Reagent-based DOS: Developing a diastereoselective methodology to access spirocyclic- and fused heterocyclic ring systems

Article abstract of DOI:10.1002/asia.201200385

Herein, we report a diversity-oriented-synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N-heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N-heterocycles. The two-step sequence starts with a chiral-bicyclic-lactam-directed enolate-addition/substitution step. This step is followed by a ring-closure onto the built-in scaffold electrophile, thereby leading to stereoselective carbocycle- and spirocycle-formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug-like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell-lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry. Uno, DOS, tres: An enolate-mediated strategy was used to synthesize biologically relevant cyclic scaffolds. In silico analysis was used to evaluate the compounds in terms of, for example, polar surface area and chemical diversity. Copyright

Full text of DOI:10.1002/asia.201200385

DOI: 10.1002/asia.201200385
Reagent-Based DOS: Developing a Diastereoselective Methodology to
Access Spirocyclic- and Fused Heterocyclic Ring Systems**
V. Surendra Babu Damerla,[a, c] Chiranjeevi Tulluri,[b] Rambabu Gundla,[a, c] Lava Naviri,[a]
Uma Adepally,[b] Pravin S. Iyer,[a] Y. L. N. Murthy,[c] Nampally Prabhakar,[a] and
Subhabrata Sen*[a]
In memory of Dr. Albert I Meyers
Abstract: Herein, we report a diversi-
ty-oriented-synthesis (DOS) approach
for the synthesis of biologically rele-
vant molecular scaffolds. Our method-
ology enables the facile synthesis of
fused N-heterocycles, spirooxoindo-
lones, tetrahydroquinolines, and fused
N-heterocycles. The two-step sequence
starts with a chiral-bicyclic-lactam-di-
step. This step is followed by a ring-clo-
sure onto the built-in scaffold electro-
phile, thereby leading to stereoselective
carbocycle- and spirocycle-formation.
We used in silico tools to calibrate our
compounds with respect to chemical di-
versity and selected drug-like proper-
ties. We evaluated the biological signif-
icance of our scaffolds by screening
them in two cancer cell-lines. In sum-
mary, our DOS methodology affords
new, diverse scaffolds, thereby resulting
in compounds that may have signifi-
cance in medicinal chemistry.
Keywords: bicyclic compounds
biological activity fused-ring
systems · lactams · spiro compounds
·
·
rected
enolate-addition/substitution
Introduction
later Schreiber[3b] have pioneered library-generation by
using the DOS approach. Popular DOS strategies include
the build/couple/pair (B/C/P) concept pioneered by Nielsen
and Schreiber,[4] the “click, click, cyclize” strategy by
Hanson and co-workers,[6] and others by the groups of Park,
Shair, and Spring.[5]
Small molecules make excellent drugs because of their abili-
ty to modulate the functions of proteins in living systems.[1]
There is an ongoing effort in the chemical community to dis-
cover new chemical scaffolds that will access new chemical
space and reveal interesting biological activity. Diversity-ori-
ented synthesis (DOS) provides an ideal platform to access
new compounds and has demonstrated great utility in the
generation of structurally complex- and skeletally diverse
small molecules.[2] Efficient synthetic strategies, coupled
with rational design, leads to the generation of small mole-
cules with architectural diversity and complexity, as well as
acceptable physicochemical properties. Evans et al.[3a] and
Biologically active spirocyclic indoles, tetrahydroquino-
lines, and N-fused polycyclic ring-systems provide a good
platform to demonstrate the utility of our DOS methodolo-
gy.[7] Spiroxoindolines Elacomine and Horsfiline (Scheme 1)
are known to have multiple biological activities (as antima-
larial agents, inhibitors of p53:MDM2 receptors, and as anti-
microbial agents for both plant- and human pathogens).[8]
1,2,3,4-tetrahydroquinoline (THQ) structures (such as those
present in Oxamniquine, Nicainopril, and Virantmycin,
Scheme 1) are present in nature and exhibit antitumor- and
antibiotic properties, bradykinin antagonism, and activity
against a-adrenergic, histaminergic, and muscarinic recep-
tors.[9] Fused N-heterocycles show promising antiphlogistic
activity in rats.[10] We wanted to keep our scaffolds as close
to the “rule of three” as possible (M<300; HBDꢀ3 and
HBAꢀ3; clogP=3; number of rotatable bondsꢀ3; polar
surface area=60 ꢀ2). These parameters are generally ac-
cepted to be the most appropriate in creating libraries of
fragments.[11] Linear enantioselective syntheses of these scaf-
folds have been reported previously.[12] However, to the best
of our knowledge, this is the first reagent-based DOS meth-
odology that allows access to these structurally diverse mo-
lecular scaffolds through common intermediates (1 and 2).
We achieve skeletal diversity through a sequence that uses
either alkylation, Michael addition, or an SNAr reaction on
[a] V. S. B. Damerla, Dr. R. Gundla, L. Naviri, P. S. Iyer, N. Prabhakar,
Dr. S. Sen
GVK Biosciences Pvt Ltd.
Department of Medicinal Chemistry
28 A IDA Nacharam, Hyderabad (India)
Fax : (+91)4027152999
E-mail: Subhabrata.sen@gvkbio.com
[b] C. Tulluri, Prof. U. Adepally
Institute of Science and Technology
Jawaharlal Nehru Technological University
Kukatpally, Hyderabad, Andhra Pradesh (India)
[c] V. S. B. Damerla, Dr. R. Gundla, Prof. Y. L. N. Murthy
Department of Chemistry, Food, Drugs and Water
College of Science and Technology, Andhra University
Vishakhapatnam (India)
[**] DOS: Diversity-oriented synthesis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200385.
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a 9:1 diastereomeric ratio (the
diastereomers were separable
by column chromatography). In
turn, compound 2 was synthe-
sized by acylation of compound
1
with methyl chloroformate
and LDA at À788C.[13] By using
two different hydrogenation
conditions, the fused- and spiro
templates (4, 4a, 5, and 5a)
were readily synthesized. Initial
hydrogenation of compound 3
(H2-Pd/C, 10% w/w), followed
by in situ cyclization of the re-
Scheme 1. Biologically active spirooxoindoles, tetrahydroquinolines, and pyrroloquinolinolines.
chiral bicyclic lactams (1 and 2), followed by cyclization of
the intermediates (after reduction of the nitro group) to
give polycyclic systems. The highlight of our methodology is
a three-step synthesis of five distinct natural-product-in-
spired scaffolds. This methodology has an attractive steps-
per-scaffold efficiency whilst providing access to chemically
complex molecules.
sulting amine, provided the desired spirolactam (4a) and
fused bispyrrolidine (5a). Spirolactam 4a (70:30) was the
major product under neutral hydrogenation condition (with
EtOAc or isopropanol as the solvent). On the other hand,
during acidic hydrogenation (AcOH), the formation of com-
pound 5a was favored (60:40). Deprotection of the inter-
mediates (4a and 5a) with TFA generated compounds 4 and
5, respectively (Scheme 3).
In contrast, the synthesis of the interesting C7-aminoaryl-
substituted fused ring system was initiated by alkylation of
bicyclic lactam 1 with 2-nitrobenzylbromide in the presence
of LDA at À788C to generate compound 6 in 80% yield as
a 98:2 diastereomeric mixture (Scheme 4). NOE studies of
compound 6 confirmed the absolute configuration at the C7
position as S (see the Experimental Section). Reduction of
the nitro group with 3 equivalents of LAH, followed by in
situ cyclization, generated the desired fused system (7) in
Results and Discussion
Four unique bicyclic-lactam-based intermediates, com-
pounds 3, 6, 21, and 22, were made according to the proce-
dure shown in Scheme 2. Intermediate 3 was synthesized by
Michael addition of the enolate of acyl bicyclic lactam 2
(generated with lithium diisopropylamide (LDA) in THF)
to nitrostyrene at À788C in approximately 50% yield and
Scheme 2. Progression of the DOS methodology.
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Reagent-Based DOS of Spirocycles and Fused Heterocycles
good diastereoselectivity (>90%). The absolute configura-
tion of these molecules was established by X-ray crystallog-
raphy of one of the representative compounds (13) for
which the single crystal was generated in MeCN (Scheme 5).
Our group has previously established that C7-aminoaryl-
substituted spiro-oxoindolone systems are readily accessible
by nucleophilic aromatic substitution at the C7 position of
bicyclic lactam 2.[13] Accordingly, we reacted lactam 2 with
sodium hydride and electron-poor fluorobenzenes (2,4-nitro-
fluorobenzene
and
5-bromo-2,4-dinitrofluorobenzene),
which, in turn, generated the desired exo-arylated com-
pounds (21 and 22). X-ray crystallography analysis of com-
pound 21 (the single crystal was generated in MeCN) al-
lowed its unequivocal assignment (Scheme 6).[13] Reduction
of lactams 21 and 22 by using 10% Pd/C and ammonium
formate generated the desired spiro-oxoindolones (23 and
24, respectively). Final deprotection with TFA generated al-
cohols 25 and 26, respectively (Scheme 6).
We set out to determine the diversity in the chemical
space that was covered by our scaffolds by using in silico al-
gorithms. We wanted to evaluate their diversity quotient
with respect to commercial drugs. Thus, we compared our
molecules, in a scatter-plot, against 1011 FDA-approved
drugs (from our GOSTAR database).[14a]
Scheme 3. Michael-addition/cyclization-mediated synthesis of scaffolds 4,
4a, 5, and 5a.
We evaluated our library in terms of four parameters: hy-
drogen-bond donors (HBD), -acceptors (HBA), log D, and
polar surface area (PSA; Figure 1). Our compounds fell into
the most populated areas of the plots. The absence of outli-
ers suggests that this methodology yields compounds that
are inclined to have drug-like properties.[14b]
The plots indicate that the end compounds are significant-
ly diverged from the starting bicyclic lactams, thereby ex-
ploring new chemical space.
The polar surface area of a small molecule is an important
contributor to ligand/receptor binding at active sites. PSA
has a direct correlation with membrane-permeability and,
therefore, serves as a reliable indicator of drug-availability
across various biological barriers. Charge-distribution on
molecular surfaces also plays a significant role in binding-af-
finity to active sites. Therefore, we decided to calculate the
electrostatic profiles of the surfaces of our molecules by pro-
jecting the Gasteiger–Marsili charge-distribution onto the
Connolly surface that was generated by using the
MOLCAD tool in SYBYL and plotting the PSA distribu-
tions.[15] Our scaffolds had PSAs that spanned acceptable
values for CNS (central nervous system)- and non-CNS-pen-
etrating orally active drugs.[16] Scheme 7 shows four select
scaffolds that have a PSA range of 37–170 ꢀ2. In addition,
the surface electrostatic potential maps indicate diverse
shapes and electron-densities that allow these scaffolds to
be potential biological modulators across a wide spectrum
of therapeutic targets.
Scheme 4. Synthesis of rigid pyrroloquinoline scaffolds.
56% yield. Removal of the chiral auxiliary was achieved
upon treatment of compound 7 with trifluoroacetic acid
(TFA) to generate alcohol 8 in 86% yield.
We attempted to build in more diversity at this stage by
reducing compound 6 into the corresponding amine (9),
converting it into the benzaldehyde imine (10), and finally
subjecting it to a base-mediated 1,6-ring-closing intramolec-
ular addition to the imine. This process generated the corre-
sponding spirotetrahydroquinoline (11), which contained
a chiral quaternary C center. We attempted the cyclization
of the crude imine (10) with various bases (Et3N, K2CO3,
Cs2CO3, and KH) at various temperatures (70–808C) and
obtained the desired products in extremely low yield (2–
5%). However, by using microwave heating at 1608C with
tBuOK as the base, we obtained the desired product, spiro-
tetrahydroquinoline 11, in 76% yield and 95% de. Depro-
tection with TFA generated alcohol 12 in 67% yield. With
the optimized cyclization conditions in hand, we converted
several crude imines into their corresponding spirotetrahy-
droquinolines (11–20) in decent yields (about 65%) and
Another objective of our study was to develop methods
to prepare compounds that have the potential to be biologi-
cally active. We realize that it is unrealistic to expect to gen-
erate potent molecules by using synthetic efforts that are
not directed at a particular biological target. However, we
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hoped that our scaffolds may
provide hits that are useful for
further elaboration into drug
leads. Spirocyclic pyrrolidine
frameworks feature in marine
alkaloids, some of which show
anti-cancer activity. Therefore,
we decided to screen our com-
pounds against two cancer cell
lines to evaluate if they had any
bioactive potential. We used
the MCF-7 (breast cancer) and
HeLa (human epithelial) cell-
lines for biological evaluation.
The cell-lines were procured
from the Cell-Line Bank of the
National Center for Cellular
Sciences (NCCS), Pune, India.
These cells were cultured in
RPMI À1640, DMEM media
that contained 10% fetal
bovine serum (FBS) at 378C in
a CO2 incubator in the presence
or absence of test compounds.
Cytotoxicity was measured by
assay with 3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyl tetrazoli-
um bromide (MTT), according
to the method reported by
Mosmann in 1983.[17]
The cells in the exponential
phase of growth were exposed
to etoposide. The duration of
exposure is commonly deter-
Scheme 5. Synthesis of chiral tetarhydroquinolines from the 1,6-electrocyclization reaction.
Scheme 6. Synthesis of spirooxoindolones.
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Reagent-Based DOS of Spirocycles and Fused Heterocycles
Figure 1. Comparison of our molecules in terms of six drug-like properties relative to 1011 FDA-approved drugs from the GOSTAR database.
Scheme 7. Surface electrostatic potentials of compounds 4, 8, 11, and 23. These compounds were mutually aligned as shown. The surface corresponds to
the H2O-accessible Connolly surface and the color indicates the Gasteiger–Marsili charge-distribution: electronegative areas are in red, electropositive
areas are in blue.
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Table 1. Cellular evaluation of the compounds against the HeLa and MCF-7 cell-
lines.
mined as the time required for minimal damage to
occur, but is also influenced by the stability of the
drug. After removal of the drug, the cells are al-
lowed to proliferate for between two- and three
population-doubling times (PDTs) to distinguish
between cells that remain viable and are capable of
proliferation and those that remain viable but
cannot proliferate. The number of surviving cells is
then determined indirectly by reduction of MTT
dye. Once the MTT-formazan has been dissolved in
a suitable solvent, the amount of MTT-formazan
produced is determined spectrophotometrically.
The cells (2ꢂ104) were seeded in each well that
contained the medium (0.1 mL) in 96-well plates
(Greiner CELLSTAR, Sigma–Aldrich, Bangalore,
India). After 24 h, different test concentrations
(2.5–100 mgmLÀ1) were added and the cell-viability
was assessed. MTT (10 mL per well), at a concentra-
tion of 5 mgmLÀ1, was added into the wells and the
plates were incubated at 378C for an additional 4 h.
The medium was discarded and formazan blue,
which formed in the cells, was dissolved with di-
methyl sulfoxide (DMSO; 1 mL). The rate of color
production was measured at 570 nm in a spectropho-
tometer (Spectra MAX Plus; Molecular Devices;
supported by SOFTmax PRO-3.0). Etoposide and
DMSO were used as positive- and vehicle-controls,
respectively. The percentage inhibition of cell-via-
bility was determined with reference to the control
values. The data were subjected to linear-regression
Compound
Structure
Mw
PSA
IC50 [mm]
IC50 [mm]
HeLa cell-line MCF-7 cell-line
2
261.27
55.84
9.3
N
16.1
47.5
U
7
290.36
396.48
24.83
n.a.[a]
11
41.57 42.2
n.a.[a]
12
308.37
61.36
89.05
7.3
N
8.9
N
18
20
398.45
352.43
n.a.[a]
58.7
48.5
70.59 25.4
84.66 28.5
analysis and the regression lines were plotted to 23
obtain the best straight-line fit. The IC50 (inhibition
of cell viability) concentrations were calculated by
using the respective regression equation.
335.36
414.25
31.7
Of the fourteen compounds that were tested (2,
4a, 7–8, 11–20, 23, 24, and 26), nine showed some
potency (Table 1). Compounds 2, 12, and 26
showed reasonable potency in both cell-lines (7–
16 mm). Compounds 20 and 23 were significantly
less potent in both cell-lines. Compounds 7, 18, and
24 only showed weak potency against MCF-7 cells,
whereas compound 11 only showed weak potency
24
84.66
n.a.[a]
63.3
16.8
26
326.15 104.45 11.2
against HeLa cells. Whilst the sample size preclud-
ed firm determination of the structure activity rela-
tionship (SAR), a few trends do emerge: Activity is
[a] n.a.: not available.
reasonable for compounds that contain three rings
(compounds 2 and 26), less so for those that contain
four rings (compounds 12 and 18), and falls sharply for com-
pounds that contain five- or six rings (compounds 7, 11, and
23). Bicyclic lactams (except the core, compound 2) are sub-
optimal in terms of their potency (26 versus 23 and 24; 11
versus 12). Spirotetrahydroquinolines (12 versus 18 and 20)
do not appear to tolerate steric hindrance around the
Conclusions
In summary, we have developed a two-step sequence, start-
ing with a chiral-bicyclic-lactam-directed enolate-addition/
substitution reaction, thereby leading to the stereoselective
formation of carbocycles and spirocycles. A main objective
of this work, that is, to explore new- and diverse chemical
space, has been achieved (for ESP data, see Scheme 7; for
drug-like properties, see Figure 1). In addition, we have
demonstrated that these new scaffolds and their derivatives
À
phenyl THQ bond. We plan to use these observations to
design better inhibitors.
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Reagent-Based DOS of Spirocycles and Fused Heterocycles
(400 MHz, CDCl3): d=2.06–2.12 (dd, 1J=2.1 Hz, 2J=2.4 Hz, 1H), 2.21–
2.23 (t, J=7.6 Hz, 1H), 2.65–2.68 (m, 1H), 3.39–3.41 (m, 1H), 3.54–3.61
(m, 1H), 3.85–4.01 (m, 3H), 5.63 (s, 1H), 7.21–7.23 (m, 2H), 7.32–7.41
(m, 6H), 7.43–7.45 (m, 2H), 8.39 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=27.8, 44.0, 51.06, 55.93, 62.0, 70.7, 86.42, 125.97,127.93,
128.39, 128.47, 128.71, 129.65, 135.99, 138.90, 173.60, 174.57 ppm; HRMS
(ES+): m/z calcd for C21H21N2O3: 349.147 [M+H]+; found: 349.149. 5a:
Rf =0.1 (petroleum ether/EtOAc, 50:50); 1H NMR (400 MHz,
[D6]DMSO): d=2.19–2.26 (m, 1H), 2.34–2.40 (m, 1H), 2.83 (m, 1H),
3.62–3.67 (m, 2H), 3.95–4.07 (m, 2H), 4.21–4.25 (m, 1H), 5.60 (s, 1H),
7.20–7.28 (m, 2H), 7.30–7.41 (m, 6H), 7.42–7.48 (m, 2H), 10.2 ppm (brs,
1H); 13C NMR (100 MHz, [D6]DMSO): d=179.54, 145.65, 142.69, 130.41,
129.53, 129.22, 127.85, 127.25, 126.26, 123.18, 119.15, 118.06, 87.98. 74.06,
60.90, 58.37, 40.31, 33.12, 27.25 ppm; HRMS (ES+): m/z calcd for
C21H23N2O4: 367.158 [M+H]+; found: 367.153.
show some biological activity in selected cancer cell-lines.
This DOS methodology provides hits as starting points for
medicinal-chemistry campaigns.
Experimental Section
General Methods
Air- and moisture-sensitive reactions were carried out in oven-dried
glassware that were sealed with rubber septa under a positive pressure of
dry argon. Sensitive liquids and solutions were transferred by syringe.
Reactions were stirred with Teflon-coated magnetic stirrer bars. Elevated
temperatures were maintained by using Thermostat-controlled silicon oil
baths. Organic solutions were concentrated on a rotary evaporator with
a desktop vacuum pump. THF, Et2O, dioxane, benzene, and toluene were
distilled from sodium and benzophenone prior to use. CH2Cl2 was dis-
tilled from CaH2 prior to use. Analytical TLC was performed on
0.25 mm silica-gel G plates with a 254 nm fluorescent indicator. The TLC
plates were visualized by using UV light and treated with a phosphomo-
lybdic acid stain, followed by gentle heating. Purification of the products
was performed by flash chromatography on silica gel and the purified
compounds showed a single spot by analytical TLC. The diastereomeric
ratio and the regioisomeric ratio were determined by 1H NMR spectros-
copy of the crude reaction mixtures. Data for 1H NMR spectra are re-
ported as follows: chemical shift (ppm, referenced to TMS; s=singlet,
d=doublet, t=triplet, q=quartet, dd=doublet of doublets, dt=doublet
of triplets, ddd=doublet of doublet of doublets, m=multiplet), coupling
constant (Hz), and integration. Data for 13C NMR spectra are reported in
terms of chemical shift (ppm) relative to residual solvent peaks (CDCl3:
77.0 ppm).
Compound 4
Compound 4a (50 mg, 0.143 mmol) was dissolved in CH2Cl2 (0.5 mL).
TFA (32 mg, 0.280 mmol) was added to the reaction at 08C and the mix-
ture was stirred at RT for 3 h. The reaction mixture was concentrated
under reduced pressure and the resulting residue was purified by column
chromatography on silica gel (n-hexane/EtOAc, 70:30) to afford com-
pound 4 (28 mg, 0.107 mmol, 75% yield) as a pale-yellow syrup. Rf =0.1
(petroleum ether/EtOAc, 70:30) 1H NMR (400 MHz, CDCl3): d=2.06–
2.12 (dd, 1J=2.1 Hz, 2J=2.4 Hz, 1H), 2.21–2.23 (t, J=6.6 Hz, 1H), 2.65–
2.68 (m, 1H), 3.39–3.41 (m, 1H), 3.54–3.61 (m, 1H), 3.85–4.01 (m, 3H),
7.21–7.23 (m, 2H), 7.35–7.41 (m, 1H), 7.45–7.55 (m, 2H), 7.95 (s, 1H),
8.41 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=27.9, 44.1, 51.1, 55.9,
62.1, 70.8, 126.0, 128.5, 128.7, 136.0, 173.6, 174.5 ppm; HRMS (ES+): m/z
calcd for C14H17N2O3: 261.116 [M+H]+; found: 261.119.
Compound 5
Compound 5a (100 mg, 0.272 mmol) was dissolved in CH2Cl2 (1 mL).
TFA (61 mg, 0.544 mmol) was added at 08C and the mixture was stirred
at RT for 3 h. The reaction mixture was concentrated under reduced
pressure and the resulting residue was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc, 20:80) to afford compound 5 (47 mg,
0.169 mmol, 62% yield) as a white solid. Rf =0.3 (EtOAc); 1H NMR
(400 MHz, CDCl3): d=2.19–2.26 (m, 1H), 2.34–2.40 (m, 1H), 2.83 (m,
1H), 3.61–3.65 (m, 2H), 3.95–4.05 (m, 2H), 4.21–4.25 (m, 1H), 7.20–7.28
(m, 2H), 7.35–7.41 (m, 1H), 7.42–7.48 (m, 2H), 10.2 ppm (br s, 1H);
13C NMR (100 MHz, CDCl3): d=28.5, 48.4, 51.5, 56.1, 71.1, 86.8, 125.9,
126.1, 128.0, 128.7, 129.9, 133.7, 181.9 PPM; HRMS (ES+): m/z calcd for
C14H19N2O4: 279.1267 [M+H]+; found: 279.0199.
Experimental Procedures and Characterization Data for the Michael-
Addition/Cyclization-Mediated Synthesis of Scaffolds 3, 4, 4a, 5, and 5a
Compound 3
A solution of compound 2 (200 mg, 0.76 mmol) in THF (2 mL) was
added to a solution of LDA in THF (5 mL) (1.2 equiv, 98 mg, 0.91 mmol,
freshly prepared from diisopropylamine and nBuLi (1 m in n-hexane) at
-788C. The mixture was stirred at À788C for 0.5 h. Nitrostyrene
(1.5 equiv, 171 mg, 1.14 mmol) was added dropwise at À788C under a N2
atmosphere. The mixture was stirred at RT for 1 h under a N2 atmos-
phere until the starting material was completely consumed (determined
by TLC analysis). The mixture was diluted with EtOAc, extracted with
water (2ꢂ4 mL), dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by column chroma-
tography on neutral alumina (n-hexane/EtOAc, 80:20) to afford com-
pound 3 (245 mg, 0.597 mmol, 78% yield) as a white solid. Rf =0.6 (pe-
troleum ether/EtOAc, 70:30); 1H NMR (400 MHz, CDCl3): d=1.95–2.00
(m, 1H), 2.61–2.81 (m, 2H), 3.8 (s, 3H), 3.91–3.92 (m, 1H), 4.11- 4.18 (m,
1H), 4.21–4.31 (t, J=2.6 Hz, 1H), 4.95–5.00 (m, 1H), 5.29–5.40 (m, 1H),
6.21 (s, 1H), 7.23–7.40 ppm (m, 9H); 13C NMR (100 MHz, CDCl3): d=
32.7, 46.9, 53.4, 55.8, 63.5, 71.3, 86.9, 87.1, 125.9, 126.0, 128.5, 128.7, 128.8,
128.86, 128.9 129.22, 129.25,135.4, 137.5, 170.4, 171.7 ppm); HRMS
(ES+): m/z calcd for C22H23N2O6: 411.1478 [M+H]+; found: 411.1476; ee
(92%) was determined by HPLC on a chiral stationary phase (Chiralpa-
Compound 6
A solution of bicyclic lactam 1 (500 mg, 2.46 mmol) in THF (2 mL) was
added to a solution of LDA in THF (5 mL) (2 equiv, 0.52 g, 4.92 mmol,
freshly prepared from diisopropylamine and nBuLi in n-hexane) at
À788C. The mixture was stirred at À788C for 0.5 h followed by the addi-
tion of 2-nitrobenzyl bromide (1.1 equiv, 0.58 g, 2.70 mmol) at À788C
under a N2 atmosphere. The mixture was stirred at the same temperature
for 30 min under a N2 atmosphere, slowly warmed to RT, and stirred at
RT until the starting material was completely consumed (by TLC analy-
sis). The mixture was diluted with EtOAc, extracted with water (2ꢂ
4 mL), dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by column chromatography
kAD, n-hexane/isopropanol=60:40, 1 mLminÀ1
, tR =6.47 min (major),
5.57 min (minor)).
on neutral alumina (n-hexane/EtOAc, 80:20) to afford compound
6
(0.55 g, 1.62 mmol, 67% yield) as a pale-yellow liquid. Rf =0.5 (petrole-
1
um ether/EtOAc, 70:30); H NMR (400 MHz, CD3OD): d=2.06–2.15 (m,
Compounds 4a and 5a
2H), 3.05–3.15 (m, 2H), 3.40–3.46 (m, 2H), 4.06–4.17 (m, 2H), 6.15 (s,
1H), 7.29–7.44 (m, 7H), 7.52–7.56 (t, J=7.6 Hz, 1H), 7.91–7.93 ppm (d,
J=7.6 Hz, 1H); 13C NMR (100 MHz, CD3OD): d=29.02, 35.60, 47.34,
58.90, 72.23, 88.47, 125.82, 127.12, 129.07, 129.42, 129.64, 133.79, 134.18,
134.71, 140.19, 150.94, 181.20 ppm; HRMS (ES+): m/z calcd for
C19H19N2O4: 339.1267 [M+H]+; found: 339.1096.
Compound 3 (0.15 g, 0.37 mmol) was added to a solution of 10% Pd/C
(20 mg) in MeOH (2 mL) at RT under a N2 atmosphere and the mixture
was hydrogenated at 20 psi for 6 h at RT. The suspension was filtered
through a pad of Celite and concentrated under reduced pressure. The
resulting residue was purified by column chromatography on neutral alu-
mina (n-hexane/EtOAc, 80:20) and on EtOAc to afford compounds 4a
(61 mg, 0.175 mmol, 48% yield) and 5a (37 mg, 0.10 mmol, 28% yield)
as white solids. 4a: Rf =0.7 (petroleum ether/EtOAc, 70:30); 1H NMR
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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Subhabrata Sen et al.
FULL PAPER
Compound 7
Compound 11
Compound
Compound 6 (200 mg, 0.59 mmol) was added to a solution of 10% Pd/C
(40 mg) in MeOH (2 mL) at RT under a N2 atmosphere and the mixture
was hydrogenated at 20 psi for 8 h at RT. The suspension was filtered
through a pad of Celite and concentrated under reduced pressure to
yield the crude amine. The amine was dissolved in THF (2 mL) and treat-
ed with LiAlH4 (1m in THF, 0.60 mmol, 23 mg) at 08C. The reaction mix-
ture was slowly warmed to RT and stirred for 4 h. Once the starting ma-
terial was completely consumed (by TLC analysis), the reaction mixture
was quenched with EtOAc (0.2 mL), filtered through a pad of Celite, and
the filtrate was concentrated under reduced pressure. The resulting resi-
due was purified by column chromatography on neutral alumina (n-
hexane/EtOAc, 80:20) to afford compound 7 (69 mg, 0.236 mmol, 40%
9
(0.250 g, 0811 mmol) and benzaldehyde (0.172 g,
1.622 mmol) were mixed in toluene (6.25 mL) under an argon atmos-
phere. The reaction mixture was heated at reflux (1208C) for 2 h and
concentrated under reduced pressure. The resulting residue was dissolved
in tert-butanol (0.5 mL). Finally, potassium tert-butoxide (0.090 g,
0.811 mmol) was added and the reaction mixture was heated in a micro-
wave. The mixture was purified by column chromatography on neutral
alumina (petroleum ether/EtOAc, 95:5) to afford compound 11 (225 mg,
70% yield). Rf =0.6 (petroleum ether/EtOAc, 80:20); 1H NMR
(400 MHz, [D6]DMSO): d=1.71–1.76 (m, 1H), 2.39–2.44 (m, 1H), 2.88–
2.93 (d, J=16.8 Hz, 1H), 3.47–3.51 (t, J=8.4 Hz, 1H), 3.84–3.88 (t, J=
6.8 Hz, 1H), 4.09–4.12 (t, J=7.2 Hz, 1H), 4.52 (s, 1H), 6.05 (s, 1H), 6.48–
6.62 (m, 3H), 6.91–6.94 (m, 2H), 7.09–7.23 (m, 5H), 7.30–7.44 ppm (m,
5H); 1H NMR (400 MHz, [D6]DMSO): d=1.71–1.76 (m, 1H), 2.41–2.45
(m, 1H), 2.89–2.93 (d, J=16.0 Hz, 1H), 3.47–3.51 (t, J=8.0 Hz, 2H),
3.81–3.84 (t, J=6.8 Hz, 1H), 4.09–4.13 (t, J=7.6 Hz, 1H), 4.52 (s, 1H),
6.04 (s, 1H), 6.50–6.54 (t, J=7.2 Hz, 1H), 6.60–6.62 (d, J=8.4 Hz, 1H),
6.92–6.96 (m, 2H), 7.09–7.24 (m, 5H), 7.31–7.45 ppm (m, 5H); 13C NMR
(75 MHz, CD3OD): d=34.66, 39.37, 52.86, 56.87, 61.96, 73.71, 87.95,
114.33, 117.73, 119.12, 127.03, 127.36, 128.00, 128.66, 128.86, 128.90,
129.36, 129.55, 129.70, 130.02, 130.25, 139.91, 142.79, 145.29, 179.04 ppm;
HRMS (ES+): m/z calcd for C26H25N2O2: 397.183 [M+H]+; found:
397.181.
1
yield) as a white solid. Rf =0.5 (petroleum ether/EtOAc, 70:30); H NMR
(300 MHz, CDCl3): d=1.81–1.98 (m, 1H), 2.41–2.61 (m, 2H), 2.91–3.01
(m, 1H), 3.31–3.48 (m, 2H), 3.62–3.72 (m, 1H), 3.80–3.90 (d, J=8.9 Hz,
1H), 3.98–4.02 (m, 1H), 4.41–4.58 (m, 1H), 5.58–5.65 (d, J=1.8 Hz, 1H),
7.02–7.15 (m, 2H), 7.21–7.42 ppm (m, 7H); 13C NMR (100 MHz, CDCl3):
d=137.27, 128.94, 128.50, 128.15, 127.63, 127.41, 127.15, 127.07, 125.08,
123.94, 123.34, 114.60, 62.77, 61.25, 60.33, 58.42, 53.94, 45.02, 29.40, 28.97,
22.29, 22.06 ppm; HRMS (ES+): m/z calcd for C19H21N2O: 293.157
[M+H]+; found: 293.160. The ee (99.5%) was determined by HPLC on
a chiral stationary phase (ChiralpakAD, n-hexane/isopropanol=70:30,
1 mLminÀ1, tR =9.14 min (major)).
Compound 13
Compound 8
Compound 9 (0.250 g, 0811 mmol) and 2-methoxy benzaldehyde (0.275 g,
2.029 mmol) were stirred in toluene (6.25 mL) under an argon atmos-
phere. The reaction mixture was heated at reflux (1208C) for 2.5 h and
concentrated under reduced pressure. The resulting residue was dissolved
in tert-butanol (0.5 mL). Potassium tert-butoxide (0.090 g, 0.811 mmol)
was added and the reaction mixture was heated in a microwave. The mix-
ture was purified by column chromatography on neutral alumina (petro-
leum ether/EtOAc, 80:20) to afford compound 13 (262 mg, 76% yield).
Rf =0.5 (petroleum ether/EtOAc, 70:30); 1H NMR (300 MHz, CDCl3):
d=1.70–1.76 (m, 1H), 2.50–2.56 (d, J=16.2 Hz, 1H), 2.64–2.71 (m, 1H),
3.13–3.19 (d, J=16.2 Hz, 1H), 3.33 (s, 3H), 3.40–3.45 (t, J=8.1 Hz, 1H),
3.97–4.01 (m, 1H), 4.22–4.30 (m, 2H), 5.06 (s, 1H), 6.23 (s, 1H), 6.55–
6.58 (d, J=7.8 Hz, 1H), 6.65–6.76 (m, 3H), 7.01–7.07 (m, 2H), 7.15–7.20
(m, 2H), 7.32–7.39 (m, 3H), 7.44–7.47 ppm (m, 2H); 13C NMR
(100 MHz, CD3OD): d=34.48, 38.97, 51.78, 53.76, 55.05, 57.13, 74.22,
88.83, 110.73, 113.94, 113.04, 117.33, 118.40, 121.08, 127.95, 128.25, 128.97,
129.41, 129.45, 129.87, 130.63, 131.80, 140.62, 145.49, 157.96, 179.77 ppm;
HRMS (ES+): m/z calcd for C27H27N2O3: 427.194 [M+H]+; found:
427.190.
Compound 7 (100 mg, 0.341 mmol) was dissolved in CH2Cl2 (1 mL). TFA
(77 mg, 0.682 mmol) was added to the reaction at 08C and the mixture
was stirred at RT for 3 h. The reaction mixture was concentrated under
reduced pressure and the resulting residue was purified by column chro-
matography on silica gel (n-hexane/EtOAc, 60:40) to afford compound 8
(42 mg, 0.204 mmol, 60% yield) as a colorless syrup. Rf =0.5 (petroleum
ether/EtOAc, 50:50); 1H NMR (300 MHz, CDCl3): d=1.81–1.98 (m, 1H),
2.41–2.61 (m, 3H), 2.91–3.01 (dd, 1J=8.8 Hz, 2J=6.5 Hz, 1H), 3.31–3.48
(m, 2H), 3.62–3.72 (dd, 1J=2.1 Hz, 2J=2.7 Hz, 1H), 3.80–3.90 (d, J=
8.9 Hz, 1H), 3.98–4.02 (m, 1H), 4.41–4.58 (dd, 1J=1.2 Hz, 2J=1.2 Hz,
1H), 7.20–7.51 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=28.9, 29.4,
45.2, 53.9, 61.2, 81.2, 118.5, 121.3, 121.9, 125.0, 128.9, 137.3 ppm; HRMS
(ES+): m/z calcd for C12H17N2O: 205.1263 [M+H]+; found: 205.1265.
Compound 9
To a dried three-necked flask was added a solution of compound 6 (1 g,
2.95 mmol) in MeOH (10 mL) under an argon atmosphere and 10% Pd/
C (0.5 g) at RT. The reaction mixture was stirred at the same tempera-
ture for 3 h under a hydrogen atmosphere at 20 psi. The reaction mixture
was filtered through a pad of Celite and concentrated under reduced
pressure. The resulting residue was purified by column chromatography
Compound 15
Compound 9 (0.10 g, 0.324 mmol) and 2,3,4-tri-methoxy benzaldehyde
(0.127 g, 0.647 mmol) were stirred in toluene (2.5 mL) under an argon at-
mosphere. The reaction mixture was heated at reflux (1208C) for 3 h and
concentrated under reduced pressure. The resulting residue was dissolved
in tert-butanol (0.2 mL). Potassium tert-butoxide (0.036 g, 0.324 mmol)
was added and the reaction mixture was heated in a microwave. The mix-
ture was purified by column chromatography on neutral alumina (petro-
leum ether/EtOAc, 80:20) to afford compound 15 (102 mg, 65% yield).
Rf =0.5 (petroleum ether/EtOAc, 50:50); 1H NMR (400 MHz, CD3OD):
d=1.56–1.61 (m, 1H), 2.53–2.57 (d, J=16.0 Hz, 1H), 2.91–2.94 (m, 1H),
3.33–3.38 (m, 1H), 3.51–3.54 (m, 1H), 3.60 (s, 6H), 3.81–3.83 (m, 1H),
3.90 (s, 3H), 4.01–4.05 (m, 1H), 4.89 (s, 1H), 6.04 (s, 1H), 6.56–6.64 (m,
2H), 6.81–6.83 (d, J=8.8 Hz, 1H), 6.87–6.89 (m, 2H), 6.93–6.99 (m, 2H),
7.19–7.25 (m, 3H), 7.48–7.50 ppm (d, J=8.8 Hz, 1H); 13C NMR
(75 MHz, CD3OD): d=33.11, 40.31, 53.65, 53.79, 56.53, 58.37, 60.89,
61.47, 74.05, 87.97, 108.03, 114.98, 118.05, 119.15, 123.18, 126.25, 127.24,
127.85, 129.22, 129.52, 130.40, 139.53, 142.68, 145.65, 153.41, 155.07,
179.50 ppm; HRMS (ES+): m/z calcd for C29H31N2O5: 487.215 [M+H]+;
found: 487.210.
on neutral alumina (n-hexane/EtOAc, 70:30) to afford compound
9
(0.79 g, 2.581 mmol, 87% yield) as a yellow syrup. Rf =0.5 (petroleum
ether/EtOAc, 50:50); 1H NMR (400 MHz, [D6]DMSO): d=2.01–2.04 (t,
J=5.6 Hz, 2H), 2.64–2.72 (m, 1H), 2.87–2.99 (m, 2H), 3.38–3.42 (t, J=
8.8 Hz, 1H), 4.02–4.18 (m, 2H), 4.86 (s, 2H), 6.09 (s, 1H), 6.47–6.51 (t,
J=14.8 Hz, 1H), 6.61–6.63 (d, J=7.2 Hz, 1H), 6.89–6.94 (m, 2H), 7.3–
7.4 ppm (m, 5H); HRMS (ES+): m/z calcd for C19H21N2O2: 309.152
[M+H]+; found: 309.157.
General Procedure for the Synthesis of Chiral Tetrahydroquinolines
To a dried three-necked flask fitted with a reflux condenser was added
compound 9 (1.00 mmol) and aryl benzaldehyde (2–3 equiv) in toluene
(7.5 mL) under an argon atmosphere. The reaction mixture was heated at
reflux (1208C) for 2–3 h and concentrated under reduced pressure. The
resulting residue was dissolved in tert-butanol (0.6 mL). Potassium tert-
butoxide (1 equiv) was added to the reaction at RT and the mixture was
stirred for 15 min at RT before being transferred into a microwavable
vial and heated in a microwave at 1608C for 20–30 min. The reaction
mixture was filtered through a pad of Celite and concentrated under re-
duced pressure. The resulting residue was purified by column chromatog-
raphy on neutral alumina (n-hexane/EtOAc) to afford the product.
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Chem. Asian J. 0000, 00, 0 – 0
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Reagent-Based DOS of Spirocycles and Fused Heterocycles
Compound 17
pound 14 (116 mg, 73% yield). Rf =0.2 (petroleum ether/EtOAc, 70:30);
1H NMR (400 MHz, [D6]DMSO): d=1.35–1.38 (m, 1H), 2.10–2.20
(m,2H), 2.78–2.82 (d, J=16.0 Hz, 1H), 3.50–354 (m, 1H), 3.69 (s, 3H),
4.66–4.69 (t, J=5.2 Hz, 1H), 4.79 (s, 1H), 6.36–6.37 (m, 1H), 6.43–6.47 (t,
J=7.2 Hz, 1H), 6.53–6.55 (d, J=8.4 Hz, 1H), 6.75–6.79 (t, J=8.0 Hz,
1H), 6.83–6.85 (d, J=8.4 Hz, 1H), 6.88–6.96 (m, 2H), 7.12–7.16 (t, J=
7.2 Hz, 1H), 7.48 ppm (s, 1H); 13C NMR (75 MHz, CD3OD): d=33.90,
38.04, 52.52, 54.04, 55.40, 66.09, 78.79, 110.77, 113.77, 117.07, 118.62,
121.15, 128.08, 128.72, 129.20, 130.45, 132.38, 145.37, 158.24, 180.90 ppm;
HRMS (ES+): m/z calcd for C20H23N2O3: 339.163 [M+H]+; found:
339.167.
Compound 9 (0.20 g, 0.649 mmol) and 2,4,5-tri-methoxy benzaldehyde
(0.32 g, 1.62 mmol) were stirred in toluene (5 mL) under an argon atmos-
phere. The reaction mixture was heated at reflux (1208C) for 3 h and
concentrated under reduced pressure. The resulting residue was dissolved
in tert-butanol (0.4 mL). Potassium tert-butoxide (0.072 g, 0.649 mmol)
was added and the reaction mixture was heated in a microwave. The mix-
ture was purified by column chromatography on neutral alumina (petro-
leum ether/EtOAc, 70:30) to afford compound 17 (199 mg, 63% yield).
Rf =0.5 (petroleum ether/EtOAc, 50:50); 1H NMR (400 MHz, CD3OD):
d=1.71–1.76 (m, 1H), 2.51–2.55 (d, J=16 Hz, 1H), 2.68–2.73 (m, 1H),
3.04–3.08 (d, J=16 Hz, 1H), 3.32 (s, 3H), 3.36 (s, 3H), 345–3.49 (t, J=
8.4 Hz, 1H), 3.80 (s, 3H), 4.07–4.10 (m, 1H), 4.23–4.26 (m, 1H), 4.94 (s,
1H), 6.07 (s, 1H), 6.49 (s, 1H), 6.54–6.61 (m, 2H), 6.75 (s, 1H), 6.94–6.98
(m, 2H), 7.34–7.41 ppm (m, 5H); 13C NMR (100 MHz, CD3OD): d=
35.27, 38.93, 52.28, 53.81, 55.96, 56.63, 56.92, 57.27, 74.12, 88.91, 98.01,
114.15, 114.17, 117.54, 118.86, 122.90, 127.90, 128.12, 129.49, 129.87,
130.43, 140.47, 143.85, 145.59, 150.50, 152.76, 179.82 ppm; HRMS (ES+):
m/z calcd for C29H31N2O5: 487.215 [M+H]+; found: 487.211.
Compound 16
Compound 15 (0.15 g, 0.308 mmol) was dissolved in CH2Cl2 (1.5 mL) and
TFA (0.15 mL) was added to the reaction mixture at 08C. The mixture
was purified by column chromatography on silica gel (petroleum ether/
EtOAc, 60:40) to afford compound 16 (85 mg, 69% yield). Rf =0.4 (pe-
troleum ether/EtOAc, 30:70); 1H NMR (400 MHz, CD3OD): d=1.33–
1.39 (m, 1H), 2.00–2.06 (m, 1H), 2.42–2.46 (d, J=16 Hz, 1H), 2.53–2.59
(m, 1H), 2.81–2.84 (m, 1H), 3.21–3.25 (m, 1H), 3.36–3.41 (m, 2H), 3.78
(s, 3H), 3.85 (s, 6H), 4.88 (s, 1H), 6.53–6.62 (m, 2H), 6.76–6.78 (d, J=
8.8 Hz, 1H), 6.91–6.95 (m, 2H), 7.40–7.42 ppm (d, J=8.8 Hz, 1H);
13C NMR (75 MHz, CD3OD): d=33.11, 40.31, 53.63, 53.79, 56.53, 58.37,
60.89, 61.47, 74.05, 108.03, 114.98, 118.05, 119.15, 126.25, 127.24, 127.83,
129.22, 129.52, 142.63, 145.65, 153.41, 155.07, 179.53 ppm; HRMS (ES+):
m/z calcd for C22H27N2O5: 399.184 [M+H]+; found: 399.180.
Compound 19
Compound 9 (0.250 g, 0.811 mmol) and 2-ethoxybenzaldehyde (0.243 g,
1.623 mmol) were stirred in toluene (6.25 mL) under an argon atmos-
phere. The reaction mixture was heated at reflux (1208C) for 3 h and
concentrated under reduced pressure. The resulting residue was dissolved
in tert-butanol (0.5 mL). Potassium tert-butoxide (0.090 g, 0.811 mmol)
was added and the reaction mixture was heated in a microwave. The mix-
ture was purified by column chromatography on neutral alumina (petro-
leum ether/EtOAc, 80:20) to afford compound 19 (264 mg, 74% yield).
Rf =0.7 (petroleum ether/EtOAc, 50:50); 1H NMR (400 MHz, CD3OD):
d=0.93–0.97 (t, J=6.8 Hz, 3H), 1.71–1.76 (m, 1H), 2.50–2.55 (d, J=
16.4 Hz, 1H), 2.62–2.67 (m, 1H), 3.09–3.13 (d, J=16.0 Hz, 1H), 3.42–3.46
(t, J=8 Hz, 1H), 3.67–3.71 (m, 1H), 3.78–3.82 (m, 1H), 3.89–3.93 (m,
1H), 4.21–4.24 (m, 1H), 5.09 (s, 1H), 6.09 (s, 1H), 6.55–6.58 (m, 2H),
6.67–6.70 (t, J=7.6 Hz, 1H), 6.78–6.80 (d, J=7.6 Hz, 1H), 6.94–6.98 (m,
2H), 7.11–7.16 (m, 2H), 7.33–7.42 ppm (m, 5H); 13C NMR (100 MHz,
CD3OD): d=14.87, 35.50, 38.63, 51.86, 54.15, 56.99, 64.53, 74.13, 88.75,
111.92, 114.18, 117.44, 118.81, 121.14,127.64, 128.08, 129.32, 129.43,
129.70, 130.44, 131.63, 140.32, 145.69, 157.38, 180.02 ppm; HRMS (ES+):
m/z calcd for C28H29N2O3: 441.210 [M+H]+; found: 441.212.
Compound 18
Compound 17 (0.10 g, 0.205 mmol) was dissolved in CH2Cl2 (1.0 mL) and
TFA (0.1 mL) was added. The mixture was purified by column chroma-
tography on silica gel (petroleum ether/EtOAc, 60:40) to afford com-
pound 18 (56 mg, 68% yield). Rf =0.3 (petroleum ether/EtOAc, 30:70);
1H NMR (400 MHz, CD3OD): d=1.49–1.55 (m, 1H), 2.00–2.04 (m, 1H),
2.33–2.38 (m, 1H), 2.42–2.47 (d, J=16.4 Hz, 1H), 2.99–3.03 (d, J=
16.4 Hz, 1H), 3.35–3.39 (m, 1H), 3.45–3.49 (m, 2H), 3.56 (s, 3H), 3.77 (s,
3H), 3.82 (s, 3H), 4.88 (s, 1H), 6.52–6.60 (m, 3H), 6.84 (s, 1H), 6.93–
6.97 ppm (m, 2H); 13C NMR (100 MHz, CD3OD): d=35.27,38.93, 52.28,
53.81, 55.96, 56.63, 56.92, 57.27, 74.12, 98.01, 114.15, 114.17, 117.54,
118.86, 122.90, 129.49, 129.87, 130.43, 143.85, 145.59, 150.50, 152.76,
179.82 ppm; HRMS (ES+): m/z calcd for C22H27N2O5: 399.184 [M+H]+;
found: 399.188.
General Procedure for Opening a Chiral Auxiliary of
Tetrahydroquinolines
Compound 20
The tetrahydroquinoline (11, 13, 15, 17, or 19; 1 mmol) was dissolved in
CH2Cl2 (1 mL). TFA (0.1–0.3 mL) was added to the reaction at 08C and
the mixture was stirred at RT for 2–3 h. The reaction mixture was con-
centrated under reduced pressure and the resulting residue was purified
by column chromatography on silica gel (n-hexane/EtOAc, 60:40) to
afford the product.
Compound 19 (0.20 g, 0.454 mmol) was dissolved in CH2Cl2 (2.0 mL) and
TFA (0.2 mL) was added to the reaction mixture at 08C. The mixture
was purified by column chromatography on silica gel (petroleum ether/
EtOAc, 70:30) to afford compound 20 (140 mg, 88% yield). Rf =0.6 (pe-
troleum ether/EtOAc, 50:50); 1H NMR (400 MHz, CD3OD): d=0.87–
0.93 (t, J=7.6 Hz, 3H), 1.50–1.61 (m, 2H), 2.01–2.06 (m, 1H), 2.30–2.40
(m, 2H), 3.03–3.07 (d, J=16.0 Hz, 1H), 3.39–3.43 (m, 1H), 3.56–3.59 (m,
1H), 3.69–3.75 (m, 1H), 3.96–4.02 (q, J=6.8 Hz, 2H), 5.03 (s, 1H), 6.51–
6.62 (m, 2H), 6.75–6.81 (m, 2H), 6.91–6.99 (m, 2H), 7.10–7.15 ppm (m,
2H); 13C NMR (400 MHz, CD3OD): d=14.87, 35.50, 38.63, 51.86, 54.16,
56.99, 64.53, 74.25, 111.92, 114.18, 117.44, 118.81, 121.14, 129.32, 129.45,
129.70, 130.44, 131.63, 145.69, 157.38, 180.02 ppm; HRMS (ES+): m/z
calcd for C21H25N2O3: 353.178 [M+H]+; found: 353.171.
Compound 12
Compound 11 (0.1 g, 0.252 mmol) was dissolved in CH2Cl2 (1 mL). TFA
(0.1 mL) was added and the mixture was purified by column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 75:25) to afford compound
12 (62 mg, 80% yield). Rf =0.4 (petroleum ether/EtOAc, 70:30);
1H NMR (300 MHz, CD3OD): d=1.56–1.64 (m, 1H), 2.26–2.33 (m, 1H),
2.60–2.69 (m, 1H), 2.96–3.04 (d, J=15.2 Hz, 1H), 3.09–3.16 (m, 1H),
3.28–3.36 (m, 1H), 3.43–3.49 (m, 1H), 4.32 (s, 1H), 6.53–6.59 (m, 2H),
6.92–6.96 (m, 2H), 7.22–7.32 ppm (m, 5H); 13C NMR (100 MHz,
CD3OD): d=35.61, 37.73, 47.15, 53.77, 62.14, 65.94, 114.42, 117.61,
119.71, 127.81, 128.49, 128.73, 128.94, 129.11, 129.33, 129.47, 130.16,
143.05, 145.55, 180.46 ppm; HRMS (ES+): m/z calcd for C19H21N2O2:
309.152 [M+H]+; found: 309.150.
Compound 24
Compound 22 (0.20 g, 0.395 mmol) was dissolved in THF (2 mL). Ammo-
nium formate (37 mg, 0.592 mmol) and 10% Pd/C (40 mg) was added to
the reaction and the mixture was heated at reflux for 12 h. Once the
starting material was completely consumed (by TLC analysis), the reac-
tion was exposed to air and filtered through a pad of Celite. The filtrate
was diluted with EtOAc and washed with water. The organic layer was
dried over anhydrous sodium sulfate, evaporated under reduced pressure,
and the resulting residue was purified by column chromatography on
neutral alumina (n-hexane/EtOAc, 50:50) to afford compound 24
(109 mg, 0.263 mmol, 67% yield) as a white solid. Rf =0.4 (EtOAc);
Compound 14
Compound 13 (0.2 g, 0.469 mmol) was dissolved in CH2Cl2 (2 mL) and
TFA (0.2 mL) was added. The mixture was purified by column chroma-
tography on silica gel (petroleum ether/EtOAc, 70:30) to afford com-
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Subhabrata Sen et al.
FULL PAPER
1H NMR (300 MHz, CDCl3): d=2.41–2.61 (m, 2H), 3.61–3.68 (t, J=
8 Hz, 1H), 4.26–4.32 (m, 1H), 4.41–4.52 (m, 1H), 5.12–5.45 (brs, 1H),
6.15 (s, 1H), 6.92–6.93 (d, J=4 Hz, 1H), 7.25–7.35 (m, 5H), 10.41 (s,
1H); 13C NMR (100 MHz, CDCl3): d=176.44, 174.41, 149.84, 143.01,
138.74, 128.68, 128.44, 126.17, 123.25, 116.88, 103.94, 96.00, 86.71, 71.50,
61.36, 56.74, 33.45 ppm; HRMS (ES+): m/z calcd for C19H17N3O3Br:
414.037 [M+H]+; found: 414.040.
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Compound 26
Compound 25 (0.10 g, 0.241 mmol) was dissolved in CH2Cl2 (1.0 mL).
TFA (0.2 mL) was added to the reaction at 08C and the mixture was
stirred at RT for 2.5 h. The reaction mixture was concentrated under re-
duced pressure and the resulting residue was purified by column chroma-
tography on silica gel (n-hexane/EtOAc, 30:70) to afford compound 26 as
a
syrup in 80% yield. Rf =0.2 (n-hexane/EtOAc 30:70); 1H NMR
(400 MHz, CD3OD): d=2.18–2.24 (m, 2H), 3.40–3.48 (m, 2H), 3.71–3.82
(m, 1H), 4.78–4.85 (m, 1H), 5.34 (s, 1H), 6.34 (s, 1H), 7.18 (s, 1H), 8.20
(s, 1H), 10.41 ppm (s, 1H); 13C NMR (400 Hz, CD3OD): d=14.87, 35.50,
38.63, 51.86, 54.16, 56.99, 64.53, 74.25, 111.92, 114.18, 117.44, 118.81,
121.14, 129.32, 129.45, 129.70, 130.44, 131.63, 145.69, 157.38, 180.02 ppm;
HRMS (ES+): m/z calcd for C12H13N3O3Br: 326.006 [M+H]+; found:
326.009.
Acknowledgements
The authors acknowledge GVK Biosciences Pvt. Ltd. for funding and Dr.
Raghuram S. Tangirala for his useful suggestions.
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Received: April 30, 2012
Revised: June 27, 2012
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

FULL PAPER
Diversity-Oriented Synthesis
V. Surendra Babu Damerla,
Chiranjeevi Tulluri, Rambabu Gundla,
Lava Naviri, Uma Adepally,
Pravin S. Iyer, Y. L. N. Murthy,
Nampally Prabhakar,
Subhabrata Sen*
&&&& — &&&&
Reagent-Based DOS: Developing
a Diastereoselective Methodology to
Access Spirocyclic- and Fused Hetero-
cyclic Ring Systems
Uno, DOS, tres: An enolate-mediated
strategy was used to synthesize biologi-
cally relevant cyclic scaffolds. In silico
analysis was used to evaluate the com-
pounds in terms of, for example, polar
surface area and chemical diversity.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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