An efficient method has been developed for the solution and liquid phase syntheses of a biopolymer mimetic consisting of “α-aza-amino acids” linked in a repetitive manner to form what we term an azatide oligomer. To construct this biopolymer mimetic, three stages of research were pursued as follows:  (1) development of general synthetic procedures that allowed the synthesis of a wide variety of Boc-protected aza-amino acid monomers, (2) optimization of solution phase procedures for the coupling of aza-amino acids in a repetitive manner, and (3) design and synthesis of a linker that would support azatide synthesis using a liquid phase synthetic format. The successful completion of these three phases of research demonstrates that oligoazatides can now be rapidly assembled on a homogeneous polymeric support. The long term prospectus of this new biopolymer is the exploration of peptide structure as well as a potential source of new peptidomimetic libraries.

A concept termed liquid-phase combinatorial synthesis (LPCS) is described. The central feature of this methodology is that it combines the advantages that classic organic synthesis in solution offers with those that solid-phase synthesis can provide, through the application of a linear homogeneous polymer.

Insoluble polymer-reagents and catalysts have achieved wide recognition and acclaim. 1 However, as successful as insoluble reagent and catalyst supports have been there are limitations associated with such species. 2 An alternative to insoluble polymer-bound reagents or catalysts is soluble polymer bound ligands, reagents, or catalyst supports, 3 the difference being that reactions are carried out homogeneously and separation of the homopolymer from reaction products can be achieved by taking advantage of the properties of the polymer chain. We have been interested in applying soluble polymers in the arena of combinatorial synthesis. As such we recently introduced what we term "liquid phase combinatorial synthesis" or LPCS. 4 The cornerstone of LPCS is a linear homopolymer [polyethylene glycol monomethyl ether (MeO-PEG)] which serves a dual role as both a terminal protecting group and a solublizing agent for any compound(s) synthesized on the support. Using this approach, we have synthesized combinatorial peptide, small molecule, 4 and peptidomimetic libraries. 5 The ligand-accelerated catalytic (LAC) asymmetric dihydroxylation (AD) of olefins based on cinchona alkaloid ligands was described by Sharpless in 1988; 6 since this seminal report, the AD reaction has been further developed to include application to a wider range of olefins, improved enantiomeric efficiency, and overall simplicity of operation. 7 From the standpoint of cost, ligand and/or metal recovery and recycling are of prime interest because the cinchona alkaloid ligand and osmium tetroxide are the most expensive components of the procedure. In this regard, several groups have reported the catalytic asymmetric dihydoxylation of olefins using insoluble polymer bound cinchona alkaloid-ligands. 8 While it was hoped that this methodology would provide convenience and improve the economics of the process, it was deemed less than satisfactory because of increased reaction times, highly variable yields, and lower enantioselectivity 9 than had previously been obtained with its solution phase counterpart.The problems associated with LAC in which the ligand is localized by attachment to an insoluble polymer can be understood by considering the basic tenet upon which this concept is based. 10 By definition, the LAC phenomenon requires that the addition of a ligand increases the reaction rate of an already existing catalytic transformation. Both the ligandaccelerated and the nonaccelerated reactions operate in solution simultaneously and in competition with each other. Obviously, if the ligand does not have equivalent access to all the reaction compartments where the substrate, metal oxidant, and olefin reside, the most fundamental requirement for a successful ligand accelerated catalysis scenario is not met. For the present case, this means that the chiral ligand resides only in the insoluble phase, while the OsO 4 and olefin are in solution and free to react anywhere. In this situation the optimal LAC conditions can probably never be achieved even when using...

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