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Review

The Chiral Pool in the Pictet–Spengler Reaction forthe Synthesis of β-Carbolines

Renato Dalpozzo

Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Arcavacata di Rende (Cs) 87030,Italy; [email protected]; Tel.: +39-0984-492055

Academic Editors: Carlo Siciliano and Constantinos AthanassopoulosReceived: 27 April 2016; Accepted: 24 May 2016; Published: 27 May 2016

Abstract: The Pictet–Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde orketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine,the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence,these compounds are generally enantiopure, thus the asymmetric synthesis of these compoundshave been attracting the interest of organic chemists. This review aims to give an overview of theasymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compoundsboth from natural sources and from asymmetric syntheses to assemble the reaction partners.

Keywords: Pictet-Spengler reaction; asymmetric synthesis; β-carboline; alkaloids

1. Introduction

The reaction named the Pictet–Spengler reaction (PSR) was discovered by Amè Pictet and TheodorSpengler in 1911. They heated β-phenylethylamine and formaldehyde dimethylacetal in the presenceof hydrochloric acid and recovered 1,2,3,4-tetrahydroisoquinoline as the product (Scheme 1) [1].

Molecules 2016, 21, 699; doi:10.3390/molecules21060699 www.mdpi.com/journal/molecules

Review

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines Renato Dalpozzo

Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Arcavacata di Rende (Cs) 87030, Italy; [email protected]; Tel.: +39-0984-492055

Academic Editors: Carlo Siciliano and Constantinos Athanassopoulos Received: date; Accepted: date; Published: date

Abstract: The Pictet–Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine, the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, these compounds are generally enantiopure, thus the asymmetric synthesis of these compounds have been attracting the interest of organic chemists. This review aims to give an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assemble the reaction partners.

Keywords: Pictet-Spengler reaction; asymmetric synthesis; β-carboline; alkaloids

1. Introduction

The reaction named the Pictet–Spengler reaction (PSR) was discovered by Amè Pictet and Theodor Spengler in 1911. They heated β-phenylethylamine and formaldehyde dimethylacetal in the presence of hydrochloric acid and recovered 1,2,3,4-tetrahydroisoquinoline as the product (Scheme 1) [1].

NH2

CH2(OMe)2HCl

NH Scheme 1. The Pictet–Spengler reaction.

For over a century, it has been used for the synthesis of a large variety of aza-heterocyclic compounds. A seminal asymmetric synthesis was already presented in the work of Pictet and Spengler, when they tested phenylalanine and tyrosine in their reaction. Tryptamine as the amine component was introduced 20 years later [2], allowing the creation of the 1,2,3,4-tetrahydro-β-carboline skeleton, and, consequently, the synthesis of many indole alkaloids of enormous physiological and therapeutic significance [3].

After the work of Pictet and Spengler, the first asymmetric PSR was only performed in 1977, when an enzyme of the Pictet–Spenglerase class was discovered [4]. The enzyme-catalyzed PSR’s has been recently reviewed [5].

During the last two decades, the increasing development of the asymmetric synthesis by chiral catalysts or chiral precursors has produced remarkable progress in developing new and highly enantioselective PSRs. This review aims to provide an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assembly the reaction partners. However, external asymmetric induction by chiral catalysts on symmetric derivatives can also be used in PSR [6–10], but these examples will not be covered in this review.

Scheme 1. The Pictet–Spengler reaction.

For over a century, it has been used for the synthesis of a large variety of aza-heterocycliccompounds. A seminal asymmetric synthesis was already presented in the work of Pictet and Spengler,when they tested phenylalanine and tyrosine in their reaction. Tryptamine as the amine componentwas introduced 20 years later [2], allowing the creation of the 1,2,3,4-tetrahydro-β-carboline skeleton,and, consequently, the synthesis of many indole alkaloids of enormous physiological and therapeuticsignificance [3].

After the work of Pictet and Spengler, the first asymmetric PSR was only performed in 1977, whenan enzyme of the Pictet–Spenglerase class was discovered [4]. The enzyme-catalyzed PSR’s has beenrecently reviewed [5].

During the last two decades, the increasing development of the asymmetric synthesis by chiralcatalysts or chiral precursors has produced remarkable progress in developing new and highlyenantioselective PSRs. This review aims to provide an overview of the asymmetric PSR, in which thechirality arises from optically pure amines or carbonyl compounds both from natural sources and fromasymmetric syntheses to assembly the reaction partners. However, external asymmetric induction bychiral catalysts on symmetric derivatives can also be used in PSR [6–10], but these examples will notbe covered in this review.

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Molecules 2016, 21, 699 2 of 18

The Pictet–Spengler reaction starts from the formation of an imine, which, under the acidicreaction conditions, is turned into an iminium ion followed by nucleophilic attack by the aryl groupand cyclization. In the case of tryptamine, the attack on the iminium ion can occur either directly atposition 2 (Scheme 2, red pathway) or at position 3 of the indole to form a spiroindolenine (Scheme 2,blue pathway) [11,12]. However, spiroindolenine undergoes fast rearrangement, and the carboniumion is the final product anyway [13,14].

Molecules 2016, 21, 699 2 of 18

The Pictet–Spengler reaction starts from the formation of an imine, which, under the acidic reaction conditions, is turned into an iminium ion followed by nucleophilic attack by the aryl group and cyclization. In the case of tryptamine, the attack on the iminium ion can occur either directly at position 2 (Scheme 2, red pathway) or at position 3 of the indole to form a spiroindolenine (Scheme 2, blue pathway) [11,12]. However, spiroindolenine undergoes fast rearrangement, and the carbonium ion is the final product anyway [13,14].

NH

NH2 RCHOH+

NH

N

R

H+

NH

NH

R

NH

NH

RNH

NH

RNH

NH

R

Scheme 2. The mechanism of the Pictet–Spengler reaction.

2. Starting from Tryptophan Derivatives

The first natural chiral source used to prepare β-carbolines was tryptophan and its derivatives. In fact, since 1979, Cook and co-workers studied the reaction of these compounds with aldehydes [14–18]. Thus, they found that the steric bulk of the carbonyl compounds, and the substituents either at the Nb nitrogen atom or at the ester group governed the diastereoselectivity of the PSR, leading preferentially to trans-1,2,3-trisubstituted tetrahydro-β-carbolines under thermodynamic stereocontrol (Scheme 3).

NH

NHR

CO2R1

R2CHO

NH

NR

R2

CO2R1

NH

NR

R2

CO2R1

NH

NHR

R2

CO2R1

NH

NHR

R2

CO2R1

NH

NR

R2

CO2R1

Scheme 3. Diastereoselectivity of the PSR of tryptophan derivatives and cis to trans epimerization in the PSR.

If the reaction mechanism involved the spiroindolenine, the trans-isomer of which is more stable, the following ring expansion was therefore stereospecific. When a mixture of isomers was obtained, the thermodynamically more stable trans isomer could be exclusively obtained by epimerization of the cis isomer under acidic conditions [19–21]. Between the two possible mechanisms of the epimerization process, the protonation of the Nb, followed by ring-opening and closure to give the more stable isomer was demonstrated to occur (Scheme 3). There was no evidence of an alternative protonation of the indole-nitrogen (Na) with an olefinic isomerization. However, under these conditions the racemization of the products was possible [22]. By this methodology, besides the application of Cook’s group to the preparation of natural products [18,23–28], a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B was synthesized by Waldmann and co-workers [29].

The total synthesis of (−)-affinisine oxindole was also completed in an enantiospecific fashion from D-tryptophan in 10% overall yield. The key step was an asymmetric Pictet–Spengler reaction carried out under Cook’s conditions on a 300-gram scale [18], followed by diastereospecific oxidative-rearrangement of the tetrahydro-β-carboline to a spiroxindole (Scheme 4). The most interesting



The first natural chiral source used to prepare β-carbolines was tryptophan and its derivatives.In fact, since 1979, Cook and co-workers studied the reaction of these compounds with aldehydes [14–18].Thus, they found that the steric bulk of the carbonyl compounds, and the substituents either at the Nbnitrogen atom or at the ester group governed the diastereoselectivity of the PSR, leading preferentiallyto trans-1,2,3-trisubstituted tetrahydro-β-carbolines under thermodynamic stereocontrol (Scheme 3).

Molecules 2016, 21, 699 2 of 18

The Pictet–Spengler reaction starts from the formation of an imine, which, under the acidic reaction conditions, is turned into an iminium ion followed by nucleophilic attack by the aryl group and cyclization. In the case of tryptamine, the attack on the iminium ion can occur either directly at position 2 (Scheme 2, red pathway) or at position 3 of the indole to form a spiroindolenine (Scheme 2, blue pathway) [11,12]. However, spiroindolenine undergoes fast rearrangement, and the carbonium ion is the final product anyway [13,14].

NH

NH2 RCHOH+

NH

N

R

H+

NH

NH

R

NH

NH

RNH

NH

RNH

NH

R



The first natural chiral source used to prepare β-carbolines was tryptophan and its derivatives. In fact, since 1979, Cook and co-workers studied the reaction of these compounds with aldehydes [14–18]. Thus, they found that the steric bulk of the carbonyl compounds, and the substituents either at the Nb nitrogen atom or at the ester group governed the diastereoselectivity of the PSR, leading preferentially to trans-1,2,3-trisubstituted tetrahydro-β-carbolines under thermodynamic stereocontrol (Scheme 3).

NH

NHR

CO2R1

R2CHO

NH

NR

R2

CO2R1

NH

NR

R2

CO2R1

NH

NHR

R2

CO2R1

NH

NHR

R2

CO2R1

NH

NR

R2

CO2R1

Scheme 3. Diastereoselectivity of the PSR of tryptophan derivatives and cis to trans epimerization in the PSR.

If the reaction mechanism involved the spiroindolenine, the trans-isomer of which is more stable, the following ring expansion was therefore stereospecific. When a mixture of isomers was obtained, the thermodynamically more stable trans isomer could be exclusively obtained by epimerization of the cis isomer under acidic conditions [19–21]. Between the two possible mechanisms of the epimerization process, the protonation of the Nb, followed by ring-opening and closure to give the more stable isomer was demonstrated to occur (Scheme 3). There was no evidence of an alternative protonation of the indole-nitrogen (Na) with an olefinic isomerization. However, under these conditions the racemization of the products was possible [22]. By this methodology, besides the application of Cook’s group to the preparation of natural products [18,23–28], a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B was synthesized by Waldmann and co-workers [29].

The total synthesis of (−)-affinisine oxindole was also completed in an enantiospecific fashion from D-tryptophan in 10% overall yield. The key step was an asymmetric Pictet–Spengler reaction carried out under Cook’s conditions on a 300-gram scale [18], followed by diastereospecific oxidative-rearrangement of the tetrahydro-β-carboline to a spiroxindole (Scheme 4). The most interesting

Scheme 3. Diastereoselectivity of the PSR of tryptophan derivatives and cis to trans epimerization inthe PSR.

If the reaction mechanism involved the spiroindolenine, the trans-isomer of which is more stable,the following ring expansion was therefore stereospecific. When a mixture of isomers was obtained,the thermodynamically more stable trans isomer could be exclusively obtained by epimerization of thecis isomer under acidic conditions [19–21]. Between the two possible mechanisms of the epimerizationprocess, the protonation of the Nb, followed by ring-opening and closure to give the more stable isomerwas demonstrated to occur (Scheme 3). There was no evidence of an alternative protonation of theindole-nitrogen (Na) with an olefinic isomerization. However, under these conditions the racemizationof the products was possible [22]. By this methodology, besides the application of Cook’s group tothe preparation of natural products [18,23–28], a new class of inhibitors of Mycobacterium tuberculosisprotein tyrosine phosphatase B was synthesized by Waldmann and co-workers [29].

The total synthesis of (´)-affinisine oxindole was also completed in an enantiospecific fashionfrom D-tryptophan in 10% overall yield. The key step was an asymmetric Pictet–Spengler reactioncarried out under Cook’s conditions on a 300-gram scale [18], followed by diastereospecific

Molecules 2016, 21, 699 3 of 18

oxidative-rearrangement of the tetrahydro-β-carboline to a spiroxindole (Scheme 4). The mostinteresting feature of this methodology was that the presence or absence of the Nb-benzyl protectinggroup permitted access into either the chitosenine series or the alstonisine series [30].

Molecules 2016, 21, 699 3 of 18

feature of this methodology was that the presence or absence of the Nb-benzyl protecting group permitted access into either the chitosenine series or the alstonisine series [30].

NH

NHBn

CO2MeOHC CO2Me

1.2. MeONa

NH

N

Ph

OH

H

1. t-BuOCl, Et3N2. AcOH/MeOH

Yield = 93%

1. H2/Pt on C2. t -BuOCl, Et3N3. AcOH/MeOH

NH

NH

O

OH

H

Yield = 70%

HNO

OMeMeO

MeON

OH

OH

HH

H

chitosenine

N

NH

O

H

H

O

O

H

H

alstonisine

HNO

N

HH

H

OH

affinisine oxindole

NH

N

OPh

OH

H

Scheme 4. Synthesis of the chitosenine, alstonisine and affinisine skeletons.

If Cook developed and studied the reaction condition for the “thermodynamic control”, the reaction conditions for “kinetic control” were developed by Bailey. An excellent cis stereocontrol was obtained, thus overcoming the need for unnatural D-tryptophan as the source of chirality [31–34]. The highest “kinetic control” was achieved with allyl esters of tryptophan and aryl aldehydes, very likely owing to a favorable π-stacking between the allyl/aryl groups, thus permitting the cyclization of the diaxial intermediate. As a consequence, only a small energetic difference between the axial and equatorial positions should be exist in the transition states of this reaction, if the modest stabilization through π-stacking might be sufficient to confer the cis-control. This hypothesis was also supported by the same cis-control observed in (S)-3-amino-4-(1H-indol-3-yl)butanenitrile reaction, in which a nitrile/aryl π-stacking is also possible [33]. Bailey’s conditions were also applied to the synthesis of many natural products [22,31–35].

It is worth mentioning also the concise asymmetric synthesis of the indole alkaloids (+)-geissoschizine and (+)-Na-methylvellosimine starting from D-tryptophan through a pseudo PSR. The synthesis involved the preparation of a dihydrocarboline iminium salt followed by a highly selective attack at C-3 of a vinyl ketene acetal from the face opposite to the carboxyl group at C-5 (Scheme 5) [36,37].

Very recently, Balalaie et al. used L-tryptophan propargyl ester and hydrazide in a Pictet–Spengler reaction in the presence of TFA, under “kinetic control”. The cis-tetrahydro-β-carboline propargyl esters were obtained as pure stereoisomers in 52%–73% yields (seven examples); whereas the carboline hydrazides were obtained in 65%–85% yields (five examples) as a mixture of cis and trans isomers with a ratio of 2:1 [38].

Shi and co-workers accomplished a high stereoselective Pictet–Spengler reaction of D-tryptophan methyl ester hydrochloride with piperonal and Cialis™ was thus efficiently synthesized in three steps in 82% overall yield [39]. The yield and cis stereoselectivity were solvent dependent and a cis:trans = 99:1 could be obtained when the reaction was performed in acetonitrile or nitromethane. The large difference of solubility of the diastereomers was accounted for the shift of the equilibrium between these two hydrochloride salts to the less soluble cis product.

Scheme 4. Synthesis of the chitosenine, alstonisine and affinisine skeletons.

If Cook developed and studied the reaction condition for the “thermodynamic control”, thereaction conditions for “kinetic control” were developed by Bailey. An excellent cis stereocontrol wasobtained, thus overcoming the need for unnatural D-tryptophan as the source of chirality [31–34].The highest “kinetic control” was achieved with allyl esters of tryptophan and aryl aldehydes, verylikely owing to a favorable π-stacking between the allyl/aryl groups, thus permitting the cyclizationof the diaxial intermediate. As a consequence, only a small energetic difference between the axial andequatorial positions should be exist in the transition states of this reaction, if the modest stabilizationthrough π-stacking might be sufficient to confer the cis-control. This hypothesis was also supportedby the same cis-control observed in (S)-3-amino-4-(1H-indol-3-yl)butanenitrile reaction, in whicha nitrile/aryl π-stacking is also possible [33]. Bailey’s conditions were also applied to the synthesis ofmany natural products [22,31–35].

It is worth mentioning also the concise asymmetric synthesis of the indole alkaloids(+)-geissoschizine and (+)-Na-methylvellosimine starting from D-tryptophan through a pseudo PSR.The synthesis involved the preparation of a dihydrocarboline iminium salt followed by a highlyselective attack at C-3 of a vinyl ketene acetal from the face opposite to the carboxyl group at C-5(Scheme 5) [36,37].

Very recently, Balalaie et al. used L-tryptophan propargyl ester and hydrazide in a Pictet–Spenglerreaction in the presence of TFA, under “kinetic control”. The cis-tetrahydro-β-carboline propargylesters were obtained as pure stereoisomers in 52%–73% yields (seven examples); whereas the carbolinehydrazides were obtained in 65%–85% yields (five examples) as a mixture of cis and trans isomers witha ratio of 2:1 [38].

Shi and co-workers accomplished a high stereoselective Pictet–Spengler reaction of D-tryptophanmethyl ester hydrochloride with piperonal and Cialis™ was thus efficiently synthesized in threesteps in 82% overall yield [39]. The yield and cis stereoselectivity were solvent dependent anda cis:trans = 99:1 could be obtained when the reaction was performed in acetonitrile or nitromethane.The large difference of solubility of the diastereomers was accounted for the shift of the equilibriumbetween these two hydrochloride salts to the less soluble cis product.

Molecules 2016, 21, 699 4 of 18Molecules 2016, 21, 699 4 of 18

NH

NH2

CO2H

1. HCO2H, Ac2O2. HCO2H, HCl

60% NH

NH

CO2H

1.2. Me2C=CH2, H2SO4

OTBDMS

OMe

NH

NH

CO2t-Bu

CO2Me

59%

NH

N

MeO2C OH

H

(+)-geissoschizine

NMe

N

CHO

(+)-Na-methylvellosimine

Scheme 5. Key step in the synthesis of (+)-geissoschizine and (+)-Na-methylvellosimine.

Then, the reaction was extended to thirteen aldehydes, both aromatic and aliphatic, and high stereoselectivities and yields could be obtained, but the predominance of the cis- or trans-isomer was not predictable. It should be noted that yields were improved by performing the process in a modified two-step procedure: firstly the PSR was performed in isopropanol leading to epimeric mixtures and then the mixtures were submitted to a crystallization-induced asymmetric transformation of their hydrochloride salts [40]. The same research group applied this crystallization-induced asymmetric transformation to the stereoselective PSR of L-tryptophan methyl ester hydrochloride with 3-hydroxybenzaldehyde (Scheme 6). It is worth noting that unprotected or acetyl-protected aldehyde was transformed into the cis-derivative, whereas, benzoyl- or allyl-protected aldehyde afforded the trans-derivative, under the same conditions. Finally, HR22C16, a mitotic kinesin Eg5 inhibitor, could be readily synthesized from the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline [41]. This procedure was also efficiently applied to the synthesis of a series of tetrahydro-β-carboline diketopiperazines as single isomers starting from L-tryptophan methyl ester hydrochloride and six aldehydes [42].

NH

NHCl

CO2Me

+

CHO

RO

R=H,AcPhMe/MeNO2reflux

R=Bz, AllylPhMe/MeNO2reflux

NH

NH2Cl

CO2Me

i-PrOHreflux

RO

NH

NH2Cl

CO2Me

RO

NH

N

HO

N

O

O

Bu

HR22C16

NH

NH2Cl

CO2Me

ROYield = 93-95%99:1 dr

Yield = 95-96%99:1 dr

Scheme 6. Stereoselective PSR by crystal-induced asymmetric transformation.

(S)-Tryptophanol was used as the starting material and as the source of chirality in the enantioselective two-step route to indolo[2,3-a]quinolizidines. After the stereoselective cyclo-condensation with methyl 4-ethyl-5-oxopentanoate, the resulting indole piperidone underwent intramolecular α-amidoalkylation on the indole 2-position under kinetic control, to give the 6,12b-trans indoloquinolizidine derivative (Scheme 7) [43]. It is worth noting that the use of BF·Et2O instead of HCl changed the stereoselectivity producing the 6,12b-cis isomer. Analogous results were obtained with dimethyl 3-(1-oxobutan-2-yl) pentanedioate.


Then, the reaction was extended to thirteen aldehydes, both aromatic and aliphatic, and highstereoselectivities and yields could be obtained, but the predominance of the cis- or trans-isomerwas not predictable. It should be noted that yields were improved by performing the process ina modified two-step procedure: firstly the PSR was performed in isopropanol leading to epimericmixtures and then the mixtures were submitted to a crystallization-induced asymmetric transformationof their hydrochloride salts [40]. The same research group applied this crystallization-inducedasymmetric transformation to the stereoselective PSR of L-tryptophan methyl ester hydrochloridewith 3-hydroxybenzaldehyde (Scheme 6). It is worth noting that unprotected or acetyl-protectedaldehyde was transformed into the cis-derivative, whereas, benzoyl- or allyl-protected aldehydeafforded the trans-derivative, under the same conditions. Finally, HR22C16, a mitotic kinesin Eg5inhibitor, could be readily synthesized from the enantiomerically pure (1R,3S)-1,3-disubstitutedtetrahydro-β-carboline [41]. This procedure was also efficiently applied to the synthesis of a series oftetrahydro-β-carboline diketopiperazines as single isomers starting from L-tryptophan methyl esterhydrochloride and six aldehydes [42].

Molecules 2016, 21, 699 4 of 18

NH

NH2

CO2H

1. HCO2H, Ac2O2. HCO2H, HCl

60% NH

NH

CO2H

1.2. Me2C=CH2, H2SO4

OTBDMS

OMe

NH

NH

CO2t-Bu

CO2Me

59%

NH

N

MeO2C OH

H

(+)-geissoschizine

NMe

N

CHO

(+)-Na-methylvellosimine


Then, the reaction was extended to thirteen aldehydes, both aromatic and aliphatic, and high stereoselectivities and yields could be obtained, but the predominance of the cis- or trans-isomer was not predictable. It should be noted that yields were improved by performing the process in a modified two-step procedure: firstly the PSR was performed in isopropanol leading to epimeric mixtures and then the mixtures were submitted to a crystallization-induced asymmetric transformation of their hydrochloride salts [40]. The same research group applied this crystallization-induced asymmetric transformation to the stereoselective PSR of L-tryptophan methyl ester hydrochloride with 3-hydroxybenzaldehyde (Scheme 6). It is worth noting that unprotected or acetyl-protected aldehyde was transformed into the cis-derivative, whereas, benzoyl- or allyl-protected aldehyde afforded the trans-derivative, under the same conditions. Finally, HR22C16, a mitotic kinesin Eg5 inhibitor, could be readily synthesized from the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline [41]. This procedure was also efficiently applied to the synthesis of a series of tetrahydro-β-carboline diketopiperazines as single isomers starting from L-tryptophan methyl ester hydrochloride and six aldehydes [42].

NH

NHCl

CO2Me

+

CHO

RO

R=H,AcPhMe/MeNO2reflux

R=Bz, AllylPhMe/MeNO2reflux

NH

NH2Cl

CO2Me

i-PrOHreflux

RO

NH

NH2Cl

CO2Me

RO

NH

N

HO

N

O

O

Bu

HR22C16

NH

NH2Cl

CO2Me

ROYield = 93-95%99:1 dr

Yield = 95-96%99:1 dr


(S)-Tryptophanol was used as the starting material and as the source of chirality in the enantioselective two-step route to indolo[2,3-a]quinolizidines. After the stereoselective cyclo-condensation with methyl 4-ethyl-5-oxopentanoate, the resulting indole piperidone underwent intramolecular α-amidoalkylation on the indole 2-position under kinetic control, to give the 6,12b-trans indoloquinolizidine derivative (Scheme 7) [43]. It is worth noting that the use of BF·Et2O instead of HCl changed the stereoselectivity producing the 6,12b-cis isomer. Analogous results were obtained with dimethyl 3-(1-oxobutan-2-yl) pentanedioate.


(S)-Tryptophanol was used as the starting material and as the source of chirality in theenantioselective two-step route to indolo[2,3-a]quinolizidines. After the stereoselective cyclo-condensationwith methyl 4-ethyl-5-oxopentanoate, the resulting indole piperidone underwent intramolecularα-amidoalkylation on the indole 2-position under kinetic control, to give the 6,12b-transindoloquinolizidine derivative (Scheme 7) [43]. It is worth noting that the use of BF¨ Et2O instead ofHCl changed the stereoselectivity producing the 6,12b-cis isomer. Analogous results were obtainedwith dimethyl 3-(1-oxobutan-2-yl)pentanedioate.

Molecules 2016, 21, 699 5 of 18Molecules 2016, 21, 699 5 of 18

NH

NH2

OH MeO2C CHO

EtPhMe, reflux

Yield = 87%87:13 dr

NH

N

O

O

Et

HCl,EtOH

Yield = 74%82:18 dr

NH

N

OH

Et

H O

NH

N

OH

Et

H O

Yield = 93%94:6 dr

BF3.Et2OCH2Cl2

Scheme 7. (S)-Tryptophanol in the enantioselective synthesis of indolo[2,3-a]quinolizidines.

The stereoselective synthesis of enantiomerically pure (5S,11bS)-indolo[2,3-a]indolizidinones was accomplished by a diastereoselective α-amidoalkylation reaction (Scheme 8). The substituent on carbon atom C-11b influenced the stereoselection, in fact no substitution on C-11b led to the cis-diastereomers [44].

NH

NH2

TBDPSOO

O

O1.

2. MeLi

NH

NH

TBDPSO

O

O

BF3.Et2O

Overall yield = 17%single stereoisomer

NH

N

OH

O NH

N

OTBDPSO

Me

11b

5

Scheme 8. (S)-Tryptophanol in the enantioselective synthesis of indolo[2,3-a]indolizidinones.

Besides aldehydes, also ketones or oxazinanes/oxazolidines can be employed in the Pictet–Spengler reaction. For instance, cyclization of the imines prepared by the condensation of L-tryptophan methyl ester and aryl methyl ketones quantitatively furnished a mixture of (1R,3S) and (1S,3S)-1-aryl-3-isopropoxycarbonyl-1-methyl-1,2,3,4-tetrahydro-β-carbolines (1:1 to 5:1 dr) [45]. Again kinetic and thermodynamic controls governed the diastereoisomeric ratio being the (1R,3S)-diastereomer the most thermodynamically stable. Equilibration should occur under acidic conditions according to the pattern depicted in Scheme 3. Oxazinanes/oxazolidines were used as synthetic equivalents of aldehydes especially for aldehydes difficult to handle.

The stereochemical outcome was similar to that observed with simple aldehydes under thermodynamic control (72%–92% yields with 97:3 to 99:1 trans:cis ratio), while kinetic control is enhanced by sonication (68%–84% yields, up to 9:91 trans:cis ratio) [46].

3. Starting from Chiral Carbonyl Compounds

Besides derivatives of tryptophan, various chiral carbonyl compounds were used in order to induce enantioselectivity [47]. The total synthesis of (R)-pyridindolol, (R)-pyridindolol K1, and (R)-pyridindolol K2 (Scheme 9) in 66%, 41%, and 55% overall yield, respectively, was an example. In fact, although both the starting materials (L-tryptophan methyl ester and (S)-2,3-O-isopropylidene-


The stereoselective synthesis of enantiomerically pure (5S,11bS)-indolo[2,3-a]indolizidinoneswas accomplished by a diastereoselective α-amidoalkylation reaction (Scheme 8). The substituenton carbon atom C-11b influenced the stereoselection, in fact no substitution on C-11b led to thecis-diastereomers [44].

Molecules 2016, 21, 699 5 of 18

NH

NH2

OH MeO2C CHO

EtPhMe, reflux

Yield = 87%87:13 dr

NH

N

O

O

Et

HCl,EtOH

Yield = 74%82:18 dr

NH

N

OH

Et

H O

NH

N

OH

Et

H O

Yield = 93%94:6 dr

BF3.Et2OCH2Cl2


The stereoselective synthesis of enantiomerically pure (5S,11bS)-indolo[2,3-a]indolizidinones was accomplished by a diastereoselective α-amidoalkylation reaction (Scheme 8). The substituent on carbon atom C-11b influenced the stereoselection, in fact no substitution on C-11b led to the cis-diastereomers [44].

NH

NH2

TBDPSOO

O

O1.

2. MeLi

NH

NH

TBDPSO

O

O

BF3.Et2O

Overall yield = 17%single stereoisomer

NH

N

OH

O NH

N

OTBDPSO

Me

11b

5


Besides aldehydes, also ketones or oxazinanes/oxazolidines can be employed in the Pictet–Spengler reaction. For instance, cyclization of the imines prepared by the condensation of L-tryptophan methyl ester and aryl methyl ketones quantitatively furnished a mixture of (1R,3S) and (1S,3S)-1-aryl-3-isopropoxycarbonyl-1-methyl-1,2,3,4-tetrahydro-β-carbolines (1:1 to 5:1 dr) [45]. Again kinetic and thermodynamic controls governed the diastereoisomeric ratio being the (1R,3S)-diastereomer the most thermodynamically stable. Equilibration should occur under acidic conditions according to the pattern depicted in Scheme 3. Oxazinanes/oxazolidines were used as synthetic equivalents of aldehydes especially for aldehydes difficult to handle.

The stereochemical outcome was similar to that observed with simple aldehydes under thermodynamic control (72%–92% yields with 97:3 to 99:1 trans:cis ratio), while kinetic control is enhanced by sonication (68%–84% yields, up to 9:91 trans:cis ratio) [46].


Besides derivatives of tryptophan, various chiral carbonyl compounds were used in order to induce enantioselectivity [47]. The total synthesis of (R)-pyridindolol, (R)-pyridindolol K1, and (R)-pyridindolol K2 (Scheme 9) in 66%, 41%, and 55% overall yield, respectively, was an example. In fact, although both the starting materials (L-tryptophan methyl ester and (S)-2,3-O-isopropylidene-


Besides aldehydes, also ketones or oxazinanes/oxazolidines can be employed in the Pictet–Spenglerreaction. For instance, cyclization of the imines prepared by the condensation of L-tryptophan methylester and aryl methyl ketones quantitatively furnished a mixture of (1R,3S) and (1S,3S)-1-aryl-3-isopropoxycarbonyl-1-methyl-1,2,3,4-tetrahydro-β-carbolines (1:1 to 5:1 dr) [45]. Again kinetic andthermodynamic controls governed the diastereoisomeric ratio being the (1R,3S)-diastereomer the mostthermodynamically stable. Equilibration should occur under acidic conditions according to the patterndepicted in Scheme 3. Oxazinanes/oxazolidines were used as synthetic equivalents of aldehydesespecially for aldehydes difficult to handle.

The stereochemical outcome was similar to that observed with simple aldehydes underthermodynamic control (72%–92% yields with 97:3 to 99:1 trans:cis ratio), while kinetic control isenhanced by sonication (68%–84% yields, up to 9:91 trans:cis ratio) [46].


Besides derivatives of tryptophan, various chiral carbonyl compounds were used in order toinduce enantioselectivity [47]. The total synthesis of (R)-pyridindolol, (R)-pyridindolol K1, and(R)-pyridindolol K2 (Scheme 9) in 66%, 41%, and 55% overall yield, respectively, was an example.In fact, although both the starting materials (L-tryptophan methyl ester and (S)-2,3-O-isopropylidene-

Molecules 2016, 21, 699 6 of 18

glyceraldehyde) are chiral, the source of chirality in the products was the L-glyceraldehyde, becausethe chirality of tryptophan is lost during the aromatization of the six-membered nitrogen ring [48].

Molecules 2016, 21, 699 6 of 18

glyceraldehyde) are chiral, the source of chirality in the products was the L-glyceraldehyde, because the chirality of tryptophan is lost during the aromatization of the six-membered nitrogen ring [48].

NH

NH2

CO2Me2. p-TsCl/pyridine3. K2CO3

NH

N

CO2Me

1.O O

OHC

O

O

Yield = 79%

NH

N

OR1

OH

OR

pyridindolol: R= R1= Hpyridindolol K1 R= R1= Acpyridindolol K2 R= Ac, R1= H

Scheme 9. Total syntheses of (R)-pyridindolol, (R)-pyridindolol K1, and (R)-pyridindolol K2.

Tetrahydro-β-carbolines prepared from tryptamine and protected α-aminoaldehydes derived from L-glutamic acid were also studied (Scheme 10) [49]. The cis-diastereomer was mainly formed independently from the size of the protecting group with carbamates, in particular with Cbz group the cis-isomer is recovered as single diastereomer. On the other hand, pyrrole or phthalimide protecting groups overturned diastereoselectivity and, in particular, the trans-diastereomer was exclusively obtained from pyrrole-protected aminoaldehydes.

NH

NH2 NR1R2

CHO

ROCTFA N

H

NH

NR1

R2

R=O-t-Bu, NEt2 Yield = 62-81%

+NH

NH

NR1

R2

R1-R2= pyrrole, Pht100:0 to 93:7

R1=Cbz, Boc, CO2Me, Troc,R2=H 100:0 to 86:14 dr

COR COR

Scheme 10. Diastereoselective PSR with chiral amino-aldehydes.

Later further studies on the PSR of D- and L-tryptophan with α-amino aldehydes derived from D- and L-amino acids showed that when both substrates have the same configuration (L,L or D,D, ‘mismatched’ situation), the trans diastereomer prevailed in the mixture of cis and trans-β-carbolines (65:35 to 100:0). In the ‘matched’ situation (L,D or D,L), only the cis diastereomer is recovered. A Felkin-Ahn model could explain this product distribution [50].

During a stereocontrolled 18-step total synthesis of (−)-eudistomin C, Fukuyama and co-workers developed a Brønsted acid-catalyzed diastereoselective PSR of a tryptamine derivative with Garner aldehyde (Scheme 11) [51]. It is worth noting that with TFA the undesired diastereomer was the major product (3:1 dr), thus authors screened various conditions and found that the reaction afforded the desired diastereomer in the presence of a catalytic amount of dichloroacetic acid.

NH

MeO

Br

BocN O

OHC

Cl2CHCO2HPhMe

92:8 dr

NH

N O

MTM

BocNO

MeO

BrNH

N

HO

Br

S

O

H2N

HH

(-)-Eudistomin C

NHOMTM

Scheme 11. Diastereoselective PSR of a tryptamine derivative with Garner aldehyde.


Tetrahydro-β-carbolines prepared from tryptamine and protected α-aminoaldehydes derivedfrom L-glutamic acid were also studied (Scheme 10) [49]. The cis-diastereomer was mainly formedindependently from the size of the protecting group with carbamates, in particular with Cbz group thecis-isomer is recovered as single diastereomer. On the other hand, pyrrole or phthalimide protectinggroups overturned diastereoselectivity and, in particular, the trans-diastereomer was exclusivelyobtained from pyrrole-protected aminoaldehydes.

Molecules 2016, 21, 699 6 of 18


NH

NH2


NH

N

CO2Me

1.O O

OHC

O

O

Yield = 79%

NH

N

OR1

OH

OR




NH

NH2 NR1R2

CHO

ROCTFA N

H

NH

NR1

R2


+NH

NH

NR1

R2



COR COR




NH

MeO

Br

BocN O

OHC

Cl2CHCO2HPhMe

92:8 dr

NH

N O

MTM

BocNO

MeO

BrNH

N

HO

Br

S

O

H2N

HH

(-)-Eudistomin C

NHOMTM

Scheme 11. Diastereoselective PSR of a tryptamine derivative with Garner aldehyde.


Later further studies on the PSR of D- and L-tryptophan with α-amino aldehydes derived fromD- and L-amino acids showed that when both substrates have the same configuration (L,L or D,D,‘mismatched’ situation), the trans diastereomer prevailed in the mixture of cis and trans-β-carbolines(65:35 to 100:0). In the ‘matched’ situation (L,D or D,L), only the cis diastereomer is recovered.A Felkin-Ahn model could explain this product distribution [50].

During a stereocontrolled 18-step total synthesis of (´)-eudistomin C, Fukuyama and co-workersdeveloped a Brønsted acid-catalyzed diastereoselective PSR of a tryptamine derivative with Garneraldehyde (Scheme 11) [51]. It is worth noting that with TFA the undesired diastereomer was the majorproduct (3:1 dr), thus authors screened various conditions and found that the reaction afforded thedesired diastereomer in the presence of a catalytic amount of dichloroacetic acid.

Molecules 2016, 21, 699 6 of 18


NH

NH2


NH

N

CO2Me

1.O O

OHC

O

O

Yield = 79%

NH

N

OR1

OH

OR




NH

NH2 NR1R2

CHO

ROCTFA N

H

NH

NR1

R2


+NH

NH

NR1

R2



COR COR




NH

MeO

Br

BocN O

OHC

Cl2CHCO2HPhMe

92:8 dr

NH

N O

MTM

BocNO

MeO

BrNH

N

HO

Br

S

O

H2N

HH

(-)-Eudistomin C

NHOMTM

Scheme 11. Diastereoselective PSR of a tryptamine derivative with Garner aldehyde. Scheme 11. Diastereoselective PSR of a tryptamine derivative with Garner aldehyde.

Molecules 2016, 21, 699 7 of 18

Stork’s group prepared (´)-reserpine starting from (S)-3-cyclohexenecarboxylic acid, by modifyingtheir racemic synthesis (Scheme 12) [52].

Molecules 2016, 21, 699 7 of 18

Stork’s group prepared (−)-reserpine starting from (S)-3-cyclohexenecarboxylic acid, by modifying their racemic synthesis (Scheme 12) [52].

CO2H

O

BnO OTsCHO

MeO2C OH

OMe

NHMeO

NH2

HN

MeO

N

OTsMeO2C

OHMeOCN-

NHMeO

MeO2C

OH

OMe

NNC

heat

HN

MeO

MeO2C

OH

MeO

NCN

H+,rt

NH

MeO

MeO2C

OH

OMe

N

H HN

MeO

MeO2C

OHMeO

NH

NH

MeO

MeO2C

O

OMe

N

HO

OMeMeO

MeO

(-)-reserpine

Scheme 12. Key steps in the synthesis of (−)-reserpine.

Interestingly, a reserpine-isoreserpine mixture is recovered if PSR occurred before closure of ring D, as well as if a tight iminium ion pair was formed before undergoing PSR. A “naked” iminium ion, instead, could assume the correct chair-axial conformation to lead to the correct C-3 stereochemistry.

Finally, an alternative route to the tetrahydro-β-carboline scaffold has been recently proposed with amino acid L-alanine or L-proline as the source of chirality. The synthesis contemplated the de novo construction of the indole ring with the appropriate substituents to give the PSR in the final step. A gram-scale total synthesis of (S)-eleagnine [53] and (S)-harmicine [54] in enantiopure form (>99% ee) was achieved.

4. Chiral Auxiliaries

The ideal chiral auxiliaries require ready availability, affordable cost, and, preferably, the accessibility of both enantiomers, as well as appropriate and efficient methods for their removal without affecting the optical integrity of the newly generated stereogenic center once the Pictet–Spengler reaction has been carried out, but these simple requirements seriously restrict the number of potentially useful candidates.

Scheme 12. Key steps in the synthesis of (´)-reserpine.

Interestingly, a reserpine-isoreserpine mixture is recovered if PSR occurred before closure of ring D,as well as if a tight iminium ion pair was formed before undergoing PSR. A “naked” iminium ion,instead, could assume the correct chair-axial conformation to lead to the correct C-3 stereochemistry.

Finally, an alternative route to the tetrahydro-β-carboline scaffold has been recently proposedwith amino acid L-alanine or L-proline as the source of chirality. The synthesis contemplated thede novo construction of the indole ring with the appropriate substituents to give the PSR in the finalstep. A gram-scale total synthesis of (S)-eleagnine [53] and (S)-harmicine [54] in enantiopure form(>99% ee) was achieved.

4. Chiral Auxiliaries

The ideal chiral auxiliaries require ready availability, affordable cost, and, preferably, theaccessibility of both enantiomers, as well as appropriate and efficient methods for their removal withoutaffecting the optical integrity of the newly generated stereogenic center once the Pictet–Spenglerreaction has been carried out, but these simple requirements seriously restrict the number of potentiallyuseful candidates.

Molecules 2016, 21, 699 8 of 18

The first attempt dates back to 1994 and used Nb-α-methylbenzyl substituted 5,6-dimethoxy-tryptamine, which provided a 60:40 dr [55]. Then the reaction conditions were optimized and the bestresults (up to 86:14 and 69:31 dr for aromatic and aliphatic aldehydes, respectively) were obtainedusing trifluoroacetic acid in benzene at reflux (Scheme 13) [56]. Moreover, the auxiliaries benzyl- and1-naphthyl-1-ethylamine provided similar diastereocontrol for aliphatic aldehydes (70:30 dr) [57].

Molecules 2016, 21, 699 8 of 18

The first attempt dates back to 1994 and used Nb-α-methylbenzyl substituted 5,6-dimethoxy-tryptamine, which provided a 60:40 dr [55]. Then the reaction conditions were optimized and the best results (up to 86:14 and 69:31 dr for aromatic and aliphatic aldehydes, respectively) were obtained using trifluoroacetic acid in benzene at reflux (Scheme 13) [56]. Moreover, the auxiliaries benzyl- and 1-naphthyl-1-ethylamine provided similar diastereocontrol for aliphatic aldehydes (70:30 dr) [57].

NH

NH Ph

RCHOPhH, reflux

NH

N Ph

RH

NH

N

RPh

Scheme 13. -α-Methylbenzylamine as chiral auxiliary.

Chiral sulfoxides provided β-carbolines in 57%–63% yields and >98% ee (S-isomer) after removal of the auxiliary. It should be noted that camphorsulfonic acid was used as the acid catalyst. However, it did not influence stereochemistry, because either racemic or pure (+)-isomer gave the same diastereomeric ratio of the N-sulfinyl-β-carboline (Scheme 14) [58].

NH

NH

SO

Tol

RCHOCSA

NH R

Yield = 57-83%

N S

O

TolEtOH/H+

NH R

NH

Yield = 86-93%>98% ee

R= Me, Et, Pr, Bu, i-Pr,i -Bu, n-C5H11, c-C6H11

Scheme 14. Chiral sulfoxide as chiral auxiliary.

(S)-Tetrahydro-β-carbolines were also obtained from Pictet–Spengler reaction using a chiral carbamate of tryptamine (Scheme 15). In particular, (−)-8-phenylmenthylcarbamate was found superior to (−)-menthylcarbamate. Reaction conditions for auxiliary cleavage were not reported [59]. The transition state A was invoked to explain the stereoselectivity. If a 4-phenoxyphenyl substituent was present in the chiral auxiliary, the steric interactions favored the transition state B leading to (R)-isomers as the major product.

OPh

HN

HNO

OPh

RCHOTMSCl

Yield = 53-97%61:39 to 95:5 dr

NH

N

RO

O

Ph

O

O

N

R

NH

O

O

N

HN

R

A

B Scheme 15. (−)-8-Phenylmenthylcarbamate as chiral auxiliary.

N,N-phthaloyl-aminoacids could act as the chiral auxiliary when imines from tryptamine are treated with their chloride in the presence of titanium alkoxide. The reaction conditions were suitable for both aliphatic and aromatic aldehydes. However, removal of the auxiliary was obtained with LiAlH4 in only 66% yield (Scheme 16) [60]. The obtained carboline was R-configured that is enantiomeric with that obtained in the previous examples.


Chiral sulfoxides provided β-carbolines in 57%–63% yields and >98% ee (S-isomer) after removalof the auxiliary. It should be noted that camphorsulfonic acid was used as the acid catalyst. However,it did not influence stereochemistry, because either racemic or pure (+)-isomer gave the samediastereomeric ratio of the N-sulfinyl-β-carboline (Scheme 14) [58].

Molecules 2016, 21, 699 8 of 18


NH

NH Ph

RCHOPhH, reflux

NH

N Ph

RH

NH

N

RPh



NH

NH

SO

Tol

RCHOCSA

NH R

Yield = 57-83%

N S

O

TolEtOH/H+

NH R

NH

Yield = 86-93%>98% ee




OPh

HN

HNO

OPh

RCHOTMSCl

Yield = 53-97%61:39 to 95:5 dr

NH

N

RO

O

Ph

O

O

N

R

NH

O

O

N

HN

R

A




(S)-Tetrahydro-β-carbolines were also obtained from Pictet–Spengler reaction using a chiralcarbamate of tryptamine (Scheme 15). In particular, (´)-8-phenylmenthylcarbamate was foundsuperior to (´)-menthylcarbamate. Reaction conditions for auxiliary cleavage were not reported [59].The transition state A was invoked to explain the stereoselectivity. If a 4-phenoxyphenyl substituentwas present in the chiral auxiliary, the steric interactions favored the transition state B leading to(R)-isomers as the major product.

Molecules 2016, 21, 699 8 of 18


NH

NH Ph

RCHOPhH, reflux

NH

N Ph

RH

NH

N

RPh



NH

NH

SO

Tol

RCHOCSA

NH R

Yield = 57-83%

N S

O

TolEtOH/H+

NH R

NH

Yield = 86-93%>98% ee




OPh

HN

HNO

OPh

RCHOTMSCl

Yield = 53-97%61:39 to 95:5 dr

NH

N

RO

O

Ph

O

O

N

R

NH

O

O

N

HN

R

A



Scheme 15. (´)-8-Phenylmenthylcarbamate as chiral auxiliary.

N,N-phthaloyl-aminoacids could act as the chiral auxiliary when imines from tryptamine aretreated with their chloride in the presence of titanium alkoxide. The reaction conditions weresuitable for both aliphatic and aromatic aldehydes. However, removal of the auxiliary was obtainedwith LiAlH4 in only 66% yield (Scheme 16) [60]. The obtained carboline was R-configured that isenantiomeric with that obtained in the previous examples.

Molecules 2016, 21, 699 9 of 18

Molecules 2016, 21, 699 9 of 18

NH

N

RNPht

ClOC

R1

+

R1=Me, i-Pr, t-BuR= Me, Et, i-PrPh, 4-NO2Ph,4-ClPh

Ti(i-PrO)4

Yield = 30-99%82:18 to >99:1 dr

NH

N

RO

R1

NPhtLiAlH4

NH

NH

R

NH

N

R

H

O

R2

N

HO

TiO

i-Pr-O O-i-PrO-i-Pr

O-i-Pr

Scheme 16. N,N-Phthaloyl-aminoacids as chiral auxiliaries.

Tryptamine and 5-methoxytryptamine reacted with optically pure malonaldehyde monocycloacetals to give after Pictet–Spengler condensation and removal of the chiral auxiliary (R)-carbolines in 89% yield (Scheme 17) [61].

OO

NHCOPh

CHO

NH

NH2X

X=H, MeO

1.2. MeOH

NH

NH

X

OMe

MeOYield = 89%only (R)

Scheme 17. Malonaldehyde monocycloacetals as chiral auxiliary.

A quite different use of chiral auxiliary was recently introduced by Cook research group [62–64]. They achieved benzo-substituted tryptophan derivatives by Larock indole synthesis of 2-iodo-N-Boc-anilines and propargyl-substituted Schöllkopf chiral auxiliary. Then the tryptophan derivative was used in PSR inside the synthesis of numerous natural products (Scheme 18 reports an example).

OMe

I

NH

Boc

+

N

N

OEt

EtO

R

NH

NH

CO2BnOMe

I

OHC

MeO2C

SPh

SPh

Yield = 90%

HN

NCO2Bn

IMeO2CSPhPhS

OMe

NH

N Et

MeO2C

OMe

mitragynine

MeO

Scheme 18. Synthesis and use of a tryptophan derivative in the synthesis of mitragynine.

Finally, another synthesis of β-carbolines is worth of mention, although it is not a proper Pictet–Spengler reaction. In fact, cyclo-condensation reactions between 2-acyl-3-indoleacetic acid derivatives and (R)-phenylglycinol provided tetracyclic lactams, which could easily be converted into enantioenriched 1-substituted tetrahydro-β-carboline alkaloids (Scheme 19) [65]. The most relevant feature of this reaction was the ring-opening reaction with retention of configuration under reductive conditions.


Tryptamine and 5-methoxytryptamine reacted with optically pure malonaldehydemonocycloacetals to give after Pictet–Spengler condensation and removal of the chiral auxiliary(R)-carbolines in 89% yield (Scheme 17) [61].

Molecules 2016, 21, 699 9 of 18

NH

N

RNPht

ClOC

R1

+


Ti(i-PrO)4

Yield = 30-99%82:18 to >99:1 dr

NH

N

RO

R1

NPhtLiAlH4

NH

NH

R

NH

N

R

H

O

R2

N

HO

TiO

i-Pr-O O-i-PrO-i-Pr

O-i-Pr



OO

NHCOPh

CHO

NH

NH2X

X=H, MeO

1.2. MeOH

NH

NH

X

OMe




OMe

I

NH

Boc

+

N

N

OEt

EtO

R

NH

NH

CO2BnOMe

I

OHC

MeO2C

SPh

SPh

Yield = 90%

HN

NCO2Bn

IMeO2CSPhPhS

OMe

NH

N Et

MeO2C

OMe

mitragynine

MeO




A quite different use of chiral auxiliary was recently introduced by Cook research group [62–64].They achieved benzo-substituted tryptophan derivatives by Larock indole synthesis of 2-iodo-N-Boc-anilines and propargyl-substituted Schöllkopf chiral auxiliary. Then the tryptophan derivativewas used in PSR inside the synthesis of numerous natural products (Scheme 18 reports an example).

Molecules 2016, 21, 699 9 of 18

NH

N

RNPht

ClOC

R1

+


Ti(i-PrO)4

Yield = 30-99%82:18 to >99:1 dr

NH

N

RO

R1

NPhtLiAlH4

NH

NH

R

NH

N

R

H

O

R2

N

HO

TiO

i-Pr-O O-i-PrO-i-Pr

O-i-Pr



OO

NHCOPh

CHO

NH

NH2X

X=H, MeO

1.2. MeOH

NH

NH

X

OMe




OMe

I

NH

Boc

+

N

N

OEt

EtO

R

NH

NH

CO2BnOMe

I

OHC

MeO2C

SPh

SPh

Yield = 90%

HN

NCO2Bn

IMeO2CSPhPhS

OMe

NH

N Et

MeO2C

OMe

mitragynine

MeO




Finally, another synthesis of β-carbolines is worth of mention, although it is not a properPictet–Spengler reaction. In fact, cyclo-condensation reactions between 2-acyl-3-indoleacetic acidderivatives and (R)-phenylglycinol provided tetracyclic lactams, which could easily be convertedinto enantioenriched 1-substituted tetrahydro-β-carboline alkaloids (Scheme 19) [65]. The mostrelevant feature of this reaction was the ring-opening reaction with retention of configuration underreductive conditions.

Molecules 2016, 21, 699 10 of 18

Molecules 2016, 21, 699 10 of 18

N

CO2H

O

RR1

R=Me, PrR1=Me, Bn

OHPh

NH2PhH, reflux

Yield = 60-66%

N

R1

N

O

Ph

R

O

AlCl3/LiAlH4

Yield = 60-94%

N

R1

N Ph

R

O

OH

N

N

O

O

AlH2H

Ph

RR1

R1=Bn1. Na/NH3 liq

2. H2/Pd(OH)2

Yield = 71-73%

NH

NH

R

O

Scheme 19. Cyclo-condensation of 2-acyl-3-indoleacetic acids with (R)-phenylglycinol.

5. Preparing Chiral Compounds Beforehand

The previous sections reported classical chiral pool synthesis. All those reactions employed common chiral starting materials, the chirality of which is preserved in the remainder of the reaction sequence, or alternatively achiral compounds are transformed into chiral substrates by addition of easy removable auxiliary.

In the recent years, the development of asymmetric organocatalysis allowed the preparation of many structural different compounds, especially chiral carbonyl compounds. These compounds could find application in the efficient construction of enantioenriched tetrahydro-β-carbolines by PSR.

For instance, the organocatalytic conjugate addition of a nucleophile derived from tryptamine amide to cinnamaldehydes yielded a hemiaminal with two stereogenic centers (Scheme 20) [66,67]. The Pictet–Spengler cyclization was performed under both kinetic (hydrochloric acid at −78 °C) and thermodynamic control (trifluoroacetic acid at 70 °C) leading to the synthesis of alkaloid scaffolds. Unfortunately, β-alkyl-substituted acroleins decomposed in this reaction. It should be noted that, under thermodynamic control, diastereomer ratios depended on the reaction time and temperature, thus authors supposed that the α-epimer (kinetic product) was formed initially, and then it epimerized to the thermodynamically more-stable β-epimer.

NH

NH

O

EtO2C

NH

Ph

Ph

OTMS

(20 mol%)

NH

NO

MeO2CR

OHCHOR

NH

R

CO2Me

N

H

O

NH

R

CO2Me

N

H

O

kinetic product

thermodynamic product

X

X=H, 5,6-(MeO)2R=Ph, 4.NO2Ph, 4-AcO-3-MeOPh,

4-MeOPh, 3,4-Cl2Ph, 2-furyl

X

X

X

Yield = 42-73%up to 90:10 dr90-98% ee

HCl

TFA

Scheme 20. Enantioselective synthesis of indolo[2,3a]quinolizidines.

This strategy was then applied to the synthesis of many indole alkaloids by the use of 5-hydroxypent-2-enal as the unsaturated aldehyde [68]. Depending on the reaction conditions, three out of four possible epimers of the corresponding quinolizidine alkaloids were enantio- and diastereoselectively prepared.

The group of Wu successfully attempted the reaction of Franzén with β-ketoamides instead of malono-monoamides, accessing to (2R,12bS)-indolo[2,3-a]quinolizidines in 56%–95% yields and 77%–98% ee (12 examples) [69]. Two points are worth noting: (i) conversely from the products obtained by Franzén, the C-2 was not asymmetric, because the enol form of the ketone was always recovered; (ii) pent-2-enal also worked in this reaction, although an inseparable 1:1 mixture of keto and enol form was recovered in 81% yield.



The previous sections reported classical chiral pool synthesis. All those reactions employedcommon chiral starting materials, the chirality of which is preserved in the remainder of the reactionsequence, or alternatively achiral compounds are transformed into chiral substrates by addition ofeasy removable auxiliary.

In the recent years, the development of asymmetric organocatalysis allowed the preparation ofmany structural different compounds, especially chiral carbonyl compounds. These compounds couldfind application in the efficient construction of enantioenriched tetrahydro-β-carbolines by PSR.

For instance, the organocatalytic conjugate addition of a nucleophile derived from tryptamineamide to cinnamaldehydes yielded a hemiaminal with two stereogenic centers (Scheme 20) [66,67].The Pictet–Spengler cyclization was performed under both kinetic (hydrochloric acid at ´78 ˝C) andthermodynamic control (trifluoroacetic acid at 70 ˝C) leading to the synthesis of alkaloid scaffolds.Unfortunately, β-alkyl-substituted acroleins decomposed in this reaction. It should be noted that,under thermodynamic control, diastereomer ratios depended on the reaction time and temperature,thus authors supposed that the α-epimer (kinetic product) was formed initially, and then it epimerizedto the thermodynamically more-stable β-epimer.

Molecules 2016, 21, 699 10 of 18

N

CO2H

O

RR1

R=Me, PrR1=Me, Bn

OHPh

NH2PhH, reflux

Yield = 60-66%

N

R1

N

O

Ph

R

O

AlCl3/LiAlH4

Yield = 60-94%

N

R1

N Ph

R

O

OH

N

N

O

O

AlH2H

Ph

RR1

R1=Bn1. Na/NH3 liq

2. H2/Pd(OH)2

Yield = 71-73%

NH

NH

R

O



The previous sections reported classical chiral pool synthesis. All those reactions employed common chiral starting materials, the chirality of which is preserved in the remainder of the reaction sequence, or alternatively achiral compounds are transformed into chiral substrates by addition of easy removable auxiliary.

In the recent years, the development of asymmetric organocatalysis allowed the preparation of many structural different compounds, especially chiral carbonyl compounds. These compounds could find application in the efficient construction of enantioenriched tetrahydro-β-carbolines by PSR.

For instance, the organocatalytic conjugate addition of a nucleophile derived from tryptamine amide to cinnamaldehydes yielded a hemiaminal with two stereogenic centers (Scheme 20) [66,67]. The Pictet–Spengler cyclization was performed under both kinetic (hydrochloric acid at −78 °C) and thermodynamic control (trifluoroacetic acid at 70 °C) leading to the synthesis of alkaloid scaffolds. Unfortunately, β-alkyl-substituted acroleins decomposed in this reaction. It should be noted that, under thermodynamic control, diastereomer ratios depended on the reaction time and temperature, thus authors supposed that the α-epimer (kinetic product) was formed initially, and then it epimerized to the thermodynamically more-stable β-epimer.

NH

NH

O

EtO2C

NH

Ph

Ph

OTMS

(20 mol%)

NH

NO

MeO2CR

OHCHOR

NH

R

CO2Me

N

H

O

NH

R

CO2Me

N

H

O

kinetic product

thermodynamic product

X

X=H, 5,6-(MeO)2R=Ph, 4.NO2Ph, 4-AcO-3-MeOPh,

4-MeOPh, 3,4-Cl2Ph, 2-furyl

X

X

X

Yield = 42-73%up to 90:10 dr90-98% ee

HCl

TFA


This strategy was then applied to the synthesis of many indole alkaloids by the use of 5-hydroxypent-2-enal as the unsaturated aldehyde [68]. Depending on the reaction conditions, three out of four possible epimers of the corresponding quinolizidine alkaloids were enantio- and diastereoselectively prepared.

The group of Wu successfully attempted the reaction of Franzén with β-ketoamides instead of malono-monoamides, accessing to (2R,12bS)-indolo[2,3-a]quinolizidines in 56%–95% yields and 77%–98% ee (12 examples) [69]. Two points are worth noting: (i) conversely from the products obtained by Franzén, the C-2 was not asymmetric, because the enol form of the ketone was always recovered; (ii) pent-2-enal also worked in this reaction, although an inseparable 1:1 mixture of keto and enol form was recovered in 81% yield.


This strategy was then applied to the synthesis of many indole alkaloids by the use of 5-hydroxypent-2-enal as the unsaturated aldehyde [68]. Depending on the reaction conditions,three out of four possible epimers of the corresponding quinolizidine alkaloids were enantio- anddiastereoselectively prepared.

The group of Wu successfully attempted the reaction of Franzén with β-ketoamides insteadof malono-monoamides, accessing to (2R,12bS)-indolo[2,3-a]quinolizidines in 56%–95% yields and77%–98% ee (12 examples) [69]. Two points are worth noting: (i) conversely from the products obtainedby Franzén, the C-2 was not asymmetric, because the enol form of the ketone was always recovered;

Molecules 2016, 21, 699 11 of 18

(ii) pent-2-enal also worked in this reaction, although an inseparable 1:1 mixture of keto and enol formwas recovered in 81% yield.

The same research group then surmised that the coupling between malonate and α,β-unsaturatedaldehydes could be performed before attaching malonate itself to tryptamine. Thus, they developeda diastereoselective cascade sequence for the preparation of cis-indolo[2,3-a]quinolizidines, in whichMichael addition of malonate to α,β-unsaturated aldehydes was the first step, then PSR followedand lactamization was the final reaction step (Scheme 21). Also in this reaction, β-alkyl-substitutedα,β-unsaturated aldehydes can be employed [70]. Then they extended the scope of this reaction to thesynthesis of enantioenriched α-hemiaminal from α,β-unsaturated aldehydes and β-ketoesters, whichin turn were cyclized with tryptamine in the presence of acid [71]. The stereochemistry of the productswas defined in the Michael addition step and the diastereoselectivity of the PSR was shaped by thekinetically controlled reaction conditions (Scheme 22). Instead of classical Jørgensen-Hayashi catalyst,its 3,5-bis(trifluoromethyl) derivative was sometimes employed.

Molecules 2016, 21, 699 11 of 18

The same research group then surmised that the coupling between malonate and α,β-unsaturated aldehydes could be performed before attaching malonate itself to tryptamine. Thus, they developed a diastereoselective cascade sequence for the preparation of cis-indolo[2,3-a]quinolizidines, in which Michael addition of malonate to α,β-unsaturated aldehydes was the first step, then PSR followed and lactamization was the final reaction step (Scheme 21). Also in this reaction, β-alkyl-substituted α,β-unsaturated aldehydes can be employed [70]. Then they extended the scope of this reaction to the synthesis of enantioenriched α-hemiaminal from α,β-unsaturated aldehydes and β-ketoesters, which in turn were cyclized with tryptamine in the presence of acid [71]. The stereochemistry of the products was defined in the Michael addition step and the diastereoselectivity of the PSR was shaped by the kinetically controlled reaction conditions (Scheme 22). Instead of classical Jørgensen-Hayashi catalyst, its 3,5-bis(trifluoromethyl) derivative was sometimes employed.

CO2R2

NH

PhPh

OTMS

(20 mol%)

CHOR

CO2R2

CHO CO2R2

R

CO2R2

NH

NH2

TFA

X

Yield = 27-86%77-99% ee

HN

RCO2Me

NH

O

X

N

HN

X

OR2OCO2R

2

R

H

R=Ph, 4-BrPh, 4-FPh, 2,4-Cl2Ph, 4-MePh,4-MeO-C6H4, 2-Br-C6H4CH=CH,4-F-C6H4CH=CH, Me, Et, n-Pr

R2=Me, Et, Bn, X=H, MeO, Br Scheme 21. Syntheses of indoloquinolizidines by a Pictet-Spengler/lactamization cascade.

R1 CO2R2

O

NH

PhPh

OTMS

(20 mol%)

CHOR

OR1

R2O2C

R

OH

NH

NH2

PhCO2H

HN

R

R2O2C

N

H

R1

XX

Yield = 51-95%80-96% ee

R=Ph, 4-BrPh, 4-NO2Ph 2,4-Cl2Ph, 3-furyl, Me, Pr, CO2EtR1=Me, Pr

NHN

R1

CO2R2R

XNH

R1

CO2R2R

XN

H

H

Scheme 22. One-pot three-component Michael addition–Pictet–Spengler sequence.

Rueping attempted this reaction with 1,3-cyclohexandiones [72]. The substrate scope was found to be general (20 examples) and optically active indoloquinolizidines were isolated as single diastereomers in 64%–85% yields with 78% to >99% ee. The absolute configuration of the indoloquinolizidines was determined by the X-ray analysis as (12bS,14R). The diastereoselectivity was attributed again to steric repulsion taking place between the incoming indole nucleophile and the protons of C-13.

In this Michael/Pictet–Spengler sequence, another explored substrate was α-oxo-γ-butyrolactam. The corresponding butyrolactam-fused indoloquinolizidines were recovered in 53%–87% yields with 75:25 to >95:5 dr and 90%–97% ee of the predominant (4R,5aR)-isomer (16 examples) [73]. Interestingly, the enantiomer (i.e., that arising from unnatural proline) of the classical Jørgensen-Hayashi catalyst was employed. With regard to the mechanism, authors assumed a stereoselective Re-facial Michael addition of iminium ion to the enol of α-oxo-γ-butyrolactam. Then tautomerization and hydrolysis formed (4S)-2-hydroxy-4-alkyl-3,4,5,6-tetrahydropyrano[3,2-c]pyrrol-7(2H)-ones. This masked 1,5-dicarbonyl compound condensed with tryptamine to perform diastereoselective Pictet–Spengler reaction.

Scheme 21. Syntheses of indoloquinolizidines by a Pictet-Spengler/lactamization cascade.

Molecules 2016, 21, 699 11 of 18

The same research group then surmised that the coupling between malonate and α,β-unsaturated aldehydes could be performed before attaching malonate itself to tryptamine. Thus, they developed a diastereoselective cascade sequence for the preparation of cis-indolo[2,3-a]quinolizidines, in which Michael addition of malonate to α,β-unsaturated aldehydes was the first step, then PSR followed and lactamization was the final reaction step (Scheme 21). Also in this reaction, β-alkyl-substituted α,β-unsaturated aldehydes can be employed [70]. Then they extended the scope of this reaction to the synthesis of enantioenriched α-hemiaminal from α,β-unsaturated aldehydes and β-ketoesters, which in turn were cyclized with tryptamine in the presence of acid [71]. The stereochemistry of the products was defined in the Michael addition step and the diastereoselectivity of the PSR was shaped by the kinetically controlled reaction conditions (Scheme 22). Instead of classical Jørgensen-Hayashi catalyst, its 3,5-bis(trifluoromethyl) derivative was sometimes employed.

CO2R2

NH

PhPh

OTMS

(20 mol%)

CHOR

CO2R2

CHO CO2R2

R

CO2R2

NH

NH2

TFA

X

Yield = 27-86%77-99% ee

HN

RCO2Me

NH

O

X

N

HN

X

OR2OCO2R

2

R

H

R=Ph, 4-BrPh, 4-FPh, 2,4-Cl2Ph, 4-MePh,4-MeO-C6H4, 2-Br-C6H4CH=CH,4-F-C6H4CH=CH, Me, Et, n-Pr

R2=Me, Et, Bn, X=H, MeO, Br Scheme 21. Syntheses of indoloquinolizidines by a Pictet-Spengler/lactamization cascade.

R1 CO2R2

O

NH

PhPh

OTMS

(20 mol%)

CHOR

OR1

R2O2C

R

OH

NH

NH2

PhCO2H

HN

R

R2O2C

N

H

R1

XX

Yield = 51-95%80-96% ee

R=Ph, 4-BrPh, 4-NO2Ph 2,4-Cl2Ph, 3-furyl, Me, Pr, CO2EtR1=Me, Pr

NHN

R1

CO2R2R

XNH

R1

CO2R2R

XN

H

H


Rueping attempted this reaction with 1,3-cyclohexandiones [72]. The substrate scope was found to be general (20 examples) and optically active indoloquinolizidines were isolated as single diastereomers in 64%–85% yields with 78% to >99% ee. The absolute configuration of the indoloquinolizidines was determined by the X-ray analysis as (12bS,14R). The diastereoselectivity was attributed again to steric repulsion taking place between the incoming indole nucleophile and the protons of C-13.

In this Michael/Pictet–Spengler sequence, another explored substrate was α-oxo-γ-butyrolactam. The corresponding butyrolactam-fused indoloquinolizidines were recovered in 53%–87% yields with 75:25 to >95:5 dr and 90%–97% ee of the predominant (4R,5aR)-isomer (16 examples) [73]. Interestingly, the enantiomer (i.e., that arising from unnatural proline) of the classical Jørgensen-Hayashi catalyst was employed. With regard to the mechanism, authors assumed a stereoselective Re-facial Michael addition of iminium ion to the enol of α-oxo-γ-butyrolactam. Then tautomerization and hydrolysis formed (4S)-2-hydroxy-4-alkyl-3,4,5,6-tetrahydropyrano[3,2-c]pyrrol-7(2H)-ones. This masked 1,5-dicarbonyl compound condensed with tryptamine to perform diastereoselective Pictet–Spengler reaction.


Rueping attempted this reaction with 1,3-cyclohexandiones [72]. The substrate scope was found tobe general (20 examples) and optically active indoloquinolizidines were isolated as single diastereomersin 64%–85% yields with 78% to >99% ee. The absolute configuration of the indoloquinolizidines wasdetermined by the X-ray analysis as (12bS,14R). The diastereoselectivity was attributed again to stericrepulsion taking place between the incoming indole nucleophile and the protons of C-13.

In this Michael/Pictet–Spengler sequence, another explored substrate was α-oxo-γ-butyrolactam.The corresponding butyrolactam-fused indoloquinolizidines were recovered in 53%–87% yields with75:25 to >95:5 dr and 90%–97% ee of the predominant (4R,5aR)-isomer (16 examples) [73]. Interestingly,the enantiomer (i.e., that arising from unnatural proline) of the classical Jørgensen-Hayashi catalyst wasemployed. With regard to the mechanism, authors assumed a stereoselective Re-facial Michael additionof iminium ion to the enol of α-oxo-γ-butyrolactam. Then tautomerization and hydrolysis formed

Molecules 2016, 21, 699 12 of 18

(4S)-2-hydroxy-4-alkyl-3,4,5,6-tetrahydropyrano[3,2-c]pyrrol-7(2H)-ones. This masked 1,5-dicarbonylcompound condensed with tryptamine to perform diastereoselective Pictet–Spengler reaction.

Another organocatalytic cascade one-pot reaction sequence has been developed for theconstruction of indoloquinolizidines. In this sequence the asymmetric Michael addition, catalyzedby Jørgensen-Hayashi catalyst, provided the chiral pool for the following aza-Henry reaction,hemiaminalization, dehydration, and PSR, providing indoloquinolizidines bearing five contiguousstereocentres (Scheme 23) [74]. It should be noted that only aliphatic aldehydes were used.

Molecules 2016, 21, 699 12 of 18

Another organocatalytic cascade one-pot reaction sequence has been developed for the construction of indoloquinolizidines. In this sequence the asymmetric Michael addition, catalyzed by Jørgensen-Hayashi catalyst, provided the chiral pool for the following aza-Henry reaction, hemiaminalization, dehydration, and PSR, providing indoloquinolizidines bearing five contiguous stereocentres (Scheme 23) [74]. It should be noted that only aliphatic aldehydes were used.

RNO2

+ R1CHO

NH

Ph

Ph

OTMS

R1 CHO

RNO2

NH

NH2

4-nitrophenol(5 mol% each)

+ R1CHO

DABCO(1 equiv)

NH

N NH

N

R1R1

NO2

R

R1

1. tetramethyl-guanidine

2. TsOH

NH

N

R1

NO2

R

R1

Yield = 30-55%>95:5 dr91-98% ee

"chiral pool"

R=Ph, 4-ClPh, 4-BrPh, 4-MeOPh, 2-ClPh,2-BrPh, 3-NO2Ph, 2-thyenyl, 2-furyl

R1=Me, Et, Bn, n-C7H15

Scheme 23. One-pot enantioselective construction of indoloquinolizidine derivatives with five contiguous stereocentres.

Arai and co-workers set up a four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines [75]. Enantioenriched (R,S,S)-tryptamine was obtained from three-component coupling of an indole, nitroalkene, and aldehyde catalyzed by imidazoline-aminophenol-CuOTf by a Friedel-Crafts/Henry cascade. Then reduction of-nitro group, protection of the hydroxy function allowed the PSR with aldehydes affording (1S,3S,4R)-tetrahydro-β-carbolines (Scheme 24).

NH

RNO2+ R1CHO+ F3C CF3

OH

N

NPh

Ph

Ts

N

Ph

OH

Br

Br

(10 mol%)

(2 equiv)PhMe

NH

R

NO2

HOR1

R=Ph, n-C5H11,

R1=Ph, 4-BrPh, c-C6H11

R2=Ph, 4-BrPh, 4-NO2Ph, 4-MePh, 4, ClPh, 3-ClPh

99% ee

1. Zn, HCl, MeOH2. TESCl, imidazole 80%

NH

R

NH2

TESOR1

1. R2CHO, MgSO4

2. TFA

NH

NH

RHO

R1

R2

Yield = 38-72%>95:5 dr

CuOTf

Scheme 24. Four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines.

Jia et al. reported and example of PSR into their report on the enantioselective Friedel–Crafts alkylation of indoles with β-CF3-β-disubstituted nitroalkenes. Actually, (R)-3-(1,1,1-trifluoro3-nitro-2-phenylpropan-2-yl)-1H-indole (96% ee) was reduced and then cyclized with benzaldehyde under TFA catalysis, in 78% yield, but only a 67:33 diastereomeric ratio was achieved although the enantiomeric excess of both isomers reflected that of the starting material [76].

Scheme 23. One-pot enantioselective construction of indoloquinolizidine derivatives with fivecontiguous stereocentres.

Arai and co-workers set up a four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines [75]. Enantioenriched (R,S,S)-tryptamine was obtained from three-component couplingof an indole, nitroalkene, and aldehyde catalyzed by imidazoline-aminophenol-CuOTf bya Friedel-Crafts/Henry cascade. Then reduction of-nitro group, protection of the hydroxy functionallowed the PSR with aldehydes affording (1S,3S,4R)-tetrahydro-β-carbolines (Scheme 24).

Molecules 2016, 21, 699 12 of 18

Another organocatalytic cascade one-pot reaction sequence has been developed for the construction of indoloquinolizidines. In this sequence the asymmetric Michael addition, catalyzed by Jørgensen-Hayashi catalyst, provided the chiral pool for the following aza-Henry reaction, hemiaminalization, dehydration, and PSR, providing indoloquinolizidines bearing five contiguous stereocentres (Scheme 23) [74]. It should be noted that only aliphatic aldehydes were used.

RNO2

+ R1CHO

NH

Ph

Ph

OTMS

R1 CHO

RNO2

NH

NH2

4-nitrophenol(5 mol% each)

+ R1CHO

DABCO(1 equiv)

NH

N NH

N

R1R1

NO2

R

R1

1. tetramethyl-guanidine

2. TsOH

NH

N

R1

NO2

R

R1

Yield = 30-55%>95:5 dr91-98% ee

"chiral pool"

R=Ph, 4-ClPh, 4-BrPh, 4-MeOPh, 2-ClPh,2-BrPh, 3-NO2Ph, 2-thyenyl, 2-furyl

R1=Me, Et, Bn, n-C7H15

Scheme 23. One-pot enantioselective construction of indoloquinolizidine derivatives with five contiguous stereocentres.

Arai and co-workers set up a four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines [75]. Enantioenriched (R,S,S)-tryptamine was obtained from three-component coupling of an indole, nitroalkene, and aldehyde catalyzed by imidazoline-aminophenol-CuOTf by a Friedel-Crafts/Henry cascade. Then reduction of-nitro group, protection of the hydroxy function allowed the PSR with aldehydes affording (1S,3S,4R)-tetrahydro-β-carbolines (Scheme 24).

NH

RNO2+ R1CHO+ F3C CF3

OH

N

NPh

Ph

Ts

N

Ph

OH

Br

Br

(10 mol%)

(2 equiv)PhMe

NH

R

NO2

HOR1

R=Ph, n-C5H11,

R1=Ph, 4-BrPh, c-C6H11

R2=Ph, 4-BrPh, 4-NO2Ph, 4-MePh, 4, ClPh, 3-ClPh

99% ee

1. Zn, HCl, MeOH2. TESCl, imidazole 80%

NH

R

NH2

TESOR1

1. R2CHO, MgSO4

2. TFA

NH

NH

RHO

R1

R2

Yield = 38-72%>95:5 dr

CuOTf


Jia et al. reported and example of PSR into their report on the enantioselective Friedel–Crafts alkylation of indoles with β-CF3-β-disubstituted nitroalkenes. Actually, (R)-3-(1,1,1-trifluoro3-nitro-2-phenylpropan-2-yl)-1H-indole (96% ee) was reduced and then cyclized with benzaldehyde under TFA catalysis, in 78% yield, but only a 67:33 diastereomeric ratio was achieved although the enantiomeric excess of both isomers reflected that of the starting material [76].


Jia et al. reported and example of PSR into their report on the enantioselective Friedel–Craftsalkylation of indoles with β-CF3-β-disubstituted nitroalkenes. Actually, (R)-3-(1,1,1-trifluoro3-nitro-2-phenylpropan-2-yl)-1H-indole (96% ee) was reduced and then cyclized with benzaldehyde under TFAcatalysis, in 78% yield, but only a 67:33 diastereomeric ratio was achieved although the enantiomericexcess of both isomers reflected that of the starting material [76].

Molecules 2016, 21, 699 13 of 18

The asymmetric organocatalyzed one-pot three-component cascade reaction of tryptamines, alkylpropiolates, and α,β-unsaturated aldehydes represented another instance, in which a chiral substratewas prepared before PSR. The reaction could be carried out in a one-pot sequence leading to the(2R,12bS)-stereoisomer (Scheme 25) [77].

Molecules 2016, 21, 699 13 of 18

The asymmetric organocatalyzed one-pot three-component cascade reaction of tryptamines, alkyl propiolates, and α,β-unsaturated aldehydes represented another instance, in which a chiral substrate was prepared before PSR. The reaction could be carried out in a one-pot sequence leading to the (2R,12bS)-stereoisomer (Scheme 25) [77].

NH

X NH2

+ CO2R

CH2Cl2,rt

NH

X NHRO2C

R1CHO

NH

ArAr

OTMS

(Ar=3,5-(CF3)2Ph)

(10 mol%)

NH

X NHRO2C

OHC

R1

PhCO2H(10 mol%)20 °C

NH

N CO2R

R1H

X

Yield = 31-88%77-96% ee

X= H, Me, MeO,BrR= Me, Et, t-BuR1=Me, Et, Pr, n-C5H11, n-C6H13

MOMO(CH2)2

Scheme 25. One-pot three-component syntheses of indoloquinolizidines.

Finally, an enzymatic synthesis of optically pure C-3 methyl-substituted strictosidine derivatives, key intermediates in the biosynthesis of several pharmaceutically relevant monoterpenoid indole alkaloids, was performed. Both enantiomers of methyl tryptamine were prepared by either (R)-selective transaminase from Arthrobacter species or (S)-selective transaminase from Silibacter pomeroyi or Bacillus megaterium, thus providing the first stereogenic center at the β-carboline core with up to >98% enantiomeric excess. The chiral tryptamines were then condensed with secologanin in a diastereoselective Pictet–Spengler reaction catalyzed by strictosidine synthase from Ophiorriza pumila or Rauvofolia serpentina (Scheme 26) [78]. Strictosidine synthase clearly controlled the diastereoselectivity, in fact both enantiomers at C-3 of the amine led to an (S)-configured center at C-1 of the carboline. Finally the reaction can be carried out either in a one-pot cascade or in a stepwise fashion in up to 97% yield.

NHX

O

(S)-selectivetransaminase

(R)-selectivetransaminase

L-ala pyruvate

D-ala pyruvate

NHX

NH2

NH

NH2

X

O

OGlucose

CHO

CO2Me

+strictosidinesynthases

HN

NH

X

O

MeO2C

OGlucose

HN

NH

O

MeO2C

OGlucose

X=H, 5-OH, 5-Me6-MeO, 7-Me

Scheme 26. Stereoselective synthesis of C3-methylated strictosidine derivatives.


Finally, an enzymatic synthesis of optically pure C-3 methyl-substituted strictosidine derivatives,key intermediates in the biosynthesis of several pharmaceutically relevant monoterpenoidindole alkaloids, was performed. Both enantiomers of methyl tryptamine were prepared byeither (R)-selective transaminase from Arthrobacter species or (S)-selective transaminase fromSilibacter pomeroyi or Bacillus megaterium, thus providing the first stereogenic center at the β-carbolinecore with up to >98% enantiomeric excess. The chiral tryptamines were then condensed withsecologanin in a diastereoselective Pictet–Spengler reaction catalyzed by strictosidine synthase fromOphiorriza pumila or Rauvofolia serpentina (Scheme 26) [78]. Strictosidine synthase clearly controlled thediastereoselectivity, in fact both enantiomers at C-3 of the amine led to an (S)-configured center at C-1of the carboline. Finally the reaction can be carried out either in a one-pot cascade or in a stepwisefashion in up to 97% yield.

Molecules 2016, 21, 699 13 of 18

The asymmetric organocatalyzed one-pot three-component cascade reaction of tryptamines, alkyl propiolates, and α,β-unsaturated aldehydes represented another instance, in which a chiral substrate was prepared before PSR. The reaction could be carried out in a one-pot sequence leading to the (2R,12bS)-stereoisomer (Scheme 25) [77].

NH

X NH2

+ CO2R

CH2Cl2,rt

NH

X NHRO2C

R1CHO

NH

ArAr

OTMS

(Ar=3,5-(CF3)2Ph)

(10 mol%)

NH

X NHRO2C

OHC

R1

PhCO2H(10 mol%)20 °C

NH

N CO2R

R1H

X

Yield = 31-88%77-96% ee

X= H, Me, MeO,BrR= Me, Et, t-BuR1=Me, Et, Pr, n-C5H11, n-C6H13

MOMO(CH2)2


Finally, an enzymatic synthesis of optically pure C-3 methyl-substituted strictosidine derivatives, key intermediates in the biosynthesis of several pharmaceutically relevant monoterpenoid indole alkaloids, was performed. Both enantiomers of methyl tryptamine were prepared by either (R)-selective transaminase from Arthrobacter species or (S)-selective transaminase from Silibacter pomeroyi or Bacillus megaterium, thus providing the first stereogenic center at the β-carboline core with up to >98% enantiomeric excess. The chiral tryptamines were then condensed with secologanin in a diastereoselective Pictet–Spengler reaction catalyzed by strictosidine synthase from Ophiorriza pumila or Rauvofolia serpentina (Scheme 26) [78]. Strictosidine synthase clearly controlled the diastereoselectivity, in fact both enantiomers at C-3 of the amine led to an (S)-configured center at C-1 of the carboline. Finally the reaction can be carried out either in a one-pot cascade or in a stepwise fashion in up to 97% yield.

NHX

O

(S)-selectivetransaminase

(R)-selectivetransaminase

L-ala pyruvate

D-ala pyruvate

NHX

NH2

NH

NH2

X

O

OGlucose

CHO

CO2Me

+strictosidinesynthases

HN

NH

X

O

MeO2C

OGlucose

HN

NH

O

MeO2C

OGlucose

X=H, 5-OH, 5-Me6-MeO, 7-Me



Molecules 2016, 21, 699 14 of 18

6. Conclusions

The discovery by Pictet and Spengler provided chemists with a powerful method for the synthesisof natural biologically active compounds, especially in the total synthesis of alkaloids. Over 100 yearssince its discovery and until today, there has always been high demand for the development of newefficient catalytic systems Impressive results have been obtained with the asymmetric Pictet–Spenglerreaction starting from chiral tryptamine and carbonyl compounds derivatives. In the last years,however, the classical “chiral pool” methodology, which starts from naturally occurring compounds,has been replaced by asymmetric synthesis from achiral starting materials and chiral acids orhydrogen-bond donors. Cascade multi-component reactions resemble the classical “chiral pool”methodology, since they allow the preparation of enantioenriched compounds, before Pictet–Spenglercyclization. On the other hand a large number of modern syntheses allow the creation of the asymmetriccarbons in a single-step reaction.

Conflicts of Interest: The author declares no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:

Ac AcetylBoc tert-ButoxycarbonylBz BenzoylCbz BenzyloxycarbonylCSA Camphorsulfonic acidDABCO 1,8-DiazabicyclooctaneMTM MethylthiomethylPht PhthalimideTBDMS tert-ButyldimethylsilylTBDPS tert-ButyldiphenylsilylTES TriethylsilylTFA Trifluoroacetic acidTol 4-Methylphenyl (Tolyl)Troc 2,2,2-TrichloroethoxycarbonylTs Methylphenylsulfonyl (Tosyl)

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http://dx.doi.org/10.1021/ol101922h


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the chiral pool in the pictet–spengler reaction for the ... · a seminal asymmetric synthesis was...

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