Synthesis of enantiomerically enriched indolines and tetrahydroisoquinolines from (S)-amino acid-derived chiral carbocations: An easy access to (3S,4R)-demethoxy-3-isopropyl diclofensine

Article abstract of DOI:10.1039/c4ob00922c

Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective Friedel-Crafts reaction is promoted by a Lewis acid (AlCl₃) offering trans-diastereoselectivity. The rate of the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enantiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine. This journal is

Full text of DOI:10.1039/c4ob00922c

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Synthesis of enantiomerically enriched indolines
and tetrahydroisoquinolines from (S)-amino acid-
derived chiral carbocations: an easy access to
(3S,4R)-demethoxy-3-isopropyl diclofensine†‡
Cite this: Org. Biomol. Chem., 2014,
12, 8318
Sudipta Kumar Mannaa and Gautam Panda*a,b
Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in
high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective
Friedel–Crafts reaction is promoted by a Lewis acid (AlCl3) offering trans-diastereoselectivity. The rate of
the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the
amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enan-
tiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine.
Received 5th May 2014,
Accepted 18th August 2014
DOI: 10.1039/c4ob00922c
www.rsc.org/obc
plants,15 nomifensine16 (2c) and diclofensine17a (2d), and hexa-
hydropyrrolo[2,1-a]isoquinolines (2e).17b,c Many approaches
Introduction
About 70% of the new chemical entities (NCEs) introduced in
the past 25 years were directly or indirectly derived from
natural products.1,2 Due to the presence of two chiral centers,
substituted indoline and tetrahydroisoquinoline moieties lead
to four possible stereoisomers. Therefore, the development of
an efficient stereoselective method to synthesize chiral indo-
lines and tetrahydroisoquinolines continues to be a highly
desirable goal. Optically active disubstituted indolines and tetra-
hydroisoquinolines include the acetyl cholinesterase inhibi-
tors physovenine (1a) and physostigmine (1b),3,4 communesin
B,5 aspidophylline A (1c),6 and the anticancer agents diazon-
amide A (1e),7 bipleiophylline (1f),8 and echetamine chloride
(1g)9 (Fig. 1). Benzastatin E (1d) and its congeners are a family
of indoline alkaloids that were isolated from Streptomyces
nitrosporeus 30643 in 1997.10 They showed neuronal cell pro-
tecting activity that can be used to prevent brain ischemia
injury.11 Benzastatin E, another indoline alkaloid, is the most
potent inhibitor of glutamate toxicity, using neuronal hybri-
doma N18-RE-105 cells, among the benzastatin family.10
such as the Pictet–Spengler and Pommeranz–Fritsch–Bobbit
reactions for substituted tetrahydroisoquinolines have been
developed.18–20 More recently, a two-step process involving pal-
ladium-catalyzed α-arylation between dihydroisoquinolinones
and aryl halides followed by BH3 reduction of the carbonyl
group, has been reported by Hu et al.21
A literature survey revealed that the indoline-containing archi-
tectures can be rapidly accessed through catalytic hydrogen-
ation22 or hydrosilylation of the corresponding indoles,23 non-
enzymatic kinetic resolution of indolines,24 and a broad range of
convergent methodologies such as free radical promoted aryl
aminations,25 intra-molecular shifting of sulfonyl groups,26 dia-
stereoselective electrophilic cyclization processes27 or palladium-
catalyzed coupling reactions.28 Diastereoselective protonation of
chiral lactam enolates29 and radical mediated cyclization are
common routes for synthesizing tetrahydroisoquinoline-type
architectures.30 Though these processes are new in this field, for
cost effective, atom economic and thus effective preparation of
this motif, diastereoselective Friedel–Crafts cyclization remains
the mainstay. The use of π-activated alcohols, producing water as
the by-product,31,32 as a replacement for the less widely available
and more toxic organohalides is a major breakthrough in this
field. Recently Lautens et al. demonstrated asymmetric benzylic
arylation for the preparation of tetrahydrotetralins.33a,b
The 4-aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines12–14 are
present in many bioactive natural products like cherylline (2a)
and latifine (2b) which are isolated from Amaryllidaceae
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
BS 10/1, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
E-mail: gautam.panda@gmail.com, gautam_panda@cdri.res.in;
A trivalent carbocation33c with three different substituents is
termed prostereogenic. In the absence of any control from the
medium, solvent or catalyst attack from both faces of the plane
leads to a 1 : 1 mixture of the enantiomers. However, this situ-
ation is changed if one of the substituents is chiral, as the two
faces can no longer remain equivalent. Chiral benzyl carbo-
Fax: +91-522-2771941; Tel: +91-522-2772450, 2772550, Ext 4661,4662
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
†Dedicated to Prof. Ganesh Pandey on his 60th birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00922c
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Fig. 1 Important representative indoline and isoquinoline core containing natural products.
Fig. 2 Friedel–Crafts acylation through chiral carbocations.
cations with α-substituents preferentially remain in the confor- rally abundant (S)-amino acids following several synthetic
mation drawn below to avoid allylic strain between the sterically steps including Ullmann coupling, esterification of acids, ben-
more demanding substituent and the aryl ring and hence, there zylation/methylation of amines, LAH reduction of ester groups
is facial control in the nucleophilic substitution of the benzylic and Parikh–Doering oxidation (Scheme 1). After Parikh–
systems (Fig. 2). This concept has efficiently been used by Bach Doering oxidation, the crude product was used for a Grignard
et al.34 and Chung et al.35a We envisioned that N-aryl benzylic reaction without further purification (due to the instability of
carbocations derived from (S)-amino acids36 can take part in substituted aldehydes).
intra-molecular Friedel–Crafts alkylation, resulting in the stereo-
selective synthesis of indolines and tetrahydroisoquinolines.
To find the most advantageous reaction conditions for the
diastereoselective Friedel–Crafts cyclization of amino acid
derived aryl, heteroaryl and alkene substituted carbinols (8a–s,
10a–h), we tested several Lewis acids [SnCl2, Sc(OTf)3, SnCl4,
BF3·OEt2, FeCl3·6H2O, AuCl3·3H2O, AlCl3, AgOTf, Cu(OTf)2 and
In(OTf)3] under different conditions (solvent, temperature and
Lewis acid amount). A solution of the carbinol 8a was refluxed
with 0.5 equiv. SnCl2 in dry benzene, which did not provide
Results and discussion
Amino acid derived aryl, heteroaryl and alkene substituted car-
binols (8a–s, 10a–h) were prepared in good yields from natu-
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Scheme 1 Reagents and conditions: (i) amino acids, CuI, K2CO3, DMA, 48 h; (ii) K2CO3, MeI, DMF, 2 h; (iii) SOCl2, MeOH, 6 h; (iv) BnBr, K2CO3, DMF,
4–5 h; (v) Ag2O, MeI, dry DMF, 6 h; (vi) (a) LAH, dry THF, 1 h and (b) Py·SO3, DCM–DMSO (1.6 : 2 mL per mmol), Et3N, 1 h; (vii) R1-Br, Mg/I2, dry THF, rt, 1 h.
the required product. Changing the solvent to dichloroethane
(DCE) gave trace amounts of the desired indoline, while
increasing the catalyst loading to 1 equiv. in dry dichloro-
methane (DCM) at room temperature furnished the desired
indoline in a 45% yield at 70% conversion after 5 h (entry 3,
Table 1). A further increase in the reaction time, catalyst
loading and reaction temperature didn’t improve the reaction
yield.
Table 1 Optimization studies for the diastereoselective Friedel–Crafts
reaction of 11a
Thus we screened stronger Lewis acids for this diastereo-
selective transformation. When the SnCl4 loading was 1.2 equiv.,
80% of the starting material was consumed after 3–5 h and
11a was obtained in 50% yield. Milder Lewis acids like
Sc(OTf)3, FeCl3, AuCl3·3H2O and AgOTf gave the desired
product, 11a, in 25–52% yield. Subsequently, various other
catalytic systems (Lewis acids as well as protic acids) were
screened (Table 1, see ESI‡). With an increase in AlCl3 catalyst
loading (from 0.5 to 1.0 to 1.5 equiv.) in the same solvent, the
yield of 11a improved from 65% to 74% to 82%. In some
entries of Table 1, the yield of 11a was low (25–52%), thus the
diastereoselectivity was not measured.
It is noteworthy that most of the reactions with Lewis acids
were performed under a strictly inert atmosphere, as these cata-
lysts immediately react with water or moisture rather than the
substrates. Coordination of the amine and eliminated water
with the Lewis acid might increase the required amount of
Lewis acid, making the use of an extra equivalent of Lewis acid
necessary in the reaction. Based on these facts and the above
optimization results, we then turned our attention to explore
the scope of the AlCl3 catalyzed diastereoselective Friedel–
Crafts cyclization of amino acid derived electron-rich aryl,
heteroaryl and alkene substituted carbinols (8a–s, 10a–h).
A series of carbinols (8a–s, 10a–h) were used in dry DCM at
0 °C–RT, using 1.5 equiv. AlCl3 under inert atmospheric con-
ditions, furnishing the desired indolines (11a–s) and tetra-
hydroisoquinolines (12a–h) in 48–84% yields and with high
diastereoselectivity (Fig. 3).
Yielda
(%)
Entry Lewis acids
Solvents
Conditions
1
2
3
4
5
6
7
8
SnCl2 (0.5 equiv.)
Dry benzene Reflux, 30 min NR
SnCl2 (0.5 equiv.)
SnCl2 (1.0 equiv.)
Sc(OTf)3 (5 mol%)
Sc(OTf)3 (10 mol%)
SnCl4 (1.2 equiv.)
BF3·OEt2 (10 mol%)
FeCl3·6H2O (5 mol%)
DCE
Reflux, 2 h
RT, 1–5 h
RT, 1 h
Reflux, 1–3 h
RT, 3–5 h
RT, 1 h
RT, 1 h
RT, 1 h
Reflux, 1–2 h
RT, 1 h
0 °C–RT, 1 h
Trace
45b
Trace
33b
50c
Dry DCM
Dry DCM
Dry DCM
Dry DCM
Dry DCM
Dry DCM
38b
NR
9
AuCl3·3H2O (10 mol%) Dry DCM
AuCl3·3H2O (10 mol%) DCE
AlCl3 (0.5 equiv.)
AlCl3 (1.0 equiv.)
AlCl3 (1.5 equiv.)
NR
10
11
12
13
14
25b
65
Dry DCM
Dry DCM
Dry DCM
74
0 °C–RT, 5 min 82
Reflux, 1 h 52
FeCl3·6H2O (1.5 equiv.) Dry DCM
a Isolated yield of indoline (11a) after silica gel column
chromatography. NR = no reaction. b 70% starting material consumed
and the unreacted portion has been recovered. c 80% starting material
consumed and the unreacted portion has been recovered.
Interestingly, when the methodology was applied to the syn-
thesis of indolines (11a–s), one isomer was detected by chiral
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Fig. 3 Synthesis of indoline and tetrahydroisoquinoline derivatives (11a–s, 12a–h). All products were obtained with >95% de except 12c and 12c1 as
determined by 300 & 400 MHz NMR spectroscopy.
HPLC analysis of the products. When the reaction was carried
out with a mixture of the two carbinols derived from enantio-
merically pure (S-) and (R-)amino acids, analysis of chiral
HPLC experiments showed only two peaks for the two enantio-
mers of the trans- indolines (tR = 9.134 and 9.236 min in iso-
propanol : acetonitrile = 05 : 95, respectively) providing com-
plete diastereoselective Friedel–Crafts cyclization (de > 95). But
for tetrahydroisoquinoline (12c), unfortunately, this diastereo-
selectivity was low based on the products isolated by prepara-
tive thin layer column chromatography. The relative
stereochemistry of the compounds was assigned on the basis
of NOESY studies of 11g (see ESI‡). For indolines, though the
coupling constant values obtained for the coupling of two
methine protons were 7–9 Hz, NOESY experiments confirmed
the trans-selectivity. The trans-stereoselectivity of the disubsti-
tuted indolines (11a–s) and tetrahydroisoquinolines (12a–h)
Fig. 4 Proposed mechanistic pathway for the synthesis of indoline and
can be explained on the basis of the expected conformational
tetrahydroisoquinoline derivatives.
preferences in the proposed transition state (cis- giving rise to
considerably more steric hindrance) of the reaction (Fig. 4).
gives scope for further structural diversification (Fig. 5). In
order to further establish the efficiency of this process, we
applied this methodology to the synthesis of enantiomerically
As a representative example, the benzyl group of the trans-
disubstituted chiral tetrahydroisoquinoline 12a was selectively
debenzylated using H2/Pd-C affording 13a in 76% yield, which
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quartet (q) or multiplet (m). IR spectra were recorded using an
FTIR spectrophotometer in cm−1. The high resolution mass
spectra (HRMS) were recorded as ESI-HRMS (recorded as ES+)
on a mass spectrometer. Optical rotations were determined on
polarimeters using a 1 dm cell at 25 °C with chloroform and
methanol as the solvents; the concentrations mentioned are in
g per 100 mL. The enantiomeric excess was determined by
chiral column (chiralpak 1A) using 5% iso-propanol and 95%
acetonitrile as the eluent at a wavelength of 254 nm and flow
rate of 0.50 mL min−1 at 25 °C. The retention time range is
0 to 30 min. The specific rotation values of the diastereomers
and their retention time in chiral HPLC have been defined
with respect to the products.
Fig. 5 Deprotection of amine 12a.
enriched demethoxy-3-isopropyl diclofensine (trans-isomer).
Valine was first converted quantitatively to the aldehyde 9b
using standard protocols (Scheme 1). A Grignard reaction of
the aldehyde 9b with 3,4-dichlorophenyl magnesium bromide
gave the carbinol 10d in 72% yield. The intra-molecular dia-
stereoselective Friedel–Crafts alkylation of this carbinol
through the chiral benzylic carbocation gave (3S,4R)-
demethoxy-3-isopropyl diclofensine in 77% yield (12d, Fig. 3).
General experimental procedure for the synthesis of 6a–j
When a mixture of S-amino acid (1 equiv.), halobenzene
(1 equiv.), CuI (10 mol%), and K2CO3 (1.5 equiv.) was stirred in
DMA at 90 °C for 48 h, we could isolate the coupled products
3a–f in 75–92% yield.37 The respective amino acids 3a–f were
esterified by using methyl iodide (1 equiv.) and K2CO3
(2 equiv.) in DMF at room temperature within 1–2 h. After com-
pletion of the reaction (as observed by TLC), DMF was
removed in vacuo. The mixture was extracted with ethyl acetate
(3 × 30 mL), washed with brine and dried over Na2SO4. The
concentrated extract (crude product) was subjected to methyl-
ation of amine without purification. To a stirred solution of
4a–f (1.447 mmol) in dry DMF (3 mL for each mmol) was
added Ag2O (4.342 mmol) and methyl iodide (4.342 mmol) in
the dark at 0 °C and after final addition, the reaction mixture
was stirred at 0 °C to rt overnight. After completion of the reac-
tion, the resultant mixture was filtered through a celite bed,
concentrated in vacuo and purified by silica gel column
chromatography.
Conclusion
In summary, we have developed a simple and powerful syn-
thetic route that provides access to enantiomerically enriched
disubstituted indolines and tetrahydroisoquinolines from (S)-
amino acid derived chiral carbocations. This Friedel–Crafts
reaction is promoted by a Lewis acid (AlCl3) offering trans-
diastereoselectivity. The rate of the reaction and diastereo-
selectivity of the product are significantly influenced by steric
hindrance of the amino acid substituents and the nature of
the aryl groups. Further investigations are underway in our lab-
oratory to expand the applicability of this process.
Experimental section
In addition, to a stirred solution of S-amino acids (1 equiv.)
in MeOH (20 mL), SOCl2 (1.5 equiv.) was added at 0 °C, and
then the reaction mixture was stirred for 6 h. After completion
(as monitored by TLC), the reaction mixture was concentrated
in vacuo and dissolved in DMF (15 mL) and was heated to
50 °C followed by addition of benzyl bromide (1.1 equiv.) and
K2CO3 (2 equiv.). After methylation or benzylation (as
described above) of 4a–f and 5a–d, the respective amino esters
6a–j were reduced with LAH.
General remarks
All dry reactions were carried out under an argon atmosphere
in oven-dried glassware using standard gas-tight syringes, can-
nulas and septa. All reagents and solvents were purchased
from commercial sources and used without further purifi-
cation. Organic solvents were dried by standard methods.
Analytical TLC was performed using 2.5 × 5 cm aluminum
plates coated with a 0.25 mm thickness of silica gel (60F-254),
visualization was accomplished with iodine and under a UV
lamp. Column chromatography was performed using silica gel
(60–120 and 100–200 mesh). Preparative thin layer chromato-
General procedure for Parikh–Doering oxidation
graphy was performed on GF254 silica by using the requisite An ice-cooled solution of the primary alcohols (obtained from
1
distilled solvent system as mentioned below. H NMR spectra the reduction of 6a–j) (1.034 mmol) in a dry DCM and DMSO
were recorded on 200, 300 and 400 MHz spectrometers in mixture (1.6 mL DCM and 2 mL DMSO for each mmol) was
CDCl3 (all signals are reported in ppm with the internal basified by triethylamine (5.173 mmol) and finally, Py·SO3 salt
chloroform signal at 7.26 ppm as standard) at 25 °C. 13C NMR (5.173 mmol) was added and allowed to stir at room tempera-
spectra were recorded on 50, 75 and 100 MHz spectrometers in ture for 30 min. After the completion of the reaction, it was
CDCl3 (all signals are reported in ppm with the internal quenched with H2O and then extracted with DCM three times
chloroform signal at 77.00 ppm as standard) at 25 °C. In a few (3 × 30 mL). The combined organic layer was washed with
cases, tetramethylsilane (TMS) at 0.00 ppm was used as the brine, dried over anhydrous Na2SO4 and the solvent was
1
reference standard. H NMR splitting patterns are designated removed in vacuo. The crude product was used for the next
as singlet (s), doublet (d), double doublet (dd), triplet (t), step without purification.
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Typical experimental procedure for diastereoselective Friedel–
Crafts cyclization to access amino acid-derived indoline and
tetrahydroisoquinoline scaffolds (11a–s, 12a–h)
L. Shang, A. W. G. Burgett, P. G. Harran and X. Wang, Proc.
Natl. Acad. Sci. U. S. A., 2007, 104, 2068.
8 T.-S. Kam, S.-J. Tan, S.-K. Ng and K. Komiyama, Org. Lett.,
2008, 10, 3749.
9 (a) A. Ramírez and S. García-Rubio, Curr. Med. Chem., 2003,
10, 1891; (b) G. Jagetia, M. S. Baliga, P. Venkatesh,
J. N. Ulloor, S. K. Mantena, J. Genebriera and V. Mathuram,
J. Pharm. Pharmacol., 2005, 57, 1213.
10 W. G. Kim, J.-P. Kim, H. Koshino, K. Shin-Ya, H. Seto and
I.-D. Yoo, Tetrahedron, 1997, 53, 4309.
To a 0.362 molar stirred solution of carbinol (8a–s, 10a–h) in
anhydrous DCM (15 mL), 1.5 equiv. of anhydrous AlCl3 was
added at 0 °C and stirred vigorously for 5 min to 2 h. After
completion of the reaction (as observed by TLC), water was
added under ice-cold conditions and the resulting mixture was
extracted as described above. The crude reaction mixture was
purified by silica gel column chromatography as well as pre-
parative thin layer chromatography to generate the desired
products.
11 (a) W. G. Kim, J. P. Kim and I. D. Yoo, J. Antibiot., 1996, 49,
26; (b) W. G. Kim, J. P. Kim, C. J. Lim, K. H. Lee and
I. D. Yoo, J. Antibiot., 1996, 49, 20.
12 (a) K. Higuchi and T. Kawasaki, Nat. Prod. Rep., 2007, 24,
843; (b) K. W. Bentley, Nat. Prod. Rep., 2005, 22, 249;
(c) T. Ozturk, The Alkaloids, ed. G. A. Cordell, Academic
Press, New York, 2000, vol. 53, p. 120; (d) M. Chrzanowska
and M. D. Rozwadowska, Chem. Rev., 2004, 104, 3341.
13 (a) M. Ludwig, C. E. Hoesl, G. Höefner and K. T. Wanner,
Eur. J. Med. Chem., 2006, 41, 1003; (b) R. B. Herbert, in The
Chemistry and Biology of Isoquinoline Alkaloids, ed.
J. D. Philipson, M. F. Roberts and M. H. Zenk, Springer,
Berlin, 1985, p. 213; (c) M. F. Dalence-Guzman, J. Toftered,
V. T. Oltner, D. Wensbo and M. H. Johansson, Bioorg. Med.
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New York, 1972.
Acknowledgements
This research project was partly supported by the CSIR
network project (BSC 0120). Sudipta thanks the Council of
Scientific and Industrial Research (CSIR), India for research
fellowship and Mr Purushottam for HPLC analysis. We would
like to thank the referees for their valuable suggestions which
helped us to improve the quality of the presentation. Instru-
mental facilities from SAIF, CDRI is acknowledged (CDRI Com-
munication no. 8787).
14 (a) M. Tateyama, S. Ohta, T. Nagao, M. Hirobe and
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