1.4- Benzodiazepine-2-ones libraries

Ellman, J. A. Solid-Phase Synthesis of l,4-Benzodiazepine-2, 5-Ones Library Preparation and Demonstration of Synthesis Generality. J. Org. Chem. 1997, 62, 1240-1256. 

Early reported applications of this technique were the preparation of a 24-member peptide library [83], of a 125-member tripeptide-substituted cinnamic acid library tested for inhibition of tyrosine phosphatase PTP1B [83], of a 64-member peptide-like library [83] and of libraries based on a natural product, epothilone, using also new polystyrene grafted solid supports [84], Other applications, ranging from l,5-benzodiazepin-2-one library synthesis [85] to chalcone library synthesis [86], were also recently reported. Commercialization of the basic components for this technique [87] (reaction supports and vessels, tags, software, sorters, reaction stations, and so on) will ensure its quick and effective use in combinatorial chemistry and also the implementation of new technical features and possibilities for more complex and demanding applications in future. 

Herpin TF, Van Kirk KG, Salvino JM, Yu ST, Labaudiniere RF, Synthesis of a 10,000 member l,5-benzodiazepine-2-one library by the directed sorting method, J. Comb. Chem., 2 513-521, 2000. 

Novel Application of the Leuckart-Wallach Reaction for the Synthesis of a Tetrahydro-1,4-benzodiazepin-5-one Library (Type V)... 

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

Fig. 12. Sequence spaces for the sequence/structure shown in the right column, (a) Sequence for ssRNA of length 3 with monomers G and A only, (b) Part ofthe sequence space for the 1,4-benzodiazepin-2-one derivative library constructed in Ref. 156. For clarity, not all neighbor relations are shown with lines in this figure. Points which differ at one site are called 1-mutant neighbors. For example, the points marked o are all 1-mutant neighbors of the point marked .

I. Im, T. R. Webb, Y. D. Gong, J.-I. Kim, J.-C. Kim, Solid phase synthesis of tetrahydro-l,4-benzodiazepine-2-one derivatives as a beta-turn peptidomimic library,/. Comb. Chem. 2004, 6, 207-213. 

While initially the main synthetic interest resided in l,4-benzodiazepin-2-ones [1, 11-13] and l,4-benzodiazepin-2,4-diones [14—18] (and subsequently -2,3-diones ]19] and -2,5-diones ]20]), another l,5-benzodiazepin-2-one system was explored with the strategy outlined in Scheme 3 ]21]. Of particular interest is the role 4-fluoro-3-nitrobenzoic acid, a common fundamental building block central to aU of the the desired structures. Accessing diversity through one or more simple reactants common to aU members of a library has favorable practical consequences on the production phase of a combinatorial Hbrary. 

The 3-amino-l,5-benzodiazepin-2-one scaffold was attached via its benzamide nitrogen to a series of Rl-functionalized bromoacetamide resins. The sorted and recombined microreactors were further subjected to an alkylation and an acylation step. A 10,000-member library was produced. 

Scheme 1. Solid-phase synthesis of oligocarbamates and benzodiazepines starting with a resin-bound amino acid. The Fmoc-protected 4-nitrophenyl carbonate monomers derived from amino acids or amino alcohols were used in a normal solid-phase synthesis of an oligocarbamate, whereas the corresponding Nvoc-protected monomers were used in the generation of a library of 256 oligocarbamates of which one representative (Ac-Lys -Phe -Leu -Gly-OH) is shown. An array of 40 diazepines was synthesized by reacting the resin-bound amino acid with eight different 2-aminobenzophenone imines followed by cyclization. Ind = indolyl, Chx = cyclohexyl.

X-ray structures of HIV RT, so structure-based design did not seem to play a role in their discovery. The discovery of NNRTIs appears to have started with selective screening of the compound library in cell culture at Janssen Phar-maceutica in 1987, which led to the discovery of the first generation NNRTIs, the TIBO (tetrahydro-imidazo[4,5,l-jk][l,4]-benzodiazepin-2(lH)one) compounds. Two of these first generation NNRTIs, tivirapine, a TIBO deriva-... 

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