A reagent based DOS strategy via Evans chiral auxiliary: Highly stereoselective Michael reaction towards optically active quinolizidinones, piperidinones and pyrrolidinones

Article abstract of DOI:10.1039/c2ra22115b

In the present study, we have demonstrated the diversity oriented synthesis of nitrogen heterocycles viz. chiral piperidinones, quinolizidinones and diaryl pyrrolidinones from Michael adducts generated via a TiCl₄-catalyzed highly stereoselecti

Full text of DOI:10.1039/c2ra22115b

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PAPER
A reagent based DOS strategy via Evans chiral auxiliary:
highly stereoselective Michael reaction towards
optically active quinolizidinones, piperidinones and
pyrrolidinones3
Cite this: RSC Advances, 2013, 3,
2404
Subhabrata Sen,*a Siva R. Kamma,ab Rambabu Gundla,a Uma Adepally,b
Santosh Kuncha,b Sridhar Thirnathia and U. Viplava Prasadc
In the present study, we have demonstrated the diversity oriented synthesis of nitrogen heterocycles viz.
chiral piperidinones, quinolizidinones and diaryl pyrrolidinones from Michael adducts generated via a
TiCl4-catalyzed highly stereoselective Michael reaction with nitrostyrenes and an Evans chiral auxiliary. We
also reported a Cu-4,4’-(isopropyl)-substituted isopropylidene-bridged 2,2’-bis-1,3’-oxazoline catalyst
mediated catalytic asymmetric version of this reaction. In silico analysis is utilized to evaluate the diversity
of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug
like properties (viz. HBA, HBD, PSA, mol. wt., log P and log D). Finally, the molecules were screened against
microorganisms to assess their antimicrobial properties.
Received 11th September 2012,
Accepted 12th December 2012
DOI: 10.1039/c2ra22115b
www.rsc.org/advances
demonstrated the utility of this reagent-based approach as a
DOS strategy by the preparation of multiple heterocyclic
scaffolds.
Piperidinone, quinolizidinone and pyrrolidinone motifs are
Introduction
Chemical synthesis of small molecules has recently undergone
a paradigm shift (including the evolving area of diversity-
oriented synthesis (DOS)) in the generation of an architectu-
rally diverse set of organic molecules for the identification of
new ligands for a variety of biological targets.1 The diversity
oriented synthetic (DOS) methodology utilized a combination
of building block-, appendage-, stereochemical-, and skeletal-
diversity to access structurally unique compounds.2 Among
these, skeletal diversity is the most difficult to achieve, and at
the same time is considered the most useful technique,
because it provides distinct molecular scaffolds that occupy
different regions of chemical space.3 Skeletal diversity is
commonly achieved either by (a) a substrate-based approach
key structural subunits of naturally occurring biologically
active molecules.5–7 They are abundant among complex
alkaloid natural products and are used as key intermediates
for the synthesis of a variety of pharmaceutical candidates.
Hence, we were interested in strategizing a DOS based
methodology for these kinds of scaffolds. These scaffolds
adhere to the rule of three as closely as possible (M , 300; HBD
¡ 3 and HBA ¡ 3; clogP = 3; number of rotatable bonds ¡ 3;
polar surface area = 60 Å2). These parameters are generally
accepted to be the most appropriate in creating fragment
libraries.8 Both linear racemic and chiral synthesis of these
scaffolds have been reported in the past.9 However, to the best
of our knowledge, this is the first reagent-based enantioselec-
tive DOS methodology that allows access to these structurally
diverse molecular scaffolds through the common chiral imides
1, 10–12 and 14 (Scheme 1). In this regard, we report a highly
stereoselective TiCl4 catalyzed Evans–Michael reaction, with a
variety of nitrostyrenes, to generate the key intermediates 2,
15–21 and 23. We achieved skeletal diversity on these via an
asymmetric cascade reaction with cyclic and acyclic imines (to
generate the chiral piperidinone and quinolizidinone scaf-
folds), and in situ hydrogenation and lactamization (to
generate the chiral diaryl pyrrolidinones). Facile removal of
the chiral auxiliary (Evans’ oxazolidinone) makes this an
extremely efficient asymmetric pathway to access these
that employs
a common set of reagents to elaborate
functionally and structurally unique precursors or (b) a
reagent-based method that utilizes a common intermediate
that when subjected to a variety of reaction conditions or
reagents, affords different scaffolds.4 In this article we have
aPlot 28A, IDA Nacharam, Hyderabad, India. E-mail: subhabrata.sen@gvkbio.com;
organic6@hotmail.com; Fax: 91 40 2715 2999; Tel: 91 40 6628 1529
bInstitute of Science and Technology, JNTU Kukatpally, Hyderabad, Andhra Pradesh,
India
cDepartment of Organic Chemistry and FDW, Andhra University, Vizag, India.
E-mail: viplav_31049@yahoo.com
Electronic supplementary information (ESI) available. CCDC 899422. For ESI
3
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ra22115b
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Scheme 1 Diversity oriented synthesis of N-heterocycles.
scaffolds. We also demonstrated a successful catalytic asym-
metric version of Michael addition and amination on the
achiral analog 13 with a Cu-4,4’-(isopropyl)-substituted iso-
propylidene-bridged 2,2’-bis-1,3’-oxazoline catalyst (Scheme 2).
The highlight of our methodology is a 2-step synthesis of
three distinct natural product-inspired scaffolds. The metho-
dology also executed via the catalytic asymmetric Michael
addition has an attractive steps-per-scaffold efficiency to provide
access to chemically complex molecules. We further evaluated
our scaffolds via in silico studies, followed by screening them
against five pathogens.
To optimize the Michael addition, 1 was treated with
nitrostyrene in THF in the presence of various bases and
temperatures (Table 1). With a mild base like potassium
carbonate (K2CO3, 1.2 equiv.) in THF at room temperature no
Table 1 Michael reaction of nitrostyrenes
Results and discussion
The key starting material 1 was synthesized via a literature
protocol.10a
No. Base (equiv.)
T (uC)
Lewis acid
Yield (%)a drb
1
2
3
4
5
6
7
8
9
K2CO3 (1.2 eq.)
NaH (1.2 eq.)
LHMDS (1 eq.)
KHMDS (1 eq.)
rt
—
—
—
—
—
0
43
48
54
50
0
0–rt
278
"
60 : 40
62 : 38
65 : 35
65 : 35
80 : 20
65 : 35
88 : 12
95 : 5
NaHMDS (1 eq.)
"
—
—
—
—
278–0 BF3-Et2 (0.2) 56
278–0 Et2AlCl (0.2) 42
278–0 TiCl4 (0.1)
278–0 TiCl4 (0.3)
25
75
a
b
Isolated yield. Based on HPLC.
Scheme 2 Catalytic asymmetric Michael reaction.
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reaction was observed, while a significant amount of the
unreacted starting material was detected by LC-MS (Table 1,
entry 1). With NaH (1.2 equiv.) in THF (0 uC to rt) the desired
product was obtained in a moderate yield (y43%) and poor
diastereoselectivity (60%) (Table 1, entry 2). Bases such as
LHMDS, KHMDS and NaHMDS (1.0 equiv.) (Table 1, entry 3–5)
marginally improved the yield (48–54%) and diastereoselec-
tivity (62–65%). These moderate results prompted us to search
for better conditions for the reaction. We opted for a catalytic
Lewis acid mediated procedure, where we converted the imide
1 to the corresponding silyl ketene imide 3 by TMSCl (TMSOTf
can also enable a similar transformation), followed by in situ
treatment with a series of Lewis acids (TiCl4, BF3-OEt2 and
Et2AlCl) (0.1–0.25 equiv.) and 1 equiv. of nitrostyrene at 0 uC
for 12 h. The summary of the results is shown in Table 1. BF3-
OEt2 (0.2 equiv., entry 6) mediated Michael addition afforded 2
in a 56% yield and in a 80 : 20 diastereomeric ratio (dr).
Et2AlCl did not promote the reaction as efficiently (entry 7).
The use of 0.1 equiv. of TiCl4 caused a significant reduction of
the yield (entry 8). Eventually, the best result of a 75% yield
and a 95 : 5 dr was obtained when we employed 0.3 equiv. of
TiCl4 (entry 9).
Fig. 1 X-ray crystal structure of compound 17.
The absolute stereochemistry of the Michael adducts were
determined by the single crystal X-ray of compound 17 (shown
in Fig. 1 and Table 2).
A catalytic asymmetric version of the Michael reaction has
also been developed, where 13 is converted to the correspond-
ing silyl ketene imide 4, which was then treated in situ with a
Cu-4,4’-(isopropyl)-substituted isopropylidene-bridged 2,2’-bis-
1,3’-oxazoline catalyst (0.3 equiv.) and nitrostyrene to generate
the Michael adduct 22 in a 50% yield and with a 92%
diastereoselectivity (Scheme 2). The results are yet to be
optimized. We are presently investigating several other
catalyst–ligand systems to improve the yields and the
diastereoselectivity.
To explore the generic nature of the titanium catalyzed
procedure, a variety of nitro olefins were reacted with several
chiral acyl oxazolidinones, 1, 10–12 and 14.10b–e The reaction
conditions are in accordance with the optimized conditions in
Table 1. We were pleased to observe the resulting Michael
adducts, 2, 15–21 and 23 in moderate to high yields (38–86%)
and high dr (81 : 19 A 99 : 1). The results are summarized in
Table 2.
With the desired Michael adducts in hand, three distinct
scaffolds were synthesized by applying a nitro-Mannich/
lactamization cascade and in situ hydrogenation and lactami-
zation. The nitro-Mannich/lactamization cascade constituted
Table 2 TiCl4 catalyzed Michael addition of various nitro olefins with chiral
an extension of Mu¨hlstadt’s nitro-Mannich chemistry.11 In this
¨
oxazolidines
regard 2 and 3,4-dihydroisoquinoline were chosen as the
reaction partners for the optimization study. The reactions
Table 3 Synthesis and optimization of the reaction conditions for quinolizidi-
nones
Entrya
Substrate
Product
Yield (%)b
drc
1
2
3
4
5
6
7
8
9
1
"
"
"
12
"
10
11
14
2, R2 = H
72
57
86
38
48
69
75
81
48
97 : 3
95 : 5
82 : 12
99 : 1
87 : 13
97 : 3
91 : 9
88 : 12
81 : 19
15, R2 = p-OMe
16, R2 = o-Cl
17, R2 = m-OMe
18, R2 = p-OMe
19, R2 = H
20, R2 = H
21, R2 = H
Entry
Solvents
Temp
Yield (%)a
drb
1
2
3
4
5
6
Toluene
IPA
THF
THF–H2O (1 : 1)
H2O
H2O
y4
18
12
28
25
71
—
67 : 33
—
—
88 : 12
95 : 5
23, R2 = H
reflux
100 uC
70 uC
a
Reaction conditions: imide (1.0 mmol), TMSCl (1.5 mmol),
NaHMDS (1.0 mmol), THF (5 mL), TiCl4 (0.3 mmol), 0 uC, 24 h.
b
c
Isolated yield. Determined by HPLC (refer to the supplementary
a
b
information).
Isolated yields. Diastereoselectivity.
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Fig. 2 Conversion of 25 to 26 over time.
were investigated in various solvents (overnight) (Table 3). At
high temperatures in solvents like toluene and THF (entry 1
and 3, respectively), the reactions were sluggish (after 16 h,
LCMS suggested a 4–12% conversion to the desired product).
With isopropanol (IPA) (entry 2), the conversion was also very
low with a 67 : 33 dr. On shifting the reaction to aqueous
medium we observed y28% of the desired product in 1 : 1
water–THF (under reflux) (entry 4). In water at 100 uC we
observed about a 25% yield of the desired product with 88 : 12
dr (entry 5). Finally, we were pleased to isolate the desired
quinolizidinone 24 in about a 71% yield and a 95 : 5 dr at y70
uC in water in a sealed vessel for about 16 h (entry 6).
Interestingly, we also observed the unsaturated analog 26 as
the byproduct with the desired compound 25 (Table 3). On
close monitoring of the reaction by HPLC, we observed that
after about 7–10 h, y90% of 25 (represented by graph A in
Fig. 2) is formed, with about 5% of the unsaturated compound
26 (represented by graph B in Fig. 2).
Fig. 4 Normalized ratios of principal moments of inertia plotted in two
dimensional triangular graphs (NPR-analysis) using drug candidates and our
compounds.
isolated as the single product by the prolonged heating of 19
with dihydroisoquinoline (Fig. 3).
Piperidinones 24, 27–29, 31 and 37 were successfully
synthesized from imines I–V (generated in situ by reacting
ammonium acetate with the appropriate aldehydes) by
treating them with 2 in the presence of ethanol (Scheme 3).
The absolute stereochemistry of the quinolizidinones/piper-
idinones were determined by NOE of the representative
compound 24 (Fig. 3).12
A third class of heterocyclic compounds, pyrrolidinones 34–
36, were synthesized by converting the nitro adducts 2, 15 and
23 by hydrogenation followed by in situ lactamization
(Scheme 4).
With various scaffolds in hand we set out to evaluate the
skeletal diversity that is afforded by the N-heterocycles and
their related chemical descriptors, via in silico algorithms. By
virtue of possessing its own set of drug like properties, each
molecule possesses a unique point in the chemical space.
Hence, the larger the span of coverage of the chemical space by
a collection of molecules, the greater is their diversity. In order
to assess the diversity of the reported compounds we plotted
them in chemical space plots corresponding to a set of six drug
like properties (PSA, solubility, HBA, HBD, log A and log D),
relative to the 1011 FDA approved drugs as reported in the
After y15 h, y70% of 25 (plot A) and y20% of 26 (plot B)
are generated. On further heating, the unsaturated product 26
increased and after about 36 h the desired quinolizidinone 25
is completely converted to 26 (Fig. 2). In a similar approach, we
obtained 33 along with 30, and in a separate reaction 32 was
Fig. 3 Quinolizidinones and piperidinones.
Scheme 3 Synthesis of the pyrrolidinones.
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In addition to shape, space and in silico analysis of the drug
like properties, the polar surface area of a small molecule is
also a relevant descriptor for diverse biologically active
molecules involved in ligand–receptor binding. There are
several reports where a different orientation of heteroatoms in
a small molecule generates a diverse polar surface area. This
results in a difference in response towards key covalent
interactions viz. H-bonding and electrostatic interactions etc.,
and in turn displays a diverse biological activity. Hence, polar
surface areas of 25, 26, 32 and 34 (representing the different
classes of scaffold) were plotted. Surface electrostatic profiles
were calculated by projecting the Gasteiger–Marsili charge
Scheme 4 Synthesis of the pyrrolidinones.
distribution onto
a Connolly surface generated via the
MOLCAD tool in SYBYL. The scaffolds we synthesized had a
PSA that ranges between acceptable values of CNS and non-
CNS orally active drugs. Fig. 5 shows our scaffolds that are
between 25–168 Å2, indicating their diverse shapes and
electron densities, which allow our scaffolds to be potential
biological modulators over a wide gamut of therapeutic
targets.16
GOSTAR database.13 The plots demonstrated that our collec-
tion of molecules covered a substantial area in the chemical
space (Fig. 6). They also did not cluster together with the
corresponding nitro adducts that they were derived from.
Additionally, quinolizidinones, piperidinones and pyrrolo-
dinones were plotted according to the normalized principal
moment of inertia (PMI) formalism of Sauer and Schwartz.14
The molecular shape and biological activity are interconnected
and correlated. The principal moments of inertia (PMI) is a
topological descriptor and normalized ratios of the principal
moments of inertia (NPR) can be considered to describe the
molecular shape of the compounds. It is an expedient and
visual way to showcase diversity corresponding to the area of
Another objective of this investigation was to develop
strategies to synthesize compounds that have the potential to
be biologically active. We understand that it is unrealistic to
expect to generate bioactive molecules by using synthetic
methods that are not directed towards any biological target. At
the same time we hoped that our molecules may provide hits
that are useful for further elaboration into drug leads.
Pyrrolidinone, quinolizidinone and piperidinone frameworks
randomly feature in natural products, which show antibacter-
ial activity. Therefore, we decided to screen our compounds
against five bacterial strains, Pseudomonas aeruginosa,
Klebsiella pneumonia, Staphylococcus aureus, Enterococcus fae-
calis and Escherichia coli. Anti-microbial activity was deter-
mined by the well diffusion method as per the National
Committee for Clinical Laboratory Standards [National
Committee for Clinical Laboratory Standards (NCCLS), 1993,
Performance Standards for effects Antimicrobial Disc
Susceptibility Tests]. The pour plate method of microbial
inoculation was conducted using 30 ml of microbial culture for
25–30 ml of Mueller–Hinton agar medium. Wells of 5 mm
diameter were punched using a borer, and our molecules (0.2
mg dissolved in 20 ml of DMSO) were added to each well. The
wells containing the solvent DMSO served as negative controls
and Ciprofloxacin was used as a positive control. The plates
were incubated at 37 uC for 24 h. The anti-microbial activity of
the compounds was assessed by measuring the diameter (mm)
of the zone of inhibition around the well and by calculating
chemical space covered by a collection of molecules.14
A
screening collection has a high degree of molecular shape
diversity built in, which increases the probability of a wide
range of biological activity. The PMI calculation involved
aligning each molecule to the principal moment axes in SYBYL
and then normalized PMI values were calculated by a software
developed in-house.15 In this regard Fig. 4 exhibits a large
coverage of shape space for our N-heterocycles 24–32, which
were derived from the Michael adducts 2 and 15–23, thereby
demonstrating the diversity achieved by this methodology. Our
collection of molecules can be segregated into three classes of
scaffolds; piperidinones (24, 27, 28, 29, 31), quinolizidinones
(25, 26, 30, 32 and 33) and pyrrolidinones (34–36).
The plot demonstrates that the FDA approved drugs cover
the left edge of the PMI space and so do our collection of
molecules (taking shapes intermediate between rods and
discs). They cover a wide area, thereby demonstrating the
diversity achieved via our methodology.
Fig. 5 Polar surface area (PSA) of our collection of molecules.
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Fig. 6 Comparison of the in silico generated med-chem attributes between our compound selection and y1000 FDA approved drugs.
the area of inhibition (pR2 2 pr2, where R is the radius of the
zone of inhibition and r is the radius of the well).
20 mm against all the tested bacteria. The relative inactivity of
our molecules against the pathogens S. Aureus and E. Coli
indicates selective inhibition (32, which is the most active in
our collection, shows an activity of 10 mm in both).
As indicated in the table above, among the molecules in our
collection 24, 32, 33 and 35 showed significant activity against
various bacterial species. This is further illustrated in Table 5
containing the MIC (minimum inhibitory concentration)/MBC
(minimum bactericidal concentration) of our compounds,
which were determined on the organisms that showed
maximum susceptibility to our compounds. Even though this
is not a medicinal chemistry study, these results do establish
Results obtained in the present study revealed that our
tested compound collection possess potential antibacterial
activity against P. Aeruginosa, K.Pneumonia, S. Aureus, E.
Faecalis and E. Coli (Table 4). In general, our compound
collection viz. 24, 27, 30, 31, 32, 33 and 35 showed significant
activity against P. Aeruginosa. The highest activity of 20 mm
was exhibited by 32 and the lowest of 10 mm by 31 and 27.
Compound 24, 32 and 33 were active against K. Pneumonia,
with the highest activity of 15 mm exhibited by 33.
Piperidinone 27 and the unsaturated quinolizidinone 32 along
with pyrrolidinones 34 and 35 also exhibited activity against E.
Faecalis. 32 showed a varied zone of inhibition from 7 mm to
that this is
a viable strategy for the rapid access of
architecturally diverse scaffolds suitable for biological screen-
Table 4 Antibacterial activity of our compounds against bacterial species tested by a well diffusion assay
Diameter (mm)/zone (mm2) of inhibition
Microrganism
Compounds
P. Aeruginosa
K. Pneumoniae
S. Aureus
E. Faecalis
E. Coli
24
27
28
29
30
31
32
33
12.1/93.3
10.1/58.9
9.4/43.8
9.5/51.2
—
10.2/58.9
20/294.4
14/134.2
11/75.4
9/43.9
10/58.9
—
—
—
—
—
12/93.4
15/157.0
—
8/18.8
—
8.5/37.1
7/18.8
—
7.3/18.9
7/18.8
8.1/30.6
6.9/18.6
—
9/43.9
8/30.6
—
7.1/18.8
—
9.1/58.9
7.4/19.2
10.1/58.9
9.1/43.9
—
7.1/18.9
8.1/30.6
8.4/31.2
6.1/8.6
7.1/18.8
13/113.1
12/93.4
14/134.2
10/58.9
13.4/113.0
35
37
—
—
Ciprofloxacin
14.02/134.2
15.03/157.1
14/134.2
19.2/283.4
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Table 5 Determination of MIC and MBC by the tube dilution method
Compounds
Organism
MIC (mM)
MBC (mM)
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24
27
28
29
31
32
33
30
35
37
P. Aeruginosa
"
"
"
"
"
"
E. Coli
E. Faecalis
"
1.58 ¡ 0.1
1.62 ¡ 0.1
0.63 ¡ 0.03
0.76 ¡ 0.03
0.61 ¡ 0.03
0.83 ¡ 0.02
1.56 ¡ 0.08
1.40 ¡ 0.07
1.45 ¡ 0.07
0.62 ¡ 0.03
3.16 ¡ 0.15
3.24 ¡ 0.16
2.52 ¡ 0.12
3.04 ¡ 0.15
2.44 ¡ 0.12
3.32 ¡ 0.16
3.12 ¡ 0.15
2.8 ¡ 0.14
2.91 ¡ 0.14
1.24 ¡ 0.06
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ings, which can provide activities ideal for further investiga-
tion as potential lead compounds for med-chem programmes.
Conclusion
In summary, we have developed an efficient TiCl4 catalyzed
method for the Michael addition of Evans oxazolidinones with
nitro olefins. We have also demonstrated a catalytic asym-
metric version of this reaction with good yields and decent
diastereoselectivity. To evaluate the potential of these nitro
adducts as building blocks for diversity oriented synthesis
(DOS) they were further converted to biologically relevant
heterocycles viz. quinolizidinones, piperidinones and pyrroli-
dinones under facile reaction conditions. In silico analysis is
utilized to evaluate the diversity of the set of compounds
against shape space (PMI), polar surface area (PSA) calcula-
tions and relevant drug like properties (viz. HBA, HBD, PSA,
mol. wt., log P and Log D). Finally, the molecules were
screened against microorganisms to assess their biological
activity.
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Acknowledgements
The authors acknowledge GVK Bioscience for the funding.
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