Pictet-Spengler reaction of tryptamines

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. 

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

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. ... 

In 2008, a similar asymmetric Pictet-Spengler reaction was applied to the total synthesis of (+)-yohimbine (209) (11 steps, 14% overall yield), an important member of the monoterpenoid indole alkaloids as shown in Scheme 17.35 [82]. The synthesis involved two key steps, which are the acyl-Pictet-Spengler reaction of tryptamine derivative 199 with aldehyde 203 (97% ee) and a stereoselective intramolecular Diels-Alder reaction of 206 with the simultaneous generation of four new stereogenic centers [83]. 

Eric N. Jacobsen of Harvard University has devised a family of catalysts for the enantioselective Pictet-Spengler reaction of tryptamine 21. He has now (Organic Lett. 2008, 10, 745) used this approach to prepare the triene 22 in 94% ee. The Diels-Alder cyclization of 22 proceeded with high diastereocontrol to give 23, the immediate precursor of (-)-yohimbine 24. 

In addition to (V-acyUminium ions, the protioiminium ions (X19) could be activi-ated in a similar anion-binding mechanism (Scheme 2.79). The same group then developed chiral thiourea (289a)-catalyzed two-component Pictet-Spengler reaction of tryptamines 21 and aldehydes under mild conditions. Benzoic acid used as the cocatalyst provided the products desired, with excellent results [110a]. Later, Lee... 

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. 

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. 

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 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 Pictet-Spengler reaction is a form of intermolecular Friedd-Crafts alkylation reaction. An example of this is the ionic liquid catalyzed and Levns acid catalyzed one-pot Pictet-Spengler reactions of tryptophan methyl ester or tryptamine vnth aliphatic and aromatic aldehydes [59]. Short reaction times were achieved with the aid of microwave irradiation (Scheme 5.2-17). 

Strictly catalytic enantioselective Pictet-Spengler cyclizations of tryptamine imi-nes have been rather elusive to date. The most successful results were achieved with A-acyliminium intermediates and thiourea catalysts. The reactions proceed through... 

In 2007, the Jacobsen group reported a thiourea-catalyzed Pictet-Spengler reaction in a four-step total synthesis of (+)-harmicine (202), in which the key Pictet-Spengler cyclization of tryptamine derivative indole 199 using thiourea 200 as a catalyst gave the jS-indolyl ethyl hydroxylactams 201 in 97% ee (Scheme 17.34) [81]. The reduction of lactam 201 completed the synthesis of (+)-harmicine (202). 

The same protocol was also applied successfully to the total synthesis of (-i-)-yohimbine (447) (388) (A chiral phosphoric acid-catalyzed approach towards this target was discussed earlier (see Scheme 99)). hi contrast to Hiemstra s approach employing a later stage organocatalytic Pictet-Spengler reaction (385), Jacobsen s synthesis of 447 commenced with the thiourea 473-catalyzed acyl-Pictet-Spengler reaction between tryptamine 468 and the protected hydroxyaldehyde 474. Intermediate 475 was then employed successfully to access (-i-)-yohimbine (447) in a total of 11 steps and in 14% overall yield (Scheme 104) (388). 

When the aldehyde partner of the Pictet-Spengler reaction with tryptamine is the terpene secologanin, strictosidine is formed as an entry toward the vast monoterpene indole alkaloids [32, 33]. Hydrolysis of the glucosidic part releases the strictosidine aglycone bearing an aldehyde, while imin-ium formation and further cyclization and reduction can lead to ajmalicine (from oxocyclization) or yohimbine (from car-bocyclization). These alkaloids are referred to as from the Corynanthe type, with the monoterpene carbon skeleton unmodified. Although it misses one carbon and has a very... 

The final natural product that will be discussed herein to demonstrate the applicability of asymmetric organocatalysis to assemble the monoterpenoid part of indole alkaloids is (H-)-yohimbine (282) (Scheme 6.46). Yohimbine is a well-known monoterpenoid indole alkaloid that has been isolated from several natural sources and for which the first total synthesis dates back to the 1950s [140]. Two organocatalytic total syntheses of this important natural product have been reported recently by the groups of Jacobsen and Hiemstra [141,142], Jacobsen s synthesis of 282 commenced with the thiourea 170a-catalyzed acyl-Pictet-Spengler reaction between tryptamine 283 and the protected hydroxyaldehyde... 

Intermediate 285 was then employed successfully to access (+)-yohimbine (282) (Scheme 6.46A) [141]. Hiemstra s synthesis of this challenging target employed the phosphoric acid 143a-catalyzed Pictet-Spengler reaction of aldehyde 286 and tryptamine derivative 287 to install the tertiary stereogenic center in 84% ee (Scheme 6.46B). Intermediate 288 was then converted to yohimbine (282) by analogy to Jacobsen s report [142]. 

Wanner et al. developed an efficient Pictet-Spengler reaction of secondary amines and aldehydes via the formation of active sulfenyliminium ions in situ from N-sulphenyltryptamine 16, catalyzed by chiral Brpnsted acids 5d (Scheme 2.6b) [9a], The enantioselectivity may be delivered from asymmetric counterion-directed catalysis [9a], Based on a similar strategy, they achieved the total synthesis of (+)-yohimbine via a phosphoric acid-catalyzed Pictet-Spengler reaction, which employed an A -(5-oxy-2,4-pentadienyl)tryptamine derivative and methyl 5-oxo-2(phenylseleno)pentanoate as starting materials [9b],... 

Hermkens, P.H.H., van Maarseveen, J.H., Kruse, C.G., and Scheeren, H.W. (1989) Intramolecular Pictet-Spengler reaction of N-alkoxy tryptamines I. Synthesis of ( )-deamino-debromo-eudistomin L. Tetrahedron Lett., 30, 5009-5012. 

The binolphosphoric acid (257) catalysed Pictet-Spengler reaction of an iV-(5-oxy-2,4-pentadienyl)tryptamine derivative (254) with methyl 5-oxo-2-(phenylseleno)pentanoate (255) led to the formation of tetrahydro-) -carboline (256) in a 92 8 enantiomeric ratio (Scheme 66). ... 

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). 

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