PYRROLIDINE-CONTAINING MONOMERS AND OLIGOMERS

Abstract: Novel pyrrolidine monomers bearing various functional groups are used to prepare oligomeric structures. The pyrrolidine monomers can be joined via standard phosphate linkages including phosphodiester, phosphorothioate, and phosphoramidate linkages. Useful functional groups include nucleobases as well as polar groups, hydrophobic groups, ionic groups, aromatic groups and/or groups that participate in hydrogen-bonding.

Description: PYRROLIDINE-CONTAINING MONOMERS AND OLIGOMERS CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of United States application serial number 08/180,134, filed January 11, 5 1994. The contents of the foregoing patent application are incorporated herein by reference. FIELD OF THE INVENTION This invention is directed to pyrrolidine monomeric 0 units and to oligomers constructed from them. The oligomers can be synthesized to have either random or predefined sequences of monomeric units and can be joined via phosphate linkages, including phosphorothioate, phosphodiester and phosphoramidate linkages. Each of the monomeric units can 5 include a chemical moiety thereon for binding of the oligomeric structures to proteins, nucleic acid, and other biological targets. In preferred embodiments, the compounds of the invention act as inhibitors of enzymes such as phospholipase A 2 and are used for the treatment of 0 inflammatory diseases including atopic dermatitis and inflammatory bowel disease. BACKGROUND OF THE INVENTION Phospholipases A 2 (PLA 2 ) are a family of enzymes that hydrolyze the sn-2 ester linkage of membrane phospholipids 5 resulting in release of a free fatty acid and a lysophospholipid (see, Dennis, E.A., The Enzymes, Vol. 16, pp. 307-353, Boyer, P.D., ed. , Academic Press, New York, 1983) . Elevated levels of type II PLA 2 are correlated with a number of human inflammatory diseases. The PLA 2 -catalyzed reaction is the rate-limiting step in the release of a number of pro- inflammatory mediators. Arachidonic acid, a fatty acid commonly linked at the sn-2 position, serves as a precursor to leukotrienes, prostaglandins, lipoxins and thromboxanes. The lysophospholipid can be a precursor to platelet-activating factor. PLA 2 is regulated by pro-inflammatory cytokines and, thus, occupies a central position in the inflammatory cascade ( see, e . g. , Dennis, ibid. ; Glaser, et al . , TiPs Reviews 1992, 14, 92; and Pruzanski, et al . , Inflammation 1992, 16, 451) . All mammalian tissues evaluated thus far have exhibited PLA 2 activity. At least three different types of PLA 2 are found in humans: pancreatic (type I) , synovial fluid (type II) and cytosolic. Studies suggest that additional isoenzymes exist. Type I and type II, the secreted forms of PLA 2 , share strong similarity with phospholipases isolated from the venom of snakes. The PLA 2 enzymes are important for normal functions including digestion, cellular membrane remodeling and repair, and in mediation of the inflammatory response. Both cytosolic and type II enzymes are of interest as therapeutic targets. Increased levels of the type II PLA 2 are correlated with a variety of inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and septic shock, suggesting that inhibitors of this enzyme would have therapeutic utility. Additional support for a role of PLA 2 in promoting the pathophysiology observed in certain chronic inflammatory disorders was the observation that injection of type II PLA 2 into the footpad of rats (Vishwanath, et al . , Inflammation 1988, 12, 549) or into the articular space of rabbits (Bomalaski, et al . , J. Immunol . 1991, 146, 3904) produced an inflammatory response. When the protein was denatured before injection, no inflammatory response was produced. The type II PLA 2 enzyme from synovial fluid is a relatively small molecule (about 14 kD) and can be distinguished from type I enzymes ( e . g. , pancreatic) by the sequence and pattern of its disulfide bonds. Both types of enzymes require calcium for activity. The crystal structures of secreted PLA 2 enzymes from venom and pancreatic PLA 2 , with and without inhibitors, have been reported (Scott, et al . , 5 Science 1990, 250 , 1541) . Recently, the crystal structure of PLA 2 from human synovial fluid has been solved (Wery, et al . , Nature 1991, 352, 79) . The structures clarify the role of calcium and amino acid residues in catalysis. The calcium acts as a Lewis acid to activate the scissile ester carbonyl 10 and bind the lipid, and a His-Asp side chain dyad acts as general base catalyst to activate a water molecule nucleophile. This is consistent with the absence of any acyl enzyme intermediates, and is also comparable to the catalytic mechanism of serine proteases. The catalytic residues and the 15 calcium ion are at the end of a deep cleft (ca. 14 A) in the enzyme. The walls of this cleft contact the hydrocarbon portion of the phospholipid and are composed of hydrophobic and aromatic residues. The positively-charged amino-terminal helix is situated above the opening of the hydrophobic cleft. 20 Several lines of evidence suggest that the N-terminal portion is the interfacial binding site, ( see, e . g. , Achari, et al . , Cold Spring Harbor Symp . Quant . Biol . 1987, 52 , 441; Cho, et al . , J. Biol . Chem. 1988, 263 , 11237; Yang, et al . , Biochem . J. 1989, 262 , 855; and Noel, et al . , J. Am . Chem . Soc . 1990, 25 112 , 3704) . Much work has been reported in recent years on the study of the mechanism and properties of PLA 2 -catalyzed hydro¬ lysis of phospholipids. In in vi tro assays, ' PLA 2 displays a lag phase during which the enzyme adsorbs to the substrate 30 bilayer and a process called interfacial activation occurs. This activation may involve desolvation of the enzyme/lipid interface or a change in the physical state of the lipid around the cleft opening. The evidence favoring this hypo¬ thesis comes from studies revealing that rapid changes in PLA 2 35 activity occur concurrently with changes in the fluorescence of a membrane probe (Burack, et al . , Biochemistry 1993, 32, 583) . This suggests that lipid rearrangement is occurring during the interfacial activation process. PLA 2 activity is maximal around the melting temperature of the lipid, where regions of gel and liquid-crystalline lipid coexist. This is also consistent with the sensitivity of PLA 2 activity to tem- perature and to the composition of the substrate, both of which can lead to structurally distinct lipid arrangements separated by a boundary region. Fluorescence microscopy was used to simultaneously identify the physical state of the lipid and the position of the enzyme during catalysis (Grainger, et al . , FEBS Lett . 1989, 252, 73) . These studies clearly show that PLA 2 binds exclusively at the boundary region between liquid and solid phase lipid. While the hydrolysis of the secondary ester bond of 1, 2-diacylglycerophospholipids catalyzed by the enzyme is relatively simple, the mechanistic and kinetic picture is clouded by the complexity of the enzyme-substrate interaction. A remarkable characteristic of PLA 2 is that maximal catalytic activity is observed on substrate that is aggregated (i.e., phospholipid above its critical micelle concentration) , while low levels of activity are observed on monomeric substrate. As a result, competitive inhibitors of PLA 2 either have a high affinity for the active site of the enzyme before it binds to the substrate bilayer or partition into the membrane and compete for the active site with the phospholipid substrate. Although a number of inhibitors appear to show promising inhibition of PLA 2 in biochemical assays ( see, e . g. , Yuan, et al . , J. Am . Chem . Soc . 1987, 109 , 8071; Lombardo, et al . , J. Biol . Chem. 1985, 260, 7234; Washburn, et al . , ' J. Biol . Chem . 1991, 266, 5042; Campbell, et al . , J. Chem . Soc , Chem . Commun . 1988, 1560; and Davidson, et al . , Biochem . Biophys . Res . Commun . 1986, 137, 587) , reports describing in vivo activity are limited (see, e . g. , Miyake, et al . , J. Pharmacol . Exp . Ther . 1992, 263 , 1302) . Traditional structure activity relationship type drug discovery gives unambiguous products but yet requires the preparation of numerous individual test candidates. The preparation of each structure requires significant amounts of time and resources. Another drug discovery approach, de novo design of active compounds based on high resolution enzyme structures, generally has not been successful. Yet another approach involves screening complex fermentation broths and plant extracts for a desired biological activity. The advantage of screening mixtures from biological sources is that a large number of compounds can be screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. One disadvantage is that many different samples must be screened and numerous purifications must be carried out to identify the active component, which often is present only in trace amounts. In order to maximize the advantages of each classical approach, new strategies for combinatorial unrandomization have been developed by several groups. Selection techniques have been used with libraries of peptides ( see, e . g. , Geysen, et al . , J. Immun . Meth . 1987, 102 , 259; Houghten, et al . , Na ture 1991, 354 , 84; and Owens, et al . , Biochem . Biophys . Res . Commun . 1991, 181 , 402) and nucleic acids ( see, e . g, , Wyatt, et al . , (in press) Proc . Na tl . Acad . Sci . USA; and Ecker, et al . , Nucleic Acids Res . 1993, 21 , 1853) . These selection techniques involve iterative synthesis and screening of increasingly simplified subsets of oligomers. In using these selection techniques, subsets are assayed for activity in either cell-based assays, or for binding or inhibition of purified protein targets. One technique, called SURF (Synthetic Unrandomization of Randomized Fragments; see, e . g. , Ecker, et al . , ibid . , involves the synthesis of subsets of oligomers containing a known residue at one fixed monomer position and equimolar mixtures of residues at all other positions. For a library of oligomers four residues long containing three monomers (A, B, C) , three subsets would be synthesized (NNAN, NNBN, NNCN, where N represents equal incorporation of each of the three monomers) . Each subset is then screened in a functional assay and the best subset is identified ( e . g. , NNAN) . A second set of libraries is synthesized and screened, each containing the fixed residue from the previous round, and a second fixed residue (e.g. ANAN, BNAN, CNAN) . Through successive rounds of screening and synthesis, a unique sequence with activity in the assay can be identified. OBJECTS OF THE INVENTION It is an object of this invention to provide novel pyrrolidine monomeric units. It is another object of the invention to provide novel pyrrolidine monomeric units that can be incorporated into novel oligomeric structures. It is a further object to provide novel pyrrolidine monomeric units that can be linked together via phosphorus- containing backbones. It is still another object to provide novel pyrrolidine based oligomers that include a diversity of functional moieties thereon for binding to biological sites of interest. BRIEF DESCRIPTION OF THE INVENTION Compounds of the invention include monomeric compounds of structure I: Z wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support; Y is H or a hydroxyl protecting group; Z is L- L , 1 -G 1 , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; L- L is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms; L 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms; G- L is halogen, OR- L , SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC(=NH)NR 3 R 4 , CH=0, C(=0)0R 5 , CH(NR 3 R 4 ) (C(=0) OR 5 ) , C(=0)NR 3 R 4 , a metal coordination group, or a phosphate group; G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ; R- L is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is L- L , G 3 , L- L -G- 3 or G 3 -L 1 -G 3 ; G 3 is C(=0) , C(=S) , C(O) -0, C(0) -NH, C(S) -0, C(S) -NH or S(0) 2 ' n is 0 or 1. In preferred embodiments, Y is an acid labile hydroxyl blocking group such as a trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl group. X preferably is a phosphoramidite. In certain preferred embodiments, n is 1 and Q is carbonyl, thiocarbonyl, carboxy, acetyl or succinyl . In one preferred group of compounds, Z includes a nitrogen-containing heterocycle such as an imidazole, pyrrole or carbazole ring. In a further preferred group, Z includes a purine or a pyrimidine nucleobase such as adenine, guanine, cytosine, uridine or thymine. In another preferred group of compounds, Z includes an unsubstituted or amine-substituted alkyl group, or an aryl group having 6 to about 20 carbon atoms. • In yet another preferred groups of compounds, Z includes fluorenylmethyl, phenyl, benzyl, alkyl-substituted benzyl, polyethylene glycol, glutamyl, or NR 3 R 4 groups. Further compounds of the invention include oligomeric compounds of structure II: wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, a solid support, a conjugate group, or an oligonucleotide; Y is H, a hydroxyl protecting group, a conjugate group or an oligonucleotide; E is O or S; EE is 0 " , or N(Y 0 )T 0 ; Y 0 is H, or [Q 2 ] - i - Z 2 ; T 0 is [Q k -Z- L , or together Y 0 and T 0 are joined in a nitrogen heterocycle; Q- L and Q 2 independently, are C 2 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 4 -C 7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C 7 -C 14 aralkyl; jj and kk independently, are 0 or 1; Z- L and Z 2 , independently, are H, C 1 -C 2 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C 14 aryl, C 7 -C 15 aralkyl, a halogen, CH=0, OR-, SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , CH(NR 3 R 4 ), NHC(=NH)NR 3 R 4 , CH(NH 2 )C(=0)OH, C(=0)NR 3 R 4 , C(=0)OR 5 , a metal coordination group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; Z is L- L , L- L -G- L , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; L- L is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms; L 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms; G x is halogen, OR x , SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC(=NH)NR 3 R 4 , CH=0, C(=0)OR s , CH(NR 3 R 4 ) (C (=0)OR 5 ) , C(=0)NR 3 R 4 , a metal coordination group, or a phosphate group; G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ; R. is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is -, G 3 , L- L -G- J or G 3 -L 1 -G 3 ; G 3 is C(=0) , C(=S) , C(O) -0, C(O) -NH, C(S) -0, C(S) -NH or S(0) 2 ; n is 0 or 1; and m is 1 to about 50, preferably 1 to about 25. Further compounds of the invention include chimeric oligomeric compounds having a central region comprising a phosphodiester or a phosphorothioate oligodeoxynucleotide interspaced between flanking regions comprising the above- described monomeric or oligomeric structures. The invention further includes processes for preparing randomized oligomeric compounds including the steps of selecting a group of monomers as described above and coval- ently bonding at least two of the monomers of said group. In preferred processes, the Z moiety of at least one monomer of said group is different from the Z moiety of another monomer of said group. The compounds of the invention can be used as inhibitors of various enzymes including phospholipase A 2 enzyme. As inhibitors of phospholipase A 2 , the compounds are useful for the treatment of inflammatory diseases including atopic dermatitis and inflammatory bowel disease. The oligomeric compounds of the invention can be used in diagnostics since they are capable of specifically hybridizing to nucleic acids of interest in the etiology of diseases . The compounds of the invention also can be used as research probes and primers, especially for the study of enzyme biochemistry and protein-nucleic acid interactions. BRIEF DESCRIPTION OF THE DRAWINGS The numerous objects and advantages of the present invention may be better understood by those skilled in the art by reference to the accompanying figures, in which: Figure 1 describes synthetic processes for oligomeric compounds according to the invention. DETAILED DESCRIPTION OF THE INVENTION The monomeric compounds of the invention each include a pyrrolidine moiety that, in turn, bears a number of functional groups. Certain of these groups are used to link adjacent pyrrolidine moieties and form oligomeric structures. Typically, the groups used to effect such linkage are primary and secondary hydroxyl groups. During oligomer synthesis, the primary hydroxyl group typically is blocked with a protecting group and the secondary hydroxyl group is reacted with an activated phosphate group such as a /3-cyanoethyl phosphor- amidate group. As used herein, the term activated phosphate group is intended to denote a phosphate group that bears a chemical modification thereon to enhance its reactivity with nucleophiles. Similarly, the term activated phosphite group denotes a phosphite group that bears a chemical modification to enhance its reactivity with nucleophiles. Numerous such modifications are known in the art. The monomeric compounds of the invention preferably are covalently bound using phosphate linkages. This permits coupling via either solution phase or solid phase chemistries. Representative solution phase techniques are described in United States Patent No. 5,210,264, issued May 11, 1993 and commonly assigned with this invention. Representative solid phase techniques are those typically employed for DNA and RNA synthesis utilizing standard phosphoramidite chemistry, ( see, e . g. , Protocols For Oligonucleotides And Analogs, Agrawal, S., ed., Humana Press, Totowa, NJ, 1993.) A preferred synthetic solid phase synthesis utilizes phosphoramidites as activated phosphates. The phosphoramidites utilize P 111 chemistry. The intermediate phosphite compounds are subsequently oxidized to the P v state using known methods. This allows for synthesis of the preferred phosphodiester or phosphorothioate phosphate linkages depending upon oxidation conditions selected. Other phosphate linkages can also be generated. These include phosphorodithioates, phosphotriesters, alkyl phosphonates, phosphoroselenates and phosphoramidates. An acid labile protecting group such as a member of the trityl family preferably can be used for protection of the primary hydroxyl group. The trityl family includes at least trityl, monomethoxytrityl, dimethoxytrityl and trimethoxy- trityl. The dimethoxytrityl group is preferred and can be added by reacting the primary hydroxyl group with 4,4'- dimethoxytrityl chloride. Other hydroxyl protecting groups can be used, such as those described by Beaucage, et al . , Tetrahedron 1992, 48 , 2223. The pyrrolidine moieties bear functional groups in addition to those that form inter-pyrrolidine linkages. When the monomeric compounds are linked together, these functional groups provide diverse properties ("diversity") to the resulting oligomeric compounds. The functional groups include hydrogen-bond donors and acceptors, ionic moieties, polar moieties, hydrophobic moieties, aromatic centers, and electron-donors and acceptors. Together, the properties of the individual monomers contribute to the uniqueness of the oligomers in which they are found. Thus, a library of such oligomers would have a myriad of properties, i.e., "diversity. " Collectively, the properties of the individual monomers that together form an oligomer contribute to the uniqueness of such oligomer and impart certain characteristics thereto for interaction with cellular, enzymatic or nucleic acid target sites. In other aspects of the present invention the use of acid labile groups which are stable to the trichloroacetic acid treatment used for DMT removal such as BOC-type protecting groups are used. They are stable to extended TCA treatment, but are removed by trifluoroacetic acid solutions (e.g. 5% in CH 2 C1 2 ) . Another protecting group class which is compatible to this methodology is the Allyl class. These groups are cleaved using transition metal catalysts. This type of protecting group is particularly valuable in cases where the selective deprotection of a particular functional group is desired while the oligomer is still attached to the solid support, allowing a new reactive site to be uncovered. Additional protecting group tactics are possible: e.g. photolabile protecting groups are also compatible with this methodology. Nitrogen heterocycles suitable for use as the functional group include imidazole, pyrrole, pyrazole, indole, lH-indazole, cϋ-carboline, carbazole, phenothiazine, and phen- oxazine groups. A more preferred group of nitrogen heterocycles includes imidazole, pyrrole, and carbazole groups. Imidazole groups are especially preferred. Purines and pyrimidines according to the invention include adenine, guanine, cytosine, uridine, and thymine, as well as other synthetic and natural nucleobases such as xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halo uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudo uracil) , 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5- trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine. Further purines and pyrimidines include those disclosed in United States Patent No. 3,687,808, those disclosed in the Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J.I., ed. John Wiley & Sons, 1990, and those disclosed by Englisch, et al . , Angewandte Chemie, International Edi tion 1991, 30, 613. Alkyl, alkenyl, and alkynyl groups according to the invention include but are not limited to substituted and unsubstituted straight chain, branch chain, and alicyclic hydrocarbons, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and other higher carbon alkyl groups. Further examples include 2-methylpropyl, 2-methyl-4- ethylbutyl, 2,4-diethylpropyl, 3-propylbutyl, 2,8- dibutyldecyl, 6, 6-dimethyloctyl, 6-propyl-6-butyloctyl, 2- methylbutyl, 2-methylpentyl, 3-methylpentyl, 2-ethylhexyl and other branched chain groups, allyl, crotyl, propargyl, 2-pen- tenyl and other unsaturated groups, cyclohexane, cyclopentane, adamantane as well as other alicyclic groups, 3-penten-2-one, 3-methyl-2-butanol, 2-cyanooctyl, 3-methoxy-4-heptanal, 3- nitrobutyl, 4-isopropoxydodecyl, 4-azido-2-nitrodecyl, 5-mer- captononyl, 4-amino-l-pentenyl as well as other substituted groups. Aryl groups according to the invention include but are not limited to substituted and unsubstituted aromatic hydrocarbyl groups such as phenyl and naphthyl groups. Aralkyl groups include but are not limited to groups having both aryl and alkyl functionality, such as benzyl and xylyl groups. Metal coordination groups according to the invention include but are not limited to hydroxamic acids, catecholamide, acetylacetone, 2, 2' -bipyridine, 1,10- phenanthroline, diacetic acid, pyridine-2-carboxamide, isoalkyldiamine, thiocarbamato, oxalate, glycl, histidyl and terpyridyl . Other metal coordination groups are known, as for example see Mellor, D.P. , Chemistry of Chelation and Chelating Agents in International Encyclopedia of Pharmacology and Therapeutics, Section 70, The Chelation of Heavy Metals, Levine, W.G. Ed., Pergamon Press, Elmford, N.Y. , 1979. Solid supports according to the invention include controlled pore glass (CPG) , oxalyl-controlled pore glass (see, e . g. , Alul, et al . , Nucleic Acids Research 1991, 19, 1527) , TentaGel Support -- an aminopolyethyleneglycol derivatized support ( see, e . g. , Wright, et al . , Tetrahedron Letters 1993, 34 , 3373) or Poros -- a copolymer of polystyrene/divinylbenzene. A number of substituent groups can be introduced into compounds of the invention in a protected (blocked) form and subsequently de-protected to form a final, desired compound. In general, protecting groups render chemical functionality inert to specific reaction conditions and can be appended to and removed from such functionality in a molecule without substantially damaging the remainder of the molecule. See, e . g. , Green and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley & Sons, New York, 1991. For example, amino groups can be protected as phthalimido groups or as 9- fluorenylmethoxycarbonyl (FMOC) groups and carboxyl groups can be protected as fluorenylmethyl groups. Representative hydroxyl protecting groups are described by Beaucage, et al . , Tetrahedron 1992, 48, 2223. Preferred hydroxyl protecting groups are acid-labile, such as the trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl groups. Substituent groups according to the invention include but are not limited to halogen (Cl, Br, F) , hydroxyl (OH) , thiol (SH) , keto (C=0) , carboxyl (COOH) , ethers, thioethers, amidine (C(=NH)NR 3 R 4 , guanidine (NHC(=NH)NR 3 R 4 , glutamyl CH(NR 3 R 4 ) (C(=0)OR 5 ) , nitrate (ON0 2 ) , nitro (N0 2 ) , nitrile (CN) , trifluoromethyl (CF 3 ) , trifluoromethoxy (0CF 3 ) , O-alkyl, S- alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino (NH 2 ) , azido (N 3 ) , hydrazino (NHNH 2 ) , hydroxylamino (ONH 2 ) , sulfoxide (SO) , sulfone (S0 2 ) , sulfide (S-) , disulfide (S-S) , silyl, heterocyclic, alicyclic and carbocyclic. Preferred substituents include halogens, alcohols and ethers (0R X ) , thiols and thioethers (SR 2 ) , amines (NR 3 R 4 ) , amidines [C(=NH)NR 3 R 4 ] , guanidines [NHC (=NH)NR 3 R 4 ] , aldehydes (CH=0) , acids [C(=0)OH] , esters [C(=0)0R 5 ] , amides [C(=0)NR 3 R 4] and glycine [CH(NH 2 ) (C(=0)OH) ] . In preferred embodiments, Z includes an aminoethyl, carboxyethyl, adenylmethyl, thyminylmethyl, imidazolylmethyl, benzyl, 4-hexylbenzyl, myristyl, isopropyl, or tetraethylene glycol group. Z can be directly attached to the pyrrolidine ring or can be attached via a tether, Q. Preferred tethers include alkyl and acyl (carbonyl-containing) groups. Preferred acyl groups include carbonyl, thiocarbonyl, carboxy, acetyl, and succinyl groups. The compounds of the invention can include conjugate groups covalently bound to primary or secondary hydroxyl groups. Conjugate groups of the invention include inter- calators, reporter molecules, polyamines, polyamides, poly¬ ethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugates groups include cholesterols, phospholipids, biotin, phenanthroline, phenazine, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve oligomer uptake, enhance oligomer resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve oligomer uptake, distribution, metabolism or excretion. Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed October 23, 1992, United States Patent Application Serial No. 116,801, filed September 3, 1993, and United States Patent No. 5,218,105. Each of the foregoing is commonly assigned with this application. The entire disclosure of each is incorporated herein by reference. To synthesize a combinatorial library having a large degree of chemical diversity is an important aspect of the present invention. Chemical diversity is introduced at one level by varying the nature of the phosphorus likage. Phosphorus linkages amenable to the present invention include phosphodiester (OPO) , phosphorothioate (OPS) , phosphoramidate (OPN) , phosphorothioamidate (SPN) , and alkylphosphonate (OPC) . The combinatorial library can be prepared with a single type of phosphorus linkage, or with different linkages at each position of the oligomer. For example, a single OPS linkage can be selectively introduced at any position in a OPO oligomer. In fact, all possible combinations of OPO, OPS, OPN, SPN and OPC linkages can be introduced selectively into the oligomers. The presence or absence of a type of linkage at a particular position in an oligomer will have a profound effect on the properties of the molecule. In the case of phosphoramidate linked libraries, a further level of diversity is possible due to the ability to have substituents on the nitrogen atom of the OPN linkage. Thus it is possible to introduce a wide variety of amines each time a OPN linkage is present in an oligomer. It is possible to have the same amine substituents at each OPN linkage or a different amine at each position. Chemical diversity can be generated at several levels in SURF libraries. We have described below the preparation of a large number of monomers. These monomers have been prepared to explore two aspects of chemical diversity: first a wide number of functional groups are available, covering a range of chemical properties. Second, these functional groups can be attached to different linker portions designed to display, or present them in space in different ways, allowing variable flexibility. The following section describes a third level of diversity, the inter-residue linkage itself. It is to be understood that the methods used to introduce any of the linkage types are compatible. Specifically, by using the proper conditions, it is possible to introduce phosphate linkages including OPO, OPS, OPN, SPN and OPC linkages at will at any position in an oligomer, independently of the sequence of the oligomer. This is possible because the chemical reaction which defines the nature of the linkage is separate from the attachment of the monomer to the reactive group on the solid support (whether linker or the previous monomer) . Specifically, when a phosphoramidite monomer is treated with tetrazole and added to the solid support which has a free hydroxyl group, a phosphite triester is obtained. This phosphite triester can then be treated with Iodine (formulated in the same way as for DNA synthesis on an automated synthesizer) , giving a phosphodiester after ammonia deprotection. Alternatively, the phosphite triester can be treated with benzodithiole-3-one-l, 1-dioxide to give the corresponding phosphorothioate. Hydrogen phosphonate chemistry has the advantage of allowing additional chemical modifications to be introduced into oligomers. Oligonucleotide phosphodiesters and phos- phorothioates have been prepared using this approach, (see Froehler, B. C, Matteucci, M. D. Tetrahedron Lett . 1986, 27, 469-472) , as well as oligonucleotide phosphoramidates (see Froehler, B. C. Tetrahedron Lett . 1986, 27, 5575-5579. Letsinger, R. L., Singman, C. N. , Histand, G. , Salunkhe, M. J. Am. Chem . Soc . 1988, 110 , 4470-4471. The synthesis of oligomers containing both phosphodiesters and phosphoramidates was reported, as well as the use of phosphoramidite chemistry in conjunction with the synthesis of phosphoramidates (see Jung, P. M., Histand, G. , Letsinger, R. L. Nucleosides & Nucleotides, 1994, 13 , 1597-1605) . In this latter work, alternating phosphodiester and phosphoramidate oligomers were prepared by coupling phosphoramidites and H-Phosphonates to the growing oligomer, followed by the appropriate oxidation step. In general, however, all the examples described thus far have incorporated the same amine substitution at all phosphoramidate linkages in the oligomer. These studies have shown the feasibility of using the phosphoramidate bond as an additional site for the incorporation of diverse functional groups. A wide variety of amines can be used in the oxidative step, and the monomers of the present invention support the necessary chemistry. Thus, for the preparation of combinatorial libraries incorporating phosphoramidate linkages, the monomers of the present invention are converted to the corresponding H-Phosphonate monoesters. In one aspect of the present invention this is accomplished using PC1 3 and imidazole as the phosphitylating reagent (see Garegg, P. J. , Regberg, T., Stawinski, J. , Strόmberg, R. Chem . Scr. 1986, 26, 59-62) . These H-phosphonates monomers are oligomerized on solid support by activation with pivaloyl chloride, adamantoyl chloride or other appropriate activating agent . The intermediate H-Phosphonate diesters are oxidized to the phosphate diesters in high yields using iodine in aqueous pyridine. This allowed for the comparison of the coupling efficiency of the H-phosphonate and phosphoramidite methods. Essentially the same coupling efficiency is achieved with both methodologies. The H-phosphonate diesters are converted to phosphoramidates by the use of a 10% solution of the appropriate amine in pyridine/CCl 4 (1:1) . Under these conditions, a H-phosphonate diester is oxidized to a phosphoryl chloride via an Arbuzov reaction, followed by displacement of the chloride by a primary or secondary amine. The second step has proven to be quite general, with a wide variety of amines giving satisfactory yields. Moreover, the yield of phosphoramidate is comparable to the yield of phosphodiester. Several types of libraries are available through this methodology. The simplest kind is a library made from a set of monomers of the present invention (a set of 4 to 16 or more monomers is typically used) of 2 to 10 or more monomer units in length, which is substituted at phosphorus with a single amine. These libraries are prepared by split bead synthesis, following the H-phosphonate synthesis protocol rather than phosphoramidite chemistry. The intermediate H-phosphonate diesters are left intact until the final step. At that point the oligomer library pools are oxidized with CCl 4 /Pyridine containing 10% of the appropriate primary or secondary amine. This has the result of converting all the interresidue linkages to phosphoramidates. The library therefore is composed of all possible sequences of the monomers, separated into subsets unique at a fixed position, linked together by a constant phosphoramidate linkage. It should be evident that the final properties of the library will be determined by the choice of amine used in the oxidation step. Thus, water solubility, pharmacokinetics and pharmacodynamics of the library components can be modulated by the choice of amine. It is also possible to prepare oligomer libraries with mixed linkages by having an intermediate oxidation step (see Gryaznov, S. M. , Sokolova, N. I. Tetrahedron Lett. 1990, 31 , 3205-3208; Gryaznov, S. M. , Potapov, V. K. Tetrahedron Lett. 1991, 32, 3715-3718; Farooqui, F., Sarin, P. S., Sun, D., Letsinger, R. L. Bioconjugate Chem. , 1991, 2, 422-426; Iso, Y. , Yoneda, F., Ikeda, H. , .Tanaka, K. , Fuji, K. Tetrahedron Lett . 1992, 33 , 503-506) . Thus, a portion of the oligomer library is synthesized by H-phosphonate chemistry, which can be oxidized with (R 2 NH, CCl 4 /Py or S8, CS 2 /TEA or H 2 0, CCl 4 /Py) , and a second portion of the library synthesized and oxidized with a second set of reagents. This creates a chimeric library, where a segment of the random oligomers in each subset has a different linkage than the rest of the molecule. By extension of this methodology, it is possible to incorporate a different linkage at each position of the oligomer library by having a different oxidation step after each monomer coupling. The linkage can be combinatorialized by performing a separate oxidation on a portion of the H- phosphonate diester-linked solid support, followed by pooling of the subsets in the same way that the monomer positions are randomized. Thus, each monomer and the linkage between them can be randomized by a split synthesis strategy. Monomeric compounds of the invention can be used to prepare oligomeric compounds having either preselected sequences or sequences determined via combinatorial strategies. One useful combinatorial strategy is the above- noted SURF strategy, which is disclosed and claimed in United States Patent Application Serial No. 749,000, filed Aug. 23, 1991, and PCT Application US92/07121, filed Aug. 21, 1992, both of which are commonly assigned with this application. The entire disclosure of these applications are herein incor¬ porated by reference. Illustrative of the SURF strategy is a 2'-0-methyl oligonucleotide library (see, Ecker et. al. , ibid. ) shown in Table I, below. Table I describes the selection of a 2'-0- methyl oligonucleotide for binding to an RNA hairpin. The K D 's, i . e . , the binding constants, were determined by gel shift. "X" is used to indicate the position being varied and underlining is used to indicate positions that become fixed during successive iterations of the SURF strategy. TABLE I K D (mM) Subsets X=A X=C X=G X=T Round 1 NNNNXNNNN 22 1£ >100 >100 Round 2 NNNNCNXNN >10 4 >10 >10 Round 3 NNXNCNCNN >10 ^5 >10 >10 Round 4 NNCXCNCNN >10 0.15 >10 >10 Round 5 NNCCCXCNN 0.08 >1 0.4 >1 Round 6 NNCCCACXN 0.05 >0.5 0.08 >0.5 Round 7 NXCCCACAN >0.1 >0.1 0.03 >0.1 Round 8 NGCCCACAX 0.05 0.02 0.05 0.04 Round 9 XGCCCACAC 0.03 0.05 0.02 0.01 This SURF strategy has not been used for libraries except those that employ naturally-occurring nucleotides as phosphodiesters or phosphorothioates as monomeric units. Other combinatorial strategies have only been used for libraries that employ amino acids as monomeric units. One aspect of the present invention is the inclusion of monomeric compounds having structure I in the above- described SURF strategy. The functional groups appended to these monomeric compounds can be incorporated into the libraries while retaining the advantages of automated phosphoramidite oligomer synthesis. These functional groups can effect interactions of the following types : hydrogen-bond donor and acceptor, ionic, polar, hydrophobic, aromatic, and electron donors and acceptors. Preferred functional groups include aminoethyl, carboxyethyl, adenylmethyl, thyminyl- methyl, imidazolylmethyl, benzyl, myristyl, isopropyl, and tetraethylene glycol groups. One advantage of the present invention is that the simple design of monomeric compounds of the inventions allows for combining rational drug design with screen mechanisms for thousands of compounds. This is achieved by using the compounds of the invention in a combinatorial techniques such as the SURF strategies. In one preferred embodiment, functional groups appended to the monomeric compounds of the invention are selected for their potential to interact with, and preferably inhibit, the enzyme PLA 2 . Thus, the compounds of the invention can be used for topical and/or systematic treatment of inflammatory diseases including atopic dermatitis and inflammatory bowel disease. In selecting the functional groups, advantage can be taken of PLA 2 's preference for anionic vesicles over zwit- terionic vesicles. In selecting the backbone that bears these functional groups, further advantage can be taken of fact that the natural substrate of PLA 2 contains a phosphate group. Therefore, phosphodiester or phosphorothioate and other phos¬ phate linked oligomers preferably are selected, providing a negatively charged compound for binding with the positively charged interfacial binding site of PLA 2 . Certain compounds of the invention include aromatic functional groups to facilitate binding to the cleft of the PLA 2 enzyme, ( see, Oinuma, et al . , J. Med. Chem. 1991, 34 , 2260; Marki, et al . , Agents Actions 1993, 38, 202; and Tanaka, et al . , J. Antibiotics 1992, 45, 1071) . Benzyl and 4- hexylbenzyl groups are preferred aromatic groups. The compounds of the invention can further include hydrophobic functional groups such as tetraethylene glycol groups. Since the PLA 2 enzyme has a hydrophobic channel, hydrophobicity is believed to be an important property of inhibitors of the enzyme. In certain embodiments of the invention, hydroxy pyrrolidine phosphoramidite monomeric compounds having structure I are incorporated into libraries of oligomeric compounds and increasingly less complex subsets of oligomers are identified in combinatorial screening techniques such as the above-described SURF technique by successive rounds of screens. In one preferred embodiment, a library of oligomeric compounds functionalized with aminoethyl, carboxyethyl, adenyl- methyl, thyminylmethyl, tetraethylene glycol, imidazolyl- methyl, benzyl, isopropyl, myristyl or 4-hexylbenzyl groups are prepared and assayed for inhibition of PLA 2 activity. The PLA 2 assay can be effected using a combinatorial screening strategy such as the SURF strategy. For this assay, the oligomer libraries are screened for inhibition of human type II PLA 2 enzymatic activity. Typically, these libraries contain about 8000 different compounds. Successive iterations of the SURF technique is effected to select unique oligomers from the library. The libraries additionally can be screened in other in vi tro assays to determine further mechanisms of inhibition. Upon identification of oligomers in a first phase of screening, further modifications can be made to the contents of the oligomer libraries. For example, if a first iteration of screening results in an active compound that contains a benzyl group, then in subsequent iterations of the screen this aromatic residue can then be varied using substituted benzyl groups. In this way, structural activity is identified in a stepwise manner to define potent inhibitors of the enzymatic activity. To maximize the identification of a tight binding oligomeric inhibitor of PLA 2 via a combinatorial approach, an array of functional groups typically are included in a randomized library. The oligomers are assembled in a manner analogous to oligonucleotide synthesis by the coupling of monomeric, phosphoramidate units wherein the normal nucleotide structure is replaced by more diverse chemical groups. In some of the monomeric units, the nucleobases of nucleotides have been retained. In other, the nucleobases are replaced with other functional groups selected to provide different ligand-ligand interactions than that provided by the nucleobases. The sugar moiety of a normal nucleotide is replaced by a hydroxy pyrrolidine unit, i.e. a prolinol, to form a unique prolinol-phosphate backbone. This methodology provides for a convergent preparation of a large number of monomers bearing a wide variety of functional groups. Where necessary, functional groups are protected with base labile protecting groups to allow one-step deprotection of the oligomer upon completion of the synthesis. As noted above, monomeric compounds having structure I can be linked with one another to form homopolymeric structures or they can be linked with nucleotides and/or other moieties to form heteropolymeric structures. For example, chimeric structures can be formed that include one or more regions or "stretches" of the monomeric units of invention joined to one or more regions or "stretches" of naturally occurring or synthetic oligonucleotides or to other synthetic or natural oligomeric compounds such as peptides, peptoids, peptide nucleic acids, oligo and/or polysaccharides. Further, oligomeric compounds having structure II can be incorporated into chimeric structures along with the compounds disclosed in the patent application entitled "Monomeric Diols And Phosphate Linked Oligomers Formed Therefrom, " bearing attorney docket ISIS-0868 and the patent application entitled "Oligonucleotide Mimics Having Nitrogen-Containing Linkages, " bearing attorney docket ISIS-1014. The foregoing patent applications are filed concurrently with this application, are commonly assigned, and are incorporated herein by reference. In one embodiment of the invention, oligomeric compounds are synthesized as shown in Figure 1. This synthetic strategy emphasizes attachment of widely different functional groups to a rigid hydroxyprolinol intermediate. Each monomer unit contains a primary hydroxyl that is pro¬ tected as a dimethoxytrityl (DMT) ether and a secondary hydroxyl that is converted to a cyanoethyl-diisopropylamino phosphoramidite. Trans-hydroxyproline 1 is protected as the fluorenylmethyl carbamate (Fmoc) , and the carboxylate function is reduced using borane in refluxing tetrahydrofuran (THF) . Diol 3 is then selectively protected at the primary hydroxyl as a DMT, and the Fmoc group of 4 is removed using piperidine in dimethylformamide (DMF) . A substituted carboxylic acid is then covalently linked to the nitrogen of intermediate 5 using standard peptide coupling methods (see Bodansky, M. , Principles of Peptide Synthesis, 1984, Springer-Verlag, Berlin) . Functional groups (R) that require protection are derivatized using base labile protecting groups . Monomers 6 are converted to the phosphoramidites 7 under standard con- ditions (see Oligonucleotide synthesis, a practical approach, Gait, M.J. Ed., 1984, IRL Press, Oxford) . These phosphor¬ amidites are then oligomerized, either in predetermined sequences using standard oligonucleotide type synthetic procedures on a DNA synthesizer, a solution phase reaction, or combinatorial techniques such as the above-described SURF technique. Monomer units bearing protected or unprotected functional groups are prepared as per procedures described in the examples provided below. If the functional group is such that it will react with other moieties or reagents during phosphitylation or oligomerization, the functional group is appropriately protected with a protecting group. Such protecting group is then removed upon completion of the synthesis of oligomeric compound. To detect an active sequence generated via a combin¬ atorial technique, the concentration of the active molecule is selected to be of sufficiently great that the molecule can be detected within the sensitivity of the chosen assay. As will be recognized, the number of unique oligomer sequences within a subset produced via a combinatorial technique depends on the length of the oligomer and the number of different monomers employed. The number of sequences can be determined by raising the number of monomers to a power equal to the number of random positions. This is illustrated in Table II. Table II also indicates the concentration of each sequence when the subset concentration is 100 μM, a typical high-test concentration. We have found that the number of monomers and their length can be based upon an estimate of the expected IC 50 (i.e., a concentration at which 50% of enzyme activity is inhibited) that is desirable in a final oligomeric compound. For an expected IC 50 of 100 nM, the complexities shown in Table II are acceptable, that is, the libraries shown in Table II have complexities that would allow detection of a unique sequence with an IC 50 of about 100 nM or less. TABLE II Complexity of Libraries Sequences nM Each Sequence Length Per Subset At 100 μM Subset 5 Monomers 4-mer 125 800 5-mer 625 160 6 Monomers 4-mer 216 463 5-mer 1,296 77 7 Monomers 4-mer 343 291 8 Monomers 4-mer 512 195 10 Monomers 4-mer 1,000 100 If five monomers are selected for a library, then the library will have a length of five monomer units, XNNNN, where N is an equal molar mixture of monomer units and X is a different monomer unit in each of the five subsets. For ease in synthesis, the fixed position can be selected as the right end of the molecule. After assay for inhibition of PLA 2 activity as described below, position X is fixed with the residue giving the greatest inhibition and the next subset is synthesized and screened. The fixed position then shifts towards the left end of the oligomer as unrandomization proceeds. Five rounds of synthesis and screening are required to determine a unique inhibitor. The monomer units of the invention are linked to form oligomeric compounds using standard phosphoramidite chemistry that is used for standard synthesis of oligonucleotides. Since the coupling rates of functionalized prolinol monomers may vary, the reactivity of the individual monomers can adjusted such that equal molar incorporation of each monomer at each randomized position is effected. Adjusting for the reactivity of the monomers can be effected as in Examples 107 nd 108. A further technique for effecting such adjustment is also disclosed in the United States patent application entitled "Random Oligonucleotide Libraries And Methods Of Making The Same," bearing attorney docket number ISIS-1009. The foregoing patent application is being filed concurrently with this application, is commonly assigned, and is incorporated herein by reference. In a SURF screening strategy the amount of oligomer is selected such that the concentration of each subset in the initial round of screening is relatively high (about 100 μM) . It is presently preferred to synthesize oligomers using a DNA synthesizer. On such synthesizers the oligomers are most conveniently synthesized on a 1 to 4 μmol scale. Given the concentration of a subset of libraries at about 100 μm, the assays preferably are performed in a small volume of less than about 200 μL. Exemplary compounds of the invention are prepared in the following examples, which are not intended to be limiting. EXAMPLE 1 N-Fmoc- rans-4-Hydroxy-L-Proline trans -4-Hydroxy-L-proline (5.00 g, 38.2 mmol) and NaHC0 3 (8.00 g, 95.2 mmol) were suspended in 150 ml H 2 0/Dioxane (1:1) . Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise. The temperature of the reaction was not allowed to rise above 25°C during the addition. The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHC0 3 solution and 50 ml water. The solution was then extracted with 100 ml diethyl ether. The aqueous layer was acidified to pH 1 with concentrated HC1, and extracted twice with ethyl acetate, and the organic extracts washed with brine. The solution was dried with MgS0 4 , filtered and the solvent removed in vacuo. The pure product crystallized from the concentrated solution. Yield: 13.4 g (100%) . X H NMR: (CDC1 3 , 200 MHz) δ 7.75-7.15 (8H, m, ArH) , 4.55-4.05 (5H, m, ArCHCH 2 , H2, H4), 3.65-3.45 (2H, m, 2 H5) , 2.35-2.10 (2H, m, 2 H3) . EXAMPLE 2 N-Fmoc-3-Hydroxypyrrolidine-5-Methanol To a solution of N-Fmoc- rans-4-hydroxy-L-proline (13.4 g, 38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol, 5.78 g, 7.22 ml) dropwise at room temperature. After the evolution of H 2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2x100 ml methanol. The resulting crystalline product weighed 12.0 g (35.3 mmol, 93%) . X H NMR: (CDC13, 200 MHz) δ 7.85-7.25 (8H, m, ArH), 4.50-4.10 (5H, m, ArCHCH2, H3, H5) , 3.80-3.40 (4H, m, 2 H2, 2 H6), 2.15-1.95 (1H, m, H2a) , 1.80-1.60 (1H, m, H2b) . EXAMPLE 3 N-Fmoc-5-Dimethoxytrityloxymethyl-3-Hydroxypyrrolidine The diol, N-Fmoc-3-hydroxypyrrolidine-5-methanol (10.59g, 31.2 mmol) was coevaporated with dry pyridine (2 X 50 ml) , redissolved in 200 ml dry pyridine, and cooled in an ice bath. Dimethoxytrityl chloride (11.0 g, 32.5 mmol) was added in portions over 30 min, and the solution stirred at 0 °C overnight. Methanol was then added (10 ml), and the solvent removed under reduced pressure. The resulting gum was redissolved in toluene (100 ml) , filtered to remove the pyridinium hydrochloride and taken to dryness again. The residue was dissolved in CH 2 C1 2 (300 ml) , washed with 150 ml 0.1 M citric acid solution, 150 ml sat NaHC0 3 , brine, and dried with MgS0 4 followed by evaporation. The residue was crystallized from methanol and dried to give (15.4 g, 23.9 mmol, 77%) . EXAMPLE 4 5-Dimethoxytrityloxymethyl-3-Hydroxypyrrolidine To a solution N-Fmoc-5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (3.40 g, 5.30 mmol) in 15 ml DMF was added piperidine (1.09 ml, 0.935 g, 11.0 mmol) . The solution was stirred at room temperature for 1 hour, water (100 ml) added, and the aqueous solution extracted with ethyl acetate (2 X 75 ml) . The organic extracts were washed with aqueous NaHC0 3 , brine, dried with MgS0 4 and evaporated. The residue was purified by flash column chromatography using a gradient of 1 → 3% MeOH in CH 2 Cl 2 containing 0.5% triethylamine. Pure product was obtained (1.86 g, 84%) . X H NMR: (CDC1 3 , 200 MHz) δ 7.42-6.80 (13 H, ArH) , 4,35 (1H, m, H5), 3.77 (6H, s, 2 OCH 3 ) , 3.62 (1H, m, H3) , 3.13-2.88 (4H, m, 2 H6, 2 H2), 1.87 (1H, q, H4a) , 1.65 (1H, m, H4b) . EXAMPLE 5 N-Palmitoyl-5-Dimethoxytrityloxymethyl-3-Hydroxypyrrolidine To the amino alcohol 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (0.50 g, 1.19 mmol) dissolved in 5 ml dry pyridine was added chlorotrimethylsilane (0.227 ml, 194 mg, 1.79 mmol), with stirring for 1 hour. The carboxylic acid component (e.g. palmitic acid, 359 mg, 1.40 mmol) , hydroxy- benzotriazole (209 mg, 1.55 mmol) and dimethylaminopropyl- ethylcarbodiimide (EDC) (281 mg, 1.80 mmol) were dissolved in 5 ml DMF (if necessary 5 ml CH 2 C1 2 co-solvent added) and stirred for 1 hour. This solution was then added to the pyridine solution of 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine, and the solution stirred until complete disappearance of the starting material. The reaction was stopped by addition of 5 ml sat NaHC0 3 and after 15 minutes the solution was diluted with water (100 ml) , extracted with ethyl acetate (2x75 ml) , washed with NaHC0 3 , brine, dried and evaporated. The product was purified by silica gel chromato¬ graphy using ethyl acetate/hexane (EtOAc/Hex) as eluant . 1 H NMR: (CDC1 3 , 200 MHz) (2 rotamers, 3'-0-TMS) δ 7.43-7.13, 6.88-6.74 (13 Ar-H) , 4.67, 4.51, 4.40, 4.13 (4 m, 2H, H3, H5) , 3.90-3.67 (m, IH, H2a) , 3.80 (s, 6H, OCH 3 ) , 3.45 (m, 2H, H2b, H6a) , 3.12 (m, IH, H6b) , 2.34-1.78 (m, 4H, H4a, H4b, COCH 2 ) , 1.65, 1.25 (2 s, 26 H, CH 2 ) , 0.87 (t, CH 3 ) , 0.10 (s, 9H, OSi (CH 3 ) 3 ) . EXAMPLE 6 N-Isobutyroyl-5-Dimethoxytrityloxymethyl-3-Hydroxypyrrolidine To a solution of N-hydroxysuccinimide (15 mmol, 1.72 g) in 250 ml pyridine was added isobutyryl chloride (13 mmol, 1.39 g, 1.36 ml) . A precipitate formed. Diisopropylethyl- amine (20 mmol, 2.58 g, 3.5 ml) was added, the mixture cooled to 0 °C, and 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.00 g, 11.9 mmol) added. The solution was stirred until the starting material was consumed. The reaction was quenched with sat NaHCO-,, and the solvent evaporated. The residue was extracted twice with ethyl acetate, washed with portions of water, NaHC0 3 , 0.1M citric acid, NaHC0 3 , brine, dried with MgS0 4 and evaporated. 1 H NMR: (CDC1 3 , 200 MHz) (2 rotamers, 3'-0-TMS) d 7.43-7.13, 6.88-6.74 (13 Ar-H), 4.75, 4.52, 4.37, 4.16 (4 m, 2H, H3, H5), 3.78 (s, 6H, OCH 3 ) , 3.88-3.78 (m, IH, H2a) , 3.68-3.34 (m, 2H, H2b, H6a) , 3.28-2.93 (m, IH, H6b) , 2.67, 2.58 (2 m, IH, COCH(Me) 2 ) , 2.18-1.80 (2 m, 2H, H4a, b) , 1.15, 0.98 (2 q, 6H, COCH(CH 3 ) 2 ), 0.10 (d, 9H, OSi(CH 3 ) 3 ) . EXAMPLE 7 N - ( Phenyl ac e tyl ) - 5 - Dimethoxytri tyloxymethyl - 3 - Hydroxy ¬ pyrrolidine Phenylacetic acid ( 1 . 50 g , 11 mmol ) and HOBT ( 1 . 63 g , 12 mmol ) were dissolved in 100 ml CH 2 C1 2 and EDC ( 15 mmol , 2 . 88 g) was added . After 15 min , 5 -dimethoxytrityloxymethyl - 3-hydroxypyrrolidine was added, followed by DIEA (20 mmol, 3.5 ml) . The reaction was stirred until the starting material was consumed, and quenched with 10 ml NaHC0 3 . The mixture was extracted twice with ethyl acetate, washed with NaHC0 3 , brine, 5 dried with MgS0 4 , and evaporated. The product was purified by flash chromatography to give 4.0 g product (75%) . 1 H NMR: (CDC1 3 , 200 MHz) (2 rotamers, 3'-0-TMS) d 7.43-7.13, 6.88-6.74 (13 Ar-H), 4.67, 4.49, 4.37, 4.13 (4 m, 2H, H3, H5), 3.78 (s, 6H, 0CH 3 ) , 3.78-3.50 (m, 2H, H2a, b) , 3.66, (s, 2H, CH 2 Ar) 10 3.35 (q, IH, H6a) , 3.12 (m, IH, H6b) , 2.14-1.70 (m, 2H, H4a, b) , 0.10 (d, 9H, OSi(CH 3 ) 3 ) . EXAMPLE 8 Succinic acid Fluorenylmethyl Ester Fluorenemethanol (10.0 g, 51.0 mmol) was dissolved in 15 150 ml CH 2 C1 2 , and succinic anhydride (5.6 g, 56 mmol) was added. The solution was stirred for 6 h, and a further portion of succinic anhydride (2.5 g, 25 mmol) was added, and stirring continued overnight. The reaction appeared complete by TLC. The solvent was then removed, and the residue 20 extracted with ethyl acetate, washed with 1% HCl, water, brine, dried (MgS0 4 ) and evaporated to an oil which crystallized on standing. A quantitative yield of crude product was obtained which was used without further purification. 25 EXAMPLE 9 N- (Fluorenylmethylsuccinoyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine Succinic acid fluorenylmethyl ester (4.27 g, 14.4 mmol) and HOBT (2.14 g, 15.8 mmol) were dissolved in 100 ml CH 2 C1 2 . 30 EDC was added (3.03 g, 15.8 mmol), and the solution stirred for 30 min. DIEA (2.79 ml, 2.07 g, 16 mmol) was added, followed by 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.00 g, 12 mmol) . After 30 min, sat NaHC0 3 was added (10 ml) and the solvents removed 10 minutes later. The residue was 35 extracted with ethyl acetate, washed with NaHC0 3 , brine, dried with MgS0 4 , and evaporated. The product was purified by flash chromatography (2% MeOH in CH 2 C1 2 ) to give 6.1 g product (8.7 mmol, 73%) . X H NMR: (CDC1 3 , 200 MHz) (2 rotamers) d 7.80-6.80 (21 Ar-H), 4.62, 4.46, 4.21 (3 m, 2H, H3, H5), 4.41-4.28 (m, 5 3H, CH 2 CH) , 3.78 (s, 6H, OCH 3 ) , 3.92, 3.71, 3.54, 3.41, 3.16 (5 m, 4H, H2a,b, H6a,b) , 2.88-2.75 (m, 4H, COCH 2 H 2 CO) , 2.50- 1.93 (4m, 2H, H4a, b) . EXAMPLE 10 (Nl-Thymine) -2-Acetic Acid 10 Methyl bromoacetate (25.5 g, 15.2 ml, 160 mmol) was added to a suspension of K 2 C0 3 (44.2 g, 320 mmol) and thymine (20.2 g, 160 mmol) in 500 ml dry DMF with stirring overnight. The suspension was filtered and the solvent removed under reduced pressure. The residue was suspended in 120 ml H 2 0 and 15 30 ml 4 N HCl, stirred for 30 minutes and filtered again. The solid was suspended in 250 ml H 2 0, to which was added 100 ml 2.5 M NaOH. The solution was heated to boiling, cooled and acidified to pH 1 with concentrated HCl. The precipitate was dried in vacuo to give 13.6 g (73.6 mmol, 46%) pure product. 20 X H NMR: (DMS0-d6, 200 MHz) δ 7.48 (s, IH, H6), 4.37 (s, 2H, CH 2 ) , 1.76 (s, 3H, CH 3 ) . EXAMPLE 11 N- [ (Nl-Thymine) -2-acetyl] -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine 25 Thymine acetic acid (1.36 g, 7.4 mmol) and HOBT (1.08g, 8.0 mmol) were dissolved in 25 ml DMF, and EDC (1.72 g, 9.0 mmol) was added. A thick white precipitate formed, and stirring was continued for 1 h. In a separate flask, 5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine (2.59 g, 6.17 0 mmol) and TMS-Cl (9.0 mmol, 0.98 g, 1.14 ml) were stirred for one hour in 20 ml pyridine, and added to the DMF solution. The combined solution was stirred overnight at RT, and quenched with 10 ml NaHC0 3 . After 1 hr, the solution was diluted with water, and extracted twice with ethyl acetate, 5 washed with NaHC0 3 , 0.1 M citric acid, NaHC0 3 , brine, dried with MgS0 4 and evaporated. The product was isolated by flash chromatography (3% MeOH / CH 2 C1 2 ) to give 3.07 g (85%) . 1 H NMR: (DMSO-d6, 200 MHz) (2 rotamers) d 7.50-6,80 (C6H, 13 Ar- H) , 4.60-4.40, 4.28 (m, 3H, COCH 2 , H5) , 4.15 (m, IH, H3) , 3.70 (s, 6H, OCH 3 ) , 3.66 (m, IH, H2a) , 3.45-2.94 (m, 4H, H2a,b, H6a,b), 2.08-1.82 (m, 2H, H4a, H4b) , 1.65 (s, 3H, (C5)CH 3 ) . EXAMPLE 12 N-Fmoc-3-Aminopropionic Acid Sodium bicarbonate (2.52 g, 30 mmol) and 3- aminopropionic acid (1.00 g, 11.2 mmol) were dissolved in 50 ml water and 50 ml dioxane was added. A solution of fluorenylmethyl chloroformate (3.10 g, 12.0 mmol) in 50 ml dioxane was added dropwise with stirring. After 6 hours the solution was diluted with water (100 ml) and saturated bicarbonate solution (50 ml) , extracted once with diethyl ether, and the aqueous layer acidified to pH 2 with concentrated HCl . The cloudy solution was extracted with ethyl acetate (2 X 100 ml) , washed with brine and dried with MgS0 4 . After evaporation a mixture of the title product and the peptide dimer was obtained. The pure product was obtained by flash chromatography. X H NMR: (CDC1 3 , 200 MHz) δ 7.95-7.26 (8H, m, ArH), 7.40-7.15 (3H, m, CHCH 2 O),3.20 (2H, t, J=8 Hz, CH 2 N) , 2.40 (2H, t, J=8 Hz, HOOCCH 2 ) . EXAMPLE 13 N-Fmoc-3 -A inopropionoyl-5-Dimethoxytrityloxymethyl-3- Hydroxypyrro1idine This compound was prepared as per the procedure described in Example 5 using N-Fmoc-3-aminopropionic acid as the carboxylic acid component. 1 H NMR: (CDC1 3 , 200 MHz) (2 rotamers) δ 7.80-6.80 (21 Ar-H) , 5.40 (br s, IH, CONH) , 4.62, 4.51 (2 m, IH, H5), 4.41-4.28 (m, 3H, CH 2 CH),4.20 (m, IH, H3) , 3.78 (s, 6H, OCH 3 ) , 3.92, 3.65 (2 m, 2H, H2a) , 3.70-3.30 (m, 4H, H2b, COCH 2 CH 2 NHCO, H6a) , 3.15 (m, IH, H6b) , 2.60-1.90 (3m, 4H, H4a,b, COCH 2 CH 2 NHCO) . EXAMPLE 14 N-Imidazolyl-2-Acetic acid Imidazole (3.7 g, 54 mmol) was added to a suspension of sodium hydride (2.6 g of a 60% dispersion in oil, 60 mmol) 5 in 50 ml dry THF. Bromoacetic acid (3.4 g, 24 mmol) was then added and the mixture stirred overnight. Water (1 ml) was then added and the solvent removed under reduced pressure. The residue was taken up in water (50 ml, pH >10) , extracted with ether and the organic layer discarded. The aqueous layer 10 was acidified to pH 1 with concentrated HCl and extracted again with ether. The aqueous layer was evaporated to dryness. The oily residue was dissolved in absolute ethanol (EtOH) to precipitate NaCl, and recrystallized from acetone/methanol to give 1.22 g (7.5 mmol, 30%) pure product 15 as the hydrochloride. 1 H NMR: (DMSO-d6, 200 MHz) δ 9.20 (s, H2), 7.76 (d, J = 1.5 Hz), 7.69 (d, J = 1.5 Hz), 5.20 (s, CH 2 ) .0 EXAMPLE 15 N- (l-Imidazolyl-2-Acetyl) -5-Dimethoxytrityloxymethyl-3- 20 Hydroxypyrrolidine Imidazoleacetic acid (1.00 g, 6.15 mmol) and HOBT (l.Olg, 7.5 mmol) were dissolved in 25 ml DMF, and EDC (1.76 g, 9.2 mmol) was added. A thick white precipitate formed, and stirring was continued for 1 h. In a separate flask, 5- 25 dimethoxytrityloxymethyl-3-hydroxypyrrolidine (2.52 g, 6.0 mmol) and TMS-Cl (7.5 mmol, 0.82 g, 0.95 ml) were stirred for one hour in 20 ml Pyridine, and added to the DMF solution. The combined solution was stirred overnight at RT, and quenched with 10 ml NaHC0 3 . After 1 hr, the solution was 30 diluted with water, and extracted twice with ethyl acetate, washed with NaHC0 3 , 0.1 M citric acid, NaHC0 3 , brine, dried with MgS0 4 and evaporated. The product was isolated by flash chromatography (5% Me0H/CH 2 Cl 2 ) to give 2.07 g (65%) . H NMR: (DMS0-d6, 200 MHz) (2 rotamers) d 7.50-6,80 (3 Imidazole-H, 35 13 Ar-H) , 4.90 (ABq, 2H, COCH 2 ) , 4.44 (m, IH, H5) , 4.28 , 4.15 (m, IH, H3), 3.70 (s, 6H, OCH 3 ) , 3.66 (m, IH, H2a) , 3.39 (m, IH , H2b ) , 3 . 35 - 3 . 00 (m , 2H , H6 a , H6b ) , 2 . 08 - 1 . 82 (m , 2H , H4a , H4b ) . EXAMPLE 16 (9-Adenine) -2-Aσetic Acid Ethyl Ester 5 Sodium hydride (8.20 g 60% in oil, 205 mmol) was added to a suspension of adenine (25.0 g, 185 mmol) in 500 ml DMF. After vigorous stirring for 2 hours using a mechanical stirrer, H 2 evolution stopped and a thick slurry was obtained. Ethyl bromoacetate (55.6 g, 36.9 ml, 333 mmol) was added 10 dropwise over 3 hours, and stirring continued for a further 1 hour. Water (10 ml) and H 2 S0 4 were added to pH 4. The solvent was evaporated and the residue suspended in 500 ml H 2 0, filtered and washed with water. The residue was recrystallized from 400 ml ethanol to give 23.8 g (108 mmol, 15 58%) pure product. EXAMPLE 17 (N6-Benzoyl-9-Adenine) -2-Acetic Acid To a suspension of (9-adenylyl) -2-acetic acid ethyl ester (6.06 g, 27.4 mmol) in 250 ml dry pyridine was added 20 benzoyl chloride (9.60 ml, 11.6 g, 82 mmol) , and the solution stirred for 4 hours at room temperature. Methanol (25 ml) was added and the solvents evaporated. The residue was dissolved in ethyl acetate (2 X 250 ml), washed with 0.1 N HCl, H 2 0, saturated NaHC0 3 , brine, and dried with Na 2 S0 4 . The organic 25 extracts were evaporated and the solid residue was redissolved in 250 ml THF at 0°C, to which was added 100 ml 1M NaOH. The solution was stirred at 0°C for 1 hour and acidified to pH 1 with concentrated HCl, and the aqueous portion extracted once with ether. The product, which began to crystallize almost 30 immediately, was collected by filtration to yield 4.96 g (61%) . 'H MR: (DMS0-d6, 200 MHz) δ 8.86, 8.84 (d, H2, H8) , 8.1 (d, 2H, J = 7.0 Hz, ArH) , 7.69-7.58 (m, 3H, Ar-H) , 5.22 (s, 2H, CH 2 ) . EXAMPLE 18 N- t (N-6-Benzoyl-9-Adeninyl) -2-Acetyl] -5-Dimethoxytrityloxy¬ me hyl-3-Hydroxypyrro1idine (N-6-Benzoyl-9-Adeninyl) -2-acetic acid (2.76 g, 9.30 mmol) and HOBT (1.49 g, 11.0 mmol) were dissolved in 50 ml DMF, and DCC (2.89 g, 14.0 mmol) was added. A thick white precipitate formed, and stirring was continued for 1 h. In a separate flask, 5-dimethoxytrityloxymethyl-3 - hydroxypyrrolidine (3.00 g, 7.15 mmol) and TMS-Cl (8.6 mmol, 0.93 g, 1.09 ml) were stirred for one hour in 50 ml Pyridine, and added to the DMF solution. The combined solution was stirred overnight at RT, and quenched with 25 ml NaHC0 3 . After 1 hr, the solution was diluted with water, and extracted twice with ethyl acetate, washed with NaHC0 3 , 0.1 M citric acid, NaHC0 3 , brine, dried with MgS0 4 and evaporated. The product was isolated by flash chromatography (2% MeOH / CH 2 C1 2 ) to give 2.03 g (42%) . ** Η NMR: (DMSO-d6, 200 MHz) (2 rotamers) d 8.67, 8.34 (2 s, 2H, Adenine H2, H8) 8.04 (d, 2H, Benzoyl H2, H6) , 7.54 (m, 3H, Benzoyl H3,4, 5) , 7.35-7.10, 6.84 (13 Ar-H) , 5.22 (ABq, 2H, COCH 2 ) , 4.50, 4.34 (2 m, IH, H5), 4.23 , 4.15 (2 m, IH, H3) , 4.05, 3.80 (m, IH, H2a) , 3.70 (s, 6H, OCH 3 ) , 3.93, 3.55 (m, IH, H2b) , 3.35, 3.18 (m, 2H, H6a) , 3.28, 2.98 (m, IH, H6B) , 2.30-1.84 (4 m, 2H, H4a, H4b) . EXAMPLE 19 N-4-Benzoylcytosine Cytosine hemihydrate (12.0 g, 100 mmol) was coevaporated with pyridine and resuspended in 250 ml dry pyridine. Benzoyl chloride (58 ml, 70.3 g, 500 mmol) was added dropwise (exothermic) . The solution was stirred at RT overnight, and water (50 ml) carefully added. The solvent was evaporated, and the residue dissolved in 700 ml H 2 0 containing 55 g NaOH. The solution was stirred for 1 h after complete dissolution of the material . Concentrated HCl was then added to pH 4.0, the white precipitate was collected and boiled in 1 liter EtOH, cooled to RT and filtered to give 16.1 g product (75%) . • EXAMPLE 20 N-4-Benzoyl-1-Cytosine-2-Acetic acid To a suspension of N-4-Benzoylcytosine (15.0 g, 69.7 mmol) and K 2 C0 3 (9.7 g, 70 mmol) in 500 ml DMF was added methyl bromoacetate (6.6 ml, 10.7 g, 70 mmol) . The suspension was stirred vigorously for 3 days, filtered and evaporated. The residue was treated with water (120 ml) , and 10 ml 4N HCl for 15 min, and the solid collected by filtration. The residue was resuspended in 120 ml water, and 60 ml 2N NaOH added. The suspension was stirred at RT for 45 min, until all the solids had dissolved. The solution was acidified to pH 2 with cone HCl, filtered, and the solid dried in vacuo at 60 °C to give 11.6 g product (61%) . EXAMPLE 21 N- [ (N-4-Benzoyl-l-Cytosine) -2-Acetyl] -5-Dimethoxytrityl- oxymethyl-3-Hydroxypyrrolidine (N-4-Benzoyl-l-Cytosine) -2-acetic acid (3.85 g, 14.0 mmol) and HOBT (2.25 g, 16.6 mmol) were dissolved in 50 ml DMF, and EDC (3.83 g, 20.0 mmol) was added. A thick white precipitate formed, and stirring was continued for 1 h. In a separate flask, 5-dimethoxytrityloxymethyl-3-hydroxy¬ pyrrolidine (5.00 g, 11.9 mmol) and TMS-Cl (13 mmol, 1.41 g, 1.65 ml) were stirred for one hour in 50 ml Pyridine, and added to the DMF solution. The combined solution was stirred overnight at RT, and quenched with 25 ml NaHC0 3 . After 1 hr, the solution was diluted with water, and extracted twice with ethyl acetate, washed with NaHC0 3 , 0.1 M citric acid, NaHC0 3 , brine, dried with MgS0 4 and evaporated. The product was isolated by flash chromatography (2% MeOH / CH 2 C1 2 ) to give 6.10 g product (75%) . EXAMPLE 22 N-2-Isobutyroyl-9-Guanine-2-Acetic Acid To a suspension of 2-amino-6-chloropurine (10 mmol) and K 2 C0 3 (15 mmol) in DMF (25 ml) is added ethyl bromoacetate (10 mmol) . The mixture is stirred vigorously for 24 hours, filtered and the solvent evaporated. The residue is resuspended in 25 ml pyridine and isobutyroyl chloride added (20 mmol) . After stirring for 18 hours, water is added and the solvent removed. The residue is suspended in IN HCl and heated to reflux for 1 hour. The suspension is then cooled to 0°C, NaOH added to pH 12, and the suspension stirred for 1 hour. The solution is acidified to pH 3, and the product is collected by filtration. EXAMPLE 23 N- [ (N2-Isobutyroyl-9-Guanine) -2-Acetyl] -5-Dimethoxytrityloxy¬ methyl-3-Hydroxypyrrolidine The title compound is prepared as per the procedure of Example 5 using N2-isobutyroyl-9-guanine-2-acetic acid as the carboxylic acid component. EXAMPLE 24 Benzyl 3,6,9,12-Tetraoxatridecanoate Triethyleneglycol monomethyl ether (10 mmol) and benzyl bromoacetate (11 mmol) are added to a suspension of anhydrous K 2 C0 3 (15 mmol) in 50 ml anhydrous DMF. The suspension is stirred at room temperature overnight. Water is added and the emulsion is extracted with ethyl acetate (3 X 200 ml) , washed with water, brine, and dried with MgS0 4 . The solvent is evaporated and the residual oil purified by flash chromato¬ graphy to give the title compound. EXAMPLE 25 3,6,9,12-Tetraoxatridecanoic Acid Benzyl-3, 6, 9, 12-Tetraoxatridecanoate (5 mmol) is dissolved in methanol (50 ml) and 10% palladium on carbon is added (100 mg catalyst/mmol) . The suspension is shaken under 30 psi H 2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification. EXAMPLE 26 N- [3,6,9,12-Tetraoxatridecanoyl] -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine The title compound is prepared via the procedure of Example 5 using 3, 6, 9, 12-tetraoxatridecanoic acid as the carboxylic acid component . EXAMPLE 27 Benzyl Bis- [ (2-Pyridyl) -2-ethyl] -Aminoacetate To a suspension of K 2 C0 3 (15 mmol) in 25 ml DMF was added 2,2' -bis (2-pyridylethyl) -amine (10 mmol) followed by benzyl bromoacetate (12 mmol) . The suspension was stirred for 4 hours at room temperature. Water was then added, and the suspension extracted with ethyl acetate (2 X 100 ml) , washed with 5% Na 2 C0 3 , water, brine, dried with MgS0 4 and the solvents removed. The product was obtained as an oil in quantitative yield. Product was identified by NMR. EXAMPLE 28 Bis (2- (2-Pyridyl)ethyl) -Aminoacetic Acid Benzyl bis- [ (2-pyridyl) -2-ethyl] -aminoacetate (5 mmol) is dissolved in methanol (50 ml) and 10% palladium on carbon is added (100 mg catalyst/mmol) . The suspension is shaken under 30 psi H 2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification. EXAMPLE 29 N- [Bis (2- (2-Pyridyl)ethyl) -Aminoacetyl] -5-Dimethoxytrityloxy¬ methyl-3-Hydroxypyrrolidine This compound is prepared via the procedure of Example 5 using bis (2- (2-pyridyl) ethyl) -aminoacetic acid as the carboxylic acid component. EXAMPLE 30 N- (Toluenesulfonyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine Chlorotrimethylsilane (6.0 mmol) is added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.0 mmol) in 25 ml dry pyridine. After stirring one hour, toluenesulfonyl chloride (6.0 mmol) is added in portions, and stirring continued for two hours. The reaction is quenched with saturated aqueous NaHC0 3 , and the mixture stirred until the silyl ethers were hydrolyzed. The solvent is removed in vacuo, and the residue partitioned between water and ethyl acetate. The organic layer is washed with NaHC0 3 , water, brine and dried with Na 2 S0 4 . The solvent is removed and the resulting oil purified by flash chromatography, using a gradient of MeOH in CHC1 3 . EXAMPLE 31 N- (Trifluoromethanesulfonyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine Chlorotrimethylsilane (6.0 mmol) is added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.0 mmol) and triethylamine (15 mmol) in 50 ml dry CH 2 C1 2 . After 1 hour the solution is cooled to -78°C, and trifluoromethanesulfonic anhydride (5.5 mmol) is added dropwise. The cooling bath is removed and the mixture allowed to warm to room temperature. The crude product is dissolved in pyridine and NaHC0 3 solution is added to hydrolyze the TMS ether. The solvent is evaporated, the residue partitioned between ethyl acetate and water, washed with NaHC0 3 , brine and dried with MgS0 4 . The residue is purified by flash chromatography using a gradient of methanol in CHC1 3 . EXAMPLE 32 N-Benzyl-5-Dimethoxytrityloxymethyl-3-Hydroxypyrrolidine Chlorotrimethylsilane (6.0 mmol) is added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.0 mmol) , imidazole (5 mmol) and triethylamine (15 mmol) in 25 ml dry DMF. After stirring one hour the solvent is removed in vacuo, and the residue redissolved in acetonitrile (25 ml) and triethylamine (10 mmol) . Benzyl bromide (6.0 mmol) is added, and stirring continued overnight. The reaction is quenched with saturated aqueous NaHC0 3 , and the mixture stirred until the silyl ethers were hydrolyzed. The solvent is removed in vacuo, and the residue partitioned between water and ethyl acetate. The organic layer is washed with NaHC0 3 , water, brine and dried with Na 2 S0 4 . The solvent is removed and the resulting oil purified by flash chromatography, using a gradient of MeOH in CHC1 3 . EXAMPLE 33 N- (Aminocarbonyl) -5-Dimethoxytrityloxymethyl-3-Hydroxypyrrol¬ idine Chlorotrimethylsilane (6.0 mmol) is added dropwise to a solution of 5-DMT-hydroxypyrrolidine (5.0 mmol) and triethylamine (15 mmol) in 50 ml dry CH 2 C1 2 . After one hour, dimethylaminopyridine (1 mmol) is added followed by trimethylsilyl isocyanate (5.5 mmol) . The solution is stirred until the starting material is consumed. The solvent is removed in vacuo and the crude product redissolved in pyridine and NaHC0 3 solution to hydrolyze the TMS ethers. The solvent is evaporated, the residue partitioned between ethyl acetate and water, washed with NaHC0 3 , brine and dried with MgS0 4 . The residue is purified by flash chromatography using a gradient of methanol in CHC1 3 . EXAMPLE 34 N- (Methylaminothiocarbonyl) -5-Dimethoxytrityloxymethyl-3-Hy¬ droxypyrrolidine Chlorotrimethylsilane (6.0 mmol) is added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.0 mmol) and triethylamine (15 mmol) in 50 ml dry CH 2 C1 2 . After one hour, dimethylaminopyridine (1 mmol) is added followed by methylisothiocyanate (5.5 mmol) . The solution is stirred until the starting material is consumed. The solvent is removed in vacuo and the crude product redissolved in pyridine and NaHC0 3 solution to hydrolyze the TMS ethers. The solvent is evaporated, the residue partitioned between ethyl acetate and water, washed with NaHC0 3 , brine and dried with MgS0 4 . The residue is purified by flash chromatography using a gradient of methanol in CHC1 3 . EXAMPLE 35 N- (Benzyloxycarbonyl) -3-Hydroxypyrrolidine-5-Methanol To a solution of N-CBz-4-hydroxy-L-proline (38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol) dropwise at room temperature. After the evolution of H 2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2X100 ml MeOH. The product was obtained as a viscous oil in quantitative yield and identified by NMR. EXAMPLE 36 N- (Benzyloxycarbonyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine N- (Benzyloxycarbonyl) -3-hydroxypyrrolidine-5-methanol (35.3 mmol) was coevaporated with dry pyridine (2X50 ml), re- dissolved in 200 ml dry pyridine, and cooled in an ice bath. Dimethoxytrityl chloride (38 mmol) was added in portions over 15 minutes, and the solution stirred at room temperature overnight. Methanol was then added (10 ml) , and the solvent removed under reduced pressure. The resulting gum was redissolved in toluene (100 ml) , filtered to remove the pyridinium hydrochloride and taken to dryness again. The residue was chromatographed (0 to 1.5% MeOH/CH 2 Cl 2 ) to give the product. The product was identified by NMR. EXAMPLE 37 N-α- (FMOC) -glutamic acid γ-benzyl ester To a solution of γ-benzyl glutamate (10 mmol) in 50 ml dioxane and 50 ml water is added triethylamine (25 mmol) , followed by a solution of fluorenylmethyl chloroformate (11 mmol) in 50 ml dioxane. The mixture is vigorously stirred until the starting material is consumed. The solution is acidified to pH 2 with concentrated HCl, extracted with ethyl acetate (2 X 250 ml) , washed with brine, dried with MgS0 4 and evaporated. The product is used without purification. EXAMPLE 38 N-α- (FMOC) -γ-benzyl-L-glutamic acid fluorenylmethyl ester N-α- (FMOC) -glutamic acid γ-benzyl ester (5 mmol) , fluorenylmethanol (5.5 mmol) and dimethylaminopyridine (0.5 mmol) are dissolved in 50 ml CH 2 C1 2 . Dimethylaminopropyl ethyl carbodiimide (EDC, 6.0 mmol) is added, and the solution stirred at room temperature. After complete consumption of the starting material the solution is diluted with CH 2 C1 2 , washed with 1% HCl, water and brine, dried with MgS0 4 and evaporated. The residue is purified by flash chromatography using ethyl acetate and hexane as eluant. EXAMPLE 39 N-α- (FMOC) -L-glutamic acid a-fluorenylmethyl ester N-α- (FMOC) -γ-benzyl-L-glutamic acid fluorenylmethyl ester (5 mmol) is dissolved in methanol (50 ml) and 10 . % Palladium on carbon is added (100 mg catalyst/mmol) . The suspension is shaken under 30 psi H 2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification. EXAMPLE 40 N- (N-α-Fmoc-α-Fluorenylmethyl-γ-glutamyl) -5-Dimethoxytrityl¬ oxymethyl-3-Hydroxypyrrolidine The title compound is prepared by the procedure of Example 5 using N-α- (FMOC) -L-glutamic acid a-fluorenylmethyl ester as the carboxylic acid component. EXAMPLE 41 N-Carbazolyl-2-Acetic acid The title compound is prepared as per Example 14 using carbazole as the starting heterocycle. EXAMPLE 42 N- (N-Carbazolyl-2-Acetyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine This compound is prepared as per the procedure described in Example 5 using N-carbazolyl-2-acetic acid as the carboxylic acid component. EXAMPLE 43 N-Pyrrolyl-2-Acetic acid The title compound is prepared as per Example 14 using pyrrole as the starting heterocycle. EXAMPLE 44 N- (N-Pyrrolyl-2-Acetyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy- pyrrolidine This compound is prepared as per the procedure described in Example 5 using N-pyrrolyl-2-acetic acid as the carboxylic acid component. EXAMPLE 45 N- (2 -Naphthylacetyl) - 5 -Dimethoxytrityloxymethyl - 3 -Hydroxy¬ pyrrolidine 2 -Naphthylacetic acid ( 3 . 35 g, 18 mmol ) and HOBT ( 2 . 70 g, 20 mmol , dried under vacuum at 50 °C 24 h) were suspended in 100 ml CH 2 C1 2 . EDC ( 3 . 83 g , 20 mmol ) was added followed by diisopropylethylamine (3.4 ml, 2.5 g, 20 mmol) , and the suspension stirred at RT. The DMT-hydroxyprolinol (5.00 g, 12 mmol) was then added after 15 min. After 1 h stirring the reaction was complete by TLC, and the reaction quenched with sat NaHC0 3 (10 ml) . The solvent was removed after 1 h, the residue was extracted with ethyl acetate, washed with sat NaHC0 3 , water and brine. The organic layer was dried with MgS0 4 , evaporated, and purified by flash chromatography (EA/Hex 3:1) to give pure product (6.7 g, 98%) . λ E NMR: (DMS0-d6, 200 MHz) (2 rotamers) d 7.8-6.75 (20 H, Ar-H) , 4.40 (IH, m, H3) , 4.32, 4.20 (IH, m, H5) , 3.80 (2H, q, C0CH 2 ) , 3.74 (6H, s, 0CH 3 ) , 3.50 (IH, m, H2a) , 3.35 (2H, m, H2b, H6a) , 3.05 (IH, m, H6b) , 2.00, (IH, m, H4a) , 1.83 (IH, m, H4b) . EXAMPLE 46 N- (Methanesulfonyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine 5-Dimethoxytrityloxymethyl-3-hydroxypyrrolidine (5.00 g, 12 mmol) and pyridine (1.46 ml, 1.42 g, 18 mmol) were dissolved in 150 ml CH 2 C1 2 and cooled to 0 °C. Freshly distilled methanesulfonyl chloride (0.97 ml, 1.43 g, 12.5 mmol) was added dropwise, and the solution allowed to warm to RT. The reaction was quenched with water, evaporated, and extracted with ethyl acetate, washed with NaHC0 3 , water and brine, dried (MgS0 4 ) and evaporated. The product was purified by flash chromatography (EA/Hex, 2:1) to give 4.33 g product (73%) . X H NMR: ( CDCl 3 , 200 MHz) d 7.38-6.80 (13 H, ArH) , 4.48 (IH, m, H3) , 3.96 (IH, m, H5) , 3.70 (8H, s, 2 OCH 3 ) , 3.56 (IH, dd, H6a) , 3.48 (2H, dd, H6b ), 3.30 (2H, m, 2 H6) ,2.86 (s, 3H, CH 3 ) , 2.13 (2H, m, 2 H4) . EXAMPLE 47 N-Trifluoroacetyl-Glycine Triethylammonium salt To a suspension of glycine (1.50 g, 20 mmol) in 100 ml dry methanol were added triethylamine (3.5 ml, 2.5 g, 25 mmol) and ethyl trifluoroacetate (3.0 ml, 3.55g, 25 mmol) . The mixture,was stirred overnight to give a homogeneous solution. The solvents were removed and the resulting oil coevaporated with toluene to remove traces of methanol . The product was used without purification. EXAMPLE 48 N- (N' -Trifluoroacetylglycyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine Trifluoroacetylglycine triethylammonium salt N- trifluoroacetyl-glycine triethylammonium salt (20 mmol) was dissolved in 100 ml CH 2 C1 2 . N-Hydroxysuccinimide (2.30 g, 20 mmol) and DMAP (0.25 g, 2 mmol) were added, followed by EDC (4.2 g. 22 mmol) . After 30 min stirring at RT, DIEA was added (4.35 ml, 3.25 g, 25 mmol) followed by 5-dimethoxytrityloxy- methyl-3-hydroxypyrrolidine (5.0 g, 12 mmol) . After 30 min the starting material was consumed, and the reaction was quenched with 10 ml sat NaHC0 3 . After 15 min the solvents were removed, and the residue extracted with ethyl acetate, washed with NaHC0 3 , 0.1 M citric acid, NaHC0 3 , water, brine and dried with MgS04. Pure product was obtained in 87% yield (5.95 g, 10.4 mmol) . X H NMR: (DMSO-d6, 200 MHz) (2 rotamers) d 7.40-6.80 (13 Ar-H),4.39, 4.25 (2 m, 1 H, H3),4.12 (m, IH, H5) , 3.95 (q, 2H, COCH 2 N) , 3.70 (s, 6H, OCH 3 ) ,3.60 (m, IH, H2a) , 3.35, 3.27 (2m, IH, H2b) , 3.12 (m, IH, H6a) , 2.98 (m, IH, H6b) , 1.95, 1.85 (2m, 2H, H4) . EXAMPLE 49 2-Dimethoxytrityl ethanol Anhydrous ethylene glycol (2.45 ml, 44 mmol) was dissolved in 250 ml Pyridine and cooled to 0 °C. TEA (7 ml, 50 mmol) and DMAP (250 mg) were added, followed by DMT-Cl (7.4 g, 22 mmol) in portions over 30 min. The solution was stirred at 0 °C for 2 h, 10 ml water added and the solvent evaporated. The residue was extracted with EtOAc, washed with NaHC03, water, brine, dried with MgS04 and evaporated. The residue was coevaporated with toluene. The product was purified by flash chromatography to give 5.5 g product (70%) . H NMR (CDCI 3 ) ; d 7.50-7.20, 6.90-6.80 (m, 13 H, ArH) , 3.80 (s, 6 H, OCH 3 ) , 3.75 (t, 2H, CH 2 OH) , 3.25 (t, 2H, DMTOCH 2 ) . EXAMPLE 50 2-Dimethoxytrityl ethanol hemisuccinate Triethylammonium salt A solution of 2-0- (dimethoxytrityl) ethanol (l.O g, 2.77 mmol) , triethylamine (0.4 ml, 3 mmol) , and 4-dimethylamino¬ pyridine catalyst (120 mg, 1 mmol) in dry dichloroethane was treated with succinic anhydride (410 mg, 0.41 mmol) . The mixture was stirred at 50 °C for 1.5 hr and then cooled to room temperature. The mixture was kept at room temperature for 16 hrs. The mixture is filtered and the filtrate was purified by silica gel flash column chromatography using chloroform-methanol-triethylamine to yield the title compound as a triethylammonium salt. 1 H NMR: (CDC1 3 ) δ 7.50-7.20, 6.90- 6.80 (m, 13 H, ArH) , 4.26 (t, 2H, CH 2 OCO) , 3.80 (s, 6 H, OCH 3 ) , 3.25 (t, 2H, DMTOCH 2 ) , 3.05 (q, 6H, N(CH 2 CH 3 ) 3 ) , 2.70 (m, 4H, OOCCH 2 CH 2 COO) , 1.25 (t, 9H, N(CH 2 CH 3 ) 3 . EXAMPLE 51 2-Dimethoxytrityl ethanol H-Phosphonate A solution of imidazole (4.29 g, 63 mmol) in dry acetonitrile at 0 °C (100ml) was treated dropwise with PC1 3 (1.77 ml, 20.3 mmol) over a period of 30 minutes. The resulting solution is further treated with triethylamine (9.06 ml, 65 mmol) . To the thick slurry was added 2-0- (dimethoxy- trityl) ethanol (2.10 g, 5.81 mmol) in anhydrous acetonitrile (150 ml) slowly over a period of 30 minutes. The mixture is allowed to warm to room temperature and stirred for 15 minutes. The mixture is quenched with 1M TEAB and the mixture is evaporated in vacuo to a minimum volume and extracted with dichloromethane (2x150 ml) . The dichloromethane extracts are washed with TEAB and evaporated in vacuo. The residue was purified by flash column chromatography using a gradient of 0% to 5% methanol in dichloromethane/1% triethylamine to yield 1.3 g purified material (43%) . -K NMR (CDC1 3 ) ; d 7.50-7.20, 6.90-6.80 (m, 13 H, ArH) , 6.96 (d, IH, J PH = 624 Hz, PH) , 4.06 (m, 2H, CH 2 OP) , 3.80 (s, 6 H, OCH 3 ) , 3.25 (t, 2H, DMTOCH 2 ) , 3.05 (q, 6H, N(CH 2 CH 3 ) 3 ) , 1.25 (t, 9H, N(CH 2 CH 3 ) 3 ) . 31 P NMR (CDC1 3 ) ; 5.89. 5 EXAMPLE 52 N- (l-Methylpyrrole-2-Carbonyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine To a stirred solution of l-Methylpyrrole-2-carboxylic acid (1.88 g, 15.0 mmol) and HOBT (3.45 g, 18.0 mmol) in 75 10 ml CH 2 C1 2 was added EDC (2.43 g, 18.0 mmol) and DIEA (3.2 ml, 2.3 g, 18 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (5.00 g, 11.9 mmol) was added in portions over 5 min, and stirred for 1 h. The reaction was quenched after 1 h with 10 ml NaHC0 3 , evaporated and the residue 15 extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS04 and evaporated. The product was purified by flash chromatography using EtOAc/ Hexane (4:1) as eluant to give 6.2 g product (99%) . *H NMR: ( DMSO d6, 200 MHz) d 7.38-6.80 (13 H, ArH), 6.95, 6.44, 6.03 (3H, pyrrole-H) , 4.48 (IH, m, H3) , 204.28 (IH, m, H5) , 3.77 (11H, s, 2 0CH 3 2 H2, N-CH 3 ) , 3.20 (IH, m, H6a) , 2.95 (2H, m, H6b ) , 2.05 (IH, m, H4a) , 1.95 (IH, m, H4b) . EXAMPLE 53 3,6, 9-Trioxadecyl-4-Toluenesulfonate 25 Toluenesulfonyl chloride (7.15 g, 37.5 mmol) was added to a solution of triethyleneglycol monomethyl ether (5.0 ml, 5.13 g, 31.2 mmol) in 100 ml pyridine. The solution was stirred at RT overnight, the solvent removed and the residue extracted twice with CH 2 C1 2 , washed with 0.IN HCl, water, 30 NaHC03, brine, dried with MgS04 and evaporated. 4.5 g crude product was obtained (45%) . X H NMR: ( CDC1 3 , 200 MHz) d 7.80 (d, 2H, ArH), 7.33 (d, 2H, ArH), 4.15 (t, 2H, TsOCH 2 ) , 3.80- 3.45 (m, 10H, OCH 2 ) , 3.36 (d, 3H, OCH 3 ) , 2.44 (s, 3H, ArCH 3 ) . EXAMPLE 54 N- (3,6, 9-Trioxadecyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (4.20 g, 10 mmol) and 3, 6, 9-Trioxadecyl-4-Toluenesulfonate were dissolved in 30 ml THF, K 2 C0 3 added (4.2 g, 30 mmol) and the suspension heated to reflux overnight with stirring. A further 2.0 g 3, 6, 9-Trioxadecyl-4-Toluenesulfonate was added and the solution refluxed a further 4 hours. The solids were filtered, the solvent evaporated and the product purified by flash chromatography using 1% TEA in EtOAc as eluant to give 4.18 g product (75%) . 'H NMR: ( CDC1 3 , 200 MHz) d 7.45-6.80 (m, 13H, ArH) , 4.35 (br m, IH, H3), 3.80-3.50 (m, 22H, 0CH 3 , H2a,b, H6a,b, OCH 2 ) , 3.35 (d, 3H, OCH 3 ) , 2.57 (br, 2H, NCH 2 ) , 2.10-1.80 (bs, 2H, H4a,b) . EXAMPLE 55 4-Benzoyloxyphenylacetic acid Hydroxyphenylacetic acid (7.61 g, 50 mmol) and NaHC0 3 (10.1 g, 120 mmol) were dissolved in 250 ml water. The pH was adjusted to 9 with 2N NaOH. The solution was cooled to 0 °C, and benzoyl chloride (6.40 ml, 7.73 g, 55 mmol) added dropwise in 5 minutes. The Ph was maintained at 9 by the periodic addition of 2N NaOH. After 20 min the ice bath was removed and stirring continued for 1 h. The solution was acidified to pH 2, and the precipitate collected. 10.1 g product was obtained (79%) . EXAMPLE 56 N- (4-Benzoyloxyphenylacetyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine To a stirred solution of 4-Benzoyloxyphenylacetic acid (3.84 g, 15.0 mmol) and HOBT (3.45 g, 18.0 mmol) in 75 ml CH 2 C1 2 was added EDC (2.43 g, 18.0 mmol) and DIEA (3.2 ml, 2.3 g, 18 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (5.00 g, 11.9 mmol) was added in portions over 5 min, and stirred for 1 h. The reaction was quenched after 1 h with 10 ml NaHC0 3 , evaporated and the residue extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS04 and evaporated. The product was purified by flash chromatography using EtOAc/ Hexane (4:1) as eluant to give 7.2 g product (92%) . NMR: ( CDCl 3 , 200 MHz) (2 rotamers) d 8.20-6.80 (22 H, ArH), 4.55, 4.45 (2m, IH, H3) , 4.40, 4.22 (2m, IH, H5) , 3.77 (s, 6H, OCH 3 ) , 3.65 (abq, 2H, COCH 2 Ar) , 3.85, 3.50, 3.42, 3.20, 3.15 (4H, H2a, H2b, H6a, H6b) , 2.15, 1.90 (2m, 2H, H4a, H4b) . EXAMPLE 57 Nd-BOC-Guanidinoacetic acid A suspension of Glycine ethyl ester hydrochloride (2.0 g, 14 mmol) , N, N' -Bis-BOC-1-guanylpyrazole (Wu, Y. , Matsueda, G.R., Bernatowicz, M. Synth. Commun . 1993, 23 , 3055-60) . (6.9 g, 22 mmol) and triethylamine (3.0 ml, 2.2 g, 21 mmol) were stirred vigorously in 120 ml DMF at RT overnight. Water was added and the solution was extracted twice with EtOAc, washed with 0.1N HCl, water, NaHC0 3 , Brine, dried with MgS0 4 and evaporated. The residue was redissolved in 30 ml THF and 30 ml water containing 0.75 g NaOH was added, the mixture stirred vigorously for 4 h. The basic solution was diluted with 75 ml water and washed twice with 50 ml EtOAc. The aqueous layer was acidified to pH2, extracted twice with EtOAc, washed with water, brine, dried with MgS04 and evaporated to give pure product (2.69 g, 89%) . EXAMPLE 58 N- (Nd-BOC-Guanidinoacetyl) -5-Dimethoxytrityloxymethyl-3- Hydroxypyrrolidine To a stirred solution of Nd-BOC-Guanidinoacetic acid (2.69 g, 8.5 mmol) and HOBT (1.35 g, 10.0 mmol) in 75 ml CH 2 C1 2 was added EDC (1.92 g, 10.0 mmol) and DIEA (1.75 ml, 1.29 g, 10 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (3.2 g, 7.7 mmol) was added in portions over 5 min, and stirred for 1 h. The reaction was quenched after 1 h with 10 ml NaHC0 3 , evaporated and the residue extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS04 and evaporated. The product was purified by flash chromatography using 3% MeOH in CH 2 C1 2 as eluant to give 4.4 g product (64%) . X H NMR: (CDC1 3 , 200 MHz) (2 rotamers) d 7.42-6.80 (13 H, ArH) , 4.58, 4.43 (IH, 2 m, H3) , 4.34, 4.12 (IH, 2 m, H5) , 3.90, 3.70 (2H, 2 m, COCH 2 N) , 3.72 (6H, s, OCH 3 ) , 3.55 (IH, m, H2a) , 3.40 (2H, m, H2b, H6a) , 3.15 (IH, d, H6b) , 2,28-1.90 (2H, 3 m, 2 H2) , 1.40 (9 H, s, C(CH 3 ) 3 ) . EXAMPLE 59 N- (3-Pyridylcarbonyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine A solution of nicotinoyl chloride hydrochloride (1.85 g, 10.5 mmol) in 75 ml pyridine was added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (4.20 g, 10 mmol) and triethylamine (3.0 ml, 2.2 g, 21 mmol) in 50 ml pyridine. The solution was stirred at RT for 1 h, quenched with water (5 ml) and evaporated. The residue was extracted twice with EtOAc, washed with 0.1M citric acid, NaHC03, brine, dried with MgS04 and evaporated. The product was obtained by flash chromatography using 3% MeOH + 0.5% TEA in CH 2 C1 2 as eluant. X H NMR: (DMSO-d6, 200 MHz) d 8.65, 7.92, 7.52 (4H, Py-H) , 7.42-6.80 (13 H, ArH) , 4.43 (IH, m, H3) , 4.30 (IH, m, H5), 3.70 (7H, 2 0CH 3 , H2a) , 3.30 (2H, m, H2b, H6a) , 3.12 (dd, IH, H6b) , 2.10 (m, 2H, H4) . EXAMPLE 60 N- (2-Acetamido-4-Methyl-5-Thiazolesulfonyl) -5-Dimethoxytrityl¬ oxymethyl-3-Hydroxypyrrolidine 2-Acetamido-4-Methyl-5-Thiazolesulfonyl chloride (956 mg, 3.95 mmol) was dissolved in 50 ml CH 2 C1 2 and 5 ml pyridine. This solution was added dropwise to a solution of 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (1.678 g, 4.00 mmol) and triethylamine (0.83 ml, 0.61 g, 6.0 mmol) in 40 ml CH 2 C1 2 at 0 °C. After the addition was complete the solution was warmed to RT for 1 h, quenched with 10 ml water and evaporated. The reside was extracted with EtOAc, washed with 0.1 M citric acid, NaHC0 3 , brine, dried and evaporated. The product was purified by flash chromatography using 3% MeOH in CH 2 C1 2 as eluant to give 1.57 g product (62%) . X H NMR: ( CDC1 3 , 200 MHz) d 7.42-6.80 (13 H, ArH), 4.42 (IH, m, H3) , 54.07 (IH, m, H5), 3.77 (6H, s, OCH 3 ) , 3.70-3.25 (4H, m, 2H2, 2H6) , 2.50 (3H, s, CH 3 ) , 2.20 (3H, s, COCH 3 ) , 2.07 (2H, m, H4) . EXAMPLE 61 N- (N' ,N'-Di ethylglycyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy- 0 pyrrolidine To a stirred suspension of N,N-Dimethylglycine (1.24 g, 12.0 mmol) and HOBT (2.03 g, 15.0 mmol) in 75 ml CH 2 C1 2 was added EDC (2.88 g, 15.0 mmol) and DIEA (2.6 ml, 1.94 g, 15 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3-hydroxy- 5 pyrrolidine (4.61 g, 11.0 mmol) was added in portions over 5 min, and stirred. The reaction was quenched after 1 h with 10 ml NaHC0 3 , evaporated and the residue extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS04 and evaporated. 4.15 g product was obtained (75%) . X H NMR: ( 0 CDC1 3 , 200 MHz) d 7.42-6.80 (13 H, ArH), 4.50 (2H, m, H3, H5) , 3.80 (6H, s, OCH 3 ) , 3.68 (2H, d, C0CH 2 ) , 3.45 (IH, m, H2a) , 3.15 (2H, m, H2b, H6a) , 2.92 (IH, q, H6b) , 2.32, 2.24 (6H, 2 s, N(CH 3 ) 2 ), 2.15 (IH, m, H4a) , 1.95 (IH, m, H4b) . EXAMPLE 62 5 N- (Trifluoroacetyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (4.19 g, 10 mmol) , ethyl trifluoroacetate (1.8 ml, 2.13 g, 15 mmol) and triethylamine (1 ml) were stirred in 50 ml methanol at RT 0 overnight. The solvent was removed and the residue purified by flash chromatography (2% MeOH/CH 2 Cl 2 ) to give 4.92 g product (93%) . X E NMR: ( CDC1 3 , 200 MHz) d 7.42-6.80 (13 H, ArH), 4.68 (IH, m, H5) , 4.45 (IH, m, H3) , 3.77 (8H, s, 2 OCH 3, 2 H2), 3.62 (IH, q, H6a) , 3.13 (2H, q, H6b ) , 2.35 (IH, m, H4a) , 2.05 (IH, m, H4b) . EXAMPLE 63 N- (3-Indoleacetyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy¬ pyrrolidine To a stirred solution of Indole-3-acetic acid (1.05 g, 6.0 mmol) and HOBT (0.95 g, 7.0 mmol) in 75 ml CH 2 C1 2 was added EDC (1.34 g, 7.0 mmol) and TEA (1.4 ml, 1.01 g, 10 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3-hydroxy¬ pyrrolidine (2.1 g, 5.0 mmol) was added in portions over 5 min, and stirred for 1 h. The reaction was quenched after 1 h with 10 ml NaHC0 3 , evaporated and the residue extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS04 and evaporated. The product was recrystallized from a minimal volume of EtOAc to give 1.97 g product (68%) . X H NMR: ( DMSO- d6, 200 MHz) d 10.85 (s, IH. indole-NH) , 7.53-6.75 (17H, ArH) , 4.35, 4.28 (2m, IH, H3) , 4.16 (m, IH, H5) , 3.70 (s, 6H, OCH 3 ) , 3.67 (abq, 2H, COCH 2 ) , 3.47, 3.18, 3.07, 2.96 (4m, 4H, H2a,b, H6a,b) , 1.90, 1.80 (2m, 2H, H4a,b) . EXAMPLE 64 N- (N-BOC-Glycyl) -5-Dimethoxytrityloxymethyl-3-Hydroxy- pyrrolidine To a stirred solution of BOC-glycine (1.05 g, 6.0 mmol) and HOBT (0.95 g, 7.0 mmol) in 75 ml CH 2 C1 2 was added EDC (1.34 g, 7.0 mmol) and TEA (1.4 ml, 1.01 g, 10 mmol) . After 30 min, 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine (2.1 g, 5.0 mmol) was added in portions over 5 min, and stirred for 1 h. The reaction was quenched after 1 h with 10 ml NaHC0 3 , . evaporated and the residue extracted twice with EtOAc, washed with NaHC0 3 , brine, dried with MgS0 4 and evaporated. The product was purified by flash chromatography (3% MeOH/CH 2 Cl 2 ) to give 2.68 g product (93%) . X H NMR: ( DMSO-d6, 200 MHz) d 7.35-6.85 (13H, ArH) , 6.70 (t, IH, BOCNH) , 4.40, 4.25 (2m, IH, H3) , 4.16 (m, IH, H5) , 3.70 (s, 8H, COCH 2 N, OCH 3 ) ,3.54, 3.27, 3.10, 3.00 (4m, 4H, H2a,b, H6a,b) , 1.95, 1.85 (2m, 2H, H4a,b) , 1.38 (s, 9H, OtBu) . EXAMPLE 65 Phosphoramidite Synthesis: General procedure The alcohol, e.g. an N-substituted 5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine (5.0 mmol) was dissolved in 50 ml dry CH 3 CN and 2-cyanoethyl-N, N, N' , N' -tetraisopropyl- phosphorodiamidite (1.9 ml, 6.0 mmol) added, followed by diisopropylammonium tetrazolide (340 mg, 2.0 mmol) . The solution was stirred until the alcohol was completely consumed (1-16 h) , the solvent evaporated, and the residue applied to a silica gel column. The product was eluted with a mixture of EtOAc/Hexane containing 0.5% TEA. EXAMPLE 66 H-phosphonate Synthesis: General procedure 1 Imidazole (6.81 g, 100 mmol) was dissolved in 400 ml dry CH 3 CN and cooled to 0 °C. Phosphorus trichloride (2.62 ml, 4.12 g, 30 mmol) was added dropwise, followed by triethylamine ( 21 ml, 15.2 g, 150 mmol) . A thick slurry developed to which was added over 15 min a solution of alcohol, e.g. an N-substituted 5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine (10 mmol) in 50 ml CH 3 CN. Once the addition was complete, the ice bath was removed and the solution stirred at RT for 30 min. The reaction was stopped by the addition of 100 ml 1M triethylammonium bicarbonate (pH 7-8) buffer. The solvent was removed and the residue coevaporated with 100 ml Pyridine + 5 ml TEA, then 100 ml toluene. The residue was then dissolved in 0.05M TEAB., extracted (3X200 ml) with CH 2 C1 2 , and the extract washed with 0.05M TEAB. The organic phase was dried with MgS04 and concentrated under reduced pressure. The product could be further purified by flash chromatography using a gradient of MeOH (1-10%) in CH 2 C1 2 + 1% TEA. EXAMPLE 67 H-phosphonate Synthesis: General procedure 2 Phosphorus trichloride (1.3 ml, 2.06 g, 15 mmol) was added dropwise to a solution of triethylamine ( 21 ml, 15.2 g, 150 mmol) in 150 ml CH 2 C1 2 . 1, 2,4-Triazole (3.45 g, 50 mmol) was added, and the mixture cooled to 0 °C after 30 min. A solution of the alcohol, e.g. an N-substituted 5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine (5.0 mmol) in 30 ml CH 2 C1 2 was added over 15 min. Once the addition was complete the solution was stirred for 30 min. The reaction was stopped by the addition of 100 ml 1M triethylammonium bicarbonate (pH 7-8) buffer, the two phase system stirred vigorously for 30 min. The product was extracted (3x200 ml) with CH 2 C1 2 , and the organic extract washed with 0.05M TEAB. The organic phase was dried with MgS04 and concentrated under reduced pressure. The product was purified by flash chromatography using a gradient of MeOH (1-10%) in CH 2 C1 2 + 1% TEA. EXAMPLE 68 N-Palmitoyl-5-Dimethoxytrityloxymethylpyrrolidine-3-0- [(N,N- Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound was prepared as per the procedure of Example 65 using N-palmitoyl-5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine of Example 5 as the starting material. EXAMPLE 69 N-Phenylacetyl-5-Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound was prepared as per the procedure of Example 65 usingN-phenylacetyl-5-dimethoxytrityloxymethyl- 3-hydroxypyrrolidine of Example 7 as the starting material. 31 P NMR CDC1 3 δ 148.68, 148.26 and 147.72 (two rotamers) . EXAMPLE 70 N- ( Fluorenylmethylsuccinoyl ) -Dimethoxytrityloxymethyl - pyrrolidine-3 -O- [ (N, N-Diisopropylamino) -2 -Cyanoethoxyphos- phite] The title compound was prepared as per the procedure of Example 65 using N- (fluorenylmethylsuccinoyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 9 as the starting material. 31 P NMR CDC1 3 δ 148.6, 148.4, 148.1, 148.0 EXAMPLE 71 N- [ (N-1-Thymine) -2-acetyl] -5-Dimethoxytrityloxymethyl- pyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxy- phosphite] The title compound was prepared as per the procedure of Example 65 using N- [ (N-1-thymine) -2-acetyl] -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 11 as the starting material. EXAMPLE 72 N- (N-Fmoc-3 -Aminopropionoyl) -Dimethoxytrityloxymethyl- pyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos- phite] The title compound was prepared as per the procedure of Example 65 usingN 1 - (N-Fmoc-3-Aminopropionoyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 13 as the starting material. 31 P NMR CDC1 3 δ 148.82, 148.61 and 148.07 (two rotamers) . EXAMPLE 73 N- (N-Imidazolyl-2-Acetyl) -Dimethoxytrityloxymethylpyrrolidine- 3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound was prepared as per the procedure of Example 65 using N- (l-imidazolyl-2-acetyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 15 as the starting material. 31 P NMR CDC1 3 δ 149.2, 148.8, 148.1 and 147.4 (two rotamers) . EXAMPLE 74 N- (Isobutyroyl) -Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N- Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound was prepared as per the procedure of Example 65 using N- (isobutyroyl) -5-dimethoxytrityloxy¬ methyl-3-hydroxypyrrolidine of Example 6 as the starting material. 31 P NMR CDC1 3 δ 148.6, 148.0, 147.8 and 146.8 (two rotamers) . EXAMPLE 75 N- [ (N6-Benzoyl-9-Adenine) -2-Acetyl] -Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos- phite] The title compound was prepared as per the procedure of Example 65 using N- [ (N6-benzoyl-9-adeninyl) -2-acetyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 18 as the starting material. EXAMPLE 76 N- [ (N4-Benzoyl-1-Cytosine) -2-Acetyl] -Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos- phite] The title compound was prepared as per the procedure of Example 65 using N- [ (N4-benzoyl-1-cytosine) -2-acetyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 21 as the starting material . EXAMPLE 77 N- [ (N2-Isobutyroyl-9-Guanylyl) -2-Acetyl] -Dimethoxytrityloxy- methylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxy- phosphite] The title compound is prepared as per the procedure of Example 65 using N- [ (N2-isobutyroyl-9-guanylyl) -2-acetyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 23 as the starting material. EXAMPLE 78 N- (3,6,9,12-Tetraoxatridecanoyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos- phite] The title compound is prepared as per the procedure of Example 65 using N- (3, 6, 9,12-tetraoxatridecanoyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 26 as the starting material . EXAMPLE 79 N-{Bis [2- (2-Pyridyl)ethyl] -Aminoacetyl}-Dimethoxytrityloxy- methylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxy- phosphite] The title compound is prepared as per the procedure of Example 65 using N- {bis [2- (2-pyridyl) ethyl] -aminoacetyl}-5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 29 as the starting material. EXAMPLE 80 N- (Trifluoromethanesulfonyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos- phite] The title compound is prepared as per the procedure of Example 65 using N- (trifluoromethanesulfonyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 31 as the starting material. EXAMPLE 81 N- (Benzyl) -5-Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N- Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (benzyl) -5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine of Example 32 as the starting material. EXAMPLE 82 N- (Aminocarbonyl) -5--Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (aminocarbonyl) -5-dimethoxytrityloxymethyl- 3-hydroxypyrrolidine of Example 33 as the starting material. EXAMPLE 83 N- (Methylaminothiocarbonyl) -2-Acetyl] -Dimethoxytrityloxy- methylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxy¬ phosphite] The title compound is prepared as per the procedure of Example 65 using N- (methylaminothiocarbonyl) -2-acetyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 34 as the starting material. EXAMPLE 84 N- (Benzyloxycarbonyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- O- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (benzyloxycarbonyl) -5-dimethoxytrityloxy¬ methyl-3-hydroxypyrrolidine of Example 36 as the starting material . EXAMPLE 85 N- (N-α-Fmoc-α-Fluorenylmethyl-γ-glutamyl) -5-Dimethoxytrityloxy- methylpyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxy- phosphite] The title compound is prepared as per the procedure of Example 65 using N- (N-cK-Fmoc-α-fluorenylmethyl-γ-glutamyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 40 as the starting material. EXAMPLE 86 N- (Toluenesulfonyl) -5-Dimethoxytrityloxymethylpyrrolidine-3-0- t (N, N-Diisopropylamino) -2 -Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (toluenesulfonyl ) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 36 as the starting material . EXAMPLE 87 N- (N-Carbazolyl-2 -Acetyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (N-Carbazolyl-2-Acetyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 42 as the starting material . EXAMPLE 88 N- (N-pyrrolyl-2-acetyl) -5-Dimethoxytrityloxymethylpyrrolidine- 3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (N-pyrrolyl-2-acetyl) -5-dimethoxytrityl- oxymethyl-3-hydroxypyrrolidine of Example 44 as the starting material. EXAMPLE 89 N- (2-Naphthylacetyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- 0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound was prepared as per the procedure of Example 65 using N- (2-naphthylacetyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 45 as the starting material. 31 P NMR CDC1 3 δ 148.5, 148.0, 147.5. EXAMPLE 90 N- (Methanesulfonyl) -5-Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (methanesulfonyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 46 as the starting material. 31 P NMR CDC1 3 δ 149.2, 147.7. EXAMPLE 91 N- (N' -Trifluoroacetylglycyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (N' -trifluoroacetylglycyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 48 as the starting material. 31 P NMR CDC1 3 δ 149.0, 148.5. EXAMPLE 92 N- (1-Methylpyrrole-2-Carbonyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (l-methylpyrrole-2-carbonyl) -5-dimethoxy- trityloxymethyl-3-hydroxypyrrolidine of Example 52 as the starting material. 31 P NMR CDC1 3 δ 148.2, 147.8. EXAMPLE 93 N- (3,6,9-Trioxadecyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- 0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (3, 6, 9-trioxadecyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 54 as the starting material . EXAMPLE 94 N- (4-Benzoyloxyphenylacetyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (4-benzoyloxyphenylacetyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 56 as the starting material. 31 P NMR CDC1 3 δ 148.7, 148.4, 148.2, 147.7. EXAMPLE 95 N- (Nd-BOC-Guanidinoacetyl) -5 -Dimethoxytrityloxymethyl - pyrrolidine- 3-0- [ (N, N-Diisopropylamino) -2 -Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (Nd-BOC-guanidinoacetyl) -5 -dime thoxytrityl¬ oxymethyl -3 -hydroxypyrrolidine of Example 58 as the starting material . EXAMPLE 96 N- (3-Pyridylcarbonyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- O- [ (N, N-Diisopropylamino) -2 -Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (3 -pyr idyl carbonyl) -5 -dimethoxytrityl¬ oxymethyl -3 -hydroxypyrrolidine of Example 59 as the starting material . EXAMPLE 97 N- (2-Acetamido-4-Methyl-5-Thiazolesulfonyl) -5 -Dimethoxytrityl - oxymethylpyrrolidine-3 -O- [ (N, N-Diisopropylamino) -2-Cyano- ethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (2-acetamido-4-methyl-5-thiazolesulfonyl) - 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 60 as the starting material. EXAMPLE 98 N- (N' ,N' -Dimethylglycyl) -5-Dimethoxytrityloxymethyl- pyrrolidine-3-O- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphos¬ phite] The title compound is prepared as per the procedure of Example 65 using N- (N' ,N' -dimethylglycyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 61 as the starting material . EXAMPLE 99 N- (Trifluoroacetyl) -5-Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (trifluoroacetyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 62 as the starting material . EXAMPLE 100 N- (3-Indoleacetyl) -5-Dimethoxytritγloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (3-indoleacetyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 63 as the starting material . EXAMPLE 101 N- (N-BOC-Glycyl) -5-Dimethoxytrityloxymethylpyrrolidine-3-0- [ (N,N-Diisopropylamino) -2-Cyanoethoxyphosphite] The title compound is prepared as per the procedure of Example 65 using N- (N-BOC-Glycyl) -5-dimethoxytrityloxymethyl- 3-hydroxypyrrolidine of Example 64 as the starting material. EXAMPLE 102 N- (2-Naphthylacetyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- O-Hydrogenphosphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 65 using N- (2-naphthylacetyl) -5-dimethoxytrityloxy¬ methyl-3-hydroxypyrrolidine of Example 45 as the starting material. 31 P NMR CDC1 3 δ 3.77, J PH =610 Hz. EXAMPLE 103 N- (N' -Trifluoroacetyl) -5-Dimethoxytrityloxymethylpyrrolidine- 3-O-Hydrogenphosphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 65 using N- (N' -trifluoroacetyl) -5-dimethoxytrityloxy methyl -3 -hydroxypyrrolidine of Example 62 as the starting material. 31 P NMR CDC1 3 δ 3.85, J PH =623Hz. EXAMPLE 104 N- (N' ,N' -Dimethylglycyl) -5 -Dimethoxytrityloxymethyl- pyrrolidine-3-O-Hydrogenphosphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 67 using N- (N' ,N' -dimethylglycyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine of Example 61 as the starting material. 31 P NMR CDC1 3 δ 3.77, J PH -=613 Hz. EXAMPLE 105 N- (Nd-BOC-Guanidinoacetyl) -5-Dimethoxytrityloxymethyl¬ pyrrolidine-3-O-Hydrogenphosphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 67 using N- (Nd-BOC-guanidinoacetyl) -5-dimethoxytrityl- oxymethyl-3-hydroxypyrrolidine of Example 57 as the starting material. 31 P NMR CDC1 3 δ 3.82, J PH =618. EXAMPLE 106 N- (4-Benzoyloxyphenylacetyl) -5 -Dimethoxytrityloxymethyl - pyrrolidine-3 -O-Hydrogenphosphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 67 using N- (4-Benzoyloxyphenylacetyl) -5 -Dimethoxy¬ trityloxymethyl -3 -Hydroxypyrrolidine of Example 56 as the starting material. 31 P NMR CDC1 3 δ 3.86, J PH =625 Hz. EXAMPLE 107 N- (2-Acetamido-4-Methyl-5-Thiazolesulfonyl) - 5 -Dimethoxytri tyl¬ oxymethylpyrrolidine- 3 -0-HydrogenphosphonateTriethylammonium salt The title compound is prepared as per the procedure of Example 67 using N- (2-acetamido-4-methyl-5-thiazolesulfonyl) - 5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine of Example 60 as the starting material. 31 P NMR CDC1 3 δ 3.77, J PH =610. EXAMPLE 108 N- (3-Pyridylcarbonyl) -5-Dimethoxytrityloxymethylpyrrolidine-3- O-Hydrogenphoεphonate Triethylammonium salt The title compound is prepared as per the procedure of Example 67 using N- (3-pyridylcarbonyl) -5-dimethoxytrityloxy¬ methyl-3-hydroxypyrrolidine of Example 59 as the starting material. 31 P NMR CDC1 3 δ 3.86, J PH =624. EXAMPLE 109 Synthesis of Hydrogenphoshponates Using the procedure of Example 67 the following compounds are converted to the DMT-hydrogenphosphonate from their respective DMT compounds previously synthesized above. N-Isobutyroyl-5-dimethoxytrityloxymethyl - 3 - hydroxypyrrolidine,N-palmitoyl-5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine, N- (phenylacetyl) -5-dimethoxytrityloxy- methyl-3-hydroxypyrrolidine, N- (fluorenylmethylsuccinoyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N- [(Nl- thymine) -2-acetyl] -5-dimethoxytrityloxymethyl-3-hydroxy¬ pyrrolidine, N-Fmoc-3-aminopropionoyl-5-dimethoxytrityloxy- methyl-3-hydroxypyrrolidine, N- (l-imidazolyl-2-acetyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N- [ (N-6- benzoyl-9aAdeninyl) -2-acetyl] -5-dimethoxytrityloxymethyl-3 - hydroxypyrrolidine, N- [ (N-4-benzoyl-l-cytosine) -2-acetyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N- [ (N2-iso- butyroyl-9-guanine) -2-acetyl] -5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine, N- [3,6,9, 12-tetraoxatridecanoyl] -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N- [bis (2- (2- pyridyl) ethyl) -aminoacetyl] -5-dimethoxytrityloxymethyl-3- hydroxypyrrolidine,N- (toluenesulfonyl) -5-dimethoxytrityloxy- methyl-3-hydroxypyrrolidine, N- (trifluoromethanesulfonyl) -5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N-benzyl-5- dimethoxytrityloxymethyl-3-hydroxypyrrolidine, N- (amino¬ carbonyl) -5-dimethoxytrityloxymethyl-3-hydroxypyrrolidine,N- (methylaminothiocarbonyl) -5-dimethoxytrityloxymethyl-3-hy- droxypyrrolidine, N- (benzyloxycarbonyl) -5-dimethoxytrityl¬ oxymethyl-3-hydroxypyrrolidine, N- (N-α-Fmoc-o!-fluorenylmethyl- γ-glutamyl ) - 5 -dimethoxytrityloxymethyl - 3 -hydroxypyrrolidine , N- (N- carbazolyl - 2 -acetyl ) - 5 -dimethoxytrityloxymethyl - 3 - hydroxypyrrolidine , N- (N-pyrrolyl-2 -acetyl ) -5-dimethoxy- trityloxymethyl-3 -hydroxypyrrolidine , N- (methanesulfonyl ) -5- dimethoxytrityloxymethyl - 3 -hydroxypyrrolidine , N- (N' - trif luoroacetylglycyl ) - 5 - dimethoxytrityloxymethyl - 3 - hydroxy - pyrrolidine , N- (1-methylpyrrole- 2 -carbonyl ) -5-dimethoxy- trityloxymethyl- 3 -hydroxypyrrolidine, N- (3 , 6 , 9-trioxadecyl) -5- dimethoxytrityloxymethyl- 3 -hydroxypyrrolidine , N- (3 -indole- acetyl ) -5 -dimethoxytrityloxymethyl -3 -hydroxypyrrolidine , and N- (N-BOC - glycyl ) - 5 -dimethoxytrityloxymethyl - 3 -hydroxy¬ pyrrolidine . EXAMPLE 110 Standard Oligomer Coupling Cycle Using Standard DNA Synthesis Protocols The oligomeric macromolecules of the invention are synthesized on an automated DNA synthesizer (Applied Bio- systems model 380B) as is done with standard oligonucleotides using standard phosphoramidate chemistry with oxidation by iodine ( see, Oligonucleotide Synthesis, A Practical Approach, M.J. Gait., ed. , Oxford University Press, New York, 1990) . For phosphorothioate oligomers, the standard oxidation bottle is replaced by 0.2 M solution of 3H-1, 2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the step wise thiation of the phosphite linkages. The thiation wait step is increased to 68 sec and is followed by the capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55°C (18 hours) , the oligomers are purified by precipitation twice out of 0.5 M NaCl solution with 2.5 volumes ethanol. Analytical gel electrophoresis is effected in 20% acrylamide, 8 M urea, 454 mM Tris-borate buffer, pH=7.0. Phosphodiester and phosphorothioate oligomers are judged from polyacrylamide gel electrophoresis as to material length. EXAMPLE 111 Synthesis of Sequence Specific Pyrrolidine Oligomer Having Phosphodiester Linkages "Aforvirsen" is an anti-papilloma agent having the nucleobase sequence: TTG CTT CCA TCT TCC TCG TC. A pyrrolidine phosphodiester linked oligomer of this preselected sequence is prepared using the T, A, C and G reagents from Examples 71, 75, 76 and 77, respectively, as per the procedure of Example 110 using iodine as the oxidation reagent to give the phosphodiester linked oligomeric compound having the "Aforvirsen" sequence. EXAMPLE 112 Synthesis of Sequence Specific Pyrrolidine Oligomer Having Phosphorothioate Linkages A pyrrolidine phosphorothioate-linked oligomer of sequence TTG CTT CCA TCT TCC TCG TC is prepared using the T, A, C and G reagents from Examples 71, 75, 76 and 77, respectively, as per the procedure of Example 110 using 3H- 1,2-benzodithiole-3-one 1,1-dioxide as the oxidation reagent to give the phosphorothioate linked oligomeric compound. Example 113 Preparation of N- (2- [1-Tyrosinyl] -acetyl) -2-hydroxymethyl- pyrrolidine-4 -morpholinophosphoramidate- thymidine- phosphodiester-thymidine Trimer. A controlled pore glass resin derivatized with a 3' -5' phosphodiester linked dimer of thymidine [5' -Dmt-O-T-O-P (=0) - O-T-CPG] was synthesized in a standard manner. Two aliquots of this resin (each 24.6 mg, 47.5 mmole/g resin) were separately detritylated using 3 % trichloroacetic acid in dichloromethane and then sequentially washed with anhydrous acetonitrile and pyridine. Each was vigorously agitated with 1 mL of a solution of the N- (2- [1-Tyrosinyl] acetyl) -2-0- dimethoxytrityloxymethyl-pyrrolidin e-3- H-phosphonate monomer (25 mM) in adamantoyl chloride (50 mM) and pyridine for five minutes. The resins were then washed repeatedly with anhydrous pyridine and blown dry with argon gas . To one column was added 1 mL of iodine/pyridine/water (2/90/8) solution and agitated vigorously; to the second column was added 1 mL of morpholine/carbon tetrachloride/pyridine (1/5/5) solution and both were agitated for 30 minutes. The columns were subsequently washed with pyridine and acetonitrile and then blown dry with argon gas. Products were cleaved from the CPG by treatment with 1 mL of concentrated ammonium hydroxide for 30 minutes. The ammonia solutions were evaporated to dryness and then treated with 80 % acetic acid in water for 30 minutes to remove the trityl group An aliquot of the solution from the first column exhibited a single peak in an HPLC analysis (27.8 min, Vyadec C-18, 260 nm, linear gradient of ammonium acetate (pH 7) -acetonitrile, 0-75 % acetonitrile in 52 minutes) corresponding to the phosphodiester trimer. A similar analysis yielded a pair of HPLC peaks (39.7 and 39.9 min) corresponding to the phosphoramidate diastereomeric trimers. In a parallel set of experiments using the HPP-Tyrosine H-phosphonate monomer and the 5' -Dmt-O-T-O-P(=0) -O-T-CPG , the coupled resins were oxidized to the phosphodiester trimer or to the phosphoramidate trimer using dimethyl amine/carbon tetrachloride. These experiments yielded the phosphodiester trimer and the unresolved dimethylamine phosphoramidate trimers at 12.4 min by an HPLC analysis, under the conditions described before. EXAMPLE 114 Derivatization of LCAA CPG With 2-0- (Dimethoxytrityl) - ethylsuccinate Half Ester 2-0- (Dimethoxytrityl) ethylsuccinate half ester triethylammonium salt (135 mg) was dissolved in dichloromethane (5 ml) . 4-Dimethylaminopyridine catalyst (40 mg, 0.2 mmol) was added followed by toluene diisocyanate (.029 ml, 0.2 mmol) . The mixture was shaken for 18 min. Long chain alkyl amine controlled pore glass (LCAA CPG) (1.0 g) was added and the mixture was shaken with the exclusion of light for 16 hrs. The mixture was filtered and washed with dichloromethane and then diethylether (3x10 ml each) . The CPG was shaken for 16 hrs in pyridine/water (4:1) , filtered, and rinsed with pyridine (5x5 ml) . A 10 mg of the dried CPG was treated with 3% trichloroacetic acid in dichloromethane. The presence of the trityl ion qualitatively verified the derivatization. The loading was measured to be 30 μmol/g by measuring the absorbance of the dimethoxytrityl cation. EXAMPLE 115 Hydrogen phosphonate Coupling: General Procedure. 1 A portion of solid support (CPG or other polymeric support e. g. TentaGel) derivatized with a DMT protected alcohol linked via a succinate linker (lμmol) was loaded into a DNA synthesis column, and attached to an automated DNA synthesizer programmed to perform the following functions. 1) Wash with dichloromethane 2) DMT group was removed with 3% trichloroacetic acid in dichloromethane. 3) Wash with dichloromethane and CH 3 CN/Pyridine (1:1) . 4) Coupling: addition of alternating portions of 0.2 M Adamantoyl chloride or Pivaloyl chloride in CH 3 CN/Py (1:1) and 0.05 M H-phosphonate monomer in CH 3 CN/Py (1:1) for 1 min. 5) Wash with CH 3 CN/Pyridine (1:1) . 6) Repeat steps 1 through 5 until the full sequence is completed. The product of this sequence of reactions is an H- phosphonate diester which is oxidized by one of several methods including those described below. Oxidation procedure 1: Phosphodiester The solid support-bound H-phosphonate diester is treated (manually or automatically) with equal volumes of Froehler, B. C. In Methods in Molecular Biology, vol 20 : Protocols for Oligonucleotides and Analogs . Agrawal, S. Ed.; Humana Press: Totowa, 1993, 63-80. solution A (0.2 M I 2 in THF) and solution B (N-methylmorpho- line/H 2 0/THF 1:1:8) for 5 min, followed by equal volumes of solution A and solution C (TEA/H 2 0/THF 1:1:8) for 5 min, followed by washing with CH 3 CN/Py (1:1) . Oxidation procedure 2: Phosphorothioate The solid support-bound H-phosphonate diester is treated (manually or automatically) with a solution of S 8 in CS 2 /Lutidine for 30 min. The solid support is then washed with CH 3 CN/Py (1:1) . Oxidation procedure 3: Phosphoramidate The solid support-bound H-phosphonate diester is treated (manually or automatically) with a solution of the required amine (10 % V/V) in CCl 4 /Pyridine 1:1 for 15-30 min. The solid support is then washed with CH 3 CN/Py (1:1) . Synthesis of Phosphoramidate Library with Uniform PN- Substitution, X PN (N PN ) n N The library is synthesized on Ethylene glycol CPG or on Universal Support CPG (Zeneca, Cambridge, UK) using an automated DNA synthesizer. The solid support is separated into a number of portions equal to the number of monomers used. Each monomer is coupled to the support using the H- phosphonate coupling general procedure. The portions are mixed and redivided for the next coupling. In this way, the random oligomers are synthesized until the fixed position is reached. The support is again split into portions and each monomer coupled. Additional monomers can be added after the fixed position by performing the couplings to the individual pools. Additional random positions can be added to the oligomer by further splitting each of the pools and recombin- ing after coupling, taking care not to mix pools with different fixed positions. Once the oligomer assembly is complete, the H-phosphonate linkages in the individual subsets need to be oxidized, following general procedure 3. This has the result of producing the same phosphoramidate linkage between each residue in the library. By following oxidation general procedure 1 or 2 instead, an all phosphodiester or all phosphorothioate library is produced. The library pools are then cleaved from the solid support, purified and assayed for activity as described previously. Synthesis of Phosphoramidate Library with fixed PN- Substitution, X PN1 -N PN2 - (N PNn ) m -N Synthesis of a phosphoramidate library using DMT- hydroxyprolinol-H-phosphonate monomers (P-Amidate: HPP, Variable amines, X PN1 -N PN2 - (N PNn ) m -N) . The library is synthesized on Ethylene glycol CPG or on Universal Support CPG (Zeneca, Cambridge, UK) using an automated DNA synthesizer. The solid support is separated into a number of portions equal to the number of monomers used (X) . Each monomer is coupled to the support using the H-phosphonate coupling general procedure. The portions are recombined, and the H-phosphonate diester linkage is converted to a phosphoramidate using Oxidation procedure 3. These steps are repeated (split, couple, combine) , followed by Oxidation procedure 3 using a different amine for each randomized position in the oligomer. At the fixed position, the support is split, the monomers are coupled, but the subsets are kept separate for the oxidation step. After cleavage and workup, one obtains a library with randomized monomers and a different substituent at each phosphoramidate linkage. It is also possible to introduce phosphodiester and phosphorothioate linkages at any position in the oligomer library by substituting the appropriate oxidation procedure. Synthesis of Phosphoramidate Library with Variable PN- Substitution, X PNn - (N PNn ) m -N The library is synthesized on Ethylene glycol CPG or on Universal Support CPG (Zeneca, Cambridge, UK) using an automated DNA synthesizer. The solid support is separated into a number of portions equal to the number of monomers used. Each monomer is coupled to the support using the H- phosphonate coupling general procedure. The portions are recombined, mixed and separated into portions. Each portion is oxidized with a different amine following oxidation procedure 3, followed by combining and mixing of the supports. These steps (split, couple, mix, split, oxidize, mix) are repeated are repeated until the fixed position. The support is then split into portions, the monomer coupled, and the resin portions split again for oxidation following procedure 3. After workup, each subset has a unique monomer residue and phosphoramidate linkage, and an equimolar amount of each monomer and amine in the randomized portion. It is also possible to incorporate phosphodiester and phosphoramidate linkages randomly into the oligomers by oxidizing a portion of each H-phosphonate diester by following procedure 1 or 2. EXAMPLE 116 Incorporation Of Monomeric Units Into Oligomeric Structure Using Combinatorial Technique - General Procedure A solid support (universal support from Cambridge Research Biochemicals) is separated into portions of equal weight. The number of portions equals the number of monomers in the combinatorial library. Each portion is reacted with a desired amidites using tetrazole as catalyst, followed by oxidation of the phosphite triester to the phosphate as per the standard coupling cycle of Example 110 above. The DMT ether is cleaved using trichloroacetic acid in CH 2 C1 2 to regenerate the hydroxyl group at the end of the extended oligomer. The extent of the coupling reaction is optimized to be ≥90% completed by varying the amidite concentration and total equivalents and the coupling time. After a coupling, the support is mixed thoroughly, then divided equally and amidites are again reacted individually to a portion of the support. This cycle is repeated for each random position until the 'fixed' position is reached. At the 'fixed' position of the oligomer, each amidite is reacted individually to a portion of the support, but the portions are not mixed. Instead, each subset is further divided into the number of portions corresponding to the number of monomers. Each portion of support is then reacted with a different amidite, followed by mixing as above. Repeating this cycle for each of the different subsets of supports results in randomization in positions following the fixed position in the sequence. The resulting subsets are unique only in the fixed position. At completion of the oligomer synthesis, the oligomers are cleaved from the solid support and phosphate protecting groups are removed by incubation for 1-2 hours at room temperature in concentrated ammonia. Supernatant containing the oligomer is then removed from the silica and incubated at 55°C for 6-16 hours to cleave the protecting groups from the residues. The oligomer is desalted and protecting groups are removed by HPLC size exclusion chromatography. EXAMPLE 117 Evaluation Of Coupling Efficiency Of Phosphoramidite Monomers The following method is used to evaluate the hydroxyprolinol phosphoramidites or other phosphoramidites for suitability of use in a random sequence solid state oligomer synthesis. A solid-phase synthesis support containing an internal reference is used to determine coupling efficiency, estimate the extinction coefficient, and evaluate coupling- product quality of the test phosphoramidite monomers as follows: A test monomer-support is selected as is an internal standard. Using dT as a symbol of thymidine, dC as a symbol for deoxy cytidine and other abbreviations as note in the text below, in an illustrative test system, thymidine bound to CPG, identified as dT-CPG, is used for the test monomer-support and 5'-0-acetyl capped cytosine bound to CPG, identified as 5'-Ac- dC-CPG, is used for the internal standard. Reactive dT-CPG is mixed with a lesser molar equivalent of unreactive 5' -Ac-dC-CPG. The unreactive 5'-Ac-dC-CPG internal standard allows for accurate determination of unreacted dT present before and after a coupling reaction. The peak area of dT can be identified as j . and the peak area of dC identified as A c . The initial ratio of peak areas for dT and dC, i.e., (Aj./A c ) 0 , is determined by cleavage, deprotection, and HPLC analysis of an aliquot of the CPG mixture. Measurements are taken at a wavelength of 260 nm. Relative moles of dC can be identified as C, and relative moles of dT can be identified as T. These are calculated from peak areas, A c and A j , respectively, using known extinction coefficients: C = A c /e c and T = A^/ e T . Thus the relative peak area or molar amount of dT initially present can always be calculated from the peak area of dC: T 0 = (C) [(T/C) 0 ] also, (C) (T/C) = (Ac/e c ) [(A τ /e τ )/(A c /e c )] = (A c /e c ) ( T /A C ) ) (e c /e τ ) thus, (C) [(T/C) 0 3 = (Ac/e c )) [ (A T /A C ) 0 ] (e c ,e τ ) = (Ac/e τ ) [ (A T /A C ) 0 ] An amidite monomer of interest, identified as X, is reacted with an aliquot of the CPG mixture. Reacted CPG is cleaved and deprotected with ammonia, then analyzed by HPLC to determine the area under the peak for dC, i.e., A c ; area under the peak for unreacted dT, i.e., A,--.-.; and area under the peak for X-T dimer, i . e . , A xτ . These values are used to calculate coupling efficiency, C. E. ; and X-T dimer extinction coefficient e xτ . The coupling efficiency, C. E. , is defined by the ratio of reacted dT, i.e., T r , to total dT, i . e . , T 0 . Thus C. E. = T r /T 0 . Coupling efficiency can be determined from the relative moles of unreacted dT present before, i . e . , T 0 , and after, i.e., T ur , coupling with X; all three are related by the equation T 0 = T r + T ur . Since C. E. is a unit-less value, HPLC peak areas can be used instead of relative molar quantities to perform the calculation: C. E. = (T r /T 0 ) = (T 0 /T 0 ) - (T ur /T 0 ) = 1 -(T ur /T 0 ) = 1 - (A Tur /e τ ) / ( p o/e-r) = 1 - ( ^Y I . (Ac) [ (A T /A C ) 0 ] ] The foregoing are all measurable quantities. The extinction coefficient e for X, i.e., e x . τ , in the given HPLC solvent system is determined from the C. E. for X and the relative areas of the HPLC peaks. The amount of X-T is equal to the amount of T that has reacted, e for dimer X-T is defined -as the peak area A xτ divided by the moles of X-T dimer present XT, and is calculated as follows: XT = T r = ( C . E . ) (T 0 ) e χτ = (A XT /XT) = (A XT )/(C.E.) (T 0 ) = (A XT )/(C.E.) (C) [(T/C) 0 ] = (A xτ ) / ( C. E. ) (A c /e τ ) [ ( p/A c ) 0 ] These, again, are all measurable quantities. Finally, the quality of the coupling-product X-T can be evaluated from the appearance of the HPLC chromatogram. Significant peaks (those summing >10% of product-peak area) other than those expected might also be addressed. Often they are the desired X-T dimer that retains protective groups. Disappearance of these peaks with extended ammonia treatment will confirm that the monomer requires extended ammonia deprotection beyond the standard time. In other cases the extra peaks can be identified as undesirable side-products or in some case they cannot be identified. Generally, coupling efficiency of less than about 90%, a required ammonia deprotection time of greater than a few days, or the occurrence of side-products amounting to greater that 10% (by UV absorbance) can be selected as initial guidelines to judge the possibility of excluding an amidite from consideration for use in a particular set of amidites used in generating random oligomeric compounds. EXAMPLE 118 Evaluation Of Coupling Efficiency Of Illustrative Pyrrolidine Phosphoramidite Monomer The phenylacetylhydroxyprolinol phosphoramidite of Example 69 was coupled to a dT-CPG solid-phase synthesis support forming dimers and trimers. Coupling was effected as per the general procedure of Example 110. Synthesis of the dimers and trimers was performed with an ABI 394 DNA synthesizer (Applied Biosystems, Foster City, CA) using standard DNA synthesis reagents and synthesis protocols, with the exception of an extended (5 minute) coupling time added to the synthesis cycle. The oligomers were cleaved from solid support by treatment with concentrated ammonia for 3 days at 4°C. The supernatant was removed from the support and heated in a sealed vial at 55°C for eight hours. This solution was cooled, and most of the ammonia removed by evaporation. The oligomers were analyzed directly on reversed-phase HPLC column (Waters Nova-Pak Phenyl, cat. #10656; Millipore Corp., Milford, MA) using a gradient of 1% to 75% acetonitrile in 0.1 M ammonium acetate, pH 7, over 50 minutes. The HPLC system was a Waters with a 991 detector, 625 LC pump, and 714 WISP auto- injector. Calculations were performed using data collected at a wavelength of 260 nm. In an iteration of this procedure, a dimer of the benzylhydroxyprolinol coupled to dT was synthesized as described above with the terminal DMT group removed to give a free terminal hydroxyl. The resulting crude mixture was analyzed by HPLC. Identification of all but one of the HPLC chromatogram peaks was made. The coupling efficiency and extinction coefficient of the dimer was determined using the general procedure described in Example 110, above, as follows: C. E. = 1 - (A^-.) / (Ac) [ (A T /A C ) 0 ] = 1 - (7.20)/(16.16) (5.57) = 0.92 (92%) e χτ = ( JΠ .) / ( C . E . ) (Ac/ e τ ) [ (A T /A C ) 0 ] = ( 68 . 34 ) / ( . 92 ) ( 7 . 20 / 8 . 71 ) ( 5 . 57 ) = 16.1 M^cm ' lO- 3 ) The quality of the product was thus within a preselected ≥90% 5 limit. The unaccounted for "impurity" material, represented only about 5% of the total area of the product peaks. EXAMPLE 119 PLA 2 assay Phospholipase A2 (PLA2) enzymes are responsible for the 10 hydrolysis of the sn-2 linkage of membrane phospholipids. PLA2-catalyzed reaction is the rate-limiting step in the release of a number of pro-inflammatory mediators, and type II PLA2 is implicated in the pathogenesis of several human inflammatory diseases. Library subsets were screened for 15 inhibition of the activity of type II PLA2 and a unique inhibitor was identified. The oligomer libraries were screened for inhibition of PLA 2 in an assay using E. coli cells labeled with 3 H-oleic acid as the substrate. Franson et al . , J. Lipid Res . 1974, 15, 20 380; and Davidson et al . , J. Biol . Chem . 1987, 262 , 1698. Type II PLA 2 (originally isolated from synovial fluid) , expressed in a baculovirus system and partially purified, serves as a source of the enzyme. A series of dilutions (in water) of each of the oligomeric pools was made: 10 μL of each 25 oligomer was incubated for 5 minutes at room temperature with a mixture of 10 μL of PLA 2 , 20 μL 5 x PLA 2 , buffer (500 mM Tris, pH 7.0-7.5, 5 mM CaC12) and 50 μL water. Each of the oligomer samples was run in duplicate. At this point, 10 μL of 3 H-labeled E. coli cells was added. This mixture was 30 incubated at 37°C for 15 minutes. The enzymatic reaction was halted with the addition of 50 μL of 2 M HCl and 50 μL of fatty acid-free BSA (20 mg/mL PBS) , vortexed for 5 seconds and centrifuged at high speed for 5 minutes. A 165 μL portion of each supernatant was then put into a scintillation vial 35 containing 6 mL of scintillant (Scintiverse) and cpms were measured in a Beckman Liquid Scintillation Counter. As a control, a reaction without oligomer was run alongside the other reactions as well as a baseline reaction containing neither oligomer nor PLA 2 enzyme. Cpms were corrected for by subtracting the baseline from each reaction data point. The results are shown in Table III. TABLE III Round Sequence* Most Active X= IC 50 (μM) 1 XNNNNdT egOC 40 2 (egOC)XNNNdT egOC 5 3 (egOC) (egOC)XNNdT egOC 1.5 *N represents an equimolar mixture of eglM, egOC, egNH, hpPH, hpSU and hpNY, wherein hpPH is N-Phenylacetyl-5-Dimethoxy- trityloxymethylpyrrolidine-3-O- [ (N,N-diisopropylamino) -2- cyanoethoxyphosphite] , hpSU is N- (fluorenylmethylsuccinoyl) - dimethoxytrityloxymethylpyrrolidine-3-O- [ (N,N-diisopropyl- amino) -2-cyanoethoxyphosphite] , and hpNY is the unsubstituted hydroxyprolinol phosphoramidite. The first round selected (egOC)NNNNdT as the most active subset with an IC 50 of 40 μM. The next round led to the determination of the monomer unit in the second position of the oligomer, i.e. egOC, with an eight-fold improvement in activity and an IC 50 of 5 μM. The third round of synthesis and selection led to the identification of (egOC) (egOC) - (egOC)NNdT as the most active subset with a still further improved IC 50 of 1.5 μM. Further rounds can be used to identify a unique oligomer with the greatest activity in the PLA 2 assay. EXAMPLE 120 Verification Of Assay The PLA 2 test system of Example 119 as verified using phosphorothioate oligonucleotides with one or more strings of guanosine nucleotides (at least 3 per string) . Libraries of these oligonucleotides were deconvoluted using the SURFs screening strategy and were shown to have an inhibitory effect on the PLA 2 enzyme. Knowing that phosphorothioate oligo¬ nucleotides inhibit PLA 2 with some sequence specificity, an eight nucleotide phosphorothioate library consisting of the four natural bases was used to test the assay system for suitability as a SURF screen. This library had been synthesized for use in another system and all subsets were not still available (indicated by dashes in Table IV, below) . Using the SURF method, it was confirmed that a stretch of guanosines were necessary for inhibition of PLA 2 activity by the phosphorothioate oligonucleotide (Table IV, below) . The assay was sensitive and accurate enough to discrim¬ inate between subsets of oligomers so that an inhibitory sequence could be selected. In each of the first three rounds of selection, the most active subset was readily determined. After 5 rounds, there was little difference in the activity of the subsets with at least 5 G's in a row, suggesting that the terminal positions are not critical for the inhibitory activity. The IC 50 of the "winner" improves (enzyme activity decreases) as more of the positions are fixed. As a test of the reproducibility of the assay, an eight nucleotide phosphorothioate oligonucleotide of a single sequence (TTGGGGTT) was assayed with each round of testing. This oligonucleotide acted as an internal control of the accuracy of the assay; the IC 50 was 8 μM in each assay. TABLE IV Inhibition of PLA- Activity by Library Subsets IC 50 (mM) X=A X=G X=C X=T Round 2 NNGNXNNN >50 25 »50 >50 Round 3 NNGXGNNN 10 >50 Round 4 NNGGGXNN 18 Round 5 NAGGGGXN 4 2 4 4 NGGGGGXN 2.5 2 3 3 NCGGGGXN 5 4 5 5 NTGGGGXN 19 5 17 15 EXAMPLE 121 Assay of Library of Pyrrolidine Oligomeric Compounds Against PLA 2 A library containing the novel prolinol monomers is tested in the PLA 2 assay for identification of inhibitors of type II PLA 2 . Confirmation of the "winner" is made to confirm that the oligomer binds to enzyme rather than substrate and that the inhibition of any oligomer selected is specific for type II PLA 2 . An assay using 14 C-phosphatidyl ethanolamine ( 14 C-PE) as substrate, rather than E. coli membrane, is used to insure enzyme rather than substrate specificity. Micelles of 14 C-PE and deoxycholate are incubated with the enzyme and oligomer. 14 C-labeled arachidonic acid released as a result of PLA 2 -catalyzed hydrolysis is separated from substrate by thin layer chromatography and the radioactive product is quan- titated. The "winner" is compared to phosphatidyl ethanol¬ amine, the preferred substrate of human type II PLA 2 , to confirm its activity. PLA 2 from other sources (snake venom, pancreatic, bee venom) and phospholipase C, phospholipase D and lysophospholipase can be used to further confirm that the inhibition is specific for human type II PLA 2 . EXAMPLE 122 Hybridization probe for the detection of specific mRNA in biological sample For the reliable, rapid, simultaneous quantification of multiple varieties of mRNA in a biological sample without the need to purify the mRNA from other cellular components, a mRNA of interest from a suitable biological sample, i.e., mRNA of a blood borne virus, a bacterial pathogen product in stool, urine and other like biological samples, is identified using standard microbiological techniques. An oligomeric compound of the invention complementary to the nucleic acid sequence of this mRNA is prepared as per the above examples. The oligomeric compound is immobilized on insoluble CPG solid support utilizing the procedure of Pon, R.T., Protocols for Oligonucleotides and Analogs, Agrawal, S., Ed., Humana Press, Totowa, NJ, 1993, p 465-496. Using the method of PCT application WO 93/15221, a known aliquot of the biological sample under investigation is incubated with the insoluble CPG support having the oligomer thereon for a time sufficient to hybridize the mRNA to oligomer and thus to link the mRNA via the oligomer to the solid support. This immobilizes mRNA present in the sample to the CPG support. Other non- immobilized materials and components are then washed off the CPG with a wash media suitable for use with the biological sample. The mRNA on the support is labelled with ethidium bromide, biotin or a commercial radionucleotide and the amount of label immobilized on the CPG support is measured to indicate the amount of mRNA present in the biological sample. Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention. EXAMPLE 123 Leukotriene B 4 assay Leukotriene B 4 (LTB 4 ) has been implicated in a variety of human inflammatory diseases, and its pharmacological effects are mediated via its interaction with specific surface cell receptors. Library subsets were screened for competitive inhibition of radiolabeled LTB 4 binding to a receptor preparation. A Nenquest™ Drug Discovery System Kit (NEN Research Products, Boston, MA) was used to select an inhibitor of the interaction of Leukotriene B 4 (LTB 4 ) with receptors on a preparation of guinea pig spleen membrane. [ 3 H] Leukotriene B 4 reagent was prepared by adding 5 mL of ligand diluent (phosphate buffer containing NaCl, MgCl 2 , EDTA and Bacitracin, pH 7.2) to 0.25 mL of the radioligand. The receptor preparation was made by thawing the concentrate, adding 35 mL of ligand diluent and swirling gently in order to resuspend the receptor homogenously. Reagents were kept on ice during the course of the experiment, and the remaining portions were stored at -20°C. The library subsets were diluted to 5 μM, 50 μM and 500 μM in phosphate buffer (lx PBS, 0.1% azide and 0.1% BSA, pH 7.2), yielding final test concentrations of 0.5 μM, 5 μM and 50 μM, respectively. Samples were assayed in duplicate. [ 3 H] LTB 4 (25 μL) was added to 25 μL of either appropriately diluted standard (unlabeled LTB 4 ) or library subset. The receptor suspension (0.2 mL) was added to each tube. Samples were incubated at 4°C for 2 hours. Controls included [ 3 H] LTB 4 without receptor suspension (total count vials) , and sample of ligand and receptor without library molecules (standard) . After the incubation period, the samples were filtered through GF/B paper that had been previously rinsed with cold saline. The contents of each tube were aspirated onto the filter paper to remove unbound ligand from the membrane preparation, and the tubes washed (2 x 4 mL) with cold saline. The filter paper was removed from the filtration unit and the filter disks were placed in appropriate vials for scintillation counting. Fluor was added, and the vials shaken and allowed to stand at room temperature for 2 to 3 hours prior to counting. The counts/minute (cpm) obtained for each sample were subtracted from those obtained from the total count vials to determine the net cpm for each sample. The degree of inhibition of binding for each library subset was determined relative to the standard (sample of ligand and receptor without library molecules) . The results are shown in Tables V. TABLE V Round Sequence* Most Active X= IC 50 (μM) 1 XNNNNdT egOC 15 2 (egOC)XNNNdT egOC 7 3 (egOC) (egOC)XNNdT eglM 2 *N represents an equimolar mixture of egOC, eglM, egNH, hpPH, hpSU and hpNY. The first two rounds of synthesis and selection were useful in the determination of the first two monomer units of the oligomer, i.e. (egOC) (egOC)NNNdT, with an IC 50 of 7 μM. The next round led to the selection of an oligomer with an improved IC 50 of 2 μM. Further rounds can be performed for the identification of a unique oligomer with the best activity.

Claims: WE CLAIM: 1. A compound having structure I : wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support; Y is H or a hydroxyl protecting group; Z is L- L , L- L -G- L , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; L x is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms; L 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms; G- L is halogen, OR lf SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC(=NH)NR 3 R 4 , CH=0, C(=0)OR 5 , CH(NR 3 R 4 ) (C(=0)0R 5 ) , C(=0)NR 3 R 4 , a metal coordination group, or a phosphate group; G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ; R- L is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is L 1; G 3 , L- L -G-- or G- J -L- L -G--,; G 3 is C(=0) , C(=S) , C(O)-0, C(0)-NH, C(S)-0, C(S)-NH or S(0) 2 ; and n is 0 or 1. 2. The compound of claim 1 wherein Y is a hydroxyl protecting group. 3. The compound of claim 2 wherein Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl . 4. The compound of claim 1 wherein X is H, an activated phosphite group, or a solid support. 5. The compound of claim 4 wherein X is a phosphoramidite. 6. The compound of claim 1 wherein n is 1 and Q is carbonyl, carboxy, acetyl or succinyl . 7. The compound of claim 1 wherein Z is a nitrogen- containing heterocycle. 8. The compound of claim 7 wherein said heterocycle is imidazole, pyrrole, or carbazole. 9. The compound of claim 8 wherein Z is imidazole. 10. The compound of claim 1 wherein Z is a purine or a pyrimidine. 11. The compound of claim 10 wherein Z is adenine, guanine, cytosine, uridine, or thymine. 12. The compound of claim 11 wherein Q is acetyl. 13. The compound of claim 1 wherein Z is alkyl having 1 to about 20 carbon atoms. 14. The compound of claim 1 wherein Z is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms. 15. The compound of claim 14 wherein Z is fluorenylmethyl, phenyl, or benzyl. 16. The compound of claim 1 wherein Z is polyethylene glycol or glutamyl . 17. A compound having structure II: wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, a solid support, a conjugate group, or an oligonucleotide; Y is H, a hydroxyl protecting group, a conjugate group or an oligonucleotide; E is 0 or S; EE is 0 " , or N(Y 0 )T 0 ; Y 0 is H, or [Q 2 ] j:j -Z 2 ; T 0 is [Q kk -Zi / or together Y 0 and T 0 are joined in a nitrogen heterocycle ; Q- L and Q 2 independently, are C 2 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 4 -C 7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C 7 -C 14 aralkyl; 5 jj and kk independently, are 0 or 1; Z x and Z 2 , independently, are H, C- L -C 2 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C 14 aryl, C 7 -C 15 aralkyl, a halogen, CH=0, OR-, SR 2 , NR 3 R 4 , C (=NH)NR 3 R 4 , CH(NR 3 R 4 ) , NHC(=NH)NR 3 R 4 , CH(NH 2 ) C(=0)OH, C(=0)NR 3 R 4 , C(=0)0R 5 , a metal coordination 10 group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; Z is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, alkynyl having 2 to about 15 20 carbon atoms, aryl having 6 to about 20 carbon atoms, OR l; SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC(=NH)NR 3 R 4 , CH=0, C(=0)OR 5 , CH(NR 3 R 4 ) (C(=0)OR 5 ) , C(=0)NR 3 R 4 , OH, SH, SCH 3 , NR 3 R 4 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, a polyethylene glycol 20 group or metal coordination groups; R- L is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; 25 R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is alkyl having 1 to about 6 carbon atoms, acyl 30 having 1 to about 6 carbon atoms, C(0)-0, C(0)-NH, C(S)-0, C(S) -NH, or S(0) 2 ; n is 0 or 1; and m is 1 to about 50, preferably 1 to about 25. 18. The compound of claim 17 wherein Y is a hydroxyl 35 protecting group. 19. The compound of claim 18 wherein Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl. 20. The compound of claim 17 wherein X is H, an activated phosphite group, or a solid support. 21. The compound of claim 20 wherein X is a phosphoramidite. 22. The compound of claim 17 wherein n is 1 and Q is acyl and is carbonyl, thiocarbonyl, carboxy, acetyl or succinyl. 23. The compound of claim 17 wherein Z is a nitrogen- containing heterocycle. 24. The compound of claim 23 wherein said nitrogen- containing heterocycle is imidazole, pyrrole or carbazole. 25. The compound of claim 24 wherein Z is imidazole. 26. The compound of claim 17 wherein Z is a purine or a pyrimidine. 27. The compound of claim 26 wherein Z is adenine, guanine, cytosine, uridine or thymine. 28. The compound of claim 27 wherein' Q is acetyl. 29. The compound of claim 17 wherein Z is alkyl having 1 to about 20 carbon atoms. 30. The compound of claim 17 wherein Z is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms. 31. The compound of claim 30 wherein Z is fluorenylmethyl, phenyl, or benzyl. 32. The compound of claim 17 wherein Z is polyethylene glycol or glutamyl. 33. The compound of claim 17 wherein m is 1 to about 25. 34. The compound of claim 17 wherein E is O. 35. The compound of claim 17 wherein E is S. 36. The compound of claim 17 wherein said Z groups of are in a predetermined sequence. 37. The compound of claim 17 wherein said Z groups of are in a random sequence. 38. A process for preparing a randomized oligomeric compound comprising: selecting a group of monomers having structure I : wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support; Y is H or a hydroxyl protecting group; Z is alkyl having 1 to about 20 carbon atoms, alkyl having 2 to about 20 carbon atoms, alkynyl having 2 to about 20 carbon atoms, aryl having 6 to about 20 carbon atoms, OR-,, SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC (=NH)NR 3 R 4 , CH=0, C(=0)OR 5 , CH(NR 3 R 4 ) (C(=0)OR 5 ) , C(=0)NR 3 R 4 , OH, SH, SCH 3 , NR 3 R 4 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, a polyethylene glycol group or metal coordination groups; R- L is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is alkyl having 1 to about 6 carbon atoms, acyl having 1 to about 6 carbon atoms, C(0)-0, C(0)-NH, C(S)-0, C(S) -NH, or S(0) 2 ; and n is 0 or 1; and covalently bonding at least two monomers of said group to form said compound. 39. The process of claim 38 wherein the Z moiety of at least one monomer of said group is different from the Z moiety of another monomer of said group. 40. The process of claim 38 wherein said randomized oligomeric compound includes from 2 to 50 of said monomers. 41. An oligomeric compound prepared by the process of claim 38 wherein said compound includes from 2 to 25 of said monomers. 42. A chimeric oligomeric compound having a central region comprising a phosphodiester or a phosphorothioate oligodeoxynucleotide interspaced between flanking regions having structure II: wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, a solid support, a conjugate group, or an oligonucleotide; Y is H, a hydroxyl protecting group, a conjugate group or an oligonucleotide; E is 0 or S; EE is 0 " , or N(Y 0 )T 0 ; Y 0 is H, or [Q 2 ] i i - Z 2 ; T 0 is [Q kk "" z ι / or together Y 0 and T 0 are joined in a nitrogen heterocycle; Q- L and Q 2 independently, are C 2 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 4 -C 7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C 7 -C 14 aralkyl; jj and kk independently, are 0 or 1; Z- L and Z 2 , independently, are H, C^ , alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C 14 aryl, C 7 -C 15 aralkyl, a halogen, CH=0, OR- L , SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , CH(NR 3 R 4 ), NHC(=NH)NR 3 R 4 , CH(NH 2 )C(=0)OH, C(=0)NR 3 R 4 , C(=0)OR 5 , a metal coordination 5 group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; Z is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, alkynyl having 2 to about 10 20 carbon atoms, aryl having 6 to about 20 carbon atoms, OR l; SR 2 , NR 3 R 4 , C(=NH)NR 3 R 4 , NHC (=NH)NR 3 R 4 , CH=0, C(=0)OR 5 , CH(NR 3 R 4 ) (C(=0)OR 5 ) , C(=0)NR 3 R 4 , OH, SH, SCH 3 , NR 3 R 4 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, a polyethylene glycol 15 group or metal coordination groups; R- L is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; 20 R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is alkyl having 1 to about 6 carbon atoms, acyl 25 having 1 to about 6 carbon atoms, C(0)-0, C(0)-NH, C(S)-0, C(S) -NH, or S(0) 2 ; n is 0 or 1; and m is 1 to about 50, preferably 1 to about 25.

Inventors: ACEVEDO OSCAR L, HEBERT NORMAND, ACEVEDO, OSCAR, L., HEBERT, NORMAND
Applicants: ACEVEDO OSCAR L, HEBERT NORMAND, ISIS PHARMACEUTICALS INC, ACEVEDO, OSCAR, L., HEBERT, NORMAND, ISIS PHARMACEUTICALS, INC.
Application year: 1995
Main classification: C07D207
IPC codes: A61K31, A61P29, A61P43, C07D207, C07D233, C07D401, C07D403, C07D413, C07D417, C07D473, C07D521, C07F9, C08G79