2.1.3
Use of Tryptophan as the Starting Material
The synthetic access to the ergot alkaloids could have been limited by the
selection of the raw materials. Thus, an informal synthesis of lysergine from a
more accessible starting material, tryptophan, which is the biosynthetic precursor, was reported [32]. The methyl ester of lysergic acid has been obtained
from tryptophan in ten steps [33]. The authors have also reported the first total
synthesis of setoclavine from tryptophan [34]. The total syntheses of lysergine,
setoclavine, and lysergic acid have been described [11]. Tryptophan, protected
as its dihydro, dibenzoyl derivative is dehydrated to the corresponding
azlactone, which undergoes stereoselective intramolecular Friedel-Crafts
acylation to give a tricyclic ketone intermediate. A spiromethylene lactone is
formed by Reformatsky reaction that represents the branching point of the
syntheses to different ergot alkaloids. The synthesis of optically active ergot
alkaloids from l-tryptophan was possible because of the high selectivity of the
reactions.
Enantiomerically pure 4-alkyl substituted derivatives of tryptophan required
for the asymmetric syntheses of ergot alkaloids has been obtained [35]. The
author used the method [36] to produce 4-alkyl substituted indoles and combined this organometallic reaction with an enantioselective enzymatic
methoxyprop-2¢-en-1¢-yl)-4-(1¢-hydroxy-2¢-trimethylsilymethyl-prop-2¢-en-1¢yl)-indoles from 4-carbomethoxyindole has been described [37]. The use of
these benzylic alcohols for intramolecular cation-olefine cycloadditions
yielding either a tetracyclic or a tricyclic product was also demonstrated.
A methodology [38] was presented to obtain 4-substituted intermediates for
the synthesis of claviciptic acid via an N-protected indole-Cr(CO) 3 complex.
The addition of a nucleophile to this complex leads to a regioselective introduction of a substituent at C-4 or C-7 on the indole ring. Racemic lysergine and
lysergic acid diethylamide (LSD) were synthesized by a cobalt catalyzed cocyclization of 4-ethynyl-3-indoleacetonitriles with alkynes [39]. The total synthesis
of optically active claviciptic acids was reported [40], which involves (S)-4bromotryptophan as a key intermediate and occurs via 4-(1¢,1¢-dimethyl-1¢hydroxy-2-propenyl-3-yl)-tryptophan, the synthetic equivalent of the naturally
occurring 4-(g,g-dimethylallyl)tryptophan (DMAT), the first pathway-specific
intermediate in ergot biosynthesis.
2.1.4
1,3,4,5-Tetrahydrobenzo[cd]indoles
The simplified analogs of ergot alkaloids such as 1,3,4,5-tetrahydrobenzo[cd]indoles containing an amino substituent at position 4 possess interesting biological properties like affinity for dopamine or serotonin receptors.
Bicyclic and tricyclic ergoline partial structures were synthesized [41] and it
was proved that the rigid pyrroethylamine moiety of the ergolines is the
portion of the molecule responsible for dopamine agonist activity.
Progress and Prospects of Ergot Alkaloid Research
7
Use of Tryptophan as the Starting Material
The synthetic access to the ergot alkaloids could have been limited by the
selection of the raw materials. Thus, an informal synthesis of lysergine from a
more accessible starting material, tryptophan, which is the biosynthetic precursor, was reported [32]. The methyl ester of lysergic acid has been obtained
from tryptophan in ten steps [33]. The authors have also reported the first total
synthesis of setoclavine from tryptophan [34]. The total syntheses of lysergine,
setoclavine, and lysergic acid have been described [11]. Tryptophan, protected
as its dihydro, dibenzoyl derivative is dehydrated to the corresponding
azlactone, which undergoes stereoselective intramolecular Friedel-Crafts
acylation to give a tricyclic ketone intermediate. A spiromethylene lactone is
formed by Reformatsky reaction that represents the branching point of the
syntheses to different ergot alkaloids. The synthesis of optically active ergot
alkaloids from l-tryptophan was possible because of the high selectivity of the
reactions.
Enantiomerically pure 4-alkyl substituted derivatives of tryptophan required
for the asymmetric syntheses of ergot alkaloids has been obtained [35]. The
author used the method [36] to produce 4-alkyl substituted indoles and combined this organometallic reaction with an enantioselective enzymatic
methoxyprop-2¢-en-1¢-yl)-4-(1¢-hydroxy-2¢-trimethylsilymethyl-prop-2¢-en-1¢yl)-indoles from 4-carbomethoxyindole has been described [37]. The use of
these benzylic alcohols for intramolecular cation-olefine cycloadditions
yielding either a tetracyclic or a tricyclic product was also demonstrated.
A methodology [38] was presented to obtain 4-substituted intermediates for
the synthesis of claviciptic acid via an N-protected indole-Cr(CO) 3 complex.
The addition of a nucleophile to this complex leads to a regioselective introduction of a substituent at C-4 or C-7 on the indole ring. Racemic lysergine and
lysergic acid diethylamide (LSD) were synthesized by a cobalt catalyzed cocyclization of 4-ethynyl-3-indoleacetonitriles with alkynes [39]. The total synthesis
of optically active claviciptic acids was reported [40], which involves (S)-4bromotryptophan as a key intermediate and occurs via 4-(1¢,1¢-dimethyl-1¢hydroxy-2-propenyl-3-yl)-tryptophan, the synthetic equivalent of the naturally
occurring 4-(g,g-dimethylallyl)tryptophan (DMAT), the first pathway-specific
intermediate in ergot biosynthesis.
2.1.4
1,3,4,5-Tetrahydrobenzo[cd]indoles
The simplified analogs of ergot alkaloids such as 1,3,4,5-tetrahydrobenzo[cd]indoles containing an amino substituent at position 4 possess interesting biological properties like affinity for dopamine or serotonin receptors.
Bicyclic and tricyclic ergoline partial structures were synthesized [41] and it
was proved that the rigid pyrroethylamine moiety of the ergolines is the
portion of the molecule responsible for dopamine agonist activity.
Progress and Prospects of Ergot Alkaloid Research
7