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Synthesis 2023; 55(02): 240-245
DOI: 10.1055/a-1896-8449
short review
Special Issue dedicated to Prof. Alain Krief

Chiral 1,4-Oxazino[4,3-a]indoles as a Challenging Scaffold: Syntheses and Properties

Aurélien Dupeux
,
Veronique Michelet  ∗

This work was supported by the Centre National de la Recherche Scientifique (CNRS) and the University Côte d’Azur. We gratefully acknowledge the University Côte d’Azur for a grant to A. Dupeux.
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Dedicated to Professor Alain Krief on the occasion of his 80th birthday

Abstract

In the last few decades, there has been an increasing interest in the development of new syntheses of oxazinoindoles, a tricyclic backbone bearing an indole core structure fused with a morpholine ring, in particular because these molecules have interesting bioactive properties, such as antidepressant, anti-inflammatory, or antitumor activity. There are a few reported racemic strategies for the synthesis of oxazinoindoles, but only four reports of enantioselective syntheses. This short review presents an overview of these enantioselective strategies as well as the evaluation of chiral oxazinoindoles for their bioactive properties.

1 Introduction

2 Racemic Syntheses and Evaluation of Chiral Oxazinoindoles after Separation

3 Enantioselective Catalytic Syntheses of Oxazinoindoles

4 Conclusion


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Key words

oxazinoindoles - bioactive molecules - chirality - chiral separation - asymmetric syntheses
1

Introduction

Indole-based polycyclic backbones often exhibit a wide range of activities.[1] Specifically, the tricyclic skeleton resulting from the combination of an indole and an N-fused morpholine, called an oxazinoindole, has been presented in the last few decades as a very interesting scaffold for its biological properties such as antidepressant activity 1, anti-inflammatory activity 2, and antitumor activity 3 (Scheme [1]).[2]

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Véronique Michelet is Professor at University Côte d’Azur since 2017. Her research interests combine fundamental and applied aspects of catalysis for the development of new synthetic methodologies for the formation of carbon–carbon and carbon–heteroatom bonds. Gold catalysis is one of her favorite research topics. Aurélien Dupeux joined the group of Prof. V. Michelet in 2019 at the University Côte d’Azur for his Ph.D. studies. His current research concerns gold catalysis and asymmetric synthesis. He will join the group of Professor Mark Lautens as a post-doctoral fellow.
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Scheme 1 Examples of oxazinoindoles with biological activity

Throughout the reports on their synthesis, several strategies have been applied for the construction of such a challenging scaffold (Scheme [2]). The main ones, start from an indole-based molecule for the construction of the C ring (5, 6, and 7, Scheme [2]), which could be achieved with different disconnections.[3] The construction of the B ring was also achieved taking advantage of the carbon α to the nitrogen (8 and 9, Scheme [2]).[4] Finally, some strategies starting from aniline derivatives allow the construction of the B and C rings successively (10 and 11, Scheme [2]).[5] Although the synthesis of achiral oxazinoindoles has been described in the literature,[6] there are as yet only a few reports of enantioselective strategies. In this short review, we will present different strategies for the synthesis of chiral oxazinoindoles and we also examine the importance of chirality in biological activity.

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Scheme 2 Selected retrosyntheses for the construction of oxazinoindoles

# 2

Racemic Syntheses and Evaluation of Chiral Oxazinoindoles after Separation

In 2015, the Jones group described the synthesis and biological evaluation of oxazinoindoles for their bioactive properties on sphingosine-1-phosphate receptors (S1P1), which are important for the treatment of autoimmune diseases.[7] The different oxazinoindoles tested were derived from the 3-(1-(2-hydroxyethyl)-1H-indol-2-yl)acrylate derivative 12, obtained in a modest 33% yield via a Michael cyclization reaction. A postfunctionalization of this derivative yielded seventeen molecules. Three of them, showed a good biological activity with an EC50 of 0.04 nM. The two enantiomers of compound 13 were separated by chiral phase preparative chromatography, without determination of the configuration of the stereogenic center, and tested for their biological activity (Scheme [3]). Enantiomers 13a and 13b were tested against S1P1 and showed really good properties with IC50 of 0.23 nM and 0.01 nM, respectively. The 13b enantiomer also showed an interesting activity on β-arrestin with an EC50 of 0.83 nM. The latter was observed to be orally bioavailable in rats when administered as a suspension in 0.5% methylcellulose in sterile water. In addition, this molecule showed a half-life of 3.4 h, considered acceptable by the authors. This compound is a promising candidate for further biological evaluations.

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Scheme 3 Bioactive properties of chiral oxazinoindoles derivatives on sphingosine-1-phosphate receptors (S1P1)
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Scheme 4 Intermolecular oxa-Pictet–Spengler reaction for the synthesis of chiral oxazinoindole after diastereomeric separation

In 2016, the groups of Li, Zhang, and Guo also reported the synthesis of chiral oxazinoindoles and their evaluation as selective neuroprotective agents.[8] Inspired by the work of Gharpure in 2011,[3g] they obtained chiral oxazinoindoles in two steps via an intermolecular oxa-Pictet–Spengler reaction. The scatole molecule 14 was deprotonated using NaH and used with (S)- or (R)-methyloxirane to give chiral (S)- or (R)-1-(3-methyl-1H-indol-1-yl)propan-2-ol 15 which was further engaged in the oxa-Pictet–Spengler reaction in the presence of an aromatic aldehyde and BF3·Et2O. They envisaged that the presence of the chiral methyl group could induce a stereoselectivity in the cyclization process, but unfortunately both diastereomers 16a,b were obtained in similar ratio. However, they could be easily separated by column chromatography (Scheme [4]). Only aromatic aldehydes were used in this report because an aryl group was anticipated to increase the molecular rigidity and allow π-π stacking to the enzyme. These derivatives were tested biologically against neuronal damage, induced by the production and accumulation of β-amyloid peptide aggregates, which may be involved in Alzheimer’s disease. The study showed that some oxazinoindole derivatives 17–19 were excellent candidates as neuroprotective agents.[9] It is also important to mention that in many cases, biological tests showed that the trans molecules had no biological activity while their cis counterparts showed excellent activity.


# 3

Enantioselective Catalytic Syntheses of Oxazinoindoles

Whereas chiral (and achiral) oxazinoindole derivatives have often shown good biological activities, only few reports have described their synthesis via an asymmetric version. Since 2010, the asymmetric synthesis of oxazinoindole has not been widely investigated. The first group that mentioned such a scaffold was the Bandini group. They developed a strategy to obtain pyrazinoindolone derivatives 21 via an asymmetric phase-transfer-catalyzed intramolecular N-alkylation (Scheme [5a]).[10] They found that the use of a benzylcinchonium bromide derivative permit excellent yields and enantiomeric excess (7 examples from 75–93% and 75–98% e.e.). Throughout the rationalization of the observed induction of chirality, they studied an indolyl ester derivative 22. The objective was to demonstrate the influence of the amide moiety in the control of enantioselectivity. Switching from an amide group to an ester group resulted in a decrease of the electron density of the carbonyl, which resulted in a lower induction of chirality with only 59% e.e. (Scheme [5b]). However, the absolute configuration of the chiral center of oxazinoindole 23 was not determined.

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Scheme 5 First chiral synthesis of oxazinoindole via asymmetric phase-transfer process

In 2013, the Bandini group published a new approach for the construction of the oxazinoindole scaffold by the successive construction of the B and C rings starting from aniline derivatives 24.[5a] The use of a catalytic amount of XPhosAu(I)NTf2 complex allowed the construction of the B ring via a hydroamination reaction leading to the indole moieties. Then a dehydrative alkoxylation reaction gave the oxazinoindole scaffold with only water as a side product. This synthetic sequence was applied to obtain 15 oxazinoindoles 25a–k with a huge diversity of substitution (Scheme [6a]). In particular, a key precursor of an antidepressant described by Demerson group in 1975 was successfully obtained using this methodology in good yield (71%).[2a] The proposed mechanism went through an indolyl-diol intermediate and from this together with capacity of chiral gold complexes to promote stereoselective allylic alkoxylation reactions,[11] they developed an enantioselective synthesis of an oxazinoindole by replacing the CH2CH2OH unit with an allylic alcohol. Commercially available chiral C 2-symmetric biphosphines were reacted with Me2SAuCl and used in the presence of a halogen scavenger (Scheme [6b]). After optimization of the silver salt, solvent, and temperature, a combination of (S)-DTBM-SEGPHOS-(AuCl)2 and AgNTf2 (5 mol% each) in toluene with various allylic alcohols 28 resulted in the best induction of enantioselectivity in products 29, which were obtained with 78–98% e.e. (Scheme [6c]).[12] This strategy was the first metal-catalyzed enantioselective synthesis of chiral oxazinoindole with excellent enantiomeric excess.

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Scheme 6 Gold-catalyzed asymmetric cascade reactions

Also in 2013, the Scheidt group reported a tandem isomerization/Prins strategy for the construction of tricyclic indole scaffolds.[13] A cooperative catalysis using an iridium(III) catalyst and a Brønsted acid was successfully applied to C2-, C3-, and N-bridge indole allylic ether derivatives. The optimal condition were 1 mol% of [IrH2(THF)2(PPh2Me)2]PF6 and Bi(OTf)3 in THF. In the case of the N-bridged indole allylic ether derivatives 30, oxazinoindoles 31a–e were synthesized in 70–90% yield (Scheme [7a]). A modification of the Brønsted acid Bi(OTf)3 to a chiral phosphoric acid was investigated in order to perform an enantioselective version of this reaction. A low induction of chirality was obtained via the one-pot isomerization/cyclization. A sequential reaction sequence was considered with the isolation of the isomerized intermediate to yield the (E)-isomer 33. Then through an extensive screening of the phosphoric acid and the conditions, it found that the chiral phosphoric acid TRIP in toluene at room temperature gave the highest enantioselectivity (Scheme [7b]). They also mentioned that a diminution of the temperature did not improve the chiral induction. This strategy was the second example of an enantioselective oxa-Pictet–Spengler reaction[14] using an oxacarbenium/chiral phosphate counterion approach.

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Scheme 7 Synthesis of oxazinoindole via tandem isomerization/Prins strategy

In 2021, our group reported a new gold-catalyzed domino cycloisomerization/alkoxylation for the rapid construction of functionalized oxazinoindoles.[15] Inspired by the work of Abbiati on the reactivity of aldehyde-yne derivatives in the presence of an excess of Na wire in alcohols, we have investigated a more sustainable process.[3a] The use of aldehyde-yne with a cationic gold catalyst has often been used to build heterocycles, and if a second nucleophile, such as an alcohol, is added then this allows domino reactions.[16] We found that the use of IPrAu(MeCN)BF4 in DCE with primary alcohols at –20 °C allowed the selective formation of oxazinoindoles 36 in good to excellent yields (Scheme [8a]). This methodology enabled a wide range of diversity over the indole core and over the substitution of the alkyne moiety. In particular, this process tolerated electron-donating and electron-withdrawing groups. In addition, bromo groups were also tolerated and this would permit various further functionalizations. This strategy was extended to an enantioselective version by changing the catalyst with the atropoisomeric complex (S)- or (R)-DTBM-SEGPHOS-(AuCl­)2 (Scheme [8b]).[15] Good to excellent yields were obtained and very good enantiomeric excess were reached, up to 86% e.e. Few limitations were observed: the use of an aliphatic chain on the alkyne 38c and the use of methanol as nucleophile 39d resulted in a small reduction of the enantioselectivity, respectively 59% and 65% e.e. Moreover, the use of secondary alcohols or indole scaffold bearing a methyl group at C3 of the indole did not provide any enantioenriched oxazinoindoles. In addition, we determined the sense of the enantioinduction by Electronic Circular Dichroism (ECD): the use of (R)-DTBM-SEGPHOS-(AuCl)2 with AgSbF6 gives (R)-oxazinoindoles 38a–e while (S)-DTBM-SEGPHOS-(AuCl)2 allowed the formation of (S)-oxazinoindoles 39a–d. Other studies and analyses of these molecules for their bioactive properties are in progress in our team.

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Scheme 8 Gold-catalyzed asymmetric domino cycloisomerization/alkoxylation

# 4

Conclusion

In this short review we have highlighted the importance of the construction of chiral oxazinoindoles. Indeed, these molecules often exhibit a wide range of biological activities. Moreover, the chirality might also have a huge impact on the properties of a molecule. Enantioselective strategies for the construction of such scaffold are therefore very important. Presently, only few reports have shown appealing synthetic methods with modest to excellent induction of chirality. An extension of these studies as well as novel methodologies will converge towards interesting new strategies and will provide new data for bioactive properties.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Veronique Michelet
University Côte d’Azur, Institut de Chimie de Nice
UMR 7272 CNRS, Valrose Park, Nice 06108 CEDEX 2
France   

Publication History

Received: 02 June 2022

Accepted after revision: 11 July 2022

Accepted Manuscript online:
11 July 2022

Article published online:
03 August 2022

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   Permissions and Reprints All articles of this category
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Véronique Michelet is Professor at University Côte d’Azur since 2017. Her research interests combine fundamental and applied aspects of catalysis for the development of new synthetic methodologies for the formation of carbon–carbon and carbon–heteroatom bonds. Gold catalysis is one of her favorite research topics. Aurélien Dupeux joined the group of Prof. V. Michelet in 2019 at the University Côte d’Azur for his Ph.D. studies. His current research concerns gold catalysis and asymmetric synthesis. He will join the group of Professor Mark Lautens as a post-doctoral fellow.
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Scheme 1 Examples of oxazinoindoles with biological activity
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Scheme 2 Selected retrosyntheses for the construction of oxazinoindoles
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Scheme 3 Bioactive properties of chiral oxazinoindoles derivatives on sphingosine-1-phosphate receptors (S1P1)
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Scheme 4 Intermolecular oxa-Pictet–Spengler reaction for the synthesis of chiral oxazinoindole after diastereomeric separation
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Scheme 5 First chiral synthesis of oxazinoindole via asymmetric phase-transfer process
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Scheme 6 Gold-catalyzed asymmetric cascade reactions
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Scheme 7 Synthesis of oxazinoindole via tandem isomerization/Prins strategy
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Scheme 8 Gold-catalyzed asymmetric domino cycloisomerization/alkoxylation