Pyrrolidine and piperidine based chiral spiro and fused scaffolds via build/couple/pair approach

Article abstract of DOI:10.1039/c3ra47714b

A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse heterocyclic small molecules is described. The strategy involved the build-couple-pair approach involving an S _NAr, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and spirocyclic nitrogen heterocycles. A post-pair phase has been incorporated to generate more polar compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the shape-space diversity of our scaffolds with respect to a commercial database and observed extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of our molecules which is an indicator for drug cell permeability.

Full text of DOI:10.1039/c3ra47714b

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PAPER
Pyrrolidine and piperidine based chiral spiro and
fused scaffolds via build/couple/pair approach†
Cite this: RSC Adv., 2014, 4, 10619
Rajinikanth Mamidala,b V. Surendra Babu Damerla,b Rambabu Gundla,b
c
d
a
*
M. Thirumala Chary, Y. L. N. Murthy and Subhabrata Sen
A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse
heterocyclic small molecules is described. The strategy involved the “build–couple–pair” approach
involving an SNAr, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed
by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and
spirocyclic nitrogen heterocycles. A “post-pair” phase has been incorporated to generate more polar
compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the
Received 17th December 2013
Accepted 1st February 2014
shape-space diversity of our scaffolds with respect to
a commercial database and observed
DOI: 10.1039/c3ra47714b
extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of
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our molecules which is an indicator for drug cell permeability.
described in this article. The bicyclic lactams 1a and 1b can be
generated easily from the condensation of (i) R-(6-hydroxy-
Introduction
methy)-piperidinone and (ii) R-pyroglutaminol with benzalde-
hyde.5 Followed by acylation with a-chloroformate to afford 2a
and 2b.6,7 These chiral acyl bicyclic lactams, by virtue of their
susceptability towards enolate mediated nucleophilic reactions
at the carbon a- to the amide bond are extremely popular
intermediates to synthesize various nitrogen and oxygen
heterocycles.8 In our case we coupled them (2a/2b) with
appropriate reagents via an array of efficient intermolecular
reactions such as (i) Michael addition; (ii) aromatic nucleophilic
substitution (SNAr); and (iii) Mannich reaction, to generate
more densely functionalized scaffolds. Finally, functional group
(FG) pairing afforded skeletally and stereochemically diverse
scaffolds containing, disparate physicochemical properties
(Scheme 1).
Interactive abilities of small molecules with biomacromolecules
like DNA and RNA are a critical factor in analysing biological
processes.1 They form the fundamental platform of modern
pharmaceutical science. These supercial three-dimensional
interactions have inspired diversity oriented synthesis (DOS), to
design molecules that mimic them.2 Due to the unbiased nature
of DOS libraries they exhibit a varied range of physicochemical
and biological properties, and hence can be used for screening
to identify novel compounds.3
In recent years, build/couple/pair (B/C/P) algorithm of DOS
has evolved as an extremely successful technique to generate
architecturally and stereochemically diverse scaffolds.4 We
envisioned a collection of diverse shaped chiral spiro- and fused
scaffolds via the B/C/P strategy. Scheme 1 illustrates our strategy
where the “build” phase generates stereochemically diverse
chiral bicyclic lactams 1a and 1b as building blocks. In the
“couple” phase, the building blocks are equipped with orthog-
onal functionalities via enolisation–substitution and nal
“pairing” involved intramolecular cyclization onto the inbuilt
scaffold electrophile between the embedded functionalities to
generate higher order, more complicated structures.
We wanted our scaffolds to abide by the “rule of three” as
close as possible (M < 300; HBD # 3 and HBA # 3; c log P ¼ 3;
2
˚
number of rotatable bonds # 3; polar surface area ¼ 60 A ).
These are acceptable med-chem attributes for creating fragment
based libraries.9 Chiral synthesis of only cyclotryptamines (15a/
15) have been reported earlier.10 However, to the best of our
knowledge, this is the rst B/C/P based DOS methodology that
provides access to all of these structurally diverse molecular
scaffolds through common intermediates (1a and 1b).
The ready availability of these acyl bicyclic lactam precursors
from chiral aminols is key to the success of the B/C/P strategy
aDepartment of Chemistry, Shiv Nadar University, Dadri, UP, India. E-mail:
subhabrata.sen@snu.edu.in
bGVK Bioscience, 28A IDA Nacharam, Hyderabad, AP, India
cJNTU-H College, Nachupally, Karimnagar, AP, India
dAndhra University, Vishakhapatnam, AP, India
Results and discussion
The coupling phase of the strategy initiated with simple
alkylation of 1a, 2a and 2b with o-nitroarylbenzyl bromide to
generate the corresponding alkylated intermediates 3, 4 and 5
respectively (Scheme 2). Exo-3 which is obtained from
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47714b
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Scheme 1 The build/couple/pair strategy for the synthesis of novel spiro- and fused scaffolds.
Scheme 2 Scaffold 8, 9 and 10 from alkylation of chiral bicyclic lactam 1a, 2a and 2b.
o-nitrobenzylation of 1a, by ash column chromatography of publications.6 There we have also reported the relative cong-
1 : 1 exo–endo mixture was reduced to amine under hydroge- uration of 6 by single crystal X-ray analysis. We used 6 for the
nation condition (10% w/w Pd–C, H2 at atm. pr.) (Scheme 2). synthesis of spiroxoindolinones (via Pd–C mediated hydroge-
The crude amine was treated with lithium aluminium hydride nation of the nitro group on the benzene ring that led to an in
(LAH) at 50ꢀ and was transformed into a tetrafused carbocycle situ lactamization). Such hydrogenation was not an option for
8. We envisioned this conversion via an acyliminium cation our present effort. We envisioned an approach that would
mediated pathway as depicted in the Scheme 2. For repre- initiate with the ester reduction followed by the reduction of the
sentative purpose we chose to move ahead with the exo- nitro group and nally acylimine cation mediated cyclization of
diastereomer of 3 to generate 8, as shown in Scheme 2.
6. Careful exploration of reagents (viz. diisobutylaluminium
Intermediates 4 and 5 were generated with high diaster- hydride [DIBAL-H, no conversion], Red-Al [no conversion],
eoselectivity (diastereomeric ratio ꢁ98 : 2). The relative cong- super hydride [no conversion], borane–DMS [no conversion])
uration was established via NOE (refer ESI†). Hydrogenation of prompted us to identify LAH as the most suitable reducing
the aryl nitro groups, afforded the amines, which cyclize in situ agent which facilitated this transformation to 15a, all be it in
with the built in adjacent electrophilic carbonyl carbon of the extremely poor yield of 12% and 95 : 5 dr (Scheme 3).
ester to generate the spiro-compounds 9 and 10 with no loss of
chirality.
To access 7, chiral acyl bicyclic lactam 2b was treated with
NaH at 0 ꢀC and the resulting enolate was reacted with
For the synthesis of cyclotryptamine 15a we used arylated nitrostyrene. It was generated in decent yield (ꢁ66%) and
¨
intermediate 6, which was already reported in one of our early high diastereoselectivity (ꢁ95%). Finally using Multstadt's
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3D structures to identify global/local minima by applying the
CHARMm force eld. The resulting 3D structures were used to
calculate the three principal moments of inertia; the PMI values
are sorted in ascending magnitude, that is, I1, I2, and I3.
Normalized PMI ratios (NPR) were calculated by dividing the
two smaller PMI values (I1 and I2) by the largest PMI value (I3)
and generated two characteristic values for each compound (I1/
I3 and I2/I3). These values were plotted against each other and
the resulting graph formed an isosceles triangle that was
dened by its three corners, wherein the vector [I1/I3, I2/I3] was
equal to [1, 1], [0.5, 0.5], and [0, 1] (Fig. 1c) The three corners of
the isosceles triangle of the PMI plot are dominated by rods,
spheres, and discs, respectively (the shapes are representations
of the overall shape of the constituent molecules). FDA
approved drugs tend to occupy evenly over the shapes between
rods and discs. Fig. 1 shows the coverage and distribution of
majority of our scaffolds (1b, 8–9 and 12–16).
Scheme 3 Synthesis of cyclotryptamine 15a.
nitro-Mannich lactamization cascade we could transform 7
into the 5-5-6 spiro-scaffold 11.11 In this sequence 7 is reacted
with benzyl imine generated in situ by treating benzaldehyde
with ammonium acetate in ethanol at 80 ꢀC to afford the
desired product 11 as a single diastereomer (ꢁ99%) with 76%
yield. The relative conguration of the compound is derived
from NOE/1H NMR (refer ESI†) data and is depicted in the
scheme below (Scheme 4).
Along with shape, a DOS library should be prudent to
possess physical properties for screening and promote follow-
up chemistry. Transformational handle such as an alcoholic
group is deliberately incorporated in the nal compounds (12–
16). In addition to structural and stereochemical diversity, this
is a third diversity attribute in our library imbibed via a “post-
pairing phase.” This polar, alcohol group augment the solubility
of these compounds, and will also serve as hydrogen-bonding
donors (HBD) and acceptors (HBA), thereby improving binding
affinity against bio-macromolecular targets. Last but not the
least, this functional group was envisioned to facilitate scaffold
proliferation (growing and transformation) into drug-like
compounds.
Molecular architecture and biological activity go hand in
hand.12 Hence, screening libraries with higher degree of built-in
molecular-shape diversity transcribe into a greater probability
of discovering compounds with biological activity. In order to
assess the overall diversity level of our library we used a
computational method based on the normalized principal
moment of inertia (PMI) formalism of Sauer and Schwartz.13
The PMI calculations involved aligning each molecule to the
principal moment axes in SYBYL and the normalized PMI
values were calculated by using in-house soware. The
commercial compounds were the FDA-approved drugs curated
from the GOSTAR (GVK Bio Online Structure Activity
Relationship)™ database.14 These compounds along with our
scaffolds were imported into DS 3.1 and converted into 3D
structures. Energy minimization was performed for all of these
Our collection of scaffolds can be classied into two types of
architectures, spiro- (9–11 and 13, 14 and 16), and fused (8, 12,
15a and 15). The gure above illustrates a wide distribution of
our scaffolds across the PMI plot. It is noteworthy that majority
of the scaffolds (1b and 12–14) from the post pair phase overlay
on the same space as the FDA approved drugs, thereby
emphasizing their drug like attributes. However there are quite
a few outliers viz. 8, 9, 15 and 16. Interestingly these outliers
consisted of both the spiro- and fused compounds. The advent
of these outliers indicates a novel therapeutic domain that is yet
to be investigated. We further hope that the similar shapes of
some of our scaffolds to those of FDA-approved drugs will
increase the likelihood of discovering biologically relevant
molecules by using this method.
The polar surface area (PSA) of a molecule is the surface sum
of all polar atoms, viz. oxygen and nitrogen, and hydrogens
attached to them. In pharmaceutical chemistry it is a commonly
used metric for evaluating drug's cell permeability and an
important contributor to ligand/receptor binding at active sites.
˚
In general molecules with a PSA > 140 A is poor in permeating
Fig. 1 Assessment of the diversity of our scaffolds via polar moment of
Scheme 4 Conversion of Michael adduct 7 into 11.
inertia.
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Fig. 2 Polar surface area and electrostatic potential of our scaffolds.
˚
cell membranes. For molecules with PSA < 60 A are more likely potential biological modulators across a wide spectrum of
to penetrate the blood–brain barrier and are preferred to act on therapeutic targets (Fig. 2).
receptors in the central nervous system. In order to assess the
Finally in a bid to evaluate the diversity quotient of our
diversity of these scaffolds w.r.t their polar surface area we scaffold library (green squares) we compared them in scattered
calculated the electrostatic proles of the surfaces of our plots against randomly selected compounds from FDA
molecules by projecting the Gasteiger–Marsili charge-distribu- approved drugs (red circles), macrocyclic natural products
tion onto the Connolly surface that was generated by using the (solid blue triangles) natural product database (blue triangles)
MOLCAD tool in SYBYL and plotting the PSA distributions.15
A
and from commercial databases such as ChemDiv (green cross)
˚
˚
wide distribution of PSAs from 15 A to 240 A in addition, to and ChemBridge (blue square). The incorporation of these
diverse surface electrostatic potential maps indicate diverse additional compound sets in the analysis enables us to compare
shapes and electron-densities that allow these scaffolds to be the chemical space covered by the collections and also provides
Fig. 3 Principal Component Analysis (PCA) to assess the diversity of our library against various chemical database.
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ketyl under nitrogen and methylene chloride was freshly
distilled from calcium hydride under nitrogen. Analytical thin
layer chromatography was performed with Merck silica gel
plates (0.25 mm thickness) with PF254 indicator. Compounds
were visualized under UV lamp or by iodine treatment. Column
chromatography was carried out on 60–120 mesh silica gel with
technical grade solvents, which were distilled prior to use.
1H NMR spectra were recorded on Bruker 300 Ultrashield™ at
300 MHz. 13C NMR spectra were obtained on the same instru-
ment at 75.5 MHz in CDCl3 solution with tetramethylsilane
(1H NMR spectra) and [D6]DMSO or CDCl3 (13C NMR spectra) as
an internal reference, unless otherwise stated. Chemical shis
(d) are reported in ppm. All 13C NMR spectra were measured
with complete proton decoupling. Data are reported as follows:
s ¼ singlet, d ¼ doublet, t ¼ triplet, m ¼ multiplet.
Scheme 5 Post pairing of the scaffolds.
Compound 4. A solution of monoacylated bicyclic lactam 2a
(443 mg, 1.53 mmol), was dissolved in THF (4 mL). Sodium
hydride (60% in mineral oil) (55 mg, 2.29 mmol) was added to
some perspective to the positions of the library compounds in
chemical space with respect to known biologically active
regions. 2D molecular descriptors (via MOE) viz. log P, PSA, HBA
(hydrogen bond acceptor), HBD (hydrogen bond donor) and etc.
of all these compounds were calculated, followed by principal
component analysis (PCA) of the values were obtained.16 Fig. 3
exhibits a scatter plot of the compound collections. From the
plots it is quite obvious that our library compounds cover a
relatively large area of chemical space, indicating the successful
incorporation of a high degree of molecular diversity into the
synthesis.
ꢀ
ꢀ
the reaction mixture at ꢂ5 C. The mixture was stirred at 0 C
for 20 minutes. 2-Nitrobenzylbromide (1.99 mmol, 428 mg) was
then added to the reaction mixture at the same temperature
under N2. The mixture was allowed warm to rt and was stirred
for 1 h under N2. Once TLC (thin layer chromatography)
conrms the complete consumption of the starting material,
the reaction mixture was quenched with water (10 mL). It was
then diluted with ethyl acetate (10 mL) and the organic phase
was separated, dried with anh. Na2SO4, concentrated in vacuo
and subjected to ash column chromatography (eluted with
20% EtOAc in petroleum ether) to yield 5 (487 mg, 75%) as a
colourless liquid. 1H NMR (400 MHz, CDCl3): d 1.12–1.19 (t, 3H),
1.99–2.21 (m, 2H), 3.53–3.62 (m, 3H), 3.63–3.95 (m, 3H), 4.21–
4.35 (m, 2H), 7.28–7.35 (m, 3H), 7.36–7.42 (m, 5H), 7.43–7.48
(m, 1H), 7.86–7.88 (m, 1H); 13C NMR (100 MHz, CDCl3): d 171.9,
169.5, 135.2, 137.9, 129.7, 129.7, 128.7, 128.4, 126.0, 125.9, 88.3,
88.1, 71.7, 57.9, 56.9, 53.0, 51.8, 51.0, 27.6, 27.5; LCMS (ES+)
exact mass calculated for [M + H]+ (C23H24N2O6) requires (m/z)
425.1634 found (m/z) 425.50.
Conclusions
Herein we have reported B/C/P based facile DOS synthesis of
novel and privileged spiro- and fused scaffolds from pyrroldine
and piperidine based chiral auxiliaries. The diversity of scaffold
library when assessed via PMI and PCA against FDA approved
drugs demonstrated a wide coverage of chemical space. A post
pairing phase generated scaffolds with polar handle that facil-
itates further proliferation of these scaffolds into novel drug like
compounds. The apogee of our methodology is a three-step
synthesis of ten distinct natural-product-inspired scaffolds.
This methodology has excellent steps per scaffold efficiency of
1.7 whilst generating chemically complex molecules (Scheme 5).
Compound 5. A solution of monoacylated bicyclic lactam 2b
(1.53 mmol, 400 mg), was dissolved in THF (4 mL). Sodium
hydride (60% in mineral oil) (55 mg, 2.29 mmol) was addedꢀto
ꢀ
the reaction mixture at ꢂ5 C. The mixture was stirred at 0 C
for 20 minutes. 2-Nitrobenzylbromide (1.99 mmol, 428 mg) was
then added to the reaction mixture at the same temperature
under N2. The mixture was allowed warm to rt and was stirred
for 1 h under N2. Once TLC (thin layer chromatography)
conrms the complete consumption of the starting material,
the reaction mixture was quenched with water (10 mL). It was
Experimental section
General information
All reactions were carried out under an atmosphere of nitrogen then diluted with ethyl acetate (10 mL) and the organic phase
in ame-dried glassware with a magnetic stirrer. Reactive was separated, dried with anh. Na2SO4, concentrated in vacuo
liquids were transferred by syringe or cannula and were charged and subjected to ash column chromatography (eluted with
to the reaction ask through rubber septa. Common chemicals 20% AcOEt in pet. ether) to yield 5 (527 mg, 87%) as a colourless
1
were obtained from Sigma-Aldrich Chemical Company and liquid. H NMR (400 MHz, CD3OD): d 2.39–2.45 (m, 1H), 2.54–
used without purication. Compounds 1a, 1b, 2a, 2b, 3 and 6 2.59 (m, 1H), 3.53–3.62 (m, 3H), 3.74 (s, 1H), 3.77–3.79 (s, 3H),
were prepared by a standard literature protocol.16 Lithium 4.14–4.20 (m, 1H), 6.13 (s, 1H), 7.26–7.29 (m, 2H), 7.33–7.38 (m,
hexamethyldisilylamide (LDA) was obtained from Spectrochem 5H), 7.39–7.44 (m, 1H), 7.86–7.88 (d, J ¼ 8 Hz, 1H); 13C NMR
Ltd. and used without purication. Tetrahydrofuran (THF) was (100 MHz, CD3OD) d 175.6, 172.5, 151.9, 139.4, 134.1, 133.7,
freshly distilled prior to use from sodium and benzophenone 131.4, 129.8, 129.5, 129.4, 127.1, 125.8, 88.2, 72.9, 63.0, 57.8,
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53.6, 35.7, 33.2; LCMS (ES+) exact mass calculated for [M + H]+ 6.88 (d, J ¼ 8 Hz, 1H), 6.98–7.02 (m, 1H), 7.16–7.19 (m, 2H),
(C21H20N2O3) requires (m/z) 397.1321, found (m/z) 397.02.
7.28–7.42 (m, 3H), 7.51–7.58 (m, 2H), 8.15 (s, 1H); 13C NMR
Compound 7. A solution of 2b (200 mg, 0.76 mmol) in THF (100 MHz, CDCl3): d 171.15, 167.30, 137.99, 135.96, 128.88,
(2 mL) was added to a solution of 1.2 eq. of LDA (98 mg, 128.68, 128.50, 127.69, 126.73, 126.40, 123.46, 121.54, 114.95,
0.91 mmol) (freshly prepared from diisopropylamine and n- 89.25, 72.64, 56.30, 50.10, 34.72, 28.01, 22.50; LCMS (ES+)
BuLi) at ꢂ78 ꢀC. The mixture was stirred at ꢂ78 ꢀC for 0.5 h. 1.5 exact mass calculated for [M + H]+ (C21H20N2O3) requires (m/z)
eq. of nitrostyrene (171 mg, 1.14 mmol) was added drop wise at 349.1474, found (m/z) 349.0.
ꢀ
ꢂ78 C under N2. The mixture was allowed to stir at rt for 1 h
Compound 10. Compound 5 (0.505 mmol, 200 mg) was
under N2 until the starting material was consumed by TLC added to a solution of 10% Pd–C (20 mg) in methanol (2 mL) at
analysis. The mixture was diluted with ethyl acetate, extracted rt under N2 and the mixture was hydrogenated at 20 psi over a
with water (2 ꢃ 4 mL), dried with anh. Na2SO4 concentrated period of 6 h at rt. Once the reaction is over, the suspension was
under reduced pressure. The resulting residue was puried by ltered through celite pad, concentrated in vacuo. The crude
neutral alumina column chromatography (hexane–ethyl acetate was puried by ash column chromatography with 25% EtOAc–
¼ 80/20) to afford pure white solid (245 mg, 0.597 mmol) of 4, hexane as eluent to afford 10 as yellowish gummy solid (160 mg,
with 78% yield. Rf ¼ 0.6 (PE–AcOEt ¼ 70 : 30). 1H NMR 0.48 mmol) in 94% yield. Rf ¼ 0.45 (hexane–EtOAc ¼ 75 : 25). 1H
(400 MHz, CDCl3): d 1.95–2.00 (m, 1H), 2.61–2.81 (m, 2H), 3.8 (s, NMR (300 MHz, DMSO-D6): d 2.15–2.21 (m, 1H), 2.59–2.69 (m,
3H), 3.91–3.92 (m, 1H), 4.11–4.18 (m, 1H), 4.21–4.31 (t, J ¼ 2H), 3.16–3.20 (m, 1H), 3.51–3.61 (t, J1 ¼ 6 Hz, J2 ¼ 8 Hz, 1H),
2.6 Hz, 1H), 4.95–5.00 (m, 1H), 5.29–5.40 (m, 1H), 6.21 (s, 1H), 4.18–4.38 (m, 2H), 6.12 (s, 1H), 6.82–6.95 (m, 2H), 7.05–7.19 (m,
7.23–7.40 (m, 9H); 13C NMR (100 MHz, CDCl3): d 32.7, 46.9, 53.4, 2H), 7.32–7.42 (m, 5H), 10.44 (s, 1H); 13C NMR (100 MHz,
55.8, 63.5, 71.3, 86.9, 87.1, 125.9, 126.0, 128.5, 128.7, 128.8, DMSO-D6) 177.5, 140.2, 138.8, 130.1, 129.7, 129.3, 128.9, 127.4,
128.86, 128.9, 129.22, 129.25, 135.4, 137.5, 170.4, 171.7; HRMS 124.1, 122.5, 116.0, 88.6, 72.7, 57.6, 56.5, 49.8, 49.7; LCMS (ES+)
(ES+) exact mass calculated for [M + H]+ (C22H23N2O6) requires exact mass calculated for [M + H]+ (C20H18N2O3) requires (m/z)
(m/z) 411.1478, found (m/z) 411.1476.
335.1317, found (m/z) 335.01.
Compound 8. Compound 3 (207.91 mg, 0.59 mmol) was
Compound 11. Nitro adduct 7 (410 mg, 1.00 mmol),
added to a solution of 10% Pd–C (40 mg) in methanol (2 mL) at ammonium acetate (5 eq.) and benzaldehyde (0.15 mL,
rt under N2 and the mixture was hydrogenated at 20 psi over a 1.5 mmol) were taken in ethanol (5.4 mL) under nitrogen. The
period of 8 h at rt. The suspension was ltered through celite resulting mixture was heated in a sealed vessel and reuxed for
pad concentrated under reduced pressure to yield the crude 10 h. Aer which it was cooled to rt. The mixture was diluted
amine 3a which, was dissolved in THF (2 mL) and treated with with water and extracted with CH2Cl2 (10 mL ꢃ 3). The
LAH (1 M in THF) (23 mg, 0.60) at 0 ꢀC. The reaction mixture was combined extracts were dried over anhydrous sodium sulfate,
slowly warmed to rt and stirred for 4 h. Once TLC indicates the ltered, and concentrated under reduced pressure. The result-
total consumption of the starting material the reaction mixture ing residue was puried by silica gel column chromatography
was quenched with ethyl acetate (0.2 mL) ltered through celite (pet. ether–ethyl acetate ¼ 1/1) to afford 130 mg of pure product
1
pad and the ltrate was concentrated under reduced pressure. 11. H NMR (300 MHz, CDCl3): d 1.78–1.82 (t, J ¼ 8 Hz, 1H),
The resulting residue was puried by neutral alumina column 2.01–2.15 (dd, J ¼ 4 Hz, 1H), 2.92–3.01 (m, 1H), 3.81–3.88 (t, J ¼
chromatography (hexane–ethyl acetate ¼ 80/20) to afford pure 4 Hz, 1H), 3.99–4.10 (d, J ¼ 12 Hz, 1H), 4.16–4.21 (m, 1H), 5.10–
white solid (69 mg, 0.23 mmol), with 30% yield. Rf ¼ 0.42 5.15 (d, J ¼ 1.8 Hz, 1H), 5.98 (s, 1H), 6.51–6.61 (m, 1H), 7.28–
1
(hexane–EtOAc ¼ 70 : 30). H NMR (300 MHz, CDCl3): d 1.62– 7.52 (m, 15H); 13C NMR; 170.2, 161.8, 135.8, 133.1, 130.2, 129.1,
2.15 (m, 5H), 2.72–2.85 (m, 3H), 3.42–3.52 (m, 1H), 3.78– 128.8, 128.5, 127.4, 127.3, 127.1, 115.9, 115.7, 115.6, 114.9,
3.81 (m, 1H), 3.95 (s, 1H), 7.25–7.30 (m, 5H), 7.42–7.48 (m, 1H), 114.7, 92.1, 60.2, 56.1, 53.9, 52.8, 36.7, 28.4, 28.1; LCMS (ES+)
7.51–7.59 (m, 1H), 7.82 (s, 1H), 8.12–8.15 (d, J ¼ 4 Hz, 1H), exact mass calculated for [M + H]+ (C28H25N3O5) requires (m/z)
8.88 (s, 1H); 13C NMR (100 MHz, CDCl3): d 151.7, 134.3, 134.2, 484.1794, found (m/z) 483.79.
129.2, 128.8, 128.6, 127.3, 127.4, 127.0, 62.7, 57.5, 50.9, 33.0,
29.7, 29.6; LCMS (ES+) exact mass calculated for [M + H]+ solved in DCM (1 mL) treated with TFA (0.2 mL) at 0 ꢀC and
(C20H22N2O) requires (m/z) 307.1732 found (m/z) 306.94. stirred for 1 h at rt. The mixture diluted with dichloromethane
Compound 12. Compound 8 (153.2 mg, 0.5 mmol) was dis-
Compound 9. Compound 4 (200 mg, 0.47 mmol) was added (DCM) (10 mL) and was extracted with water (2 ꢃ 10 mL). The
to a solution of 10% Pd–C (20 mg) in methanol (2 mL) at rt organic phase was dried (Na2SO4), concentrated in vacuo and
under N2 and the mixture was hydrogenated at 20 psi over a subjected to ash column chromatography (eluted with 70%
period of 6 h at rt. Once the reaction is over, the suspension AcOEt in pet. ether) to yield 12 (60 mg, 55%) as a greyish solid. Rf
was ltered through celite pad, concentrated in vacuo. The ¼ 0.12 (hexane–EtOAc ¼ 70 : 30). 1H NMR (300 MHz, CDCl3): d
crude was puried by ash column chromatography with 25% 1.72–1.98 (m, 4H), 2.72–2.85 (m, 3H), 3.42–3.52 (m, 1H), 3.81 (s,
EtOAc–hexane as eluent to afford 9 as colourless gummy solid 2H), 7.51–7.59 (m, 1H), 7.61–7.68 (m, 1H), 7.72–7.78 (m, 1H),
(134 mg, 0.38 mmol) in 82% yield. Rf ¼ 0.35 (hexane–EtOAc ¼ 7.81–7.84 (m, 1H), 8.22–8.32 (m, 1H), 9.41 (s, 1H); 13C NMR
75 : 25). 1H NMR (300 MHz, CDCl3): d 1.51–1.72 (m, 2H), 1.95– (100 MHz, CDCl3): d 128.8, 128.5, 127.4, 127.3, 126.4, 124.6,
2.15 (m, 4H), 2.81–2.88 (d, J ¼ 24 Hz, 1H), 3.58–3.68 (t, J ¼ 124.5, 58.2, 55.9, 33.7, 33.1, 27.4, 25.8, 25.2, 23.2; LCMS (ES+)
12 Hz, 1H), 3.78–3.82 (d, J ¼ 18 Hz, 1H), 3.95–4.12 (m, 1H), exact mass calculated for [M + H]+ (C13H18N2O) requires (m/z)
4.32–4.39 (t, J1 ¼ 12 Hz, J2 ¼ 8 Hz, 1H), 6.45 (s, 1H), 6.78– 219.1419, found (m/z) 219.04.
10624 | RSC Adv., 2014, 4, 10619–10626
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Compound 13. Compound 9 (174 mg, 0.5 mmol) was dis-
RSC Advances
subjected to ash column chromatography (eluted with 70%
AcOEt in pet. ether) to yield 15 (10 mg, 90%) as a white solid. 1H
NMR (300 MHz, CDCl3): d 1.91–2.01 (m, 1H), 2.61–2.79 (m, 1H),
2.81–2.88 (m, 1H), 2.90–3.01 (m, 1H), 3.22–3.32 (d, J ¼ 12 Hz,
1H), 3.58–3.65 (m, 1H), 3.81–3.88 (m, 1H), 6.78–6.84 (m, 12H),
6.99–7.18 (m, 2H); 13C NMR (100 MHz, CDCl3): d 149.6, 136.4,
128.9, 128.6, 128.5, 128.4, 127.8, 124.0, 119.8, 111.7, 63.2, 60.8,
54.8, 51.4, 45.9, 29.6, 19.0.
solved in DCM (1 mL) treated with TFA (0.2 mL) at 0 ꢀC and
stirred for 1 h at rt. The mixture diluted with dichloromethane
(DCM) (10 mL) and was extracted with water (2 ꢃ 10 mL). The
organic phase was dried (Na2SO4), concentrated in vacuo and
subjected to ash column chromatography (eluted with 70%
EtOAc in hexane) to yield 13 (143 mg, 55%) as a white solid. 1H
NMR (100 MHz, CDCl3): d 1.88–2.12 (m, 2H), 3.10–3.18 (m, 2H),
3.31–3.42 (m, 1H), 3.55–3.75 (t, J ¼ 14 Hz, 1H), 4.02–4.18 (m,
1H), 4.31–4.41 (m, 1H), 4.42–4.52 (d, J ¼ 10 Hz, 2H), 4.78–4.81
(m, 1H), 7.02–7.42 (m, 5H), 8.02–8.38 (bs, 1H); LCMS (ES+) exact
mass calculated for [M + H]+ (C14H16N2O3) requires (m/z)
261.1161, found (m/z) 261.32.
Compound 16. Compound 11 (241 mg, 0.5 mmol) was dis-
solved in DCM (7 mL) treated with triuoroacetic acid (TFA) (1.5
mL) at 0 C and stirred for 1 h at rt. The mixture diluted with
ꢀ
dichloromethane (DCM) (25 mL) and was extracted with water
(2 ꢃ 30 mL). The organic phase was dried (Na2SO4), concen-
trated in vacuo and subjected to ash column chromatography
(eluted with 70% AcOEt in pet. ether) to yield 16 (130 mg, 80%)
as a colourless oil. 1H NMR (300 MHz, DMSO-D6) 1.41–1.49 (m,
1H), 1.81–1.86 (m, 1H), 2.82–2.92 (m, 1H), 3.80–3.85 (m, 1H),
4.09–4.15 (m, 1H), 4.19–4.21 (d, J ¼ 6 Hz, 1H), 4.98–5.01 (m, 1H),
Compound 14. Compound 10 (167.2 mg, 0.5 mmol) was
dissolved in DCM (1 mL) treated with TFA (0.2 mL) at 0 ꢀC and
stirred for 1 h at rt. The mixture diluted with dichloromethane
(DCM) (10 mL) and was extracted with water (2 ꢃ 10 mL). The
organic phase was dried (Na2SO4), concentrated in vacuo and
subjected to ash column chromatography (eluted with 70%
AcOEt in pet. ether) to yield 14 (68 mg, 55%) as a white solid. 1H
NMR (300 MHz, DMSO-D6) d 1.87–1.94 (m, 1H), 2.07–2.13 (m,
1H), 3.14–3.19 (q, 2H, J ¼ 5.1 Hz), 3.32–3.39 (m, 1H), 3.51–3.57
(m, 1H), 4.75–4.79 (t, 1H, J ¼ 5.7 Hz), 6.83–6.93 (m, 2H), 7.11–
6.36–6.42 (t, J ¼ 18 Hz, 1H), 7.21–7.59 (m, 10H), 7.82 (s, 1H). 13
C
NMR 170.5, 164.2, 139.1, 135.8, 128.1, 127.9, 127.6, 126.8, 126.5,
119.1, 118.9, 115.2, 93.8, 63.1, 55.9, 53.6, 53.5, 52.1, 37.6, 29.3,
29.2; LCMS (ES+) exact mass calculated for [M
+
H]+
(C21H21N3O5) requires (m/z) 396.1481, found (m/z) 396.1.
7.16 (m, 2H), 7.95 (bs, 1H), 10.23 (s, 1H), 10.85–11.1 (m, 1H); 13
C
NMR (75 MHz, CD3OD) d 35.0, 36.5, 52.7, 55.0, 66.4, 116.7,
123.2, 124.2, 129.3, 130.0, 138.7, 173.5, 178.3; LCMS (ES+) exact
mass calculated for [M + H]+ (C13H14N2O3) requires (m/z)
247.1004, found (m/z) 247.2.
Acknowledgements
We acknowledge GVK Bioscience for nancial support.
Compound 15a. To an ice-cooled solution of compound 6
(166.2 mg, 0.389 mmol) in dry THF (3 mL) was added LAH (98
mg, 2.55 mmol) under a stream of nitrogen gas in three almost-
equal portions. The ice bath was removed and the reaction
mixture was stirred at rt for 1 h and then at 50 ꢀC for next 2 h, by
which time, complete consumption of compound 6 had
occurred (TLC analysis). Then, the reaction mixture was cooled
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10626 | RSC Adv., 2014, 4, 10619–10626
This journal is © The Royal Society of Chemistry 2014