Rebek synthesis

J. Rebek, Jr., (1987) first developed a new synthesis of Kemp s acid and then extensively explored its application in model studies. The synthesis involves the straightforward hydrogenation (A. Steitz, 1968), esterification and methylation of inexpensive 1,3,5-benzenetricar-boxylic acid (trimesic acid 30/100 g). The methylation of the trimethyl ester with dimethyl sulfate, mediated by lithium diisopropylamide (V. J. Shiner, 1981), produced mainly the desired aff-cis-1,3,5-trimethyl isomer, which was saponified to give Kemp s acid. 

Rebek, J., Jr., Tai, D.R, Shue, Y.K. (1984) Synthesis of Ergot Alkaloids from Tryptophan. Journal of the American Chemical Society, 106, 1813-1819. 

R Rebek, D Feitler. Mechanism of the carbodiimide reaction, n. Peptide synthesis on the solid support. J Am Chem Soc 96, 1606, 1974. 

DS Kemp, S-W Wang, J Rebek, RC Mollan, C Banquer, G Subramanyam. Peptide synthesis with benzisoxazolium salts-II. Activation chemistry of 2-ethyl-7-hydroxy-benzisoxazolium fluoroborate coupling chemistry of 3-acyloxy-2-hydroxy-V-ethyl-benzamides. Tetrahedron 30, 3955, 1974. 

Carell, T., Wintner, E.A., Sutherland, A.J., Rebek, J. Jr, Dunayevskiy, Y.M., and VouROS, P. New promise in combinatorial chemistry synthesis, characterization, and screening of small-molecule libraries in solution. Chem. Biol. 1995, 2, 171-183. 

For quite some time most synthetic efforts to prepare cavitand-type hosts led to compounds that were only soluble in low polarity solvents. Because of their potential biological relevance, interest on the synthesis of water-soluble cavitands developed quickly, but only recently a number of accessible hosts has become available. We will describe here recent work done by us on Gibb s octaacid, deep-cavity cavitand58 and Rebek s water-soluble cavitand.59 The structures of these compounds are shown in Fig. 3.10. 

As one example, the observation of hydrogen bonding [7] in natural systems such as peptide helices and DNA base pairs led to a theoretical understanding of this phenomenon. This understanding has permitted the use of hydrogen bonding in synthesis, leading to the preparation of such diverse structures as Rebek s capsules [8], Lehn s supramolecular polymers [9], and Whitesides rosettes [10]. 

Wintner EA, Rebek J Jr, Combinatorial libraries in solution polyfunctionalized core molecules, in Combinatorial Chemistry Synthesis and Application (Eds. S.R. Wilson, A.W. Czarnik), pp. 95-118, 1997, John Wiley Sons, Inc., New York. 

Shipps GW Jr, Pryor KE, Xian J, Skyler DA, Davidson EH, Rebek J Jr, Synthesis and screening of small molecule libraries active in binding to DNA, Proc. Natl. Acad. Sci. USA, 94 11833-11838, 1997. 

Carell, T., Wintner, E. A., Bashir-Hashemi, A., and Rebek, J. J. (1994). A novel procedure for the synthesis of librais containing small organic molecules. Angew. Chem. lnt. Ed. Eng. 33, 2059-2061. 

The encapsulation of chemical space on the scale of simple molecules has been a topic of considerable interest for more than two decades. For the formation of capsules two independent strategies have emerged covalent synthesis and self-assembly. The groups of Cram [8], Collet [9], and Sherman [10] have synthesized capsules capable of encapsulating up to three small molecular guests [11]. Rebek and co-workers pioneered the use of self-assembly to produce a variety of assemblies held together by hydrogen bonds [12-15], Multi-component systems have... 

Figure 5 Examples of scaffold decoration for the solution-phase synthesis of pooled combinatorial libraries from Rebek and Isis. In both cases, biologically active compounds were identified...

More unique are the xanthene and cubane cores (Figure 5) chosen by Rebek for the solution-phase synthesis of highly pooled combinatorial libraries in a single step. By iterative deconvolution, a thrombin inhibitor was identified from this complex collection. Similarly, workers at Isis reported the functionalization of a novel polyazacyclophane core, which led to the discovery of antibacterial leads. Clearly, in both these cases, the hits are structurally unrelated to common drug-discovery scaffolds. 

Renslo AR, Tucci EC, Rudkevich DM, Rebek J Jr. Synthesis and assembly of self-complementary cavitands. J. Amer. Chem. Soc. 2000 122 4573-4582. 

In contrast with other electrophilic additions, the peracid epoxidation is syn-stereospecific. With sterically strongly hindered alkenes the reaction takes place on the less sterically hindered side. In other cases, the stereochemistry of the reaction is affected by polar effects or the geometry of the transition state. Important conclusions regarding the mechanism of the reaction can be drawn from the steric pathways in the synthesis of the oxiranes. This has been dealt with comprehensively by Berti, who reviewed the topic up to 1971, with special emphasis on the peracid oxidation. A noteworthy account of the topic of peracid epoxidation is given in a review by Rebek. ... 

Rebek and coworkers have also recently published a procedure for the synthesis of libraries of small organic molecules, and have designed a screening method for the isolation of active compounds from such libraries. A trypsin inhibitor with a X of 9 pM was found from the screening of a library [97]... 

Jacoby (187) and the Hamilton group (188-191) suggested that bis- or tris-aromatic residues could serve as scaffolds for helical mimetics. Che et al. have examined a variety of aromatic-based scaffolds as potential helix mimetics (192). Rebek and coworkers have suggested a central pyridazine ring (193) as well as a heterocyclic piperazine-based scaffold (194). Ahn and Han developed a facile synthesis of benzamides as potential helix mimetics (195). 

Restorp, P., and Rebek, J. (2008) Synthesis of a-helix mimetics with four side-chains. Bioorg. Med. Chem. Lett. 18, 5905-5911. 

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