.41-3.34 (m, 1H),
2.97 (dd, J = 7.1, 6.8 Hz, 1H), 2.71 (dd, J = 7.3, 7.1 Hz, 1H),
carbonitrile (1aa): Method A. Styrene oxide (150 mg, 1.25
mmol) and amine a (287 mg, 1.87 mmol). Purification by silica
gel chromatography (isocratic, 4% MeOH/CHCl
amino alcohol 1aa (311 mg, 91%) as a clear oil. TLC: R
(
(
13
3
)
produced
0.25
). IR (thin film) 3332, 2241, 1658 cm . H-NMR
): δ 7.41-7.25 (m, 5H), 4.77-4.75 (m, 2H), 3.53-
.51 (m, 1H), 3.49 (s, 2H), 3.38-3.31 (m, 2H), 2.99 (dd, J = 7.3,
.8 Hz, 1H), 2.76 (dd, J = 7.1, 6.8 Hz, 1H), 2.26-2.06 (m, 4H).
3
2.28-2.24 (m, 4H). C-NMR (100 MHz, CDCl ): δ 170.3, 141.2,
f
131.4, 127.5, 121.2, 118.1, 71.3, 57.3, 51.0, 46.5, 45.3, 29.8,
-1
1
+
1:9 MeOH/CHCl
400 MHz, CDCl
3
25.1 ppm. ESI-MS m/z (rel int): (pos) 352.1 ([M+H] , 100); (neg)
–
3
350.1 ([MH] , 100). HRMS (ESI): Calculated for:
+
3
6
C
15
H19BrN
3
O
2
:
352.06552, found: 352.06628. Absolute
difference (ppm): 2.18.
1
3
C-NMR (100 MHz, CDCl
3
): δ 170.3, 142.3, 128.3, 127.4,
1
27.3, 125.8, 118.2, 71.9, 57.4, 51.0, 46.4, 45.3, 29.7, 25.0 ppm.
(2S)-1-((2-hydroxy-3-phenoxypropyl)glycyl)pyrrolidine-2-
carbonitrile (5aa): Method A. 2-(phenoxymethyl)oxirane (150
mg, 1.00 mmol) and amine a (230 mg, 1.50 mmol). Purification
+
ESI-MS m/z (rel int): (pos) 274.1 ([M+H] , 100); (neg) 272.1
–
+
2
(
[MH] , 100). HRMS (ESI): Calculated for:
C
15
H
20
N
3
O
:
274.15500, found: 274.15447. Absolute difference (ppm): 1.96.
by silica gel chromatography (isocratic, 4% MeOH/CHCl
3
)
produced amino alcohol 5aa (294 mg, 97%) as a clear oil. TLC:
-
1
(
-
2S)-1-((2-(4-fluorophenyl)-2-hydroxyethyl)glycyl)pyrrolidine
2-carbonitrile (2aa): Method A. 2-(4-fluorophenyl)oxirane (150
R
f
0.26 (1:9 MeOH/CHCl
3
). IR (thin film) 3321, 2243, 1653 cm .
1
H-NMR (400 MHz, CDCl ): δ 7.52-7.50 (m, 2H), 6.95-6.91 (m,
3
mg, 1.09 mmol) and amine a (250 mg, 1.63 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl
produced amino alcohol 2aa (275 mg, 87%) as a clear oil. TLC:
3H), 4.75 (t, J = 6.8 Hz, 1H), 4.08 (ddt, J = 7.1, 6.8, 6.6 Hz, 1H),
3.98 (d, J = 6.8 Hz, 2H), 3.51-3.49 (m, 1H), 3.43 (s, 2H), 3.32-
3
)
3.29 (m, 1H), 2.93 (dd, J = 7.1, 6.4 Hz, 1H), 2.77 (dd, J = 6.6,
-
1
13
R
f
0.24 (1:9 MeOH/CHCl
3
). IR (thin film) 3322, 2243, 1639 cm .
): δ 7.38 (dd, J= 5.9, 1.6 Hz, 2H), 7.01
dd, J= 5.7, 1.5 Hz, 2H), 4.79 (dd, J = 7.1, 6.8 Hz, 1H), 4.69 (dd,
J = 7.2, 7.1 Hz, 1H), 3.59-3.52 (m, 1H), 3.49 (s, 2H), 3.45-3.38
3
6.4 Hz, 1H), 2.26-2.08 (m, 4H). C-NMR (100 MHz, CDCl ): δ
1
H-NMR (400 MHz, CDCl
3
170.4, 158.5, 129.3, 120.7, 118.2, 114.4, 70.0, 68.4, 52.2, 52.1,
(
46.3, 45.2, 29.6, 24.9 ppm. ESI-MS m/z (rel int): (pos) 304.2
+
–
([M+H] , 100); (neg) 302.2 ([MH] , 100). HRMS (ESI):
+
(
m, 1H), 2.99 (dd, J = 7.1, 6.8 Hz, 1H), 2.75 (dd, J = 7.3, 7.1 Hz,
16 22 3 3
Calculated for: C H N O : 304.16557, found: 304.16591.
1
3
1
1
5
(
(
H), 2.32-2.12 (m, 4H).
C-NMR (100 MHz, CDCl
3
): δ 170.4,
Absolute difference (ppm): 1.11.
62.7 (d, J = 244 Hz, 1C), 138.0, 127.5, 118.1, 115.2, 71.3,
7.5, 51.1, 46.7, 45.3, 29.8, 25.1 ppm. ESI-MS m/z (rel int):
(S)-1-(((S)-2-hydroxy-3-phenoxypropyl)glycyl)pyrrolidine-2-
carbonitrile (6aa): Method A. (S)-2-(phenoxymethyl)oxirane
(150 mg, 1.00 mmol) and amine a (230 mg, 1.50 mmol).
Purification by silica gel chromatography (isocratic, 4%
+
–
pos) 292.1 ([M+H] , 100); (neg) 290.1 ([MH] , 100). HRMS
+
ESI): Calculated for:
C
15
H19FN
3
O
2
:
292.14558, found:
292.14578. Absolute difference (ppm): 0.68.
MeOH/CHCl
clear oil. TLC: R
3
) produced amino alcohol 6aa (285 mg, 94%) as a
0.28 (1:9 MeOH/CHCl ). IR (thin film) 3331,
2241, 1656 cm . H-NMR (400 MHz, CDCl ): δ 7.32-7.28 (m,
(
-
2S)-1-((2-(4-chlorophenyl)-2-hydroxyethyl)glycyl)pyrrolidine
2-carbonitrile (3aa): Method A. 2-(4-chlorophenyl)oxirane (150
f
3
-1
1
3
mg, 0.97 mmol) and amine a (223 mg, 1.46 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl
produced amino alcohol 3aa (269 mg, 90%) as a clear oil. TLC:
2H), 6.95-6.89 (m, 3H), 4.77 (t, J = 6.8 Hz, 1H), 4.11 (ddt, J =
7.1, 6.8, 6.6 Hz, 1H), 3.98 (d, J = 6.8 Hz, 2H), 3.53-3.51 (m, 1H),
3.45 (s, 2H), 3.37-3.27 (m, 1H), 2.93 (dd, J = 7.1, 6.3 Hz, 1H),
3
)
-
1
13
R
f
0.26 (1:9 MeOH/CHCl
3
). IR (thin film) 3334, 2244, 1659 cm .
H-NMR (400 MHz, CDCl 7.29 (d, J= 5.9 Hz, 2H), 7.23 (d,
J= 5.7 Hz, 2H), 4.75 (dd, J = 7.3, 6.6.6 Hz, 1H), 4.68 (dd, J =
2.82 (dd, J = 6.6, 6.3 Hz, 1H), 2.28-2.08 (m, 4H). C-NMR (100
1
3
MHz, CDCl
3
): δ 170.3, 158.5, 129.3, 120.7, 118.2, 114.4, 70.0,
68.4, 52.1, 51.1, 46.3, 45.2, 29.6, 25.0 ppm. ESI-MS m/z (rel
+
–
7
1
1
.1, 6.6 Hz, 1H), 3.55-3.50 (m, 1H), 3.45 (s, 2H), 3.41-3.34 (m,
int): (pos) 304.2 ([M+H] , 100); (neg) 302.2 ([MH] , 100). HRMS
+
H), 2.99 (dd, J = 7.1, 6.4 Hz, 1H), 2.73 (dd, J = 7.1, 6.8 Hz,
(ESI): Calculated for:
C H
16 22
N
3
O
3
:
304.16557, found:
1
3
H), 2.28-2.08 (m, 4H).
3
C-NMR (100 MHz, CDCl ): δ 1704,
304.16516. Absolute difference (ppm): 1.34.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600969
FULL PAPER
(
2S)-1-((2-hydroxy-3-(o-tolyloxy)propyl)glycyl)pyrrolidine-2-
(205 mg, 1.34 mmol). Purification by silica gel chromatography
carbonitrile (7aa): Method A. 2-((o-tolyloxy)methyl)oxirane (150
mg, 0.91 mmol) and amine a (210 mg, 1.37 mmol). Purification
(isocratic, 4% MeOH/CHCl
(267 mg, 93%) as a clear oil. TLC: R 0.28 (1:9 MeOH/CHCl
IR (thin film) 3331, 2441, 1655 cm . H-NMR (400 MHz, CDCl
3
) produced amino alcohol 10aa
f
3
).
):
-1 1
by silica gel chromatography (isocratic, 4% MeOH/CHCl
3
)
3
produced amino alcohol 7aa (270 mg, 93%) as a clear oil. TLC:
δ 6.88-6.73 (m, 4H), 4.73 (dd, J = 6.9, 6.8 Hz, 1H), 4.04-4.00 (m,
1H), 3.85 (s, 2H), 3.52 (dt, J = 6.8, 6.6 Hz, 1H), 3.37 (s, 2H),
3.38 (dt, J = 6.8, 6.6 Hz, 1H), 2.82 (dd, J = 6.9, 6.6 Hz, 1H), 2.73
-1
R
f
0.25 (1:9 MeOH/CHCl
3
). IR (thin film) 3335, 2242, 1657 cm .
H-NMR (400 MHz, CDCl ):  7.14-7.09 (m, 2H), 6.84-6.80 (m,
H), 4.76 (dd, J = 6.8, 6.6 Hz, 1H), 4.08-4.04 (m, 1H), 3.98 (dd,
J = 7.1, 6.9 Hz, 1H), 3.96 (dd, J = 7.2, 6.9 Hz, 1H), 3.52-3.49 (m
1H), 3.41 (s, 2H), 3.38-3.34 (m, 1H), 2.91 (dd, J = 7.1, 6.5 Hz,
1
3
1
3
2
(dd, J = 7.1, 6.6 Hz, 2H), 2.18–2.06 (m, 4H). C-NMR (100
MHz, CDCl ): δ 170.4, 157.6 (d, J = 237 Hz, 1C), 154.7, 118.2,
3
,
115.7, 115.5, 115.4, 70.8, 68.5, 52.2, 51.2, 46.3, 45.3, 29.6, 24.9
+
1
4
1
2
1
H), 2.82 (dd, J = 7.1, 6.4 Hz, 1H), 2.22 (s, 3H), 2.20-2.06 (m,
ppm. ESI-MS m/z (rel int): (pos) 322.1 ([M+H] , 100); (neg)
13
–
+
H). C-NMR (100 MHz, CDCl
3
): δ 170.4, 156.6, 130.6, 126.7,
320.1 ([MH] , 100). HRMS (ESI): Calculated for: C16
H21FN
3
O
3
:
26.6, 120.6, 118.2, 111.0, 70.0, 68.6, 52.3, 51.3, 46.3, 45.3,
322.15615, found: 322.15596. Absolute difference (ppm): 0.59.
+
9.7, 25.0, 16.2 ppm. ESI-MS m/z (rel int): (pos) 318.2 ([M+H] ,
–
00); (neg) 316.2 ([MH] , 100). HRMS (ESI): Calculated for:
(2S)-1-((3-(3,4-difluorophenoxy)-2-hydroxypropyl)glycyl)
+
3
C
17
H
24
N
3
O
: 318.18122, found: 318.18104. Absolute difference
pyrrolidine-2-carbonitrile
(11aa):
Method A.
2-((3,4-
(
ppm): 0.55.
difluorophenoxy)methyl)oxirane (150 mg, 0.81 mmol) and amine
a (185 mg, 1.21 mmol). Purification by silica gel chromatography
(
2S)-1-((3-(benzyloxy)-2-hydroxypropyl)glycyl)pyrrolidine-2-
(
isocratic, 4% MeOH/CHCl
3
) produced amino alcohol 11aa
0.28 (1:9 MeOH/CHCl ).
H-NMR (400 MHz,
):  6.96 (dd, J = 9.3, 5.7 Hz, 1H), 6.68 (ddd, J = 9.3, 6.4,
.8 Hz, 1H), 6.55 (dd, J = 6.4, 5.6 Hz, 1H), 4.71 (dd, J = 7.1, 6.6
Hz, 1H), 3.96 (ddt, J = 7.1, 6.8, 6.6 Hz, 1H), 3.81 (d, J = 6.8 Hz,
carbonitrile (8aa): Method A. 2-((benzyloxy)methyl)oxirane
150 mg, 0.91 mmol) and amine a (210 mg, 1.37 mmol).
Purification by silica gel chromatography (isocratic, 4%
MeOH/CHCl ) produced amino alcohol 8aa (252 mg, 87%) as a
clear oil. TLC: R 0.29 (1:9 MeOH/CHCl ). IR (thin film) 3333,
242, 1657 cm . H-NMR (400 MHz, CDCl 7.38-7.32 (m,
(
246 mg, 90%) as a clear oil. TLC: R
f
3
(
-1
1
IR (thin film) 3332, 2243, 1653 cm .
CDCl
3
3
f
3
5
-1
1
2
5
1
3
H), 4.77 (dd, J = 6.8, 6.6 Hz, 1H), 4.57 (s, 2H), 3.87-3.81 (m,
H), 3.54-3.47 (m, 3H), 3.41 (s, 2H), 3.38-3.34 (m, 1H), 2.80
2H), 3.50 (dt, J = 6.8, 6.4 Hz, 1H), 3.41 (s, 2H), 3.32 (dt, J = 6.8,
6
.4 Hz, 1H), 2.80 (dd, J = 7.1, 6.4 Hz, 1H), 2.71 (dd, J = 6.6, 6.4
(
dd, J = 7.1, 6.6 Hz, 1H), 2.68 (dd, J = 7.3, 6.6 Hz, 1H), 2.28-
1
3
1
3
Hz, 1H), 2.24-2.06 (m, 4H).
3
C-NMR (100 MHz, CDCl ): δ
2
1
4
1
C
(
3
.13 (m, 4H). C-NMR (100 MHz, CDCl ): δ 170.4, 138.0,
170.4, 154.9, 149.7 (d, J = 246 Hz, 1C), 144.3 (d, J = 238 Hz,
28.3, 127.7, 127.6, 118.2, 73.3, 72.6, 69.0, 52.3, 51.2, 46.3,
+
5.3, 29.7, 25.0 ppm. ESI-MS m/z (rel int): (pos) 318.2 ([M+H] ,
1C), 118.2, 117.1,116.9, 109.8, 109.7, 104.2, 70.9, 68.3, 52.1,
–
00); (neg) 316.2 ([MH] , 100). HRMS (ESI): Calculated for:
51.2, 46.3, 45.3, 29.7, 24.9 ppm. ESI-MS m/z (rel int): (pos)
+
3
+
–
17
H
24
N
3
O
: 318.18122, found: 318.18179. Absolute difference
3
40.2 ([M+H] , 100); (neg) 338.2 ([MH] , 100). HRMS (ESI):
ppm): 1.81.
+
Calculated for: C16
H
20
F
2
N
3
O
3
: 340.14672, found: 340.14725.
Absolute difference (ppm): 1.53.
(
2S)-1-((2-hydroxy-3-(4-methoxyphenoxy)propyl)glycyl)
(9aa): Method A.
methoxyphenoxy)methyl)oxirane (150 mg, 0.83 mmol) and
amine (191 mg, 1.25 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl ) produced amino
alcohol 9aa (258 mg, 93%) as a clear oil. TLC: R 0.28 (1:9
pyrrolidine-2-carbonitrile
2-((4-
(
2S)-1-((2-hydroxy-3-(3,4,5-trifluorophenoxy)propyl)glycyl)
pyrrolidine-2-carbonitrile (12aa): Method A. 2-((3,4,5-
trifluorophenoxy)methyl)oxirane (150 mg, 0.73 mmol) and amine
a (169 mg, 1.10 mmol). Purification by silica gel chromatography
a
3
f
1
-
1
(isocratic, 4% MeOH/CHCl
3
) produced amino alcohol 12aa
0.26 (1:9 MeOH/CHCl ).
H-NMR (400 MHz,
): δ 6.53 (dd, J = 9.5, 5.9 Hz, 2H), 4.73 (dd, J = 7.1, 6.8
MeOH/CHCl
400 MHz, CDCl
Hz, 1H), 4.04-4.00 (m, 1H), 3.96 (s, 2H), 3.76 (s, 3H), 3.52 (dt, J
6.8, 6.6 Hz, 1H), 3.41 (s, 2H), 3.38 (dt, J = 6.8, 6.6 Hz, 1H),
.93-2.84 (m, 2H), 2.78-2.72 (m, 2H), 2.26-2.08 (m, 4H).
3
). IR (thin film) 3332, 2241, 1658 cm . H-NMR
(
234 mg, 89%) as a clear oil. TLC: R
f
3
(
3
): δ 6.88-6.78 (m, 4H), 4.75 (dd, J = 7.1, 6.8
-1
1
IR (thin film) 3317, 2245, 1657 cm .
CDCl
3
=
Hz, 1H), 4.04 (ddt, J = 7.1, 6.8, 6.4 Hz, 1H), 3.87 (d, J = 6.8 Hz,
2H), 3.50 (dt, J = 6.8, 6.4 Hz, 1H), 3.45 (s, 2H), 3.32 (dt, J = 6.8,
2
1
3
3
C-NMR (100 MHz, CDCl ): δ 170.5, 153.9, 152.7, 118.2,
6
.4 Hz, 1H), 2.88 (dd, J = 7.1, 6.4 Hz, 1H), 2.73 (dd, J = 6.8, 6.4
1
4
1
C
(
15.5, 115.4, 114.6, 114.5, 70.8, 68.6, 55.6, 52.2, 51.3, 46.4,
1
3
+
3
Hz, 1H), 2.31-2.11 (m, 4H). C-NMR (100 MHz, CDCl ): δ
5.3, 29.8, 25.0 ppm. ESI-MS m/z (rel int): (pos) 334.2 ([M+H] ,
–
170.4, 152.8 (d, J = 240 Hz, 1C), 151.2 (d, J = 233 Hz, 1C),
134.6 (d, J = 224 Hz, 1C), 118.2, 99.3, 99.2, 71.0, 68.1, 52.0,
00); (neg) 332.2 ([MH] , 100). HRMS (ESI): Calculated for:
+
4
17
H
24
N
3
O
: 334.17613, found: 334.17552. Absolute difference
5
1.2, 46.4, 45.3, 29.7, 25.0 ppm. ESI-MS m/z (rel int): (pos)
ppm): 1.84.
+
–
358.1 ([M+H] , 100); (neg) 356.1 ([MH] , 100). HRMS (ESI):
+
Calculated for: C16
19 3 3 3
H F N O : 358.13730, found: 358.13691.
(
2S)-1-((3-(4-fluorophenoxy)-2-hydroxypropyl)glycyl)
(10aa): Method A.
fluorophenoxy)methyl)oxirane (150 mg, 0.89 mmol) and amine a
Absolute difference (ppm): 3.9.
pyrrolidine-2-carbonitrile
2-((4-
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European Journal of Organic Chemistry
10.1002/ejoc.201600969
FULL PAPER
(
2S)-1-((2-hydroxy-3-(naphthalen-1-yloxy)propyl)glycyl)
bond between Pro-AMC thus releasing the fluorescent
aminomethylcoumarin (AMC). The inhibitors, DPP4 enzyme and
substrate were dissolved in the 100 mM HEPES buffer (pH 7.5,
pyrrolidine-2-carbonitrile (13aa): Method A. 2-((naphthalen-1-
yloxy)methyl)oxirane (150 mg, 0.75 mmol) and amine a (172
mg, 1.12 mmol). Purification by silica gel chromatography
(
(
IR (thin film) 3320, 2239, 1658 cm .
CDCl
7
6
J = 7.1, 6.8 Hz, 2H), 4.15 (dddd, J = 7.1, 6.8, 6.6, 6.4 Hz, 1H),
3
1
(
0
.1 mg/ml BSA). Inhibitor stock concentration was dissolved in
00% DMSO followed by working serial dilution starting at 1%
isocratic, 4% MeOH/CHCl
249 mg, 94%) as a yellow oil. TLC: R
3
) produced amino alcohol 13aa
0.25 (1:9 MeOH/CHCl ).
H-NMR (400 MHz,
): δ 8.26 (d, J = 5.8 Hz, 1H), 7.76 (d, J = 5.8 Hz, 1H), 7.49-
.45 (m, 2H), 7.41 (d, J = 6.4 Hz, 1H), 7.29 (t, J = 6.4 Hz, 1H),
.79 (d, J = 5.8 Hz,1H), 4.68 (dd, J = 7.1, 6.2 Hz, 1H), 4.22 (dd,
1
f
-
3
1
1
DMSO. The final concentrations of enzyme and substrate used
were 0.003 ng/µL and 50 µM, respectively. The assay was
performed in an opaque 384-Well plate with final volume of 100
µL in all wells. All samples were assayed in triplicates. A
background well was created with 10 µL of Gly-Pro-AMC
substrate plus 90 µL buffer; a 100% activity well was created
with 10 µL of DPP4 enzyme and 10 µL of Gly-Pro-AMC
substrate plus 80 µL buffer; and inhibitor wells were created with
3
.45-3.41 (m, 3H), 3.19-3.15 (m, 1H), 3.05 (dd, J = 7.1, 6.6 Hz,
1
3
H), 2.93 (dd, J = 6.8, 6.6 Hz, 1H), 2.22-1.98 (m, 4H). C-NMR
): δ 170.4, 154.2, 134.3, 127.4, 126.3, 125.8,
100 MHz, CDCl
3
1
25.4, 125.2, 121.8, 120.4, 118.2, 104.9, 70.2, 68.6, 52.3, 51.3,
1
0 µL of DPP4 enzyme, 10 µL of inhibitor and 10 µL Gly-Pro-
4
6.3, 45.2, 29.6, 24.9 ppm. ESI-MS m/z (rel int): (pos) 354.2
+
–
(
[M+H] , 100); (neg) 352.2 ([MH] , 100). HRMS (ESI):
AMC substrate plus 70 µL buffer. The order of the addition to the
well was buffer, enzyme, inhibitor and finally the substrate to
initiate the reaction. The plate was covered and centrifuged for
+
Calculated for:
Absolute difference (ppm): 1.69.
20 24 3 3
C H N O : 354.18122, found: 354.18062.
3
0 seconds at 800xg followed by incubation for 30 mins at 37°
(
2S)-1-((2-hydroxy-3-phenylpropyl)glycyl)pyrrolidine-2-
C. The fluorescence was the measured on the SpectraMax M5
with excitation wavelength of 360 nm and emission wavelength
of 460 nm with an auto cut-off wavelength setting on the
instrument at 37° C. IC50 values were analyzed using Graphpad
Prism 6 by a fit of reaction rates to a four-parameter Hill
equation by nonlinear regression.
carbonitrile (14aa): Method A. 2-benzyloxirane (150 mg, 1.12
mmol) and amine a (257 mg, 1.68 mmol). Purification by silica
gel chromatography (isocratic, 4% MeOH/CHCl
3
)
produced
0.26
amino alcohol 14aa (289 mg, 90%) as a clear oil. TLC: R
f
-1
(
1:9 MeOH/CHCl
3
). IR (thin film) 3334, 2241, 1655 cm .
1
3
H-NMR (400 MHz, CDCl ): δ 7.29-7.18 (m, 5H), 4.73 (dd, J =
6
2
1
1
4
1
.9, 6.6 Hz, 1H), 3.89 (dt, J = 6.8, 6.4 Hz, 1H), 3.54-3.50 (m,
H), 3.38 (s, 2H), 2.82-2.73 (m ,4H), 2.59 (dd, J = 6.9, 6.6 Hz,
1
3
3
H), 2.37-2,13 (m, 4H). C-NMR (100 MHz, CDCl ): δ 170.4,
Acknowledgements
38.4, 129.3, 128.2, 126.1, 118.2, 70.7, 54.9, 51.0, 46.3, 45.2,
+
1.3, 29.7, 24.9 ppm. ESI-MS m/z (rel int): (pos) 288.2 ([M+H] ,
The donors of the American Chemical Society Petroleum
Research Fund financially supported these research efforts. We
are also thankful to Dr. John F. Eng at Princeton University for
his help with HRMS analysis.
–
00); (neg) 286.2 ([MH] , 100). HRMS (ESI): Calculated for:
+
2
C
16
H
22
N
3
O
: 288.17065, found: 288.17032. Absolute difference
(
ppm): 1.17.
(
2S)-1-((3-(furan-2-ylmethoxy)-2-hydroxypropyl)glycyl)
Keywords: DPP4 • Cyanopyrrolidines • Epoxide Opening • β-
Amino Alcohols • Diabetes Therapeutics
pyrrolidine-2-carbonitrile (15aa): Method A. 2-((oxiran-2-
ylmethoxy)methyl)furan (150 mg, 0.97 mmol) and amine a (224
mg, 1.46 mmol). Purification by silica gel chromatography
[
1] Del Prato, S.; Barnett, A. H.; Huisman, H.; Neubacher, D.;
(
isocratic, 4% MeOH/CHCl
3
) produced amino alcohol 15aa (257
0.28 (1:9 MeOH/CHCl ). IR (thin
film) 3363, 2243, 1652 cm . H-NMR (400 MHz, CDCl ): δ 7.38
s, 1H), 6.28-6.26 (m, 2H), 4.71 (dd, J = 6.9, 6.5 Hz, 1H), 4.42
s, 2H), 3.78 (ddt, J = 7.1, 6.8, 6.4 Hz, 1H), 3.52-3.49 (m, 2H),
Woerle, H.-J.; Dugi, K. A.Diabetes Obes. Metab. 2011, 13,
mg, 86%) as a clear oil. TLC: R
f
3
258−267.
-1
1
3
[2] World Health Organization, National Diabetes Statistics
Report, Fact sheet number 314, September 2014.
(
(
[
3] (a) Ahren, B. Exp. Opin. Emerging Drugs 2008, 13 (4),
93−607. (b) Zettl, H.; Schubert- Zsilavecz, M.; Steinhilber,
5
3
2
.43-3.41 (m, 2H), 3.38 (s, 2H), 2.71 (dd, J = 6.9, 6.2 Hz, 1H),
D. ChemMedChem 2010, 5, 179−185. (c) Devasthale, P.;
Wang, Y.; Fevig, J.; Feng, J.; Wang, A.; Harrity, T.; Egan,
D.; Morgan, N.; Cap, M.; Fura, A.; Klei, H. E.; Kish, K.;
Weigelt, C.; Sun, L.; Levesque, P.; Moulin, F.; Li, Y.-X.;
Zhaler, R.; Kirby, M. S.; Hamann, L. G. J. Med. Chem.
2013, 56, 7343-7357.
13
.60 (dd, J = 6.5, 6.2 Hz, 1H), 2.24-2,08 (m, 4H). C-NMR (100
): δ 170.4, 168.1, 157.3, 151.4, 142.7, 118.2, 110.2,
09.4, 72.3, 68.9, 65.1, 56.5, 52.1, 51.2, 46.4, 45.3, 29.7, 25.0
MHz, CDCl
1
3
+
ppm. ESI-MS m/z (rel int): (pos) 308.2 ([M+H] , 100); (neg)
3
–
06.2 ([MH] , 100).
[
4] (a) Dhillon, S. Drugs 2010, 70 (42), 489−512. (b) Kim, D.;
Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He,
H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyon, K.;
Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.;
Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M.
J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. J.
Biochemical DPP4 Assay: The enzymatic inhibition of DPP4
was measured in vitro by the endpoint fluorometric assay using
substrate Gly-Pro-AMC (MW: 329.4). The enzyme cleaves the
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600969
FULL PAPER
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Madar, D. J.; Kopecka, H.; Pireh, D.; Yong, H.; Pei, Z.; Li,
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o
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European Journal of Organic Chemistry
10.1002/ejoc.201600969
FULL PAPER
Layout 2:
FULL PAPER
DPP4 Inhibitors*
Joseph R. Lizza, Savan V. Patel,
Catherine F. Yang and Gustavo Moura-
Letts*
Page No. – Page No.
Direct Synthesis of Cyanopyrrolidinyl
β-Amino Alcohols for the
Development of Novel Diabetes
Therapeutics
This study demonstrates a novel synthetic approach for the efficient and selective
synthesis of cyanopyrrolidinyl amino alcohols from easily accessible starting
materials. The biochemical studies on these analogues have shown that the
proposed scaffold is highly potent against DPP4 and opens the door for the
development of libraries of cyanopyrrolidinyl amino alcohols as competitive
diabetes therapeutics.
*Novel DPP4 inhibitors by highly selective synthesis of Cyanopyrrolidinyl β-Amino Alcohols
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