Method of making polymers having specific properties

A method of making a polymer having specific physiochemical properties by forming a first module having a structure which includes at least two structural diversity elements suitable to impart a desired physical property to a polymer which is made from said monomer; and reacting one or more modules to form a polymer having specific physiochemical properties. The base module can be formed by reacting a first compound having at least one structural diversity element and a first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction. Specifically, an aminimide compound, an oxazolone compound or derivatives thereof are useful as base modules in the invention.

FIELD OF THE INVENTION 
The present invention relates to a novel method of controlled 
polymerization to produce encoded synthetic polymers, involving the 
stepwise assembly of discrete modules having selected structural features 
in a manner so as to produce a polymer having (1) a precisely ordered 
sequence of structural units; or (2) a precisely ordered sequence of 
structural units and a specific uniform chain length and molecular weight, 
depending on the particular strategy chosen; and (3) resultant 
physiochemical and biological properties which are the sum of the 
individual properties of the modules and their specific arrangement in the 
polymer. 
BACKGROUND OF THE INVENTION 
Existing polymerization methods fall into one of two basic types; (1) 
Addition or Chain Growth Polymerization; and (2) Condensation or 
Step-Growth Polymerization. 
Chain growth polymerizations most commonly utilize monomers possessing 
reactive carbon-carbon double bonds, although other species, such as 
cyclic ethers , e.g., ethylene and propylene oxide and aldehydes, e.g., 
formaldehyde, can be polymerized in this way. These chain-growth 
polymerizations are characterized by the fact that the free radical, ionic 
or metal complex intermediates involved in the process are transient and 
can not be isolated. A generalized example for a simple free radical 
initiated vinyl polymerization is shown below: 
##STR1## 
Step-growth polymerizations involve reactions which occur between molecules 
containing multiple reactive groups which can react with each other. An 
example of this is the well-known reaction of a glycol and a dibasic 
aromatic acid to give a polyester. 
It can be readily seen that the use of multiple reactive monomers 
possessing groups with similar or equivalent reactivities with this method 
produces a mixture of individual polymer species having random 
arrangements of monomeric sequences and only statistical control of the 
resulting stoichiometric make-up. 
While many different variations of these two classes of polymerization 
reaction schemes exist, e.g. initiation may be cationic, radical, anionic, 
sequential aldol, ring-opening or displacement, and many different 
reactive species may be employed, e.g. electron deficient alkenes, 
epoxides, polyamines, hydroxyesters, etc., all of these variations possess 
a common limiting feature--they all rely on a statistical or average 
stoichiometric control of the final polymeric product. This is achieved 
through the careful selection and control of the reaction conditions, such 
a concentration of monomers, agitation conditions, catalyst level, 
time/temperature cycles, etc.. These existing polymerization methods do 
not have any ability to control the exact constitution or length of any 
specific individual polymer chain. The properties of the polymers produced 
via these processes are, in fact, a statistical average of the properties 
of a complex mixture of subtly differing individual polymer species having 
a range of molecular weights and containing differing combinations and 
sequences of monomers along the chains. Even in the simplest example of a 
step growth polymerization involving only two reactants, where the product 
is a polymer containing a single repeating structural motif, the product 
obtained will consist of a statistical mixture of a large number of 
individual molecules each having differing lengths and molecular weights. 
In spite of these limitations, those skilled in the art have developed 
strategies by which these methods can be exploited. Average chain length 
can be controlled roughly by the ratio of initiator to monomer, or by 
quenching with an additive giving a range of molecular weights. 
Macroscopic properties can be modulated by the addition of comonomers 
which are incorporated randomly into the backbone. However, these methods 
possess no ability to have discreet or even reproducible microsequence 
control , and the "address" of a singular functionality added to the 
polymerization reaction is statistically determined. 
Most natural biological polymers, such as oligonucleotides, proteins and 
polysaccharides, on the other hand, contain precise sequences of monomer 
units which confer the polymer with highly specific functional properties, 
including a specific three dimensional structure. Recent advances in the 
understanding of the complex mechanisms of biochemical processes and of 
the underlying structure-function relationships of biological polymers 
involved in the replication (DNA-DNA), storage (DNA), transcription 
(DNA-RNA), translation (RNA-protein), communication, recognition, control 
(proteins, peptides, carbohydrates) and function (proteins, 
oligosaccharides) of all biological systems have illuminated the exquisite 
sensitivity of these polymers to microsequence variations. A classic 
example of this is sickle cell anemia which has been shown to be due to a 
single point mutation in the genetic sequence encoding for the beta chain 
of hemoglobin. As a result of this mutation, the abnormal hemoglobin 
contains a single valine in place of a glutamine in the sequence of the 
protein. This results in an abnormal shape for the hemoglobin, producing 
the characteristic sickle-shaped cells and the resulting tragic 
pathological consequences 
The biosynthesis of these biopolymers can be viewed, at a molecular level, 
to consist of a highly organized series of individual catenation steps, 
each carried out with specific reactants under highly controlled 
conditions and mediated by biocalytic agents, principally enzymes. All of 
the monomers necessary for the construction of these biological polymers 
are present in the vicinity of the reaction area and are carried by 
chaperone molecules to the site of their incorporation into the growing 
chain, where they are released and coupled. Since these polymers were 
designed by nature to carry out their highly specific functions under 
physiological conditions (water at pH 7 and physiological temperatures, 
etc.), and have been programmed by nature to be subject to natural 
biochemical transformations, such as proteolytic decomposition, they are 
usually not robust (notable exceptions include structural polymers such as 
chitin, cotton, skin, silk, hair and other structural materials) and are 
easily decomposed or denatured by exposure to non-physiological 
conditions, such as elevated temperatures, organic solvents, extremes of 
pH, etc.. As a result, these molecules are generally ill suited for tasks 
other than their proper biochemical ones. 
Simply put, the makers of polymers, while being able to statistically 
achieve good and consistent macroscopic properties in the polymeric 
materials which they produce, have not had any way, up to this point, to 
control the microscopic make-up of their product. Nature, in producing 
biomacromolecules, has evolved systems which allow exquisite control over 
both the microscopic make-up and the macro-structure of its functional 
polymers. However, these polymers are severely limited in the variety of 
uses to which they may be applied by their chemical constitution, their 
lack of stability towards chemical and biochemical agents and their 
sensitivity to changes in environmental conditions, such as temperature. 
In addition, the nature of natural scaffolds and substituents and their 
sensitivity to the chemical conditions necessary to manipulate and to 
transform them severely limits their utility in producing new materials 
from these components. 
SUMMARY OF THE INVENTION 
This invention relates to a method of making a polymer having specific 
physiochemical properties by forming a base module having a structure 
which includes at least two orthogonal reactivity or structural diversity 
elements suitable to impart a desired physiochemical property to a polymer 
which is made from said monomer; and reacting one or more modules to form 
a polymer having specific properties. The module is preferably an 
aminimide compound, an oxazolone-compound, or a derivative thereof. The 
module is prepared from first and second components which provide the 
orthogonal reactivity elements. The module may contain 2, 3, 4 or more 
orthogonal reactivity elements, depending on the desired performance 
properties of the resultant polymer. 
The polymer chains are started with a terminus or starter module containing 
a single reactivity element and are capped at the desired point in the 
synthesis with a second terminus or capping module containing a single 
reactivity element in order to control the length of the chain. 
The base module can be formed by reacting a first compound having at least 
one structural diversity element and a first reactive group, with a second 
compound having at least one structural diversity element and a second 
reactive group, wherein the first and second groups combine by an addition 
reaction. 
Preferably, the first compound is produced by forming an oxazolone compound 
having at least one structural diversity element attached thereto and 
reacting it with a nucleophile or carbonyl compound which contains at 
least one structural diversity element to form a base module having one of 
the following structures: 
##STR2## 
wherein at least two of the unconnected lines are connected to structural 
diversity elements. 
Alternatively, it is also preferred to provide the first compound as an 
aminimide-forming compound having at least one structural diversity 
element attached thereto and to react it with an oxazolone or an oxirane 
compound, which contains at least one structural diversity element to form 
a base module having one of the following structures: 
##STR3## 
wherein at least two of the unconnected lines are connected to structural 
diversity elements. 
In particular, this method can be used to make polymers having a designed 
water solubility. This invention still further relates to the polymers 
produced according to these methods. Still further, this invention relates 
to uniform polymers comprising a multitude of long chain molecules each of 
which have the same molecular weight and the same length. 
This ability to produce polymeric chains of specific sequence and 
composition has great utility in the fabrication of a new generation of 
functional oligomeric and polymeric materials for a wide spectrum of 
applications, such as drugs, chiral recognition elements, catalysts, 
separations tools, biomaterials, fibers, plastics, membranes, beads and 
gels.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention discloses a fundamentally new approach to the 
fabrication of oligomeric and polymeric molecules involving (1) the use of 
modular units which can contain at least two orthogonally reactive 
elements and are capable of bearing a wide variety of structural 
information, such as specific geometry, functionality, substituents, etc. 
(2) the stepwise assembly of polymers from these modules (a) by carrying 
out catenation or coupling reactions one step at a time or (b) by 
constructing "sub assemblies" of modular units one step at a time and 
connecting them together in a concerted manner in such a way that the 
resulting polymer has a controlled (encoded) microsequence and a resultant 
overall functional activity, which is the sum of the functional activities 
of the constituent modular parts. This approach involves the design and 
construction of a scaffolding superstructure which sets the basic spacing 
and geometry of the molecule and serves to arrange and orient the attached 
substituent groups in a manner suitable to achieve the desired functional 
property and, simultaneously, serves to allow the incorporation of desired 
pendant substituents in the appropriate positions having the appropriate 
desired relationships to each other and to the scaffold to produce the 
desired functional effect in the final polymer. 
In this application, the term "polymer" is used to refer to any catenated 
structure containing a sufficient number of modules to carry enough 
structural information to impart the desired property to the resulting 
polymer, usually consisting of a minimum of three monomers plus two 
terminus (starter and capping) modules. 
A key element of this method is the presence of at least two orthogonal 
reactivity elements in the modules. Orthogonal reactivity elements are 
defined as those elements which are either (A) multiple reactive groups 
which are capable of being "turned on" independently of each other or (B) 
multiple differing reactive states which may be addressed or brought into 
being at different times or under different conditions in the catenation 
sequence. It is highly desirable, although not absolutely necessary, that 
the individual reactions be high-yielding addition reactions with no 
by-products, so that isolation and purification steps are not necessary 
between cycles. The two basic schemes are illustrated below: 
A. Multiple Reactive Groups 
##STR4## 
Where R1 and R2=groups capable of undergoing addition reactions with each 
other, and A, B, C, D are either monomeric modules or "sub assemblies" 
containing multiple modules stitched together in a sequence specific 
manner. 
B. Multiple Reactive States 
##STR5## 
Where R1 and R2 are groups capable of undergoing addition reactions with 
each other, and A, B, C, D are either monomeric modules or "sub 
assemblies" containing multiple modules stitched together in a sequence 
specific manner. 
These reactive orthagonalities allow each discrete addition reaction to be 
carried to completion before the next individual addition reaction is 
undertaken. If desired, the intermediate products may be isolated 
following each individual step. In this critical respect this method is 
fundamentally different from both chain and step-growth polymerization 
methods. 
In addition to the stepwise sequential construction of polymers one unit at 
a time as illustrated, this method may be utilized to construct oligomeric 
"sub assemblies" having designed microsequences, and properties. These may 
then be connected together in a separate step to produce higher order 
assemblies, which may themselves again be connected together to, 
ultimately form a polymer having the desired set of properties. This 
strategy requires that one of the orthogonal reactivity elements on each 
sub-unit be either protected with an appropriate removable blocking group 
or contain a third orthogonally reactive group. These reactions may be 
carried out with modules containing &gt;2 orthogonally reactive elements to 
produce three dimensionally cross linked networks and structures. 
Alternatively these sub assemblies may be combined with appropriately 
functionalized "classical" modules to produce hybrid polymers. 
A new approach to the stepwise sequential construction of novel oligomeric 
and polymeric molecules is described. This approach involves the 
development of a process whereby molecular building blocks which contain 
appropriate atoms and functional groups and posses at least two 
orthogonally reactive elements are connected together in a stepwise 
sequential fashion to allow the modular assembly of oligomers and polymers 
with tailored properties; each module contributing to the overall 
properties of the assembled molecule. This approach to molecular 
construction is applicable to the synthesis of all types of molecules, 
including but not limited to mimetics of peptides, proteins, 
oligonucleotides, oligosaccharides, classical polymers, variants, hybrids 
of these and to fabricated structures and materials useful in materials 
science. It is analogous to the modular construction of a mechanical 
device that performs a specific operation wherein each module performs a 
specific task contributing to the overall operation of the device. 
Examples of suitable modules containing appropriate orthogonally reactive 
elements for utilization in this method are as given below: 
Several of the specific modular chemistries chosen to illustrate and 
exemplify the invention are capable of bearing and maintaining chiral 
centers throughout the various steps involved. Where this is the case, the 
chirality will be shown. This is not intended to limit the scope of the 
invention to chiral materials, since there are a large number of 
variations and applications where structural stereocontrol is not required 
or where achiral materials are employed. 
POLYMERS PRODUCED FROM OXAZOLONES 
Oxazolone Modules 
A type of oxazolone module appropriate for use in the present invention may 
be represented by the following general structure: 
##STR6## 
where R & R' are the same or different and X represents either a group 
having orthagonal reactivity to the oxazolone ring or a structural moiety, 
depending on which of two possible assembly strategies is chosen, as 
outlined below. R.sup.1 and R.sup.2 differ from one another and taken 
alone each signifies one of the following: alkyl including cycloalkyl and 
substituted forms thereof; aryl, aralkyl, alkaryl, and substituted or 
heterocyclic versions thereof; preferred forms of R1 and R2 are the side 
chain substituents occuring in native polypeptides, oligonucleotides, 
variants or mimetics of these, carbohydrates, pharmacophores, variants or 
mimetics of these, or any other side chain substituent which can be 
attached to a scaffold or a backbone to produce a desired interaction with 
a target system. 
The substituents R & R' may be of a subset of hydrophilic substituents such 
as, but not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, 
thioethyl, thiomethyl;carboxymethyl, carboxyethyl, ethylcarboxamido, 
methylcarboxamido; aminomethyl, aminoethyl, aminopropyl, 
guanindinylpropyl, guanidinylbutyl; mono-, di-, and triaminobenzyl, mono-, 
di-, and trinitrobenzyl; mono-, di-, tri-, and tetrahydroxy benzyl, mono- 
or polyhydroxyaryl (e.g. pyrogallol); heteroaryl (e.g. alkylpyridines, 
imidazole, alkyltryptophans); alkyl nucleotides; all substituted 
pyrimidylalkyl and substituted purinealkyl moieties; mono-, di-, and 
oligosaccharide (e.g. N-methylfucosamine, maltose and the calicheamicin 
recognition sequence respectively); alkylsulfonates, alkylphosphonates; 
a-polyfluoroketones; secondary, tertiary and quaternaryamines; hydrazincs 
and the hydrazinium salts R and R' may also come from the subset 
consisting of hydrophobic substituents such as, but not limited to: 
hydrogen; methyl, ethyl propyl, isopropyl, butyl, sec-butyl, isobutyl, 
tert-butyl, pentyl, iso-, sec-, and neopentyl, hexyl, heptyl, octyl, 
nonyl, decyl, etc.; vinyl, propenyl, butenyl or other alkenyl groups; 
acetylenic side chains; aromatic polycyclics (e.g. biphenyl, binaphthyl, 
naphthylphenyl, phenylnaphthyl); fused aromatic polycyclics(e.g. 
anthracene, phenylene, pyrene, acenaphthene, azulenes); fused polycyclics 
(e.g. decalin, hydrindanes, steroids); phenyl, alkylphenyl, phenylalkyl; 
benzyi, mono-, di-, tri-, and tetraalkylbenzyl; mono-, di-, and 
trialkoxybenzyl; heteroaryl (e.g. furyl, xanthanyl, quinolyl); 
methoxyalkyl, ethoxyalkyl, aryloxy; methylmercaptans, ethylmercaptans, 
alkyl thioethers and arylthioethers; dyes and fluorescent tags (such as 
rhodamine or fluorescein); alkyl esters, aryl esters, iralkyl esters, and 
alkylaryl esters. 
Polymerization Strategies 
These oxazolone modules may be employed to construct oligomers and polymers 
in two different ways: 
A. Ring Opening Reaction/2-Position Substituent Addition reaction: 
Oxazolones with suitable substituents at the 2-position (X=an orthagonally 
reactive group) may act as orthogonally reactive agents suitable for the 
construction of the polymers which are the subject of the present 
invention. This may be accomplished by carrying out alternating ring 
opening and 2-position substituent addition reactions with suitable 
bifunctionally reactive species. One terminus of these reactive elements 
should contain an SH, OH or NH group capable of underegoing ring-opening 
addition reaction with the oxazolone ring. The second terminus of the 
reactive element should contain a group capable of undergoing addition 
reaction with X. The choice of this second group, obviously, depends on 
the nature of the specific X group chosen in each case. Appropriate 
2-position substituents include vinyl groups, which make the oxazolone a 
Michael acceptor, haloalkyl and alkyl sulfonate esters and epoxide groups. 
This is shown below for the case of alternating ring opening and Michael 
additions to the double bond of a 4,4-disubstituted-2-vinyloxazolone by 
appropriate dinucleophillic species which produces polymeric chains. 
##STR7## 
In the above sequence of reactions, HNu.sup.1 --Z--Nu.sup.2 H represents a 
structure containing two differentially reactive nucleophilic groups, such 
as methylamino-ethylamine, 1-amino propane-3-thiol, and so on; groups 
Nu.sup.1, Nu.sup.2, Nu.sup.3 and Nu.sup.4 need not be identical and Z is a 
generalized structural group connecting HNu1 and HNu2. HNu.sup.1 
--Z--Nu.sup.2 H may contain two nucleophilic groups of differential 
reactivity, as stated above, or if Nu.sup.1 and Nu.sup.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 synthesis (e.g., for 
the nucleophilic groups such as amino, hydroxyl, thio, etc.) are useful in 
the protection of one of the Nu substituents of the structure HNu.sup.1 
--Z--Nu.sup.2 H. The product of the acylation reaction with HNu.sup.1 
--Z--Nu.sup.2 H (after Nu-deprotection, if necessary) 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 sequence of synthetic steps produces a growing 
polymeric molecule. 
The Michael reaction step is usually carried out using stoichiometric 
amounts of nucleophile AXH and the oxazolone in a suitable solvent, such 
as toluene, ethyl acetate, dimethyl formamide, an alcohol, and the like. 
The selectivities of the Michael and oxazolone ring-opening processes 
impose certain limitations on the choice of the nucleophiles shown above. 
Specifically, nucleophiles of the form ROH tend to add primarily via the 
ring-opening reaction, and usually require. acidic catalysts (e.g., BF3); 
thus, Nu2 should not be OH. Likewise, primary amines tend to add only via 
ring-opening, and Nu2 should therefore not be NH2. Secondary amines 
readily add to the double bond under appropriate reaction conditions. 
Nucleophiles of the form RSH will exclusively add via ring-opening if the 
sulfhydryl group is ionized (i.e., if the basicity of the reaction mixture 
corresponds to pH&gt;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 side-reactions. 
The ring-opening reactions can be carried out either in an organic solvent 
such as methylene chloride, ethyl acetate, dimethyl formamide (DMF) or in 
water at room or higher temperatures, in the presence or absence of acids, 
such as carboxylic, other proton or Lewis-acids, or bases, such as 
tertiary amines or hydroxides, serving as catalysts. 
An example of the application of this strategy is given below for the 
synthesis of a subunit containing four structural modules and the 
subsequent assembly of these modules into a polymer containing repeating 
sequences of these specific subunits: 
The required 4,4'-disubstituted oxazolone modules 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.: 
##STR8## 
Alternative reactive groups may be introduced at the 2-position of the 
oxazolone in this way, as shown for a benzyl substituted reactive 
substituent: 
##STR9## 
A wide variety of 4-monosubstituted azlactones may be readily prepared by 
reduction of the corresponding unsaturated derivatives obtained in high 
yield from the condensation reaction of aldehydes, ketones, or imines with 
the oxazolone formed from an N-acyl glycine (49 J. Org. Chem. 2502 (1984); 
418 Synthesis Communications (1984)) 
##STR10## 
These may be converted to 4,4'-disubstituted oxazolones by alkylation of 
the 4-position, as in the following transformation (Synthesis Commun., 
Sept. 1984, at 763; 23 Tetrahedron Lett. 4259 (1982)): 
##STR11## 
Other important bifunctionally reactive oxazolone derivatives which may be 
employed in these schemes include: 
##STR12## 
B. Alternating Sequences of Nucleophilic Oxazolone-Ring-Opening Addition 
Reactions Followed by Oxazolone-Forming Cyclization Reactions 
Alpha,Alpha'-Disubstituted Sequences 
According to this approach, oxazolone modules are catenated via 
ring-opening nucleophilic attack by the amino group of an 
alpha,alpha'-disubstituted amino acid; the resulting adduct is 
subsequently recyclized to form a terminal oxazolone (with retention of 
chirality). This is then subjected to another nucleophilic ring-opening 
catenation reaction, producing a growing polymer as shown below. This 
procedure is repeated until the desired polymer is obtained. 
##STR13## 
Wherein M is an alkali metal; each member of the substituent pairs R.sup.1 
and R.sup.2, R.sup.3 and R.sup.4, and R.sup.5 and R.sup.6 differs from the 
other and taken alone each signifies alkyl, cycloalkyl, or substituted 
versions thereof, aryl, aralkyl or alkaryl, or substituted and 
heterocyclic versions thereof; these substituent pairs can also be joined 
into a carbocyclic or heterocyclic ring; preferred forms of R1 and R2 are 
the side chain substituents occurring in native polypeptides, 
oligonucleotides, variants or mimetics of these, carbohydrates, 
pharmacophores, variants or mimetics of these, or any other side chain 
substituent which can be attached to a scaffold or a backbone to produce a 
desired interaction with a target system; X represents an oxygen, sulfur, 
or nitrogen atom; and A and B are the substituents described above. 
A chiral oxazolone derivative containing a blocked terminal amino group may 
be prepared from a blocked, disubstituted dipeptide, that was prepared by 
standard techniques known to those skilled in the art, as shown: 
##STR14## 
wherein B.sub.1 is an appropriate protecting group, such as Boc 
(t-butoxycarbonyl) or Fmoc (fluorenylmethoxycarbonyl). One may then use 
this oxazolone to acylate an amine, hydroxyl, or sulfhydryl-group in a 
linker structure or functionalized solid support, represented generically 
by AXH, using the reaction conditions described above. This acylation is 
followed by deblocking, using standard 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 present in the molecule), and the 
resulting amino group is used for reaction with a new bifunctional 
oxazolone generating a growing chiral polymeric structure, as shown below: 
##STR15## 
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 substituent pairs R.sup.1 and R.sup.2, R.sup.3 
and R.sup.4, R.sup.n-1 and R.sup.n differs from the other and taken alone 
each signifies alkyl, cycloalkyl, or functionalized versions thereof; 
aryl, aralkyl or alkaryl or functionalized including heterocyclic versions 
thereof (preferably, these R substituents mimic the side-chain of 
naturally occurring amino acids); substituent R can also be part of a 
carbocyclic or heterocyclic ring; A is a substituent as described above; 
and C is a substituent-selected from the set of structures for A; and 
B.sub.1 is a blocking or protecting group. 
Sub Assemblies 
Alternatively, modular "sub assemblies" capable of conferring higher order 
structural properties may be pre-constructed and assembled together using 
these same reaction sequences in a manner which allows control of the 
higher order structure. This is illustrated for the case of a polymer 
formed with a repeating pattern of alternating modules of the type:: 
##STR16## 
This polymer will form 3-10 helices, driven by the conformational 
restrictions imposed by the repetitive viscinal disubstitution: This 
triadic periodicity results in the formation of a helical superstructure 
which has charged sulfonate groups lined up regularly along one side of 
the helix: 
##STR17## 
This "sub assembly" strategy may be used to generate higher order polymers 
in the following manner: 
1. An oxazolone dimer containing a blocked terminal amino group may be 
prepared from a blocked disubstituted peptide, prepared using standard 
techniques known to those skilled in the art, as shown: 
##STR18## 
2. This oxazolone may be coupled with a suitable c-terminal derivative of a 
second disubstituted dipeptide, as shown, to give the 4-mer module shown: 
##STR19## 
3. This process may then be repeated with the 4-mers to produce an 8-mer 
module; repeated again to form a 16-mer module, and so on, until a 
molecule having the desired length is obtained. At any point in this 
sequence, the protecting groups can be removed and the modules can be 
catenated together to form a polymer with repeating sequences of modules, 
as shown: 
##STR20## 
In cases where solubility problems are encountered as the size of the 
modules increases, the stability of the linkages allows the use of a broad 
array of standard or "exotic" reaction solvents, such as hexamethyl 
phosphoramide. If necessary, solubilizing groups can be incorporated as 
side chain substituents or connecting modules. 
Other Reactive Elements 
At any point in the polymer syntheses shown above, a structural species, 
possessing (1) a terminal OH, --SH or --NH.sub.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 alpha, 
alpha'-disubstituted amino acid, may be inserted in the polymer backbone 
as shown below; 
##STR21## 
This process may be repeated, if desired, at each step in the synthesis 
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 cases can be dealt with effectively by one with ordinary 
skill in the art of polypeptide and peptide mimetic synthesis. For 
example, special solvents such as dipolar aprotic solvents (e.g., dimethyl 
formamide, DMF, dimethyl sulfoxide, DMSO, N-methyl pyrollidone, etc.) and 
chaotropic (molecular aggregatebreaking) agents (e.g., urea) will be very 
useful as catenations produce progressively larger molecules. 
POLYMERS PRODUCED FROM AMINIMIDES 
Stepwise sequential Reactions of 1,1-Disubstituted Hydrazines or Hydrazine 
Derivatives with Bifunctionally Reactive elements. 
The aminimide monomer structure may be represented by the formula: 
##STR22## 
where R & R' are the same or different and X & X' are from the same groups 
as R or R:' and/or represent the extension or remainder of a polymer 
chain. 
The groups R & R' may be of a subset of hydrophilic substituents such as, 
but not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, thioethyl, 
thiomethyl; carboxymethyl, carboxyethyl, ethylcarboxamido, 
methylcarboxamido; aminomethyl, aminoethyl, aminopropyl, 
guanindinylpropyl, guanidinylbutyl; mono-, di-, and triaminobenzyl, mono-, 
di-, and trinitrobenzyl; mono-, di-, tri-, and tetrahydroxy benzyl, mono- 
or polyhydroxyaryl (e.g. pyrogallol); heteroaryl (e.g. alkylpyridines, 
imidazole, alkyltryptophans); alkyl nucleotides; all substituted 
pyrimidylalkyl and substituted purinealkyl moieties; mono-, di-, and 
oligosaccharide (e.g. N-methylfucosamine, maltose and the calicheamicin 
recognition sequence respectively); alkylsulfonates, alkylphosphonates; 
a-polyfluoroketones; secondary, tertiary and quaternaryamines; hydrazines 
and the hydrazinium salts. They may also come from the subset consisting 
of hydrophobic substituents such as, but not limited to hydrogen; methyl, 
ethyl propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 
iso-, sec-, and neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; 
vinyl, propenyl, butenyl or other alkenyl groups; acetylenic side chains; 
aromatic polycyclics (e.g. biphenyl, binaphthyl, naphthylphenyl, 
phenylnaphthyl); fused aromatic polycyclics(e.g. anthracene, phenylene, 
pyrene, acenaphthene, azulenes); fused polycyclics (e.g. decalin, 
hydrindanes, steroids); phenyl, alkylphenyl, phenylalkyl; benzyl, mono-, 
di-, tri-, and tetraalkylbenzyl; mono-, di-, and trialkoxybenzyl; 
heteroaryl (e.g. furyl, xanthanyl, quinolyl); methoxyalkyl, ethoxyalkyl, 
aryloxy; methylmercaptans, ethylmercaptans, alkyl thioethers and 
arylthioethers; dyes and fluorescent tags (such as rhodamine or 
fluorescein); alkyl esters, aryl esters, aralkyl esters, and alkylaryl 
esters; polymeric support surfaces 
Polymerization of Aminimide Subunits via Acylation/Alkylation Cycles 
The following steps are involved in this synthesis: 
1. Acylation of a hydrazinium salt with a molecule capable of functioning 
both as an acylating and as an alkylating agent producing an aminimide; 
BrCH2COC1 and other bifunctional species, such as bromoalkyl isocyanates, 
2-bromoalkyl oxazolones, etc., may be used as acylating agents under the 
reaction conditions given above. 
##STR23## 
2. Reaction of the product of the above reaction with a 1,1-disubstituted 
hydrazine to form an aminimide hydrazinium salt. 
##STR24## 
3. Acylation of the product from step 2 with a bifunctional acyl derivative 
similar to those listed in step 1 above producing a dimer. 
##STR25## 
4. Repetition of steps 2 and 3 the required number of times to build the 
desired aminimide polymeric sequence. 
5. Capping of the assembled sequence if desired, for example, by reaction 
with an acylating agent, such as acetyl chloride. 
The experimental conditions (e.g. reaction-solvent, temperature and time, 
and ,purification procedures for products) for all of the above reactions 
were described above and are also well-known and practiced in the art. As 
the molecular weight of the products increases (e.g. in step 5 above) 
solubility and reaction-rate problems may develop if the reactions are run 
under the conditions that successfully gave products of much smaller 
molecular weight. As is well known from the art of peptide synthesis, this 
is probably due to conformational (folding) effects and to aggregation 
phenomena, and procedures found to work in the related peptide cases are 
expected to be very useful in the case of aminimide catenations. For 
example, reaction solvents such as DMF, or N-methyl pyrollidone, and 
chaotropic (aggregate-breaking) agents, such as urea, are expected to be 
helpful in alleviating reactivity problems as the molecular-weight of the 
product increases. 
##STR26## 
Polymerization of Aminimide Subunits via Acylation/Alkylation Cycles 
The following steps are involved in this synthesis: 
1. Alkylation of an asymmetrically disubstituted hydrazide, prepared as 
outlined above, with a molecule capable of functioning both as an 
alkylating and an acylating agent to form a racemic mixture of aminimides; 
as before the use of BrCH2COC1 is shown below, but other bifunctional 
species, such as bromoalkyl isocyanates, 2-bromoalkyl oxazolones, etc. may 
also be used. 
2. Reaction of the racemate from above with an lo asymmetrically 
disubstituted hydrazine to form the hydrazide: 
3. Alkylation of the product from step 2 with a bifunctional molecule 
capable of alkylation and acylation, which may be the same as that used in 
step 1 or different, to form a mixture of diastereomeric aminimides. 
4. Reaction of the product from step 3 with a suitable asymmetrically 
disubstituted hydrazine to form the hydrazide, as shown: 
##STR27## 
5. Repetition of steps 3, and 4 to build the desired aminimide polymer 
sequence. 
6. Capping of the sequence, if desired, using e.g. methyl bromide to 
produce a sequence such as shown below. 
##STR28## 
Polymerization of Aminimide Subunits Using Hydrazinolysis of as an Ester in 
the Presence of an Epoxide 
The following steps are involved in this synthesis: 
1. Formation of an aminimine from the reaction of an 1,1-asymmetrically 
disubstituted hydrazine with an epoxide;: 
##STR29## 
2. The aminimine is reacted with an ester-epoxide to give an aminimide; 
##STR30## 
3. Reaction of the aminimide with an asymmetrically disubstituted hydrazine 
to form an aminimide- aminimine disubstituted hydrazine to form an 
aminimide-aminimine 
##STR31## 
4. Repetition of steps 2 and 3 using the appropriate hydrazines and 
epoxy-esters in each step to produce the desired aminimide sequence. 
5. "Capping" of the final sequence, if desired, by cylation with a simple 
ester, such as methyl acetate, to produce the designed aminimide ligand 
shown: 
##STR32## 
Synthesis of Hydrazides 
1,1-disubstituted hydrazine with an activated acyl derivative or an 
isocyanate, in a suitable organic solvent, e.g. methylene chloride, 
toluene, ether, etc. in the presence of a base such as triethylamine to 
neutralize the haloacid generated during the acylation. 
##STR33## 
Activated acyl derivatives include acid chlorides, chlorocarbonates, 
chlorothiocarbonates, etc.; the acyl derivative may also be replaced with 
a suitable carboxylic acid and a condensing agent such as 
dicyclohexylcarbodiimide (DCC). 
An example of the latter is the synthesis of the trifluoromethylhydrazides 
shown below: 
##STR34## 
In this reaction a solution of 2-trifiuoroacetamidoisobutyric acid in dry 
THF is stirred and an equivalent amount of dicyclohexylcarbodiimide is 
added. The reaction is subsequently strirred for three minutes, after 
which an equimolar quantity of the1-substituted-1-methylhydrazine is added 
neat. Dicyclohexylurea precipitates immediately. The resultant suspension 
is stirred for one hour, filtered to remove the insoluble urea and the 
solvent is removed on a rotary evaporator to afford the crude hydrazide. 
The desired 1,1-disubstituted hydrazines may be readily prepared in a 
number of ways well known in the art; one is the reaction of a secondary 
amine with NH2C1 in an inert organic solvent. 
##STR35## 
A second synthetic route for the preparation of hydrazincs is alkylation of 
monoalkyl hydrazincs, shown below for methyl hydrazine: 
##STR36## 
This reaction is carried out by reacting a solution of methylhydrazine in 
THF, cooled at 0.degree. C. with a solution of an equimolar amount of the 
alkyl halide in THF added dropwise with stirring over a period of 30 
minutes. The reaction is stirred at 0.degree. C. for another 15 minutes, 
then heated to reflux and held at reflux for two hours. A water-cooled 
downward condenser is set up and approximately half of the solvent is 
removed by distillation. The residue is poured into water, which is then 
made basic by the addition of concentrated aqueous NaOH. The layers are 
separated, the aqueous phase is extracted with ether and the combined 
organic phases are washed with water, dried over MgSO.sub.4 and 
concentrated by distillation. Distillation at reduced pressure affords 
the1-substituted-1-methylhydrazine as a colorless liquid. 
Polymers Produced by Hydrazides 
Polymers containing designed sequences of substituted hydrazones may be 
produced using the following steps: 
##STR37## 
Mixed Modules 
All of the oxazolone, aminimide and hydrazide modules and monomers 
illustrated above may be mixed and matched to provide a variety of 
mixed-backbone polymers having specific properties, functionalities and 
sequences. 
Substituents 
Any of the various R and R' groups illustrated in all of the oxazolone, 
aminimide and hydrazide structures may be selected from among the 
following list: 
1 ) Amino acid derivatives of the form (AA)N, which would include, for 
example, natural and synthetic amino acid residues (N=1) including all of 
the naturally occuring alpha amino acids, especially alanine, arginine, 
asparagnine, aspartic acid, cysteine, glutamine, ghtamic acid, glycine, 
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, 
proline, serine, threonine, tryptophan, tyrosine; the naturally occuring 
disubstituted amino acids, such as amino isobutyric acid, and isovaline, 
etc.; a variety of synthetic amino acid residues, including 
alphaodisubstituted variants, species with olefinic substitution at the 
alpha position, species having derivatives, variants or mimetics of the 
naturally occuring side chains; N-Substituted glycine residues; natural 
and synthetic species known to functionally mimic amino acid residues, 
such as statine, bestatin, etc. Peptides (N=2-30) constructed from the 
amino acids listed above, such as angiotensinogen and its family of 
physiologically important angiotensin hydrolysis products, as well as 
derivatives, variants and mimetics made from various combinations and 
permutations of all the natural and synthetic residues listed above. 
Polypeptides (N=31-70), such as big endothelin, pancreastatin, human 
growth hormone releasing factor and human pancreatic polypeptide. Proteins 
(N&gt;70) including structural proteins such as collagen, functional proteins 
such as hemoglobin, regulatory proteins such as the dopamine and thrombin 
receptors. 
2) Nucleotide derivatives of the form (NUCL)N, which includes natural and 
synthetic nucleotides (N=1) such as adenosine, thymine, guanidine, 
uridine, cystosine, derivatives of these and a variety of variants and 
mimetics of the purine ring, the sugar ring, the phosphate linkage and 
combinations of some or all of these. Nucleotide probes (N=2-25) and 
oligonucleotides (N&gt;25) including all of the various possible homo and 
heterosynthetic combinations and permutations of the naturally occuring 
nucleotides, derivatives and variants containing synthetic purine or 
pyrimidine species or mimics of these, various sugar ring mimetics, and a 
wide variety of alternate backbone analogues including but not limited to 
phosphodiester, phosphorothionate, phosphorodithionate, phosphoramidate, 
alkyl phosphotriester, sulfamate, 3'-thioformacetal, 
methylene(methylimino), 3-N-carbamate, morpholino carbamate and peptide 
nucleic acid analogues. 
3 ) Carbohydrate derivatives of the form (CH)n. This would include natural 
physiologically active carbohydrates such as including related compounds 
such as glucose, galactose, sialic acids, beta-D-glucosylamine and 
nojorimycin which are both inhibitors of glucosidase, pseudo sugars, such 
as 5a-carba-2-D-galactopyranose, which is known to inhibit the growth of 
Klebsiella pneumonia (n=1), synthetic carbohydrate residues and 
derivatives of these (n=1) and all of the complex oligomeric permutations 
of these as found in nature, including high mannose oligosaccharides, the 
known antibiotic streptomycin (n&gt;1). 
4) A naturally occurring or synthetic organic structural motif. This term 
is defined as meaning an organic molecule having a specific structure that 
has biological activity, such as having a complementary structure to an 
enzyme, for instance. This term includes any of the well known base 
structures of pharmaceutical compounds including pharmacophores or 
metabolites thereof. These include beta-lactams, such as pennicillin, 
known to inhibit bacterial cell wall biosynthesis; dibenzazepines, known 
to bind to CNS receptors, used as antidepressants; polyketide macrolides, 
known to bind to bacterial ribosymes, etc. These structural motifs are 
generally known to have specific desirable binding properties to ligand 
acceptors. 
5) A reporter element such as a natural or synthetic dye or a residue 
capable of photographic amplification 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. Preferred 
reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid 
ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, 
aryl halides and oxirane groups. 
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 groups, oxirane groups, 
carboxylic acids, acid chlorides, esters, amides, lactones and lactams. 
Other organic moiety such as those defined for R and R' may also be used. 
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 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. This includes porous and non-porous 
inorganic macromolecular components, such as, for example, silica, 
alumina, zirconia, titania and the like, as commonly used for various 
applications, such as normal and reverse phase chromatographic 
separations, water purification, pigments for paints, etc.; porous and 
non-porous organic macromolecular components, including synthetic 
components such as styrene-divinyl benzene beads, various methacrylate 
beads, PVA beads, and the like, commonly used for protein purification, 
water softening and a variety of other applications, natural components 
such as native and functionalized celluloses, such as, for example, 
agarose and chitin, sheet and hollow fiber membranes made from nylon, 
polyether sulfone or any of the materials mentioned above. The molecular 
weight of these macromolecules may range from about 1000 Daltons to as 
high as possible. They may take the form of nanoparticles 
(dp=100-1000Angstroms), latex particles (dp=1000-5000Angstroms), porous or 
non-porous beads (dp=0.5-1000 microns), membranes, gels, macroscopic 
surfaces or functionalized or coated versions or composites of these. 
8) A structural moiety selected from the group including cyano, nitro, 
halogen, oxygen, hydroxy, alkoxy, thio, straight or branched chain alkyl, 
carbocyclic aryl and substituted or heterocyclic derivatives 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; 
As used herein, the phrase linear chain or branched chained alkyl groups 
means any substituted or unsubstituted acyclic carbon-containing 
compounds, including alkanes, alkenes and alkynes. Alkyl groups having up 
to 30 carbon atoms are preferred. Examples of alkyl groups include lower 
alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
iso-butyl or tert-butyl; upper alkyl, for example, cotyl, nonyl, decyl, 
and the like; lower alkylene, for example, ethylene, propylene, 
propyldiene, butylene, butyldiene; upper alkenyl such as 1-decene, 
1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl or heptenyl, and the 
like; alkynyl such as 1-ethynyl, 2-butynyl, 1-pentynyl and the like. The 
ordinary skilled artisan is familiar with numerous linear and branched 
alkyl groups, which are within the scope of the present invention. 
In addition, such alkyl group may also contain various substituents in 
which one or more hydrogen atoms has been replaced by a functional group. 
Functional groups include but are not limited to hydroxyl, amino, 
carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine 
and iodine), to mention but a few. Specific substituted alkyl groups can 
be, for example, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the 
like, polyhydroxy such as 1,2-dihydroxypropyl, 1,4-dihydroxy-1-butyl , and 
the like; methylamino, ethylamino, dimethylamino, diethylamino, 
triethylamino, cyclopentylamino, benzylamino, dibenzylamino, and the like; 
propanoic, butanoic or pentanoic acid groups, and the like; formamido, 
acetamido, butanamido, and the like, methoxycarbonyl, ethoxycarbonyl or 
the like, chloroformyl, bromoformyl, 1,1-chloroethyl, bromoethyl ,and the 
like, or dimethyl or diethyl ether groups or the like. 
As used herein, substituted and unsubstituted carbocyclic groups of up to 
about 20 carbon atoms means cyclic carbon-containing compounds, including 
but not limited to cyclopentyl, cyclohexyl, cycloheptyl, admantyl, and the 
like. Such cyclic groups may also contain various substituents in which 
one or more hydrogen atoms has been replaced by a functional group. Such 
functional groups include those described above, and lower alkyl groups as 
described above. The cyclic groups of the invention may further comprise a 
heteroatom. For example, in a specific embodiment, R2 is cycohexanol. 
As used herein, substituted-and unsubstituted aryl groups means a 
hydrocarbon ring bearing a system of conjugated double bonds, usually 
comprising an even number of 6 or more (pi) electrons. Examples of aryl 
groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, 
xylenyl and the like. According to the present invention, aryl also 
includes aryloxy, aralkyl, aralkyloxy and heteroaryl groups, e.g., 
pyrimidine, morpholine, piperazine, piperidine, benzoic acid, toluene or 
thiophene and the like. These aryl groups may also be substituted with any 
number of a variety of functional groups. In addition to the functional 
groups described above in connection with substituted alkyl groups and 
carbocylic groups, functional groups on the aryl groups can be nitro 
groups. 
As mentioned above, these structural moieties can also be any combination 
of alkyl, carbocyclic or aryl groups, for example, 1-cyclohexylpropyl, 
benzylcyclohexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 
2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like, 
Reactive Groups 
Specifically preferred reactive groups to generate the aminimide and 
oxazolone structures and the resulting base modules are listed below in 
tables 1, 2 and 3. The bonds in the structures in these figures represent 
potential points of attachment to the first and second compounds and to 
the base modules. 
Specifically preferred reactive groups to generate the aminimide and 
oxazolone structures and the resulting base modules are listed below in 
tables 1, 2 and 3. The bonds in the structures in these figures represent 
potential points of attachment for the attachment of the structural 
diversity elements to the first and second compounds and to the base 
modules. 
TABLE 1 
______________________________________ 
Oxazolone Modules 
Reactivity Groups Base Modules 
______________________________________ 
##STR38## HY (Y = N, S, O) 
##STR39## 
##STR40## 
##STR41## 
##STR42## 
##STR43## HY (Y = N, S, O) 
##STR44## 
##STR45## CO2H/Cl (ClCO2Et/Et3N) 
##STR46## 
##STR47## 
##STR48## 
##STR49## 
______________________________________ 
Represents potential points of attachment 
TABLE 2 
______________________________________ 
Aminimide Modules 
Reactivity Groups Base Modules 
______________________________________ 
COOH 
##STR50## 
##STR51## 
NCO 
##STR52## 
##STR53## 
OCOCl 
##STR54## 
##STR55## 
SCOCl 
##STR56## 
##STR57## 
##STR58## X (neutr.) 
##STR59## 
##STR60## 
##STR61## 
##STR62## 
##STR63## X (neutr.) 
##STR64## 
##STR65## 
##STR66## 
##STR67## 
##STR68## X (neutr.) 
##STR69## 
##STR70## 
##STR71## 
##STR72## 
##STR73## X (neutr.) 
##STR74## 
##STR75## 
##STR76## 
##STR77## 
##STR78## X (neutr.) 
##STR79## 
##STR80## 
##STR81## 
##STR82## 
##STR83## BASE 
##STR84## 
##STR85## COOR 
##STR86## 
##STR87## COOR 
##STR88## 
##STR89## 
##STR90## 
##STR91## 
##STR92## 
##STR93## 
##STR94## 
______________________________________ 
Represents potential points of attachment 
TABLE 3 
__________________________________________________________________________ 
Aminimide-Oxazolone Modules 
Reactivity Groups 
Base Modules 
__________________________________________________________________________ 
##STR95## 
##STR96## 
__________________________________________________________________________ 
Represents potential points of attachment 
EXAMPLE 1 
This example describes preparation of a tetramer by alternating 
ring-opening/Michael-addition reactions followed by chain polymerizations. 
##STR97## 
In the first synthetic step, a solution of b-butyrolactone (8.61 g, 0.1 
mole, 8.15 mL) in THF (150 mL) is cooled at 0.degree. C. while a solution 
of benzyl 2-aminoisobutyrate (19.3 g, 0.1 mole) in THF (100 mL) is added. 
The mixture is stirred at 0.degree. C. for two hours then room temperature 
for four hours, then is treated with tert-butyldimethylsilyl chloride ( 
15.1 g, 0.1 mole) and imidazole (13.6 g, 0.2 mole) added in alternating 
portions as the solids. The mixture is stirred overnight at room 
temperature, the solids are removed by filtration, and the filtrate is 
concentrated in vacuo. The residue is dissolved in methanol (100 mL), 
palladium on carbon catalyst (5% Pd, 500 mg) is added, and the solution 
stirred under an atmosphere of hydrogen gas until the ester is exhausted 
(reaction is monitored in progress by volume of absorbed H.sub.2 gas and 
by TLC). Following complete removal of the benzyllic functionality, the 
catalyst is removed by filtration with the aid of celite. The precipitate 
is washed with methanol (3.times.100 mL) and the combined filtrates are 
concentrated in vacuo. The residue is crystallized, then recrystallized 
from ethyl acetate to afford the protected acid (21.7 g, 0.072 mole, 72%). 
This acid is dissolved in ethyl acetate (300 mL) and cooled at 0.degree. C. 
while ethyl chloroformate (7.77 g, 0.072 mole, 6.85 mL) is added, followed 
by triethylamine (7.25 g, 0.072 mole, 9.98 mL). After cessation of gas 
evolution (ca. four hours), the triethylamine hydrochloride is removed by 
filtration and the filtrate is concentrate to afford crude 
2-(2-tert-butyldimethylsilyloxy propyl)-4,4-dimethyl-5-oxazolone as a 
yellow oil (23.4 g). Recrystallization from ethyl acetate affords the pure 
product (13.7 g, 67%, 0.048 mole). The material gave satisfactory spectral 
data (300 MHz NMR proton signals corresponding to silyl group butyl: silyl 
group methyls: oxazolone gem-dimethyl integrals 9:6:6; IR 1820 cm.sup.-1 
azlactone band). 
##STR98## 
A solution of of 95% N-methylethyienediamine (3.56 g, 48 mmol, 4.23 mL) in 
methylene chloride (75 mL) is cooled in an ice bath while a solution of 
2-(2-tert-butyldimethylsilyloxy propyl)-4,4-dimethyl-5-oxazolone (13.7 g, 
48 mmol) in methylene chloride (100 mL) is added such that the temperature 
remains below 5.degree. C. The solution is stirred at room temperature for 
15 minutes while a white precipitate forms. The mixture is stirred for an 
additional 2 h at 0.degree. C. The solids are removed by filtration and 
washed with methylene chloride (25 mL) and air dried to yield the 
ring-opened adduct (12.87 g, 36 mmol, 75%), identified by nuclear magnetic 
resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy as 
follows: NMR (CDCl.sub.3): CH.sub.3 -N/gem (CH.sub.3).sub.2 ratio 1:2; 
tert-butyldimethylsilyl--splitting pattern in 0-1 ppm region, integration 
ratios and D.sub.2 O exchange experiments diagnostic for structure. FTIR 
(nujol mull): azlactone CO band at 1820 cm.sup.-1 absent; strong amide 
bands present in 1670-1700 cm.sup.-1 region. 
##STR99## 
A solution of of the ring-opened adduct (8.98 g, 25 mmol) and 
4,4-dimethyl-2-vinylazlactone (3.48 g, 25 mmol) in benzene (50 mL) is 
heated to 70.degree. C. for 4 hours. The flask is cooled to room 
temperature and allowed to stand under an inert atmosphere for 3 days. The 
solvent is decanted off from the thick oil that forms. This oil is 
dissolved in acetone (ca 50 mL) and concentrated to produce another thick 
oil, which is concentrated under vacuum at 1 torr overnight to yield 9.34 
g of a white crystalline solid (25 mmol), identified by NMR and FTIR 
spectroscopy as 2-(N-(2-(2-(3-tert-butyldimethylsilyloxy 
butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-4,4-dimethyl-5-ox 
azolone: NMR: CH.sub.3 -N/gem (CH.sub.3).sub.2 ratio 1:4; 
tert-butyldimethylsilyl--splitting pattern in 0-1 ppm region, integration 
ratios and D.sub.2 O exchange experiments diagnostic for structure. FTIR 
(nujol mull): strong azlactone CO band at 1820 cm.sup.-1. 
Construction of the Poly(pentamer) 
##STR100## 
Polymerization of the mono(pentamer)--This material is dissolved in THF 
(500 mL) and cooled at 0.degree. C. while a solution of 
tetra-n-butylammonium fluoride (1.0 M in THF, 25 mL, 25 mmol) is added. 
The exotherm is controlled by the rate of addition of the fluoride 
reagent. The mixture is then heated briefly to 70.degree. C. and cooled to 
room temperature. Water 100 mL) is added and the layers are stirred, then 
separated. The organic phase is dried (sat'd aq NaCl, MgSO.sub.4), and 
concentrated in vacuo (18 torr, then 0.1 torr 10 hours) to afford the 
polymer (9.60 g). This material showed no signals for the 
tert-butyldimethylsilyl group in the proton NMR spectrum and the azlactone 
band was absent in the infrared spectrum. 
EXAMPLE 2 
This example illustrates the preparation of a tris(pentameric) module and 
its assembly into a polymer. 
##STR101## 
A solution of of the ring-opened adduct (8.98 g, 25 mmol) and benzyl 
3-phenyl-2-methyl-2-acrylamidopropionate (8.03 g, 25 mmol) in benzene (50 
mL) is heated to 70.degree. C. for 4 hours. The flask is cooled to room 
temperature and allowed to stand under an inert atmosphere for 3 days. The 
solvent is decanted off from the thick oil that forms. The residue is 
crystallized, then recrystallized from ethyl acetate to afford the 
protected benzyl ester adduct (15.34 g, 23 mmol, 90%) 
##STR102## 
The product is dissolved in THF (250 mL) and a solution of TBAF (1.0 M, 23 
mmol, 23 mL) is added and the reaction stirred for one hour at room 
temperature, then cooled at 0.degree. C. while a solution of 
2-(N-(2-(2-(3-tert-butyldimethylsilyloxy 
butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-4,4-dimethyl-5-ox 
azolone (11.45 g, 23 mmol)in THF (150 mL) is added with stirring. The 
reaction is stirred overnight at room temperature, then partitioned 
between water (200 mL) and THF. The aqueous phase is separated and 
extracted with ether (2.times.200 mL) and the combined organics are dried 
(sat'd aq NaCl, MgSO.sub.4) and concentrated to afford a solid (22.0 g). 
A suspension of this solid and palladium on carbon catalyst (5% Pd, 500 mg) 
in methanol (200 mL) is stirred under an atmosphere of hydrogen gas until 
the ester is exhausted (reaction is monitored in progress by volume of 
absorbed H.sub.2 gas and by TLC). Following complete removal of the 
benzylic functionality, the catalyst is removed by filtration with the aid 
of celite. The filter pad is washed with methanol (3.times.100 mL) and the 
combined filtrates are concentrated in vacuo to afford a viscous syrup 
that is used directly. 
This acid is dissolved in ethyl acetate (100 mL) and cooled at 0.degree. C. 
while ethyl chloroformate (2.32 g, 23 mmol, 2.04 mL) is added, followed by 
triethylamine (2.16 g, 23 mmol, 2.98 mL). After cessation of gas evolution 
(approximately two hours), the triethylamine hydrochloride is removed by 
filtration and the filtrate is concentrated to afford the crude product as 
a yellow oil (23.4 g). A pure sample of this product is obtained Purified 
by chromatographic purification on RP-C.sub.18 silica gel (methanol-water 
gradient elution) to give 2-(N-(2-(3-(2-(N-(2-(2-(3-tert-butyldimethyl 
silyloxybutyramido)-isobutyramido)-ethyl)-N-methyl-3 
-propanamido)-isobutyroxy)-butyramido)-isobutyramido)-ethyl-N-methyl-2-ami 
noethyl)-ethyl-4,4-dimethyl-5-oxazolone (11.43 g, 61%, 14 mmol) as an 
amorphous powder. The material gave satisfactory spectral data (300 MHz 
NMR proton signals corresponding to silyl group butyl: silyl group 
methyls: oxazolone gem-dimethyl integrals 9:6:6; IR 1820 cm.sup.-1 
azlactone band). 
##STR103## 
A solution of of the ring-opened adduct (8.98 g, 25 mmol) and benzyl 
2,4-dimethyl-2-acrylamidopentanoate (7.18 g, 25 mmol) in benzene (50 mL) 
is heated to 70.degree. C. for 4 hours. The flask is cooled to room 
temperature and allowed to stand under an inert atmosphere for 3 days. The 
solvent is decanted off from the thick oil that forms. The residue is 
crystallized, then recrystallized from ethyl acetate to afford the 
protected benzyl ester adduct (13.41 g, 21 mmol, 83%) 
##STR104## 
a solution of this product (8.94 g, 14 mmol) in THF (250 mL) and a solution 
of TBAF (1.0 M, 14 mmol, 14 mL) is added and the reaction stirred for one 
hour at room temperature, then cooled at 0.degree. C. while a solution of 
the previously prepared di-pentamer oxazolone (11.43 g, 14 mmol) in THF 
(150 mL) is added with stirring. The reaction is stirred overnight at room 
temperature, then partitioned between water (200 mL) and THF. The aqueous 
phase is separated and extracted with ether (2.times.200 mL) and the 
combined organics are dried (sat'd aq NaCl, MgSO.sub.4) and concentrated 
to afford a solid (22.0 g). 
A suspension of this solid and palladium on carbon catalyst (5% Pd, 250 mg) 
in methanol (200 mL) is stirred under an atmosphere of hydrogen gas until 
the ester is exhausted (reaction is monitored in progress by volume of 
absorbed H.sub.2 gas and by TLC). Following complete removal of the 
benzylic functionality, the catalyst is removed by filtration with the aid 
of celite. The filter pad is washed with methanol (3.times.100 mL) and the 
combined filtrates are concentrated in vacuo to afford a viscous syrup 
that is used directly. 
This acid is dissolved in ethyl acetate (100 mL) and cooled at 0.degree. C. 
while ethyl chloroformate (1.41 g, 14 mmol, 1.24 mL) is added, followed by 
triethylamine (1.31 g, 14 mmol, 1.81 mL). After ten hours, the 
triethylamine hydrochloride is removed by filtration and the filtrate is 
concentrated to afford the crude product as a tan solid (23.4 g). 
Purification by column chromatography on RP-C.sub.18 silica gel 
(methanol-water gradient elution), pooling of the appropriate fractions 
and concentration in vacuo affords pure 
2-(3-(N-(2-(2-(2-(3-(N-(2-(3-(2-(N-(2-(2-(3-tert-butyldimethylsilyloxybuty 
ramido)isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-propanoylamido)-isobuty 
roxy)-butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-propanoylami 
do)-isobutyroxy)-propanoylamido)-isobutyramido)-N-methyl-ethylamino)-ethyl) 
-4-isobutyl-4-methyl-5-oxazolone z(3.72 g, 22%, 3 mmol) as an amorphous 
powder. The material gave satisfactory spectral data (300 MHz NMR proton 
signals corresponding to silyl group butyl: silyl group methyls: oxazolone 
gem-dimethyl integrals 9:6:6; IR 1820 cm.sup.-1 azlactone band). 
Construction of the Polytris(pentamer) 
##STR105## 
Polymerization of the tris(pentamer)--This material is dissolved in THF 
(200 mL) and cooled at 0.degree. C. while a solution of 
tetra-n-butylammonium fluoride (1.0 M in THF, 3 mL, 3 mmol) is added. The 
exotherm is controlled by the rate of addition of the fluoride reagent. 
The mixture is then heated briefly to 70 .degree. C. and cooled to room 
temperature. Water (100 mL) is added and the layers are stirred, then 
separated. The organic phase is dried (sat'd aq NaCl, MgSO.sub.4), and 
concentrated in vacuo (18 torr, then 0.1 torr 10 hours) to afford the 
polymer (3.38 g). This material showed no signals for the 
tert-butyldimethylsilyl group in the proton NMR spectrum and the azlactone 
band was absent in the infrared spectrum. 
Further details on the reaction possibilities for the oxazolone and 
aminimide compounds can be found in two PCT applications PCT/US93/1259 and 
PCT/US93/12612 each filed on Dec. 28, 1993, and entitled Modular Design 
And Synthesis of Aminimide-Derived Molecules, respectively. The content of 
each of those applications is expressely incorporated herein by reference 
thereto to the extent necessary to understand the metes and bounds of this 
invention.