Asymmetric synthesis of tetrahydroquinolines through supramolecular organocatalysis

Article abstract of DOI:10.1039/c4ob00570h

Functionalized chiral tetrahydroquinolines were synthesized through supramolecular organocatalysis using quinidine-NH-thiourea 3c/l-phenylalanine 4i followed by reductive amination from the simple substrates. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00570h

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Biomolecular Chemistry
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Asymmetric synthesis of tetrahydroquinolines
through supramolecular organocatalysis†
Cite this: Org. Biomol. Chem., 2014,
12, 4300
Dhevalapally B. Ramachary* and Kodambahalli S. Shruthi
Received 15th March 2014,
Accepted 28th April 2014
DOI: 10.1039/c4ob00570h
www.rsc.org/obc
Functionalized chiral tetrahydroquinolines were synthesized
through supramolecular organocatalysis using quinidine-NH-
thiourea 3c/L-phenylalanine 4i followed by reductive amination
from the simple substrates.
Tetrahydroquinolines are privileged structural moieties found
in various natural and biologically active compounds. Some of
them have shown a variety of potent biological activities such
as antibacterial, antimalarial, antitumor, antiallergic, anti-
convulsant, antioxidant and cardiovascular activity.1 Particularly,
2-methyl-1,2,3,4-tetrahydroquinoline is found in the human
brain as an endogenous alkaloid. Functionalized chiral 2-alkyl-
tetrahydroquinolines have attracted considerable attention
from organic and medicinal chemists due to their many
pharmaceutical applications (Fig. 1).
Fig. 1 Natural products with a tetrahydroquinoline core structure and a
design plan for the asymmetric synthesis of this scaffold through supra-
molecular organocatalysis.
For the asymmetric synthesis of chiral tetrahydroquino-
lines, previous approaches mainly depend on the asymmetric
hydrogenation of the corresponding hetero-aromatic com-
pounds,2 nucleophilic addition of cyclic imines,3 or the
Povarov reaction.4 Even though a few organocatalytic reactions
have been reported,5 direct and efficient asymmetric methods
for their preparation are still a challenging task. However, to
develop a diversity platform for the asymmetric synthesis of
2,4-disubstituted tetrahydroquinolines with high selectivity, we
propose herein a synthetic plan based on the enamine
induced Michael reaction as the first step (Fig. 1). The organo-
catalytic asymmetric Michael reaction of functionalized
1-azido-2-(2-nitrovinyl)benzene 1 with ketone 2 followed by
reductive amination yields the expected product 6 (Fig. 1).
Over the past few years, the organocatalytic asymmetric
Michael reaction has become a viable tool for C–C bond for-
mation with good selectivity under mild reaction conditions.6
The standard organocatalysts for the Michael reaction include
proline derivatives or cinchona alkaloid-based primary amines
and thioureas. To execute the hypothesis of the reaction
design, first we propose the asymmetric Michael reaction, for
which we have chosen 1-azido-2-(2-nitrovinyl)benzene 1a and
acetone 2a as the model substrates with 3 and 4 as catalysts.
Surprisingly, when we performed the Michael reaction of 1a
with 14 equiv. of 2a under the standard reaction conditions,
the product 5aa was obtained in moderate to poor yields and
ees (Table 1, entries 1–6). In order to ameliorate the yield and
enantioselectivity, instead of screening new catalysts, we
initiate the use of the emerging chiral supramolecular organo-
catalysts,7 which can be assembled in situ from the easily avail-
able simple organocatalysts 3 and 4 through weak interactions.
As anticipated, treatment of 1a and 2a with Zhao’s supramole-
cular organocatalyst (each 5 mol% of catalysts 3c and 4a)7b in
benzene at 25 °C for 108 h furnished the expected keto azide
5aa in moderate yield (56%) and promising ee (49%) (Table 1,
entry 7).
Catalysis Laboratory, School of Chemistry, University of Hyderabad,
Hyderabad 500 046, India. E-mail: ramsc@uohyd.ernet.in
†Electronic supplementary information (ESI) available: Experimental procedures
and analytical data (1H NMR, 13C NMR, HRMS and HPLC) for all new com-
pounds. CCDC 955384. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c4ob00570h
Recently, asymmetric supramolecular-organocatalysis has
become an innovative tool for achieving high asymmetric
induction and faster reaction rates from reactions involving
highly functionalized starting materials, when compared to
organocatalysis.7 Disappointingly, when we performed the
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Table 1 Reaction preliminary optimizationa
Table 2 Scope of the asymmetric supramolecular catalysisa,b
Catalyst 3/4
(each 5 mol%)
Solvent
(0.3 M)
Time
(h)
Yieldb
(%) 5aa
eec (%)
5aa
Entry
1d
2e
3
3a/PhCO2H
3b/PhCO2H
3c/PhCO2H
4a
4a
4i
3c/4a
3d/4b
3c/4j
3c/4j
3c/4i
DCM
DCM
DCM
DMSO
DCM
DCM
C6H6
DCM
C6H6
DCM
CH3C6H5
DCM
DMSO
DCM
84
96
72
6
96
72
108
28
144
72
72
72
72
72
40
23
—
69
16
—
56
85
27
17
46
90
52
13
43
18
—
3
11
—
49
24
94
95
92
92
6
4f
5f
6
a Yield refers to the column-purified product. b ee was determined by
CSP-HPLC analysis.
7
8
9
10
11
12
13
14
dominates), using either 3c or 4i as the catalyst or using the
catalyst combination 3c/4q (where in 4q is methyl ester of 4i
and so does not have free-acid for weak interactions) was
ineffective in promoting the Michael reaction (Table 1, entries
3, 6, 13 and 14). These results clearly support our hypothesis
of involvement of supramolecular assembly as a catalyst.7
The principle of the supramolecular-organocatalysis was
further extended by reacting a group of functionalized 1-azido-
2-(2-nitrovinyl)benzenes 1b–h with 14 equiv. of acetone 2a
each catalyzed by 5 mol% of 3c/4i at 25 °C in DCM for 72 h
(Table 2). All the substrates 1b–h furnished the chiral keto
azides 5ba–ha in good yields and excellent ees, irrespective of
the electronic factors of the substituents present. Treatment of
1b with deuterated acetone 2a-d6 furnished the expected chiral
keto azide 5ba-d7 in 55% yield with 89% ee without much
alteration in the reaction rate (Table 2).
After synthesizing the optically pure keto azides 5, we
further transformed them into medicinally significant functio-
nalized tetrahydroquinolines 6 through reductive amination
using the Bencivenni–Nanni protocol.8 Thorough optimization
of 5aa → 6aa through single step reductive amination or two
steps aza-Wittig/hydrogenation proved that InCl3–Et3SiH in
MeOH at 0–25 °C is the suitable condition to prepare the 6aa
in good yield with high de/ee (Tables S2 and S3, see ESI-1† for
full details). We then subjected the optically pure keto azide
(−)-5aa to reductive amination conditions with triethylsilane
and InCl3 at 0–25 °C for 12 h.8b To our delight, the reductive
amination product (−)-syn-6aa was isolated in 60% yield with
3c/4i
3c/4i
3c/4q
11
a Unless stated otherwise, all reactions were carried out with 1a
(0.3 mmol), 2a (4.2 mmol, 14 equiv.), catalyst 3 or 4 (5 mol%) in DCM
at rt. b Yield refers to the column purified product. c ee was determined
by CSP-HPLC analysis. d 3a/PhCO2H (20 mol% each) was used. e 3b/
PhCO2H (10 mol% each) was used. f 20 mol% of 4a was used.
Michael reaction of 1a and 2a with known supramolecular
assembly catalysts of Ramachary’s 3d/4b7e or Zhao’s 3c/4j,7b we
obtained either less yield or low ee (Table 1, entries 8–10). To
overcome this problem, we screened different supramolecular
organocatalysts assembled in situ from the library of organo-
catalysts 3 and 4 (Tables 1 and S1†). After thorough investigation
of the asymmetric Michael reaction of 1a and 2a under the cat-
alysis of supramolecular assembly, in situ generated from 3c or
3d with sixteen amino acids 4a–p gave the interesting results
that the amino acids L-cysteine 4e, L-isoleucine 4g, L-phenylgly-
cine 4j, O-tert-butyl-L-threonine 4m, L-tryptophan 4n or L-valine
4p in combination with 3c furnished the keto azide (−)-5aa in
moderate to poor yields with high enantioselectivity (Table S1,
see ESI-1† for full details). The same reaction under the combi-
nation of 3c with the amino acid L-phenylalanine 4i in DCM
gave the keto azide (−)-5aa in 90% yield with 92% ee within
72 h as the best optimized condition (Table 1, entry 12). Intri-
guingly, deviating from this optimized condition, by switching
the solvent to DMSO (interactions arising from the solvent pre-
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Table 3 Reductive amination of the chiral keto azidesa,b,c
Scheme 1 Controlled experiments to study the N3 involvement in the
pre-transition state (pre-TS).
NO2 disturbs the supramolecular assembly and diminishes the
rate, yield and ee of the reactions (Scheme 1). We gained some
more evidence for the involvement of hypothetical pre-tran-
sition state supramolecular assembly, by careful investigation
of the on-going reaction of 1a and 2a under the 3c/4i- and 3c/
4m-catalysis using ESI-HRMS technique, which enabled us to
identify the proposed catalytic pre-transition state intermedi-
ates (Fig. S2, see ESI-1† for full details).7
a Yield refers to the column-purified product. b ee was determined by
CSP-HPLC analysis. c dr was determined based on 1H NMR or HPLC
analysis.
With controlled experimental data, herein we securely illus-
trate the mechanism of the asymmetric Michael reaction
through conformationally flexible cyclic 22-membered pre-
transition state supramolecular assembly by 3c/4i-catalysis and
the reaction most probably proceeds through the TS-1 mechan-
ism (Fig. 2). We emphasize five interactions between the sub-
strates and the catalysts to support a cyclic 22-membered pre-
transition state assembly (TS-1) to furnish the chiral keto
azides 5 over the less stable TS-2. Based on our observations,
(i) the CO2H group of L-4i undergoes hydrogen bonding with
the tert-amine group of 3c, which brings the two catalysts
closer to the reaction centre; (ii) NH groups of 3c involves the
hydrogen-bonding with both N3 and NO2 groups of 1a–h to
activate the electrophilic nature of olefin; (iii) the primary
amino group of L-4i forms enamine with acetone to activate
the nucleophilic nature; (iv) finally the NO2 group of 1a–h
undergoes hydrogen-bonding with enamine NH, thus closing
71% de and 90% ee (Table 3). The selective reductive amin-
ation strategy was demonstrated with five more substrates of 5
containing halogen, CF3 and CN substituents to furnish the
syn-tetrahydroquinolines 6 in good yields with high de/ee
(Table 3). The amine compounds, syn-6 are structural ana-
logues of natural products A–D,1 which is accentuating the
relevance of the sequential Michael-reductive amination
approach to synthesize these compounds. The structure and
absolute stereochemistry of the keto azides 5 and reductive
amination products syn-6 were confirmed by NMR analysis
and also finally confirmed by X-ray structure analysis of
(−)-syn-6ba as shown in Fig. S1 (ESI-1†).9
Furthermore we performed a few controlled experiments to
investigate the involvement of N3, NO2 and other active func-
tional groups of the substrates and the catalysts in the pre-
transition state of the Michael reaction (Scheme 1). In addition
to NO2, N3 also involves the hydrogen bonding with the N–H
group of 3c, due to this reason, the position of N3 on the aryl
is crucial for achieving the high rate and selectivity. This state-
ment was proven by obtaining very poor yields and ees of
Michael products 8aa–8ba for the longer reaction times from
the reaction of 7a–7b and 2a with the 3c/4i-catalysis
(Scheme 1). To support this, we carried out the reaction of 2a
with N3-free substrates 7c–f, which gave better results com-
pared to 7a–b and this confirms that N3 competes for hydro-
gen bonding with 3c in addition to NO2 (Scheme 1).
Surprisingly, there is no reaction observed between 2a and
ortho-NHTs substrate 7g under the optimized conditions
(Scheme 1). It appears that a topological modification in the
pre-transition state assembly by decreasing single directional
hydrogen-bonding between the N–H group of 3c and ortho-N3/
Fig. 2 Proposed reaction mechanism.
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the mobile 22-membered supramolecular cyclic pre-transition
state to control the enantioselectivity (Fig. 2).
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ð1Þ
With applications in mind, we explored the utilization of
(−)-syn-6aa and (−)-5ba-d7 in the synthesis of functionalized
drug-like compounds (+)-syn-9aa and (+)-10ba-d7 via simple
N-methylation and a click reaction, respectively (eqn (1)).10
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pharmaceuticals.
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In summary, we have demonstrated a novel and efficient
in situ generated chiral supramolecular assembly as the best cata-
lyst than its synthons for the asymmetric Michael reaction of
acetone with (E)-1-azido-2-(2-nitrovinyl)benzenes followed by
reductive amination to furnish the medicinally important syn-
2,4-disubstituted tetrahydroquinolines 6 with high yield, ees
and des. With the help of the ESI-HRMS technique and con-
trolled experiments, we have obtained strong evidence for the
in situ formation of proposed catalytic supramolecular assem-
bly from the organocatalysts. Readily in situ generated chiral
supramolecular assembly catalysts would become promising
future catalytic systems for more functionalized substrates
than organocatalysts.
We thank DST (New Delhi) for financial support. KSS thank
CSIR, New Delhi for her research fellowship.
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