Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade cyclization

Article abstract of DOI:10.1016/j.cclet.2020.11.001

We report a 2-iodoxybenzoic acid (IBX)-mediated intarmolecular oxidative spiro-fused tandem cyclization reaction of tryptophan analogs bearing an N-arylamides side-chain to rapidly afford polycyclic spiroindolines featuring multiple stereocenters includin

Full text of DOI:10.1016/j.cclet.2020.11.001

Journal Pre-proof
Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade
cyclization
Zhiguo Zhang, Xiaoqing Song, Guofeng Li, Xiang Li, Dan Zheng,
Xuna Zhao, Huanran Miao, Guisheng Zhang, Lantao Liu
PII:
S1001-8417(20)30634-3
https://doi.org/10.1016/j.cclet.2020.11.001
CCLET 5941
DOI:
Reference:
To appear in:
Chinese Chemical Letters
Received Date:
Revised Date:
Accepted Date:
6 September 2020
20 October 2020
2 November 2020
Please cite this article as: Zhang Z, Song X, Li G, Li X, Zheng D, Zhao X, Miao H, Zhang G,
Liu L, Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade cyclization,
Chinese Chemical Letters (2020), doi: https://doi.org/10.1016/j.cclet.2020.11.001
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Communication
Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade cyclization
a
a
a
a
b
a
a
Zhiguo Zhang , Xiaoqing Song , Guofeng Li , Xiang Li , Dan Zheng , Xuna Zhao , Huanran Miao ,
,a
c
Guisheng Zhang* , Lantao Liu
a
Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing
of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang 453007, China
Quality and Technique Supervision, Inspection and Testing Center of Xuchang City, Xuchang 461000, China
The College of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu 476000, China
b
c
Graphical abstract
We report a 2-iodoxybenzoic acid (IBX)-mediated intarmolecular oxidative spiro-fused tandem cyclization reaction of
tryptophan analogs bearing an N-arylamides side-chain to rapidly afford polycyclic spiroindolines featuring multiple stereocenters
including a quaternary stereocenters under mild reaction conditions.
ABSTRACT
We report a 2-iodoxybenzoic acid (IBX)-mediated intarmolecular oxidative spiro-fused tandem cyclization reaction of tryptophan analogs bearing an N-
arylamides side-chain to rapidly afford polycyclic spiroindolines featuring multiple stereocenters including a quaternary stereocenters under mild reaction
conditions. Among them, a novelty azaphosphol idine-containing spiroindoline compound is synthesized for the first time. It may open the door to azaphos
pholidine-containing spiroindoline compound of potential interest in synthetic and medicinal chemistry. A plausible mechanism is proposed.
Keywords: Spiro-Indolines, Fused Indolines, 2-Iodoxybenzoic acid, Hypervalent iodine reagents
A large number of complex indole- and indoline-containing alkaloids have been isolated from the natural products [1-4] and have
become an area of intensive interest in synthetic organic chemistry [5-9]. Currently, C3-spirocyclization toward polycyclic indoles and
indolines has been well studied [10, 11]. And C2-spirocyclization of indolines is also occasionally reported although low reactivity at
this position [12-15]. In addition, the construction of complex polycyclicindolines involving the C2- and C3-positions completed by a
multistep reaction have also been well investigated (Scheme 1a) [16-23]. Cycloaddition reaction is the most commonly used domino
process to synthesize complex polycyclic indolines with the C2- and C3-positions participating in the transformation simultaneously
(Scheme 1b) [24-31]. Synthesis of polycyclic spiroindolines with oxa- and/or aza-tandem C2- and C3-cyclizations is relatively rare
(Scheme 1c) [32-34]. In 1999, Ciufolini et al. [34] reported a total synthesis that produced oxa- and aza-polycyclic spiro-fused indolines
in the presence of BOP-Cl, Burgess reagent, and PhI(OAc) starting from tryptophan analogs and (S)-phenylalaninol (Scheme 1d). They
2
achieved five kinds of desired oxazine-containing spiro-fused cyclic structures via four steps reactions, but no more than 50% yields
were obtained in the final transformation even for adjust the substituents of the tryptophan analogs, lowering the overall yields. However,
the highlight of the reaction is the nucleophilic N and O atom on the side chain expressing electrophilicity, and reacted simultaneously
with both C2- and C3-position of indoles core in the final oxidative cyclization step. Another worthy-of-noting similar case is
Dess−Martin periodinane-mediated cyclization reaction of unsaturated anilides by Nicolaou in 2002 [35]. A plethora of phenoxazine-
containing heterocycles are accessible in 0-57% yields by employing γ,δ-unsaturated amides, urethanes, or ureas as substrates via an o-
imidoquinones species oxidized in site from the arylamide moiety. Despite these significant advances, important issues such as high
—
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Corresponding authors.
E-mail addresses: zhangzg@htu.edu.cn (Z. Zhang), zgs6668@yahoo.com (G. Zhang)

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yield, broad applicability, functional group tolerance, and process economy remain to be improved for the existing protocols [24, 36,
37]. Thus, it remains challenging to efficiently synthesize oxazine-containing polycyclicindolines relevant to biological systems
through cascade sequence with the C2- and C3-positions of the indole analogues participate in the transformation simultaneously.
Scheme 1. C2- and C3-cyclization toward polycyclic indolines.
The importance of hypervalent iodine reagents in organic synthesis has been amply demonstrated in recent years [38-44]. Recently,
we reported a series of efficient and chemoselective methods to convert various secondary N-arylamides to primary amides in high
yields with the treatment of organoiodines in mixed solvents of H O and HFIP (Scheme 1e, path a) [45, 46]. These regiospecific
2
C(aryl)-N bond cleavage reaction without touching the C(carbonyl)-N bond in the amides, not only further enriches the amino group
protecting chemistry, but also provides a way for the facile removal of the aminoquinolines (AQ) directing group under mild conditions.
3
During these research, we found a tryptophan analogs, which was derived from Pd-catalyzed AQ-directed β-C(sp )-H indolization of
aminoacid derivatives, produced the oxazine-containing polycyclic spiro-fused indolines via domino C2- and C3-oxidative cross-
coupling reaction, rather than the primary amide via C(aryl)-N bond cleavage reaction (Scheme 1e, path b). This competitive
observation motivated us to optimize the efficient tandem strategies for construction of structure diverse oxazine-containing complex
polycyclicindolines due to their importance for biomolecular and application for pharmaceutical lead discovery [47-49].
As shown in Table 1, tryptophan derivative 1a was selected as the model substrate [50]. We were pleased to see that the tandem
cyclization took place to afford the polycyclic indoline 2a in 96% yield with good diastereoisomer (dr: ca. 10:1) in the presence of 2
equiv. of IBX in mixed solvents of HFIP and H
crystallography studies (CCDC: 1890504). Compared with the results performed in the mixed solvents of HFIP and H
of 1:1, obviously, increasing solubility is helpful in improving the yield of target molecule (entry 2). As expected, the reaction did not
occur in H O due to the poor solubility of IBX (entry 3). No product was obtained in HFIP either, and a large amount of substrate was
recovered (83%) (entry 4). This observation indicated that H O is involved in the transformation [35]. Moreover, increasing the ratio
of HFIP and H O to 5:1 gave a slightly lower yield than that of 3:1 (entry 5). Other organic solvents including 2,2,2-trifluoroethanol
TFE), 2,2,3,3-tetrafluoro-1-propanol (TFP), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol (OFP) mixed with H O in the ratio of 3:1 not gave
2
O (3:1) at 60 °C for 0.5 h (entry 1). The structure of 2a was confirmed by X-ray
2
O in the ratio
2
2
2
(
2
a higher yield (entries 6-8). Reactions conducted at 25 °C and 45 °C gave slightly lower yields of 2a, besides requiring dramatically
more reaction time (entries 9 and 10).
Table 1
Reaction optimization.
a

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Entr
y
Time
(h)
Yield of
2a (%)
Recovered
of 1a (%)
Solvent
HFIP/H
3/1)
HFIP/H
1/1)
2
O
O
1
2
0.5
0.5
96
74
0
0
(
2
(
3
4
H
HFIP
2
O
2
2
NR
NR
91
83
HFIP/H
2
O
5
6
7
8
9
1.5
16
7
79
79
0
18
20
28
0
(
5/1)
TFE/H
3/1)
TFP/H
3/1)
OFP/H
3/1)
HFIP/H
3/1)
HFIP/H
3/1)
2
O
O
(
2
71
(
2
O
7
57
(
2O
24
4
77b
79c
(
2O
1
0
0
(
a
b
c
Unless otherwise indicated, reactions were conducted with 0.2 mmol of 1a and 2.0 equiv. of IBX in 2 mL of solvent at 60 °C, isolated yield.
The reaction was performed at 25 °C.
The reaction was performed at 45 °C.
With the optimal reaction conditions in hand (Table 1, entry 1), we then evaluated the scope of tryptophan analogs [51-53]. As shown
in Scheme 2, Ts-group protected tryptophan derivative 1a gave 2a in 96% yield with ca. 10:1 dr value. Preliminary exploration on the
protecting group on the N atom of indole moiety suggested that the 4-methylbenzoyl protect group also fit for the aminoacid substrates.
Compound 2b worked well to give the primary amide products in good yield. Variants of various amino groups such as BocNH- (1c),
CbzNH- (1d), and N
0% yields, respectively. The experiments of non-tryptophan analogs with a 4-methylbenzoyl protect group for the cyclization were also
performed. Compound 1f gave a slightly higher yield (2f: 94%) than that of Ts- and Ac-protected substrates 1g (2g: 89%) and 1h (2h:
3
- (1e) on the side chain were well tolerated and generated corresponding products 2c, 2d, and 2e in 76%, 63%, and
7
8
2
6%). To our delight, starting materials 1i and 1j with Me- and Br-substitution on the indole moiety also worked well, and gave products
i and 2j in 88% and 66% yields, respectively. However, N-unprotected starting material 1k failed to give desired compound 2k.
Pleasingly, phosphinamide derivative possessing an aminoquinoline unit (1l) [54] also worked, and polycyclicindolines 2l was
synthesized in 52% yield, along with small amounts of unidentified byproducts. To the best of our knowledge, this novelty
azaphospholidine-contaning spiroindoline compound is synthesized for the first time. This unusual spiroheterocycles open the door to a
series of new azaphospholidine-containing spiroindoline compound of potential application in synthetic and medicinal chemistry. In
addition, this strategy was also amenable to the building of thieno[1,4]oxazino[2,3-h]quinolinone structure (2m) although a slightly lower
yield was obtained.
In addition, we found that the substitution on the quinoline significantly affects the reaction. The reactant (1n) with an alkoxyl (MeO-)
at the 6-position afforded the desired fused cyclic product 2n in 44% yield, along with 25% primary amide byproduct 3n. The reactant
bearing a Cl- group located at the 5-position gave the target product 2o in a yield of 92%. Even the materials with the Cl- group at the 4-
position of the AQ moiety can also deliver the product 2p in moderate yield, along with a small number of primary amides byproducts
3p, which was generated by cleavage of the amide.
The scope of other substrates was also evaluated. Reaction of 1q gave the primary amide 3q in 43% yield, rather than desired polycyclic
product 2q. Interestingly, compounds 1r-1t afforded oxazine-containing polycyclicindolines 2r-2t in 30%, 60%, and 56% yields, along
with 36%, 27%, and 34% primary amide 3r-3t, respectively. In contrast, functional groups such as CF - (1u) interfered with the IBX-
3
mediated oxidation-cyclization tandem reaction with starting material largely recovered.

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Scheme 2. Extended scope of tryptophan analogs. Isolated yield on 0.2 mmol scale under the standard conditions and the dr value was determined
1
a
b
c
d
e
by H NMR. Complex mixture. Alone with some unidentified byproduct. 25% of 3n was obtained. 8% of 3n was obtained. 43% of 3n
f
g
h
i
was obtained. 36% of 3n was obtained. 27% of 3n was obtained. 34% of 1t was recovered. 93% of 1u was recovered.
Scheme 3. Attempt for complex molecular.
As a further test of the power of this strategy in building of complex molecular diversity, we enlisted the indole analogs with a longer
side chain (1v) as a substrate [55, 56] and tested the formation of the complex polycyclic 2v (Scheme 3). As a result, no target molecule
formed, and only primary amide 3v was observed (72%) [45].
As outlined in Scheme 4, the IBX-mediated spiro-fused cyclization likely starts with the reaction of amide O atom of 1a with iodo
center of IBX to form iodoimidate A by releasing one molecular of AcOH [45, 57]. Intramolecular nucleophilic attack of the oxo group
on the iodine center of A onto the ortho-position of AQ group triggers dearomatization of the aniline moiety and the cleavage of the O-
I bond to form B [35, 57]. Deprotonation and cleavage of O-I bond of B gives o-iminoquinone species C and 2-iodobenzoic acid (4) [58].
The o-imidoquinone C then engages the proximate olefin in an inverse electron demand hetero Diels-Alder reaction to furnish the
observed polycyclic 2a [35]. It should be noted that 4 was observed in the transformation as a byproduct.

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Scheme 4. Proposed mechanism.
In summary, an IBX-mediated intarmolecular oxidation spiro-fused cyclization of tryptophan analogs bearing an N-arylamides side-
chain was developed for rapidly access to polycyclic spiroindolines in moderate to excellent yields under mild conditions. This tandem
reaction features high efficiency in the construction of two stereocenters in one step including one quaternary carbon stereocenter
harboring 5-8 rings. Among them, a novel azaphosphol-idine-contaning spiroindoline compound is synthesized for the first time. It may
open the door to a series of azaphos-pholidine-containing spiroindoline compound of potential interest in synthetic and medicinal
chemistry. Mechanistic studies showed oxidation of the aryl group produced an o-iminoquinone intermediate which afforded terminal
products via intramolecular hetero Diels-Alder reaction. Overall, this strategy nicely complements the construction of structure diverse
oxazine-containing complex polycyclicindolines for biomolecular purpose in future.
Declaration of Interest Statement
We declare that we have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
Acknowledgments
We thank the National Natural Science Foundation of China (Nos. U1604285, 21772032 and 21702051), Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education of China (No. IRT1061), the 111 Project (No.
D17007), Henan Provincial Natural Science Foundation (No. 162300410180), Key Project of Henan Educational Committee (No.
1
1
8A150009), and Program for Innovative Research Team of Science and Technology in the University of Henan Province (No.
8IRTSTHN004).

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