Gold-Catalyzed Asymmetric Intramolecular Cyclization of N-Allenamides for the Synthesis of Chiral Tetrahydrocarbolines

Article abstract of DOI:10.1002/anie.201709595

Highly enantioselective gold-catalyzed intramolecular cyclization of N-allenamides was implemented by utilizing a designed chiral sulfinamide phosphine ligand (PC-Phos). This represents the first example of highly enantioselective intramolecular cyclization of N-allenamides. The practicality of this reaction was validated in the total synthesis of (R)-desbromoarborescidine A and formal synthesis of (R)-desbromoarborescidine C and (R)-deplancheine. Moreover, the catalyst system PC-Phos/AuNTf₂ proved to be specifically efficient to promote the desymmetrization of N-allenamides in excellent yields with satisfactory ee values.

Full text of DOI:10.1002/anie.201709595

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Accepted Article
Title: Gold-Catalyzed Asymmetric Intramolecular Cyclization of N-
Allenamides for the Synthesis of Chiral Tetrahydrocarbolines
Authors: Junliang Zhang, Yidong Wang, Pei-Chao Zhang, Xiaoyu Di,
Qiang Dai, and Zhan-Ming Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709595
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10.1002/anie.201709595
Angewandte Chemie International Edition
COMMUNICATION
Gold-Catalyzed Asymmetric Intramolecular Cyclization of N-
Allenamides for the Synthesis of Chiral Tetrahydrocarbolines
Yidong Wang†, Peichao Zhang†, Xiaoyu Di, Qiang Dai, Zhan-Ming Zhang and Junliang Zhang*
Figure 1. Biologically active alkaloids containing THCs.
Abstract: The highly enantioselective gold-catalyzed intramolecular
cyclization of N-allenamides was implemented utilizing a designed
Substituted tetrahydro-1H-β-carbolines (THCs) are core motifs
chiral sulfinamide phosphine ligand (PC-Phos), which, of note,
in ubiquitous biologically active alkaloids (Figure 1),[7] and
represents the first example of highly enantioselective intramolecular
building blocks for rapid synthesis of multiple scaffolds.[8]
cyclization of N-allenamides. The practicality of this reaction was
Consequently, the synthesis of enantiomerically pure substituted
THCs are in great demand.[9,10] In this context, the
validated in the total synthesis of (R)-Desbromoarborescidine A and
formal synthesis of (R)-Desbromoarborescidine
C
and (R)-
enantioselective Pictet-Spengler reaction has been deemed to
one of the most efficient approach,[10] apart from the
enantioselective hydrogenation of cyclic imines.[9c,9d] What’s
more, asymmetric intramolecular alkylation of indoles provides
another straightforward route to enantioenriched THCs. [9a]
Deplancheine. Moreover, the catalyst system PC-Phos/AuNTf2
proved to be specifically efficient to promote the desymmetrization of
N-allenamides in excellent yields with satisfactory ees.
Gold-catalyzed intramolecular cyclization of functionalized
allenes are one of the most powerful and straightforward
synthetic tool for the atom-economical construction of cyclic
skeletons in modern organic chemistry.[1,2] As opposed to the
well-documented cyclization reactions with a highly nucleophilic
functionality such as nitrogen, oxygen, or active methylene,
cyclization through functionalization of an aromatic C-H bond
has scarcely been explored.[3] N-allenamides, the unique allenic
scaffold readily from available from amide and propargyl
bromide,[4] have emerged as versatile building blocks in a variety
of transformations, including [m+2] cycloadditions/annulations
with suitable synthons.[5] Despite considerable success in
gold(I)-catalyzed intermolecular cycloaddtion reaction of N-
allenamides has been made, intramolecular process is
significantly less developed.[6] Notably, no example of
asymmetric intramolecular cyclization of N-allenamides
catalyzed by gold has been reported to date. The lack of method
for intramolecular cyclization of N-allenamides, especially in
asymmetric version, reflects wider difficulties of this proposition:
e.g., reaction manifold, substrate scope, as well as regio- and
stereocontrol.
Scheme 1. Previous and this work.
During our continuous efforts in developing asymmetric gold-
catalyzed reactions of N-allenamides, [5f,5g] we became intrigued
by the possibility of asymmetric cyclization of N-allenamides
attached with indoles (Scheme 1b). If it succeeds, the
enantioselective synthesis of THCs will be achieved. However,
this designed tactic may pose considerable challenges: (a)
chemoselective intramolecular cyclization vs intermolecular
dimerization.[11] In 2016, Kang and co-workers demonstrated
that this type of N-allenamides would undergo an intermolecular
head-to-head [2+2] dimerization between two molecular of
allenamide in a highly regio- and stereo-selective manner under
the Rh-catalysis (Scheme 1a);[11b] (b) regioselective cyclization
at C2 vs C3 positions of indole[12] and  vs  positions of N-
allenamide[4]; (c) asymmetric gold catalysis is highly challenging
due to its linear binding mode render the chiral ligand is far away
to the reactive site.[13] Herein, we wish to report an asymmetric
gold-catalyzed intramolecular cyclization of N-allenamides,
which provides a facile access to enantioenriched fused THC
derivatives in excellent yields with high ees.
[*]
Y. Wang, P. Zhang, X. Di, Q. Dai, Z.-M. Zhang, Prof. Dr. J.
Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062, China
E-mail: jlzhang@chem.ecnu.edu.cn
Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, CAS
345 Lingling Road, Shanghai 200032, China
http://faculty.ecnu.edu.cn/s/1811/t/20975/main.jspy
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
Scheme 2. Concise synthetic approach to PC-Phoses.
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10.1002/anie.201709595
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COMMUNICATION
Table 1. Investigation of chiral ligands.[a]
Table 2. Evaluation of different sulfonamide.[a]
Entry
1
PG
T (oC)
-50
t (h)
24
12
12
24
24
24
Yield[b] (%)
Ee (%)
84
Entry
1
PC-Phoses
(S,Rs)-PC1
(R,Rs)-PC1
(S,Rs)-PC2
(R,Rs)-PC2
(S,Rs)-PC3
(R,Rs)-PC3
(R,Rs)-PC1
(R,Rs)-PC1
(R,Rs)-PC1
(R,Rs)-PC1
(R,Rs)-PC1
(R,Rs)-PC1
T (oC)
25
t (h)
1
Ee (%)[b]
48
Ts (1a)
Ns (1b)
95
90
88
92
99
99
2[c]
-20
-20
-50
-50
-50
77
2
25
1
63 (70)[c]
55
3[c]
4
3,5-(CF3)2C6H2SO2 (1c)
Ms (1d)
80
3
25
1
91
4
25
1
59
5
2,4,6-Me3C6H2SO2(1e)
Tris (1f)
92
5
25
1
34
6[d]
96
6
25
1
52
[a] AgCl was filtered out. [b] Isolated yield. [c] The solubility was not good
at < -20 oC. [d] Tris = 2,4,6-iPr3C6H2SO2.
7
-20
-40
-40
-40
-50
-60
5
79 [c]
82 [c]
82 [c]
81 [c]
84 [c]
86 [c]
11). Running the reaction at -60 oC delivered a better ee but
much lower conversion (Table 1, Entry 12).
Further optimization focused on the adjustment of the
protecting group (PG) of nitrogen. Compounds 1b and 1c were
8
17
17
48
24
48
9[d]
10[e]
11
12[f]
o
not dissolved in CH2Cl2 at -50 C and thus runing the reactions
at -20 oC delivered the corresponding products in 77% and 80%
ees, respectively (Table 2, Entries 2-3). Surprisingly, a slight
increase in enantioselectivity occurred when the PG was
switched to Ms (Table 2, Entry 4, 91% ee). To our delight, a
better enantioselectivity (96% ee) was achieved with Tris instead
of Ts as protecting group (Table 2, Entry 6).
[a] All reactions were carried out with 0.1 mmol of 1a and 5 mol% of
catalyst in 2.0 mL CH2Cl2. [b] Determined by HPLC analysis. [c] AgCl was
filtered out. [d] AgSbF6 was used. [e] AgOTf was used. [f] 50%
conversion, 48% yield.
To confirm the feasibility of this strategy, N-allenamide 1a was
exposed to a cationic Au(I) system (Ph3PAuCl/AgSbF6), which
resulted in conversion to ()-2a in 90% yield rather than the
dearomative cyclization or dimerization products. Encouraged by
this result, we next focused on the asymmetric version of this
cyclization. To our disappointment, evaluation of a range of gold
complexes derived from privileged chiral bis(phosphine) ligands,
phosphoramidites or other chiral trivalent phosphine ligands all
failed to enhance the enantioselectivity (up to 36% ee).
Gratifyingly, the performance of chiral ligands designed by our
group (Ming-Phos, Xiang-Phos, etc).[14] give promising up to
44% ee (see the supporting information for details).
Thus,
a
related but structurally novel sulfonamide
monophosphine ligand (named PC-Phos) was then designed by
merging the moieties of Ming-Phos with commonly used and
privileged ligand Xant-Phos, which broadens the space and
change the angle between phosphine and sulfinamide (Scheme
2). Notably, PC-Phos could be easily prepared in gram-scale
from commercially available 9,9-dimethylxanthene in two ‘one-
pot’ synthesis, that is, diiodination, lithium-iodine exchange with
n-BuLi and subsequent treatment with ClPPh2, then a second
lithium-iodine exchange with n-BuLi, followed by addition of
chiral (Rs)-sulfinimines, furnishing two diastereoisomeric PC1–
PC3 in moderate yields. To our delight, these PC-Phoses were
more effective for enantioselective induction (34-63% ees),
although the enantioselectivity was still far from ideal (Table 1,
Entries 1-6). In addition, the performance of (R, Rs)-PC-Phoses
were better than the (S,Rs)-PC-Phoses. Notably, the
enantioselectivity could be inmproved to 70% ee, when AgCl
was filtered out (Table 1, Entry 2). A variation of the silver salts
from AgNTf2 to AgOTf and AgSbF6 did not bring benefit to the
enantioselectivity (Table 1, Entries 9-10). The ee was increased
to 84% after lowering the temperature to -50 oC (Table 1, Entry
Scheme 3. Exploration of Substrates Scope. Reaction conditions: 1 (0.2
mmol), chiral gold complexes (5 mol%), CH2Cl2 (4 mL), -50 oC, AgCl was
filtered out; [a] Isolated yield, [b] Ee was determined by HPLC. [c] PG =
2,4,6-Me3C6H2SO2.
After the optimal reaction condition was established, the
generality of this asymmetric cyclization was investigated by
variation of the substitution patterns on indole moiety (Scheme
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10.1002/anie.201709595
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Determined by HPLC analysis.
3). In general, the substrate scope is quite general and all the
cyclization can be conducted in excellent yields (up to 99%
yield) with good to excellent enantioselectivities (up to 97% ee).
Electron-donating groups (OMe, OBn) at 4-, 5-, 6-positions of
the indole ring were well tolerated, delivering the cyclization
products in excellent yield with high enantioselectivity (2g-2k). A
variety of diverse aryl or alkyl substituted indoles were also
evaluated and the desired products were isolated in up to 99%
yield with up to 96% ee (2l-2r). Moreover, electron-withdrawing
groups such as F and Br at the 6-position still performed well (2s,
2t). Finally, the reaction of N-allenamide 1u with a gem-dimethyl
subunit at the -position could also works well, furnishing the
desired product 2u in 99% yield with 93% ee.
Gold-catalyzed asymmetric desymmetrizative cyclization has
drawn extensive interest during the past decade.[15] Thus we
wondered whether our catalyst system of (R,Rs)-PC1/AuNTf2
can be applied to the desymmetrizative cyclization of N-
allenamides 3. To our delight, the desired desymmetrization
products 4a-4e were obtained in high yields (up to 99%) with up
to 95% ee and high diastereoselectivity, which further enlarged
the reaction scope.
Scheme 5. Proposed Asymmetric Induction Model.
In light of the structures of the chiral ligand (R,Rs)-PC1 and
the product 2, a catalytic model was proposed for the reaction
(Scheme 5). The phosphine of the ligand and the N-allenamide
1 coordinate to AuI center. Meanwhile, the sulfonyl group would
form a hydrogen bonding with the hydrogen atom of the catalyst.
The Si face of allenamide is shielded by the 4-MeOC6H4 group
of the ligand and the indole group attack takes place at the Re
face to form the product (R)-2 with excellent enantioselectivity.
Scheme 4. Exploration of substituted N-allenamides.
Next, we attempted the reactions of - or substituted N-
allenamides (Scheme 4). The reaction of γ-disubstituted N-
allenamide 1v could give the desired product 2v but in only 15%
yield with 30% ee and 1-amido diene 2v'' via isomerization as
the major product under the standard conditions.4e,4f Notably, the
cycloaddition product 2v' was obtained in 49% ee by using
(S,S,S)-Ls 25 ligand.4e In contrast, the temperature should be
improved to 80 oC for the cyclization of -substituted N-
allenamide 1w, leading to the desired cyclization product 2w in
45% yield in only 2% ee and a trace amount of dinene 2w' (see
other conditions in the SI).
Table 3. Gold-catalyzed desymmetrization reaction.[a]
Scheme 6. Synthetic applications of the products.
To illustrate the utility of the new methodology, we next turned
to apply the products towards the enantioselective synthesis of
Entry
R3 (3)
D.r.
13:1
10:1
7:1
Yield (%)[b]
99 (4a)
94 (4b)
97 (4c)
95 (4d)
97 (4e)
Ee (%)[c]
95
(R)-Desbromoarborescidine A-C and (R)-Deplancheine.[16]
A
1
2
3
4
5
H (3a)
gram-scale reaction of 1f proceeds smoothly, delivering 1.322 g
of (R)-2f in 95% yield with 96% ee (Scheme 6). Towards the (R)-
Deplancheine, (R)-2f was deprotected and alkylated with allyl
bromide 5 to produce (R)-6, which unfortunately proved inert in
the intramolecular reaction (see details in Supporting Informa-
tion). Therefore, we modified our synthetic strategy. (R)-2f was
deprotected and acylated, affording (R)-7 in 56% overall yield in
two steps. Next, RCM of (R)-7 with Grubbs II catalyst and
5-OMe (3b)
5-Me (3c)
6-Me (3d)
6-F (3e)
86
92
22:1
9:1
93
94
[a] Reaction conditions: 3 (0.2 mmol), chiral gold complexes (5 mol%),
CH2Cl2 (4 ml), -50 oC, AgCl was filtered out; [b] Isolated yield. [c]
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10.1002/anie.201709595
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Zhang, R. P. Hsung, Chem. Rev. 2013, 113, 4862; For the synthetic
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subsequent hydrogenation delivered (R)-8 in 85% yield with
91% ee in two steps. In addition, an alternate path to (R)-8 and
its successful elaboration to (R)-Deplancheine by such a
sequence was reported by Argade.[16d] Moreover, (R)-
Desbromoarborescidine
A was obtained in 94% yield by
reduction of δ-lactam carbonyl group of (R)-8. Finally, (R)-8
could also deliver the (R)-Desbromoarborescidine C via a 7-
steps synthetic protocol in good overall yield according to the
reported procedure.[16d] In order to optimize the synthetic route of
(R)-Desbromoarborescidine C, the Tris group was replaced with
CO2Me to provide (R)-9 in 60% yield. Then (R)-9 was
transformed via CM with 3-buten-1-ol and hydrogenation to (R)-
10, which could generate (R)-Desbromoarborescidine C in 68%
yield over two steps. [16d]
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In summary, we have developed an asymmetric gold(I)-
catalyzed intramolecular cyclization of N-allenamides for the
efficient synthesis of chiral tetrahydrocarbolines with the use of a
well-designed,
easily
available
PC-Phos.
Notably,
enantioselective desymmetrization of N-allenamides was also
achieved in good yields with high ees and moderate to excellent
diastereoselectivities. Furthermore, synthetic applications of the
synthetic valuable THCs products to the key building block for
asymmetric total synthesis of (R)-Desbromoarborescidine A and
[6]
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(R)-
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We gratefully acknowledge the funding support from NSFC
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Keywords: Gold • Enantioselectivity • Cyclization • Allenamides
•Tetrahydrocarboline
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Entry for the Table of Contents (Please choose one layout)
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Yidong Wang, Peichao Zhang, Xiaoyu
Di, Qiang Dai, Zhan-Ming Zhang and
Junliang Zhang**
Page No. – Page No.
Gold-Catalyzed
Asymmetric
Intramolecular Cyclization of N-
Allenamides for the Synthesis of
Chiral Tetrahydrocarbolines
The first example of highly enantioselective gold-catalyzed intramolecular cyclization of
N-allenamides was implemented utilizing PC-Phos. The practicality of this reaction was
validated in the total synthesis of (R)-Desbromoarborescidine A.
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