stereoselective synthesis of B-CARBOLINE

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					                             International Congress Series 1304 (2007) 46 – 59


           Variety of natural products derived from
         tryptophan and stereoselective synthesis of
            tetrahydro-β-carboline derivatives of
                 pharmacological importance
     Piotr Roszkowski a , Stefan Czarnocki a , Jan K. Maurin b,c ,
    Aleksandra Siwicka a , Anna Zawadzka a , Joanna Szawkało a ,
            Andrzej Leniewski a , Zbigniew Czarnocki a,⁎
                  Faculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
                     National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
                            Institute of Atomic Energy, 05-400 Otwock-Świerk, Poland

Abstract. The use of chiral inductors belonging to different classes of compounds is elaborated.
Tetrahydro-β-carboline derivatives were constructed stereoselectively by the use of (R)-1-
arylethylamine and L-amino acids. Asymmetric transfer hydrogenation was proven highly effective
in enantioselective synthesis of several alkaloids. © 2007 Elsevier B.V. All rights reserved.

Keywords: Alkaloids; Biomimetic synthesis; Chirality transfer; Stereocontrolled synthesis; Organocatalysis;
Metal complexes; Secondary metabolites; L-tryptophan

1. Introduction

   One of the most challenging topics in modern organic chemistry is the synthesis of natural
products. Despite the considerable exploration within this field to date, there is still a need
for further development of alternative, preferably biomimetic and/or catalytic ways for
preparation of bioactive compounds.
   Among the numerous families of natural products, isoquinoline and β-carboline alkaloids
seem to attract the biggest attention due to their abundant presence in plants and even in the

 ⁎ Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96.
   E-mail address: (Z. Czarnocki).
0531-5131/ © 2007 Elsevier B.V. All rights reserved.
                P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59       47

animal kingdom, along with their often important physiological activities [1]. Their bioactivity
ranges from highly toxic, for example strychnine [2], to antihypertensive, for example
ajmalicyne [3] and reserpine [4], and the cytotoxic activity shown by vincoleucoblastine and
vincristine used for cancer chemotherapy [5,6]. All these medicinal alkaloids (Scheme 1) are
basically indole derivatives formed from tryptamine provided by tryptophan and a terpenoid
part provided by the iridoid glucoside secologanin. Tryptamine and secologanin are condensed
to form stereoselectively strictosidine, which is the common precursor of all indole alkaloids
[7]. The biodifferentiation of enantiomers together with clinical applications and regulatory
pressure upon the pharmaceutical industry, constitute important reasons for the preparation of
tetrahydroisoquinolines and of tetrahydro-β-carboline in their enantiomerically pure forms.

2. Stereoselective synthesis from popular chiral inductors

   The tetrahydro-β-carboline skeleton is a common structural feature of numerous
secondary metabolites, including Vinca-, Rauwolfia- and Harman-alkaloids. Many of these
bases possess a tremendous value to pharmacology and were attractive synthetic targets for
both academic and industrial research groups. In the synthesis of this class of compounds,
the chirality on the C-1 carbon atom was often introduced by the use of chiral adjuvant in a
stochiometric amount serving as a chiral building block or diastereoinducing auxiliary. All
“classical” methods for tetrahydro-β-carboline framework formation were modified by the
introduction of the stereochemistry source. The Pictet–Spengler, Bischler–Napieralski and
the Pomeranz–Fritsch cyclizations gained the highest popularity [8]. Natural hydroxyacids
constitute an important group of enantiopure compounds that have generated a tremendous
impact on organic stereochemistry. Among them, tartaric and malic acids were most
frequently used as cheap and relatively configurationally stable reagents available in both
enantiomeric forms. They can be used as resolving agents, chiral building blocks, chiral
auxiliaries and ligands for asymmetric transformations [9]. Surprisingly, the stereoselective
synthesis of tetrahydroisoquinoline and β-carboline systems has not taken advantage of the

                       Scheme 1. Selected L-tryptophan secondary metabolites.
48                 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59

Scheme 2. Reaction sequence leading to diastereoselective synthesis of tetrahydro-β-carboline derivatives (9a,b
and 10a,b).

reach chemistry of these acids except in only a few examples [10–13]. Other compounds that
were used as chiral auxiliaries in asymmetric synthesis of isoquinoline and β-carboline
derivatives are amino acids. Many examples of the use of α-amino acids in different optical
activation methods were already thoroughly summarized. In the detailed works by Coppola
and Schuster [14] and later by Rozwadowska [15], the vast amount of references was
reviewed. In asymmetric transformations the enantiopure 1-phenylethylamine and its
congeners still remain attractive chirality sources. Their use as resolving agents, chiral
ligands in catalytic processes and synthetic chiral auxiliaries in stereodifferentiating
reactions of prochiral substrates has been the subject of in-depth reviews [16].

2.1. (R)-1-phenylethylamine and its analogs as chiral auxiliaries in diastereoselective
synthesis of tetrahydro-β-carboline derivatives

   In the field of the stereoselective synthesis of pharmacologically relevant compounds, we
presented recently the application of α-phenylethylamine (α-PEA) in the preparation of
enantiomerically pure lortalamine analogs [17] and (R)-(−)-mianserin [18] — both
compounds being well-known antidepressants. The Bischler–Napieralski cyclization
followed by a diastereoselective reduction of the imine bond were the key steps in
enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine that were carried out
in our laboratory [19].
   Being encouraged by positive results of using α-PEA in the stereoselective formation of
isoquinoline alkaloids, we decided to extend this procedure to tetrahydro-β-carboline
analogs. The synthetic sequence started with the reaction of tryptamine 1 with diethyl
oxalate followed by the treatment with (R)-1-phenylethylamine to afford diamide 5 almost
quantitatively (Scheme 2). After careful optimization we found that the subsequent
                   P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59              49

Table 1
Diastereoselectivity in the reduction with various borohydrides
Entry                                  Reducing reagent                                     9(10)a:9(10)b
1                                      NaBH4                                                62:38 (66:34)
2                                      NaBH(CH3COO)3                                        75:25 (76:24)
3                                      NaBH[(CH3)2CHCOO]3                                   66:34 (64:36)
4                                      NaBH[(CH3)3CCOO]3                                    78:22 (83:17)

Bischler–Napieralski cyclization gave the best results when performed in refluxing
dichloromethane with POCl3.
   The resulting hydrochloride salt of imine 7 was treated with sodium borohydride in EtOH
and a pair of diastereomeric amines 9a and 9b was formed in 62:38 ratio respectively, based
upon the 1H NMR spectrum taken on the crude reaction mixture. The ratio of 9a and 9b was
affected neither by a prolonged contact with a strongly basic solution of the reducing agent
nor by the solvent variations, and observations ruled out the possibility of an asymmetric
transformation. Disappointingly, the diastereoselectivity was not improved significantly
when the hydrides NaBH(AcO)3, NaBH(i-PrCOO)3 and NaBH(t-BuCOO)3 were applied.
   Fortunately, the mixture of isomers could be effectively separated by column chroma-
tography affording pure and stable compounds 9a and 9b. The configuration at C-1 in both
compounds was assigned indirectly based on the comparison of the 1H and 13C NMR
spectroscopic data and the specific rotation values with those recorded for the isoquinoline
series prepared previously by us [19] and for which the stereochemistry was established by X-
ray studies. Seeking further improvement in stereoselectivity, we decided to apply the same
synthetic sequence using (R)-(+)-1-(-1-naphthyl)ethylamine 4 as a chiral auxiliary, another
well-known and effective chiral inductor [17]. Thus, compound 8 was prepared in good yield
from tryptamine 1 and was consecutively subjected to a series of reactions affording
diastereomers 10a and 10b. The results were summarized in Table 1.
   In contrast to previous results in the isoquinoline series [19], the increase of steric
parameters, neither in the reducing agent molecule nor in the imine-containing target derivative
8, gave a significant improvement of the stereochemical outcome. In a search for a feasible
explanation of the above observation we investigated the problem using quantum chemical
methods. We performed a molecular modelling to find the optimal geometry of 7. The
procedure consisted of a consecutive molecular mechanic search through a conformational
space and ab initio calculations used for conformers to optimize their geometries [20].

                   Fig. 1. Lowest energy conformer of imine 7 by Haetree–Fock 6–31G⁎⁎.
50               P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59

            Scheme 3. The construction of chiral nonracemic β-carbolines from L-amino acids.

   The lowest energy conformer of imine 7 is shown in Fig. 1. A strong hydrogen bond
between the amide carbonyl group and the indole NH define the basic shape of the reacting
part of the molecule causing the chiral auxiliary part to adopt a remote position from the
imine moiety. Apparently, such a disfavoring interaction was not present in the isoquinoline
analog of imine 7, allowing us to achieve much better chirality induction [19].

2.2. L-amino acids as chiral inductors in stereoselective synthesis of tetrahydro-β-carboline

   Amino acids are of fundamental importance due to their versatility and their widespread
use in organic synthesis. Many methods utilize amino acids as a substantial fragment of the
final molecule, as the chiral ligands, or as part of the catalyst applied in sub-molar amounts.
The Pictet–Spengler reaction starting from L-tryptophan (the use of its enantiomer is known
but much less common), appears to be the most direct way of forming a chiral β-carboline
skeleton [21,22].
   Among other amino acids, L-proline is the second most frequently used chiral adjuvant
after tryptophan enantiomers. The proline molecule plays more often a chirality-inducing
role than being a chiral building block. Simple amino acids like L-alanine and L-valine
could also provide a high level of the chiral induction while being used as building blocks
                 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59        51

                Fig. 2. 1H NMR of the crude reaction mixture of compounds 19a and 19b.

2.2.1. L-alanine and L-valine as chiral inductors in stereoselective synthesis of β-carboline
    Following the contemporary approach of applying biogenic amino acids into the
synthesis of the alkaloidal system, we would like to present our recent results in constructing
indole derivatives in a stereoselective way using amino acids as chiral inductors. This work
is connected with the construction of psychoactive compounds found in the human body, so-
called mammalian alkaloids, and is of considerable interest to neurochemistry.
    Recently, we proposed a general method for the construction of isoquinoline and β-
carboline systems, which utilized natural amino acids as the source of chirality [23–25].
    As shown in Scheme 3, the first step consisted of the preparation of amides 13, 14, from N-
blocked-N-methyl-L-amino acids in the presence of BOP as a coupling mediator and
subsequent deblocking of the nitrogen atom under hydrogenolytic conditions. This sequence
proved to be extremely efficient, according to the enantiomeric integrity as well as to the
chemical yield. Subsequent BOP-mediated coupling of amides 13 or 14 with phenylpyruvic
acid gave ketoamides 15 or 16 easily isolated from the reaction mixture. Initial attempts to apply
the Pictet–Spengler-type condensation with methanolic hydrogen chloride solution provided
low diastereoselectivity. Thus, we decided to change the solvent into the aprotic one and to
manipulate with temperature conditions. Accordingly, we found that the best diastereoselec-
tivity was obtained when ethyl acetate was applied as a solvent at room temperature.
    The diastereomeric mixture of L-alanine derivatives 19a and 19b had a ratio of 91:9
while those derived from L-valine (20a and 20b) had a ratio of 93:7 (in both cases
diastereoisomer ratio was established on the basis of 1H NMR of the crude reaction mixture
(Fig. 2).

                        Fig. 3. X-ray analysis of the major diastereoisomer 20a.
52              P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59

             Scheme 4. The construction of chiral nonracemic β-carbolines from L-proline.

    The X-ray analysis of the predominant diastereomer 20a revealed the (R)-configuration
at the newly created stereogenic center (Fig. 3).

2.2.2. L-proline as chiral inductor in the stereoselective synthesis of β-carboline
    Due to our previous findings in the field of isoquinoline alkaloids [24], we expected
better stereochemical outcome along with the opposite diastereomeric preference in the
case of the use of L-proline as a chiral inductor. The Pictet–Spengler reaction catalyzed by
hydrogen chloride in ethyl acetate afforded the mixture of diastereomers 25a and 25b in a
ratio of 93:7 (Scheme 4).
    In a search for a compound forming suitable crystals for rentgenographic study, we
prepared the chloroderivative 26a in 41% overall chemical yield and in 98% de. Subsequent
X-ray analysis confirmed the previously postulated (S) configuration at C-1 atom (Fig. 4).

                  Fig. 4. Structure and X-ray analysis of major diastereoizomer 26a.
                    P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59                        53

Scheme 5. The different chirality induction in the Pictet–Spengler reaction from acyclic L-amino acids and L-proline.

   In summary, several tetrahydroisoquinoline and β-carboline derivatives bearing a
quaternary carbon atom were prepared in a stereoselective way under the chiral influence of
L-amino acids. The biomimetic type Pictet–Spengler condensation was accompanied by
1,4-chirality transfer which in several cases proceeded in surprisingly high efficiency
approaching 100% de with good-to-excellent chemical yield.
   The stereochemistry of the final diketopiperazines strongly depended on the structure of
L-amino acids used: acyclic amino acids gave predominantly the (R)-configuration at the
newly created stereogenic center, whereas L-proline afforded the formation of the opposite
configuration (Scheme 5). This interesting feature allows the diastereodivergent creation of
chirality within these reactions. Again, the X-ray analysis proved to be an indispensable
tool for the stereochemical assignments.

3. Enantioselective synthesis of β-carbolines by asymmetric transfer hydrogenation

    Transition-metal catalyzed asymmetric transfer hydrogenation (ATH) has emerged as an
efficient and practical method for the enantioselective reduction of prochiral ketones and
imines to secondary alcohols and amines. In recent years, a considerable number of chiral
metal complexes have been prepared and examined as catalysts in the reduction reactions [26].
    The most successful catalysts so far are based on [RuCl2(arene)]2 combined with chiral,
enantiomerically pure 1,2-amino alcohols or mono-N-sulfonated 1,2-diamines (e.g.,
TsDPEN) [27,28] — Scheme 6.
    The most common hydrogen source for the catalytic transfer hydrogenation of ketones is
2-propanol, although the use of formic acid, in particular a 5:2 formic acid/triethyl amine
azeotropic mixture, is usually the preferred reductant because of the favorable irreversible

3.1. Enantioselective synthesis of 1-alkyl-tetrahydro-β-carbolines

   The tetrahydro-β-carboline skeleton is a common structural feature of numerous
secondary metabolites, including Vinca-, Rauvolfia-, and Harman-type alkaloids. Many of
54              P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59

                          Scheme 6. The most effective ligands used in ATH.

these bases have a tremendous value to pharmacology and were attractive synthetic targets
for both academic and industrial research groups. Recently, it was shown that several
tetrahydro-β-carbolines have the ability to bind with high affinity to serotonin receptors in
the central nervous system. This is probably responsible for their observed neuroactivity
    On the other hand, the derivatives of biologically important amines (e.g., catechola-
mines) and long-chain fatty acids have gained considerable interest in recent years as a new
family of lipids [30]. Bioactive fatty acid amides have been recently suggested to play an
important role in the nervous system [31]. The possibility that neurotransmitters exist in N-
acylated forms was postulated in 1998 by Pokorski and Matysiak [32]. Pokorski and
Czarnocki [33] have recently shown on the basis of radioactive labeling that N-
acyldopamines can easily move through the brain–blood barrier and may therefore play a
role as pro-drugs capable of slow-release of dopamine within the brain.
    During our collaboration with biochemical investigators the need arose for the synthesis
of an analogous series of tetrahydro-β-carbolines, possibly in a stereoselective way. In this
respect, the Bischler–Napieralski-based methodology appeared quite attractive since it
provided the prochiral environment for enantioselective reductions of the imine moiety
    Tryptamine was subjected to reactions with fatty acids to afford appropriate amides in
good yield. All amides were then treated in a Bischler–Napieralski cyclization condition
(POCl3, CH2Cl2 or P2O5, toluene) yielding relatively stable imines 32a–f. They were then
subjected to the asymmetric transfer hydrogenation protocol (Scheme 7) according to the
procedure described by Noyori et al. [35].
    The stereochemistry of the catalyst determined that of the amine formed. As such,
products with (1R) configuration were obtained when (S,S)-28 was used, whereas the (1S)
isomers were obtained under the influence (R,R)-28. The results of reductions were
summarized in Table 2. The amines were then transformed into their derivatives with the
(R)-Mosher acid chloride in order to determine the diastereomeric ratios in 1H NMR
                    P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59                 55

                   Scheme 7. Asymmetric transfer hydrogenation of 3,4-dihydro-β-carbolines.

spectra. The Mosher amide of amine (1R)-33c was also obtained in a form of monocrystal
suitable for X-ray crystallography that served for an unambiguous stereochemistry
assignment [34].

3.2. Enantioselective synthesis of (+)-harmicine and (+)-desbromoarborescidine A

   The basic fraction of the ethanolic extract from the leaves of the Malaysian plant Kopsia
griffithii exhibits a profound anti-leishmania activity [36]. Among several nitrogen bases
found in this extract, (R)-(+)-harmicine (+)-38 is suspected to be responsible for the
pharmacological profile of the plant. An elegant synthesis of the racemic harmicine has
recently been published [36]. Also, (S)-(−)-harmicine (−)-38 was made using a chiral 1-
allyl-1,2,3,4-tetrahydro-β-carboline as the starting material [37].
   The second alkaloid desbromoarborescidine 39, containing indolo [2,3-a] quinolizine
heterocyclic ring system, was isolated from the bark of Dragontomelum mangiferum [37].

Table 2
Asymmetric transfer hydrogenation of imines
Imine        Ru (II) catalyst with     Amine          Yield % e         ee % f   Configuration d   [α]23

32a          (S,S)-27                  (1R)-33a       84                N98      R                 +55.6 a
32a          (R,R)-27                  (1S)-33a       82                N98      S                 − 56.8 a
32a          (1R,2S)-29                (1R)-33a       30                 39      R                 +22.0 a
32a          (1S,2S)-30                (1R)-33a       28                 37      S                 − 20.6 a
32a          (R,R)-31                  (1S)-33a       98                 71      S                 − 40.0 a
32b          (S,S)-27                  (1R)-33b       79                N98      R                 +72.7 b
32b          (R,R)-27                  (1S)-33b       88                N98      S                 − 73.5 b
32c          (S,S)-27                  (1R)-33c       85                N98      R                 +54.7 b
32c          (R,R)-27                  (1S)-33c       81                N98      S                 − 54.0 b
32d          (S,S)-27                  (1R)-33d       79                N98      R                 +33.7 c
32d          (R,R)-27                  (1S)-33d       77                N98      S                 − 34.0 c
32e          (S,S)-27                  (1R)-33e       84                N98      R                 +25.8 c
32e          (R,R)-27                  (1S)-33e       77                N98      S                 − 26.5 c
32f          (S,S)-27                  (1R)-33f       70                N98      R                 +10.2 c
     EtOH, c = 2.
     EtOH c = 1.0.
     CHCl3 c = 1.0.
     By comparison of [α]D sign and X-ray analysis of 33c derivative.
     Isolated yield of pure compounds.
     On the basis of 1H NMR of Mosher's amides.
56                P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59

        Scheme 8. Enantioselective synthesis of (R)-(+)-harmicine and (+)-desbromoarborescidine A.

   The synthetic pathway of these alkaloids used by us contain as a first step the condensation
of γ-butyrolactone or δ-varelolactone with tryptamine to afford hydroxyamides 34 and 35.
Subsequent Bischler–Napieralski cyclization of 34 or 35 in POCl3 gave, after a short work-
up, iminium salts 36 or 37. The asymmetric transfer hydrogenation of 36 and 37 under
standard conditions using (S,S)-28 as the catalyst gave (+)-harmicine (+)-19 in 81% chemical
yield and (+)-desbromoarborescidine A (+)-22 in 84% chemical yield (Scheme 8) [38].
   The maximum value of the enantiomeric excess (determined by the basis of 1H NMR
experiments with phosphinothioic acid for amine 38 and its selenium analog for amine 39)
was only 79 and 83% respectively, despite our optimization efforts. Fortunately, after single
crystallization, the enantiopure alkaloids could be obtained [38].
   Final absolute stereochemistry assignment was done by X-ray crystallography. The
result that indicated the (R) configuration is in accordance with the data collected for
analogous heterocyclic systems (Fig. 5a and b).

     Fig. 5. a. The absolute stereochemistry of (R)-(+)-38. b. The absolute stereochemistry of (R)-(+)-39.
                   P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59                  57

                                 Scheme 9. Total synthesis of (+)-trypargine.

3.3. Enantioselective synthesis of (+)-trypargine

   (−)-Trypargine is an optically active and unique 1-substituted tetrahydro-β-carboline
derivative isolated from the African frog Kassina senegalensis [39] and Eudistoma sp.
Ascidian [40]. Trypargine has been reported to be toxic to mice (LD50 16.9 mg/kg,
intravenous administration) and to block voltage gated sodium currents in squid axon
membrane in a potential-dependent manner [41].
   The group of Ishikawa reported total synthesis of (−)-trypargine started from tryptophan
but this method was multistep and tedious [41,42].
   In our enantioselective synthesis of (+)-trypargine we applied the asymmetric hydrogen
transfer process using chiral complex (S,S)-28 — Scheme 9. The enantiopure amine 42 was
obtained in good yield. Its enantiomeric purity was confirmed by 1H NMR investigations with
(+)-(R)-t-buthylphenylphosphinothioic acid as a chiral solvating agent. The final product was
formed after deprotection with hydrazine followed by guanidylation with N,N'-bis(Boc)-S-
methylisothiourea [43] and subsequent deprotection of the guanidine moiety.


   Financial support from grants PBZ-KBN-126/T09/2004/13 and KBN-1315/T09/2005/
29 is gratefully acknowledged.


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