Water as an efficient medium for the synthesis of tetrahydro-b-carbolines via Pictet–Spengler reactions I Biswajit Saha, Sunil Sharma, Devesh Sawant and Bijoy Kundu * Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India Received 5 October 2006; revised 11 December 2006; accepted 19 December 2006 Available online 23 December 2006 Abstract—A mild and efficient protocol for the Pictet–Spengler reaction in water using an acid catalyst has been described. The con- densation of tryptophan, tryptamine, and N b -benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-b-carbolines in good isolated yields. A salient feature of the water mediated Pictet–Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer. Ó 2007 Elsevier Ltd. All rights reserved. The Pictet–Spengler reaction 1 is a widely used method for C–C bond formation. 2 In general, it is a two-step method and involves acid catalyzed condensation of an aliphatic amine attached to a sufficiently reactive aro- matic nucleus with aldehydes. It is now established as a method of choice for the construction of tetrahydro-b- carboline (THBC) and -isoquinoline frameworks; how- ever, the current literature mostly relates to the synthesis of THBC. The latter is found abundantly in the plant and animal kingdom, and many exhibit potent biologi- cal activities. 3 1,2,3,4-Tetrahydro-b-carboline-3-carbox- ylic acids, generally found in foods, arise from the condensation of L-tryptophan and aldehydes. 4 Research in the last two decades has described the occurrence of tetrahydro-b-carbolines and b-carbolines in biological tissues and fluids, 5 in fruit- and meat-derived products such as juices, jams 6 and sausages. 7 These compounds are readily produced, as a result of a reaction between tryptophan and/or tryptamine and aldehydes, during the production, processing and storage of food prod- ucts. 8 It has been argued that dietary sources provide tetrahydro-b-carbolines that may subsequently accumu- late in biological tissues and fluids. Natural products with a b-carboline nucleus possess widespread and potent biological activities. The reported effects of this class of compounds comprise antineoplastic (tubulin binding), 9,10 anticonvulsive, hypnotic and anxiolytic (benzodiazepine receptor ligands), 11,12 antiviral, 3a antimicrobial 5 as well as topoi- somerase-II inhibition, 13 inhibition of cGMP-dependent processes, 14 and antiplasmodial activity. 15,16 The incre- asing popularity of the Pictet–Spengler reaction has been fueled by the ubiquitous nature of nitrogen- containing compounds in drugs and natural products. 17 In this context, several groups have studied the detailed mechanistic aspects of this reaction and have developed a number of diastereo- and enantioselective methods for the Pictet–Spengler cyclization. 18,19 However, despite the diverse synthetic routes in both protic and aprotic solvents reported so far for this reaction, the strategy has not been investigated in water. The use of water as a medium for this extensively used C–C bond forming reaction would greatly contribute to the development of an environmentally friendly process since it is cheap, readily available, and nontoxic. Indeed, industry prefers to use water as a solvent rather than toxic organic sol- vents and in recent years, water has been demonstrated as an ideal medium for many organic transformations even if starting materials and products appear to be insoluble. 20 Many organic reactions such as Claisen rearrangement, aldol condensation, benzoin condensa- tion, and Diels–Alder cycloaddition exhibit rate enhancement in water. 21 Recently, a comprehensive 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.12.112 Keywords: Pictet–Spengler cyclization; b-Carboline; Stereoselective reaction; Mannich bases. q CDRI Communication No. 7124. * Corresponding author. Tel.: +91 522 2612411–18x4383; fax: +91 522 2623405; e-mail: bijoy_kundu@yahoo.com Tetrahedron Letters 48 (2007) 1379–1383