Oxidative asymmetric formal aza-Diels–Alder reactions of tetrahydro-β-carboline with enones in the synthesis of indoloquinolizidine-2-ones

Article abstract of DOI:10.3390/molecules23092228

Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Diels–Alder reaction for enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-β-carbolines and α,β-unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-catalyzed formal aza-[4 + 2] cycloaddition, providing a step-economical strategy for the synthesis of these valuable heterocyclic products.

Full text of DOI:10.3390/molecules23092228

molecules
Communication
Oxidative Asymmetric Formal Aza-Diels–Alder
Reactions of Tetrahydro-β-carboline with Enones in
the Synthesis of Indoloquinolizidine-2-ones
Xiang Wu * ID , Shi-Bao Zhao, Lang-Lang Zheng and You-Gui Li *
Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of
Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, China;
zsbhfut@mail.hfut.edu.cn (S.-B.Z.), zhengll@mail.hfut.edu.cn (L.-L.Z.)
*
Correspondence: wuxiang@hfut.edu.cn (X.W.); liyg@hfut.edu.cn (Y.-G.L.); Tel./Fax: +86-551-6290-1450 (X.W.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 26 July 2018; Accepted: 29 August 2018; Published: 1 September 2018
Abstract: Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Diels–Alder reaction for
enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-
β-carbolines
and -unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed
α,β
amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-
catalyzed formal aza-[4 + 2] cycloaddition, providing a step-economical strategy for the synthesis of
these valuable heterocyclic products.
Keywords: aza-Diels–Alder reaction; indoloquinolizidine-2-ones; enantioselective catalysis; cooperative
catalysis; ruthenium
1. Introduction
Aza-Diels–Alder reaction is one of the most efficient and direct approaches for the synthesis
of six-membered N-heterocycles, especially in the syntheses of biologically active natural products
and pharmaceutical compounds [
been rarely applied in the synthesis of indoloquinolizidine derivatives [10
a unique nitrogen-containing skeleton, is often embedded in indole alkaloids—such as reserpine
dihydrocorynantheol , and hirsutine —which exhibit a wide range of biological activities
(Figure 1) [13 15]. In 2006, Itoh and co-workers described a proline-catalyzed asymmetric formal
aza-Diels–Alder reaction for the synthesis of ent-dihydrocorynantheol 16 17]. In 2013, Jacobsen et al.
1–
9
]. Despite all these advantages, aza-Diels–Alder reaction has
–12]. Indoloquinolizidine,
1,
2
3
–
2
[
,
reported a highly enantio- and diastereoselective synthesis of indololizidine compounds through the
formal aza-Diels–Alder reaction of cyclic imines with enones catalyzed by a bifunctional primary
aminothiourea (Scheme 1a) [18], which has been approved to be an efficient and practical method by
a successful enantioselective total synthesis of reserpine
reaction, an emerging efficient approach combining two processes of oxidative generation of imines
and subsequent cycloaddition, has been applied in synthesis of N-heterocycles [20 36]. In this
process, C–C and C–N bonds are formed simultaneously via direct oxidative functionalization of
C–H [37 39] and N–H bonds, and tedious pre-functionalization and intermediate purification are
avoided. In continuation of our ongoing studies on the oxidative cycloadditions for the synthesis of
structurally complex compounds [24 36], herein we report the Ru-catalyzed tandem amine oxidative
dehydrogenation/formal aza-Diel–Alder reaction for enantio- and diastereoselective synthesis of
indoloquinolizidine-2-ones from -unsaturated ketones , in which the cyclic imine dienophiles
were generated in situ from tetrahydro-β-carbolines 4 by oxidation (Scheme 1b).
1 [19]. Recently, the oxidative aza-Diels–Alder
–
–
,
6
α
,β
5
I
Molecules 2018, 23, 2228; doi:10.3390/molecules23092228
www.mdpi.com/journal/molecules

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Figure 1. Selected indole alkaloids containing indoloquinolizidine motifs.
Scheme 1. Asymmetric formal aza-Diels–Alder reaction for the synthesis of Indoloquinolizidine-2-ones.
2. Results and Discussion
At the beginning of this work, we evaluated the model reaction of tetrahydro-
with enone 5a, in the presence of acetic acid, using tert-butyl hydroperoxide (TBHP) in decane as the
oxidant and primary amine-thiourea as the bifunctional catalyst which allows dual activation of
the reaction components by the hydrogen bond donor and primary amine (Table 1) [18 19 36]. In the
presence of the oxidant alone, the desired formal aza-Diels–Alder product could not be obtained
β-carboline 4
T
,
,
6
(entry 1). In the presence of Cu salt, the diastereoisomers 6aa and 7aa were obtained in 22% yield
with poor diastereomeric ratio (dr) and enantioselectivities (entry 2). Ruthenium complexes exhibit
cytochrome P450-like activity to catalyze selective oxidative demethylation of tertiary methyl amines
in the presence of peroxides or molecular oxygen [40
employed in the reaction system, the desired products could be obtained in moderate yields with
moderate dr and ee (entries 3 5). Among these, RuCl2(PPh3)3 gave the best enantioselectivety (69% ee
–42]. When several r4uthenium catalysts were
−
of 6aa and 66% ee of 7aa) albeit in lower yield and poorer dr (entry 5). Interestingly, when the amount
of acetic acid decreased to 15 mol %, the ee values increased significantly to 87% and 83% respectively
and the yield and dr were both improved slightly (entry 6 vs. entry 5). Compared to PhCOOH,
o-F-PhCOOH or the absence of acid, CH3CO2H gave the best results in the reaction (entry 6 vs. entries
7–9). Several oxidants were further investigated, among them only TBHP could afford the desired
products effectively (entry 6 vs. entries 10–12). Final evaluation of the solvents showed that toluene
was the most suitable medium to give the best results (entry 6 vs. entries 13–16). When the reaction
solution was diluted to 0.2 M in toluene, the best yield (73%) and enatioselectivities (94% ee of 6aa and
90% ee of 7aa) were obtained with moderate diastereomeric ratio (entry 17).

Molecules 2018, 23, 2228
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Table 1. Optimization of the reaction conditions *.
Acid
(mol %)
Yield **
(%)
dr ***
(6aa:7aa)
ee **** (%)
(6aa/7aa)
Entry
Metal Salt
Oxidant Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17 ˆ
–
CH3COOH (30)
CH3COOH (30)
CH3COOH (30)
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
PhI=O
DDQ
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
–
22
44
50
37
40
32
30
24
–
–
–
Cu(OAc)2
RuCl3·xH2O
1.8:1
3.4:1
1.8:1
1.3:1
2:1
15/14
27/35
60/59
69/66
87/83
79/76
71/71
51/51
–
[RuCl2(p-cymene)]2 CH3COOH (30)
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
CH3COOH (30)
CH3COOH (15)
PhCOOH (15)
o-F-PhCOOH (15)
–
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
CH3COOH (15)
1:1
2.8:1
2.2:1
–
–
–
1.8:1
6:1
10:1
8:1
–
–
–
trace
17
7
11
21
73
89/89
64/70
75/72
70/70
94/90
CHCl3
CH3CN
CH2Cl2
toluene
1.8:1
* Unless indicated otherwise, the reaction of
4 (0.2 mmol), 5a (0.3 mmol), thiourea catalyst T (0.03 mmol), metal
salt (0.004 mmol), acid and oxidant (0.2 mmol) were carried out in 0.25 mL of solvent at 0 ◦C over 72 h. ** Yields of
isolated diastereomeric mixture following flash column chromatography on silica gel. *** Determined by 1H-NMR
analysis. **** Determined by HPLC analysis. ˆ 1 mL of anhydrous toluene was used.
Having established the optimal reaction conditions, the generality of this oxidative formal
aza-Diel–Alder reaction for enones was then investigated. A variety of aryl-substituted enones 5b
reacted smoothly with tetrahydro- -carboline under the optimized conditions to afford products
6ab an in moderate to satisfactory yields with good diastereoselectivities and high enantioselectivities
-n
β
4
-
(Table 2). Regardless of the position of the methyl group on the phenyl ring, moderate yields and high
ee values were obtained (entries 2–4). Electron-withdrawing groups in the different positions of the
phenyl ring afforded the corresponding products 6af-ai with good results (entries 5–8). Interestingly,
substrate 5j with five fluorine atoms on the phenyl ring or the substrates 5k and 5l with two substituents
on the phenyl rings gave the desired products with excellent diastereoselectivities (>10:1) in moderate
yields. Moreover, α,β-unsaturated ketones bearing 2-thiophene or 2-furan also performed well and
led to the products with good stereochemical outcomes (6am and 6an). Importantly, linear alkyl
group subtituted enone 5o could also undergo the reaction smoothly and afford the product 6ao with
excellent diastereoselectivities (>10:1) and good enantioselectivity, albeit the yield was low relatively,
even prolonging reaction time to 96 h. Some other enones such as 5-methyl-3-methylenehexan-2-one
and (E)-1-phenylpent-1-en-3-one have been employed in the reaction, unfortunately, no desired
products were obtained (see Supplementary Materials). The absolute configuration of
6 and 7 was
established according to the retention time in HPLC using chiral columns and comparison with the
data obtained for the same known products reported by Jacobsen et al. [18].
Similar to the results of the 1,2,3,4-tetrahydroisoquinolines [36], under oxidative conditions,
tetrahydro-β-carbolines afforded corresponding (4R,12bS)-6 as the major stereoisomer having
a cis-H/H relationship which is different from the outcomes of the formal aza-Diels–Alder
reaction of imines with enones [18]. Therefore, the same plausible mechanism can be proposed
(Figure 2). Intermediate imine
B (dihydro-β-carboline) can be formed through the oxidation of 4

Molecules 2018, 23, 2228
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by oxoruthenium (IV) intermediate
A
which is generated from the Ru(II) catalyst in the presence of
TBHP. Then, imine
B enters another catalytic cycle and undergoes a formal aza-Diels–Alder reaction
with enone, which is similar to the pathway hypothesized by Jacobsen’s group. Finally, the Ru
complex present in the reaction mixture promotes epimerization at C-4, leading to the thermodynamic
(4R,12bS)-adducts (6) after liberation from the thiourea catalyst T. The epimerization can take place by
either retro-Mannich/Mannich or amine β-elimination/conjugated addition sequences [18].
Table 2. Scope of various α,β-unsaturated ketones *.
Yield
** (%)
dr ***
(6:7)
ee **** (%)
(6/7)
Entry
5
R
t (h)
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
C6H5
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-ClC6H4
p-BrC6H4
p-CF3C6H4
m-NO2C6H4
C6F5
48
72
72
72
72
48
36
72
48
72
72
60
48
96
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
6aj
6ak
6al
6am
6an
6ao
31
36
41
61
34
65
35
37
57
45
45
48
42
24
1:1
1.8:1
1:1
1.5:1
1:1
1.2:1
1.6:1
1:1
>10:1
>10:1
>10:1
1.3:1
1:1
96/91
82/95
88/92
94/96
93/91
85/87
86/93
94/85
86
92
85
89/93
96/95
85
2,3-Cl2C6H3
2,4-(NO2)2C6H3
2-thienyl
2-furyl
CH=CMe2
>10:1
* Reaction conditions:
4 (0.2 mmol), 5 (0.3 mmol), T (0.03 mmol), AcOH (0.03 mmol), RuCl2(PPh3)3 (0.004 mmol),
and TBHP (0.2 mmol) in toluene (1.0 mL) at 0 ◦C. ** Yields of isolated diastereomeric mixture following flash column
chromatography on silica gel. *** Determined by 1H-NMR analysis. **** Determined by HPLC analysis.
Figure 2. Proposed reaction pathway.

Molecules 2018, 23, 2228
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3. Materials and Methods
NMR spectra were recorded on Aglient-600 MHz (Agilent Technologies, PaloAlto, CA, USA)
or Brucker-400 MHz spectrometer (Bruker, Billerica, MA, USA) using CDCl3 as solvent and TMS as
internal standard unless otherwise stated. Mass spectra were recorded on a Thermo LTQ Orbitrap XL
(ESI+) (Bruker, Billerica, MA, USA). HPLC analysis was performed on Agilent 1200 (UV detection
monitored at 210 nm) (Waters, Milford, MA, USA). Chiralpak OD-H, AD-H, and IC-H columns were
purchased from Daicel Chemical Industries, LTD. (Shanghai, China) Specific optical rotations ([
α
])
◦
were measured using a Perkin-Elmer 341 polarimeter (PerkinElmer, Waltham, MA, USA) at 25 C with
a sodium lamp (D line, 589 nm). Column chromatography was performed on silica gel (200–300 mesh)
eluting with ethyl acetate and petroleum ether. TLC was performed on glass-backed silica plates.
Ketone substrates were prepared according to the literature report [43]. Thiourea
T was prepared
according to the literature report [18]. 9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was prepared
according to the literature report [44,45].
Typical procedure for the ruthenium-catalyzed enantioselective oxidative formal aza-Diels–Alder
reactions: Thiourea
T (14.0 mg, 0.03 mmol, 0.15 equiv.), tris(triphenylphosphine)ruthenium (II)
dichloride (3.8 mg, 0.004 mmol, 0.06 equiv.), 9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (
4
)
(65.2 mg, 0.2 mmol, 1.0 equiv.), (E)-4-(4-methoxyphenyl)but-3-en-2-one (5a) (52.8 mg, 0.3 mmol,
1.5 equiv.) were loaded into a tube equipped with a stir bar. A stock solution of glacial acetic acid
in anhydrous toluene (0.5 M) was added in one portion at room temperature via syringe (60 µL,
0.03 mmol AcOH, 0.15 equiv.). Anhydrous toluene (1 mL) was then added. The reaction mixture was
stirred at 0 ◦C◦for 10 min, then the solution of tert-butyl hydroperoxide in decane (5.5 M) was added
dropwise at 0 C via syringe (32
0 C for 72 h. The crude mixture was concentrated and was purified through column chromatography
µ
L, 0.2 mmol TBHP, 1 equiv.) over 45 min. The reaction was stirred at
◦
on silica gel (petroleum ether/EtOAc = 30/1 to 5/1) to afford title compounds 6aa and 7aa.
4. Conclusions
In conclusion, we have presented the diastereo- and enantioselective oxidative formal aza-
Diels–Alder reaction of tetrahydro-β-carboline and α,β-unsaturated ketones under the cooperative
catalysis of Ru(II) salt and chiral aminothiourea in the presence of TBHP, yielding functionalized
(4R,12bS)-indoloquinolizidine-2-ones. The practical protocol of asymmetric oxidative formal aza-
Diels–Alder enlarges the substrate scope and offers interesting new opportunities to synthesize the
natural products and pharmaceutical compounds further.
Supplementary Materials: Electronic Supplementary Information (ESI) are available online: General and
characterization data, 1H- and 13C-NMR spectra for all compounds, are available online.
Author Contributions: S.B.Z. and L.L.Z. performed the experiments and analyzed the data. X.W. and Y.G.L.
wrote the paper. All of the authors read and approved the final version of the manuscript before submission.
Funding: This research was funded by financial support from the National Natural Science Foundation of China
(NNSFC) (grant [21672049]).
Acknowledgments: We gratefully thank Hefei University of Technology for financial support.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds 6 and 7 are available from the authors.
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