An indoxyl-based strategy for the synthesis of indolines and indolenines

Article abstract of DOI:10.1002/anie.201505173

An indoxyl-based strategy for the synthesis of indolines and indolenines via unprecedented aza-pinacol and aza-semipinacol rearrangements was developed. This method provides direct access to the core structures of several classes of indole alkaloids. The synthetic utility was demonstrated by the divergent synthesis of an array of functionalized polycyclic structures from a common intermediate and the formal total synthesis of the indoline natural product minfiensine. The reversed reactivity of indoxyl as a building block compared to that of indole offers a conceptually distinct disconnection strategy for indoline- and indolenine-containing heterocycles and natural products. Making other arrangements: The chemical synthesis of a diverse range of functionalized indolines/indolenines and the formal total synthesis of the indoline natural product minfiensine were achieved by using an indoxyl-based strategy that proceeds via unprecedented aza-pinacol rearrangements. This method provides direct access to the core structures of several classes of indole alkaloids by employing conceptually distinct bond disconnections.

Full text of DOI:10.1002/anie.201505173

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505173
German Edition: DOI: 10.1002/ange.201505173
Synthetic Methods
An Indoxyl-Based Strategy for the Synthesis of Indolines and
Indolenines
Yuanyuan Yu, Guang Li, Long Jiang, and Liansuo Zu*
Abstract: An indoxyl-based strategy for the synthesis of
indolines and indolenines via unprecedented aza-pinacol and
aza-semipinacol rearrangements was developed. This method
provides direct access to the core structures of several classes of
indole alkaloids. The synthetic utility was demonstrated by the
divergent synthesis of an array of functionalized polycyclic
structures from a common intermediate and the formal total
synthesis of the indoline natural product minfiensine. The
reversed reactivity of indoxyl as a building block compared to
that of indole offers a conceptually distinct disconnection
strategy for indoline- and indolenine-containing heterocycles
and natural products.
methods that have tremendously facilitated the chemical
synthesis of related natural products include palladium-
catalyzed asymmetric Heck reactions by the Overman
group,[4a,b] carbene-mediated cyclopropanations by the Qin
group,[2b, 4c,k] interrupted Fischer indolization by the Garg
group,[3d,4g,h] organocatalytic Diels–Alder reactions by the
MacMillan group,[4d,m] and intramolecular oxidative coupling
by the Ma group.[4j,l]
The majority of developed approaches toward the shown
indolines and indolenines center on the transformation of the
related indole derivatives or the construction the indole-type
nucleus as the key strategy. New approaches employing
different building blocks could offer alternative and distinct
disconnection strategies to indolines and indolenines and thus
facilitate the chemical synthesis of related natural products.
Compared to indoles, indoxyls are heterocycles that have
been far less investigated. Unlike indoles, in which C3 is most
nucleophilic and C2 becomes electrophilic after C3 is
activated, indoxyls are nucleophilic at C2 and electrophilic
at C3.[5] The reversed reactivity of indoxyl compared to that of
indole lays the basis for the development of unique discon-
nection strategies. Herein, we report an indoxyl-based
strategy that proceeds via unprecedented aza-pinacol and
aza-semipinacol rearrangements for the preparation of indo-
lines and indolenines based on the hydrocarbazole frame-
work.
I
ndolines and indolenines based on a hydrocarbazole frame-
work (Figure 1) are key structural features of akuammiline
alkaloids and the Strychnos alkaloid minfiensine.[1,2] The
intricate polycyclic structures and interesting biological
activities of these complex natural products have attracted
significant attention from synthetic chemists in recent years,
leading to innovations in synthetic strategies[3] and stunning
achievements in total synthesis.[4] Representative synthetic
Our strategy, which utilizes the unique reactivity of
indoxyls for the synthesis of indolines and indolenines, is
depicted in Scheme 1. We conceived that the shown indolines/
indolenines could be furnished through aza-pinacol or aza-
semipinacol rearrangements of the corresponding tertiary
alcohol A or trisubstituted alkene B, which in turn could be
readily generated through the synthetic elaboration of
indoxyls. Although the pinacol and semipinacol rearrange-
ments are powerful tools for constructing quaternary car-
bons,[6] their analogues the aza-pinacol and aza-semipinacol
Figure 1. Representative natural products containing indolines/indole-
nines.
[*] Y. Yu,[+] Dr. G. Li,[+] L. Jiang, Prof. Dr. L. Zu
Department of Pharmacology and Pharmaceutical Sciences
School of Medicine, Tsinghua University, Beijing, 100084 (China)
E-mail: zuliansuo@biomed.tsinghua.edu.cn
Prof. Dr. L. Zu
Collaborative Innovation Center for Biotherapy, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital
West China Medical School, Sichuan University, Chengdu (China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505173.
Scheme 1. Indoxyl-based strategy towards indolines and indolenines.
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rearrangements enjoy much less success owing to the
instability of the resultant imine, the weak driving force,
and unpredictable side reactions.[7] While the scattered known
examples mainly focus on extremely strained substrates, aza-
pinacol and aza-semipinacol rearrangements involving ring
expansion from a 5-membered ring to a 6-membered ring, as
shown in Scheme 1, have been challenging. Mechanistically
related to our design is the inventive work of the Driver
group, which utilizes transition-metal-catalyzed ester migra-
tion for the synthesis of indolenines.[8]
A model reaction of 1a was carried out first (Table 1) to
produce an indoline with a fused lactone (2a), which
represents the core structure of alstolactine A and lancifer-
Table 1: Optimized reaction conditions.[a]
Entry
Acid
Solvent
Yield [%][b]
1
2
3
4
5
6
7
TFA
TFA
TFA
TFA
DMF
1,4-dioxane
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
70
97[c]
88
90[d]
TFA
4.0 M HCl in dioxane
TFA
Scheme 2. Synthesis of indolines and indolenines based on the hydro-
carbazole framework via aza-pinacol rearrangements.
[a] Reaction conditions: The specified acid (0.4 mL) was added to
a solution of 1a (0.15 mmol) in 3.0 mL solvent. The resulting mixture
was stirred at RT for 5 min and then heated to 408C for 5 h. [b] The yields
were calculated by 1H NMR using 1,3,5-trimethoxyl-benzene as the
internal standard. [c] Yield of isolated product after silica-gel chroma-
tography. [d] Yield of isolated product for the gram-scale synthesis
(1.43 g, 2a). TFA=trifluoroacetic acid, Boc=tert-butoxycarbonyl.
nitrile, aryl, and alkyl) proved to be efficient substrates
(Scheme 2). The deprotection/aza-pinacol rearrangement
cascade sequence proceeded smoothly, generating indolines
with different fused rings (2a–d) and indolenines with rich
functionality (2e–2i), which represent the core structures of
alstolactine A, aspidophylline A, vincorine, minfiensine, and
many other akuammiline natural products. In addition,
substrates bearing a bromide substituent on the phenyl ring
were also investigated, furnishing products with synthetic
handles for further elaboration (2j–2l). Moreover, the related
aza-pinacol rearrangements with substrates containing an
additional fused phenyl ring at the 5-membered ring were
accompanied by automatic aerobic oxidation,[11] thereby
affording the ketones 2m and 2n with good yields. Further
decoration of the 5-membered ring and related transforma-
tions are reported in Scheme 4.
Besides using Boc as the protecting group, which was
cleaved during the reaction, an alkyl substituent or other
protecting groups, such as a methyl carbamate, on the
nitrogen atom were also well tolerated (Scheme 3a), and
the corresponding reactions furnished protected indolines
(2o, 2p) in high yields. Besides tertiary alcohols, trisubstituted
alkenes also turned out to be suitable substrates, and the
related aza-semipinacol rearrangements (upon protonation)
proceeded very well, generating 2a and 2e in comparable
yields to those obtained by aza-pinacol rearrangement.
ine[9] (structure not shown in Figure 1) and has been
challenging to access by other approaches. We envisioned
that in the presence of a suitable acid, the cascade sequence
involving cleavage of both protecting groups, aza-pinacol
rearrangement, and cyclization of the carboxylic acid onto the
resulting imine could occur in a single operation, thereby
generating 2a with remarkable efficiency. To our delight, after
several attempts, we observed the formation of the desired
product 2a in 70% yield when using TFA as the acid and
acetonitrile as the solvent (entry 4). Further optimization in
terms of solvents, acids, concentration, and temperature led to
the identification of optimized reaction conditions: the
reaction was carried out in dichloromethane at 408C in the
presence of TFA, delivering 2a in 97% yield (entry 5). The
structure of 2a was unambiguously confirmed by X-ray
structure analysis.[10] It should be noted that the reaction can
be carried out on a gram scale with excellent yield (entry 7).
Under optimized reaction conditions, the substrate scope
was investigated. Avariety of tertiary alcohols 1 with different
side chains (carboxylic ester, alcohol, protected amines,
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approach for the synthesis of functionalized indolines and
indolenines. As illustrated in Scheme 4, compound 3 was
prepared in good yield through two-step synthetic
a
sequence[12] involving double allylation followed by Grubbs
metathesis, utilizing the nucleophilic reactivity of C2 of the
Boc-protected indoxyl. Next, electrophilic addition with
acetonitrile occurred at the C3 carbonyl to produce tertiary
alcohol 4, which was subsequently transformed into 5 by aza-
pinacol rearrangement accompanied by an alkene isomer-
ization. Divergently, 6 was made by diastereoselective
dihydroxylation[13] of 4 and converted into 7 in a similar
manner upon dehydration. It should be noted that the
synthetic transformation of 6 into 7 proceeded with excellent
diastereoselectivity, thus highlighting the potential for the
development of a highly efficient chirality-transfer process
with a preinstalled chiral center. Nitrile 4 was further
elaborated to tosyl amine 8 through a three-step manipula-
tion: reduction of the nitrile, protection of the resultant
amine, and dihydroxylation of the alkene. The cascade
reaction of 8, which involves deprotection/aza-pinacol rear-
rangement/cyclization, afforded 9 in 94% yield. Divergently,
10 was generated from 8 in good yield simply by adding
molecular sieves to the reaction, presumably through a pro-
cess involving intermediate C. Under forcing conditions, 10
was further transformed into 11, which is a unique polycyclic
structure that would be challenging to synthesize by other
approaches. Thus, from a common intermediate 4, which is
readily prepared through the synthetic elaboration of indoxyl,
several functionalized indoline/indolenines were successfully
constructed in a chemically divergent manner.[14]
Scheme 3. Different protecting groups and substrates for the aza-
semipinacol rearrangements.
Next, we turned our attention to the chemical synthesis of
minfiensine, a complex alkaloid that has received consider-
able attention from the synthetic community owing to its
unique interconnected indoline ring system. Since its first
isolation,[1f] the natural product has become a molecular
benchmark to inspire the development of novel synthetic
strategies and calibrate the utility of these methods in the
synthesis of complex molecules. Several elegant approaches
have been developed by the groups of Overman, Qin,
MacMillan, Qiu/Zhang, and Padwa, and successfully applied
to the total synthesis of this natural product.[4a–f] In this
context, we chose minfiensine as a synthetic target to further
demonstrate the utility of our indoxyl-based strategy and
envisioned that conceptually distinct bond disconnections
could be realized via aza-pinacol rearrangement (Scheme 5).
From the common intermediate 4, reduction of the nitrile and
protection of the resultant amine afforded 12, which was
further transformed into 13 upon SN2 alkylation. Diastereo-
selective dihydroxylation of 13 furnished 14 as a single isomer
in excellent yield, which led to the formation of ketone 15
directly in a highly efficient manner. This remarkable single-
step transformation highlights a cascade process involving
deprotection/aza-pinacol rearrangement/elimination to fur-
nish a transient intermediate D,[15] which is isomerized to 15
upon semipinacol-type rearrangement under acidic condi-
tions. Finally, protection of the nitrogen atom followed by
removal of the nosyl group and an intramolecular cyclization
delivered 16, which represents the key advanced intermediate
employed in Overman and Qiu’s total synthesis.
Scheme 4. Divergent synthesis of functionalized indolines/indolenines
from a common intermediate. TBAB= tetrabutylammonium bromide,
LDA=lithium diisopropylamide, LAH=lithium aluminum hydride,
TEA=triethylamine, Ts =4-toluenesulfonyl, NMO=4-methylmorpho-
line N-oxide.
(Scheme 3b). These complementary results further demon-
strated the generality of the reaction and provide more
options for retrosynthetic design.
One appealing advantage of the current approach is that
the unique reactivity of indoxyl could be utilized for the
synthesis of more complicated substrates and thus offer
a distinct disconnection strategy and complexity-generating
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How to cite: Angew. Chem. Int. Ed. 2015, 54, 12627–12631
Angew. Chem. 2015, 127, 12818–12822
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Scheme 5. Formal total synthesis of minfiensine. Ns=2-nitrobenzene-
sulfonyl, THF=tetrahydrofuran.
In conclusion, an indoxyl-based strategy for the synthesis
of indolines and indolenines via unprecedented aza-pinacol
and aza-semipinacol rearrangements was developed. This
strategy allows direct access to the core structures of several
classes of indole alkaloids. From a common intermediate 4,
which is readily elaborated from indoxyl, the chemical
synthesis of a diverse range of unique polycyclic structures
and the formal total synthesis of the indoline natural product
minfiensine were achieved, thus demonstrating the utility of
this complexity-generating approach. We believe that the
unique reactivity of indoxyl as a building block compared to
that of indole could offer an alternative and distinct dis-
connection strategy for indoline/indolenine-containing natu-
ral products. Research along these lines, as well as the
development of an asymmetric variant of the aza-pinacol
rearrangement by using chiral acids, is currently underway
within our group.
Acknowledgements
The authors are grateful to Tsinghua University, “1000
Talents Recruitment Program”, Collaborative Innovation
Center for Biotherapy (Tsinghua University and Sichuan
University) and National Natural Science Foudation of China
(Grant No. 21302107) for financial support.
Keywords: aza-pinacol rearrangement · indolenines · indolines ·
indoxyl · synthetic methods
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Received: June 6, 2015
Published online: August 28, 2015
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