Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Polymers from only ethylenic monomers or processes of...
Reexamination Certificate
2000-05-05
2002-11-19
Wu, David W. (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Polymers from only ethylenic monomers or processes of...
C526S172000, C526S173000, C558S381000, C502S155000, C502S167000
Reexamination Certificate
active
06482908
ABSTRACT:
BACKGROUND
The present invention generally relates to the synthesis of functionalized cyclic olefins via template-directed ring-closing metathesis (“RCM”) or template-directed depolymerization of functionalized unsaturated polymers, and to the synthesis of functionalized polymers by ring-opening metathesis polymerization (“ROMP”). More specifically, the present invention relates to specific crown-ether analogs possessing a site of unsaturation, and specific poly(ethylene glycol) analogs (“PEG analogs”) possessing regularly spaced sites of unsaturation which may optionally include peptide fragments or other bioactive molecules.
Functionalized Cyclic Olefins
Functionalized cyclic molecules are an important class of compounds that are used extensively as metal-complexing species. These molecules have many uses including analytical chemistry titrations, removal of ions from solutions and soils, iron binding in hemoglobin, magnesium binding in chlorophyll, and for medicinal uses such as antimicrobial agents against gram-positive bacteria, fungi, viruses and the like. One particularly useful class of functionalized cyclic molecules are crown ethers which also find important uses as solubilizers for metals in organic transformation reactions. See
Crown Ethers and Analogs
, Patai, S. and Rappoport, Z. Eds; John Wiley & Sons: New York, 1989, which is incorporated herein by reference and contains many examples of technically and scientifically important functionalized cyclic molecules including crown-ethers, crown-thioethers, porphyrins, lariats, cryptands, sandwich complexes and the like.
When the functionalized cyclic molecules contain a site of unsaturation, as in the case of functionalized cyclic olefins, the site of unsaturation may be used for further chemical modification of the molecule. In addition, functionalized cyclic olefins may also be used as the starting materials for polymer synthesis via a ROMP reaction. As will be discussed in detail below, this is an important advantage since the ROMP of functionalized cyclic olefins provides a new method for synthesizing high molecular weight functionalized polymers which possess regularly spaced sites of unsaturation and regularly spaced functional groups. The sites of unsaturation of the polymer may be used for further chemical modification or may be used for covalent cross-linking of the polymer strands. In addition, the regularly spaced functional groups of the polymer may be used for further processing of the polymer. For example, the functional groups may be reacted together to cross-link the polymer strands, may be reacted with further components to modify the physical and chemical properties of the polymer, or if the polymer contains certain biologically active functional groups, may be used as biological receptor sites allowing the polymer to selectively adhere to different cell types.
Synthesizing functionalized cyclic olefins that possess a definite stereochemistry (i.e., cis or trans at the site of unsaturation) is also desirable since the differing conformation of the cis and trans isomers may give rise to different chelating properties for the functionalized cyclic olefins. In addition, the stereochemistry may also affect product yield. For example, in ROMP reactions of crown ether analogs, cis starting materials result in substantially higher polymer yields than the trans starting materials.
Recently, a novel class of metathesis catalysts based on ruthenium and osmium carbenes complex catalysts have been developed which are stable in the presence of a variety of functional groups. These catalysts are described in more detail below and their use has allowed for the synthesis of functionalized cyclic olefins.
Although the discovery of these catalysts has enabled the synthesis of functionalized cyclic olefins with five, six, seven, and eight membered rings, for all but these smallest sized rings, the conventional RCM approach typically results in low yields. In addition, entropic factors disfavor RCM reaction of larger sized rings and in many cases this gives rise to very small yields of ring-closed product when the ring size is greater than about seven. Moreover, large volumes of solvent are often required since the conventional reactions are usually run at high dilution to ensure the RCM reaction pathway is favored over the alternative reaction pathways of acyclic diene metathesis polymerization (ADMET) and ROMP of the cyclic olefin product.
In U.S. patent application Ser. No. 08/654,712 (which is incorporated herein by reference), a method developed by Grubbs, Miller, and Blackwell overcomes some of these drawbacks of the RCM reaction scheme for larger sized rings. In this method, acyclic diene starting materials are modified to possess a covalently-bonded conformational constraint. This constraint acts to favor the RCM reaction pathway over the other competing pathways and makes the RCM reaction more entropically favorable. Although successful at overcoming the problem of competing reactions and entropic factors, these covalent modification methods have serious drawbacks including the fact that the starting material must necessarily include a covalently-bonded conformational constraint. This restriction adds to the complexity of synthesizing the starting material and may severely restrict the acyclic dienes which may be used as RCM substrates. In addition to complicating the synthesis of the starting materials, the covalent conformational constraint must also be removed from the product cyclic olefin. The breaking of the covalently-bonded constraint may require extremely harsh reaction conditions which may cause further reactions of the functionalized olefin. In fact, in some cases this post processing of the cyclic olefins may be impossible to achieve or may at the very least, result in a much lower overall yield of cyclic product.
In summary, functionalized cyclic olefins are important for at least two reasons. First, the unsaturated molecules are analogs of saturated functionalized cyclic molecules such as crown-ethers and the site of unsaturation allows for further chemical modification of the molecule. Second, the unsaturated molecules may be used as the starting materials for a new method of synthesizing functionalized polymers possessing regularly spaced sites of unsaturation and regularly spaced functional groups. Functionalized cyclic olefins with small ring size (less than about seven) can be synthesized via the RCM of functionalized acyclic dienes; however, in many cases this method results in low yields when applied to larger sized rings due to the competing ROMP and ADMET pathways. In an effort to minimize the effect of the competing pathways the reaction can be run at high dilution. However, this leads to the use of large amounts of solvent. One method that is applicable to the synthesis of functionalized cyclic olefins with larger ring size includes the introduction of a covalent conformational constraint into the starting diene; however, this method has the important drawback that the covalent constraint must be removed from the cyclic olefin product. This post processing reaction may be costly, time consuming, and may damage the cyclic olefin product.
To overcome these drawbacks of the conventional methods, there therefore exists a need for a method for synthesizing functionalized cyclic olefins that is not limited to synthesizing only small ring size products, may not be required to be run at high dilution, and does not require starting materials that include covalent conformational constraints. In addition to these needs, it is also desirable that the method yield functionalized cyclic olefins with a definite stereo-chemistry at the olefin bond; preferably, a cis conformation.
Functionalized Unsaturated Polymers
Functionalized unsaturated polymers are also an important class of compounds. One illustrative example of polymers that may be synthesized using the methods of the present invention is PEG analogs, which may have important uses as a cell-selective biomaterial (i.e., as materials that can
Grubbs Robert H.
Marsella Michael J.
Maynard Heather D.
California Institute of Technology
Harlan R.
Wu David W.
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