Enantioselective Synthesis of 3a-Amino-Pyrroloindolines by Copper-Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines

Article abstract of DOI:10.1002/anie.201508570

A direct asymmetric dearomative amination of tryptamines with O-(2,4-dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr-bisoxazoline complex as a catalyst, affording 3a-amino-pyrroloindolines in good to excellent enantioselectivity under mild reaction conditions. Furthermore, the synthetic value of this method was demonstrated in the total synthesis of (-)-psychotriasine in a highly concise manner. A direct asymmetric dearomative amination of tryptamines with O-(2,4-dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr-bisoxazoline complex as a catalyst, affording 3a-amino-pyrroloindolines in good enantioselectivity under mild reaction conditions. The synthetic value of this method was demonstrated in the total synthesis of (-)-psychotriasine in a highly concise manner.

Full text of DOI:10.1002/anie.201508570

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201508570
German Edition: DOI: 10.1002/ange.201508570
Synthetic Methods
Enantioselective Synthesis of 3a-Amino-Pyrroloindolines by Copper-
Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines
Chuan Liu, Ji-Cheng Yi, Zhong-Bo Zheng, Yong Tang,* Li-Xin Dai, and Shu-Li You*
Abstract: A direct asymmetric dearomative amination of
tryptamines with O-(2,4-dinitrophenyl)hydroxylamine (DPH)
was achieved using CuBr-bisoxazoline complex as a catalyst,
affording 3a-amino-pyrroloindolines in good to excellent
enantioselectivity under mild reaction conditions. Further-
more, the synthetic value of this method was demonstrated in
the total synthesis of (À)-psychotriasine in a highly concise
manner.
by employing an asymmetric Ireland–Claisen rearrangement
as a key step.[4e] Meanwhile, Baran and co-workers have made
great progress in the total synthesis of psychotrimine,[4b]
kapakahine F[4c] and kapakahine B[4c] through direct indole–
aniline coupling reactions. Recently, Liao, Deng, and their co-
workers reported a unified strategy for the syntheses of (À)-
psychotriasine and (+)-pestalazine B, based on the advanced
intermediates of 3a-amino-pyrroloindolines.[4i]
From a synthetic perspective, 3a-amino-pyrroloindoline is
a key intermediate for the synthesis of these natural
products.[6] However, to date, only limited enantioselective
methodologies have been developed for the synthesis of 3a-
amino-pyrroloindoline derivatives.[7] In 2012, the enantiose-
lective synthesis of 3a-amino-pyrroloindoline derivatives was
first reported by Antilla and co-workers[7a] using a chiral
phosphoric-acid-catalyzed dearomatization reaction of trypt-
amine derivatives with DEAD (diethyl azodicarboxylate).
Later Tosteꢀs group[7b] disclosed a highly enantioselective
synthesis of C3-diazenated pyrroloindolines by a chiral anion
phase-transfer (CAPT) catalysis technique. Then, 3a-amino-
pyrroloindolines could be obtained through a reduction
reaction.[4i]
P
yrroloindolines exist as key frameworks in a large number
of indole alkaloids and pharmacological compounds[1] that
exhibit interesting biological properties.[2] Among those, 3a-
amino-pyrroloindoline and derivatives[3] are privileged struc-
tures (Figure 1) that have attracted considerable attention[4]
owing to their distinctive structures and remarkable anti-
bacterial and antitumor properties.[3e,f, 5] For example, (+)-psy-
chotrimine was first synthesized by Takayama and co-workers
Despite these achievements, the development of direct
approaches to construct protecting-group-free 3a-amino-
pyrroloindolines remains highly desirable, and the catalytic
asymmetric version has not been reported.[8] In line with our
interest in developing catalytic asymmetric dearomatization
(CADA) reactions,[9,10] we envisioned that the unprotected
3a-amino-pyrroloindolines could be afforded by direct asym-
metric dearomative amination of tryptamines with O-(2,4-
dinitrophenyl)hydroxylamine (DPH) 2, which has been
elegantly introduced as an amination reagent by Ess, Kürti,
Falck, and their co-workers (Scheme 1).[11] Herein, we report
our preliminary results on the enantioselective synthesis of
3a-amino-pyrroloindolines by copper-catalyzed intermolecu-
lar asymmetric dearomative amination of tryptamines.
Our initial studies focused on testing the reaction between
tryptamine 1a and DPH with various chiral copper com-
plexes.[12] These efforts led to the identification of bisoxazo-
line L1 as a promising ligand. Further evaluation of copper
source (Table 1, entries 1–9) revealed that CuBr is optimal,
affording product 3a in 53% yield and 63% ee (Table 1,
entry 4). Encouraged by these results, different solvents were
further examined, and the polar protic solvent 2,2,2-trifluor-
oethanol was found to be the best one in terms of enantio-
selectivity (73% ee; Table 1, entry 14). Furthermore, different
chiral bisoxazoline ligands were evaluated, and chiral ligands
were found to play a critical role in the enantioselective
control. Compound 3a was obtained in 75% ee with cyclo-
propane-linked ligand L2 (Table 1, entry 19), and in 78% ee
Figure 1. Representative 3a-amino-pyrroloindoline-containing natural
products.
[*] Dr. C. Liu, J.-C. Yi, Dr. Z.-B. Zheng, Prof. Dr. Y. Tang, Prof. L.-X. Dai,
Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: tangy@sioc.ac.cn
slyou@sioc.ac.cn
Prof. Dr. Y. Tang, Prof. Dr. S.-L. You
Collaborative Innovation Center of
Chemical Science and Engineering
Tianjin (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508570.
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with indano scaffold ligand L3 (Table 1, entry 20). To our
delight, when methyl groups were introduced (ligand L4), the
ee was improved to 84% (Table 1, entry 21). Finally, ligand L5
with isopropyl groups was found to be the best one, providing
product 3a in 43% yield and 88% ee (Table 1, entry 22).
Conducting the reaction at À208C further enhanced the
enantioselectivity to 92% ee (Table 1, entry 23). When
methanol and 2,2,2-trifluoroethanol were used as co-sol-
vents,[12] product 3a was obtained in 65% yield and 90% ee
(Table 1, entry 24). Notably, reaction in methanol alone gave
an increased yield but decreased enantioselectivity (68%
yield, 84% ee; Table 1, entry 25).
With the optimized reaction conditions in hand (Table 1,
entry 24), we turned to explore the substrate scope (Table 2).
Typical electron-withdrawing N-protecting groups (R2 =
CO2Me, Boc, Ts, CO2Ph) on the side chain of tryptamine
were all well tolerated, providing the desired 3a-amino-
pyrroloindoline products in good to excellent ee and moder-
ate yields (86–90% ee, 40–65% yield; Table 2, 3a–
d). Furthermore, the reactions of substrates bearing
either an electron-rich (R1 = Me, Bn, allyl) or
electron-poor (R1 = CO2Me) substituent on the
indole nitrogen atom proceeded smoothly (81–
92% ee, 42–50% yield; Table 2, 3e–h).
Scheme 1. Proposed copper-catalyzed asymmetric dearomative amina-
tion of tryptamines.
Table 1: Optimization of the reaction conditions.[a]
Next, the substrate scope of substituted trypt-
amines was explored. Tryptamine derivatives bear-
ing either an electron-donating group (5-MeO, 5-
Me, 6-Me, 7-Me) or an electron-withdrawing group
(4-Cl, 4-Br, 5-F, 5-Cl, 5-Br, 6-F, 6-Cl, 7-Br) on the
indole core were found to be well tolerated, afford-
ing the corresponding 3a-amino-pyrroloindolines in
moderate yields with excellent enantioselectivity
(33–69% yield, 82–95% ee; Table 3). Notably, the
compatibility of the Br substituent provides the
potential for further transformation by cross-cou-
pling reactions. Although the yields are moderate,
the reactions in general are clean by TLC (thin layer
chromatography) detection, and the products are
easy to be purified. The moderate yields are likely
due to the formation of unidentified oligomers and
the side reactions of primary amines 3 with DPH.
The synthetic value of this methodology has
been demonstrated by the total synthesis of (À)-
psychotriasine. In the presence of (CuOTf)2·PhMe,
3a-amino-pyrroloindoline 3a was reacted with dia-
ryliodonium salt 4, affording compound 5 in 64%
yield,[4i] which was then converted to compound 6 by
a Larock annulation reaction (Scheme 2).[4d] Further
reduction of 6 with LiAlH4 gave (À)-psychotriasine
in 85% yield. Such an asymmetric total synthesis of
(À)-psychotriasine features 31.8% overall yield in
four steps from methyl (2-(1H-indol-3-yl)ethyl)car-
bamate (1a). Furthermore, the total synthesis of
(À)-psychotriasine suggested the absolute configu-
ration of product 3a as (3S,8R).[3h,12]
Entry
[Cu]
Solvent
L
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Cu(OTf)·0.5PhMe
[Cu(CH3CN)4PF6]
CuCl
CuBr
CuI
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP/EtOH
HFIP
MeOH
EtOH
i-PrOH
CF3CH2OH
EtOAc
toluene
CH3CN
DCM
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH/MeOH
MeOH
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L5
L5
L5
21
14
66
53
trace
17
21
15
20
54
44
23
21
43
trace
5
14
trace
50
60
57
50
61
63
–
51
53
55
47
70
71
55
51
73
–
–
51
–
75
78
84
88
92
90
84
CuTc
Cu(OAc)2
Cu(acac)2
Cu(Cl4O)2·6H2O
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
24[d,e]
25[d]
51
43
44
65
CuBr
68
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), metal (10 mol%), L
In conclusion, we have developed a copper-
catalyzed direct asymmetric dearomative amination
of substituted tryptamines with DPH for the syn-
thesis of 3a-amino-pyrroloindolines, a privileged
(11 mol%) in solvent (3.0 mL) at rt, unless otherwise noted. After 8 h, another batch
of 2 (0.1 mmol) was added in one portion. [b] Isolated yields. [c] Determined by
HPLC analysis. [d] Reaction at À208C. [e] CF3CH2OH (1.5 mL) and MeOH (1.5 mL)
were used as co-solvents.
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Table 2: Substrate scope: N-protecting groups.[a]
Scheme 2. Total synthesis of (À)-psychotriasine.
Foundation of China (21332009, 21421091) for generous
financial support.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), CuBr (0.02 mmol),
L5 (0.022 mmol) in CF3CH2OH (1.5 mL) and MeOH (1.5 mL) at À208C.
After 8 h, another batch of 2 (0.1 mmol) was added in one portion. Yield
refers to isolated products. The ee values were determined by HPLC
analysis.
Keywords: asymmetric catalysis · copper · dearomatization ·
pyrroloindolines · tryptamines
How to cite: Angew. Chem. Int. Ed. 2016, 55, 751–754
Angew. Chem. 2016, 128, 761–764
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[a] Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), CuBr (0.02 mmol),
L5 (0.022 mmol) in CF3CH2OH (1.5 mL) and MeOH (1.5 mL) at À208C.
After 8 h, another batch of 2 (0.1 mmol) was added in one portion. Yield
refers to isolated products. The ee values were determined by HPLC
analysis.
structure present in various indole alkaloids. This method
provides facile access to structurally diverse 3a-amino-pyrro-
loindolines in good to excellent enantioselectivity and mod-
erate yields under mild reaction conditions. Furthermore, the
synthetic value of this new method was demonstrated in the
total synthesis of (À)-psychotriasine in a highly concise
manner.
Acknowledgements
We thank the National Basic Research Program of China (973
Program 2015CB856600) and the National Natural Science
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Received: September 13, 2015
Revised: November 4, 2015
Published online: November 25, 2015
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