Tryptamine Pictet-Spengler reaction

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

In 2007, Hiemstra et al. established a catalytic asymmetric Pictet-Spengler reaction that proceeds via (V-sulfenyliminium ions (Scheme 15) [27], Treatment of iV-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f (5 mol%, R = 3,5-(CF3)2-CgH3) afforded tetrahydro-P-carbohnes. After completion of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot... 

Based on the previous findings by Koomen [21], the Hiemstra group subsequently reported the Pictet-Spengler reaction of N-tritylsulfenyl tryptamines and various aliphatic and aromatic aldehydes by 11 (Scheme 5.11) [22]. Notably, the authors found that stabilization of the N-sulfenyliminium ion by the sulfenyl substituent facilitated preferential cyclization over enamine formation. 

The Pictet-Spengler reaction of tryptamines or tryptophans with aldehydes (23) often proceeds under so-called physiological conditions (pH 6-7), and it has proved to be the most efficient route to TBCs. 

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

Scheme 3.23 Enantioselective Pictet Spengler reaction of tryptamine derivatives with aldehydes.

Since the previous racemic and chiral syntheses of deoxytubulosine (31) were reviewed (1), Brown and Jones (68) have reported the synthesis of ( )-deoxytubulosine [( )-31] and its I -epimer (129) by Pictet-Spengler reaction of ( )-protoemetine [( )-6] (Section III,A) with tryptamine. For a study on the biosynthesis of tubulosine (26), Bhakuni etal. (114) prepared didemethyl-deoxytubulosine (131) from deoxytubulosine (31) by demethyl-ation with HBr in AcOH. Both 131 and 31 were then tritiated in an acid-catalyzed exchange reaction to furnish [aryl- H]didemethyl-deoxytubulo-sine and [aryl- H]deoxytubulosine, respectively. 

Pictet-Spengler reaction of 2,5-anhydro-D-mannose (55) and tryptamine hydrochloride (56) at ambient temperature affected the tetrahydropyri-dine ring formation of the (li ) and (15)-l-(a-D-arabinofuranosyl)-l,2,3,4-tetrahydro-/3-carboline 57 [830C2721, 83JCS(CC)601] (Scheme 18). 

The Pictet-Spengler reaction is important for the preparation of tetrahydro-(3-carbolines and tetrahydroquinolines. List and co-workers applied phosphoric acid catalysis to the Pictet-Spengler reaction starting from geminally disubstituted tryptamines (Equation 10.41) [85, 86], The presence of the bis(ethoxycarbonyl) group facilitated the cyclization reactions by virtue of the Thorpe-Ingold effect. Both aliphatic and aromatic aldehydes turned out to be good substrates. 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

Pictet-Spengler reaction for preparation of tetrahydro-(3-carbolines is rendered enan-tioselective by one of the BINOL-phosphate, as previously reported. A modified version describes the effectiveness of IH with tryptamine protected in the form of a triphenylmethanesulfenamide. ... 

Friedel-Crafts reaction. Iodine is a mild catalyst for the Pictet-Spengler reaction of tryptamine with ketones to generate tetrahydro-P-carbolines at room temperature. ... 

The acid-catalyzed Pictet-Spengler reaction between tryptamine derivatives and aldehydes is a well-established method for preparing tetrahydro-p-carboline (THpC) derivatives." Our first trials were aimed at using the bisnlfite adduct as the carbonyl sonrce in order to minimize the number of process steps. The reaction was performed by reacting the 5-methyltryptamine hydrochloride with an excess (1.3 eqniv) of the sodium bisulfite adduct in EtOH at reflnx, in the presence of one extra eqnivalent of HCl. The rac-THpC was simply isolated as a hydrochloride salt by filtration of the reaction mixture (Scheme 6.8). 

The formation of impnrity b is clearly linked to the presence of an excess of HCl, which presumably blocks the formation of the imine intermediate for the Pictet-Spengler reaction by shifting the eqnilibrium toward the protonated form of the tryptamine. Under these circumstances, reaction at the other nucleophilic site (i.e., the position 2 of the indole nucleus) occurs to ultimately yield b. 

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