Synthesis of novel and conformationally constrained bridged amino acids as compact modules for drug discovery

Article abstract of DOI:10.1016/j.tetlet.2015.12.097

As novel scaffolds with rigid inherent three-dimensional conformation, the bridged amino acid building blocks containing both morpholine and pyrrolidine motifs, 2-oxa-5-azabicyclo[2.2.1]heptane-4-carboxylic acid 1 and 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 2, were first synthesized as compact modules for future applications in the optimization of physicochemical and pharmacokinetic properties of drug candidates in drug discovery.

Full text of DOI:10.1016/j.tetlet.2015.12.097

Accepted Manuscript
Synthesis of Novel and Conformationally Constrained Bridged Amino Acids as
Compact Modules for Drug Discovery
Guolong Wu, Buyu Kou, Guozhi Tang, Wei Zhu, Hong C. Shen, Haixia Liu,
Taishan Hu
PII:
S0040-4039(15)30512-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.097
TETL 47144
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 October 2015
13 December 2015
24 December 2015
Please cite this article as: Wu, G., Kou, B., Tang, G., Zhu, W., Shen, H.C., Liu, H., Hu, T., Synthesis of Novel and
Conformationally Constrained Bridged Amino Acids as Compact Modules for Drug Discovery, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.097
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Synthesis of Novel and Conformationally
Constrained Bridged Amino acids as
Compact Modules for Drug Discovery
†
†
Guolong Wu , Buyu Kou , Guozhi Tang, Wei Zhu, Hong C. Shen, Haixia Liu* and Taishan Hu*
Bridged building blocks
Fragments

1
Tetrahedron Letters
Synthesis of Novel and Conformationally Constrained Bridged Amino Acids as
Compact Modules for Drug Discovery
†
†
Guolong Wu , Buyu Kou , Guozhi Tang, Wei Zhu, Hong C. Shen, Haixia Liu and Taishan Hu
Roche Pharmaceutical Research & Early Development, Department of medicinal chemistry, Roche Innovation Center Shanghai, 720 Cailun Road, Building 5,
Pudong, Shanghai, P. R. China, 201203
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
As novel scaffolds with rigid inherent three-dimensional conformation, the bridged amino acid
building blocks containing both morpholine and pyrrolidine motifs, 2-oxa-5-
azabicyclo[2.2.1]heptane-4-carboxylic acid 1 and 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic
acid 2, were first synthesized as compact modules for future applications in the optimization of
physicochemical and pharmacokinetic properties of drug candidates in drug discovery.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Amino acid
Bridged building block
Compact module
Conformationally constrained
There has been increasing awareness of drug-like properties
in the medicinal chemistry community since Lipinski’s seminal
1
paper on “rule of five”. As key determining factors for quality of
2
small-molecule drug candidates, physicochemical properties
have important impact on compound’s performance in humans
related to ADMET (absorption, distribution, metabolism3,
excretion and toxicity) characteristics and target engagement.
Optimization of physicochemical and pharmacokinetic properties
of drug candidates should occur early and could be as important
as that of target affinity and selectivity. A number of
Aprepitant
Finafloxacin
4
computational approaches for compound property prediction are
Bridged amino acids
utilized to guide compound selection and optimization.
Nevertheless, the optimization process of small molecular entities
remains a considerable challenge. One way to address this issue
is to develop building block libraries which cover a broad range
of scaffolds with distinct properties and can be readily
incorporated into drug candidates to modulate compound
profiles. The recent identification of novel and diversified
Lisinopril
Perindopril
Asenapine
Figure 1. Parmaceuticals containing aliphatic heterocycles, bridged amino
9
acids of interest and their calculated lowest energy conformations
Morpholine and pyrrolidine, as very popular scaffolds in
medicinal chemistry, are widely applied in marketed drugs
5
7
8
building blocks, such as spirocyclic and oxetane containing
(Figure 1). And their carboxylic acid substituted derivatives, as
in the case of Lisinopril and Perindopril in Figure 1, are also
widely used in the drug discovery. To modulate conformational
constraint of those fragments, we are particularly interested in a
series of bridged amino acids such as compounds 1 and 2
6
modules, opens up new chemical space and offers multiple
options for medicinal chemists to manipulate physicochemical
and pharmacokinetic properties and eventually improve quality of
small-molecule drug candidates.
(
Figure 1). Conformational analysis shows that the [2.2.1]-
bridging pattern in compound 1 locks morpholine in a boat-like
conformation, while [3.2.1]-bridging pattern in
—
——

Corresponding authors.
Tel.: +86-21-38954910; fax: +86-21-50790292;
E-mail: haixia.liu@roche.com (H. Liu)
taishan.hu@roche.com (T. Hu)
†
These authors contribute equally to the work.

2
Tetrahedron
1
I
III
(
)
n
n = 1 or 2
2
II
IV
Figure 2. Retrosynthetic analysis of bridged amino acids 1 and 2
9
o
compound 2 adopts a chair-like conformation (Figure 1). In
addition, the inherent out-of-plane three dimensionality of the
bridged scaffold may have advantages over traditional flat
15min; (g) TBAF, THF, 80 C, overnight; (h) oxalyl chloride, DMSO, Et
3
N,
O;
o
CH
2
Cl
2
, -78 C to rt; (i) NaClO
2
, NaH
2
PO
3
∙2H
2
O, cyclohexane, t-BuOH/H
2
o
(j) BnBr, K
2
CO
3
, DMF, 60 C; (k) Pd/C, H
2
, MeOH.
10
(
hetero)aromatic ring systems. Moreover, the conformation
The synthesis of compound 1 commenced with the allylation
of diethyl 2-(N-(tert-butoxycarbonyl)amino)malonate 3 with allyl
restriction of the bridged systems may help reduce entropy
penalty upon binding to a target protein. So it is very worthwhile
to develop an efficient synthesis of those conformational
restricted motifs and explore their impact to physicochemical and
pharmacokinetic properties, which to the best of our knowledge,
are not reported in the public domain. Herein we report the first
synthesis of the two novel bridged α-amino acids with distinct
11
bromide (Scheme 1), which was followed by N-Boc-
deprotection and benzylation to afford compound 4 with modest
yield over three steps. The ethyl esters of compound 4 were
reduced with LiAlH to yield diol, which was further protected
4
with tert-butyldimethylsilyl (TBS) group to afford compound 5.
The subsequent halogen-mediated cyclization of homoallyl
amine 5 was investigated with NBS in acetonitrile at room
temperature. The reaction proceeded very fast, and presumably
both 4-exo azetidine 6 and 5-endo pyrrolidine 7 could be formed
rigid
conformations,
2-oxa-5-azabicyclo[2.2.1]heptane-4-
and 3-oxa-8-azabicyclo[3.2.1]octane-5-
carboxylic acid
1
carboxylic acid 2.
12
The retrosynthetic analysis of the bridged bicyclic scaffolds 1
and 2 is illustrated in Figure 2. In general, similar synthetic
approaches were adopted for both building blocks. The
morpholine ring formation could be achieved via an
according to the literature report. However, we were unable to
characterize those potential products due to decomposition of the
crude mixture during silica gel chromatography. Therefore, the
crude mixture was directly used in the next step and treated with
TBAF at elevated temperature. As expected, the TBS
deprotection and morpholine ring formation took place in one-pot
to afford the desired bridged scaffold 8 as the only isolated
product. Here we assumed intermediate 6 could be converted to
intermediate 7 via an unstable and reactive aziridinium bromide
N
intramolecular S 2 reaction. The key intermediates I and II were
synthesized by
a
halogen-mediated ring cyclization of
intermediates III and IV, respectively. The latter two, in turn, can
be prepared in a few steps from commercially available N-Boc-
aminomalonate and alkenyl bromides.
13
1
0, and 7 was the actual precursor for compound 8. The free
primary hydroxyl group in compound 8 was further transformed
14
a, b,c
to carboxylic acid in moderate yield by Swern oxidation and
15
5
5%
successive Pinnick-Lindgren oxidation . To facilitate the
purification, the carboxylic acid was masked as a less polar and
easily handled benzyl ester to provide compound 9. Global
deprotection under catalytic hydrogenation condition furnished
the final building block 2-oxa-5-azabicyclo[2.2.1]heptane-4-
carboxylic acid 1.
3
4
6
5% d, e
f
Next we investigated the synthesis for building block 2
2
(Scheme 2). Olefin 12 with one more CH unit was successfully
prepared according to similar procedures as the synthesis of
compound 5. Treatment of 12 with NBS led to complete
consumption of the starting material as monitored by TLC.
Interestingly, a mass corresponding to aziridinium 14 was
detected by LC/MS. However, the following one-pot
deprotection and morpholine ring formation in the presence of
TBAF was very sluggish and only trace amount of the desired
product 15 was observed by LC/MS. We speculated that the
bromide 13 was unstable as the basic nitrogen could readily
attack the neighboring bromine-bearing carbon to form a [3.1.0]
bicyclic aziridinium bromide 14. Unfortunately, upon treatment
with TBAF at high temperature, the presumed aziridinium 14
was decomposed to give a complex mixture. In contrast, bromide
7
6
5
g
29%
h-j
2%
k
4
90%
1
8
9
1
0
7
was relatively stable and probably had low propensity to form a
much more constrained [2.1.0] bicyclic aziridinium salt 10 under
the same condition (Scheme 1). To address this problem, we
envisioned to trap the potential aziridinium species 14 with an
Scheme 1. Preparation of compound 1. Reagents and conditions: (a) NaH,
o
allybromide, THF, 80 C; (b) TFA, CH
CH CN; (d) LiAlH , THF; (e) TBSCl, Et
2
Cl
2
; (c) benzyl bromide, K
2 3
CO ,
3
4
3
N, CH
2
Cl ; (f) NBS, CH CN, rt,
2
3

3
external nucleophile, and then diminish the nucleophilicity of the
nitrogen by switching N-benzyl protecting group to unreactive N-
carbamate before the intramolecular etherification. Thus
addition, these structures contain both embedded morpholine
and pyrrolidine thus serving as novel replacement of either motif
in medicinal chemistry. The unique conformations and their
potential impacts on biological activity upon incorporation into
small molecule drug candidates will add further value into both
scaffolds. In the future design and synthesis, the location of the
carboxyl group could be tuned and placed to β- or γ- position of
the nitrogen which would provide further opportunities to
modulate basicity of the nitrogen and control the relative
orientation of substituents on both nitrogen and carboxyl group.
The application of these two building blocks in drug discovery is
ongoing, and their impacts on physicochemical properties as well
as pharmacokinetics will be evaluated and disclosed in due
course.
compound 12 was treated with I
then NaOAc at elevated temperature. To our delight, compound
6 was obtained in 45% isolated yield presumably via
regioselective opening of the aziridine ring at the less hindered
2 3
in the presence of NaHCO and
1
16
position by acetate. Further N-Bn and O-Ac deprotection
reactions were followed by N-Boc protection to give alcohol 17
in 89% yield. The free hydroxyl group of 17 was converted to O-
Ts leaving group, and the following one-pot TBS-deprotection
and morpholine ring formation proceeded uneventfully in the
o
presence of TBAF at 60 C with moderate yield. Again the free
alcohol of compound 18 was oxidized to carboxylic acid via
1
7
15
Dess-Martin oxidation and then Pinnick-Lindgren oxidation .
The final N-Boc deprotection furnished compact module 3-oxa-
8
-azabicyclo[3.2.1]octane-5-carboxylic acid 2 with 45% yield
Acknowledgments
over 3 steps.
The work was supported by Hoffmann-La Roche AG. The
authors would like to thank Ms Leimin Wang for NMR studies,
Dr. Wenzhe Lv and Mr. Sheng Zhong for high resolution MS
studies.
(
)2
a-c
8%
4
3
11
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o
bromo-1-butene, THF, 80 C; (b) TFA, CH
2
Cl
2
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2
CO
3
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CH
3
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, THF; (e) TBSCl, imidazole, CH
2
Cl
2
; (f) NBS, CH
3
CN,
o
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, NaHCO
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, CH
3
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o
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