Solid-Phase Pictet-Spengler Reactions

TetrahydroisoquinoHnes and tetrahydro-(3-carbohnes, which represent exceedingly medicinally relevant building blocks, are mostly prepared according to the well-known Pictet-Spengler reaction [398]. A number of solid-phase applications of this reaction have been published in the recent literature, and thus it deserves a supplementary paragraph to those on the more general N-acyhminium and iminium ion chemistry (see above). 

in looking for derivatives of Fumitremorgin C (FTC), a potential anticancer drug, investigations have been undertaken in order to establish the importance of the alkenyl side chain in position C-3 [399]. 

Due to the fact that a,[3-unsaturated aldehydes are not compatible with the classical Pictet-Spengler reaction conditions, the generation of a highly reactive N-acyliminium ion, derived from an a,[3-unsaturated imine via its acylation, could represent a viable strategy to overcome the aforementioned issue. 

Ganesan and Bonnet [400] have reported a similar N-acyliminium ion-mediated Pictet-Spengler reaction. Again, r-tryptophan linked to a polystyrene-Wang resin through the carboxylic group (557) was first reacted with a number of aldehydes in 

Interestingly, starting from a ds/trans mixture of the initial carboline, a trans/ trans mixture of the final carboHnehydantoin was obtained, with an opposite value for the optical rotation. In order to rationahze this observation, the authors invoked epimerization at the stereocenter a- to the carbonyl in the ds isomer, affording the thermodynamically more stable trans product 

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For recent examples involving solid-phase Pictet-Spengler reactions, see ref [407]. 

Scheme 26 Hydroformylation/Pictet-Spengler reaction on solid phase - Access to ft-carbolins...

A solid-phase-supported version of the Pictet-Spengler reaction has been demonstrated for the synthesis of mono- and disubstituted tetrahydro-P-carbolines [40,41], Disubstituted quinolines have been prepared via solid-phase synthesis utilizing three classes of building blocks aiyl methyl ketones, (Q-functionalized acids, and primary amines [42],... 

Nielsen, T. E., Diness, F., Meldal, M. The Pictet-Spengler reaction in solid-phase combinatorial chemistry. Current Opinion in Drug Discovery Development 2003, 6, 801-814. 

Nielsen, T. E., Meldal, M. Solid-Phase Intramolecular N-Acyliminium Pictet-Spengler Reactions as Crossroads to Scaffold Diversity. J. Org. Chem. 2004, 69, 3765-3773. 

Many of today s drugs are heterocyclic compounds. Heterocyclic compound libraries are therefore the focus of many pharmaceutical companies drug discovery processes. Benzodiazepines were the first heterocyclic compounds prepared by solid-phase chemistry [2,3,6]. Since then, solid-phase routes to many heterocyclic structures have been published using well-established solution-phase protocols e.g. Pictet-Spengler reaction in the preparation of tetrahydro-P-carbolines. 

Saframycin belongs to a family of complex polycyclic alkaloids endowed with spectacular antiproliferative activity. The successful demonstration that analogues of the natural product are clinically effective for the treatment of solid tumors has stimulated intense efforts towards the total synthesis and medicinal chemistry of these alkaloids. Myers and Lanman adapted their solution phase synthesis of saframycin to a ten-step solid phase synthesis, leading to the preparation of 16 analogues [40]. The key steps are two Pictet-Spengler reactions, which are used... 

Kane, T.R. et al., Solid-phase synthesis of 1,2,3,4-tetrahydroisoquinohne derivatives employing sup-port-bound tyrosine esters in the Pictet-Spengler reaction, J. Comb. Chem., 6, 564, 2004. 

FIGURE 2.7 The Pictet-Spengler reaction on solid-phase provides access to libraries of compounds with the tetrahydro-P-carboline skeleton. This has been a fruitful area for lead discovery, as shown by the examples... 

Kundu B, Sawant D, Chhabra R (2005) A modified strategy for Pictet-Spengler reaction leading to the synthesis of imidazoquinoxalines on solid phase. J Comb Chem 7(2) 317-321. doi 10. 1021/cc049851j... 

A recent example of the application of solid phase Suzuki reactions to the synthesis of pharmaceutically important biaryl compounds was shown by Nielsen et aL [115]. A range of aryl-substituted pyrroloisoquinolines were synthesized from biarylalanine precursors in high purity (Scheme 39). This involved a Suzuki coupling of sohd-supported iodophenylalanine derivatives containing a masked aldehyde to various boronic acids, followed by hberation of the aldehyde, TFA-mediated intramolecular Pictet-Spengler reaction, and cleavage. 

Nielsen TE, Meldal M. Solid-phase intramolecular iV-acyli-minium Pictet-Spengler reactions as crossroads to scaffold diversity. J. Org. Chem. 2004 69 3765-3773. 

Wang, H. and Ganesan, A., The V-acyhminium Pictet-Spengler condensation as a multicomponent combinatorial reaction on solid phase and its application to the synthesis of demethoxyfumitremorgin C analogs, Org. Lett., 1, 1647, 1999. 

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