Application of PictetâSpengler Reaction to Indole-Based Alkaloids

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Application of Pictet-Spengler Reaction to Indole Based Alkaloids Containing Tetrahydro-#-carboline Scaffold in Combinatorial Chemistry R Nishanth Rao, Barnali Maiti, and Kaushik Chanda ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00184 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 10, 2017

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ACS Combinatorial Science

Application of Pictet-Spengler Reaction to Indole Based Alkaloids Containing Tetrahydro-β-carboline Scaffold in Combinatorial Chemistry R Nishanth Rao, Barnali Maiti, Kaushik Chanda* Department of Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, India Email: [email protected] This article is dedicated to my PhD mentor Prof Chung Ming Sun for his contribution in combinatorial chemistry Abstract Indole based alkaloids are well known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-β-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole based alkaloids as well as highly marketed drugs. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of these privileged tetrahydro-β-carboline scaffolds. To date there are numerous research reports that have been published on the synthesis of the tetrahydro-β-carboline scaffold both on solid phase as well as in solution phase. Moreover rapid growth has been observed for the enantioselective synthesis of tetrahydro-β-carboline scaffold using chiral organocatalysts. In this review, efforts have been taken to shed light on the latest information available on different strategies to synthesize tetrahydro-β-carboline both on solid phase and in solution phase during the last 20 years. Furthermore, we believe that the present synthetic methodologies covered in this review will help to improve the status of this privileged tetrahydro-β-carboline scaffold in its use for drug discovery.

Graphical Abstract

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Introduction Organic chemists play a major role in drug discovery process owing to developing the fast synthesis of diverse libraries in automated format, concise processes, easy workup procedure, and simple isolation and purification technique along with eco-friendly chemistry.1 In order to expedite current synthesis methods, several new techniques, such as microwave assisted synthesis,2 ionic liquid supported synthesis,3 polymer-supported synthesis,4 multicomponent reaction,5 and combinatorial synthesis6 have emerged. The impact of combinatorial chemistry for swift generation of a variety of complex natural products inspired by drug-like molecule libraries for the purpose of drug discovery programs in the pharmaceutical industry are well known. The combination of synthetic organic chemistry and combinatorial chemistry has enabled the synthesis of natural product-like compounds with improved biological properties and also identified the novel scaffolds for the drug discovery process.7 Moreover, polymeric approach to supported synthesis is a core technology of combinatorial chemistry. It was originated in 1963, based from landmark achievement of Merrifield’s solid-phase peptide synthesis (SPPS). This technique is popular for the synthesis of tens of thousands of individual compounds.8 In 1992, Ellman and his group for the first time reported the solid-phase synthesis of small heterocyclic molecules and extended this methodology to the solid-phase organic synthesis (SPOS) from solid phase peptide synthesis.9 The key advantages associated with solid-phase organic synthesis are easy purification procedure, rapid generation of organic molecules, and the possibility of using excess of reagents to guarantee the completion of reactions. Despite of these advantages, the solid-phase organic synthesis (SPOS) has suffered some drawbacks such as heterogeneous reaction conditions, non linear kinetics, solvation problems. However, in order to overcome such drawbacks, numerous synthetic strategies have been developed using PEG, ionic liquids and fluorous supports. Indole based alkaloids are the largest class of alkaloids well known in the literature and are classified into two types such as nonisoprenoid, and isopenoids.10 Polysubstituted optically active tetrahydro-β-carboline derivatives classified as nonisoprenoid are the common structural motif in most indole based alkaloids. As depicted in Figure 1, functionalization of the C-1 position of tetrahydro-β-carboline derivatives are generally encountered in natural product based indole alkaloids and commercial drugs such as Tadalafil, and Etodolac.11 2


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Figure 1. Bioactive C-1 functionalized tetrahydro-β-carboline derivatives through the PictetSpengler Cyclization Strategy. The Pictet-Spengler reaction constitutes one of the most important, practical and versatile synthetic strategies utilized in the synthesis of natural products and drug molecules. The importance of the Pictet-Spengler reaction is due to two reasons: the first being nature utilizes the enzyme “Pictet spenglerases” to develop important intermediates useful for biological pathways for small molecules such as reserpine, and strictosidine, and the second reason is due to its use in the creation of bioactive structures for the development of new medicines such as Tadalafil, and Etodolac with a stereocentre adjacent to an aromatic ring.12 In 1911, for the first time Amé Pictet and Theodor Spengler discovered the reaction of β-phenethylamine 1 with formaldehyde dimethyl acetal 2 using HCl as an acid catalyst to obtain the 1-methyl-1,2,3,4tetrahydroisoquinoline (THIQ) 3 scaffold which was later extended to N-alkyl, N-acyl and Nsulfonyl derivatives of β-phenethylamine 1.13 By 1928, Tatsui synthesized the 1-methyl-1,2,3,4tetrahydro-β-carboline (THBC) scaffold 6 from tryptamine 4, and aldehydes 5 in presence of an acid catalyst to demonstrate the extension of the Pictet-Spengler reaction to tryptamine as depicted in Scheme 1.14 The mechanism of reaction involves the initial formation of an iminium ion (A) followed by electrophilic substitution at the 2-position.

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Me

+ NH2

MeO

1

HCl NH

OMe 2

3

NH2

4

NH R

N H

5

6

NH+

N R N H A

CH3

H+

+ RCHO N H

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N H

R

+

NH

N H R H

Scheme 1. Acid catalyzed Pictet-Spengler Reaction After deprotonation, the desired tetrahydro-β-carboline product is formed showing an early example of a 6-endo-trig reaction favored by Baldwin’s rule.15 Other than aldehydes, the PictetSpengler reaction also employs ketones, masked aldehydes such as enol ethers, hemiaminals, halomethyl methyl ethers, α- aminonitriles, and α-halo-α-phenylthio derivatives as the primary component for the synthesis of tetrahydro isoquinoline (THIQ) as well as for tetrahydro-βcarboline (THBC) scaffolds.16 Moreover, the stereoselective synthesis of complex indole alkaloids has gained immense interest in synthetic organic chemistry community from the year 1990 onwards. Numerous synthetic strategies have already been reported in the literature for the highly stereoselective syntheses of tetrahydro-β-carboline (THBC) with different substitution patterns at the heterocyclic ring system.17 Cook and his group demonstrated the numerous examples of substrate-controlled diastereoselective version of the classical Pictet−Spengler reaction using the L-tryptophan esters as directing groups.18 However, very few review articles are available in the literature on the synthesis of tetrahydro-β-carboline (THBC) derivatives which basically cover the solid phase as well as solution phase chemistry.15b,19 Tetrahydro-βcarboline (THBC) derivatives with substitution at 1-position are diverse with high abundance in nature and useful intermediates for the preparation of a wide range of complex heterocycles. Unfortunately, there is no single review concerning the different synthetic strategies such as solid phase, solution phase organocatalytic, and metal catalyzed synthesis of tetrahydro-β-carboline (THBC) derivatives were published in the literature. The present review deals with the main innovations regarding the synthesis of tetrahydro-β-carboline (THBC) scaffolds through solid phase as well as solution phase approaches. According to our belief, this review article will pave the way for the access to numerous strategies leading to the synthesis of tetrahydro-β-carboline 4


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(THBC) fused scaffolds with substantial appeal to become a possible drug candidate. Further, this review will highlight the key developments and challenges to the future design of tetrahydroβ-carboline (THBC) fused heterocyclic scaffolds.

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Synthesis of tetrahydro-β-carboline scaffolds on solid phase/fluorous phase/ionic liquid phase

Tetrahydro-β-carboline (THBC) or its derivatives have been reported to exhibit antiprotozoal, antiviral, anticancer, serotonin receptor (5HT) antagonism and α-adrenergic receptor antagonism properties.20 The synthesis of tetrahydro-β-carboline (THBC) or its derivatives commences with cyclization of tryptamine derivatives with carbonyl compounds via the Pictet-Spengler cyclization strategy in presence of an acid catalyst installing only one diversity element. Our objective is to discuss the efficient methodologies involved for the solid-phase synthesis of tetrahydro-β-carboline (THBC) or its derivatives formed by the combinatorial pathway. Due to this reason, we are discussing the solid supported synthesis of tetrahydro-β-carboline (THBC) or its fused derivatives with multiple structural diversity by various groups. In 1996, Mayer et al utilized the Wang resin 7 as the solid support to load the Fmoc-L-Tryptophan 8 using a simple coupling strategy to obtain the polymer bound intermediate 9 in Scheme 2.21 Fmoc deprotection of the polymer bound intermediate 9 was achieved using 20% piperidine in DMF followed by Pictet-Spengler cyclization reaction with carbonyl compounds catalyzed by 1% solution of TFA in CH2C12 to obtain the polymer conjugates 10. The Pictet-Spengler cyclization reaction with aldehydes finished in 1-2 h where as the ketones took almost 2 to 3 days for completion due to the lower electrophilicity of the ketone moiety. Cleavage of the polymer support was accomplished in 95% TFA/H2O for 2 h to obtain the tetrahydro-β-carboline (THBC) derivatives 11 with two diastereomers for aldehydes.

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Scheme 2. Mayers solid phase synthesis of tetrahydro-β-carboline (THBC) derivatives. In the same year, Yang group utilized the merrifield resin-bound NHBoc protected tryptophan 12 as the primary precursor as depicted in Scheme 3.22 Deprotection of Boc group from polymeric resin 12 using the 1:1 ratio of normal acidic conditions (TFA/CH2Cl2) obtained the polymer bound TFA salt 13 along with a significant amount of t-butylated indole. However, the use of indole suppressed the formation of alkylated indole. The polymer bound intermediate 13 then underwent the Pictet-Spengler cyclization reaction with aldehydes obtained the polymer conjugates 10. Finally, the amide derivatives of tetrahydro-β-carbolines (THBC) 14 from the resin were obtained with 70% ethylamine in water and THF at room temperature for 8 h.

Scheme 3. Yangs solid phase synthesis of tetrahydro-β-carboline (THBC) derivatives. In 1998, Yagar et al used the Pictet-Spengler cyclization strategy for the synthesis of tetrahydroβ-carboline-3-carboxamides (THBC) and 2,3-bi-lactams on a 4-hydroxythiophenol-linked solid support.23 As shown in Scheme 4, the acylation of the polymeric support with L-Boc-tryptophan 15 followed by NHBoc deprotection and the Pictet-Spengler cyclization with a variety of 6


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aldehydes provided the tetrahydro-β-carboline 10. The 2nd point of diversity was achieved from the cleavage of polymeric resin with primary amines resulted the amide 16. Additionally the synthetic methodology was further diversified by using the N-acylation of tetrahydro-β-carboline 10 with Boc-protected α and β-amino acid derivatives followed by the Boc deprotection to obtain the polymer bound derivatives 17. Subsequent neutralization with Et3N in CH2Cl2 resulted in the intramolecular cyclization and cleavage to obtain the 6- and 7-membered tetrahydro-β-carboline fused bi-lactams 18a and 18b respectively.

Scheme 4. Yagar solid phase synthesis of tetrahydro-β-carboline-3-carboxamides (THBC) and 2,3-bi-lactams derivatives. The same year Kooman and his group developed the solid phase synthetic strategy to Fumitremorgin, Verruculogen and Tryprostatin Analogs based on a traceless approach.24 As depicted in Scheme 5, the polymer anchored tetrahydro-β-carboline 10 underwent N-acylation with Fmoc protected L-amino acid in the presence of an excess of DIPEA at room temperature in NMP to obtain the polymer conjugates 19.

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Scheme 5. Solid phase synthetic strategy to Fumitremorgin, Verruculogen and Tryprostatin Analogs based on a traceless approach. Furthermore, Fmoc-deprotection, subsequent cyclization and the traceless cleavage occurred in 5% piperidine in THF solution at room temperature to obtain the natural product analogs 20 in high yields. The Pictet-Spengler cyclization reaction with ketones under identical condition yielded the tetrahydro-β-carbolines at a lower rate. It was to be noted that the final tetracyclic scaffolds 20 were obtained in four diastereoisomers except for the proline residue which could be due to the racemisation of the stereogenic centre of the finally introduced building block along with the two diastereoisomers obtained during the Pictet-Spengler cyclization reaction. At the end, a 42 member single library as diastereomeric mixtures was obtained by parallel synthesis in the MULTIBLOCK. In 1999, Ganesan and his coworkers developed the N-acyliminium Pictet−Spengler cyclization strategy as a synthetic tool on solid phase for the synthesis of natural product demethoxyfumitremorgin C analogues.25 As depicted in Scheme 6, the deprotection of polymer immobilized Fmoc-L-Tryptophan 9 using 20% piperidine in CH2Cl2 followed by reaction with aldehydes and trimethyl orthoformate obtained the polymer bound imine intermediate 21. Further, the treatment of the imine intermediate 21 with Fmoc-L-proline acid chloride 22 induced the N-acyliminium Pictet-Spengler reaction to generate the Fmoc proline bound tetrahydro-β-carboline derivatives 23. Subsequent synthetic steps involved the piperidine mediated Fmoc deprotection with concomitant traceless cyclative cleavage so as to obtain the natural product demethoxyfumitremorgin C 24 and its trans epimers. The same methodology was applied to synthesize the analogues of demethoxyfumitremorgin C by replacing the proline unit with other amino acids.

8


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Fmoc Cl N H CO 2 NHFmoc

H CO2

1. 20% Piperidine/CH2Cl2 r.t.

22

N

2. R1CHO, HC(OCH3)3

N H

N H

O

Pyridine, CH2Cl2

R1 21

9

O H

O H CO 2 N N H

R1

H

20% Piperidine/CH2Cl2 r.t.

N

N N N

N O Fmoc

N H

23

R1

N H

H

H O

O

24

Demethoxyfumitremorgin C

Scheme 6. Solid phase synthesis of natural product demethoxyfumitremorgin C analogues via the N-acyliminium Pictet−Spengler cyclization. The overall yield of tetrahydro-β-carboline derivatives is satisfactory with almost in a (1:1) cis:trans ratio. It is to be noted that the solid-phase N-acyliminium Pictet-Spengler cyclization reaction is tolerant for a variety of electron-deficient and electron rich aromatic aldehydes along with saturated and unsaturated counterparts. In 2002, same author reported the synthesis of hydantoin fused tetrahydro-β-carboline derivatives on solid phase.26 In this methodology, instead of Fmoc-L-proline acid chloride the polymer immobilized intermediate 21 reacted with p-nitrophenyl chloroformate 25 to obtain the carbamate 26 with (1:1) cis:trans ratio as shown in Scheme 7. However, both the cis and trans isomer of polymer immobilized carbamates 26 were reacted with primary amine in presence of Et3N as base and DMF as solvent in a traceless fashion to obtain the trans tetrahydro-β– carbolinehydantoins derivatives 27. This could be due to the epimerization of the cis carbamate adjacent to the carbonyl center to the thermodynamically more stable trans-carbamate derivatives.

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Scheme 7. Solid phase synthesis of hydantoin fused tetrahydro-β-carboline derivatives via the Nacyliminium Pictet−Spengler cyclization. The same year Schultz and his group developed a novel methodology of safety catch linkage for confining the tryptamine derivatives by vinylsulfonylmethyl polystyrene resin.27 The safetycatch term applied to a solid phase linker has several advantages such as the excellent control over the timing of product release, highly stable to both strongly acidic and basic reaction medium, and mild chemical conditions allowing the intact deliverance of final products. Moreover, instead of normal single step reaction, the safety-catch linker is cleaved by performing two different reactions. In the Scheme 8, treating the various tryptamines 4 with vinylsulfonylmethyl polystyrene resin 28 obtained the safety-catch linkage derivatives 29 which were quite stable in acidic condition. Treating the intermediate 29 with aldehydes in 1-10% trifluoroacetic acid in CH2Cl2 at room temperature for 12 h obtained the tetrahydro-β-carboline scaffold 30 via the Pictet-Spengler cyclization reaction. Polymer free tetrahydro-β-carboline scaffolds 31 were obtained by activation of the resin followed by Hoffman elimination reaction under basic condition. Electron-rich substituents on indole derivatives required 1% TFA/CH2Cl2 as compared to electron-neutral or electron-withdrawing substituents which required 5-10% TFA/ CH2Cl2.

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Scheme 8. Safety-catch linkage strategy for solid phase synthesis of tetrahydro-β-carboline. Subsequently in the year 2004, Meldel et al developed a novel solid-phase intramolecular PictetSpengler reaction.28 The primary precursor 34 for the Pictet-Spengler reaction was obtained in a usual way. As shown in Scheme 9, the masked aldehyde protected N-Boc-1,3-oxazinanes 35 used as a building blocks for the generation of solid-supported aldehydes 36. Upon exposed to acidic treatment on polymer immobilized intermediate 36, the masked part of aldehyde functionality is released and rapidly underwent the nucleophilic attack from amide nitrogen for the formation of a highly reactive cyclic N-acyliminium ion as an intermediate. Subsequently, a stereoselective intramolecular Pictet-Spengler cyclization reaction took place to obtain the interesting tetracyclic tetrahydro-β-carboline scaffolds 37 on solid support.

Scheme 9. Solid-Phase Intramolecular Pictet-Spengler Reaction to tetracyclic tetrahydro-βcarboline scaffolds. 11



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Lesma and his co-workers developed the combinatorial library of 6-hydroxy-tetrahydro-βcarbolines from L-5-OH-tryptophan scaffold via solid-phase synthetic method.29 The methodology is based on utilizing the aminomethyl polystyrene 38 as solid phase resin and the Pictet-Spengler cyclization reaction to obtain the combinatorial library with three points of structural diversity. As depicted in Scheme 10, the commercially available L-5hydroxytryptophan 39 was chosen as the primary precursor attached to the solid support via loading on to the 5-OH moiety instead of carboxylic group for developing possible diversity on the solid phase to obtain the intermediate 40. The first point of structural diversity was introduced by amidation or esterfication of carboxyl moiety of intermediate 40 with substituted alcohols or amines to obtain the intermediate 41. After removal of Fmoc group from intermediate 41, the access to the tetrahydro-β-carbolines was achieved via Pictet-Spengler reaction with aldehydes to result in intermediate 42. Finally the polymeric cleavage of intermediate 42 was achieved in 35% ethylamine in water and THF to obtain the ester or amide derivatives of 6-hydroxy-tetrahydro-β-carbolines 43 with three points of structural diversity. The synthetic strategy allows the installation of diversities at the C-1 position of the carboline skeleton as well as, at the N-2 and at the carboxylic group for easy preparation of potentially large arrays of small molecules.

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O NH2

1. Succinic anhydride CH2Cl2, 12 h

N H

2. NHS, DMAP, CH2Cl2, 3 h 3. L-5-OH-tryptophan 39, DMAP CH2Cl2, DMF, 2 h

38

COOH O O 40

N H

O O

O OR

O

N H

NHFmoc 1. 10% piperidine in DMF, 3h

O N H

O N H

O

N H

NH

42

O

O NHR

1. 10% piperidine in DMF, 3h NHFmoc

O O

N H

O

N H

R1 O

or

NH R NH

O N H

2. R1CHO, 1% TFA in CH2Cl2 12 h

N H

OR

O O

2. R1CHO, 1% TFA in CH2Cl2 12 h

41 or

1. BOP, TEA, DMF, R-NH2 12 h or 1. DIC, HOBT, DMF, ROH, 12 h

NHFmoc

R1

42

41 O 1. R2-X, DIPEA, CH2Cl2, 6h X=CN, Cl

O OR

HO

N R2

2. 35% Et3N in H2O-THF N H

NHR

HO

N R2

or N H

R1

R1

43

43

Scheme 10. Solid phase synthesis of 6-hydroxy-tetrahydro-β-carbolines from L-5-OHtryptophan scaffold In 2006, Sun et al developed the traceless and stereo selective syntheses of a combinatorial library of thio and oxo hydantoin fused tetrahydro-β-carboline derivatives by microwave irradiation on PEG support.30 Recently, a highly efficient cyclization-cleavage methodology has been developed for the traceless synthesis by reducing the number of synthetic steps. The key advantages associated with traceless syntheses are ample in terms of smart choice of reactant and reaction condition followed by easy recovery of the desired products sans post cleavage workup.31 As designed in Scheme 11, the commercially available NHBoc protected L-tryptophan 15 was loaded on PEG-4000 a soluble support via ester coupling strategy to obtain the intermediate 44. It was believed that the nucleophilic amino group was required for the generation of β-carboline skeleton via [5+1] approach. Subsequently, the NHBoc deprotection and the Pictet-Spengler cyclization were achieved in one-pot manner under microwave irradiation for 20 min. During the one-pot cyclization, the in-situ generated amine was reacted with aldehyde to form an imine which further underwent an acid-catalyzed intramolecular 13



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cyclization. The polymer immobilized tetrahydro-β-carboline derivatives 45 were obtained with (1:1) cis:trans ratio with one point of diversity. Further, the next diversity was introduced by constructing the terminal thiohydantoin ring across the N-2/C-3 bond of the tetrahydro-βcarboline skeleton. The traceless cyclization was achieved by the reaction of polymer immobilized tetrahydro-β-carboline derivatives 45 with various isothiocyanates under microwave irradiation to obtain the trans tetracyclic scaffold 46 in good yield. However, the same strategy applied to isocyanates obtained a mixture of cis and trans tetrahydro-βcarbolinehydantoin 47. It is interesting to observe that the cis/trans diastereomeric ratio in the Pictet-Spengler cyclization reaction depends on the acidity of the reaction medium, steric volume of the ester function, and the substituent on the nitrogen of the tryptophan moiety. However, it was observed that the MW irradiation of the reaction mixtures favors the thermodynamically stable trans isomers than the cis isomers. The observed 100% trans diastereoselectivity for compounds 46 under the MW irradiations has been confirmed by 13C NMR, COSY and HPLC experiment.

Scheme 11. PEG supported synthetic route to oxo and thio hydantoin fused tetrahydro-βcarboline 46 and 47. Furthermore, Meldel and coworkers developed a solid phase methods for the synthesis of polycyclic compounds containing tetrahydro-β-carboline scaffolds.32 In this methodology, amino aldehydes masked with 3-boc-(1,3)-oxazinane synthesized from amino acids, and amino alcohols 14


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were converted to pentafluorophenyl carbamate to serve as a urea precursor. Acidic treatment of intermediate 48 generated the aldehyde moiety which immediately underwent the intramolecular Pictet-Spengler cyclization with tryptophan residue via N-carbamyliminium ion afforded the tetrahydro-β-carbolines 49 with high diastereomeric excess as shown in Scheme 12. The methodology has been extended to substituted indoles, benzenes, pyrene, furan, thiophenes, and benzothiophene with comparable stereoselectivity and purity.

Scheme 12. Solid phase synthesis of polycyclic compounds containing tetrahydro-β-carboline scaffold. Again Sun group demonstrated the Pictet-Spengler cyclization strategy using less reactive ketones for the synthesis of hydantoin fused tetrahydro-β-carboline derivatives on PEG support in 2007.33 As shown in Scheme 13, the Fmoc protected L-tryptophane 8 was loaded onto the PEG-4000 under the activated DCC/DMAP amino acid-coupling condition followed by the deprotection of Fmoc moiety using 10% piperidine in CH2Cl2 to obtain the compound 50.

Scheme 13. PEG supported synthetic route to oxo hydantoin fused tetrahydro-β-carboline with ketones as carbonyl fragment. 15



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Compound 50 underwent the Pictet-Spengler cyclization with substituted ketones in refluxing CHCl3 for 15 h to obtain the polymer conjugates 51. Compared to aldehydes, the Pictet-Spengler reaction with ketones was sluggish which took longer hours for completion. The second point of structural diversity was installed by reacting compound 51 with substituted isocyanates in the presence of Et3N at room temperature to yield the tetrahydro-β-carbolinehydantoin 52 in traceless fashion. In this protocol, the substitutents of the ketone moiety dictate the stereochemisty of the product molecule. Depending on the large size differences of the two substituents on the ketone moiety, the product orientation was found in trans conformation to minimize the steric hindrance. At the same time, the small size difference resulted in two diastereomers with trans being the major product which was confirmed by the analysis of 1H NMR and HPLC experiments. Fluorous tag strategy34 has drawn wide spread attention as it is an efficient tool to abridge the separation and purification of organic reaction mixtures in the synthetic chemistry. Compared to solid supports, the advantages associated with fluorous tagged molecules are their inert natures, solubility in most organic solvents, maintaining homogeneous reaction conditions, accurate control of stoichiometry, monitoring the progress of the reaction by standard analytical techniques etc. Sun et al developed the combinatorial library of a novel fluorous and traceless synthesis of tetrahydro-β-carbolinehydantoin analogues.35 The Scheme 14 demonstrated the attachment of the 3-(perfluorooctyl)propanol 53 with NHBoc-L-tryptophan 15 followed by sequential NH boc deprotection, nucleophilic addition, and the Pictet-Spengler cyclization with various aldehydes obtained the cis and trans stereoisomers of tetrahydro-β-carbolines 55. The treatment of tetrahydro-β-carbolines 55 with substituted isocyanates using Et3N as base at room temperature condition resulted in traceless cleavage of fluorous tag along with the tetrahydro-βcarbolinehydantoin 47. Using an excess of isocyanates resulted in the formation of urea containing indole 56.

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Scheme 14. Synthetic route towards the tetrahydro-β-carbolinehydantoins 47 on fluorous tag. In 2009, for the first time, Sun et al developed the green synthetic strategy for the synthesis of tetrahydro-β-carboline derivatives on ionic liquid support.36 Due to the heterogeneity and low loading capacity of solid phase, researchers have directed their attention towards the ionic liquid supported synthesis which retained the advantages over the solution phase chemistry.3 The readily available 3-hydroxyethyl-(1-methylimidazolium)-tetrafluoroborate [HEMIm]BF4 57 is selected as a suitable ionic liquid (IL) support for multistep combinatorial synthesis. Coupling of Boc protected L-tryptophan 15 to hydroxyl ethyl methyl imidazolium tetrafluoroborate [HEMIm]BF4 57 under the activated DCC/DMAP amino acid-coupling condition, the ionic liquid immobilized intermediate 58 is obtained. As discussed in Scheme 15, for the generation of β-carbolines 59 by [5+1] approach, NHBoc deprotection and subsequent cyclization with aldehydes was carried out in one pot manner using 20 % TFA in H2O-IPA (1:1) under microwave irradiation for 20-30 minutes. However, the ketones required the more harsh condition to complete intramolecular cyclization due to the lower electrophillicity of the ketone functionality. To create the second diversity point in target structures, the terminal oxo and thiohydantoin moieties are constructed across the ionic liquid immobilized β-carbolines 59 with the addition of isocyanates and thioisocyanates at the second stage of the reactions in water/isopropanol co-solvents in mild basic medium. Finally, the traceless cleavage of ionic liquid obtained the tetracyclic scaffolds 60 in high yields and high purity.

17



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H

BF4 N + N

OH

IL

OH

+ HN

57

O

Page 18 of 68

DCC/DMAP CH3CN

OH NHBoc

H

MW, 80 oC, 12 min N H

15

O

O NHBoc

IL

58 H O

1. TFA , IPA/H2O (1:1) MW, 80 oC, 10 min

H

O

o

2. R1COR2 MW, 80 -130 C, 10 - 20min

O

IL

NH R2

N H R1

R3-N=C=X, Et3N IPA/ H2O(1:1) MW, 80 oC, 12min

59

N H R1

N R3 N R2 X X = O or S 60 (trans)

Scheme 15. Ionic liquid supported oxo and thio hydantoin fused tetrahydro-β-carbolines. In 2009, the same group developed the structural analogues of tadalafil containing two diversity points from soluble polymer support employing the Pictet-Spengler cyclization reaction.37 As drawn in Scheme 16, the polymer bound intermediate 51 underwent N-acylation with chloro acetyl chloride to obtain the intermediate 61. Subsequent reaction of intermediate 61 with primary amines went efficiently with intramolecular N-heterocyclization with various in-situ generated α-alkyl, arylalkyl and heteroalkyl amides to obtain the structural analogues of tadalafil 62 in traceless fashion. However, the attempted synthesis of seven membered 2,6diazepinediones 65 with 3-chloro propionyl chloride failed. Instead of obtaining the desired Nchloropropionyl conjugates, N-acrolyl conjugates 63 were found. The polymer conjugates 63 were further reacted with the primary amine moiety resulted in the generation of N-acyl conjugates 64 which were confirmed by the polymer cleavage using 1% KCN in MeOH solution.

18


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H

O

O PEG

O NH R2

N H R1

Cl

CH2Cl2, MW

2

H

Cl , Et3N

N R2

N H R1

O

O O O

PEG 2

R3NH2

N

CH2Cl2, MW

N H

Cl

51 R2=H for aldehyde cis:trans=1:1

61 R2=H for aldehyde cis:trans=1:1

R3

N R2 R1 O 62

R2=H for aldehyde cis:trans=1:1

O Cl Cl , Et3N CH2Cl2, r.t./reflux

O PEG

O

H

H

N

R1 R2

O

O

O 1.R3NH2 Cl(CH2)2Cl, reflux

NH

2. 1% KCN in MeOH r.t., 12 h

N N H

O O

R2 R1 NHR3

2 64

63

R3 N

N H

N R2 R1 O Not Obtain 65

Scheme 16. Soluble polymer supported synthesis of structural analogues of tadalafil In 2013, Sun group again demonstrated the diastereoselective synthesis of bridged polycyclic skeletons 53 via the Pictet-Spengler cyclization/tandem acylation and intramolecular Diels−Alder reaction on soluble support.38 As depicted in Scheme 17, the polymer immobilized compound 48 underwent the Pictet-Spengler cyclization with 5-substituted furan-2-carbaldehyde 66 in the presence of TFA in refluxing CHCl3 under microwave irradiation to obtain the desired tetrahydro-β-carboline scaffold 67 in cis/trans (1:1.15) diastereomeric ratio. Subsequently, the diastereomeric mixture of tetrahydro-β-carboline 67 was treated with substituted acryloyl chloride 68 at ambient temperature using Et3N as base in CH2Cl2 obtained cis and trans isomer of α,β-unsaturated amide 69. The trans isomer of compound 69 spontaneously underwent intramolecular [4+2] Diels−Alder cycloaddition in one pot manner to obtain the exo product of polymer bound intermediate 70 where as the cis isomer of N-acylated product 69 remained unreacted. The cleavage of polymer support using 1% KCN in MeOH at room temperature obtained the exo product of hexacyclic bridged indole skeleton 71 in good yield along with cis isomer of N-acylated product 72.

19



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O H O PEG

R1

O

H

O

O NH2

PEG

O

R1

PEG

O

O

N

+ PEG

H

H

O

O N

H

H

NH

NH

69 (cis:trans)

NH

70 O H

1% KCN, MeOH

O

N N H

H

69 (cis) O H

O

O

N H H

O

O

N

+

H

R1

O

O

O

N

r.t.

67 (cis:trans)

O H

O

Cl 68 Et3N, CH2Cl2, r.t.,

O

R1

H

2

NH

R1

O O

O

HN

66

48

PEG

H

O

2 TFA, CHCl3, MW

NH

Page 20 of 68

O

R1

R1 72(cis)

71

Scheme 17. Diastereoselective synthesis of bridged polycyclic skeletons on PEG support Sun group developed the natural product-inspired hydantoin-fused tetrahydroazepino indoles using solution phase chemistry in 2015.39 As depicted in Scheme 18, the Pictet-Spengler cyclization of L-tryptophan methyl ester 73 with ethyl bromopyruvate 74 in TFA afforded a mixture of bromomethylated product 75 (1S, 3S) along with a tetrahydroazepino indoles product 76 in 1 : 2 ratio. However, by refluxing the bromomethylated product 75 in the presence of KI and K2CO3 in CH3CN for 30 min, the tetrahydroazepino indoles product 76 is obtained in high yield. Further, the diversification of tetrahydroazepino indoles 76 was undertaken through a onepot urea formation-cyclization strategy utilizing different isocyanates and isothiocyanates and isoselenocynates. The reaction of intermediate 76 with different isocyanates or isothiocyanates and isoselenocynates in presence of Et3N as base in CH2Cl2 solution for 15 h under room temperature condition afforded the hydantoin-fused tetrahydroazepino[4,5-b]indoles 77 in good yield.

20


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O H

Br

O O

NH2

N H

H

OEt

O H

O

O

O

O 74 N H

TFA, CHCl3, 30 min

73

NH

+

NHO

N H

OEt Br 75(1S,3S)

O 1:2

OEt 76

KI, K2CO3 CH3CN, reflux, 30 min

O H

O

O NH

H

R1 N C X

N

Et3N, CH2Cl2, r.t, 16 h

N H

X=O, S, Se O

N

N H

OEt

X X=O, S, Se

O 76

R1

OEt 77

Scheme 18. Solution phase synthesis of oxo, thio and seleno hydantoin fused tetrahydroazepino[4,5-b]indoles.

•

Synthesis of tetrahydro-β-carboline scaffolds on solution phase by metal catalysis

Asymmetric metal-catalyzed reactions have played a significant role in synthesizing the biologically important molecules. The advantage associated with metal catalysts is due to the dual properties of the metal which can act either as lewis acid or lewis base. However, in addition to the reactivity, the catalysts can be fine tuned by changing the ligands attached to the metals. Traditionally the synthesis of tetrahydro-β-carboline scaffolds via the acid catalyzed Pictet–Spengler reaction is known in the literature but a few reports are available in the literature for the metal catalyzed synthesis of this desired scaffold. For the first time 1996, Noyori et al introduced the asymmetric reduction under catalytic transfer hydrogenation conditions, catalyzed by chiral Ru(II) catalyst to obtain the two derivatives of tetrahydro-β-carboline scaffolds in good yields and excellent enantioselectivity.40 In the year 2006, Youn showed the synthesis of tetrahydro-β-carboline scaffolds via mild and an efficient AuCl3/AgOTf-catalyzed acyl PictetSpengler reactions in good yields.41 As depicted in Scheme 19, the imine substrate 78 derived from the tryptamine underwent cyclization reaction in the presence of AuCl3/AgOTf in 1,2dichloroethane at 80 oC to obtain the tetrahydro-β-carboline moiety 79 in low yields. The 21



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Page 22 of 68

problem associated with the low yields is due to the reactivity of the imine substrate which was overcome by the addition of acyl chloride to the reaction mixture. Furthermore, the imine substrate 78 underwent the acyl-Pictet-Spengler reaction with acetyl chloride in the presence of AuCl3/AgOTf in 1,2-dichloroethane at room temperature to obtain the tetrahydro-β-carboline moiety 80 in good yields. Other acylating agents such as acetic anhydride or ethyl chloroformate were not effective in the cyclization reaction. The mechanism of the reaction proceeds an electrophilic pathway involving an imine activation by coordinating gold(III) complex to obtain the tetrahydro-β-carboline derivatives.

N N H 78

R

uCl 3 % A gOTf l o 10 m ol% A h o , 24 20 m 0 C 8 , l H 2C H 2C ClC 1m 2 m ol% Au o Ac Cl, l% A Cl3 gO 2,6 Tf r,t. -lu t ,1 2 h idine

NH N H

R

79 Low yields

N Ac N H

R 80

55-75 % yield

Scheme 19. AuCl3/AgOTf catalyzed synthesis of tetrahydro-β-carboline. In 2006, Ronchi, et al developed the Pd catalysed intramolecular allylation for the enantioselective synthesis of tetrahydro-β-carboline derivatives.42 As depicted in Scheme 20, the substituted indole derivative 81 with allyl substitution at 2-position underwent Pd-catalyzed allylation to obtain the tetrahydro-β-carboline 82 intramolecularly in high yields with excellent enantiomeric excesses up to 97%. Subsequently this methodology is also applicable for the synthesis of tetrahydro-γ-carboline derivatives also.

Scheme 20. Pd catalyzed enantioselective synthesis of tetrahydro-β-carboline derivatives. In the year 2007, Dixon group established an Au(I)-catalyzed N-acyl iminium ion cyclization cascade for the rapid synthesis of tetrahydro-β-carboline fused polycyclic derivatives.43 As 22


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depicted in Scheme 21, Au(I)-catalyzed cyclization of alkynoic acids 83 was chosen as the first step in a synthetic sequence leading to an N-acyl iminium ion which underwent the immediate cyclization to obtain the tetrahydro-β-carboline fused polycyclic compounds. Treating the toluene solution of 1 mol% AuPPh3Cl/AgOTf with alkynoic acids 83 followed by the addition of tryptamine 4 under refluxing conditions for 48 h obtained the desired tetrahydro-β-carboline fused polycyclic compounds 84. However, under room temperature conditions the desired tetrahydro-β-carboline fused polycyclic compounds 84 was not obtained which required high temperature to overcome the activation barrier of N-acyl iminium ion. Moreover, when the same reaction was carried out with nonterminal alkynoic acid, the desired cyclization cascade proceeded successfully with a mixture of the possible two regioisomers in good yield.

Scheme 21. Au(I)-catalyzed N-acyl iminium ion cyclization cascade for the synthesis of tetrahydro-β-carboline fused polycyclic derivatives. To synthesize the tetrahydro-β-carbolines via the Pictet-Spengler cyclization reaction using aldehydes, hydroformylation has only scarcely been used.44 In the year 2008, a tandem hydroformylation–Pictet–Spengler cyclization was developed for the synthesis of tetrahydro-β-carbolines from the tryptamine 4 or tryptamine methyl ester 73 and olefin 85 in Scheme 22. The reaction of olefin 85 with the tryptophan methyl ester 73 in toluene using 1 mol % of Rh(acac)(CO)2 and 30/10 bar of CO/H2 pressure at 80 °C obtained two different products 87 and 88 instead of usual tetrahydro-β-carbolines 86. The reduction of intermediate Schiff base is faster in the formation of 87 and 88 than the electrophilic attack of imine to indole. Surprisingly, when the tandem reaction was performed in polar solvents such as CH2Cl2, THF or MeOH, in almost (1:1) cis:trans ratio of tetrahydro-β-carbolines 86 were obtained in all cases.

23



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Scheme 22. Rh catalyzed tandem hydroformylation/Pictet-Spengler reaction In 2011, Tu and coworkers developed an unusual regiodivergent annulations approach on 3phenoxy alkynyl indoles with N-protection catalyzed by Au catalyst.45 As shown in Scheme 23, the 3-phenoxy alkynyl indoles substrate 89 with electron donating group such as Bn underwent C3-site selective annulations reaction by Au(I) catalyst to afford the spiro-tetrahydro-β-carboline derivatives 90 whereas the same substrate with electron withdrawing group such as –COOMe obtained the spiro-pseudoindoxyl compound 91. To optimize the reaction conditions, several catalysts were used out of which only the use of AuPPh3Cl/AgOTf (5 mol %) as catalyst in CH2Cl2 resulted the desired product. In this methodology, an unusual 1,2-phenoxy migration took place during Au(I) catalyzed C3-selective annulations of 3-phenoxy alkynyl indoles substrate with the electron donating group to obtain the spiro-tetrahydro-β-carboline in good yield.

24


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Tf O n g /A B Cl ) R= 3 h % PP ol u A 5m (

C C3 H2 C -a l2 , nn r. ul t at io n

Page 25 of 68

CH C2 2 C A -a l2 , (5 uPP nnu r.t mo h lat io l% 3 Cl/ ) R Ag n =C OT O f 2M e

Scheme 23. Au(I) catalyzed regiodivergent annulations of 3-phenoxy alkynyl indoles with Nprotecting group. In the same year, Nielsen et al. discovered the Ru catalyzed tandem ring closing metathesis/isomerization followed by the N-acyliminium cyclization to obtain the tetrahydro-βcarboline fused tetracyclic architecture.46 As planned in Scheme 24, the substrate 92 which contains an indole moiety with reactive π-nucleophiles underwent ring closing metathesis followed by isomerization with Ru catalyst under the refluxing toluene solvent to obtained the enamide 93. Further isomerization of the intermediate generated the N-acyliminium intermediate followed by rapid intramolecular cyclization with tethered N-atom and carbon nucleophiles of indole moiety to obtain the tetrahydro-β-carboline fused tetracyclic molecules 94.

25



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Page 26 of 68

Scheme 24. Ru catalyzed tandem ring closing metathesis/isomerization/N-acyliminium cyclization to obtain the tetrahydro-β-carboline fused heterocycles. The presence of a methylester group as the substitutent in tryptophan derivative 92a resulted the tetrahydro-β-carboline fused heterocycles 94a with exeellent trans diasteroselectivity. Followed by this achievement, in 2012 Nielsen and his coworkers discovered an alternative route to the classical Pictet–Spengler cyclization for the synthesis of tetrahydro-β-carboline derivatives.47 The Scheme 25 displayed the metal-catalyzed isomerization of allylic amines to form reactive iminium intermediates which was trapped by the indole nucleophile tethered to the substrate. Allylic amine tethered tryptamine derivative 95 underwent the metal catalyzed isomerization followed by iminium cyclization to form the tetrahydro-β-carboline derivatives 96 in good yields. Several metal catalysts were used such as Pd, Rh, or Ru out of which only 1 mol% of Ru(PPh3)3Cl catalyst showed the remarkable results under refluxing toluene for 23 h. However in order to diversify the existing methodology, the tryptamine derivatives 4 underwent one-pot synthetic sequence of tandem Tsuji–Trost/isomerization/ iminium cyclization reaction to obtain the tetrahydro-β-carboline derivatives 96 in good yields. N R1 R2

R4 N H

Rh(PPh3)3Cl (5 mol%) Toluene, reflux, 23 h

N R1 R2

R4 N H

R3

R3 96

95 N R1 H

R4 N H

1. AllBr, K2CO3 Toluene, reflux 16 h

N R1 R4

2. Rh(PPh3)3Cl (15 mol%) Toluene, reflux, 2 h

4

N H 96

Scheme 25. Ru(I) catalyzed synthesis of tetrahydro-β-carboline via isomerization/cyclization sequence. Liu and coworkers developed the Au(I)-catalyzed one-pot cascade methodology for the synthesis of tryptamine-fused polycyclic molecules in 2013.48 As depicted in Scheme 26, the reaction of substituted tryptamines 4 with 2-ethynylbenzoic acids or 2-ethynylphenylacetic acids 97 using Au(I) catalyst with TFA as an additive under refluxing toluene at 110 oC obtained the tetrahydroβ-carboline derivatives 98 in excellent yields. The synthetic strategy demonstrates the formation of one C–C bond and two C–N bonds with high yields and broad substrate scope. Further 26


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reduction of the carbonyl moiety in compound 98 afforded the amine derivatives 99 which showed as α1-adrenergic receptors antagonists.

Scheme 26. Synthesis of tetrahydro-β-carboline derivatives via Au(I) catalyzed tandem reaction The same year, Nielsen and his group demonstrated an aldehyde free alternative route to the classical Pictet−Spengler cyclization for the synthesis of tetrahydro-β-carboline.49 As described in Scheme 27, the allylic amides 100 underwent an efficient tandem sequence of RuH/Brønsted acid catalyzed isomerization followed by cyclization of N-acyliminium ion intermediates by a tethered indole nucleophile to obtain the 101. On the other hand, in order to diversify the said methodology, a tandem Suzuki cross-coupling/isomerization/N-acyliminium cyclization sequence for the synthesis of tetrahydro-β-carboline 101 was also studied. The application of isomerization/N-acyliminium cyclization to the L-tryptophan derivatives 103 obtained the tetrahydro-β-carboline 104 with modest diastereoselectivity depending on the nature of the substrate.

27



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Page 28 of 68

Scheme 27. Ru hydride/brønsted acid-catalyzed synthesis of tetrahydro-β-carbolines. The subsequent year, Liang and his coworkers established an efficient procedure for the Au(I) catalyzed synthesis of functionalized spiro-tetrahydro-β-carboline derivative.50 The reaction involves the Au(I) catalyzed Friedel Craft intramolecular reaction of alkynylaziridine indoles followed by hydroamination of aminoallenes to obtain the

105

spiro fused tetrahydro-β-

carboline derivative 106 as shown in Scheme 28. Because of mild reaction condition, good functional group tolerance, and operational simplicity made this protocol an attractive alternative to the classical Pictet-Spengler cyclization strategy. R4 NTs R4

R3 R3

R6 N R5 R1 N R2

NTs R6 N R5

Au(PPh3)Cl/AgSbF6 CH2Cl2, OoC 5h

r.t.

R1

105

N R2 106

Scheme 28. Au(I) catalyzed synthesis of functionalized spiro-tetrahydro-β-carboline derivative.

•

Lewis acid catalyzed synthesis of tetrahydro-β-carboline scaffolds on solution phase

In the year 1998, Nakagawa and his group for the first time developed the reagent control enantioselective Pictet-Spengler reaction for the synthesis of tetrahydro-β-carboline scaffolds.51 28


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The Scheme 29 shows the chiral lewis acid diisopinocampheylchloroborane (Ipc2BCl) was utilized for the cyclization of Z-nitrones 108 derived from Nb-hydroxytryptamine 107 to obtain the tetrahydro-β-carboline scaffolds 109. It was observed that the (+)-Ipc2BCl gave high yields and ee at low temperature. However decreasing the amount of chiral lewis acid catalyst Ipc2BCl to 0.5 eq. caused a significant reduction of yield, where as substituting the chloride ion of chiral lewis acid with fluoride or triflate did not improve the yield as well as the enantiomeric excess value. The mechanism of the reaction involves the formation of an iminium ion with coordination of the nitrone oxygen to the Ipc2BCl boron centre leads to the tetrahydro-βcarboline. It was realized that the iminium ions obtained from the electron-deficient aldehydes gave poor enantioselectivity with effective cyclizations to obtain the tetrahydro-β-carboline derivatives.

Scheme 29. Chiral lewis acid (+)-Ipc2BCl catalyzed enantioselective synthesis of tetrahydro-βcarboline scaffolds. Subsequently in 2009, Leighton et al extended the chiral Lewis acidic silane reagent as catalyst for the enantioselective Pictet-Spengler cyclization reactions for the synthesis of tricyclic tetrahydro-β-carboline derivatives.52 The tryptamine derivative 110 with α-ketoamide ketimines moiety underwent the Pictet-Spengler cyclization reaction with silane reagent 111 to obtain the quaternary stereocentre in compound 113 as depicted in Scheme 30. The NMR studies of the reaction suggested that following the O-silylation, the proton from the NH group of compound 110 transfer to the silane reagent's 111 nitrogen atom and activates the complex 112 for PictetSpengler cyclization. Electron-withdrawing groups present on the N-aryl ring increased the rate of the reaction whereas the sterically crowded aryl groups also generated the tricyclic architecture with 93% enantiomeric excess. 29



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Scheme 30. Enantioselective Pictet–Spengler cyclization of α-ketoamides supported by a silane reagent. Yan and his coworkers developed an one-pot three-component synthetic sequence of tetrahydroβ-carboline fused heterocyclic structures using anhydrous ZnCl2 as catalyst.53 As figured in Scheme 31, the reaction of tryptamines 4, ethyl or methyl propiolates 114, and α,β-unsaturated carbonyl compound 115 afforded the functionalized tetrahydro-β-carboline fused heterocyclic structure 116 in high yields with excellent diastereoselectivity. The mechanism of the reaction involves the sequential Michael addition followed by the Pictet-Spengler cyclization of the insitu generated β-enamino ester to obtain the complex heterostructure.

Scheme 31. Anhydrous ZnCl2 catalyzed one-pot three-component synthetic sequence of tetrahydro-β-carboline fused heterocyclic structures. The synthesis of tetrahydro-β-carboline derivatives via (3+3) annulation reaction catalyzed by the Sc(OTf)3 was accomplished by Wang group in 2013.54 The (3+3) annulations approach involves the reaction of readily available benzylic alcohols 117 with aziridine derivatives 118 catalyzed by Sc(OTf)3 to obtain the tetrahydro-β-carboline derivatives 119 in refluxing 1,2dichloroethane solvent for 12 h as figured in Scheme 32. This efficient new strategy offered several advantages including an alternative to the existing Pictet–Spengler cyclization strategy with (5+1) annulations approach.

30


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Scheme 32. Synthesis of tetrahydro-β-carboline derivatives via (3+3) annulation reaction catalyzed by Sc(OTf)3.

•

Organocatalytic approach for the synthesis of tetrahydro-β-carboline scaffolds on solution phase

Traditionally, the asymmetric synthesis of tetrahydro-β-carboline depends on two well established methodologies. First, the chirality has either been introduced in to the moiety diastereoselectively by substrate controlled reactions using chiral auxiliaries, or second by chiral catalysts which induces the external asymmetric induction. However, the lack of enantioselective protocols has been a long standing problem with the Pictet-Spengler cyclization. Over the past decade a large number of enantioselective approaches to the Pictet-Spengler cyclization reaction have been reported using enantiopure tryptophan esters. However, owing to the absence of stereodirecting carboxyl group, it is very difficult to achieve the enantioselective synthesis of tetrahydro-β-carboline from tryptamines. It has been observed that by introducing the chiral auxiliaries on the nitrogen atom of the ethylamino side chain of tryptamine derivatives induce diastereoselectivity. In 2000, Koomen et al demonstrated the influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet−Spengler cyclization reaction.55 As depicted in Scheme 33, the treatment of tryptamine 4 with n-BuLi and chlorotrimethylsilane in THF and followed by the reaction with the Andersen reagent 120 obtained the chiral sulfinamines 121 in good yields. The generation of tetrahydro-β-carboline 122 was achieved via the Pictet-Spengler condensation of 121 with aldehydes 5 using CSA as catalyst at -78 oC. After a single crystallization, the major diastereomers of tetrahydro-β-carboline 122 were obtained. The removal of chiral auxiliary was achieved using HCl in ethanol at 0 °C with high yield and without racemization to obtain the enantiopure tetrahydro-β-carboline 123.

31



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Page 32 of 68

Scheme 33. The Pictet-Spengler cyclization reaction with N-sulfinyl tryptamines for the synthesis of enantiopure tetrahydro-β-carbolines. In 2004, Jacobsen believed that the low reactivity of the imine substrate is the intrinsic challenge for the development of asymmetric catalyst for the Pictet-Spengler cyclization. The group for the first time reported on asymmetric catalysis of the acyl-Pictet-Spengler reaction using chiral thioureas.56 As shown in Scheme 34, the condensation between different tryptamines 4 and substituted aldehydes 5 catalyzed by chiral thioureas 124 followed by acylation obtained a small library of tetrahydro-β-carboline derivatives 125 in good yields with high enantioselectivity.

Scheme 34. Chiral thiourea catalyzed synthesis of enantiopure tetrahydro-β-carbolines List and his coworkers reported the first brønsted acid-catalyzed enantioselective Pictet-Spengler cyclization reaction to obtain the tetrahydro-β-carbolines 127 with high enantioselectivity in 2006.57 As shown in Scheme 35, the chiral substituted phosphoric acids 126 were chosen as effective catalysts for the Pictet-Spengler cyclization reaction of tryptamines 4 with a number of aliphatic and aromatic aldehydes 5. However, the diester functionality on the tryptamine was required probably for clean reaction through the Thorpe-Ingold effect. However, the tryptamine 32


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derivatives without methoxy group resulted in lower yields of the tetrahydro-β-carboline derivatives 127.

Scheme 35, Chiral phosphoric acids catalyzed enantioselective Pictet-Spengler cyclization reaction for tetrahydro-β-carbolines Subsequently in 2007, Jacobsen group reported the Pictet-Spengler type cyclization of hydroxylactams catalyzed by thiourea to obtain the highly enantioenriched indolizidinones and quinolizidinones.58 The reaction of various hydroxylactams 128 derived from a variety of succinimide and glutarimide precursors underwent asymmetric cyclization at -55 oC for 24-72 h by thiourea catalyst 124 to obtain the tetracyclic architecture 129 in good yields with high enantiomeric excess as shown in Scheme 36. The mechanism of the reaction involves the enantioselective cyclization by dissociation of the chloride counterion and forming a chiral Nacyliminium chloride-thiourea complex via thiourea catalyst to obtain the compound 129. Later the methodology has been extended for the total synthesis of (+)-Harmicine.

Scheem 36. The Pictet-Spengler type cyclization of hydroxylactams catalyzed by thiourea In the year 2007, Hiemstra and his group reported the enantioselective synthesis of tetrahydro-β carbolines via the in situ formation of N-sulfenyliminium ions using enantiopure binaphthylderived phosphoric acids.59 As shown in Scheme 37, the reaction of tryptamine derivatives 4 33



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with aliphatic aldehydes 5 underwent acid-catalyzed Pictet-Spengler cyclization reaction by substituted enantiopure binaphthyl-derived phosphoric acids 126 resulted tetrahydro-β-carbolines 130 in high yields with excellent enantiomeric excess. The mechanism of the reaction involves the stabilization of the intermediate iminium by the N-tritylsulfenyl group for promoting PictetSpengler cyclization reaction catalyzed by enantiopure binaphthyl-derived phosphoric acids. The removal of N-sulfenyl auxiliary was achieved using HCl in thiol with high yield and without racemization to obtain the enantiopure tetrahydro-β-carboline 131. Later to add the diversity in the existing methodology, a one-pot process was developed for the synthesis of a variety of substituted tetrahydro-β-carbolines with high yields and high enantiomeric excess in multi-gram scale.

Scheme 37. Enantioselective Pictet-Spengler cyclization via N-sulfenyliminium intermediates for the synthesis of tetrahydro-β-carbolines. In 2008 the same group extended the previous methodology for the synthesis of enantioenriched N-benzyl-protected tetrahydro-β-carbolines derivatives 132 from benzyl protected tryptamine 4 and various aldehydes 5.60 However, it has been found that the removal of water formed during reaction was essential for high enantioinduction seemingly because water thwarts effective association between triphenylsilyl-substituted binaphthyl based chiral catalyst and tryptamine as shown in Scheme 38. The enantiomeric excess varied with the nature of the aldehyde employed. Electron-deficient aromatic aldehydes resulted tetrahydro-β-carbolines derivatives with high enantiomeric excess. The same methodology has been extended for the synthesis of three natural products such as (-)-arboricine, (+)-yohimbine, and corynanthe alkaloid family.61 For the synthesis of (-)-arboricine, an aldehyde containing a dioxolane-protected ketone group was used for the Pictet-Spengler cyclization reaction where as for (+)-yohimbine and

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corynanthe alkaloid family, methyl 5-oxo-2-(phenylseleno)pentanoate, and methyl 5-oxo-2,2(dialkylthio)pentanoate were used respectively.

Scheme 38. Synthesis of enantioenriched N-benzyl-protected tetrahydro-β-carboline derivatives. In 2009, Dixon and his coworkers developed an efficient synthetic protocol for tetrahydro-βcarboline derivatives via brønsted acid-catalyzed N-acyliminium cascade cyclization of tryptamines and enol lactones.62 The Scheme 39 demonstrated the reaction of tryptamine derivatives 4 with enol lactones 133 in the presence of chiral phosphoric acids obtained the tetrahydro-β-carboline 134 in high yield with excellent enantiomeric excess. The mechanism of the reaction involves the formation of ketoamides with an added π-nucleophile from the tryptamine and lactones underwent enantioselective cyclizations to obtain the tetrahydro-βcarboline. This methodology is also applicable with doubly substituted enol lactones with high diastereo- and enantioselectivities.

Scheme 39. Brønsted acid-catalyzed N-acyliminium cascade cyclization of tryptamines and enol lactones In the year 2010, the same group extended the existing methodology to γ- and δ-ketoacid instead of enol lactones for the chiral brønsted acid-catalyzed N-acyliminium cascade cyclization to 35



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obtain the tetrahydro-β-carboline.63 As depicted in Scheme 40, the reaction of tryptamine 4 and racemic keto acids or esters 135 underwent the chiral brønsted acid-catalyzed Pictet-Spengler cyclization reaction for 24 h to obtain the tetrahydro-β-carboline 136 in good yield with high enantiomeric excess. However, the reduction in reaction time resulted with the isolation of enamides with one achiraI and chiral component with an enantiomeric excess of only 7%. Further, subjecting the enamide into the same reaction condition resulted with the desired product 136 with high enantiomeric excess underneath the fast, reversible formation of iminium ions.

Scheme 40. Brønsted acid-catalyzed N-acyliminium cascade cyclization of tryptamines and racemic keto acids or esters. Furthermore, Jacobsen and his cowokers demonstrated the one-pot imine formation and the subsequent Pictet-Spengler cyclization reactions cocatalyzed by a chiral thiourea and benzoic acid to obtain the tetrahydro-β-carbolines with enantiomeric excesses 85-99%.64 In 2011, Bernardi and Bencivenni demonstrated the first asymmetric synthesis of spiroindolones from tryptamines 4 and isatin derivatives 137 catalyzed by the (S)-BINOL derived phosphoric acids.65 The unique spirooxindole architecture is the core of some potent anti-malarial agents showing very good pharmacokinetic properties66 are assembled by the Pictet-Spengler cyclization in an enantioselective manner. As depicted in Scheme 41, the reaction of tryptamine 4 and isatin derivatives 137 underwent the (S)-BINOL derived phosphoric acid 138 catalyzed Pictet-Spengler cyclization reactions for 48 h in DMF solution to obtain the tetrahydro-βcarboline 139 in good yield with high enantiomeric excess. A large sets of (S)-BINOL derived phosphoric acid catalysts were screened out of which only the tris(isopropyl)phenyl substituted phosphoric acid catalyst resulted the high enantioselectivity in the Pictet-Spengler cyclization. 36


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Further, the methodology was extended to the library synthesis of enantioenriched spiroindolinones 139 using the various tryptamines with electron-withdrawing or electrondonating substitutents at the 5-position and isatin derivatives. In the same year, Franz and coworkers demonstrated the synthesis of spiroindolinones derivatives using the 5-methoxy tryptamine and isatin derivatives catalyzed by (S)- and (R)-BINOL derived phosphoric acid catalyst. However, the use of lewis acidic complexes or thiourea as catalysts proved ineffective or very little enantioselectivity was achieved respectively.67

Scheme 41. (S)-BINOL derived phosphoric acids catalyzed Pictet-Spengler cyclization reaction of tryptamines and isatin derivatives. Later in 2011, it was observed that the SPINOL-derived phosphoric acids have also used as catalysts for numerous asymmetric transformations.68 Structurally these catalysts are similar to BINOL-derived phosphoric acids, however these catalyst are highly rigid in nature as compared to others. In 2012, Wang and his group demonstrated the use of SPINOL-derived phosphoric acid as catalyst in the enantioselective Pictet-Spengler reactions to obtain N-protected tetrahydroβ-carboline derivatives.69 As depicted in Scheme 42, the reaction between N-protected tryptamines 4 and aromatic aldehyde 5 underwent the enantioselective Pictet-Spengler cyclization reaction using SPINOL-derived catalyst 140 to obtain the N-protected tetrahydro-βcarboline derivatives 141 in good yields with high enantiomeric excess. The cyclization reaction proceeded well in both polar and non-polar solvents with substituted aliphatic and aromatic aldehydes. However, it is required to protect the NH2 of tryptamine moiety with aromatic group. Moreover the synthetic methodology witnessed the dramatic loss in enantioselectivity by

37



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replacing the indole hydrogen with a methyl group. The synthetic methodology has been extended for an asymmetric total synthesis of (-)-harmicine.

O

O

P HO O HN

N R1 4

+

R2

H

O 140

4 Å MS, C6H6, 30 oC, 24 h

5

R1=H, Me

N R1

N R2

141

R1=H, 98% ee R1=Me, 30% ee

Scheme 42. SPINOL-derived phosphoric acid catalyzed Pictet-Spengler cyclization reaction of tryptamines and aldehyde derivatives. Rueping and his coworkers developed a brønsted-acid catalyzed multicomponent condensation of tryptamines, 1,3-dicarbonyl compounds and α,β-unsaturated aldehydes to obtain the stereoselective synthesis of indoloquinolizidines.70 As depicted in Scheme 43, the condensation of tryptamine 4 with ketoester 142 to form an enaminone which underwent a brønsted-acid 144 catalyzed intermolecular Michael reaction with the unsaturated aldehyde 143 to form the intermediate with new C–C bond. Further, the highly reactive iminium ion obtained from the intermediate with new C–C bond underwent the brønsted-acid 144 catalyzed Pictet–Spengler cyclization reaction to generate the tetracyclic indolo[2,3-a]quinolizidine moiety 145 in good yield with high diastereoselectivity. Similarly, Zhao et al utilized the same methodology for the proline catalyzed multicomponent Michael addition and Pictet-Spengler reaction of tryptamines, β-ketoesters and α,β-unsaturated aldehydes to obtain the highly substituted indoloquinolizidines in excellent yields with high enantioselectivities.71 Aromatic aldehydes, aliphatic and alkoxyl carbonyl substituted α,β-unsaturated aldehydes all delivered the products with high enantioselectivities.

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SiPh3 O O P OH O O

O

NH2 + N H 4

OR

SiPh3 144 CH2Cl2, r.t.,4Å MS, 2 h O 12 h

2. R1 142

143

O

N N H H

OR R1

145 >95% dr

Scheme 43. Chiral brønsted-acid catalyzed multicomponent condensation of tryptamines, 1,3dicarbonyl compounds and α,β-unsaturated aldehydes for the stereoselective synthesis of indoloquinolizidines In 2013, You and his group develop an alternative method for the synthesis of tetrahydro-βcarboline derivatives instead of the usual Pictet-Spengler cyclization strategy.72 The group demonstrated that the hydroxylactams 146 obtained from tryptamine derivatives 4 underwent brønsted acid catalyzed transfer hydrogenation reaction to obtain the enantioenriched tetrahydroβ-carboline derivatives 148 in dioxane solvent. As depicted in Scheme 44, it was believed that the enantioselective transfer hydrogenation by chiral Brønsted acid resulted with the Nacyliminium ions which were converted to the tetrahydro-β-carboline derivatives 148 with the Hantzsch ester 147 as the organic hydride source. This uniqueness of this methodology involves the ready availability of the starting materials, high yields with high enantiomeric excess and mild reaction conditions.

Scheme 44. Brønsted acid catalyzed synthesis of enantioenriched tetrahydro-β-carboline derivatives.

39



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Likewise in the same year, Dixon and his coworkers developed a Michael addition/iminium ion cyclization cascade for the synthesis of substituted of tetrahydro-β-carboline derivatives.73 As shown in Scheme 45, the reaction of substituted enones 150 with tryptamine-derived ureas 149 catalyzed by BINOL phosphoric acid obtained the tetracyclic skeleton 151 in good yields and excellent enantioselectivities. The mechanism of the reaction involves the initial Michael addition by the enones to the urea nitrogen atom distal to the indole ring followed by iminium ion formation and subsequent carbocyclization to result the tetracyclic skeleton.

Scheme 45. Michael addition/iminium ion cyclization cascade for the synthesis of substituted of tetrahydro-β-carboline derivatives. In 2014, Seidel and his group demonstrated a novel internally conjugate-base-stabilized brønsted acid catalysis strategy for the synthesis of substituted of tetrahydro-β-carboline derivatives.74 To overcome the challenges associated with the Pictet-Spengler cyclization strategy such as the low reactivity of the imine or iminium ion intermediates or to facilitate reactions of unmodified tryptamine derivatives, the catalyst has both a carboxylic functionality and an anion-recognition site. As shown in Scheme 46, the reaction of tryptamine 4 and aldehydes 5 to form imine in 12 h followed by conjugate-base-stabilized brønsted acid 152 catalyzed Pictet-Spengler cyclization reaction for 48 h to obtain the tetrahydro-β-carboline 153 in good yield with high enantiomeric excess. The mechanism of the reaction involves the protonation of imine by carboxylic acid group of the catalyst 152 to iminium ion followed by stabilization of carboxylate ion via hydrogen bonding through anion-recognition site to obtain the tricyclic scaffold 153 with high enantioselectivity.

40


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Scheme 46. Conjugate-base-stabilized brønsted acid catalyzed synthesis of substituted of tetrahydro-β-carboline derivatives In the same year, Shi et al synthesized a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety through the chiral phosphoric acid-catalyzed three-component cascade reaction.75 The synthetic protocol comprises of Michael/Pictet–Spengler reactions of isatin-derived 3-indolylmethanols 154, isatins 137, and amino-ester 155 to afford the structurally complex and diverse bispirooxindoles 157 with one quaternary and one tetrasubstituted stereogenic centers in good yields with excellent stereoselectivities as depicted in Scheme 47. The mechanism of the reaction involves the isatin-derived azomethine ylide underwent Michael reaction through the hydrogen-bonding interactions using chiral catalyst 156 with the vinyliminium intermediate generated from compound 154 to obtain a transient intermediate. The transient intermediate immediately underwent the Pictet–Spengler cyclization reaction to afford the enantioenriched (SR)-bispirooxindoles 157.

Scheme 47. Synthesis of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety catalyzed by chiral phosphoric acid in three-component cascade reaction 41



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In the subsequent year, Guinchard et al. introduced the synthesis of enantioenriched substituted tetracyclic scaffolds 161 through a direct Pd catalyzed tandem deprotection/cyclization from Nallyl tetrahydro-β-carboline 160 in Scheme 48.76 The reaction of NH-allyl tryptamine derivatives 4 with 1,n-allenaldehydes 158 possessing different substitution patterns underwent the SPINOL derived bronsted acid 159 catalyzed Pictet-Spengler cyclization reaction to obtain the N-allyl tetrahydro-β-carboline 160 with pendent allene functions in good yields and high enantiomeric excess. Subsequently, the Pd catalyzed deprotection of N-allyl group of compound 160 followed by intramolecular cyclization via a transient π-allyl-Pd intermediate afforded the various tetracyclic scaffolds. Depending upon the length of allene chain and substitution pattern, Pd catalyzed regioselective cyclizations occurred through 5-exo-, 6-exo-, or 7-endo-mechanisms. It was interesting to note that N-allyl tetrahydro-β-carbolines 160 presenting a 1,6-relationship between the amine and the allene function gave the corresponding six-membered substituted indolo[2,3a]quinolizidines 161a with good yields and diastereoselectivities via 6-exo-cyclization strategy. The N-allyl tetrahydro-β-carbolines 160 having 1,5-relationship between the amine and the allene, underwent successfully cyclizations through either a 5-exo or 7-endo-cyclization pathway depending upon the concentration and substitution pattern on allene functionality to obtain the tetracyclic scaffolds 161b and 161c respectively. The use of dimethyl barbituric acid (DMBA) as the allyl scavenger is also crucial in the generation of the π-allyl-Pd intermediate.

42


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BA M ,D )4 o C 3 Ph 40 (P l 2, Pd 2C H C

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Scheme 48. Method for the synthesis of chiral polycyclic indolic architectures.

•

Miscellaneous approach for the synthesis of tetrahydro-β-carboline scaffolds

Recently numerous reports have emerged on the synthesis of tetrahydro-β-carboline scaffolds on solution-phase devoid of any metal or chiral organocatalysts. Those procedures also received increased attention as a lead discovery and optimization tool for drug discovery programme. In the next section we are going to highlight the few of them. Nishinda and his group developed the efficient diastereoselective synthesis of tetrahydro-βcarboline via the Pictet–Spengler cyclization reaction using chiral tryptamine carbamate encouraged by trimethylchlorosilane in 2003.77 The reaction of chiral tryptamine carbamates 163 obtained from tryptamine 4 and (−)-menthyl chloroformate 162 with aldehydes 5 proceeded smoothly at −30°C to obtain the tetrahydro-β-carboline 164 with S configuration in excellent yield but with very low diastereoselectivity in Scheme 49. But the diastereoselectivity increased dramatically upto 80% while using (−)-8-phenylmenthyl group as the chiral auxiliary instead of the (−)-menthyl group with N-protected tryptamine derivatives. However, it was observed that the Pictet–Spengler cyclization reaction using (−)-8-phenoxyphenylmenthyl carbamate 163 with isobutyraldehyde 5 resulted the opposite R configuration. Probably it could be due to the readily

43



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available chiral menthyl auxiliaries 163 with the same stereochemistry which induced the opposite stereoselectivity at C-1 of the tetrahydro-β-carboline by controlling the transition state. O N R1 4

NH2 + Cl

O 162 X

O O

HN N R1

+

O

R2

TMSCl, CH2Cl2 H

-30 oC to -40 oC

5 X

163

O

S N N R1

R2

O

X

164 R1=H, X=H, 7% dr R1=Bn, X=Ph, 89% dr

O

R N N H

R2

O

Ph(p-OPh)

164 77% dr

Scheme 49. TMSCl catalyzed diastereoselective Pictet–Spengler reactions of chiral tryptamine carbamates with aldehydes In 2009, Rutjes and his cowokers synthesized the tetrahydro-β-carbolines fused pyrrolidines via solution phase approach.78 As mentioned in Scheme 50, the Knoevenagel condensation of methyl nitroacetate 165 with various aromatic aldehydes 5 containing electron rich aryl moiety obtained the α-nitro acrylates 166 as mixtures of diastereoisomers. Subsequently 1,3-dipolar cycloaddition reactions of 166 with the azomethine ylide CH2=N+(Me)CH2 resulted diastereomeric mixture of the racemic pyrrolidine 167 in 1:1 ratio. To generate the precursor 168 for tetrahydro-βcarbolines derivatives, diastereomeric mixture of the racemic pyrrolidines 167 were separated followed by reducing the nitro group under catalytic hydrogenation reaction. The intermediate 168 underwent the Pictet–Spengler cyclization reaction with formaldehyde using TFA in CH2Cl2 at room temperature to obtain the pyrrolidine fused tetrahydro-β-carbolines 169 derivatives which were further acylated to obtain the 32 member combinatorial library of compound 170.

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Scheme 50. Synthesis of tetrahydro-β-carbolines fused pyrrolidines via solution phase approach Later in 2010, Zhao et al demonstrated the diastereoselective synthesis of highly functionalized tetrahydro-β-carbolines containing indolo[2,3-r]quinolizidines with cis geometry by a PictetSpengler/lactamization cascade sequence in Scheme 51.79 The Pictet-Spengler reaction of the tryptamine 4 and aldehyde 5 using TFA as an acid catalyst resulted the amine intermediate 171 as a mixture of diastereomers which subsequently underwent lactamization cascade to afford the cis stereoisomer of tetracyclic scaffold 172 in excellent yield with high enantioselectivity. The Pictet-Spengler/lactamization cascade reaction proceeded well for aromatic-substituted aldehydes having both electron donating or electron-withdrawing substituents.

45



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Scheme 51. Diastereoselective synthesis of highly functionalized tetrahydro-β-carbolines containing indolo[2,3-r]quinolizidines. Subsequently, He and his coworkers introduced the synthesis of tetrahydro-β-carbolines from aldehydes and ketones via the α-siloxy α, β -unsaturated esters.80 As figured in Scheme 52, the αsiloxy α,β -unsaturated esters 174 were prepared conveniently from the phosphonate reagent 173 and the aldehyde or ketones 5 via the Horner–Emmons reaction. Other than aldehydes and ketones, α-ketoesters were also used for the Horner–Emmons reaction to obtain the α-siloxy α,β unsaturated esters. Subsequently, the α-siloxy α,β -unsaturated esters 174 were used for the Pictet-Spengler cyclization reaction with tryptamine HCl 4 using PTSA as catalyst in EtOH at 80 o

C for overnight to obtain the substituted tetrahydro-β-carbolines 175 in high yield.

Scheme 52. Synthesis of tetrahydro-β-carbolines from aldehydes and ketones via the α-siloxy α, β -unsaturated esters. In 2012, Ramnathan et al. demonstrated the unique brønsted acid assisted 6-exo-trig cyclization of imide derivatives of tryptamine moiety through the activation of imide carbonyl to generate the tetrahydro-β-carboline scaffolds in Scheme 53.81 The synthetic sequence commenced with the synthesis of imide derivatives of substituted tryptamines 178 from substituted aromatic hydrazine hydrochloride 176 and 2-(3-(1,3-dioxan-2-yl)propyl)isoindoline-1,3-dione 177. Further, the cyclization to the tetrahydro-β-carboline scaffold 179 was achieved by treating the intermediate 178 with TfOH in CH2Cl2 solvent for 24 h in 22% yield. However, the yield was increased upto 81% in 12 h when the reaction was carried out with TfOH (10 equiv.) in the presence of 4 A˚ molecular sieves. It was assumed that the molecular sieves may be facilitating in the formation of the fused cyclic acyl iminium ion via hydroxy lactam formation which was very difficult to isolate. Subsequently, in situ reduction of the tetrahydro-β-carboline containing hydroxy group by NaBH4/CF3COOH obtained the heterocyclic lactam 179a in good yield. 46


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Further, the methodology has been extended to the synthesis of syntheses of indole alkaloids such as (±)- harmicine and (±)-10-desbromoarborescidine-A.

Scheme 53. Brønsted acid assisted 6-exo-trig cyclization of imide derivatives of tryptamine moiety to generate the tetrahydro-β-carbolines. Kusurkar and coworkers developed the reductive Pictet Spengler cyclization reaction to obtain the natural and unnatural tetrahydro-β-carbolines derivatives in 2015.82 As depicted in Scheme 54, nitrile 180 was used instead of an aldehyde to react with tryptamine derivatives 4 in the presence of 10% Pd/C in acetic acid under hydrogen atmosphere at room temperature obtained the tetrahydro-β-carbolines derivatives 6 in good yield. Later they extended the methodology for the syntheses of natural products such as eudistomin U, canthine and (±)-harmicine.

Scheme 54. Reductive Pictet Spengler cyclization reaction of tryptamine with nitriles

•

Green synthetic approach for the synthesis of tetrahydro-β-carboline scaffolds

In 2004, Chu et al. demonstrated the diastereoselective synthesis of tetrahydro-β-carboline diketopiperazines in ionic liquid medium under controlled microwave irradiation.83 The Scheme 55 showed the three-step synthesis namely the Pictet–Spengler cyclization, Schotten–Baumann, and intramolecular ester amidation of diketopiperazine fused tetrahydro-β-carbolines 184 starting from the tryptophan methyl ester 73. The reaction of compound 73 with aldehydes 5 resulted the tetrahydro-β-carboline derivatives 181 using 10% TFA in [bdmim][PF6]/ THF (1:1) under microwave irradiation at 60 oC for 25s. Subsequent reaction of intermediate 181 with Fmoc-Pro47



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Cl 22 using DIEA (5 equiv) in [bdmim][PF6]/ THF (1:1) solvent under room temperature condition for 3 min to obtain the intermediate 182. Further deprotection of Cbz group using piperidine under microwave irradiation for 1 min obtained the diketopiperazine fused tetrahydroβ-carbolines 183 in good yields with varied cis:trans ratio.

Scheme 55. Synthesis of diketopiperazine fused tetrahydro-β-carbolines 183 in ionic liquid under microwave irradiation. A

year

later

the

same

group

reported

the

synthesis

of

fused

tetrahydro-β-

carbolinesquinoxalinones in ionic liquid as reaction medium.84 As demonstrated in Scheme 56, the reaction of compound 73 with aldehydes 5 resulted the tetrahydro-β-carboline derivatives 181 using 10% TFA in [bdmim][Tf2N] followed by the nucleophilic aromatic substitution with o-fluoronitrobenzene 184 to obtain the intermediate 185. Subsequent cyclization to the quinoxalinone fused tetrahydro-β-carbolines 186 were achieved by reducing the NO2 group of intermediate 185 by SnCl2 in [bdmim][Tf2N] /ethanol (1:1) at 70 oC for 4 hr. The overall yield of this small library of tetracyclic scaffolds were 34-55%.

48


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Scheme 56. Synthesis of quinoxalinone fused tetrahydro-β-carbolines 186 in ionic liquid. In the year 2009, Shi and his group demonstrated the unique highly stereoselective Pictet– Spengler cyclization of D-tryptophan methyl ester hydrochloride with various aldehydes to obtain the tetrahydro-β-carbolines via a crystallization induced asymmetric transformation (CIAT) process.85 As figured in Scheme 57, the Pictet–Spengler cyclization of D-tryptophan methyl ester hydrochloride 187 with substituted aldehydes 5 in isopropanol medium obtained the cis and trans isomer of tetrahydro-β-carbolines 188 in different ratios. However, in order to obtain the cis or trans isomer 189 stereoselectively, the group employed the process of crystallization-induced asymmetric transformation (CIAT) process by fine tuning the mixture of CH3NO2/toluene at 20 oC. The advantage of this methodology involves the complete isolation one isomer with high stereoselectivity and excellent yields.

Scheme 57. Two-step synthesis of cis-tetrahydro-β-carbolines-2-HCl and trans-tetrahydro-βcarbolines-2-HCl via CIAT process. 49



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In the year 2012, Jida and his coworkers demonstrated the environment-friendly efficient methodology for the racemic and asymmetric diastereoselective preparation of indole alkaloids under solvent- and catalyst-free conditions.86 As shown in Scheme 58, the tryptamine or tryptophanol derivatives 4 underwent the Pictet–Spengler reaction with ketocarboxylic acids 190 under microwave irradiation to achieve the fused tetrahydro-β-carboline derivatives 191. The key advantages associated with this methodology involve the remarkably high yields of tetrahydro-βcarboline derivatives 191 after simple extraction or by precipitation in methanol. NH2

X1 X2 O OH

R

n

R1 n=1,2 190

O X2

N H

min X2 e, 2 e r f tven Sol W, W, So lve X1 ntf re e, 2m in X1

4

HN 4

OH

H2N

X2

O

N

X1

n

N R H R1 191

OH N N H

R

O n

R1 H

191, >99% dr

Scheme 58. Solvent- and catalyst-free microwave-assisted synthesis of fused tetrahydro-βcarboline derivatives 191. In the subsequent year, Vassilikogiannakis and his group introduced a mild and highly controllable one-pot synthetic sequence to the construction of advanced nitrogen-bearing polycycles by employing simple furan substrates.87 As demonstrated in Scheme 59, the reaction of furan or its derivatives 192 with tryptamine 4 initiated by the highly selective and green oxidant, singlet oxygen resulted the fused tetrahydro-β-carboline derivatives 193 in one-pot reaction sequence with high yields. This one-pot synthetic methodology highlighted the achievement of impressive molecular complexcity using readily available starting materials.

Scheme 59. One-pot green oxidant, singlet oxygen catalyzed synthesis of fused tetrahydro-βcarboline derivatives. 50


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In 2014, Handy et al utilized the deep eutectic solvents such as the combination of either urea or glycerol with choline chloride are effective solvents/organocatalysts for the Pictet–Spengler cyclization to obtain the tetrahydro-β-carboline derivatives 6.88 As depicted in Scheme 60, it was evident that the reaction conditions are quite mild, non toxic and do not require the additional organocatalyst.

Scheme 60. Synthesis of tetrahydro-β-carboline derivatives using deep eutectic solvents (DES). Recently in the year 2014, Anderson and his group utilized the microwave irradiation for the synthesis of tetrahydro-β-carboline derivatives as depicted in Scheme 61.89 The reaction of tryptamine derivatives 4 with either aldehydes 5 or acetaldehyde dimethyl acetals 194 catalyzed by TFA in 1,2-dichloroethane under microwave irradiation obtained the tetrahydro-β-carboline derivatives 6 within short time in good yields. The advantages associated with this methodology involve the functional group tolerance and devoid of any liquid-liquid extraction or column chromatography.

Scheme 61. Microwave assisted synthesis of tetrahydro-β-carboline derivatives. In 2015, Santos et al introdueced the synthesis of enantiopure indolizinoindolones in good-toexcellent yields with excellent diastereoselectivities.90 As depicted in Scheme 62, the starting material (S)- or (R)-tryptophanol 4 underwent the cyclocondensation reaction with 2-acyl benzoic acids 190, followed by intramolecular α-amidoalkylation to obtain the enantiopure indolizinoindolones 195. The synthesized compounds were screened for in vitro activity against blood- and liver-stage malaria parasites.

51



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Scheme 62. Synthesis of enantiopure indolizinoindolones via the Pictet-Spengler cyclization reaction.

•

Multicomponent synthetic approach for the synthesis of tetrahydro-β-carboline scaffolds

Now a days multicomponent reaction (MCRs) represent a powerful tool in synthetic organic chemistry and diversity-oriented synthesis for the creation of complex molecular architectures in a highly unambiguous and efficient manner. These are defined as convergent reactions with most of the atoms significantly contribute to the newly synthesized compound. During the last few years, the research activities particularly bloomed with the introduction of efficient synthetic procedures for the synthesis of highly substituted tetrahydro-β-carbolines or its fused analogues via MCRs. In 2012, Lesma and his coworker demonstrated the multicomponent synthesis of tetrahydro-βcarboline based tetracyclic peptidomimetics using the Ugi 4-CR/Pictet–Spengler cyclization sequence.91 Here for the first time suitably N-protected 2-amino acetaldehyde was used as the carbonyl component in Scheme 63. The reaction of racemic N-protected tryptophan derived isocyanide 196 with N-protected-2-aminoacetaldehyde 197, aminoacetaldehyde diethylacetal 198 as an amine and acetic acid 199 underwent Ugi-4CR reaction in MeOH solvent at room temperature furnished the two Ugi product 200a and 200b in (1:1) ratio. After separating the Ugi product 200a and 200b by chromatography, both were subjected to the Pictet–Spengler cyclization in formic acid at 60 °C.

52


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Page 53 of 68

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COOMe NC

Bn N + H2N Cbz

+ OHC

N Boc 196

197

AcN

+ AcOH

199

COOMe O Bn NH N Cbz

+ N Boc

OEt

AcN

OEt

OEt

HCOOH, 60 oC

11

N H

HCOOH, 60 oC

COOMe N

H

10

O Bn N Cbz

11

N H

13

N Ac

H

201

Scheme

63.

OEt

200b

200a

10

MeOH, r.t.

OEt 198

COOMe O Bn NH N Cbz N Boc

OEt

Multicomponent

synthesis

of

10

COOMe N

O Bn N Cbz

N 13 Ac 202

11

N H

H

COOMe O Bn N Cbz

N

N 13 Ac 203

tetrahydro-β-carboline

based

tetracyclic

peptidomimetics using the Ugi 4-CR/Pictet–Spengler cyclization sequence. The compound 200a resulted the highly diastereoselective, unique product 201, which was determined by X-ray analysis and established as 11,10-anti, 11–13-anti configuration based on the crystallographic numbering. The compound 200b resulted only a modest diastereoselectivity for 202 with 11,10-anti, 11,13-syn configuration, and 203 with 11,10-syn, 11,13-anti configuration (dr 14%). The compounds 201, 202, and 203 were further derivatized with amino functional group for the development of conformationally constrained tryptophan-containing peptide ligands. In 2014, Ballet and his group developed the facile and efficient synthetic method for trisubstituted diketopiperazine fused tetrahydro-β-carboline derivatives stereoselectively.92 The synthetic methodology commenced with a one-pot four step reactions, employing the Ugi 4CR/followed Boc-deprotection, the Pictet–Spengler cyclization reaction and lactamization as shown in Scheme 64. The reaction of compound 15 with primary amine 204, aldehyde 5, and isocyanide 205 underwent Ugi-4CR reaction in MeOH solvent at room temperature for 18 h furnished the Ugi product followed by boc group deprotection and the subsequent Pictet– Spengler cyclization to obtain the tetrahydro-β-carboline bound intermediate. The intermediate 53



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immediately underwent lactamization reaction under microwave irradiation to obtain the trisubstituted diketopiperazine fused tetrahydro-β-carboline derivatives 206 in high yield with excellent diastereoselectivity. O

OH NHBoc + R1-NH2 + R2CHO + R3NC

N H 15

204

5

O

1. MeOH, r.t., 18 h 2. TFA, CH2Cl2, r.t., 3 h 3. R4CHO, TFA, CH2Cl2, r.t., 18 h 4. AcOH, MW, 180 oC, 80 min

205

N N H

N R4

R1 R2

O

206, upto 98% dr

Scheme 64. An efficient synthetic method for trisubstituted diketopiperazine fused tetrahydro-βcarboline derivatives. Subsequently in 2015, Chouhan and his group accomplished the synthesis of diketopiperazine fused tetrahydro-β-carboline ring systems via the Pictet–Spengler cyclization followed by an Ugi-4CR and deprotection-cyclization cascade.93 As depicted in Scheme 65, the reaction of tryptamine 4 and ethyl glyoxalate 207 via the Pictet–Spengler cyclization followed by a deesterification

reaction

to obtain the intermediate 208. Subsequently, the reaction of

intermediate 208 with aldehyde 5, amine 204, and substituted isocyanide 205 underwent Ugi 4CR reaction to obtain the Ugi product 209. Finally, a tandem deprotection-cyclization reaction cascade to generate the tetracyclic diketopiperazine fused tetrahydro-β-carboline ring system 210.

Scheme 65. Synthesis of diketopiperazine fused tetrahydro-β-carboline ring systems via the Pictet–Spengler cyclization followed by an Ugi-4CR and deprotection-cyclization cascade.

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Recently, in the year 2016, Karunakar et al have demonstrated the tetrahydro-β-carboline derivatives via an acid mediated one-pot sequential formation of C-C and C-N bond.94 The Scheme 66 shows the reaction of β-enaminone 211 and acetylenedicarboxylate 212 using p-TSA as an acid catalyst at 70 oC for 3 h to obtain the tetrahydro-β-carboline derivatives 213. The mechanism of the reaction involves the sequential formation of two C-C and one C-N bond simultaneously to obtain the tetracyclic scaffold in high yield.

Scheme 66. Synthesis of tetrahydro-β-carboline derivatives via an acid mediated one-pot sequential formation of C-C and C-N bond.

Conclusion and Outlook With the discovery of the Pictet-Spengler cyclization strategy, a range of complex natural products have been synthesized.

Moreover this reaction is particularly important for the

synthesis of indole alkaloids and its derivatives. The Pictet-Spengler reaction has been successfully applied for the construction of tetrahydro-β-carboline and its derivatives on solid support as well as in multicomponent reactions. Although a number of important synthetic advancement such as solid phase, solution phase using metal or chiral organocatalysts has been made in the synthesis of tetrahydro-β-carboline and its derivatives, new chemistry has to be developed on solid phase which does not have any solution phase counterpart. However during the last decade, a large number of chiral phosphoric acid, thioureas as catalysts have been utilized for the enantioselective synthesis of tetrahydro-β-carbolines. In this review, efforts have been taken to highlight the latest information available on the syntheses tetrahydro-β-carbolines and its derivatives from 1996 to 2016.

Recently, the need for the development of newer

synthetic methods with broad substrate scope for the synthesis of tetrahydro-β-carboline and its derivatives which should not be limited to only tryptamine derivatives has been realized. The combination of modern concepts like green chemistry, microwave assisted reusable ionic liquid 55



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supported chiral organocatalysts will help in developing an economic and more potential process to synthesis this previlege scaffold to abbreviate the ‘valley of death’. Further we believe that the present synthetic methodologies involving solid supported, metal or organocatalysts integrated in this review article will help to improve the status of this privileged tetrahydro-β-carboline scaffold in its future synthesis for drug discovery applications.

Acknowledgements The authors thank the Chancellor and Vice Chancellor of VIT University for providing opportunity to carry out this study. Further the authors wish to thank the management of this university for providing seed money as research grant. Barnali Maiti thanks DST- Govt of India for funding through DST-SERB-YSS/2015/00450. The authors thank the reviewers for giving positive comments about this manuscript.

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Application of Pictet-Spengler Reaction to Indole Based Alkaloids Containing Tetrahydro-β-carboline Scaffold in Combinatorial Chemistry R Nishanth Rao, Barnali Maiti, Kaushik Chanda*

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Application of PictetâSpengler Reaction to Indole-Based Alkaloids

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