OXAZOLONE DERIVED MATERIALS

Abstract: The design and synthesis of novel oxazolone-derived molecular modules and the use of the modules in the construction of new molecules and fabricated materials is disclosed. The new molecules and fabricated materials are molecular recognition agents useful in the design and synthesis of drugs, and have applications in separations and materials science.

Description: "OXAZOLONE DERIVED MATERIALS' 1. FIELD OF THE INVENTION The present invention relates to the logical development of biochemical and biopharmaceutical agents and of new materials, including fabricated materials such as fibers, beads, films and gels. Specifically, the invention relates to the development of molecular modules derived from oxazolone (azlactone) and related structures, and to the use of these modules in the aεse bly of molecules and fabricated materials with tailored properties, which are determined by the contributions of the individual building modules. The molecular modules of the invention are preferably chiral, and can be used to synthesize new compounds and fabricated materials which are able to recognize biological receptors, enzymes, genetic materials, and other chiral molecules, and are thus of great interest in the fields of biopharmaceuticals, separation and materials science. 2. BACKGROUND OF THE INVENTION The discovery of new molecules has traditionally focuεed in two broad areas, biologically active molecules, which are used as drugs for ' the treatment of life-threatening diseases, and new materials, which are used in commercial, especially high- technological applications. In both areas, the strategy used to discover new molecules has involved two basic r>jerations: (i) a more or less random choice of a molecular candidate, prepared either via chemical synthesis or isolated from natural sources, and (ii) the testing of the molecαlar candidate for the property or properties of interest. This discovery cycle is repeated indefinitely until a molecule possessing the desirable properties is located. In the majority of cases, the molecular types chosen for testing have belonged to rather narrowly defined chemical classes. For example, the discovery of new peptide hormones has involved work with peptides; the discovery of new therapeutic steroids has involved work with the steroid nucleus; the discovery of new surfaces to be used in the construction of computer chips or sensorε haε involved work with inorganic materials, etc. As a result, the discovery of new functional molecules, being ad hoc in nature and relying predominantly on serendipity, has been an extremely time-conεuming, laborious, unpredictable, and costly enterpriεe. A brief account of the strategies and tactics used in the discovery of new molecules is described below. The emphasis is on biologically interesting molecules; however, the technical problems encountered in the discovery of biologically active molecules as outlined here are also illustrative of the problems encountered in the discovery of molecules which can εerve as new materials for high technological applications. Furthermore, as discussed below, these problems are alεo illustrative of the problems encountered in the development of fabricated materials for high technological applications. 2.1 Drug Design Modern theories of biological activity state that biological activities, and therefore physiological states, are the result of molecular recognition events. For example, nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize resulting in double- or triple-helical structures that appear to be involved in regulation of gene expression. In another example, a biologically active molecule, referred to as a ligand, binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g. a receptor or an enzyme) , and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g. normal cell growth and differentiation, abnormal cell growth leading to carcinogenesis, blood-pressure regulation, nerve-impulse generation and propagation, etc. The binding between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions. 2.1.1 Design and Synthesiε of Nucleotides Recent interest in gene therapy and the manipulation of gene expression haε focuεed on the deεign of synthetic oligonucleotides that can be used to block or suppress gene expresεion via an antisense, ribozyme or triple helix mechanism. To this end, the seguence of the native target DNA or RNA molecule is characterized and standard methodε are uεed to εyntheεize oligonucleotideε repreεenting the complement of the deεired target seguence (see, S. Crooke, The FASEB Journal, Vol. 7, Apr. 1993, p. 533 and references cited therein). Attempts to design more stable forms of such oligonucleotideε for uεe in vivo have typically involved the addition of variouε functional groupε, e.g., halogenε, azido, nitro, methyl, keto, etc. to various positionε of the ribose or deoxyribose subunits cf. , The Organic Che iεtrv of Nucleic Acids. Y. Mizuno, Elsevier Science Publiεherε BV, Amεterdam, The Netherlandε, 1987. 2.1.2 GLYCOPEPTIDES As a result of recent advances in biological carbohydrate chemistry, carbohydrates are being increasingly viewed aε the components of living syεtemε with the enormously complex structures required for the encoding of the maεεive amountε of information needed to orchestrate the procesεeε of life, e.g., cellular recognition, immunity, embryonic development, carcinogeneεiε and cell-death. Thuε, whereaε two naturally occurring amino acidε can be used by nature to convey 2 fundamental molecular messages, i.e., via formation of the two posεible dipeptide εtructures, and four different nucleotides convey 24 molecular messageε, two different monoεaccharide subunits can give rise to 11 unique diεaccharideε, and four dissimilar monosaccharideε can give riεe to up to 35,560 unique tetramerε each capable of functioning aε a fundamental molecular meεsage in a given phyεiological system. The gangliosideε are exampleε of the verεatility and effect with which organiεms can use saccharide structures. These molecules are glycolipidε (εugar-lipid compoεites) and as such are able to position themselves at strategic locations on the cell wall: their lipid component enables them to anchor in the hydropholic interior of the cell wall, positioning their hydrophilic component in the aqueous extracellular Jiiillieu. Thus the gangliosideε (like many other εaccharideε) have been choεen to act aε cellular εentries: they are involved in both the inactivation of bacterial toxins and in contact inhibition , the latter being the complex and poorly understood process by which normal cells inhibit the growth of adjacent cells, a property lost in most tumor cells. The εtructure of ganglioεide GM, a potent inhibitor of the toxin εecreted by the cholera organiεm, featuring a branched complex pentameric structure is shown below. The oligosaccharide components of the glycoproteins (sugar-protein composites) responsible for the human blood-group antigens (the A, B, and O blood claεεeε) are shown below. BLOOD GROUP A AND B ANTIGENS BLOOD GROUP O ANTIGEN, TYPE II Interactions involving complementary proteins and glycoproteins on red blood cells belonging to incompatible blood clasεeε cause formation of aggregates, or clusterε and are the cauεe for failed tranεfuεions of human blood. Numerous other biological procesεeε and macromolecules are controlled by glycosylation (i.e., the covalent linking with εugarε) . Thus, glycoεylation of erythropoetin causes loss of the hormone's biological activity; deglycosylation of human gonadotropic hormone increaεeε receptor binding but reεults in almost complete loss of biological activity (εee Rademacher et al., Ann. Rev. Biochem 57, 785 (1988) ; and glycoεylation of three sites in tissue plasminogen activating factor (TPA) produceε a glycopolypeptide which is 30% more active than the polypeptide that has been glycosylated at two of the sites. 2.1.3 Design and Synthesiε of Mimeticε of Biological Ligandε A currently favored strategy for development of agents which can be used to treat diseaεeε involveε the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic εuch ligandε and either booεt, i.e., agonize, or εuppreεε, i.e., antagonize, the activity of the ligand. The diεcovery of εuch desirable ligand forms has traditionally been carried out either by random εcreening of moleculeε (produced through chemical synthesis or isolated from natural sourceε) , or by uεing a so-called "rational" approach involving identification of a lead- structure, usually the εtructure of the native ligand, and optimization of itε propertieε through numerouε cycleε of εtructural redesign and biological testing. Since most uεeful drugε have been diεcovered not through the "rational" approach but through the screening of randomly chosen compounds, a hybrid approach to drug discovery has recently emerged which is based on the use of combinatorial chemistry to construct huge libraries of randomly-built chemical structureε which are εcreened for εpecific biological activitieε. (S. Brenner and R.A. Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381) Moεt lead-εtructureε which have been uεed in "rational" drug deεign are native polypeptide ligandε of receptorε or enzymeε. The majority of polypeptide ligandε, eεpecially the εmall ones, are relatively unstable in physiological fluids due to the tendency of the peptide bond to undergo facile hydrolysis in acidic media or in the presence of peptidases. Thus, such ligands are decisively inferior in a pharmacokinetic εenεe to nonpeptidic compounds, and are not favored aε drugε. An additional limitation of small peptides as drugs is their low affinity for ligand acceptors. This phenomenon is in sharp contrast to the affinity demonstrated by large, folded polypeptides, e.g. proteins, for specific acceptors, e.g. receptors or enzymeε, which is in the subnanomolar range. For peptideε to become effective drugs, they must be transformed into nonpeptidic organic structures, i.e., peptide mimeticε, which bind tightly, preferably in the nanomolar range, and can withεtand the chemical and biochemical rigors of coexistence with biological fluids. Deεpite numerouε incremental advanceε in the art of peptido imetic deεign, no general εolution to the problem of converting a polypeptide-ligand structure to a peptidomimetic has been defined. At preεent, "rational" peptidomimetic design iε done on an ad hoc baεis. Using numerous redesign-εyntheεiε-εcreening cycles, peptidic ligands belonging to a certain biochemical clasε have been converted by groups ^ of organic chemists and pharmacologistε to εpecific peptidomimeticε; however, in the majority of caεeε the reεultε in one biochemical area, e.g. peptidaεe inhibitor design using the enzyme εubεtrate aε a lead, cannot be tranεferred for uεe in another area, e.g. tyroεine-kinaεe inhibitor deεign uεing the kinaεe εubεtrate as a lead. In many caseε, the peptidomi etics that reεult from a peptide εtructural lead uεing the "rational" approach co priεe unnatural α-amino acidε. Many of theεe mimeticε exhibit -~>veral of the troubleεome featureε of native peptideε (x ~ h also comprise α-amino acids) and are, thus, not favt, ad for use as drugs. Recently, fundamental research on the uεe of nonpeptidic scaffolds, such as εteroidal or εugar εtructureε, to anchor εpecific receptor-binding groupε in fixed geometric relationεhipε have been described (see for example Hirschmann, R. et al;., 1992 J. Am. Cne . Soc.. 114:9699-9701; Hirεchmann, R. et-al., 1992 J. Am. Che . Soc.. 114:9217-9218); however, the εucceεε of thiε approach remainε to be εeen. In an attempt to accelerate the identification of lead-structures, and also the identification of uεeful drug candidates through screening of randomly chosen compoundε, researchers have developed automated methods for the generation of large combinatorial libraries of peptides and certain types of peptide mimetics, called "peptoids", which are screened for a desirable biological activity. For example, the method of H. M. Geysen, (1984 Proc. Natl. Acad. Sci. USA 81:3998) employε a modification of Merrifield peptide εyntheεiε wherein the C-terminal amino acid reεidueε of the peptideε to be εyntheεized are linked to εolid-εupport particleε shaped aε polyethylene pinε; these pins are treated individually or collectively in sequence to introduce additional amino-acid reεidueε forming the deεired peptides. The peptides are then screened for activity without removing them from the pinε. Houghton, (1985, Proc. Natl. Acad. Sci. USA 82:5131; and U.S. Patent No. 4,631,211) utilizeε individual polyethylene bagε ("tea bagε") containing C-terminal amino acidε bound to a εolid support. These are mixed and coupled with the requisite amino acids using solid phase syntheεiε techniqueε. The peptideε produced are then recovered and teεted individually. Fodor et al., (1991, Science 251:767) deεcribed light- directed, εpatially addreεεable parallel-peptide εyntheεiε on a εilicon wafer to generate large arrayε of addreεεable peptideε that can be directly tested for binding to biological targets. Theεe workerε have alεo developed recombinant DNA/genetic engineering methodε for expreεεing huge peptide libraries on the surface of phageε (Cwirla et al., 1990, Proc. Natl. Acad. Sci. USA 87:6378) . In another combinatorial approach, V. D. Huebner and D.V. Santi (U.S. Patent No. 5,182,366) utilized functionalized polystyrene beads divided into portions each of which was acylated with a desired amino acid; the bead portions were mixed together and then εplit into portionε each of which was subjected to acylation with a εecond deεirable amino acid producing dipeptideε, uεing the techniqueε of εolid phaεe peptide εynthesis. By uεing thiε synthetic scheme, exponentially increasing numbers of peptideε were produced in uniform amountε which were then εeparately εcreened for a biological activity of intereεt. Zuckerman et al., (1992, Int. J. Peptide Protein Res. 91:1) also have developed similar methods for the synthesis of peptide libraries and applied these methods to the automation of a modular synthetic chemistry for the production of librarieε of N-alkyl glycine peptide derivatives, called "peptoids", which are screened for activity against a variety of biochemical targets. (See also, Symon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367) . Encoded combinatorial chemical syntheεeε have been described recently (S. Brenner and R.A. Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381). In addition to the lead structure, a very useful εource of information for the realization of the preferred "rational" drug diεcovery iε the εtructure of the biological ligand acceptor which, often in conjunction with molecular modelling calculationε, iε uεed to εimulate modeε of binding of the ligand with its acceptor; information on the mode of binding is useful in optimizing the binding propertieε of the lead-εtructure. However, finding the εtructure of the ligand acceptor, or preferably the εtructure of a complex of the acceptor with a high affinity ligand, requireε the iεolation of the acceptor or complex in the pure, cryεtalline εtate, followed by x-ray cryεtallographic analysis. The isolation and purification of biological receptors, enzymes, and the polypeptide substrateε thereof are time- conεuming, laboriouε, and expensive; success in this important area of biological chemistry depends on the effective utilization of sophiεticated εeparation technologieε. Cryεtallization can be valuable aε a εeparation technique but in the majority of caεeε, eεpecially in cases involving isolation of a biomolecule from a complex biological milieu, succeεεful separation is chromatographic. Chro atographic separations are the result of reversible differential binding of the components of a mixture aε the mixture moveε on an active natural, εynthetic, or εemiεynthetic εurface; tight- binding componentε in the moving mixture leave the εurface laεt en masse reεulting in separation. The development of substrates or supportε to be uεed in separations haε involved either the polymerization croεεlinking of monomeric moleculeε under variouε conditionε to produce fabricated materialε εuch aε beadε, gelε, or films, or the chemical modification of various commercially available fabricated materials, e.g., sulfonation of polyεtyrene beads, to produce the desired new materials. Prior art support materials have been developed to perform specific separations or typeε of εeparationε and are of limited utility. Many of these materials are incompatible with biological macromoleculeε, e.g. reverεe-phaεe silica frequently used to perform high presεure liquid chromatography can denature hydrophobic proteinε and other polypeptideε. Furthermore, many εupports are used under conditions which are not compatible with εenεitive biomoleculeε, εuch aε proteinε, enzymeε, glycoproteinε, etc., which are readily denaturable and εensitive to extreme pH's. An additional difficulty with separationε carried out uεing theεe supports is that the separation resultε are often support-batch dependent, i.e., they are irreproducible. Recently a variety of coatings and composite- forming materialε have been uεed to modify commercially available fabricated materials into articles with improved properties; however the success of this approach remains to be seen. If a chromatographic surface iε equipped with moleculeε which bind εpecifically with a component of a complex mixture, that component will be εeparated from the mixture and may subsequently be released by changing the experimental conditions, (e.g. buffers, stringency, etc.) This type of separation iε appropriately called affinity chromatography and remainε an extremely effective and widely uεed εeparation technique. It iε certainly much more εelective than traditional chromatographic techniqueε, e.g chromatography on silica, alumina, silica or alumina coated with long-chain hydrocarbons, polysaccharide and other typeε of beadε or gelε, etc. , which in order to attain their maximum εeparating efficiency need to be uεed under conditionε that are damaging to biomoleculeε, e.g. conditionε involving high preεsure, use of organic solvents and other denaturing agents, etc. The development of more powerful separation technologies depends εignificantly on breakthroughε in the field of materialε science, specifically in the design and construction of materials that have the power to recognize specific molecular εhapes under experimental conditions resembling those found in physiological media, i.e. these experimental conditions must involve an aqueous medium whose temperature and pH are close to the physiological levels and which contains none of the agentε known to damage or denature biomoleculeε. The conεtruction of these "intelligent" materials frequently involves the introduction of small molecules capable of specifically recognizing others into existing materials, e.g. surfaces, films, gelε, beads, etc., by a wide variety of chemical modifications. Alternatively, molecules capable of recognition are converted to monomers and used to create the " intelligent" materialε through polymerization reactionε. 2.2 Oxazolones Oxazolones, or azlactones, are structureε of the general formula: where A iε a functional group and n is 0 or 1 and typically 1-3. Oxazolones containing a five-membered ring and a εingle εubεtituent at position 4 are typically encountered aε tranεient intermediates which cause problematic racemization during the chemical syntheεiε of peptideε. An oxazolone can in principle contain one or two εubεtituents at the 4-poεition. When theεe εubstituents are not equivalent, the carbon atom at the 4-position iε asymmetric and two non-εuperimpoεable oxazolone εtructures (azlactones) result: Chiral oxazolones possesεing a εingle 4- εubεtituent (also known as 5(4H) -oxazolones) , derived from (chiral) natural amino acid derivatives, including activated acylamino acyl structures, have been prepared and isolated in the pure, crystalline state (Bodansky, M. ; Klausner, Y.S.; Ondetti, M.A. in "Peptide Synthesis", Second Edition, John Wiley & Sons, New York, 1976, p. 14 and references cited therein) . The facile, base- catalyzed racemization of several of these oxazolones has been studied in connection with investigations of the serious racemization problem confronting peptide syntheεiε (see Kemp, D.S. in "The Peptides, Analysis, S ynthesis, and Biology", Vol. 1, Gross, E. & Meienhofer, J. editors, 1979, p. 315). Racemization during peptide syntheεiε becomes very extensive when the desired peptide is produced by aminolysis of activated peptidyl carboxyl, as in the case of peptide chain extension from the amino terminus, e.g. I → VI shown below (see Atherton, E. ; Sheppard, R.C. " S olid Phase Peptide Synthesis, A Practical Approach", IRL Presε at Oxford University Press, 1989, pages 11 and 1 2) . An extensively studied mechanism deεcribing thiε racemization involves conversion of the activated acyl derivative (II) to an oxazolone (III) followed by facile base-catalyzed racemization of the oxazolone via a reεonance-εtabilized intermediate (IV) and aminolyεis of the racemic oxazolone (V) producing racemic peptide products (VI) . Base Proton Donor aminolysis Extensive research on the trapping of oxazolones III (or of their activated acyl precursors II) to give acylating agents which undergo little or no racemization upon aminolysiε has been carried out, and succeεses in this area (such as the use of N- hydroxybenzotriazole) have greatly advanced the art of peptide synthesis (Kemp, D.S. in "The Peptides, Analysis, Synthesis, and Biology", Vol. 1, Gross, E. & Meienhofer, J. editors, 1979, p. 315) . Thus, attempts to deal with the racemization problem in peptide synthesis have involved suppressing or avoiding the formation of oxazolone intermediates altogether. Furthermore, certain vinyl oxazolones having a hydrogen subεtituent at the 4-position can also undergo thermal rearrangements (23 Tetrahedron 3363 (1967)), which may interfere with other desired tranεfor ationε, εuch aε Michael-type additions. 3. SUMMARY OF THE INVENTION A new approach to the construction of novel molecules iε deεcribed. Thiε approach involves the development of oxazolone (azlactone) derivative molecular building blocks, containing appropriate atoms and functional groups which may be chiral and which are used in a modular assembly of molecules with tailored propertieε; each module contributing to the overall properties of the asεembled molecule. The oxazolone derivative building blockε of the invention can be uεed to synthesize novel molecules designed to mimic the three-dimensional structure and function of native ligands, and/or interact with the binding sites of a native receptor. This logical approach to molecular construction is applicable to the syntheεis of all types of moleculeε, including but not limited to imetics of peptides, proteins, oligonucleotides, carbohydrates, lipids, polymers and to fabricated materials useful in materials science. It is analogous to the modular conεtruction of a mechanical device that perfor ε a εpecific operation wherein each module performε a εpecific task contributing to the overall operation of the device. The invention is baεed, in part, on the following insights of the discoverer. (1) All ligands share a single universal architectural feature: they consist of a scaffold structure, made e.g. of amide, carbon-carbon, or phosphodieεter bonds which support εeveral functional groupε in a preciεe and relatively rigid geometric arrangement. (2) Binding modes between ligands and receptors share a single universal feature as well: they all involve attractive interactions between complementary structural elements, e.g., charge- and π- type interactions, hydrophobic and van der Waals forces, hydrogen bonds. (3) A continuum of fabricated materials exists spanning a dimenεional range from about 100 A to 1 cm in diameter compriεing various materials of conεtruction, geometrieε, morphologies, and functions, all posεeεεing the common feature of a functional εurface which iε preεented to a biologically active molecule or a mixture of moleculeε to achieve recognition between the molecule (or the deεired molecule in a mixture) and the εurface. And (4) Oxazolone derivative εtructures, heretofore regarded as unwanted intermediates which form during the syntheεiε of peptideε, would be ideal building blockε for conεtructing backboneε or εcaffoldε bearing the appropriate functional groupε that either mimic deεired ligandε, and/or interact with appropriate receptor binding sites, and for carrying out the syntheεis of the various parts of the functionalized scaffold orthogonally, provided that racemization of the oxazolone structureε is prevented or controlled. Thus, the invention iε also based, in part, on the further recognition that such derivatives of ozaxoloneε, which do not racemize, can be used as universal building blocks for the syntheεiε of εuch novel moleculeε. Furthermore, oxazolone derivativeε may be utilized in a variety of wayε acroεε the continuum of fabricated materialε deεcribed above to produce new materials capable of specific molecular recognition. These oxazolone derivatives may be chirally pure and used to synthesize molecules that mimic a number of biologically active molecules, including but not limited to peptides, proteins, oligonucleotides, polynucleotideε, carbohydrates and lipids, and a variety of other polymers aε well aε fabricated materials that are useful as new materials, including but not limited to solid supports useful in column chromatography, catalysts, solid phase immunoasεayε, drug delivery vehicles, films, and "intelligent" materials designed for use in selective separationε of variouε componentε of complex mixtureε. Working exampleε deεcribing the uεe of oxazolone-derived moduleε in the modular aεεembly of a variety of molecular εtructureε are given. The molecular εtructureε include functionalized εilica εurfaceε uεeful in the optical reεolution of racemic mixtures; peptide mimetics which inhibit human elastaεe, protein-kinaεe, and the HIV proteaεe; and polymerε formed via free- radical or condensation polymerization of oxazolone- containing monomers. In accordance with the present invention, the oxazolone-derived molecules of interest posεeεε the deεired stereochemistry and, when required, are obtained enantiomerically pure. In addition to the syntheεiε of single molecular entities, the syntheεiε of librarieε of oxazolone-derived moleculeε, using the techniques described herein or modifications thereof which are well known in the art to perform combinatorial chemistry, is also within the scope of the invention. Furthermore, the oxazolone-derived molecules possess enhanced hydrolytic and enzymatic stabilitieε, and in the case of biologically active materials, are transported to target ligand-acceptor macromolecules in vivo , without cauεing any εerious side-effects. According to the present invention, chiral oxazolones, in which the asymmetric center is a 4-disubεtituted carbon, aε well aε synthetic nonchiral oxazoloneε may be εyntheεized readily and used as molecular modules capable of controlled reaction with a variety of other molecules to produce designed chiral recognition agents and conjugates. These chiral oxazolones may also be linked together, uεing polymerizing reactionε carried out either in a εtepwiεe or chain manner, to produce polymeric biological ligand mimicε of defined seguence and stereoche iεtry. Furthermore, according to the preεent invention, 4-diεubεtituted chiral oxazoloneε are extremely useful in the asymmetric functionalization of various solid supports and biological macromolecules and in the production of various chiral polymers with useful propertieε. The products of all of these reactions are surprisingly stable in diverse chemical and enzymological environments, and uniquely suitable for a variety of superior pharmaceutical and high-technological applicationε. For applications in which the 4 poεition of the oxazolone precurεor does not need to be chiral, e.g., the construction of certain polymeric materials, the use of oxazolones in the construction of linkers for the joining of two or more pharmaceutically useful or, simply, biologically active ligands, etc., symmetric or nonchiral oxazolones are used in chemical syntheεeε. Furthermore, if the oxazolone-derived product doeε not need to incorporate the 4-poεition of the oxazolone precurεor in the enantiomerically pure εtate, oxazolone precursors which are not enantiomerically pure may be used fqr syntheseε. 4. DETAILED DESCRIPTION OF THE INVENTION To the extent neceεεary to further underεtand any portion of the detailed deεcription, the following earlier filed U.S. patent applications are expresεly incorporated herein by reference thereto: DISUBSTITUTED OXAZOLONE COMPOSITIONS AND DERIVATIVES THEREOF (Serial No. 07/906,756 filed June 30, 1992); and DIRECTED CHIRAL LIGANDS, RECOGNITION AGENTS AND FUNCTIONALLY USEFUL MATERIALS FROM SUBSTITUTED OXAZOLONES AND DERIVATIVES CONTAINING AN ASYMMETRIC CENTER (Serial No. 08/041,562 filed April 2, 1993) . 4.1 Synthesis of Chiral Substituted Oxazolones Chiral 4,4'-disubstituted oxazoloneε may be prepared from the appropriate N-acyl amino acid using any of a number of standard acylation and cyclization techniques well-known to those skilled in the art, e.g.: If the substituent at the 2-position is capable of undergoing addition reactionε, theεe may be carried out with retention of the chirality at the 4-position to produce new oxazolones. This is shown for the Michael addition to an alkenyl oxazolone as follows: where X = S or NR and A* is a functionalized alkyl group. The required chiral amino acid precursors for oxazolone syntheεiε may be produced uεing stereoselective reactions that employ chiral auxiliaries. An example of such a chiral auxiliary is (5)-(-)-l-dimethoxymethyl-2- methoxymethylpyrrolidme (SMPD) (Liebig's Ann. Chem. 1668 (1983)) as shown below, R 3 X/LDA -78°C CH 3 I NaH HCOOH wherein R 2 = CH 3 , i-Bu, or benzyl; and R 3 = CH 3 , CHF 2 , C 2 H 5 , n-Bu, or benzyl. A second example involves 5H,10bH- oxazolo[3,2-c] [1, 3 ]benzoxazine-2 (3H) ,5-diones (55 j. Org. Chem. 5437 (1990) ) , wherein R ! = phenyl or i-Pr; and R 2 = CH 3 , C 2 H,, or CH = CH—CH . Alternatively, the desired chiral amino acid may be obtained using stereoεelective biochemical , 20 transformations carried out on the racemate, syntheεized via εtandard reactionε, as shown below for a case involving a commercially-available organism (53 J. Org. Chem. 1826 (1988) ) , 25 30 L-Acid D- Amide wherein R 1 = i-Pr, i-Bu, phenyl, benzyl, p-methoxybenzyl, or phenethyl; and R = CH 3 or C 2 H 5 . Racemic mixtures of 4,4'-diεubεtituted 35 oxazoloneε may be prepared from monoεubεtituted oxazoloneε by alkylation of the 4-position, aε in the following tranεformation (Svnthesiε Commun.. Sept. 1984, at 763; 23 Tetrahedron Lett. 4259 (1982)) : Reεolution of racemic mixtureε of oxalolones may be effected using chromatography or chiral supportε under εuitable conditions which are well known in the art; using fractional crystallization of stable saltε of oxazoloneε with chiral acidε; or εimply by hydrolyzizing the racemic oxazolone to the amino acid derivative and reεolving the racemic modification using standard analytical techniques. A wide variety of 4-monoεubεtituted azlactoneε may be readily prepared by reduction of the corresponding unεaturated derivativeε obtained in high yield from the condenεation reaction of aldehydes, ketones, or imines with the oxazolone formed from an N-acyl glycine (49 J. Org. Chem. 2502 (1984) ; 418 Synthesis Communicationε (1984) ) Thuε, the art provideε a wealth of chemical and biochemical methods which can be used to produce a wide variety of enantiomeric, multifunctionalized oxazolones whoεe εubεtituents may be tailored to mimic any deεirable form of the εide chains of native polypeptides. 4.2 Synthetic Transformations of Chiral Oxazolones 4.2.1 Reactions with One or Two Nucleophiles Producing Conjugates Chiral oxazolones may be subjected to ring- opening reactions with a variety of nucleophiles producing chiral molecules as εhown below: In the s^-ucture above, Y representε an oxygen, εulfur, or nitrogen atom. R 1 and R 2 differ from one another and taken alone each εignifieε one of the followng: alkyl including cycloalkyl and εubεtituted formε thereof; aryl, aralkyl, alkaryl, and εubεtituted or heterocyclic verεions thereof; preferred forms of R 1 and R 2 are structureε mimicking the εide chainε of naturally- occurring amino acidε as well as various ring structures. The above ring-opening reaction can be carried out either in an organic εolvent εuch aε methylene chloride, ethyl acetate, dimethyl formamide (DMF) or in water at room or higher temperatures, in the presence or abεence of acidε, εuch aε carboxylic, other proton or Lewiε-acids, or bases, such as tertiary amines or hydroxides, serving aε catalysts. If εtructure BYH contains nucleophilic functional groups which may interfere with the ring-opening acylation, these groups must be temporarily protected using suitable orthogonal protection strategieε baεed on the many protecting groupε known in the art; cf., e.g., Protective Groupε in Organic Syntheεiε. 2ed. , T.W. Greene and P.G.M. Wuts, John Wiley & Sons, New York, N.Y., 1991. The substituents A and B shown may be of a variety of structures and may differ markedly in their physical or functional properties, or may be the same; they may also be chiral or εymmetric. A and B are preferably εelected from: 1) an amino acid derivative of the form (AA) n , which would include natural and εynthetic amino acid reεidues (n=l) , peptides (n=2-30) , polypeptides (n=31-70) and proteins (n>70) . These derivatives are generally connected to the amine of the amino acyl structure used to form the oxazolone through a carbonyl group, although other reactions which are known to functionalize terminal amino groups may be employed. It is recognized that certain amino acid derivatives would already contain the necesεary connecting group, such as a carbonyl, so that a direct chemical bond can be obtained to the product of the oxazolone ring opening reaction without the uεe of a connecting group. 2) a nucleotide derivative of the form (NUCL) n , which would include natural and εynthetic nucleotides (n=l) , nucleotide probes (n=2-25) and oligonucleotides (n>25) including both deoxyribose (DNA) and ribose (RNA) variants. 3) a carbohydrate derivative of the form (CH) n . Thiε would include natural physiologically active carbohydrates (glucose, galactose, etc.) including related compounds such as εialic acids, etc. (n=l) , synthetic carbohydrate residueε and derivativeε of theεe (n=l) and all of the complex oligomeric permutationε of these as found in nature (n>l) cf. Scientific American. January 1993, p. 82. 4) a naturally occurring or synthetic organic structural motif. This term includes any of the well known base structures of pharmaceutical compounds including pharmacophores or metaboliteε thereof. These structural motifs are generally known to have εpecific desirable binding properties to ligand acceptors of interest and would include εtructureε other than thoεe recited above in 1) , 2) and 3) . 5) a reporter element εuch aε a natural or synthetic dye or a residue capable of photographic amplification which poεεeεεes reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme and may be attached through the groupε without adversely interfering with the reporting functionality of the group. Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, acid chloride, isocyanate alkyl halideε, aryl halides and oxirane groupε. 6) an organic moiety containing a polymerizable group such as a double bond or other functionalities capable of undergoing condensation polymerization or copolymerization. Suitable groups include vinyl groupε, oxirane groupε, carboxylic acids, acid chlorides, esters, amides, lactones and lactamε. 7) a macromolecular component, such as a macromolecular surface or structures which may be attached to the oxazolone modules via the various reactive groups outlined above in a manner where the binding of the attached specieε to a ligand-receptor molecule is not adversely affected and the interactive activity of the attached functionality is determined or limited by the macromolecule. The molecular weight of these macromolecules may range from about 1000 Daltons to as high as possible. They may take the form of nanoparticles (d p =100- lOOoA) , latex particles (d p =100θA-500θA) , porous or non-porous beadε (d p =0.5μ-1000μ) , membraneε, gelε, macroεcopic εurfaceε or functionalized or coated verεionε or compoεiteε of theεe. Under certain circumεtances, A and/or B may be a chemical bond to a suitable organic moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such aε an aldehyde, eεter, alkyl halide, ketone, nitrile, epoxide or the like, a εuitable nucleophilic group, such as a hydroxy1, amino, carboxylate, aminde, carbanion, urea or the like, or one of the R groups defined below. In addition, A and B may join to form a ring or structure which connectε to the ends of the repeating unit of the compound defined by the preceding formula or may be separately connected to other moeities. A more generalized presentation of the composition cf the invention iε defined by the εtructure wherein: a. at least one of A and B are aε defined above and A and B are optionally connected to each other or to other compounds; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a subεtituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1. Preferably, (1) if n is 1, and X and Y are chemical bondε, A and B are different and one iε other than a chemical bond, H or R; (2) if n iε 1 and Y iε a chemical bond, G includeε a NH, OH or SH terminal group for connection to the carbonyl group and G-B iε other than an amino acid reεidue or a peptide; (3) if n iε 1 and X, Y, and G each iε a chemical bond, A and B each iε other than a chemical bond, an amino acid residue or a peptide; and (4) if n iε 1, either X or A has to include a CO group for direct connection to the NH group. These compositionε may be uεed to mimic variouε compoundε such as peptideε, nucleotides, carbohydrates, pharmaceutical compounds, reporter compounds, polymerizable compounds or subεtrates. Another composition is defined by the formula: where A, B, X, Y and G are as defined above. In one embodiment of the invention, at least one of A and B repreεents an organic or inorganic macromolecular surface functionalized with hydroxyl, sulfhydryl or amine groups. Examples of preferred macromolecular surfaces include ceramics such as silica and alumina, porous or nonporouε beads, polymers such as a latex in the form of beadε, membranes, gels, macroscopic surfaces, or coated versionε or compositeε or hybridε thereof. A general εtructure of a chiral form of these materialε iε εhown below: R 1 A CO NH TC CO Y (Surface). R 2 In another embodiment of the invention, ' the roles of A and B in the structure above are reversed, so that B is a subεtituent εelected from the liεt given above and A repreεents a functionalized surface as shown for one of the enantiomeric forms: R 1 (Surface) CO NH fC CO Y B R 2 In the description that follows, R n where n = an integer will be used to designate a group from the definition of R and R 1 . In a preferred embodiment, group A or B in the above structure is an aminimide moiety. This moiety may be introduced, for example by reacting the oxazolone with an asymmetrically subεtituted hydrazine and alkylating the resulting hydrazide, (e.g., by reaction with an alkyl halide, or epoxide) . An example of such a surface is shown below. R 1 R 3 (Surface) CO NH C CO N " N + — R 4 R 2 R 5 Preferred aminimideε are deεcribed in a PCT application entitled MODULAR DESIGN AND SYNTHESIS OF AMINIMIDE-BASED MOLECULES USEFUL AS MOLECULAR RECOGNITION AGENTS AND NEW POLYMERIC MATERIALS (attorney docket no.: 5925-005-228) and filed of even date herewith, the content of which iε expreεsly incorporated herein by reference thereto. Another embodiment of the invention relates to an oxazolone ring having the εtructure where A, R, R' and Y are aε deεcribed above and q is zero or 1. Preferably, Y is a chemical bond [see claim 36]. This ring iε uεeful for preparing the deεired oxazolone derivatives. A further embodiment of the invention exploits the capability of oxazolones with εuitable εubεtituentε at the 2-poεition to act as alkylating agents. Appropriate substituents include vinyl groupε, which make the oxazolone a Michael acceptor, haloalkyl and alkyl sulfonate-eεter and epoxide groupε. For example, Michael addition to the dc :ble bond of a chiral 2-vinyloxazolone followed by a ring opening reaction reεults in a chiral conjugate structure. This general reaction scheme, illustrated for the case of a 2-vinyl azlactone derivative, is as follows: wherein X representε a εulfur or nitrogen atom; Y represents a sulfur, oxygen, or nitrogen atom; and εubεtituentε A and B, aε described above, may adopt a variety of structureε, differing markedly in their phyεical or functional propertieε or being the εame, may be chiral or achiral, and may be preferably selected from amino acidε, oligopeptideε, polypeptideε and proteinε, nucleotideε, oligonucleotideε, ligand mimetics, carbohydrates, aminimideε, or εtructures found in therapeutic agents, metabolites, dyes, photographically active chemicals, or organic moleculeε having deεired steric, charge, hydrogen-bonding or hydrophobicity characteristics, or containing poly erizable vinyl groups. The Michael reaction described above is usually carried out using stoichio etric amountε of nucleophile AXH and the oxazolone in a εuitable εolvent, εuch as toluene, ethyl acetate, dimethyl formamide, an alcohol, and the like. The product of the Michael addition is preferably iεolated by evaporating the reaction εolvent in vacuo and purifying the material iεolated using a technique such aε recryεtallization or chromatography. Gravity- or preεsure-chromatography, on one of a variety of εupportε, e.g., εilica, alumina, under normal- or reverεed-phaεe conditions, in the presence of a suitable solvent syεtem, may be uεed for purification. The εelectivitieε of the Michael and oxazolone ring-opening processes impose certain limitations on the choice of AXH and BYH nucleophiles shown above. Specifically, nucleophiles of the form ROH tend to add primarily via the ring-opening reaction, and often require acidic catalysts (e.g., BF 3 ) ; thus, X should not be oxygen. Likewise, primary amines tend to add only via ring-opening, and X should therefore not be NH. Secondary amines readily add to the double bond under appropriate reaction conditions, but many can also cause ring-opening; accordingly, X or Y can be N provided A or B are not hydrogen. Nucleophiles of the form RSH will exclusively add via ring-opening if the sulfhydryl group iε ionized (i.e., if the baεicity of the reaction mixture correεpondε to pH ≡ 9) ; on the other hand, such nucleophiles will exclusively add via Michael reaction under non-ionizing (i.e., neutral or acidic) conditions. During the Michael addition, it is important to limit the presence of hydroxylic species in the reaction mixture (e.g., moisture) to avoid ring-opening εide-reactionε. Summarizing, AXH can be a εecondary amine or thiol, and BYH can be a primary or εecondary amine or thiol, or an alcohol. In one variant of the Michael-ring-opening sequence given above, A is a εubstituent selected from the foregoing list and BXH compriseε an organic or inorganic macromolecular surface, e.g., a ceramic, a porous or non-porous bead, a polymer such as a latex in the form of a bead, a membrane, a gel or a composite, or hybrid of these; the macromolecular surface is functionalized with hydroxyl, sulfhydryl or amine groups which serve aε the nucleophiles in the ring-opening reaction. The reaction sequence iε carried out under conditionε εimilar to thoεe given for the nonpolymeric cases; purification of the final product involves techniques used in the art to purify supportε and other εurfaces after derivatization, such as washing, dialysis, etc. The reεult of thiε reaction εequence iε a εtructure εuch as the one εhown below: In another variant, the roleε of AXH and BYH are reverεed, εo that BYH is the εubεtituent εelected from the liεt above and AXH repreεentε a functionalized εurface. Alternatively, reactive groupε may be introduced at the 2-poεition of the oxazolone ring via εuitable acylationε, as shown for the specific example of a benzoyl chloride derivative: In the caεe where X is part of a group whose reactivity is orthogonal to that of the oxazolone ring, such aε in the caεe of a benzyl chloride group, ring-opening addition with BYH may be carried out and followed by reaction with an appropriate AXH group, e.g. an amine ANH 2 , to give the product shown: If in the above sequences the benzylic electrophile 10 competes with the oxazolone ring for the nucleophile BYH, a εuitable protecting group, εhown aε Bl below, may be uεed to block an exiεting benzylic amino group in the oxazolone; εubεequent to the ring-opening addition of BYH the protected group iε removed uεing εtandard techniqueε 5 (e.g., if the protecting group is Boc, it is removed by using dilute TFA in CH 2 C1 2 ) , and the resulting product is reacted with an appropriate electrophile, e.g., A-CH 2 -Br, thus introducing substituent A into the molecule. 20 25 Deprotect 30 35 4.2.2 Catenation of Chiral Oxazolones Producing Chiral Polymers By selecting appropriate oxazolone building blocks and catenating (linking) them in one of a variety of wayε, it iε poεεible to produce polymeric functionalized εcaffoldε, of varying length and complexity, each of which mimicks a biologically important ligand and moreover possesses features which are desired of potent drugε, such as stability in physiological media, εuperior phar acokinetics, etc. The oxazolones selected for catenation contain functional groups which, when part of the oxazolone-derived scaffold, will make specific contributions to the ligand- acceptor binding interaction, as determined by previouε structural studieε on the binding interaction. Alternatively, by the judicious insertion of one or more oxazolone-derived units into a sequence of a peptide or protein, that is susceptible to hydrolysis or to enzymatic degradation, a hybrid molecule may be produced which has improved stability properties. These structures may be repreεented through the general conjugate εtructure given above; A and B repreεent the polypeptide sequences flanking the inserted oxazolone- derived unit or units. The polymeric, oxazolone-derived ligand sequenceε may be conεtructed in one of three wayε aε outlined below. 4.2.2.1 Polymerization Via Sequences of Nucleophilic Oxazolone-Ring-Opening Followed by Oxazolone-Forming Cvclization According to this approach, the oxazolone ring is opened via nucleophilic attack by the amino group of a chiral α,α*-diεubεtituted amino acid; the reεulting amide may be recyclized to the oxazolone, with retention of chirality, and subjected to a further nucleophilic ring- opening reaction, producing a growing chiral polymer as shown below: 30 35 wherein M iε an alkali metal; each member of the subεtituent pairε R 1 and R 2 , R 3 and R 4 , and R 5 and R 6 differε from the other and taken alone each εignifieε alkyl, cycloalkyl, or substituted versionε thereof, aryl, aralkyl or alkaryl, or substituted and heterocyclic versionε thereof; theεe substituent pairs can also be joined into a carbocyclic or heterocyclic ring; preferred versions of these subεtituentε are thoεe mimicking εide- chain εtructureε found in naturally-occurring amino acidε; X repreεents an oxygen, sulfur, or nitrogen atom; and A and B are the substituents described above. At any point in the polymer syntheεiε εhown above, a εtructural εpecieε, poεsesεing (1) a terminal - OH, -SH or -NH 2 group capable of ring-opening addition to the oxazolone and (2) another terminal group capable of reacting with the amino group of a chiral α,α ! - disubstituted amino acid, may be inserted in the polymer backbone as εhown below: This process may be repeated, if desired, at each εtep in the εyntheεiε where an oxazolone ring is produced. The bifunctional species used may be the same or different in the steps of the synthesis. The experimental procedures described above for oxazolone formation and use of oxazolones as acylating agents are expected to be useful in the oxazolone- directed catenations. Solubility and coupling problems that may arise in specific caseε can be dealt with effectively by one with ordinary εkill in the art of polypeptide and peptide mimetic εyntheεiε. For example, εpecial εolventε εuch aε dipolar aprotic εolventε (e.g., dimethyl formamide, DMF, dimethyl sulfoxide, DMSO, N- methyl pyrolidone, etc.) and chaotropic (molecular aggregate-breaking) agents (e.g., urea) will be very useful as catenations produce progreεεively larger moleculeε. 4.2.2.2 Polymerizations Using Bifunctional Oxazolones Containing a Nucleophilic Group Alternatively, a chiral oxazolone derivative containing a blocked terminal amino group may be prepared from a blocked, disubεtituted dipeptide, that was prepared by standard techniques known to those εkilled in the art, aε shown: wherein B, iε an appropriate protecting group, εuch aε Boc (t-butoxycarbonyl) or Fmoc (fluorenylmethoxycarbonyl) . One may then uεe thiε oxazolone to acylate an amine, hydroxyl, or εulfhydryl-group in a linker structure or functionalized solid support, represented generically by AXH, using the reaction conditions described above. Thiε acylation iε followed by deblocking, uεing εtandard amine deprotection techniques compatible with the overall structure of the amide (i.e., the amine protecting group is orthogonal with respect to any other protecting or functional groups that may be preεent in the molecule) , and the reεulting amino group iε uεed for reaction with a new bifunctional oxazolone generating a growing chiral polymeric structure, aε shown below: In the reaction shown above, Y is a linker (preferably a functionalized alkyl group) ; X is a nitrogen of suitable structure; an oxygen or a sulfur atom; each member of the subεtituent pairε R 1 and R 2 , R 3 and R 4 , R nl and R n differε from the other and taken alone each εignifies alkyl, cycloalkyl, or functionalized versions thereof; aryl, aralkyl or alkaryl or functionalized including heterocyclic versionε thereof (preferably, these R subεtituentε mimick the εide-chain of naturally occurring amino acidε) ; εubεtituent R can alεo be part of a carbocyclic or heterocyclic ring; A iε a substituent as described above; and C is a subεtituent selected from the set of structureε for A; and B, iε a blocking or protecting group. It can be εeen that the above polymerization involves introduction of two amino acid residues per polymer-elongation cycle and therefore produces ligandε with an even number of reεidues. To obtain ligands containing an odd number of reεidues, a preliminary step may be carried out with a suitable amino acid derivative as shown below, prepared via εtandard εyntheεiε. 30 35 4.2.2.3 Polymerization Using Bifunctional Oxazolones Containing an Additional Electrophilic Group When the subεtituent at the 2-position of the oxazolone (azlactone) ring is capable of undergoing an addition reaction, that proceeds with retention of the chirality of the 4-poεition, the addition reaction may be combined with a ring-opening acylation to produce chiral polymeric εequenceε. Thiε is εhown for the caεe of alkenyl azlactoneε below. In the above seguence of reactions, A denotes a εtructure of the form deεcribed above and HNu'-Z-Nu 2 H repreεentε a structure containing two differentially reactive nucleophilic groups, such as methylamino-ethylamine, 1- amino propane-3-thiol, and so on; groups Nu 1 , Nu 2 , Nu 3 and Nu 4 need not be identical and Z is a linker εtructure aε deεcribed above. Structure HNu'-Z-Nu 2 H may contain two nucleophilic groupε of differential reactivity, as εtated above, or if Nu 1 and Nu 2 are of comparable reactivity one of the nucleophilic groups is protected to prevent it from competing with the other and deprotected selectively following acylation; protecting groups commonly used in the art of peptide syntheεis (e.g., for the nucleophilic groups such as amino, hydroxyl, thio, etc.) are uεeful in the protection of one of the Nu εubstituents of the εtructure HNu'-Z-N^H. The product of the acylation reaction with HNu'-Z-Nu (after Nu-deprotection, if neceεsary) is further reacted with a new oxazolone unit in a Michael fashion, and this addition is followed by ring-opening acylation with an additional dinucleophile; repetition of this εequence of εynthetic εteps produceε a growing polymeric molecule. Reaction conditionε for carrying out theεe proceεεes are εimilar to thoεe deεcribed above for related polymerε. The above typeε of oligo erε are highly uεeful biochemically because of their structural similarity to polypeptides. The substituentε R can be choεen to tailor the εteric, charge or hydrophobicity characteriεticε of the oligomer εuch that a verεatile polypeptide mimetic reεultε. 4.2.3 Functionalization of Peptideε and Proteins Using Oxazolones In a further embodiment of the invention, the nucleophilic ring-opening of asymmetrically disubstituted oxazoloneε may be utilized to introduce a chiral reεidue or sequence in selected positions in peptides or proteins to produce hybrid moleculeε with improved hydrolytic εtability or other propertieε. The reaction of a chiral azlactone with the amino terminus of a synthetic tripeptide attached to a Merrifield support is shown below. The oxazolone used in the above aminolysiε may contain a blocked amino terminuε which, after the aminolyεis, is deblocked and used for further elongation via acylation. This synthetic variation is shown below (B, standε for a εuitable blocking group aε deεcribed above) . Ul deblock After the desired oxazolone units have been used to elongate a given polypeptide, the polypeptide syntheεis may be continued, if desired, using standard peptide-syntheεis techniques. The structure below illustrates a short polymer containing nine subunitε prepared as above and detached from the εolid phaεe εynthesis support. In the polyamide structure shown above, each of the R groups signifieε alkyl, cycloalkyl, or εubεtituted version thereof; aryl, aralkyl, alkaryl, or subεtituted including heterocyclic verεionε thereof; the R groupε can alεo define a carbocyclic or heterocyclic ring; preferred εtructureε for the R groups are those mimicking the structureε of the side-chains of naturally-occurring amino acids. The syntheses outlined above may be carried out using procedures similar to those described previouεly for related moleculeε and macromoleculeε. Alternatively, diεubstituted chiral azlactones may be utilized to introduce a variety of novel, unnatural residueε into peptideε or proteinε uεing the following multiεtep procedure: a. Synthesis of a peptide whoεe carboxyl terminal reεidue iε chiral and disubstituted, preferably via solid phase syntheεiε: b. Detachment of the peptide prepared by εolid phaεe synthesiε from the support, with reblocking of the N-terminus if neceεεary, followed by cyclization producing the oxazolone aε εhown below: c. Syntheεis of a second deεired peptide εequence on a εolid support: d. Coupling of the peptides produced in stepε (b) and (c) above, under suitable reaction conditionε, producing a novel peptide containing unnatural residues, shown below after detachment of the peptide from the support and removal of all protecting groups used during its εyntheεiε. In the εtructure above, each of the R groupε εignifies alkyl, cycloalkyl, aryl, aralkyl or alkaryl, or subεtituted or εuitably heterocyclic versions thereof; the R groups may also define a carbocyclic or heterocyclic ring; preferably the R groupε are εtructural mimeticε of the εide-chainε of naturally-occurring amino acids. Again, the reactions shown in steps a-d above are carried out using the conditions described above for related caεeε. Couplingε of peptide segments on a support or in solution are carried out using the traditional techniques from the field of peptide syntheεiε. In a variation of the above εyntheεiε, the oxazolone peptide produced in εtep (b) above may be reacted with a variety of bifunctional nucleophilic moleculeε to give acylation products as shown below: The above acylation product may be coupled with a peptide to produce novel chiral hybrids; two coupling routes may be used. (1) If A iε a group which can be condenεed with an amino group, the condenεation reaction is used for coupling. For example, if A is a carboxyl group, condensation with a peptide amine using DCC or similar reagent produces the desired product. Reaction conditionε and suitable (orthogonal) protecting groups well-known in the art, εuch as those deεcribed above, are expected to be uεeful. + HjN-Peptide-COOR DCC Deblock (2) If A iε a εuitable nucleophilic group (e.g., hydroxyl, amino, thio, etc.) it may be uεed to open a peptide oxazolone containing a protected amino terminus. In the case shown below, groups Y, A and Z of the general structure shown above have been defined as follows: Y = NCH 3 , A = SH and Z = CH 2 CH 2 : The above reactionε are run under conditionε, εimilar to thoεe deεcribed above for related peptide εyntheεeε. A great variety of molecules possesεing nucleophilic hydroxyl, thio, amino and other groups, e.g., carbohydrates, may be conjugated with peptidic and related frameworks uεing reactionε with εuitable oxazoloneε aε outlined above. Alternatively, reεidues may be attached to or inserted into peptide chains uεing oxazolones with reactive groups attached at the 2-position of the ring. This may be accompliεhed in either of two ways, as illustrated below for the case of 2-alkenyl azlactoneε. (1) Nucleophilic attack on an azlactone, that waε previouεly derivatized via a Michael addition uεing a nucleophile of general εtructure AXH, with a peptide amine: Peptide-NH 2 (2) Michael addition of a peptide nucleophile, e.g., a εulfhydryl group, to the double bond of a 2-vinyl oxazolone, followed by nucleophilic attack on the oxazolone ring by another peptide nucleophile, e.g., an amine followed by further modificationε; thiε εequence produceε polymeric molecules of a variety of εtructureε as shown below: 4.2.4 Fabrication of Ozaxolone-Derived Macromolecular Structureε Capable of Specific Molecular Recognition In an embodiment of the invention oxazolone molecular building blockε may be utilized to conεtruct new macromolecular εtructures capable of recognizing specific molecules ("intelligent macromolecules") . Theεe "intelligent macromoleculeε" may be repreεented by the following general formula: P - C - L - R where R iε a structure capable of molecular recognition; L iε a linker; P iε a macromolecular εtructure εerving aε a εupporting platform; C iε a polymeric εtructure serving as a coating which surrounds P. Structure R may be a native ligand of a biological ligand-acceptor, or a mimetic thereof, such as those deεcribed above. Linker L may be a chemical bond or one of the linker εtructures listed above, or a sequence of subunits such as amino acids, aminimide monomers, oxazolone- derived chains of atoms or the like. Polymeric coating C may be attached to the supporting platform either via covalent bonds or "shrink wrapping," i.e., the bonding that reεultε when a εurface iε εubjected to coating polymerization well known to thoεe skilled in the art. This coating element may be 1) a thin crosεlinked polymeric film 10 - 50 A in thickneεε, 2) a croεεlinked polymeric layer having controlled microporoεity and variable thickness, or 3) a controlled microporosity gel. When the εupport platform iε a microporouε particle or a membrane, as described below, the controlled microporoεity gel may be engineered to completely fill the porouε structure of the support platform. The polymeric coatings may be constructed in a controlled way by carefully controlling a variety of reaction parameters, such as the nature and degree of coating crosslinking, polymerization initiator, εolvent, concentration of reactants, and other reaction conditions, εuch aε temperature, agitation, etc., in a manner that iε well known to thoεe εkilled in the art. The εupport platform P may be a pellicular material having a diameter (dp) from 100 A to 1000 μ, a latex particle (dp 0.1 - 0.2 μ) , a icroporouε bead (dp 1 - 1000 μ) , a porous membrane, a gel, a fiber, or a continuous macroscopic εurface. Theεe may be commercially available polymeric materialε, εuch aε εilica, polyεtyrene, polyacrylateε, polyεulfoneε, agaroεe, cellulose, etc. The multisubunit recognition agentε above are expected to be very uεeful in the development of targeted therapeuticε, drug delivery εyεtemε, adjuvantε, diagnoεticε, chiral εelectorε, εeparation systems, and tailored catalystε. In the preεent specification the terms "εurface", "εubεtrate" or "εtructure" refer either to P, P linked to C or P linked to C and L aε defined above. 4.2.4.1 Chiral Alkenyl Azlactone Monomers and Polymerization Products When used on an alkenyl azlactone, the azlactone ring-opening addition reaction discuεsed above may be used to directly produce a wide variety of chiral vinyl monomers. These may be polymerized or copolymerized to produce chiral oligomers or polymerε, and may be further crosslinked to produce chiral beads, membranes, gels, coatings or compoεiteε of theεe materialε. Polymerization Other useful monomers, which may be used to produce chiral croεslinkable polymers, may be produced by nucleophilic opening of a chiral 2-vinyl oxazolone with a suitable amino alkene or other unsaturated nucleophile. Vinyl polymerization and polymer-croεεlinking techniqueε are well-known in the art (see, e.g., U.S. Patent No. 4,981,933) and are applicable to the above preferred procesεeε. R 1 . (Surface) CO- -NH- -C- ■ CO Y—B R 2 4.2.5 Combinatorial Libraries of Peptidomimetics Derived From Oxazolone Moduleε The εynthetic transformations of oxazolones outlined above may be readily carried out on solid supportε in a manner analogouε to performing εolid phaεe peptide εyntheεiε, aε deεcribed by Merrifield and otherε (see for example, Barany, G., Merrifield, R.B., Solid Phaεe Peptide Syntheεiε, in The Peptideε Vol. 2, Groεε E. , Meienhofer, J. edε., p. 1-284, Acad. Preεέ, New York 1980; Stewart, J.M., Yang, J.D., Solid Phaεe Peptide Syntheεis, 2nd ed. , Pierce Chemical Co., Rockford, Illinois 1984; Atherton, E. , Sheppard, R.C., Solid Phase Peptide Synthesiε, D. Rickwood & B.D. Ha eε edε., IRL Preεε ed. Oxford U. Preεε, l 9) . Since the aεεembly of the oxazolone-derived εtructureε is modular, i.e., t't ~ result of serial combination of molecular subunitε, huge combinatorial librarieε of oxazolone-derived oligomeric structures may be readily prepared using suitable solid- phase chemical εyntheεiε techniqueε, εuch as those of deεcribed by Lam (K.S. Lam, et al. Nature 354, 82 (1991)) and Zuckermann (R.N. Zuckermann, et al. Proc. Natl. Acad. Ser. USA. 89, 4505 (1992); J.M. Kerr, et al., J. Am Chem. Soc. 115, 2529 (1993)). Screening of these libraries of compoundε for interesting biological activities, e . g . , binding with a receptor or interacting with enzymes, may be carried out uεing a variety of approacheε well known in the art. With "εolid phaεe" librarieε (i.e., librarieε in which the ligand-candidateε remain attached to the εolid εupport particleε uεed for their synthesiε) the bead-εtaining technique of Lam may be uεed. The technique involveε tagging the ligand-candidate acceptor, e.g., an enzyme or cellular receptor of interest, with an enzyme (e.g., alkaline phosphataεe) whose activity can give rise to color prodution thus staining library support particleε which contain active ligands-candidates and leaving εupport particles containing inactive ligand- candidateε colorleεε. Stained εupport particleε are phyεically removed from the library (e.g., using tiny forceps tht are coupled to a micromanipulator with the aid of a microscope) and used to structurally identify the biologically active ligand in the library after removel of the ligand acceptor from the complex by e.g., washing with 8M guanidine hydrochloride. With "solution- phase" libraries, the affinity selection techniques described by Zuckermann above may be employed. An especially preferred type of combinatorial library is the encoded combinatorial library, which involves the εyntheεiε of a unique chemical code (e.g., an oligonucleotide or peptide) , that iε readily decipherable (e.g., by εequencing using traditional analytical methods) , in parallel with the synthesiε of the ligand-candidateε of the library. The εtructure of the code iε fully descriptive of the εtructure of the ligand and uεed to εtructurally characterize biologically active ligandε whoεe structures are difficult or impoεεible to elucidate uεing traditional analytical methodε. Coding εchemeε for conεtruction of combinatorial librarieε have been deεcribed recently (for example, εee S. Brenner and R.A. Lerner, Proc. Natl. Acad. Sci. USA 89, 5381 (1992); J.M. Kerr, et al. J. Am. Chem. Soc. 115, 2529 (1993)). Theεe and other related εchemeε are contemplated for uεe in conεtructing encoded combinatorial librarieε of oligo erε and other complex εtructureε derived from oxazoloneε. The power of combinatorial chemiεtry in generating εcreenable librarieε of chemical compoundε e.g., in connection with drug diεcovery, haε been described in several publications, including those mentioned above. For example, uεing the "εplit εolid phase syntheεis" approach outlined by Lam et al, the random incorporation of 20 oxazolones into pentameric structures, wherein each of the five subunitε in the pentamer is derived from one of the oxazolones, produces a library of 20 5 = 3,200,000 peptidomimetic ligand- candidateε, each ligand-candidate is attached to one or more solid-phase synthesis support particles and each such particle contains a single ligand-canditate type. Thiε library can be conεtructed and εcreened for biological activity in juεt a few days. Such is the power of combinatorial chemistry using oxazolone modules to construct new molecular candidateε. The following iε one of the many methodε that are being contemplated for use in constructing random combinatorial libraries of oxazolone-derived compoundε; the random incorporation of three oxazoloneε derived from the amino acidε glycine methyl-ethyl-glycine ,and isopropyl methyl glycine to produce 27 trimeric structures^linked to the support via a succinoyl linker is given as an example. (1) A εuitable εolid phase synthesis support, e.g., the chloromethyl resin of Merrifield, iε split into three equal portions. (2) Each portion iε coupled to one and one of the glycineε εhown above after converεion to the acylated t-butyl eεter derivative: (?) = polystyrene R,.R 2 = H, CH 3 , Cli 2 CH 3 , (CH 3 ) 2 CH The conditionε for carrying out the above tranεformationε are well known and used routinely in the art of peptide synthesis as described in the references given above. (3) Each amino acyl resin portion is treated with an acid solution such as neat trifluoroacetic acid (TFA), or preferably, a 1:1 mixture of TFA and CH 2 C1 2 , to remove the t-Bu blocking group. The resulting acyl amino acid resin is treated with ethyl chloroformate as described above producing the oxazolone reεin. (4) The three oxazolone reεin portionε are thoroughly mixed and the reεulting mixture iε εplit into three equal portionε. (5) Each of the reεin portions is coupled to a different glycine protected aε t-butyl eεter using the conditions deεcribed above; the amide product iε 0 deprotected as described above, for each of the reεin portionε and cyclized to the oxazolone uεing the reaction with ethyl chloroformate. (6) The reεulting reεin portionε are mixed thoroughly and then εplit again into three equal portionε. (7) Each of the reεin portionε iε coupled to a different glycine, containing a carboxyl protected as the 5 t-butyl ester, and the product iε deprotected uεing TFA aε deεcribed above; the reεin portionε are mixed producing a library containing 27 typeε of reεin beadε, each type containing a single oxazolone- derived tripeptide analog linked to the support via 0 a succinoyl linker; this linker may be severed using acidolysiε to produce a "εolution-phaεe" library of peptides whose N-terminus iε εuccinoylated Many modificationε of thiε general εcheme are enviεioned, including the direct attachment of the ligand candidateε via a C-N bond uεing a benzhydryl εupport, which would allow the εtraight forward detachment of the ligand candidateε from the εupport via acidolyεis for further study ("one-head, one-peptide-analog syntheεiε") . 4.2.6.1 Deεign and Synthesis of Oxazolone-Derived Glycopeptide Mi etics A great variety of εaccharide and polyεaccharide εtructural motifε incorporating oxazolone- derived εtructureε are contemplated including but not limited to the following. (1) Oxazolone-derived εtructureε which mimic native peptide ligandε capable of binding to εaccharide and polyεaccharide receptors using the design and synthesis techniques that are deεcribed above. (2) Oxazolone-derived εtructureε linking mono- , oligo- or polymeric εaccharideε with each other or with other structures capable of recognizing a ligand acceptor. A wealth of chemical methods for syntheεiε of the above εaccharideε are available. The art of carbohydrate chemiεtry deεcribeε numerouε εugarε of variety of εizeε with εelectively blocked functional groupε, which allowε for selective reactions with oxazolone and related species producing the desired products (see Comprehensive Organic Chemiεtry. Sir Derek Barton, Chairman of Editorial Board, Vol. 5, E. Haεlam, Ed., pp. 687-815; A. Streitwieser, CH. Heathcock, E. Kosower, Introduction to Organic Chemistry. 4th Edition, MacMillan Publ. Co., New York, pp. 903-949. For example, Brigl's anhydride εhown below can be reacted with unhindered alcoholε to produce β- glucosides uεing well-known experimental conditionε. The reεulting εugar, blocked at all poεitionε except poεition 2, can be uεed to open a εuitable oxazolone uεing the reaction conditionε deεcribed above, e.g., in the abεence or preεence of a Lewiε acid catalyst such as BF 3 in a suitable inert organic solvent (e.g., EtOAC, dioxane, etc. ) . Similarly the sugar that results from reaction of D-glucose with benzaldehyde can be readily blocked at poεitionε 1 and 6, by εequential reactions with an alcohol in the presence of acid, and tritylation using techniques well known in the art of carbohydrate chemistry. The resulting εugar, with position 3 unblocked can be used selectively as described above to derivatize a desired oxazolone structure. 2,4-O-benzylidene-D-glucose A εuitable oxazolone can alεo be riηg-opened by a εugar containing reactive amino εubstituents, i.e., an aminosaccharide or polyaminosaccharide. For example, reaction with muramic acid iε expected to proceed as follows . Similar treatment which is shown below, of the structurally interesting ambecide paromomycin, with 1 to 5 equivalents of a tailored oxazolone is expected to produce a series of novel εtructureε in which a branched tetraεaccharide εcaffold supports peptidomimetic structures derived from oxazoloneε in a geometrically defined manner. (3) Use of oxazolone-derived structures as replacements of glycosidic linkages. Selective blocking of all but one hydroxyl in a sugar allows the εelective oxidation of the hydroxyl to the carbonyl-derivative, which can then be uεed in an aldol-type condenεation reaction with a ethylene oxazolone to produce an alkene oxazolone; thiε can then be ring-opened, by e.g., the anomeric hydroxyl of a εugar to give a novel saccharide after deprotection. OLIGONUCLEOTIDES 4.2.7 Deεign and Synthesis of Oxazolone-Derived Oligonucleotide Mimetics The art of nucleotide and oligonucleotide synthesis has provided a great variety of suitably blocked and activated furanoseε and other intermediateε which are expected to be very uεeful in the construction of oxazolone-derived mimetics fComprehensive Organic Chemistry. Sir Derek Barton, Chairman of Editorial Board, Vol. 5, E. Haslam, Editor, pp. 23-176). A great variety of nucleotide and oligonucleotide structural motifs incorporating oxazolone-derived structures are contemplated including, but not limited to, the following. (1) For the synthesis of oligonucleotides containing peptidic oxazolone-derived linkers in place of the phosphate diester groupings found in native oligonucleotides, the following approach is one of many that is expected to be useful. (2) For the synthesis of structures in which an oxazolone-derived grouping is used to link complex oligonucleotide-derived units, an approach such as the following is expected to be useful. 5. Example: Characterization of the Enantiometric Purity of Oxfenacine This example teaches the use of the ring opening reaction of the pure chiral iso er azalactone (S)-(-)-4-difluoromethyl-4-benzyl-2-vinyl-5-oxazolone (1) with racemic mixtures of the methyl esters of (R)- and (S)-p-hydroxyphenylglycine to form the diastereomeric conjugateε (2) and (3) , as shown: These diastereomers can be separated by standard HPLC methods on normal-phase silica to quantitatively assay the enantiomeric composition of the starting p- hydroxyphenylglycineε from which the eεters are produced. The (S)-isomer of p-hydroxyphenylglycine (oxfenacine) is an effective therapeutic agent for promoting the oxidation of carbohydrates when this process is depressed by high fatty acid utilization levels (such as occurs in ischemic heart disease) , and is also an important chiral intermediate in the production of penicillin, amoxicillin and several other semisynthetic antibiotics, including the cephalosporins. Oxfenacine is prone to racemization, and the assay for chiral purity described in this example therefore represents a useful development and quality-control tool. 6. Example: Resolution of Racemic p-Hydroxyphenyl Glvcine Esterification of p-hvdroxyphenyl glycine 0.3 g (0.2 ml) thionyl chloride was added dropwise to 5 ml of a stirred solution of 0.4 g of the stereoisomeric mixture of 4-hydroxyphenylglycine enantiomers to be characterized in methanol and the temperature of the mixture kept between 10 and 20°C with ice cooling. The reaction was allowed to proceed at room temperature for 1 hour. The methanol was then removed at room temperature under aspirator vacuum (10 torr) on a rotary evaporator and a solid was obtained. This solid was dissolved in 10 ml of deionized water and the pH adjusted to 9.2 with 0.88 M ammonium hydroxide. The solution was then stirred for 1 hour at 10°C and the precipitated solid ester mixture was filtered off, washed with deionized water and dried at 45°C under vacuum to give 0.41 g of product (94%). Ring-Opening Addition. 0.181 g (0.001 ol) of the esterified 4-hydroxyphenylglycine prepared as outlined above was dissolved in 10 ml of peroxide-free dry dioxane. To this mixture was added 0.251 g (0.001 mol) of (S)-4-difluoromethyl-4-benzyl-2-vinyl-5-oxazolone, and the resulting solution heated at reflux for 2 hours. The dioxane was removed by rotary evaporation and 0.43 g (100%) of the pale yellow solid amide residue was isolated. HPLC Analysis. A solution of the diastereoπteric amides waε prepared in methylene chloride at a concentration of 7 mg/ l. This solution was injected into a DuPont Model 830 liquid chromatograph equipped with a detector set at 254 nm using a 20 μl loop valve injection system. The sample was chromatographed on a 25 cm x 0.4 cm stainless steel HPLC column packed with 5μ Spherisorb S5W silica gel using a 98/1/1 cyclohexane/n-butanol/isopropanol mobile phase at a flow rate of 0.9 ml/miri. The enantiomeric amide conjugates were then quantitated using a calibration curve generated with a series of synthetic mixtures containing varying ratios of the two pure enantiomerε. The pure L-isomer was purchased from Schweizerhall Inc. The pure D-isomer was prepared from the commercially available D,L-racemate obtained from MTM Reεearch Chemicalε/Lancaster Synthesiε Inc. by the method of Clark, Phillips and Steer (J. Chem. Soc.. Perkins Trans. I at 475 [1976]). f S) -4-difluoromethyl . 4-benzyl-2-vinyl-5-oxazolone 5.43 g (0.05 mol) of ethyl chloroformate was added with stirring to 13.46 g (0.05 mol) of N-acryloyl- (S)-2-difluoromethyl phenylalanine in 75 ml of dry acetone at room temperature. 7.0 ml (0.05 mol) of triethylamine were then added dropwise over a period of 10 min. , and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours). The triethylamine hydrochloride was removed by filtration, the cake was slurried in 25 ml of acetone and refiltered. The combined filtrates were concentrated to 50 ml on a rotary evaporator, refiltered, cooled to -30°C and the crystallized product was collected by filtration and dried in vacuo to give 10.05 g (80%) of (S)-4- difluoromethyl-4-benzyl-2-vinyl azlactone. NMR (CDC1 3 ) ; CH 2 = CH - chemical shifts, splitting pattern in 6 pp region and integration ratios diagnostic for structure. FTIR (mull) strong azlactone CO band at 1820 cm" 1 . N-Acryloyl-fS)-2-difluoromethyl phenylalanine. 21.5 g (0.1 mol) (S)-2-difluoromethyl phenylalanine, prepared using the method described by Kolb and Barth (Liebigs Ann. Chem. 1668 (1983)), was added with stirring to a solution of 8.0 g (0.2 mol) of sodium hydroxide in 100 ml water and stirred at this temperature until complete solubilization was achieved. 9.05 g (0.1 mol) acryloyl chloride was then added dropwise with stirring, keeping the temperature at 10- 15°C with external cooling. After addition was complete, stirring was continued for 30 min. To this solution 10.3 ml (0.125 mol) of concentrated hydrochloric acid was added over a 10-min. period, keeping the temperature at 15°C. After addition was complete, the reaction mixture was stirred an additional 30 min. , cooled to 0°C, and the solid product was collected by filtration, washed well with ice water and pressed firmly with a rubber dam. The resulting wet cake was recrystallized from ethanol/water to yield 18.8 g (70%) of N-acryloyl-(S)-2-difluoromethyl phenylalanine. NMR (CDC1 3 ) : chemical shifts, CH 2 = CH - splitting pattern and integration ratios diagnostic for structure 7. Example: Preparation of Chiral Chromatographic Stationary Phase Ring Opening Formation of Conjugate with Aminopropyl Silica 5.0 g of aminopropyl-functionalized silica was slurried in 100 ml benzene in a three-necked flask equipped with a stirrer, a heating bath, a reflux condenser and a Dean-Stark trap. The mixture heated to reflux and the water removed azeotropically. 3.69 g (0.01 mol) of (S)-4-ethyl,4-benzyl-2-(3 , ,5 l - dinitrophenyl)-5-oxazolone waε added and the mixture waε heated at reflux for 3 hourε. The mixture was subsequently cooled, and the silica collected on a Buechner filter and washed with 50 ml benzene. The wet cake was reslurried in 100 ml methanol and refiltered a total of four times. The resulting product was dried in a vacuum oven set for 30" and 60°C to yield 4.87 g functionalized silica. The bonded phase was packed into a 25 cm x 0.46 cm stainless-εteel HPLC column from methanol, and successfully used to separate a series of mandelic acid derivatives using standard conditions. (S)-4-ethyl.4-benzyl-2- (3 ' .5 '-dinitrophenyl)-5-oxazolone 1.09 g (0.01 mol) of ethyl chloroformate was added with stirring to 3.87 g (0.01 mol) N-3,5- dinitrobenzoyl-(S)-2-ethyl phenylalanine in 75 ml dry acetone at room temperature. 1.4 ml (0.01 mol) of triethylamine was added dropwise over a 10-min. period and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours). The triethylamine hydrochloride was removed by filtration and the cake was slurried with 25 ml acetone and refiltered. The combined filtrates were concentrated to 50 ml on a rotary evaporator, refiltered, cooled to -30°C and the crystallized roduct was collected by filtration and dried in vacuo to yield 2.88 g (78%) of (S)-4-ethyl-4-benzyl-2- (3' ,5'-dinitrophenyl)azlactone. NMR (CDC1 3 ) : Frequencies and integration ratios diagnostic for structure. FTIR: strong azlactone band at ca. 1820 cm 1 . N-3.5-dinitrobenzloyl- ( S)-2-ethγlphenylalanine 19.3 g (0.1 mol) of (S)-2-ethylphenylalanine, prepared from (S)-phenylalanine and ethyl iodide using the method described by Zydowsky, de Lara and Spanton (55 J. Org. Chem. 5437 (1990)) was added with stirring to a solution of 8 g (0.2 mol) sodium hydroxide in 100 ml water and cooled to about 10°C. The mixture was then stirred at this temperature until complete solubilization was achieved. 23.1 g (0.1 mol) 3,5-dinitrobenzoyl chloride was then added dropwise with stirring, keeping the temperature at 10-15°C with external cooling. After this addition was complete, stirring was continued for 30 min. To this solution was added 10.3 ml (1.25 mol) of concentrated HCl over a 10 min. period, again keeping the temperature at 15°C. During this addition a white solid formed. After the addition was complete, the reaction mixture was stirred for an additional 30 min. , cooled to 0°C and the white solid was collected by filtration, washed well with ice water and pressed firmly with a rubber dam. The resulting wet cake was recrystallized from ethanol/water and dried in a vacuum oven set for 30" at 60°C to yield 27.1 g (70%) N-3,5-dinitrobenzoyl-(S)-2- ethyl phenylalanine. Preparation of Aminopropyl-Functionalized Silica. 200 g 015M Spherosil (IBF Corporation) was added to 500 ml toluene in a one-liter three-necked round-bottomed flask equipped with a Teflon paddle stirrer, a thermometer and a vertical condenser set up with a Dean-Stark trap through a claisen adaptor. The slurry was stirred, heated to a bath temperature of 140°C and the water azeotropically removed by distillation and collected in the Dean-Stark trap. The loss in toluene volume was meaεured and compenεated for by the addition of incremental dry toluene. 125.0 g 3- aminopropyltrimethoxysilane was added carefully through a funnel and the mixture stirred and refluxed for 3 hours with the bath temperature set at 140°C. The reaction mixture was cooled to about 40°C and the reεulting functionalized silica collected on a Buechner filter. The silica was then waεhed twice with 50 ml toluene, sucked dry, reslurried in 250 ml toluene, refiltered, reslurried in 250 ml methanol and refiltered a total of three timeε. The reεulting methanol wet cake was dried in a vacuum oven set for 30" at 60°C to yield 196.4 g aminopropyl silica. 8. Example: Ring-Opening Conjugation of (S)-l-(l- naphthyl)ethylamine With The Michael-Addition Product Of A inomercapto-Functionalized Silica And (S)-4-Ethyl-4-benzyl-2-acryloyl-5-oxazolone To Produce A Chiral Chromatographic Stationary Phase Formation Of Conjugate With (S)-(!)-(1-naphthvD- ethylamine 10.0 g (S)-4-ethyl-4-benzyl-2-(ethylthiopropyl silica)-5-oxazolone was slurried in 100 ml benzene in a three-necked flask equipped with a stirrer, a heating bath, a reflux condenser and a Dean-Stark trap. The mixture was heated to reflux and the water was removed azeotropically. 3.42 g (0.02 mol) (S)-(-)- (l- naphthyl)ethylamine was added and the mixture was heated at reflux for 6 hours. The mixture was then cooled, the silica collected on a Buechner filter and washed with 100 ml benzene. The wet cake was reslurried in 100 ml methanol and refiltered a total of four times. The product waε dried in a vacuum oven set for 30" and 60°C to give 9.72 g functionalized silica. The bonded phase was packed into a 25 cm x 0.46 cm stainless-steel HPLC column from methanol and succesεfully used to separate a series of t-acceptor amine derivatives using standard conditions described in the Chromatography Catalog distributed by Regis Chemical, Morton Grove, 111. 60053 (e.g., the 3,5-dinitro benzoyl derivatives of racemic 2- amino-1-butanol + alpha methyl benzye amine) . Michael Addition by Mercaptopropyl Silica 20 g mercaptopropyl silica was added to 200 ml benzene in a 500 ml three-necked round-bottomed flask equipped with a Teflon paddle stirrer, a thermometer and a vertical condenser set up with a Dean-Stark trap through a claisen adaptor. The slurry was stirred, heated to a bath temperature of 140°C and the water azeotropically removed by distillation and collected in the Dean-Stark trap. The loss in benzene volume was measured and compensated for by the addition of incremental dry benzene. 6.88 g (0.03 mol) of (S)-4- ethyl,4-benzyl-2-vinyl-5-oxazolone was added and the mixture was stirred and refluxed for 16 hours. The reaction mixture was then cooled to about 40°C. The resulting functionalized silica was collected on a Buechner filter, washed with 50 ml benzene, sucked dry, reslurried in 100 ml of methanol and refiltered a total of four time. The resulting methanol wet cake was dried in a vacuum oven set for 30" at 60°C to yield 19.45 g oxazolone-functionalized silica. (S)-4-ethyl-4'-benzyl-2-acryloyl-5-oxazolone. 10.9 g (0.1 mol) of ethyl chloroformate was added with stirring to 24.7 g (0.1 mol) of N-acryloyl- (S)-2-ethyl phenylalanine in 250 ml dry acetone at room temperature. 14 ml (0.1 mol) of triethylamine was added dropwise over a 10-min. period and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours). The triethylamine hydrochloride was.removed by filtration and the cake was slurried with 50 ml of acetone and refiltered. The combined filtrates were concentrated to 150 ml on a rotary evaporator, refiltered, cooled to -30°C and the crystallized product was collected by filtration and dried in vacuo to yield 19.5 g (85%) (S)-4-ethyl-4-benzyl-2-vinyl-5-azlactone. NMR 9CDC1) : chemical shifts, CH 2 = CH - splitting pattern in 6 ppm region + integration ratios diagnostic for structure. FTIR + (mull) : strong azlactone CO band in 1820 cm" 1 region. Preparation of Mercaptopropyl-Functionalized Silica. 200 g of lOμ (80A) Exsil silica (Exnere Ltd.) was added to 500 ml toluene in a one-liter three-necked round-bottomed flask equipped with a Teflon paddle stirrer, a thermometer and a vertical condenser set a with a Dean- Stark trap through a claisen adaptor. The slurry was stirred, heated to a bath temperature of 1 0°C and the water was azeotropically removed by distillation and collected in the Dean-Stark trap. The loss in toluene volume was measured and compensated for by the addition of incremental dry toluene. 110.0 g of 3- mercaptopropyltrimethoxysilane was added carefully through a funnel and the mixture was stirred and refluxed for 3 hours with the bath temperature set at 140°C. The reaction mixture was then cooled to about 40°C. The resulting functionalized silica was collected on a Buechner filter, washed twice with 50 ml toluene, sucked dry, reslurried in 250 ml toluene, refiltered, reslurried in 250 ml methanol and refiltered a total of three times. The resulting methanol wet cake was dried in a vacuum oven set for 30" at 60°C to yield 196.4 g of mercaptopropyl silica. Chiral azlactone conjugates may similarly be produced using a variety of azlactone derivatives containing at the 2-poεition other groupε capable of undergoing addition (and sequential ring-opening) reactions. Exampleε of theεe groups include hydroxyalkyl, haloalkyl and oxirane groups. 9. Example: Synthesis of a Mimetic of Known Human Elastase Inhibitor Thiε example teacheε the εyntheεis of a competitive inhibitor for human elastase based on the structure of known N-trifluoroacetyl dipeptide analide inhibitors - see, e.g., 107 Eur. J. Biochem. 423 (1980); 162 J. Mol. Biol. 645 (1982) and references cited therein. N-trifluoroacetyl-fS)-2-methyl leucyl-fS) -2- ethylphenylalanyl-p-isopropylanl ide. 0.135 g (0.001 mol) 4-isopropyl analine is dissolved in the minimum amount of an appropriate solvent, such as acetonitrile, and 0.384 g (0.001 mol) of 2-(N-trifluoroacetyl-(S)-2-methyl leucyl)-(S)-4-methyl-4- benzyl-5-oxazolone dissolved in the minimum amount of the same solvent is added gradually to the stirred solution with cooling. Following addition, the reaction mixture is allowed to come to room remperature and is stirred at room temperature for 36 hours. The solvent is then removed in vacuo to yield the solid N-trifluoroacetyl- (S)-2-methyl-leucyl-(S)-2-ethylphenylalanyl analide, useful as a competitive inhibitor of human elaεtaεe in eεsentially quantitative yield. 2-(N-trifluoroacetyl-(S)-2-methvHeucyl)-fS)-4-methyl-4- benzyl-5-oxazolone. 4.1 g (0.01 mol) N-trifluoroacetyl-(S)-2- methylleucyl-(S)-2-methylphenylalanine lithium salt is slurried in 50 ml of an appropriate εolvent, εuch aε dry benzene, in a three-necked round-bottomed flaεk equipped with a εtirrer, heating bath, claisen head, downward condenser, thermometer and dropping funnel. The system is heated to 65°C, and 1.09 g (0.01 mol) of ethyl chloroformate dissolved in 10 ml dry benzene is added over a 10-min. period. Addition is accompanied by the vigorouε evolution of gas and the distillation of a benzene/ethanol azeotrope. Following the completion of the addition, heating iε continued for 30 min. The heating bath iε then removed and the εlurry is stirred for an additional 15 min. The precipitated lithium chloride is carefully removed by filtration and the cake is triturated with benzene and refiltered. The combined filtrates are εtripped using a pot temperature of 40°C to yield 3.50 g (90%) of crude oxazolone. The product was purified by recrystallization from acetone at -30°C. FTIR (mull) : Strong azlactone CO band in 1820 cm '1 region. N-trifluoracetyl-(S)-2-methvHeucγl-(S)-2- methylphenylalanine. 2.23 g (0.01 mol) 2-trifluoroacetyl-(S)-4- methyl-4-iεobutyl-5-oxazolone iε dissolved with stirring in the minimum amount of an appropriate solvent, such as acetonitrile, and 1.85 g (0.01 mol) of the lithium salt of (S)-2-methyl phenylalanine in the minimum amount of the same solvent is added gradually, and with cooling. This salt is obtained by treatment of (S)-2- methylphenylalanine (produced from (S)-phenylalanine and methyl iodide using the method of Zydoski et al., 55 J. Org. Chem. 5437 (1990)) with one equivalent of LiOH in an appropriate solvent, such as ethanol, followed by removal of the solvent in vacuo . After addition of the lithium salt, the reaction mixture is allowed to warm to room temperature and is stirred at room temperature for 36 hours. The solvent is then removed in vacuo to yield the solid N-trifluoroacetyl-(S)-2-methylleucyl-(S)-2- methylphenylalanine lithium salt in essentially quantitative yield. 2-trifluoroacetyl- tS) -4-methyl-4-isopropγl-5-oxazolone. 12.05 g (0.05 mol) of N-trifluoroacetyl-(S)-2- methyl-leucine was stirred at room temperature in 100 ml dry acetone and 5.43 g (0.05 mol) ethyl chloroformate was added. 7.0 ml (0.05 mol) of triethylamine waε added dropwise over a period of 10 min. and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours). The triethylamine hydrochloride was removed by filtration and the cake was slurried with 25 ml of acetone and refiltered. The combined filtrates were concentrated to 75 ml on a rotary evaporator, refiltered, cooled to -30°C and the crystallized product was collected by filtration and dried in vacuo to yield 10.6 g (88%) of (S)-4-methyl-4-isobutyl-2-trifluoroacetyl-5- oxazolone. FTIR (mull) : strong azlactone CO band in 1820 cm" 1 region. N-trifluoroacetyl-(S)-2-methyl-leucine. 14.5 g (0.1 mol) of (S)-2-methyl-leucine, prepared from D,L-leucine methyl ester hydrochloride uεing the method of Kolb and Barth (Liebig'ε Ann. Chem. at 1668 (1983)) waε added with stirring to a solution of 8 g (0.2 mol) of sodium hydroxide in 20 ml water, cooled to 10°C, and the mixture stirred at this temperature until complete solubilization was achieved. 13.25 g (0.1 mol) trifluoroacetyl chloride waε then added dropwise with stirring, keeping the temperature at 10°C with external cooling. After the addition waε complete, stirring was continued for 30 min. To this solution was • added, over a 10-min. period, 10.3 ml (0.125 mol) of concentrated hydrochloric acid, again keeping the temperature at 15°C During the addition, a white solid formed. After the addition was complete, the reaction mixture was stirred for an additional 30 min. and cooled to 0°C. The white solid was collected by filtration, washed well with ice water and pressed firmly with a rubber dam. The resulting wet cake was recrystallized from ethanol/water and dried in vacuo to give 17.4 g (72%) of N-trifluoroacetyl-(S)-2-methyl-leucine which was used directly in the following step in the sequence (above) . 11. Example: Synthesis of a Pepstatin Mimetic This example teaches the synthesis of an oxazolone-derived mimetic of the known aspartyl proteaεe inhibitor, pepstatin, which has the structure shown: This mimetic is useful as a competitive inhibitor for proteaseε inhibited by pepstatin. N-iεovaleryl- (S)-2-methylvaleryl-f3S.4S)-statyl- (S)-2- methyl-alanyl-(3S.4S)-statine. The Boc-protected lithium salt prepared as described below simultaneously converted to the acid form and deprotected by treatment with acid under standard deprotection conditions. 5.17 g (0.01 mol) of N- iεovaleryl-(S)-2-methy derivative added to 100 ml dry acetonitrile, stirred at room temperature and 3.17 g (0.01 mol) of the valyl-(S)-4-methyl-4-isopropyl-5- oxazolone waε added with cooling. Once addition waε complete, the mixture was heated to reflux and held at reflux for 1 hour. The solvent then stripped in vacuo to give a quantitative yield of N-isovaleryl-(S)-2- methylvalyl-(3S,4S)-statyl-(S)-2-methylalanyl-(3S,4S)- statine, useful as a pepstatin-mimetic competitive inhibitor for aspartyl proteases which are inhibited by pepstatin (see, 23 J. Med. Chem. 27 (1980) and references cited therein) . NMR (d 6 DMSO) : chemical shifts, integrations and D 2 0 exchange experiments diagnostic for structure. N-Boc- (3S.4S)-statyl- (S)-2-methylalanyl- (3S.4S)-statine lithium salt. 6.84 g (0.02 mol) of the Boc-protected oxazolone prepared below stirred in 100 ml of dry acetonitrile at room temperature and 3.62 g (0.02 mol) of the lithium salt of (3S,4S)-statine, prepared from statine using the method outlined below, was added with cooling. Once addition was complete, the mixture was heated to reflux and held at reflux for 1 hour. The solvent waε then stripped in vacuo to give a quantitative yield of N- <c-(3S,4S)-statyl-(S)-2-methylalanyl-(3S,4S)- statine lit_„um salt. Boc-protected (3S,4S)-statine, [(3S,4S)-4- amino-3-hydroxy-6- methylheptanoic acid] was produced from the commercially available amino acid, coupled with 2-methylalanine using standard peptide synthesis methods and converted to the lithium salt using the method described below. 18.30 g (0.05 mol) of this derivative was stirred in 150 ml dry acetonitrile at room temperature, 5.45 g (0.05 mol) of ethyl chloroformate and 7.0 ml (0.05 mol) of triethylamine were sequentially added with stirring and the mixture was stirred at room temperature until gaε evolution ceaεed (1.5 hourε) . The mixture was then stripped to dryness on a rotary evaporator, the residue was triturated with 100 ml of benzene, filtered to remove salts, and the filtrate was again stripped on a rotary evaporator to yield 16.4 g (96%) of crude 2-BOC-(3S,4S)-statyl-4,4-dimethyl-5- oxazolone. Analytically pure material was obtained by recrystallization from acetone at -30°C. NMR (CDC1 3 ) - chemical shifts and splitting patterns diagnostic for structure. FTIR (mull) : showε a strong azlactone CO band in the 1820 cm '1 region. N-iεovaleryl- ( S)-2-methylvalyl-(S)-4-methyl-4-iεopropyl- 5-oxazolone. 13.46 g (0.04 mol) of 2-isovaleryl-(S)-2- methylvalyl-(S)-2- methyl valine lithium salt, as prepared below, was stirred in 150 ml of dry acetonitrile at room temperature. 4.36 g (0.04 mol) of ethyl chloroformate and 5.6 ml (0.04 mol) of triethylamine were then sequentially added with stirring, and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours). The mixture was then stripped to drynesε on a rotary evaporator, the residue was triturated with 100 ml benzene, filtered to remove salts, and the filtrate was again stripped on a rotary evaporator to yield 12 g (96%) of crude N-isovaleryl-(S)- 2-methylvalyl-(S)-4-methyl-4-isopropyl-5-oxazolone. Analytically pure material was obtained by recrystallization from acetone at -30°c. NMR (CDC1 3 ) : chemical shifts and splitting patterns diagnostic for structure. FTIR (mull) : shows strong azlactone CO band in the 1820 cm" 1 region. N-isovaleryl-fS)-2-methγlvalyl-fS)-2-methyl valine lithium salt. 6.85 g (0.05 mol) of (S)-2-methylvaline lithium salt, prepared from (S)-methyl valine by the method described below, was stirred in 150 ml dry acetonitrile at room temperature and 9.93 g (0.05 mol) of the oxazolone prepared below was added portionwise with cooling. Once addition was complete, the mixture was heated to reflux and held at reflux for 1 hour. The solvent was then stripped in vacuo to give a 98% yield of N-isovaleryl-(S)-2-methylvalyl-(S)-2-methyl valine lithium εalt. This salt was used directly in the next step (above) . 2-isovaleryl-fS)-4-methyl-4-isopropyl-5-oxazolone. 2-(S)-methylvaline was prepared from (S)-valine by the method described by Kolbe and Barth fLiebigs Ann. Chem. at 1668 (1983)), and was acylated with isovaleryl chloride using standard acylation methods to produce N- isovaleryl-(S)-methylvaline, this was subsequently treated with one equivalent of LiOH in ethanol, followed by removal of the solvent in vacuo to yield the N- isovaleryl-(S)-methylvaline lithium salt. 22.3 g (0.1 mol) of this Li salt was stirred in 150 ml of dry acetonitrile at room temperature, 10.9 g (0.01 mol) of ethyl chloroformate and 14 ml (0.1 mol) of triethylamine were sequentially added with stirring, and the mixture was stirred at room temperature until gas evolution ceased (1.5 hours) . The mixture was then stripped to dryness on a rotary evaporator, the residue was triturated with 150 ml benzene, filtered to remove salts and the filtrate was again stripped on a rotary evaporator to yield 17.4 g (85%) of crude 2-isovaleryl- (S)-4-methyl-4-iεopropyl-5-oxazolone. Analytically pure material was obtained by re-crystallization from acetone at -30°C. FTIR (mull) : showε a εtrong azlactone CO band in the 1820 cm "1 region. NMR (CDC1 3 ) : chemical shifts and splitting patterns diagnostic for structure. 12. Example: Synthesis of a Mimetic Inhibitor of the HIV Protease This example teaches the synthesis of a competitive inhibitor for the HIV protease, baεed on the inεertion of a chiral azlactone reεidue into a strategically important position in the scissile position of the known substrate, Ac-Ser-Leu-Asn-Phe-Pro-Ile-Val- OMe. See, e.g., 33 J. Med. Chem. 1285 (1990) and references cited therein. deprotect eO-D-Ser-D-Leu-D-Asn- 0.341 g (1 mol) of HN-(L)-Pro-(L)-Ile-(L)-Val- OMe prepared using standard peptide-synthesis techniques, is dissolved in the minimum amount of DMF. To this mixture is added 0.229 g (1 mmol) 2-acryloyl-(S)-4-ethyl- 4-benzyl-5-oxazolone described above, and the mixture is stirred at room temperature until the Michael addition reaction has proceeded to completion (as monitored by TLC) . 0.393 g (1 mmol) of MeO-D-Ser(Bzl)-D-Leu-D-Asn-NH 2 , prepared from the BOC-protected D-amino acids using standard peptide protection and coupling chemistries (see, e.g., J. Med. Chem. 1285 (1990) and references cited therein) is then added and the mixture is heated to 60°C and stirred at this temperature for an additional 12 hours. The DMF is then removed under high vacuum and the residue is purified by standard C18 reverse-phase chromatography to yield the protected peptide. The side- chain blocking groups are subsequently removed using standard peptide deprotection techniques to yield the product MeO-D-Ser-D-Leu-D-Asn-NH-CO-(S)-Phe-[Me]-NH-CO- CH2-CH2-L-N-Pro-L-Ile-L-Val-OMe, useful as a competitive inhibitor for the HIV protease. 13. Example: Synthesis of a Mimetic Inhibitor for the HIV Protease This example teaches the synthesis of another competitive inhibitor for the HIV protease. In this case the phenyl substituent is replaced with a uracil derivative 0.82 g (1 mmol) of the uracil derivative, whose preparation is described below, is coupled through the free proline carboxylic acid group to 0.244 g (1 mmol) of 25 Ile-Val-OMe using standard peptide coupling methods. The product is purified by standard C18 reverse-phase chromatography to yield the protected peptide. The Bzl side-chain blocking group is then removed using standard deprotection techniques to yield the product shown above, 30 useful as a competitive inhibitor for the HIV protease. 35 0.47 g (1 mmol) of the (S)-(S)-proline- vinylazlactone Michael adduct iε dissolved in the minimum amount of DMF. 0.488 g (1 mmol) of MeO-D-Ser-(Bzl)-D- Leu-D-Aεn-NH 2 , prepared from the BOC-protected amino acid via εtandard peptide synthesiε techniqueε (see, e.g., 33 J. Med. Chem. 1285 (1990) and references cited therein) is then added and the mixture is heated to 60°C and stirred at this temperature for 12 hours. The DMF is then removed under high vacuum to yield 0.95 g of crude product. 2.33 g (5 mmol) of L-proline is dissolved in the minimum amount of DMF, 1.75 g (5 mmol) of racemic uracil-functionalized azlactone is added and the mixture is stirred at room temperature until the Michael addition reaction proceeds to completion (as monitored by TLC) . The DMF is then removed under high vacuum and the diastereomeric mixture is purified by standard normal- phase chromatography to give the desired (S)-(S)-Michael adduct. 3.69 g (0.01 mol) racemic N-acryloyl-2-methyl- (3'methyluracilJ-S'-alanine is stirred with 50 ml of dry acetone and 1.09 (0.01 mol) of ethyl chloroformate was added. 1.4 ml (0.01 mol) of triethylamine is added dropwise over a period of 10 min. and the mixture is εtirred at room temperature until the evolution of gas ceases (1.5 hours). The triethylamine hydrochloride is removed by filtration and the cake was slurried with 20 ml of acetone and refiltered. The combined filtrates are concentrated to 50 ml on a rotary evaporator, cooled to - 30 C C and the crystallized product collected by filtration and dried in vacuo to yield racemic 4-(2-methyl-5'- [3'methyluracil])-4-methyl-2-vinylazlactone. 17.15 g (0.05 mol) of the racemic 2-(3'- methyluracil)-5'-methylalanine ethyl ester is added with stirring to a solution of 4.0 g (0.1 mol) sodium hydroxide in 100 ml water. The mixture is stirred until complete solubilization is achieved, and then cooled to 10°C. 0.05 g 2,6-di-t-butyl-p-cresol is added as a polymerization inhibitor followed by 4.52 g (0.05 mol) acryloyl chloride, which is added dropwise with stirring, keeping the temperature at 10-15°C with external cooling. To this solution is then added over a 10-min. period 5.7 ml (0.0625 mol) concentrated hydrochloric acid, again keeping the temperature at 15°C. After the addition is complete, the reaction mixture is εtirred for an additional 30 min., cooled to 0°C, and the solid product is collected by filtration, washed well with ice water and presεed firmly with a rubber dam. The resulting wet cake is recrystallized from ethanol/water, and the wet cake is hydrolized with 6N HCL to yield 12.91 g (70%) of racemic N-acryloyl-(3'-methyluracil)-5'-methylalanine. H 3 0 + 20.5 g (0.1 mol) of the Schiff base prepared from the ethyl ester of alanine and benzaldehyde according to the method of O'Donnell et al . (23 Terahedron Lett. 4259 (1982)) and 17.4 g (0.1 mol) of 3- methyl-5-chloromethyluracil in the mimimum amount of methylene chloride is added dropwise with stirring to a mixture of finely powdered potassium hydroxide and a catalytic amount (0.01 eq) of the phase-transfer reagent C 6 H 5 CH 2 NEt 3 Cl in the same solvent at 0°C. Following addition, the mixture is stirred at 10°C until the starting material is consumed (approximately 2 hours) . An aqueous workup is followed by mild acid hydrolysis of the crude with IN HCl/Et 2 0 at 0°C for 3 hours to yield 29.5 g (86%) of the racemic α-methyl amino acid ester. Synthesiε of 3-methyl-5-chloromethyluracil A. 74.08 g (1 mol) of N-methyl urea and 216.2 g (1 mol) of diethylethoxymethylenemalonate are heated together at 122 °C for 24 hourε, followed by 170°C for 12 hours to yield the 3-methyluracil-5-carboxylic acid ethyl ester in 35% yield, following recrystallization from ethyl acetate. B. 30 g 3-methyluracil-5-carboxylic acid ethyl ester was saponified with 10% NaOH to give the free acid in 92% yield, after standard work-up and recrystallization from ethyl acetate. C. 20 g of 3-methyluracil-5-carboxylic acid was decarboxylated at 260°C to give a quantitative yield of 3-methyluracil. D. 3-methyluracil-5-carboxylic acid was treated with HCL and CH 2 0 using standard chloromethylation conditions to yield 3-methyl-5-chloromethyluracil in 52% yield, following standard work-up and recrystallization from ethyl acetate. 14. Example: Preparation of a Chiral Crosslinking Conjugate Monomer 4.59 g (0.02 mol) (S)-4-ethyl,4-benzyl-2-vinyl- 5-oxazolone as prepared in Example 3.3.3 above was added portionwise to a εtirred solution of 1.14 g (0.02 mol) allyl amine in 75 ml of methylene chloride cooled to 0°C with an ice bath. After 15 min. the mixture was allowed to warm to room temperature, and was then stirred at room temperature for 4 hours. The solvent was stripped under aspirator vacuum on a rotary evaporator to yield 5.7 g of crude monomer, identified by NMR and FTIR analyses. The product was recrystallized from ethyl acetate to yield pure white crystalline monomer, useful for fabricating crosslinked chiral gels, beads, membranes and composites for chiral separations. 15. Examples: Synthesis of Conjugate Useful in Isolation and Purification of Serotonin-Binding Receptors 28.6 g (0.1 mol) of sieve-dried octadecane thiol and 13.9 g (0.1 mol) of 2-vinyl-4,4•- dimethylazlactone are mixed in a dry round-bottomed flask equipped with a magnetic stirrer and a drying tube filled with Drierite and cooled in an ice bath. After 1 hour the mixture is allowed to come to room temperature and is held at room temperature for four days. The product is then dissolved in 250 ml of a suitable solvent, the system cooled in an ice bath, and a chilled solution of 17.62 g (0.1 mol) of serotonin in 250 ml of the same solvent is added over a 30-min period. The reaction mixture is allowed to come to room temperature over a 2- hour period and stirred at room temperature for a further 4 hours. The solvent is then removed by freeze drying to yield 60 g of the derivative which is useful as a ligand for the stabilization and isolation of serotonin-binding membrane receptor proteins. PRODUCT] 16. Example: Synthesis of a Conjugate Useful in the Isolation and Purification of the Morphine Receptor To a solution of 0.285 g (0.001 mol) of norcodeine (I) disεolved in 50 ml of the appropriate εolvent, such as benzene, is added a solution of 0.139 g (0.001 mol) of 4,4 '-dimethylvinylazlactone (II) in 10 ml of the same εolvent. The reεulting solution is heated to 70 °C and held at this temperature for 10 hourε. At the end of thiε time the solvent is removed under vacuum to yield 0.42 g of the Michael adduct (III). 0.21 g (0.0005 mol) of this adduct is added portionwise over a 30 minute period, with stirring, to 0.23 g (0.0005 mol) of lucifer yellow-CH (IV) in 50 ml of a 1:1 mixture of water and an appropriate solvent, such as acetone, adjusted to pH 7.5. at 0 °C under a nitrogen blanket. The reaction mixture is stirred at 0 °C for 1 hour and then allowed to come to room temperature. The mixture is then stirred at room temperature under a nitrogen blanket for 7 days. The solvent is removed under vacuum and the water is removed by freeze drying to give the product (V) . (V) is useful as a probe for the study of receptor proteins that bind morphine and its derivatives. 17. Example: Synthesis of Conjugate Useful in the Isolation and Purification of Proteins Binding Cibacron Blue To 4.03 g (0.01 mol) of a stirred solution of thiocholesterol in 100 ml of an appropriate solvent, such as benzene, is added a solution of 1.39 g (0.01 mol) of 2-vinyl-4,4 '-dimethyl-5-azlactone in 10 ml of the same solvent. The mixture is heated to 70 °C and stirred at this temperature for 4 hours. The solvent is completely removed under vacuum and the product (VI) is redissolved in 200 ml of dimethyl formamide. This solution is cooled in an ice bath and 8.5 g (0.01 mol) of the Cibacron Blue derivative (VII) , prepared aε deεcribed below, dissolved in 250 ml of DMF and 100 ml of triethylamine is added over a 30 min period. The reaction mixture is stirred with cooling for 1 hour, allowed to come to room temperature amd stirred for 12 hours. The mixture is then added to 1 liter of 25% NaCl in water at 0 °C and stirred for 15 min; then 100 ml of 10M hydrochloric acid is added with stirring and cooling, and the blue precipitate is collected by filtration, reslurried in l liter of water and refiltered. This extraction procedure is repeated two more times. The product (VIII) is dried at 60 °C in a vacuum oven at 30" of vacuum. (VIII) iε useful for inεerting and poεitioning the Cibacron Blue functionality, which iε a broadly versatile affinity recognition ligand in cell membranes for the study of transmembrane processes involving proteins that bind to the dye function. VII VIII 35 Preparation of Cibacron Blue Derivative fVIII) 40.0 g (0.05 mol) of Cibacron Blue F3 GA is dissolved in 1 liter of DMF at 40 °C with stirring. To this εolution iε added 26.5 g (0.23 mol) of hexamethylene diamine with stirring, followed by 4.0 g (0.05 mol) of pyridine. The reaction mixture is allowed to stir overnight and the pH is adjusted to 2.0 by the addition of 80 ml of 10M hydrochloric acid and 940 g of NaCl. 3.5 liters of water are added to precipitate the modified dye. The mixture is stirred for 1 hour and the dye is collected by filtration. The cake is waεhed with an additional 3.5 liters of water at pH 2.0 water and dried at 70 °C in a vacuum oven at 30" of vacuum to yield 34.0 g of the amino-functionalized dye (VII) . 18. Example: Synthesis of a Photoreactive Conjugate Useful in the Isolation and Purification of β-N-Acetγlglucosamidase 3.63 g (0.01 mol) of 2-acetamido-2-deoxy-l- thio-b-D-glucopyranoεe-3,4,6-triacetate (IX) and 1.39 g of 2-vinyl-4,4'-dimethylazlactone are diεεolved with stirring in 100 ml of an appropriate solvent, heated to 70 °C and held at this temperature with stirring for 12 hours. At the end of this time the mixture is cooled to room temperature and 1.53 g (0.01 mol) of dopamine, dissolved in 50 ml of the same solvent is added, with cooling and stirring, over a 30 min period. The temperature is the allowed to rise to room temperature and the reaction mixture is stirred overnight. The solvent is then removed by freeze drying to produce 6.5 g of the product (X) which is useful for the study of beta- N-acetylglucosamidase and related proteins of similar specificity, since the carbohydrate functionality can bind to these proteins (See 350 Biochim. Biophvε. Acta. 437 (1974)). The dopamine-connected catechol functionality is a photographic developer, capable of photographic amplification by means of standard techniques. 19. Example: Svntheεiε of a Ligand of Protein Kinase 100 mg of the 20-mer cysteine variant, Cys-Thr- Tyr-Ala-Asp-Phe-Ile-Ala-Ser-Gly-Arg-Thr-Gly-Arg-Arg-Asn- Ala-Ile-His-Asp, of a protein kinase natural binding peptide ligand PK (5-24) (See, 253 Science 414 (1991)), synthesized by standard peptide synthesis techniques, is shaken with 7 mg of 2-vinyl-4,4'-dimethyl azlactone in 0.5 ml of an appropriate solvent at room temperature for 6 days. At the end of this period 23 mg of Lucifer Yellow CH in 0.5 ml of water is added, and the mixture is shaken at room temperature for 6 hours. The solvents are removed by freeze drying to yield 130 mg of the bifunctional adduct (XI) , which is useful as a ligand for competitive evaluation of the binding affinity of competitive ligands for protein kinases and structurally similar proteins. Example: Synthes s of Mater als Useful as Coat ngs This example describes preparation of a coating by a ring-opening reaction followed by Michael-addition. In the first synthetic step, 8.82 g (0.113 mol) of 95% N-methylethylenediamine were disεolved in 75 ml methylene chloride with stirring and cooled to 0 °C in an ice bath. Then, 13.9 g (0.10 mol) of dimethylvinylazlactone (the starting species illustrated in Eq. 3 with R 2 = R 3 = CH 3 ) pre-cooled to 0 °C were added to the methylene chloride mixture such that the temperature remained below 5 °C. The solution was then stirred at room temperature. After approximately 15 min a white precipitate began to form. The mixture was stirred for an additional 2 h at 0 °C. A white solid was collected on a Buechner funnel, washed twice with 25 ml methylene chloride and air dried to yield 13.92 g of the ring-opened adduct, identified by nuclear magnetic resonance (NMR) and Fourier transform infrared reflection (FTIR) spectroscopy as follows: NMR (CDC1 3 ) : CH 3 -N/gem (CH 3 ) 2 ratio 1:2; CH 2 = CH - splitting pattern in 6 ppm regioin, integration ratios and D 2 0 exchange experiments diagnostic for structure. FTIR (null) : azlactone CO band at 1820 cm" 1 absent; strong amide bands present in 1670 - 1700 cm" 1 region. In the next synthetic step, 6.39 g (0.3 mol) of (I) and 4.17 g (0.3 mol) of dimethylvinylazlactone were disεolved in 50 ml of benzene and heated to 70 °C for 4 h. The flask waε cooled to room temperature, εtoppered and allowed to εtand for 3 days at room temperature. The solvent was then decanted off from the thick oil that had formed. Thiε oil was dissolved in 50 ml acetone and stripped to produce another thick oil. This latter oil was pumped on at 1 torr overnight to yield 3.53 g of a white crystalline solid, identified by NMR and FTIR spectroscopy as follows: NMR: CH 3 -N/gem (CH 3 ) 2 ratio 1:4; CH 2 = CH - splitting pattern in 6 ppm region, integration ratios and D 2 0 exchange experiments diagnostic for structure. FTIR (null) : strong azlactone CO band at 1800 cm" 1 . In the final synthetic step, 3.5 g (0.01 mol) of (II) and 1.61 g (0.01 mol) of H 2 N(CH 2 ) 3 CH(OC 2 H 5 ) 2 were disεolved in 50 ml acetone chilled to 0 °C and stirred for 4 h at 0 °C. The solution was allowed to come to room temperature and to stand for 2 days. The resulting yellowish solution was stripped and pumped on at 1 torr at room temperature overnight to produce 5.0 g of a white solid. 4.5 g of this solid were dissolved in hot ethyl acetate, brought to the cloud point with hot hexane and allowed to crystallize at room temperature overnight. 3.54 g of a white crystalline solid were obtained after collection by filtration and drying in a vacuum oven adjusted for a 30" vacuum at room temperature overnight. The final product was identified by NMR and FTIR spectroscopy as followε: NMR (CDC1 3 ) : CH 2 = CH - εplitting pattern in 6 ppm region, integration ratios and D 2 0 exchange experiments diagnostic for structure. FTIR (mull) : azlactone CO band at 1820 cm" 1 absent. 21. Example: Preparation of Coated Silica Supportε Useful in Affinity Chromatography This example describes preparation of an affinity coating from compound (III) as prepared in the previouε example. 1.76 g (0.0034 mol) of (III) and 0.328 g (0.0032 mol) of n-methylol acrylamide were dissolved in 50 ml methanol, after which 1.11 ml water were added. To this solution were added 5 g of glycidoxypropyltrimethoxysilane-functionalized silica ("Epoxy Silica") . The mixture was stirred in a rotary at room temperature for 15 min and then stripped, using a bath temperature of 44 °C, to a volatiles content of 15% as measured by weight loss (from 25-200 °C with a sun gun) . The silica, coated as a result of exposure to the mixture of ingredients, was slurried in 50 ml isooctane containing 32.0 mg VAZ0-64 (i.e., the polymerization catalyst 2,2'-azobisisobutyronitrile dissolved in 0.5 ml toluene that had been de-aerated with nitrogen. The slurry was then thoroughly de-aerated with nitrogen and subsequently stirred at 70 °C for 2 h. The coated silica was then collected by filtration and washed three times in 50 ml methanol, and air dried. Finally, the silica was heated at 120 °C for two hours to cure the coating and yield 5.4 g of coated silica. The silica contained the following attached groups: 1.5 g of the coated silica beads were shaken with 20 ml aqueous HCl (pH = 3.0) for 4 h at room temperature. The course of the reaction was followed by testing for the generation of free aldehyde with ammoniacal silver nitrate (Tollens test) . The resulting solid was collected on a Buechner filter, then reslurried and recollected until the wash water was neutral. The silica particles were then air dried to yield 1.25 g of aldehyde packing, the terminal methoxy groups having been replaced with a single aldehyde group as follows: Repligen Protein A was coupled to the aldehyde packing using the standard conditions given for the attachment of Bovine Serum Albumin in the accompanying instructionε (Technical Note No. 4151) from Chromatochem Inc., Miεεoula, MT. A one-cm glass column was packed with the Protein-A functionalized material and loaded with human IgG from PBS buffer (pH = 7.4) at a flow rate of 1.6 ml/min. The IgG was eluted in 0.01M NaOAc (pH = 3.0). The IgG was then collected and the amount measured spectrophotometrically using standard calibration curves. The meaεured capacity of the packing was 12 mg IgG per ml of column volume. 22. Example: Functionalization of Azlactone-Containing Polymers It is possible to procure existing azlactone- functionalized polymeric surfaceε (e.g., as described in U.S. Patent No. 4,737,560) and to functiona ize them according to the steps outlined above. For example, by using successive reactions with dinucleophilic species of the form HNu^Z-N^H and suitable azlactones, a surface of the form (SURFACE)-(X)-AZ, where X is a linker and Az stands for axlactone, can be transformed into the species - Ill - (SURFACE)-(X)-CONHC(CH 3 )jCONu 1 (Z)Nu 2 CH 2 CH 2 -Az which may be linked, if desired, to a biomolecule to form the following conjugate: (SURFACE) \ (X)-CONHC(CH 3 )jCONu 1 (Z)Nu 2 CH 2 CH 2 CONHC(CH 3 ) 2 CO-Biomolecule A suitable experimental procedure is as follows. The azlactone-functional support is slurried in a suitable solvent, such as CHC1 3 , and cooled to 0 °C. An amount of the bifunctional nucleophile equivalent on a molar basis to the total number of surface azlactone groups present, is dissolved in the same solvent and added with shaking. The mixture is then shaken at 0 °C for 6 hours, allowed to come to room temperature, and shaken at room temperature overnight. The support is collected by filtration, washed with fresh solvent, re¬ slurried in an appropriate solvent and one equivalent of vinylazlactone, dissolved in the same solvent, is added thereto. The mixture is then shaken, heated to 70 °C and held at this temperature for 12 hours. At the end of this time, the mixture is cooled and the support collected by filtration. The support is then waεhed thoroughly with fresh solvent and dried in vacuo . 23. Example: Preparation of a Support Useful in the Purification of Human IgG from Serum The functional beads prepared as above are suspended in pH 7.5 aqueous phosphate buffer. A solution of protein A (Repligen) in 10 mM phosphate buffer (pH 7.0) and at a concentration of 10 mg/900 μl is added, and the mixture is then gently shaken at room temperature for 3 hours. The beads are concentrated by centrifugation, the supernate decanted off and the beads washed five times with pH 7.5 aqueous phosphate buffer. The beads are then loaded into a 0.46 cm inner-diameter glass column and used to purify human IgG from serum using standard affinity-purification techniques. It should be apparent to those skilled in the art that other compositionε and processeε for preparing the compositions not specifically disclosed in the instant specification are, nevertheless, contemplated thereby. Such other compositions and processes are considered to be within the scope and spirit of the present invention, hence, the invention should not be limited by the description of the specific embodiments disclosed herein but only by the following claims.

Claims: THE CLAIMS What is claimed is: 1. A composition having the structure: wherein: a. A and B are the same or different, and each is a chemical bond; hydrogen; an electrophilic group; a nucleophilic group; R; an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component, wherein A and B are optionally connected to each other or to other structures and R is as defined below; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the rbon atom to which they are attached; d. . is a connecting group or a chemical bond which may be different in adjacent n units; and e . n >. 1 ; provided that, (1) if n is 1, and X and Y are chemical bonds, A and B are different and one is other than a chemical bond, H or R, and A and B each is other than an amino acid residue or a peptide; (2) if n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group and G-B is not an amino acid residue or a peptide; (3) if n is 1 and X, Y, and G each is a chemical bond, A and B each is other than a chemical bond, an amino acid residue or a peptide; and (4) if n is 1, either X or A haε to include a CO group for direct connection to the NH group. 2. The composition of claim 1 wherein G is chemical bond or the ring-opening reaction product of a nucleophilic group and an oxazolone and n > 2. 3. The compoεition of claim 1 wherein at leaεt one of R and R' includes a hydroxyl containing subεtituent. 4. The compoεition of claim 1 wherein X iε a carbonyl group. 5. The compoεition of claim 1 wherein G includeε a NH, OH or SH terminal group for connection to the carbonyl group. 6. The compoεition of claim 1 wherein G iε a chemical bond and Y iε a compound which includeε a NH, OH or SH terminal group. 7. The compoεition of claim 1 wherein G iε a chemical bond, Y iε an oxygen atom and B iε a hydrogen. 8. The compoεition of claim 1 wherein G includeε at leaεt one of an aromatic ring, a heterocyclic ring, a carbocyclic moiety, an alkyl group or a εubεtituted derivative thereof. 9. The compoεition of claim 1 wherein A and B are the εame. 10. The compoεition of claim 1 where R and R' are different εo that the compoεition iε chiral. 11. The composition of claim 1 wherein at least one of A and B is a terminal-structural moiety of formula T- U, wherein: a. U is selected from the group consisting of aliphatic chains having from 2 to 6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclic rings; and b. T is selected from the group consisting of OH, NH 2 , SH, (CH 3 ) 3 N + , -SO " 3 , COO " , CH 3 , H, and phenyl. 12. The composition of claim 11 wherein at least one of A and B is HO-CH 2 -(CHOH) n where n is an integer. 13. The composition of claim 1 wherein A and B are part of the same cyclic moiety. 14. The composition of claim 1 wherein n is 1 and G includes a NH, OH or SH terminal group for connection to the carbonyl group. 15. The composition of matter of claim 14 wherein G is a group containing the atom of the nucleophile used in the ring-opening reaction of an oxazolone. 16. The composition of claim 14 wherein R and R' are different so that the composition is chiral. 17. The composition of claim 1 wherein R and R' are different, X is a chemical bond and A is nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component. 18. A peptide mimetic having the structure wherein : a. A and B are the same or different, and at least one is an amino acid derivative of the form (AA) m , wherein AA is a natural or synthetic amino acid residue and m is an integer, and A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when (1) n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group and G-B is not an amino acid residue or a peptide; (2) if n is 1 and X, Y, and G each is a chemical bond, A and B each is other than a chemical bond, an amino acid residue or a peptide; and (3) if n is 1, either X or A has to include a CO group for direct connection to the NH group. 19. The composition of claim 1 wherein G is (1) Nu ! -Y-P where Nu 1 is a nucleophilic group, Y is as defined above and P is a reactive group optionally containing a protective group; or (2) as α-α-di-substituted amino acid residue. 20. The composition of claim 19 wherein P is a nucleophilic group optionally containing a protective group. 21. A nucleotide mimetic having the structure: wherein: a. A and B are the same or different, and at least one is a nucleotide derivative, wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group. 22. The nucleotide mimetic of claim 21 wherein A is a nucleotide derivate of the form (NUCL),, wherein 1 is an integer, such that (NUCL) ! is a natural or synthetic nucleotides when 1=1, a nucleotide probeε when 1=2-25 and an oligonucleotideε when 1>25 including both deoxyribose (DNA) and ribose (RNA) variants. 23. A carbohydrate mimetic having the structure: wherein: a. A and B are the same or different, and at least one is a carbohydrate derivative; wherein A and B are optionally connected to each other or to other structureε; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group. 24. The carbohydrate mimetic of claim 23 wherein A and B each is a natural carbohydrate, a synthetic carbohydrate residue or derivative thereof or a related organic acid thereof. 25. A pharmaceutical compound having the structure: wherein: a. A and B are the same or different, and at least one is an organic structural motif; wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R 1 may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attac i; i G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group. 26. The pharmaceutical compound of claim 25 wherein the structural motif of the organic compound is obtained from a pharmaceutical compound or a pharmacophore or metabolite thereof and has specific binding properties to ligands. 27. A reporter compound having the structure: wherein: a. A and B are the same or different, and at least one is a reporter element; wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e . n > 1 ; provided that, when n is 1 and Y is a chemical bond, G includeε a NH, OH or SH terminal group for connection to the carbonyl group. 28. The reporter compound of claim 27 wherein the reporter element is a natural or synthetic dye or a photographically active residues which possesses reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme and may be attached through the groups without adversely interfering with the reporting functionality of the group. 29. The reporter compound of claim 28 wherein the reactive group is amino, thio, hydroxy, carboxylic acid, acid chloride, isocyanate alkyl halide, aryl halide or an oxirane group. 30. A polymerizable compound having the structure: wherein: a. A and B are the same or different, and at least one is an organic moiety containing a polymerizable group; wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combination- thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group. 31. The polymerizable compound of claim 30 wherein the polymerizable group of the organic moiety is a vinyl group, oxirane group, carboxylic acid, acid chloride, ester, amide, lactone or lactam. 32. A substrate having the structure: wherein: a. A and B are the same or different, and at least one is a macromolecular component, wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, εulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; provided that, when n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group. 33. The substrate of claim 32 wherein the macromolecular component is a surface or structures which is attached to the oxazolone module via a reactive group • in a manner where the binding of the attached species to a ligand-receptor molecule is not adversely affected and the interactive activity of the attached functionality is determined or limited by the macromolecule. 34. The substrate of claim 32 wherein the macromolecule component has a molecular weight of at least about 1000 Daltons. 35. The substrate of claim 32 wherein the molecular component is in the form of an ceramic particle, a nanoparticle, a latex particle, a porous or non-porous beads, a membrane, a gel, a macroscopic surface or a functionalized or coated version or composite thereof. 36. A composition having the structure: wherein: a. A is a chemical bond; hydrogen; an electrophilic group; a nucleophilic group; R; an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component, wherein R is as defined below; b. Y is a chemical bond or one or more atomε of carbon, nitrogen, εulfur, oxygen or combinationε thereof; c. R and R' are the εame or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a subεtituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n unitε and have a εelected εtereochemical arrangement about the carbon atom to which they are attached; and d. q = 0 or 1. 37. The compoεition of claim 36 wherein Y includeε at leaεt one nucleophilic εpecieε which includes a nitrogen, oxygen or sulfur group attached to a -(CH 2 ) n - group where n is 1-2, and R and R' are the same or different and each is hydrogen, or an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group, or a carbocyclic or heterocyclic ring. 38. The composition of claim 36 where in Y is a chemical bond and q = O or Y is; (RING) - (CH 2 ) n where n=0-4 and (RING) designateε a diεubεtituted phenyl ring or a εubεtituted or unεubstituted aromatic, heterocyclic or alicyclic ring having 6-20 carbons, wherein A is a protecting group when Y contains a terminus which can react with the oxazolone ring. 39. A method of synthesizing a compound of the formula: B-Y-(CO-CRR'-NH) n -H wherein a. B is an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component; b. Y represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units; and e. n > 2; which method comprises the steps of: providing a first amino-blocked oxazolone of the formula: B j -NH-CRR'-oxazolone ring with R and R' reacting the first am o-blocked oxazolone under conditions that promote riπ^-opening with a compound that includes B and has a ring opening reactive moiety to form an amino-blocked ring-opened adduct; and deblocking the adduct by removing the amino-blocking group. 40. The method of claim 39 which further compriseε: providing a free amino group on the deblocked adduct; providing a εecond amino-blocked oxazolone; reacting the free amino group of the adduct with the second amino-blocked oxazolone to form a second adduct; and repeating the preceding steps, if necesεary, to provide the deεired εtructure of the compoεition. 41. The method of claim 39 which further compriεeε εelecting the compound that iε to react with the first oxazolone to include an amine, hydroxyl or sulfhydryl group to promote the ring opening; and selecting R and R' ' to be different so that a chiral molecule is obtained. 42. The method of claim 39 wherein the starting materials used are achiral or not enantiomerically pure. 43. The method of claim 39 further comprising the step of reacting the free amino group of the oxazolone with a carboxyl terminus of a peptide. 44. A method of synthesizing a compound of the form: wherein a. A and B are the same or different, and each is an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component, wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d. G is a connecting group or a chemical bond which may be different in adjacent n units; and e. n > 1; wherein the method comprises the steps of: providing an oxazolone of the formula: where A, R, R' a ined above and q=0 or 1; and reacting the oxazolone under ^nditions that promote ring-opening with a compound that includes B and has a ring opening reactive moiety to form a ring-opened adduct. 45. The method of claim 44 which further comprises: carrying out an appropriate subsequent reaction on the previous ring-opened product, wherein the subsequent reaction is: 1) in the case where G is a chemical bond, cyclizing the terminal α,α-asymmetrically disubstituted amino acid to form a terminal azlactone ring; 2) in the case where G is -Nu-Z where Nu is a group which includes sulfur, nitrogen or oxygen and Z includes a carboxyl carboxyl, isocyanate or acid halide terminus, adding the terminus of Z to the amino terminus of an α,α'- aεymmetrically disubstituted amino acid and then cyclizing the resulting amino acid to form. a terminal oxazolone ring; or 3) in the case where G is -Nu,-Z-Nu 2 -CH 2 CH 2 -CO- where Nu 1 and Nu 2 each is a group which includes sulfur, nitrogen or oxygen and Z is a connecting group, reacting the Nu 2 terminus with the vinyl group of a 4,4'-asymmetrically disubstituted 2-vinyl oxazolone under conditions that promote a Michael addition reaction to form a terminal oxazolone ring; repeating the preceding steps, if necessary, to provide the desired structure of the composition; and reacting the terminal oxazolone ring with a species of the form G"-B-YH to form the composition. 46. A method of synthesizing a compound of the formula: R I A—X-NH-C-CO-G—Y—B I R' wherein a. A and B are the same or different, and each is an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component, wherein A and B are optionally connected to each other or to other structures; b. X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof; c. R and R' are the same or different and each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, wherein R and R' have a selected stereochemical arrangement about the carbon atom -α which they are attached; and d. G is a connecting group or a chemical bond; wherein the method comprises the steps of: reacting an amino acid of the form wherein R and R' are as recited above, with a carboxylic acid, an acid halide or an oxazolone to form an adduct of the formula: A—CO—NH C COOH R' cyclizing the adduct to form an oxazolone; reacting the oxazolone with a bifunctional species of the form HX-Z-Y, wherein HX includes an amine, hydroxyl or sulfhydryl group and Y contains a reactive group capable of bonding with species B; and reacting the resultant product with species B. 47. The method of claim 46 wherein the peptide seguence is chiral. 48. A method of synthesizing a compound containing a pepide sequence which comprises the steps of: providing a substrate bound, via a CO group, to the amino terminus of an α,α'-disubstituted chiral amino acid; cyclizing the amino acid into an oxazolone; reacting the oxazolone with an alkali-metal salt of a second α,α'-disubstituted chiral amino acid to form a bound dipeptide salt; cyclizing the second α,α'-disubεtituted chiral amino acid; repeating steps (c) and (d) , if neceassary, to form the desired peptide sequence. 49. The method of claim 48 wherein the structure of the composition contains achiral centers or the composition is not obtained chirally pure. 50. The method of claim 49 which further comprises the step of releasing the composition from the substrate. 51. The method of claim 48 which further comprises the step of reacting a cyclized oxazolone intermediate with a species containing a reactive moiety of an amine, hydroxyl or sulfhydryl group. 52. The method of claim 48 wherein Y-Z-B is an aminimide. 53. The method of claim 48 wherein the peptide sequence is chiral. 54. A compound produced by the method of any one of claims 39 to 53.

Inventors: HOGAN JOSEPH C JR, HOGAN, JOSEPH, C., JR.
Applicants: HOGAN JOSEPH C JR, LEGOMER PARTNERS LP, LEGOMER PARTNERS, L.P.
Application year: 1993
Main classification: C08G69
IPC codes: A61K38, A61P31, C07C229, C07C231, C07C237, C07D209, C07D239, C07D263, C07D265, C07D413, C07D489, C07H13, C07H15, C07H21, C07J31, C07K1, C07K5, C07K7, C07K14, C08G73