Solid-phase synthesis reductive cyclization

The classic Reissert indole synthesis, involving the reductive cyclization of o-ni-trophenylpyruvic acid, has been used for synthesis of 2-ethoxycarbonyl-4-alkoxymethylindo-les.92 The modified Reissert reaction, involving the reductive cyclization of an o-nitrophenyl acetoaldehyde, has been adapted to solid-phase synthesis.93... 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

An impressive solid-phase synthesis of bicyclic guanidines has been communicated, and the approach is outlined in Scheme 20 45,46 iV-acylated dipeptides 18 were reduced to triamines by exhaustive borane reduction, then reacted with thiocarbonyldiimidazole. An intermediate thiocarbonyl was cyclized to the guanidine product in this process. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Kamal and co-workers have reported a new approach for the solid-phase synthesis of the pyrrolo[2,l-c][l,4]benzodiazepines 102 using a thiol Wang resin. The interesting feature of this approach was the reductive cleavage and cyclization achieved in the last step on reaction with DIBAL-H yields of the products 102 ranged from 57% (R = 7-OMe, 8-OBn) to 65% (R = H) <04TL7667>. 

The solid-phase version of the Madeiung indole synthesis was developed by D.A. Wacker et al. for the preparation of 2,3-disubstituted indoles.The ort/ o-substituted aniline substrate was first attached to the Bal resin using reductive amination. The resin-bound aniline was then acylated and the cyclization was brought about with a variety of bases to afford high yields of the disubstituted indoles. The products were quantitatively removed from the resin with TFAiEtsSiH (95 5). 

Scheme 15 Solid Phase Reductive Cyclization Indole Synthesis and Myers 3-Alkylidene-3H-indole 1-Oxide Synthesis...

This compilation embraces a wide variety of subjects, such as solid-phase and microwave stereoselective synthesis asymmetric phase-transfer asymmetric catalysis and application of chiral auxiliaries and microreactor technology stereoselective reduction and oxidation methods stereoselective additions cyclizations metatheses and different types of rearrangements asymmetric transition-metal-catalyzed, organocatalyzed, and biocatalytic reactions methods for the formation of carbon-heteroatom and heteroatom-heteroatom bonds like asymmetric hydroamina-tion and reductive amination, carboamination and alkylative cyclization, cycloadditions with carbon-heteroatom bond formation, and stereoselective halogenations and methods for the formation of carbon-sulfur and carbon-phosphorus bonds, asymmetric sulfoxidation, and so on. 

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