TXr u

Scheme 9.10. Solution-phase Friedel-Crafts alkylation

The Pictet-Spengler reaction is a very well-established method for the synthesis of tetrahydroisoquinolines and tetrahydro-b-carbolines both in solution and on solid support [19]. The molecules are easily prepared by intramolecular reaction of an iminium ion with an arene usually under acidic conditions. The imines are typically formed by condensing amines with (aromatic) aldehydes (see Scheme 9.11), cyclohexanones, or aryl methyl ketones [20].

Scheme 9.11. Solution-phase Pictet-Spengler reaction.

Using tryptophan as the starting material, the synthesis of tricyclic carbolines has been reported in numerous examples in the literature. Whereas reactions with aldehydes are normally complete within hours, less reactive ketones require up to several days to reach complete conversion (see Scheme 9.12) [21].

O 4 eq. ketone DCM/TFA 99:1 20' C, several days

Scheme 9.12. Solid-phase Pictet-Spengler reaction.

A Pictet-Spengler reaction has been used as the key step during the synthesis of indolyl diketopiperazine-based libraries of Fumitremorgin C analogs (see Scheme 9.13). This natural product, isolated by fermentation of the fungi Aspergillus fumi-gatus, appears to be of interest in the area of central nervous system (CNS) and cancer research and has therefore resulted in the preparation of some solid-phase combinatorial libraries [22].

1. amino acid

2. cyclo-release

1. amino acid

2. cyclo-release



Fumitremorgin C

Scheme 9.13. Solid-phase synthesis of Fumitremorgin C analogs.

Fumitremorgin C

Scheme 9.13. Solid-phase synthesis of Fumitremorgin C analogs.

The Pictet-Spengler reaction is not limited to the synthesis of six-member ring systems. Also the class of seven-member rings present in the pharmaceuti-cally important diazepine class of compounds is easily accessed by condensing aldehydes with suitably substituted aminomethylfurans (see Scheme 9.14) [23].

1. EtOH

2. HBr/HOAc

2 Br

2 Br

Scheme 9.14. Solution-phase Pictet-Spengler reaction yielding seven-member rings.

In the closely related Bischler-Napieralski reaction dihydroisoquinolines are formed. The intramolecular condensation of an acylated amine with an arene is mediated by the action of a strong dehydrating agent, usually phosphoryl chloride. It leads to dihydroisoquinolines, which can be transformed either into isoquino-lines by oxidation or into tetrahydroisoquinolines by reduction (see Scheme 9.15). The harsh reaction conditions are not generally amenable to solid-phase reactions since most linkers are not stable to a large excess of phosphoryl chloride in toluene at 80 °C [24].

Merrifield resin

Scheme 9.15. Solid-phase Bischler-Napieralski reaction.

The reaction has also been applied to solution-phase synthesis, but has found little application in library production to date [25].

In a Reissert-type reaction involving pyrrole derivatives, C-C bond formation is achieved by aromatic SE on solid support using N-oxides (see Scheme 9.16). The reaction also works with indoles and with enamines [26].

Merrifield resin

Scheme 9.15. Solid-phase Bischler-Napieralski reaction.

2. NaBH4, DCM/MeOH

2. NaBH4, DCM/MeOH

Scheme 9.16. Solid-phase Reissert reaction.


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