Pictet Spengler reaction aldehydes, tryptamine derivatives

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

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). 

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]. 

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. ... 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

Tryptophan-derived 1,2,3,4-tetrahydro-P-carboline and 3-carboline alkaloids result in foods through a Pictet-Spengler condensation (a special case of the Mannich reaction) of indoleamines, such as tryptophan and tryptamine, with aldehydes. The mechanism of the Pictet-Spengler reaction leading to... 

A somewhat related two-step method for the synthesis of areno[a]quinolizines involves the preparation of a cyclic hemiacetal from a p-dicarbonyl compound and an a,p-unsaturated aldehyde. The subsequent reaction of this hemiacetal with tryptamine in the presence of a Brpnsted acid affords the target product, probably through a Pictet-Spengler reaction, and the use of chiral Brpnsted acids has been investigated and found to lead to good enantioselections in some cases [74]. The reaction between P-amidoesters derived from tryptamine and a,p-unsaturated aldehydes affords lactams derived from the indolo[2,3-fl]quinolizin-4-one system [75]. 

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]. 

After Jacobsen reported the first example of a Pictet-Spengler reaction with the promotion of chiral thiourea catalysts (see Section 2.3.2.1), Seayad et al. applied chiral phosphoric acids to a catalytic Pictet-Spengler reaction involving geminally disub-stituted tryptamine derivatives 14 and aldehydes 3 in 2005 (Scheme 2.6a). Occupation... 

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],... 

In the first catalytic, enantioselective version of the Pictet-Spengler reaction, Jacobsen utilized the chiral thiourea derivative 171 as catalyst (Equation 12) [132], Such thioureas have emerged as a versatile class of chiral promoters and have proven to be of general utility in a number of enantioselective transformations [40], A particularly interesting feature of this study is the fact that in situ acetylation of the intermediary aldimine leads to an N-acyl iminium ion as the reactive species that subsequently undergoes cyclization. A priori, the more basic imine resulting from condensation of aldehyde 170 with tryptamine 169 would have been expected to be more likely than the N-acyl iminium ion to interact with catalyst 171. Nonetheless, the latter species was responsive to the H-donor catalyst, leading to N-acetylated tetrahydro-/ -carboline 172 in 81 % yield and 93 % ee [132],... 

The second line of circumstantial evidence quoted in support of this hypothesis is the ready formation of l,2,3,4-tetrahydro-/3-carboline derivatives under pseudo-physiological conditions of temperature, pH, and concentration. Tryptamine and aldehydes, trypt-amine and a-keto acids, and tryptophan and aldehydes condense at room temperature in a Pictet-Spengler type intramolecular Mannich reaction in the pH range 5.2-8.0 (cf. Section III, A, 1, a). It was argued that experiments of this type serve as models for biochemical reactions and may be used in evidence. 

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