Four new substituted indenyl-fluorenyl asymmetric ethylene bridged ligands have been prepared from the reaction of 1-(9-fluorenyl)-2-bromoethane and the lithium salt of the desired indenyl moiety. The ligands have been converted to the corresponding substituted asymmetric ethylene-bridged metallocenes (M = Zr, Hf). The metallocenes have been evaluated as Ziegelr-Natta type catalyst precursors for the polymerization of ethylene and propylene. The zirconocene complexes 19-21 showed very high activity for both monomers. The influence of substitution on the selectivity of the propylene polymerization has been studied. The metallocene 1-(9-fluorenyl)-2-[(2,4,7-trimethyl)-1-indenyl] ethane zirconium dichloride (21) was found to produce highly isotactic polypropylene with [mmmm] of 89%. The dimethylsilylene bridged analog of 21 (31) was prepared and was found to be less active and less stereoselective than the ethylene bridged precursor. A detailed study of the propylene polymerization behavior of the zirconocene complexes (19-21, 31) was carried out and the mechanistic aspects of polymerization are discussed. Three new zirconocenes bearing 2,4-disubstitution on the indenyl moiety have been synthesized and evaluated as (x-olefin polymerization catalysts. For the new complex, ethylene-1-(9-fluorenyl)-2-[1-(2-methyl4-phenyl)indenyl]zirconium dichloride (42), highly isotactic polypropylene with [mmmm] = 91% and Mw = 1.1 x 105 was produced in very high yield. The dimethylsilylene analog (44) while less active, gave similar results in terms of stereoregularity with a two-fold increase in MW. Two new asymmetric complexes with partially or fully substituted fluorenyl ligands have been synthesized. Dimethylsilylene-[1-(2-methyl-4-phenyl)indenyl-(9-tetrahydrofluorenyl) zirconium dichloride (51) and the octahydrofluorenyl analog 52 were highly active catalyst precursors for ethylene and propylene polymerizations with activities approaching 108 g polymer/[(mol Zr) [monomer] h]. The polypropylenes produced at room temperature were highly isotactic. Several new, novel bridged and unbridged bis-tetrahydrofluorenyl zirconocenes were synthesized. The complexes were found to be highly stable compared to some bis-fluorenylzirconocenes. Polypropylene and polyethylene were produced in good yield using the new catalyst precursors with MAO or Trityl/TIBA as co-catalysts.

The focus of this work was the synthesis and coordination of t-butyl nitroxide radicals with various paramagnetic transition metal dications to investigate the magnetic interactions in the products. The crystal structure of each coordination complex was studied to elucidate possible structural pathways for magnetic exchange. A silicon centered tetraradical, tetrakis(N-oxyl-2,2,6,6-tetramethylpiperidin-4-oxyl)silane, was synthesized and coordinated to various metal ions to yield one-dimensional coordination polymers joined through nitroxide-metal-nitroxide (3-spin) units. The Mn(II) complex showed strong antiferromagnetic (AFM) coupling within the 3-spin unit, while the Cu(II) complex showed modest ferromagnetic (FM) coupling within the unit. Both complexes showed weak AFM interactions between 3-spin units. The new radical 5-(3-[N-tert-butyl-N-aminoxyl]phenyl)pyrimidine was synthesized and coordinated to metal dications, and formed both cyclic 2:2 dimers and extended network complexes that were isolated as stable crystalline solids. The Mn(II) dimer showed strong AFM exchange within the dimer and weak FM exchange between dimer units, based on magnetic analysis by a rectangular four-spin model. A linear Curie-Weiss model for the Co(II) dimer showed strong AFM exchange within these dimer units. The Cu(II) dimer exhibited crystallographic Jahn-Teller distortion accompanied by reversible solid-state thermochromic effects that correlate qualitatively with changes in magnetic behavior with temperature. 5-(3-[N-tert-Butyl-N-aminoxyl]phenyl)pyrimidine formed zero- to three-dimensional complexes with Cu(hfac)2. Most of these were 3:2 Cu:radical complexes with different magnetic behaviors. Two-dimensional complex 25 shows a slight ferromagnetic rise, then antiferromagnetic downturn in the χT(T) plot; it also exhibits multistep behavior in the M( H) plot, with a magnetic moment higher than any comparable complex in this series. Two-dimensional complex 26 undergoes a reversible crystal lattice change from orthorhombic to monoclinic, and shows strong AFM coupling between metal-radical units, with additional AFM coupling between units. Three-dimensional complex 27 shows multi-stage magnetic M(H) behavior. Jahn-Teller distortion of Cu-radical units was noted in complexes 26 and 27. 3-(N-tert-butyl-N-aminoxyl)benzoic acid was isolated as a stable crystalline solid that forms one-dimensional chains of hydrogen bonded dimers. The radical shows antiferromagnetic exchange behavior that could be roughly fit to a Bleaney-Bowers spin pairing model. The radical adsorbs strongly but reversibly to silica based materials from nonpolar solvents.

Previously it was suggested that the reason for the superior performance, in terms of both reactivity and avoidance of loss of configuration in peptide coupling observed for 7-HOAt over HOBt or 4-HOAt was due to the involvement of a cyclic transition state at the stage of the key intermediate, the active ester [J. Am. Chem. Soc., 1993, 115 , 4397]. Synthesis of the two remaining isomers, the 5- and the 6-compounds, and examination of the reactivity of all four isomers has added further evidence in support of this theory. For example, upon conversion to the corresponding active esters, it was found that in reactions with amines, the 7-derivative stands out as being the most reactive. Similarly when used as additive for segment coupling in the presence of a carbodiimide only the 7-isomer provides for low-racemization coupling whereas the 4-, 5- and 6-HOAt derivatives show results which are similar to those of HOBt. Finally in the case of a reaction for which neighboring group effects are not pertinent, such as S N2 displacement on the methyl group of the four isomeric O-methyl ethers, the order of reactivity appears to parallel the pKa data with the 4-isomer being more reactive than the 7-isomer. ^

The work described here had as its goal the development of new techniques for very rapid synthesis of longer peptides. Current methods are often time-consuming and sometimes completely ineffective due to the incursion of peptide aggregation which may interfere with chain extension. Attention was directed to the three main problems in current methodologies: inefficient protecting groups, inefficient coupling reagents and problems due to peptide aggregation. ^ A new protecting group, more effective than the common Fmoc residue, was adopted for the present studies. An unforeseen by-product of these studies was the accidental observation that Bsmoc amino acids are more reactive than Fmoc amino acids as acylating agents as shown in competition experiments. This effect should increase the efficiency of the former for longer peptides. ^ As coupling reagent, O-HATU was adopted as the best of the currently available activators and in addition a new reagent, t-Bu-Dtp-OAt, was developed and shown to be equal in effectiveness to O-HATU. ^ The third problem, aggregation, was given the greatest amount of attention in these studies. While carrying out the first Bsmoc-based syntheses of longer peptides we identified the presence of some by-products of the same molecular weight as the target peptide. These were identified as depsipeptides which were formed at threonine positions during the final TFA treatment which removed the peptide from the resin during solid phase synthesis. The structures of these materials were proved by authentic syntheses and curiously these synthesis occurred very efficiently, showing no aggregation problems. Then the depsipeptide was converted to the desired peptide via a basic buffer. Fortunately this effect also led to greater solubility for the ester sequence thus making purification easier. Once this new technique or modifications involving the new N-dicyclopropylmethyl backbone protectant had been identified it was applied to the superfast synthesis of several difficult sequences, e.g. the JR 10-mer, the JR 26-mer, Crambin (16-46), Crambin (1-46) and the extremely difficult Aβ(1-43) amyloid peptide. ^

Since loss of configuration at the carboxylic acid residue during peptide coupling remains one of the most challenging problems in peptide synthesis whether one is concerned with stepwise or convergent synthesis, a main focus of the present work was to find an approach to overcome this difficulty. A first attempt involved an examination of the Fm group as a backbone protectant for two reasons. First, since the Fm group 43 precludes oxazolone formation it was expected that Fm amino acids could be substituted for Fmoc acids in stepwise solid phase syntheses while eliminating any chance for loss of configuration. Second, if an Fm group were introduced at the C-terminal position of a peptide segment it was expected that such segments would undergo coupling with the N-terminal amino group of a second segment without loss of chirality. Initial attention was paid to this aspect of the convergent approach to peptide synthesis. An appropriate segment was synthesized and some tests were conducted which showed loss of configuration to be minimal. Unfortunately however it was found that the synthesis of the appropriate Fm-backbone protected peptides proved to be difficult because of the large size of the Fm residue. This problem led to an examination of methods to overcome these slow coupling reactions. One of the methods examined involved the synthesis of the indazole analog 194 of HOAt 84 since it was expected that removal of one of the triazole N-atoms should allow the corresponding HATU-like uronium/guanidinium coupling species to be more efficient in directing the coupling process. A method for the synthesis of 7-aza-N-hydroxyindazole 208 was developed and the structure of the new compound established by normal methods which included a definitive X-ray structural analysis. Unfortunately it proved to be impossible to convert 208 into a stand-alone analog of HATU 99 and when 208 was used as an additive results were not encouraging. Therefore we abandoned the possible use of 208 and spent time on the development of some theoretically interesting pyrazine analogs of HOAt. Unfortunately these materials proved difficult to synthesize and this line of attack was dropped. At the time of this development we were engaged in trying to develop optimized synthetic routes to O-HAPyU 241 a reagent more effective than either N-HAPyU 242 or N-HATU 48 for coupling reactions, but which was only available in very low yield via standard methods. One of the methods examined involved study of the very fast reaction between the potassium salt of HOAt and the chlorouronium salt BTCFH 248. In this reaction the initially formed species is O-HAPyU 241 but this compound rapidly undergoes base-catalysed isomerization to the less reactive N-HAPyU 242. By working quickly it was hoped to be able to isolate the more reactive O-isomer. While carrying out these studies it occurred to us that this might be a general technique for optimizing other ordinary coupling reactions which involve the use of O-HATU 99b and O-HBTU 99a. All such O-substituted reagents are sensitive to reaction conditions and are quickly isomerized to the corresponding N-isomers. Thus the superior properties of the O-derivatives are lost. By generating these O-forms in situ we hoped for better results. In fact we were pleasantly surprised to find that precisely such results were observed. Indeed when tested on our standard models for examining the loss of chirality in segment coupling the new methods were remarkably more efficient than the standard techniques. For example in one case leading to a tripeptide 212 via [2+1] coupling the older technique always gave 5-10% of the LDL-isomer whereas our newer method can achieve this coupling with absolutely no loss of configuration. Several models were examined, even some extremely difficult ones and in all cases significant improvements were observed. These methods were also applied to solid phase syntheses of longer peptides and here again the results were superior. Thus we believe the new method represents a remarkable, even astonishing, improvement over previously described methods. ^

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