Heterocyclic-NMDA antagonists

Abstract: The present invention is directed to a class of 3-phosphono-piperidine and pyrrolidine derivatives and their use as NMDA antagonists.

Description: The present invention is directed to a class of 3-[functionalized alkylphosphono]-piperidine and pyrrolidine compounds that are useful as NMDA antagonists. Another aspect of the invention is directed to the use of these compounds in the treatment of a number of disease states. A further aspect of this invention is directed to pharmaceutical compositions containing these compounds. In EP-A 275 820 unsaturated phosphonic acids and their derivatives which are useful as NMDA antagonists are described. In accordance with the present invention a new class of NMDA antagonists has been discovered which can be described by the following formula: in which R₁ is represented by hydrogen, C₁₋₄ alkyl or CF₃; M is represented by O, N-O-R₄ or in which R₄ is represented by hydrogen, C₁₋₄ alkyl or alkylphenyl; A is represented by one of the following substituents: R₂ is represented by hydrogen, C₁-C₄ alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, substituted phenyl, or trifluoromethyl; R₃ is represented by hydrogen, C₁-C₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; R₅ is represented by hydrogen, linear C₁-C₄ alkyl, or alkylphenyl; R₆ is represented by hydrogen, C₁-C₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; or a pharmaceutically acceptable salt thereof. As used in this application: a) the terms "lower alkyl group and C₁-C₄ alkyl" refer to a branched or straight chained alkyl group containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.; b) the terms "lower alkoxy group and C₁-C₄ alkoxy" refer to a straight or branched alkoxy group containing from 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc.; c) the term "cycloalkyl" refers to a cyclohexyl or a cyclopentyl group; d) the term "substituted phenyl ring" refers to a phenyl (C₆H₅) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogens, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, OH, CN, COOR₆, and CONR₆R₇ in which R₆ and R₇ are represented by hydrogen or a C₁-C₄ alkyl. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions; e) the term "alkylphenyl substituent" refers to the following structure -(CH₂) m -C₆H₅, in which m is an integer from 1-3. This phenyl ring may be substituted in the manner described immediately above; f) the term "oxime" refers to compounds in which M is represented by N-O-R₄; g) the term "hydrazone" refers to compounds in which M is represented by N-NH-R₄; h) the term "pharmaceutically acceptable addition salt" refers to either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable basic addition salt; i) the term "halogen" refers to a fluorine or chlorine atom; j) the term "trialkylamino" refers to in which n is represented by an integer from 2-4 and Alk and Alk₁ are each independently represented by a C₁-C₄ alkyl; and k) the term "cyclohexylmethyl" refers to -CH₂-C₆H₁₂. The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I, or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and in comparison to their free base forms, generally demonstrate higher melting points. The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salt of the compounds represented by Formula I, or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. All of the compounds of Formula I contain at least two (2) asymmetric centers and thus will exist as diastereomers. Any reference to these compounds as well as their intermediates Should be construed as encompassing a racemic mixture, a specific optical isomer or a pair of enantiomers. The specific optical isomers can be synthesized as shown herein or can be recovered by techniques known in the art such as chromatography on chiral stationary phases, or resolution via chiral salt formation and subsequent separation by selective crystallization. HPLC ion exchange chromatography may be utilized to separate only the diastereomers. Examination of Formula I shows that some of the compounds contain a carbonyl function in the alkyl chain which is bonded to the 3-position of the piperidinyl ring or the pyrrolidinyl ring. These compounds will exist in a state of tautomeric equilibrium in which the carbonyl function will participate in a keto-enol equilibrium reaction. This tautomerism may be depicted as follows: As is readily apparent to those skilled in the art, the enol form of this molecule will also exist as geometrical isomers and thus can exist in either the cis or trans orientation. As is indicated by the R₃ substituent, the piperidine ring may be further substituted at positions 4, 5, or 6. R₃ may optionally represent up to 2 non-hydrogen substituents. Only one non-hydrogen substituent should be located at any one position on the piperidine ring. If two non-hydrogen substituents are present, they may be the same or different. When R₃ is a non-hydrogen substituent, then this substituent may be either syn or anti relative to the phosphono substituent. As is indicated by the dotted line in the piperidinyl structure, a double bond may exist at positions 3 or 4. Illustrative examples of compounds encompassed by Formula I include: 3-(Phosphonoacetyl)piperidine-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-4-methyl-2-carboxylic acid; 3-[1-[(Phenylmethoxy)imino]-2-phosphonoethyl]piperidine-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-5-methyl-2-carboxylic acid; 3-[(1-Methoxyimino)-2-phosphonoethyl]piperidine-5-methyl-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-2-carboxylic acid, ethyl ester; 3-(Phosphonoacetyl)piperidine-5-(1-phenylmethyl)-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-4,5-dimethyl-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-5-propyl-2-carboxylic acid; 3-[1-[(Phenylmethoxy)imino]-5-propyl-2-phosphonoethyl]piperidine-2-carboxylic acid; 3-(Phosphonoacetyl)piperidine-5-methyl-2-carboxylic acid, ethyl ester; 3-(Phosphonoacetyl)piperidine-5-propyl-2-carboxylic acid, ethyl ester; d , l - trans -3-(Phosphonoacetyl)piperidine-2-carboxylic acid; d , l - cis -3-(Phosphonoacetyl)piperidine-2-carboxylic acid; 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, methyl ester; 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester; 3(R)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester; 3(S)-(Phosphonoacetyl)piperidine-4-methyl-2(R)-carboxylic acid; 3(R)-(Phosphonoacetyl)piperidine-4-methyl-2(S)-carboxylic acid; 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester; 3(S)-(Phosphonoacetyl)piperidine-5-methyl-2(R)-carboxylic acid; d , l - cis -3-[(Diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, methyl ester; 3(S)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)piperidine-5-methyl-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)piperidine-5-benzyl-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)piperidine-3(R)-methyl-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)piperidine-5-benzyl-3(R)-methyl-2(R)-carboxylic acid; 3-(Phosphonoacetyl)-Δ3-piperidine-2(R)-carboxylic acid; 3-(Phosphonoacetyl)-Δ3-piperidine-5-methyl-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)-Δ4-piperidine-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)-3(R)-methyl-5-methyl-Δ4-piperidine-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)-3(R)-methyl-5-benzyl-Δ4-piperidine-2(R)-carboxylic acid; d , l - cis -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid; d , l - trans -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid d , l - cis -3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid; d , l - trans -3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid; d , l - cis -3-(Phosphonoacetyl)pyrrolidine-3-methyl-2-carboxylic acid; d , l - trans -3-(Phosphonoacetyl)pyrrolidine-3-methyl-2-carboxylic acid. It is preferred for A to be a saturated piperidine ring and for M to be O. R₃ and R₅ are preferably hydrogen. The preferred stereo-chemistry is 2R, 3S. The saturated piperidine compounds of Formula I in which M is represented by O and R₅ is represented by hydrogen, can be prepared utilizing techniques known in the art. One method for preparing these compounds is illustrated below in Reaction Scheme A. In Scheme A, all substituents are as previously defined unless otherwise indicated. Pg = Protecting group R₁' = C₁-C₄ alkyl or CF₃ R₂' = C₁-C₄ alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, substituted phenyl, or trifluoromethyl R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl Scheme A provides a general synthetic procedure for preparing the saturated piperidine compounds of Formula I in which M is represented by O and R₅ is represented by hydrogen. In step a, the appropriate pyridine-2,3-dicarboxylic acid derivative of structure (1) is reduced to give the corresponding piperidine-2,3-dicarboxylic acid derivative of structure (2) using techniques and procedures well known in the art. For example, the appropriate pyridine-2,3-dicarboxylic acid derivative of structure (1) is contacted with an appropriate reducing agent, such as nickel/aluminum, palladium, or platinum in the presence of hydrogen, nickel/aluminum being preferred. The reactants are typically contacted in aqueous base such as sodium hydroxide. The reactants are typically stirred together for a period of time ranging from 6 hours to 5 days and at a temperature range of from 20-38°C. The piperidine-2,3-dicarboxylic acid derivative of structure (2) is recovered from the reaction zone by removing the catalyst by filtration. It may be used in solution without isolation or recovered by extraction and purification by chromatography. In step b, the appropriate piperidine-2,3-dicarboxylic acid derivative of structure (2) is protected to give the corresponding N-protected-piperidine-2,3-dicarboxylic acid derivative of structure (3). A variety of protecting groups may be utilized such as, for example, benzyloxycarbonyl (CBZ). Other suitable protecting groups include substituted carbamates such as t-butyloxycarbonyl and phenylfluorenyl (PhF). These protecting groups may be placed on the nitrogen atom by techniques known in the art. If the protecting group is CBZ, for example, the appropriate piperidine-2,3-dicarboxylic acid derivative of structure (2) is contacted with a molar excess of benzyl chloroformate or [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] or 9-phenylfluorenyl bromide. The reactants are typically contacted in a suitable organic solvent such as aqueous dioxane. The reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours. The N-protected-piperidine-2,3-dicarboxylic acid derivative of structure (3) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by recrystallization. Alternatively, if the protecting group is N-(9-phenylfluorenyl), for example, the appropriate piperidine-2,3-dicarboxylic acid derivative of structure (2) is contacted with a molar excess of 9-phenylfluorenyl bromide, a molar excess of a suitable base such as diisopropylethylamine and a molar deficiency of lead nitrate. The reactants are typically contacted in a suitable organic solvent such as acetonitrile. The reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours. The N-(9-phenylfluorenyl)piperidine-2,3-dicarboxylic acid derivative of structure (3) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography. In step c, the 2,3-dicarboxylic acid functionality of the appropriate N-protected-piperidine-2,3-dicarboxylic acid derivative of structure (3) is dehydrated to give the corresponding N-protected-piperidino anhydride derivative of structure (4). For example, the N-protected-piperidine-2,3-dicarboxylic acid derivative of structure (3) is contacted with a molar excess of acetic anhydride. The reactants are typically stirred together for a period of time ranging from 2-3 days at temperature range of from 20-100°C under an inert atmosphere such as nitrogen. The N-protected-piperidino anhydride derivative of structure (4) is recovered from the reaction zone by evaporation of the solvent. In step d, the appropriate N-protected-piperidino anhydride derivative of structure (4) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (6). The appropriate phosphonate ester of structure (5) is one in which R₁ is represented by a C₁-C₄ alkyl or a trifluoromethyl group. These alkyl functionalities serve to act as protecting groups during the coupling reactions. One of these R₁ functions will be cleaved during the deprotection reaction of optional step h₂ which is described below and the second may also be hydrolysed if desired as described in optional step i which is described below. Alternatively, both protecting groups may be hydrolysed in one step as described in optional step g₁ which is described below. As is obvious to those skilled in the art, the particular protecting group utilized should correspond to that desired in the final product if R₁ is not to be represented by hydrogen in the final product. For example, the appropriate phosphonate ester of structure (5) is first contacted with a molar equivalent of an appropriate strongly basic reagent such as n-butyllithium. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran under an inert atmosphere such as nitrogen. The reactants are typically stirred together for a period of time ranging from 10-20 minutes and at a temperature of -78°C. At that point the reaction medium is warmed to about -10°C and a molar equivalent of the appropriate N-protected-piperidino anhydride derivative of structure (4) is then added. The reactants are typically stirred together for a period of time ranging from 1-3 hours at a temperature range of from - 78°C to -20°C. The N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (6) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by chromatography. In step e, the 2-carboxylic acid functionality of the appropriate N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (6) is protected as its benzyl or C₁-C₄ alkyl ester to give the corresponding N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7). These protecting groups can be placed on the molecule using techniques known in the art. For example, the appropriate N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (6) is contacted with a molar excess of an alkyl bromide of the formula R₂''Br, wherein R₂'' is represented by benzyl or C₁-C₄ alkyl, and a molar excess of an appropriate non-nucleophilic base such as dicyclohexyl amine. The reactants are typically contacted in a suitable aprotic solvent such as dimethylformamide in an inert atmosphere such as nitrogen. The reactants are typically stirred together for a period of time ranging from 1-4 hours and at a temperature range of from 20 to 65°C. The N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by chromatography. In step f, the N-protecting group of the appropriate N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2- carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7) is removed to give the corresponding 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8). For example, the appropriate N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7) is contacted with a molar excess of an appropriate acid such as aqueous hydrochloric acid, trifluoroacetic acid or a mixture of hydrochloric acid in dioxane. The reactants are typically stirred together at room temperature for a period of time ranging from 1-5 hours. The 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) is recovered from the reaction zone by neutralization with propylene oxide followed by filtration or by chromatography. In optional step g₁, the 2-carboxylic acid ester and both of the phosphonate ester functionalities of the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) are removed to give the 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9). For example, the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) is typically contacted with a 3 to 6 molar solution of hydrochloric acid. The reactants are typically stirred together at a temperature range of from room temperature to reflux for a period of time ranging from 1 to 30 hours. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) is recovered from the reaction medium by techniques known in the art such as precipitation as its free base with propylene oxide. It may then be purified by recrystallization from a solvent system such as, for example, ethanol/isopropanol. In optional step g₂, the 2-carboxylic acid ester functionality of the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) is removed to give the 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (10). For example, appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) is typically contacted with a 1 to 3 molar solution of hydrochloric acid. The reactants are typically stirred together at a temperature range of from room temperature to reflux for a period of time ranging from 1 to 18 hours. The 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (10) is recovered from the reaction medium by techniques known in the art such as precipitation as its free base with propylene oxide. It may then be purified by recrystallization from a solvent system such as, for example, ethanol/isopropanol. In optional step h₁, the 2-carboxylic acid functionality of the appropriate 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) is reesterified to give the 3-(phosphonoacetyl)piperidine-2-carboxylic acid, ester of structure (11). For example, the appropriate 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) is contacted with an acidic solution of the desired alcohol. The reactants are typically refluxed for a period of time ranging from 2-24 hours. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid, ester of structure (11) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by chromatography. Alternatively, the appropriate 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) can be contacted with a compound of the formula R₂Br in which R₂ represents the desired R₂ substituent. The reactants are typically contacted in dimethyl formamide in the presence of a base such as dicyclohexylamine. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid, ester of structure (11) is recovered from the reaction zone by extractive methods as is known in the art. It may be purifed by chromatography. Other suitable esterification methods may also be utilized. One of the protecting groups of the phosphonate ester, represented by R₁', is removed and depending upon the manner in which the deprotection reaction is carried out, the other protecting group represented by R₁' may also be removed. In optional step h₂, one of the phosphonate ester functionalites of the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (10) is hydrolyzed to give the corresponding 3-[(monoalkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (12). For example, appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (10) is typically contacted with a 2 to 5 molar solution of hydrochloric acid. The reactants are typically stirred together at a temperature range of from room temperature to reflux for a period of time ranging from 1 to 18 hours. The 3-[(monoalkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (12) is recovered from the reaction medium by techniques known in the art such as precipitation as its free base with propylene oxide. It may then be purifed by recrystallization from a solvent system such as, for example, ethanol/isopropanol. In optional step i, the remaining phosphonate ester functionality of the appropriate 3-[(monoalkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (12) is hydrolyzed to give the 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9). For example, appropriate 3-[(monoalkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid of structure (12) is typically contacted with a 3 to 6 molar solution of hydrochloric acid. The reactants are typically stirred together at a temperature range of from 60°C to reflux for a period of time ranging from 1 to 30 hours. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) is recovered from the reaction medium by techniques known in the art such as precipitation as its free base with propylene oxide . It may then be purified by recrystallization from a solvent system such as, for example, ethanol/isopropanol. Alternatively, all 4 protecting groups (ie. Pg, R₂'', and both R₁' functionalities) can be removed by combining step f and step g₁ and subjecting the N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7) to a vigorous acidic hydrolysis. This can be accomplished by contacting the appropriate N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (7) with a 6 molar solution of a mineral acid such as HCl for a period of time ranging from 18 to 24 hours at a temperature range of from room temperature to reflux. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid of structure (9) can be recovered from the reaction zone by techniques known in the art such as such as precipitation as its free base with propylene oxide. It may then be purified by recrystallization from a solvent system such as, for example, ethanol/isopropanol. Also, where the 2-carboxylic acid ester functionality of the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (8) is benzyl or t-butyl, both of the phosphonate ester functionalities may be removed to give the 3-(phosphonoacetyl)piperidine-2-carboxylic acid, benzyl or t-butyl ester of structure (11). For example, the appropriate 3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl or t-butyl ester of structure (8) is contacted with a molar excess of trimethylsilylbromide or trimethylsilyliodide. The reactants are typically contacted in a suitable organic solvent such as methylene chloride or acetonitrile. The reactants are typically stirred together at room temperature for a period of time ranging from 4-24 hours. The 3-(phosphonoacetyl)piperidine-2-carboxylic acid, benzyl or t-butyl ester of structure (11) is recovered from the reaction zone by techniques known in the art such as such as precipitation as its free base with propylene oxide. It may then be purified by recrystallization from a solvent system such as, for example, ethanol/isopropanol. The proper starting material for the reduction of step a is a pyridine-2,3-dicarboxylic acid derivative of structure (1), in which R₃ is represented by the same substituent as is desired in the final product. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. For example, certain pyridine-2,3-dicarboxylic acid derivatives are described in J.Med.Chem. 10 , 1065 1974 and certain phosphonate esters of structure (5) are described in Tetrahedron Letters 22 2829-31 1976. The following example presents typical syntheses as described in Scheme A. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "µL" refers to microliters; "µg" refers to micrograms; and "µM" refers to micromolar. Example 1 3-(Phosphonoacetyl)piperidine-2-carboxylic acid Step a: Piperidine-2,3-dicarboxylic acid Dissolve pyridine-2,3-dicarboxylic acid (20g, 120mmol) in 0.5N aqueous sodium hydroxide (900mL). Add nickel/aluminum powder (45g) in portions over 3 hours. Stir for 4 days, filter off the catalyst to yield the title compound in clear solution. The resulting free amine is not isolated. Step b: N-Carbobenzoxypiperidine-2,3-dicarboxylic acid Add benzyl chloroformate (20mL, 167mmol) to the above solution of piperidine-2,3-dicarboxylic acid (120mmol) along with dioxane (200mL). Stir overnight and acidify to a pH of 1 with 6N hydrochloric acid. Extract with methylene chloride (400mL) followed by ethyl acetate (200mL). Combine the organic phases and dry (MgSO₄). Evaporate the solvent in vacuo to give a clear oil (35.9g, 98%). Recrystallize (chloroform) to give the title compound as a white solid as predominantly the trans D,L compounds (10.9g). Evaporate the residue to give the title compound as a white semi-solid as approprimately a 2:1 cis/trans mixture of diastereomers. ¹H NMR (300MHz, d₆DMSO) ppm 12.9 (bs), 7.35 (m), 5.2 (m), 4.5 (s), 3.9 (d), 2.6 (s), 3.4 (m), 3.15 (s), 3.1 (m), 2.8 (m), 2.6 (m), 2.1 (m), 1.9 (m), 1.6 (m), 1.45 (m). Step c: N-Carbobenzoxypiperidine-2,3-dicarboxylic acid anhydride Dissolve the 2:1 cis/trans mixture of N-carbobenzoxypiperidine-2,3-dicarboxylic acid diastereomers (20g) in acetic anhydride (500mL) and stir overnight under a dry nitrogen atmosphere. Vacuum distill off the acetic anhydride to leave the title compound as a red glass (11.1g, 59%). ¹H NMR (90MHz, CDCl₃) ppm 7.3 (s), 5.4 (m), 5.2 (s), 4.0 (m), 3.1 (m), 2.9 (m), 2.2 (m). 1.7 (m). Step d: N-Carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid Dissolve methyl diethyl phosphonate (5.5g, 36.4mmol) in anhydrous tetrahydrofuran (150mL) and place under a dry nitrogen atmosphere. Cool to -78°C and add n-butyllithium (14.0mL of a 2.6M solution, 36.4mmol). Stir for 10 minutes and quickly add a precooled -60°C solution of N-carbobenzoxypiperidine-2,3-dicarboxylic acid anhydride (11g, 3.8mmol) in anhydrous tetrahydrofuran (150mL). Stir for 2 hours at -78°C and allow to warm to -20°C over 1-1/2 hours. Pour the reaction mixture into 1.0N hydrochloric acid (1-1/2L) and extract with methylene chloride (2X500mL). Combine the organic phases, dry (MgSO₄) and evaporate the solvent in vacuo to give the title compound. Step e: N-Carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, benzyl ester Dissolve N-carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid (36.4mmol) in dimethylformamide (200mL) and place under a nitrogen atmosphere. Add benzyl bromide (10.5mL), 81mmol) and dicyclohexyl amine (16.2mL, 89mmol) and heat to 65°C. Allow to cool slowly to room temperature and filter. Pour the filtrate into water (1-1/2L) and extract with ethyl acetate (2X500mL). Combine the organic phases and dry (MgSO₄). Evaporate the solvent in vacuo to give a brown oil. Purify by flash chromatography (ethyl acetate) to give the title compound as a yellow oil (3.6g, 19%). Step f: 3-(Phosphonoacetyl)piperidine-2-carboxylic acid Mix N-carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid benzyl ester (3.6g) and 6N hydrochloric acid (400mL) and reflux for 24 hours. Condense with a stream of nitrogen and dissolve the residue in a mixture of absolute ethanol (75mL) and isopropanol (75mL). Filter and add propylene oxide until a white precipitate develops. Filter the precipitate, wash with isopropanol and dry to give the title compound as a white powder (1.55g, 91%). MS (FAB/glycerol) 252(M+H); ¹H NMR (300 MHz, D₂0) ppm 4.6 (m), 4.4 (m), 4.3 (m), 4.15 (d), 4.05 (d), 3.85 (m), 3.75 (d), 3.7 (d), 3.65 (q), 3.45 (m), 3.4 (m), 3.1 (m), 3.05 (d), 3.0 (d), 2.85 (d), 2.45 (m) 2.4 (m), 2.2 (m), 2.1 (m), 2.05 (m), 1.95 (m), 1.85 (m), 1.8 (m), 1.75 (m), 1.6 (m), 1.55 (m), 1.45 (m), 1.2 (d), 1.115 (t). ¹³C NMR ppm 212.0, 211.9, 211.7, 174.1, 173.8, 60.3, 60.2, 59.3, 59.2, 50.7, 50.0, 46.7, 45.8, 27.2, 26.4, 25.8, 22.6, 21.0, 19.5. ³¹P NMR (decoupled) ppm 12.56 and 12.42. Anal. Calcd for C₈H₁₄NO₆P·1.5H₂0: C, 34.54, H, 6.07; N, 5.11; Found: C, 34.76; H, 5.58; N, 4.69. The saturated piperidine compounds of Formula I in which M is represented by O and R₅ is represented by hydrogen can be separated into their diastereomeric pairs as shown in Scheme B. In Scheme B, all substituents unless otherwise indicated are as previously defined. Scheme B provides a general synthetic procedure for preparing the separate diastereomeric pairs of the saturated piperidine compounds of Formula I in which M is represented by O and R₅ is represented by hydrogen. For example, the appropriate 3-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivative of structure (13) is separated to give the corresponding d , l - trans -3-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivative of structure (14a) and the corresponding d , l - cis -3-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivative of structure (14b) by High Performance Liquid Chromatography (HPLC). The proper starting material for the separation is a compound of Formula I as depicted by structure (13), in which R₃, R₁, and R₂ are represented by the same substituents as are desired in the final product. The following example presents typical syntheses as described in Scheme B. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 2 d , l - tran s -3-(Phosphonoacetyl)piperidine-2-carboxylic acid and d , l - cis -3-(Phosphonoacetyl)piperidine-2-carboxylic acid The chromatographic conditions for the separation of d , l - trans -3-(phosphonoacetyl)piperidine-2-carboxylic acid and d , l - cis -3-(phosphonoacetyl)piperidine-2-carboxylic acid are given below: Column: 10 µm Whatman Partisil SAX (250 x 4.6nm). Mobile Phase: 10/90 (v/v) acetonitrile/water, made 0.025M in hydrochloric acid. Flow Rate: 1mL/min. Detection: λ = 210nm. Injection: 2 mL of a 1mg/mL aqueous solution. Collect the fractions corresponding to the diastereomers using switching valves down stream from the detector. These valves are controlled by the HPLC system. Freeze dry the collected fractions to give the separated title compounds. d , l - trans -3-(Phosphonoacetyl)piperidine-2-carboxylic acid ¹H-NMR (300MHz, NaOD) ppm 3.16 (d, J=9.9), 3.10 (m), 3.04 (m), 2.98 (m), 2.78 (m), 2.55 (t, J=12.1), 2.14 (dm, J=12.4), 1.68 (dm, J=12.3), 1.56 (qm, J=12.4), 1.46 (m). d , l - cis -3-(Phosphonoacetyl)piperidine-2-carboxylic acid ¹H-NMR (300MHz, D₂O) ppm 3.78 (d, 1), 3.69 (m, 1), 3.38 (m, 1), 3.22-2.93 (m, 3), 2.32 (m, 1), 1.95 (m, 1), 1.79 (m, 1), 1.52 (m, 1). Those saturated piperidine compounds of Formula I in which M is represented by either an oxime or a hydrazone derivative and R₅ is represented by hydrogen can also be prepared using techniques known in the art. One method for preparing these compounds is disclosed below in Scheme C. In Scheme C, all substituents unless otherwise indicated are as previously defined. M' = -N-O-R₄ or Scheme C provides a general synthetic procedure for preparing the saturated piperidine compounds of Formula I in which M is represented by an oxime or a hydrazone derivative and R₅ is represented by hydrogen. In step a, a condensation reaction is carried out between the appropriate 3-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivative of structure (13) in which R₁, R₂, and R₃ are represented by the same substituents as is desired in the final product, and in which M is O as is depicted, and one of the oximes or hydrazones of structure (15) corresponding to the M substituent that is desired in the final product. The condensation reaction can be carried out using techniques known in the art. Typically approximately equivalent amounts of the compound of Formula I and the oxime or hydrazone of structure (15) are contacted in a buffered solution. Sodium acetate is one suitable buffer. The reaction is typically carried out at a temperature range of from 25 to 80°C for a period of time ranging from 1 to 24 h. The desired 3-[1-imino-2-phosponoethyl]piperidine-2-carboxylic acid derivative of structure (16) can then be recovered from the reaction and purified by either gel filtration or ion exchange chromatography. In optional step b, the diastereomeric pairs of the appropriate 3-[1-imino-2-phosponoethyl]piperidine-2-carboxylic acid derivative of structure (16) are separated to give the d,l-trans -3-[1-imino-2-phosponoethyl]piperidine-2-carboxylic acid derivative of structure (17a) and d,l-cis -3-[1-imino-2-phosponoethyl]piperidine-2-carboxylic acid derivative of structure (17b) as described previously in Scheme B. Starting materials for use in Scheme C are readily availiable to one of ordinary skill in the art. A synthesis for the enatiomerically pure 2(R)-, 3(S)-saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen is described in Scheme D. In Scheme D, all substituents unless otherwise indicated are as previously defined. R₂'' = -CH₃ or -CH₂CH₃ R₁' = C₁-C₄ alkyl or CF₃ Scheme D provides an alternative synthetic scheme for preparing the enatiomerically pure 2(R)-, 3(S)-saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen. In step a, the appropriate pyridine-2,3-dicarboxylic acid derivative of structure (1) is protected to give the corresponding pyridine-2,3-dicarboxylic acid, diester derivative of structure (18). For example, the appropriate pyridine-2,3-dicarboxylic acid derivative of structure (1) is contacted with a molar excess of the appropriate alcoholic hydrochloric acid. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux. The pyridine-2,3-dicarboxylic acid, diester derivative of structure (18) is recovered from the reaction zone by evaporation of the solvent. In step b, the appropriate pyridine-2,3-dicarboxylic acid, diester derivative of structure (18) is reduced to give the corresponding d,l-cis -piperidine-2,3-dicarboxylic acid, diester derivative of structure (19). For example, the appropriate pyridine-2,3-dicarboxylic acid, diester derivative of structure (18) is contacted with an appropriate reducing agent such as palladium hydroxide in the presence of hydrogen. The reactants are typically contacted in a suitable organic solvent such as methanol. The reactants are typically shaken together at a pressure of 45-50psi for a period of time ranging from 6 hours to 5 days and at a temperature range of from 20-38°C. The d,l-cis -piperidine-2,3-dicarboxylic acid, diester derivative of structure (19) is recovered from the reaction zone by evaporation of the solvent. In step c, the appropriate d,l-cis -piperidine-2,3-dicarboxylic acid, diester derivative of structure (19) is separated via an enzymatic hydrolysis into the corresponding enantiomerically pure piperidine-2(R),3(S)-dicarboxylic acid, diester derivative of structure (20a) and piperidine-2(S)-carboxylic acid-3(R)-carboxylic acid, monoester derivative of structure (20b). For example, the appropriate d,l-cis -piperidine-2,3-dicarboxylic acid, diester derivative of structure (19) is contacted with a molar excess of a suitable esterase such as porcine liver esterase. The reactants are typically contacted in a suitable buffered solvent system such as pH 7.4 phosphate buffer. The reactants are typically stirred together at room temperature for a period of time ranging from 10-48 hours. The enantiomerically pure piperidine-2(R),3(S)-dicarboxylic acid, diester derivative of structure (20a) is recovered from the reaction mixture by extractive methods as is known in the art and the enantiomerically pure piperidine-2(S)-carboxylic acid-3(R)-carboxylic acid, monoester derivative of structure (20b) can be recovered from the reaction zone by ion-exchange chromatography. In step d, the appropriate piperidine-2(R),3(S)-dicarboxylic acid, diester derivative of structure (20a) is protected to give the corresponding N-protected-piperidine-2(R),3(S)-dicarboxylic acid, diester derivative of structure (21) as described previously in Scheme A, step b. In step e, the appropriate N-protected-piperidine-2(R),3(S)-dicarboxylic acid, diester derivative of structure (21) is coupled with an appropriate phosphonate ester of structure (5) to give the corresponding N-protected-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ester of structure (22) as described previously in Scheme A, step d. In step f, the N-protecting group of the appropriate N-protected-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ester of structure (22) is removed to give the corresponding 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ester of structure (23a) as described previously in Scheme A, step f. The appropriate 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ester of structure (23a) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3(S)-[(functionalized phosphinyl)acetyl]piperidine-2(R)-carboxylic acid derivatives of Formula I prepared as described above in Scheme D may also be further functionalized into the corresponding 3(S)-[1-imino-2-phosponoethyl]piperidine-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Starting materials for use in Scheme D are readily available to one of ordinary skill in the art. The following examples present typical syntheses as described in Scheme D. These examples are intended to be illustrative only and are not intended to limit the scope of the present invention in any way. Example 3 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, methyl ester Step a: Pyridine-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-2,3-dicarboxylic acid (100g) in methanol (1.25L). Bubble in HCl gas until a solution is obtained. Reflux overnight, evaporate the solvent in vacuo and neutralize with saturated aqueous sodium hydrogen carbonate in ethyl acetate. Separate the organic phase, dry (MgSO₄) and evaporate the solvent in vacuo to give the title compound as a white solid (96.1g). ¹H NMR (90MHz, CDCl₃) ppm 8.6 (m, 1), 8.05 (m, 1), 7.4 (m, 1), 3.9 (s, 3), 3.8 (s, 3). Step b: d,l-cis -Piperidine-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-2,3-dicarboxylic acid, dimethyl ester (19g) in methanol (500mL) and treat with 20% palladium hydroxide/carbon (1.5g). Place on a Paar Hydrogenation Apparatus and hydrogenate at 50psi for 6 hours. Filter and evaporate the solvent in vacuo to give the title compound (14g). ¹H NMR (300MHz, CDCl₃) ppm 3.76 (s, 3), 3.70 (s, 3), 3.66 (d, 1), 3.06 (m, 1), 2.99 (m, 1), 2.7 (m, 1), 2.24-2.1 (m, 2), 1.79 (m, 1), 1.5 (m, 2). Step c: Piperidine-2(R),3(S)-dicarboxylic acid, dimethyl ester and Piperidine-2(S)-carboxylic acid-3(R)-carboxylic acid, monomethyl ester Dissolve d,l-cis -piperidine-2,3-dicarboxylic acid, dimethyl ester (75mg) in pH 7.4 phosphate buffer (1.5mL) and shake for 24 hours in the presence of porcine liver esterase. Evaporate to a residue, stir with ethyl acetate and filter. Evaporate the solvent in vacuo to give the title dimethyl ester compound. Alternatively, extract the residue with water and purify by ion-exchange chromatography to give the title monoester compound. Step d: N-(9-Phenylfluorenyl)piperidine-2(R),3(S)-dicarboxylic acid, dimethyl ester Dissolve piperidine-2(R),3(S)-dicarboxylic acid, dimethyl ester (5.0g, 24.8mmol) and diisopropylethylamine (3.5g, 41.8mmol) in acetonitrile (90mL) and add 4A molecular sieves. Add phenylfluorenyl bromide (8.8g, 27.3mmol) and lead nitrate (8.2g, 24.8mmol). Stir at room temperature under an argon atmosphere overnight. Add methylene chloride (150mL) and filter through celite. Wash the filtrate with saturated aqueous sodium hydrogen carbonate (2X) and saturated sodium chloride. Dry (MgSO₄), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane) to give the title compound. Step e: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, methyl ester Dissolve diethyl methylphosphonate (2.28g, 15mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (8mL of a 1.6M solution, 15mmol). Stir for 20 minutes at -78°C and add a solution of N-(9-phenylfluorenyl)piperidine-2(R),3(S)-dicarboxylic acid, dimethyl ester (2.21g, 5mmol) in anhydrous tetrahydrofuran (5mL). Stir for 1/2 hour at -78°C, quench with acetic acid (2mL) and warm to room temperature. Quench with water (50mL) and extract into ethyl acetate (100mL). Evaporate the solvent in vacuo to give a residue. Purify by silica gel chromatography to give the title compound. Step f: 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, methyl ester Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, methyl ester (1g) in acetonitrile (7mL) and water (1mL). Cool to 0°C and add, by dropwise addition, trifluoroacetic acid (7mL). Stir at 0°C for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10X100mL) and evaporate the solvent in vacuo to give the title compound. Example 4 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester and 3(R)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester Step a: Pyridine-4-methyl-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-4-methyl-2,3-dicarboxylic acid (100g) in methanol (1.25L). Bubble in HCl gas until a solution is obtained. Reflux overnight, evaporate the solvent in vacuo and neutralize with saturated aqueous sodium hydrogen carbonate in ethyl acetate. Separate the organic phase, dry (MgSO₄) and evaporate the solvent in vacuo to give the title compound. Step b: d,l-cis -Piperidine-4-methyl-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-4-methyl-2,3-dicarboxylic acid, dimethyl ester (19g) in methanol (500mL) and treat with 20% palladium hydroxide/carbon (1.5g). Place on a Paar Hydrogenation Apparatus and hydrogenate at 50psi for 6 hours. Filter and evaporate the solvent in vacuo to give the title compound. Step c: Piperidine-4-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester and Piperidine-4-methyl-2(R)-carboxylic acid-3(S)-carboxylic acid, monomethyl ester and Piperidine-4-methyl-2(S),3(R)-dicarboxylic acid, dimethyl ester and Piperidine-4-methyl-2(S)-carboxylic acid-3(R)-carboxylic acid, monomethyl ester Dissolve d,l-cis -piperidine-4-methyl-2,3-dicarboxylic acid, dimethyl ester (75mg) in pH 7.4 phosphate buffer (1.5mL) and shake for 24 hours in the presence of porcine liver esterase. Evaporate to a residue, stir with ethyl acetate and filter. Evaporate the solvent in vacuo to give the title diester compounds. Alternatively, extract the residue with water and purify by ion-exchange chromatography to give the title monoester compounds. Step d: N-(9-Phenylfluorenyl)piperidine-4-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester and N-(9-Phenylfluorenyl)piperidine-4-methyl-2(S),3(R)-dicarboxylic acid, dimethyl ester Dissolve the mixture of piperidine-4-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester and piperidine-4-methyl-2(S),3(R)-dicarboxylic acid, dimethyl ester (5.33g, 24.8mmol) and diisopropylethylamine (3.5g, 41.8mmol) in acetonitrile (90mL). Add phenylfluorenyl bromide (8.8g, 27.3mmol) and lead nitrate (8.2g, 24.8mmol). Stir at room temperature under an argon atmosphere overnight. Add methylene chloride (150mL) and filter through celite. Wash the filtrate with saturated aqueous sodium hydrogen carbonate (2X) and saturated sodium chloride. Dry (MgSO₄), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound. Step e: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester and N-(9-Phenylfluorenyl)-3(R)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester Dissolve diethyl methylphosphonate (2.28g, 15mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (8mL of a 1.6M solution, 15mmol). Stir for 20 minutes at -78°C and add a solution of the mixture of N-(9-phenylfluorenyl)piperidine-4-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester and N-(9-phenylfluorenyl)piperidine-4-methyl-2(S),3(R)-dicarboxylic acid, dimethyl ester (2.35g, 5mmol) in anhydrous tetrahydrofuran (5mL). Stir for 1/2 hour at -78°C, quench with acetic acid (2mL) and warm to room temperature. Quench with water (50mL) and extract into ethyl acetate (100mL). Evaporate the solvent in vacuo to give a residue. Purify by silica gel chromatography to give the title compounds. Step f: 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester and 3(R)-[(Diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester Dissolve the mixture of N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester and N-(9-phenylfluorenyl)-3(R)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester (1g) in acetonitrile (7mL) and water (1mL). Cool to 0°C and add, by dropwise addition, trifluoroacetic acid (7mL). Stir at 0°C for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10X100mL) and evaporate the solvent in vacuo to give the title compound. Example 5 3(S)-(Phosphonoacetyl)piperidine-4-methyl-2(R)-carboxylic acid and 3(R)-(Phosphonoacetyl]piperidine-4-methyl-2(S)-carboxylic acid Dissolve the mixture of 3(S)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(R)-carboxylic acid, methyl ester and 3(R)-[(diethoxyphosphinyl)acetyl]piperidine-4-methyl-2(S)-carboxylic acid, methyl ester (3g) in acetonitrile (20mL) and methylene chloride (20mL). Add trimethylsilyl iodide (3.5mL, 24mmol) and stir for 5 hours. Pour into water (250mL) and wash with toluene (3x250mL). Freeze dry the aqueous phase to give a solid residue. Take up the solid residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (2mL) and stir for 1 hour. Filter to give the title compound. Example 6 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester Step a: Pyridine-5-methyl-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-5-methyl-2,3-dicarboxylic acid (100g) in methanol (1.25L). Bubble in HCl gas until a solution is obtained. Reflux overnight, evaporate the solvent in vacuo and neutralize with saturated aqueous sodium hydrogen carbonate in ethyl acetate. Separate the organic phase, dry (MgSO₄) and evaporate the solvent in vacuo to give the title compound. Step b: d,l-cis -Piperidine-5-methyl-2,3-dicarboxylic acid, dimethyl ester Dissolve pyridine-5-methyl-2,3-dicarboxylic acid, dimethyl ester (19g) in methanol (500mL) and treat with 20% palladium hydroxide/carbon (1.5g). Place on a Paar Hydrogenation Apparatus and hydrogenate at 50psi for 6 hours. Filter and evaporate the solvent in vacuo to give the title compound. Step c: Piperidine-5-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester and Piperidine-5-methyl-2(R)-carboxylic acid-3(S)-carboxylic acid, monomethyl ester Dissolve d,l-cis -piperidine-5-methyl-2,3-dicarboxylic acid, dimethyl ester (75mg) in pH 7.4 phosphate buffer (1.5mL) and shake for 24 hours in the presence of porcine liver esterase. Evaporate to a residue, stir with ethyl acetate and filter. Evaporate the solvent in vacuo to give the title compound. Alternatively, extract the residue with water and purify by ion-exchange chromatography to give the title monoester compound. Step d: N-(9-Phenylfluorenyl)piperidine-5-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester Dissolve piperidine-5-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester (5.33g, 24.8mmol) and diisopropylethylamine (3.5g, 41.8mmol) in acetonitrile (90mL). Add phenylfluorenyl bromide (8.8g, 27.3mmol) and lead nitrate (8.2g, 24.8mmol). Stir at room temperature under an argon atmosphere overnight. Add methylene chloride (150mL) and filter through celite. Wash the filtrate with saturated aqueous sodium hydrogen carbonate (2X) and saturated sodium chloride. Dry (MgSO₄), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound. Step e: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester Dissolve diethyl methylphosphonate (2.28g, 15mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (8mL of a 1.6M solution, 15mmol). Stir for 20 minutes at -78°C and add a solution of N-(9-phenylfluorenyl)piperidine-5-methyl-2(R),3(S)-dicarboxylic acid, dimethyl ester (2.35g, 5mmol) in anhydrous tetrahydrofuran (5mL). Stir for 1/2 hour at -78°C, quench with acetic acid (2mL) and warm to room temperature. Quench with water (50mL) and extract into ethyl acetate (100mL). Evaporate the solvent in vacuo to give a residue. Purify by silica gel chromatography to give the title compound. Step f: 3(S)-[(Diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester (1g) in acetonitrile (7mL) and water (1mL). Cool to 0°C and add, by dropwise addition, trifluoroacetic acid (7mL). Stir at 0°C for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10X100mL) and evaporate the solvent in vacuo to give the title compound. Example 7 3(S)-(Phosphonoacetyl)piperidine-5-methyl-2(R)-carboxylic acid Dissolve 3(S)-[(diethoxyphosphinyl)acetyl]piperidine-5-methyl-2(R)-carboxylic acid, methyl ester (3g) in acetonitrile (20mL) and methylene chloride (20mL). Add trimethylsilyl iodide (3.5mL, 24mmol) and stir for 5 hours. Pour into water (250mL) and wash with toluene (3X250mL). Freeze dry the aqueous phase to give a solid residue. Take up the solid residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (2mL) and stir for 1 hour. Filter and dry to give the title compound. An alternative synthetic procedure for preparing the d,l-cis or the enatiomerically pure 2(R),3(S) and 2(S),3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen is described in Scheme E. In Scheme E all substituents unless otherwise indicated are as previously defined. R₂'' = -CH₃ or -CH₂CH₃ R₁' = C₁-C₄ alkyl or CF₃ Scheme E provides an alternative general synthetic procedure for preparing the d,l-cis or the enatiomerically pure 2(R),3(S) and 2(S),3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen. In step a, the appropriate d,l-cis -piperidine-2,3-dicarboxylic acid, diester derivative of structure (19) is protected to give the corresponding d,l-cis -N-protected-piperidine-2,3-dicarboxylic acid, diester derivative of structure (24) as described previously in Scheme A, step b. In step b, the appropriate d,l-cis -N-protected-piperidine-2,3-dicarboxylic acid, diester derivative of structure (24) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding d,l-cis -N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ester of structure (25) as described previously in Scheme A, step d. In step c, the appropriate d,l-cis -N-protected-3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ester of structure (25) is deprotected to give the corresponding d,l-cis -3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ester of structure (26) as described previously in Scheme A, step f. In optional step d, the appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ester of structure (26) is separated to give the corresponding 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid of structure (27) and the 3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(S)-carboxylic acid, ester of structure (23b) as described previously in Scheme D, step c. The appropriate 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid of structure (27) can be further functionalized as described previously in Scheme A, steps g₁ and steps h₁-i. The appropriate 3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(S)-carboxylic acid, ester of structure (23b) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate d , l - cis -3-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivatives, 3(S)-[(functionalized phosphinyl)acetyl]piperidine-2(R)-carboxylic acid derivatives and 3(R)-[(functionalized phosphinyl)acetyl]piperidine-2(S)-carboxylic acid derivatives of Formula I prepared as described above in Scheme E may also be further functionalized into the corresponding d , l - cis -3-[(1-imino-2-phosponoethyl]piperidine-2-carboxylic acid derivatives, 3(S)-[1-imino-2-phosponoethyl]piperidine-2(R)-carboxylic acid derivatives and 3(R)-[1-imino-2-phosponoethyl]piperidine-2(S)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Starting materials for use in Scheme E are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme E. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 8 d , l - cis -3-[(Diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, methyl ester Step a: d , l - cis -N-(9-Phenylfluorenyl)piperidine-2,3-dicarboxylic acid, diethyl ester Dissolve d , l - cis -piperidine-2,3-dicarboxylic acid, diethyl ester (5.0g, 24.8mmol) and diisopropylethylamine (3.5g, 41.8mmol) in acetonitrile (90mL). Add phenylfluorenyl bromide (8.8g, 27.3mmol) and lead nitrate (8.2g, 24.8mmol). Stir at room temperature under an argon atmosphere overnight. Add methylene chloride (150mL) and filter through celite. Wash the filtrate with saturated aqueous sodium hydrogen carbonate (2X) and saturated sodium chloride. Dry (MgSO₄) and evaporate the solvent in vacuo to give 12.5g red foam. Purify by silica gel chromatography (9:1 hexane/ethyl ether to 7:3 hexane/ethyl ether) to give the title compound as a white solid (8.7g); mp 177-177.5°C (hexane/ethyl ether). Step b: d , l - cis -N-(9-Phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ethyl ester Dissolve diethyl methylphosphonate (2.28g, 15mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (8mL of a 1.6M solution, 15mmol). Stir for 20 minutes at -78°C and add a solution of d , l - cis -N-(9-phenylfluorenyl)piperidine-2,3-dicarboxylic acid, diethyl ester (2.21g, 5mmol) in anhydrous tetrahydrofuran (5mL). Stir for 1/2 hour at -78°C, quench with acetic acid (2mL) and warm to room temperature. Quench with water (50mL) and extract into ethyl acetate (100mL). Evaporate the solvent in vacuo to give a residue. Recrystallize the residue (ethyl acetate) to give 0.8g of a white solid. Purify by silica gel chromatography (ethyl acetate) to give the title compound (0.5g). ¹H NMR (300MHz, CDCl₃) ppm 7.69 (dd, 2), 7.15-7.45 (m, 9), 4.1 (m, 4), 3.78 (d, ?), 3.49 (dt, 1), 2.95-3.3 (m, 4), 2.85 (s, 3), 1.7-2.15 (m, 4), 1.3 (m, 6). Step c: d,l-cis -3-[(Diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ethyl ester Dissolve d,l-cis -N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid, ethyl ester (1g) in acetonitrile (7mL) and water (1mL). Cool to 0°C and add, by dropwise addition, trifluoroacetic acid (7mL). Stir at 0°C for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10X100mL) and evaporate the solvent in vacuo to give the title compound. ¹H NMR (300MHz, CDCl₃) ppm 4.15 (m, 4), 3.71 (m, 1), 3.69 (s, 3), 2.9-3.4 (m, 4), 2.70 (m, 1), 1.9-2.2 (m, 4), 1.5 (m, 2), 1.32 (m, 6). An alternative synthetic procedure for preparing the enantiomerically pure 2(R),3(S) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen is set forth in scheme F. In Scheme F, all substituents unless otherwise indicated are as previously defined. R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl Scheme F provides an alternative general synthetic procedure for preparing the enantiomerically pure 2(R),3(S) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen. In step a, D-aspartic acid (28) is protected to give the corresponding β-methyl-D-aspartate (29) as described previously in Scheme D, step a. In step b, β-methyl-D-aspartate (29) is protected to give the corresponding α-C₁-C₄ alkyl or benzyl-β-methyl-D-aspartate acetic acid of structure (30) with the tert -butyl ester being preferred. For example, β-methyl-D-aspartate (29) is contacted with a molar excess of tert -butyl acetate and a slight molar excess of an appropriate acid such as perchloric acid. The reactants are typically stirred together at room temperature for a period of time ranging from 1-24 hours. The α- tert -butyl-β-methyl-D-aspartate acetic acid of structure (30) is recovered from the reaction zone by extractive methods as is known in the art. In step c, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-D-aspartate acetic acid of structure (30) is alkylated with the appropriate 1-bromo-3-chloropropane of structure (31) to give the corresponding α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-D-aspartate of structure (32). For example, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-D-aspartate acetic acid of structure (30) is contacted with a molar equivalent of an appropriate 1-bromo-3-chloropropane of structure (31) and a molar excess of an appropriate base such as triethylamine. The reactants are typically contacted in a suitable organic solvent such as acetonitrile. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to 80°C. The α-C₁-c₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-D-aspartate of structure (32) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography. The appropriate 1-bromo-3-chloropropane of structure (31) is one in which R₃ is the same as is desired in the final product. In step d, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-D-aspartate of structure (32) is protected to give the corresponding α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (33) as described previously in Scheme A, step b. In step e, the chloride functionality of the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (33) is exchanged to give the corresponding α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34). For example, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-chloropropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (33) is contacted with a molar excess of an iodide source, such as sodium iodide. The reactants are typically contacted in a suitable organic solvent such as acetonitrile. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to 65°C. The α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by recrystallization. In step f, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is cyclized to give the corresponding N-protected-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (35). For example, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is contacted with an appropriate base such as lithium diisopropylamine. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 2-20 hours and at a temperature range of from -78°C to -20°C. The N-protected-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (35) is recovered from the reaction zone by a low-temperature quench into an appropriate proton source, such as diisopropyl phenol, followed by acidification and extraction as is known in the art. It may be purified by silica gel chromatography. In step g, the appropriate N-(9-phenylfluorenyl)piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (35) is coupled with an appropriate phosphonate ester of structure (5) to give the corresponding N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (36) as described previously in Scheme A, step d. In step h, the appropriate N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (36) is deprotected to give the corresponding 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (37) as described previously in Scheme A, step f. The appropriate 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (37) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3(S)-[(functionalized phosphinyl)acetyl]piperidine-2(R)-carboxylic acid derivatives of Formula I prepared as described above in Scheme F may also be further functionalized into the corresponding 3(S)-[1-imino-2-phosponoethyl]piperidine-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Alternatively, the enantiomerically pure 2(S),3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). Starting materials for use in Scheme F are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme F. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 9 3(S)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid Step a: β-Methyl-D-aspartate hydrochloride Cool methanol (525mL) to -20°C and place under an atmosphere of nitrogen. Add, by dropwise addition, thionyl chloride (80mL). Add D-aspartic acid (100g, 0.75mol) in one portion and allow the reaction to warm to room temperature over approximately 1 hour. Stir for 50 minutes at room temperature and pour into anhydrous ethyl ether (1.5L). Filter the resulting solid, dissolve partly in warm ethanol (500mL) and filter again. Add the filtrate to ethyl ether (1.5L) and filter the resulting solid. Dry to give the title compound (85.3g, 62%). ¹H NMR (300MHz, CDCl₃) ppm 4.22 (t, 1), 3.67 (s, 3), 2.96 (dd, 2). Step b: α- tert -Butyl-β-methyl-D-aspartate acetic acid Suspend β-methyl-D-aspartate hydrochloride (40g, 0.22mol) in tert -butyl acetate (1.5L) and add perchloric acid (20.7mL of a 20% solution, 0.24mol). Stir at room temperature under an atmosphere of argon for 3 hours. Pour into saturated sodium hydrogen carbonate and add solid sodium hydrogen carbonate until the mixture is basic. Add ethyl ether and separate the organic phase. Extract the aqueous phase with ethyl ether, combine the organic phases and dry (MgSO₄). Evaporate the solvent in vacuo to give the title compound as a clear oil (34g). ¹H NMR (300MHz, CDCl₃) ppm 5.64 (bs, 3), 3.78 (dd, 1), 3.76 (s, 3), 2.8 (m, 2), 2.04 (s, 3), 1.46 (s, 9). Step c: α- tert -Butyl-β-methyl-N-(3-chloropropyl)-D-aspartate Mix α- tert -butyl-β-methyl-D-aspartate acetic acid (36g, 0.196mol), 1-bromo-3-chloropropane (90g), triethylamine (40g) and acetonitrile (150mL). Heat at 80°C and stir for 16 hours. Evaporate the solvent to give a residue. Take up the residue in ethyl acetate (250mL) and wash with brine (100mL), saturated sodium hydrogen carbonate (100mL) and brine (100mL). Dry (Na₂SO₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (1:1 ethyl acetate/hexane) to give the title compound (32g). ¹H NMR (90MHz, CDCl₃) ppm 3.74 (s, 3), 3.6 (m, 2), 2.8 (m, 1), 2.65 (m, 2), 1.9 (m, 2), 1.5 (s, 9). Step d: α- tert -Butyl-β-methyl-N-(3-chloropropyl)-N-(9-phenylfluorenyl )-D-aspartate Add α- tert -butyl-β-methyl-N-(3-chloropropyl)-D-aspartate 24.8g, 88.6mmol) to anhydrous acetonitrile (150mL) and place under a nitrogen atmosphere. Stir vigorously and add lead nitrate (24.8g, 74.8mmol). Simultaneously add, by dropwise addition over 5 hours, a solution of 9-phenylfluorenyl bromide (32g, 99.6mmol) in chloroform (100mL) and a solution of diisopropylethylamine (20.4mL, 117mmol) in acetonitrile. Stir overnight at room temperature. Add methylene chloride (250mL), filter and add methylene chloride (300mL) to the filtrate. Wash with saturated sodium hydrogen carbonate (2X250mL), brine (1X250mL) and saturated sodium hydrogen carbonate (1X250mL). Dry (Na₂SO₄) and evaporate to a residue. Purify by silica gel chromatography (10% hexane in methylene chloride) to give the title compound (26g). ¹H NMR (300MHz, CDCl₃) ppm 7.2-7.7 (m, 13), 3.79 (dd, 1), 3.6-3.4 (m, 2), 3.48 (s, 3), 3.2 (m, 1), 2185 (m, 1), 2.62 (dd, 1), 1.85-2.1 (m, 2), 1.8 (m, dd), 1.43 (s, 9). Step e: α- tert -Butyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate Mix α- tert -butyl-β-methyl-N-(3-chloropropyl)-N-(9-phenylfluorenyl)-D-aspartate (26g, 0.05mol), sodium iodide (50g) and anhydrous acetonitrile (250mL). Place under a nitrogen atmosphere and stir at 65°C for 16 hours. Cool and add methylene chloride (250mL). Filter and evaporate the solvent to a residue. Take up the residue in methylene chloride (300mL), wash with water (100mL), 5% sodiumthiosulphate (100mL), water (100mL) and brine (100mL). Dry (Na₂SO₄) and evaporate to a residue. Recrystallize (ethyl ether) to give the title compound (21.5g). ¹H NMR (300MHz, CDCl₃) ppm 7.2-7.8 (m, 13), 3.79 (dd, 1), 3.48 (s, 3), 2.95-3.2 (m, 3), 2.88 (m, 1), 1.8-2.3 (m, 2), 1.79 (dd, 1), 1.43 (s, 9). Step f: N-(9-Phenylfluorenyl)piperidine-2(R)- tert -butyl-3(S)-methyl ester Dissolve diisopropylamine (12mL, 85.6mmol) in anhydrous tetrahydrofuran, cool to -78°C and place under an inert atmosphere. Add n-butyllithium (52mL of a 1.6M solution in hexane, 83.2mmol) and stir at -78°C for 20 minutes. Add, by dropwise addition, a solution of α- tert -butyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate (20g, 32.7mmol) in anhydrous tetrahydrofuran (50mL). Stir at -78°C for 1 hour, warm to -38°C and stir for 3 hours. Cool to -78°C and transfer via cannula to a -78°C solution of diisopropyl phenol (30.8g, 0.17mol) in tetrahydrofuran (200mL). Stir for 1 hour and add add acetic acid (5.2mL). Warm to room temperature and quench with water (100mL). Partition between methylene chloride (500mL) and water (300mL). Separate the organic phase, dry (Na₂SO₄) and evaporate to a residue. Purify by silica gel chromatography (10% hexane in methylene chloride) to give the title compound (13.8g). ¹H NMR (CDCl₃) ppm 7.2-7.8 (m, 13), 3.82 (d, 1), 3.69 (td, 1), 3.55 (s, 3), 3.11 (m, 1), 2.91 (m, 1), 2.08 (m, 1), 1.6-1.9 (m, 2), 1.31 (m, 1), 1.03 (m, 9). Step g: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (0.57g) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (2.34mL of a 1.6M solution). Stir for 20 minutes at -78°C and add a solution of N-(9-phenylfluorenyl)piperidine-2(R)- tert -butyl-3(S)-methyl ester (0.6g, 1.24mmol) in anhydrous tetrahydrofuran (10mL). Stir for 2 hours at -78°C, quench with acetic acid (1mL) and warm to room temperature. Pour into ethyl acetate (100mL) and wash with brine (100mL) and aqueous sodium hydrogen carbonate (100mL). Evaporate to a residue and purify by silica gel chromatography (ethyl acetate) to give the title compound (0.45g). ¹H NMR (300MHz, CDCl₃) ppm 7.2-7.8 (m, 13), 4.13 (m, 4), 3.79 (d, 1), 3.73 (m, 1), 3.23 (m, 1), 3.09 (m, 1), 3.03 (dd, 1). Step h: 3(S)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid Mix trifluoroacetic acid (30mL) with acetonitrile (10mL) and add, by dropwise addition, to an ice-cold solution of N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert -butyl ester (3.5g, 5.8mmol) in acetonitrile (40mL) and water (4mL). Stir for 15 minutes, warm to room temperature and stir for an additional hour. Pour into saturated aqueous sodium hydrogen carbonate (500mL) and extract into ethyl acetate (3X200mL). Evaporate to a residue and take up the residue in acetonitrile (20mL) and methylene chloride (20mL). Place under a nitrogen atmosphere and add trimethylsilyl chloride (5mL, 35mmol). Stir overnight then add water. Stir for 15 minutes then blow to a residue with a stream of dry nitrogen. Take up the residue in water (100mL) and wash with toluene (5X100mL). Freeze dry to give a residue. Take up the residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (5mL) and filter to give the title compound. ¹H NMR (300MHz, D₂O) ppm 3.88 (d, 1), 3.73 (m, 1), 3.41 (m, 1), 3.14 (dd, 2), 3.01 (m, 1), 2.87 (m, 1), 1.98 (m, 1), 1.82 (m, 1), 1.55 (m, 1). The following compounds can be prepared in a similar fashion to that described above in Example 9 : 3(S)-(Phosphonoacetyl)piperidine-5-methyl-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)piperidine-5-benzyl-2(R)-carboxylic acid. An alternative synthetic procedure for preparing the enatiomerically pure 2(R), 3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen is set forth in Scheme G. In Scheme G, all substituents unless otherwise indicated are as previously defined. R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl Scheme G provides an alternative synthetic procedure for preparing the enatiomerically pure 2(R), 3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen. In step a, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is cyclized to give the corresponding N-(9-phenylfluorenyl)-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(R)-methyl ester of structure (38) as described previously in Scheme F, step f. In step b, the appropriate N-(9-phenylfluorenyl)piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(R)-methyl ester of structure (38) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding N-(9-phenylfluorenyl)-3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (39) as described previously in Scheme A, step d. In step c, the appropriate N-(9-phenylfluorenyl)-3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (39) is deprotected to give the corresponding 3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (40) as described previously in Scheme A, step f. The appropriate 3(R)-[(dialkoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (40) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3(R)-[(functionalized phosphinyl)acetyl]piperidine-2-carboxylic acid derivatives of Formula I prepared as described above in Scheme G may also be further functionalized into the corresponding 3(R)-[1-imino-2-phosponoethyl]piperidine-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Alternatively, the enantiomerically pure 2(S),3(S) saturated piperidine compounds of Formula I wherein R₅ is represented by hydrogen can be prepared as set forth in Scheme G by substituting α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate for α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34). The appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). Starting materials for use in Scheme G are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme G. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 10 3(R)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid, methyl ester Step a: N-(9-Phenylfluorenyl)piperidine-2(R)- tert -butyl-3(R)-methyl ester Dissolve diisopropylamine (0.6mL, 4.3mmol) in tetrahydrofuran (10mL) and cool to 0°C. Add, by dropwise addition, n-butyllithium (2.7mL of a 1.6M solution, 4.3mmol). Stir for 1/2 hour, cool to -78°C and add, by dropwise addition, a solution of α- tert -butyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate (1g, 1.6mmol) in tetrahydrofuran (10mL). Stir for 1 hour at -78°C and then for 3 hours at -30°C. Transfer rapidly, via water heated cannula, to a -78°C solution of acetic acid in tetrahydrofuran (10mL). Allow to warm to room temperature overnight. Add ethyl acetate and wash with brine. Evaporate to a residue and purify by silica gel chromatography (50:50 to 75:25 methylene chloride/hexane) to give the title compound (0.35g). Step b: N-(9-Phenylfluorenyl)-3(R)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (0.3g) in anhydrous tetrahydrofuran, cool to -78°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (1.16mL of a 1.6M solution). Stir for 1/2 hour at -78°C and add a solution of N-(9-phenylfluorenyl)piperidine-2(R)- tert -butyl-3(R)-methyl ester (0.3g, 0.62mmol) in anhydrous tetrahydrofuran (10mL). Allow to warm to -30°C and stir for 3 hours, then cool to -78°C and quench with acetic acid. Warm to room temperature, pour into ethyl ether (250mL) and wash with brine (100mL). Dry (Na₂SO₄) and evaporate to a residue. Purify by silica gel chromatography (ethyl acetate) to give the title compound (0.3g). ¹H NMR (300MHz, CDCl₃) ppm 7.15-7.75 (m, 13), 4.15 (m, 4), 3.79 (m, 1), 3.73 (m, 1), 3.05-3.2 (m, 3), 2.72 (m, 1), 1.75-2.05 (m, 3), 1.55 (m, 1), 1.35 (m, 7), 1.04 (s, 9). Step c: 3(R)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid, methyl ester Mix trifluoroacetic acid (30mL) with acetonitrile (10mL) and add, by dropwise addition, to an ice-cold solution of N-(9-phenylfluorenyl)-3(R)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert -butyl ester (3.5g, 5.8mmol) in acetonitrile (40mL) and water (4mL). Stir for 15 minutes, warm to room temperature and stir for an additional hour. Pour into saturated aqueous sodium hydrogen carbonate (500mL) and extract into ethyl acetate (3X200mL). Evaporate to a residue and take up the residue in acetonitrile (20mL) and methylene chloride (20mL). Place under a nitrogen atmosphere and add trimethylsilyl chloride (5mL, 35mmol). Stir overnight then add water. Stir for 15 minutes then blow to a residue with a stream of dry nitrogen. Take up the residue in water (100mL) and wash with toluene (5X100mL). Freeze dry to give a residue. Take up the residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (5mL) and filter to give the title compound. The 2(R),3(S) saturated piperidine compounds of Formula I wherein R₅ is represented by linear C₁-C₄ alkyl, or phenylalkyl can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme H. In Scheme H all substituents unless otherwise indicated are as previously defined. R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl Scheme H provides a general synthetic procedure for preparing the 2(R),3(S) saturated piperidine compounds of Formula I wherein R₅ is represented by linear C₁-C₄ alkyl, or phenylalkyl. In step a, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is alkylatively cyclized with the appropriate alkylating agent of the formula R₅-Hal, wherein Hal is Br or I, to give the corresponding N-(9-phenylfluorenyl)piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(R)-alkyl-3(S)-methyl ester of structure (41). The appropriate alkylating agent of the formula R₅-Hal, wherein Hal is Br or I is one in which R₅ is the same as 15 desired in the final product. For example, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is contacted with an appropriate base such as lithium diisopropylamine. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 2-20 hours and at a temperature range of from -78°C to -20°C. The N-(9-phenylfluorenyl)piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3(R)-alkyl-3(S)-methyl ester of structure (41) is recovered from the reaction zone by a low-temperature quench into an appropriate alkylating agent of the formula R₅-Hal, followed by acidification and extraction as is known in the art. It may be purified by silica gel chromatography. In step b, the appropriate N-(9-phenylfluorenyl)piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(R)-alkyl-3(S)-methyl ester of structure (41) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-3(R)-alkyl-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (42) as described previously in Scheme A, step d. In step c, the appropriate N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-3(R)-alkyl-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (42) is deprotected to give the corresponding 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-3(R)-alkyl-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (43). The appropriate 3(S)-[(dialkoxyphosphinyl)acetyl]piperidine-3(R) -alkyl-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (43) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3(S)-[(functionalized phosphinyl)acetyl]piperidine-3(R)-alkyl-2(R)-carboxylic acid derivatives of Formula I prepared as described above in Scheme H may also be further functionalized into the corresponding 3(S)-[1-imino-2-phosponoethyl]piperidine-3(R)-alkyl-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Alternatively, the enantiomerically pure 2(S),3(R) saturated piperidine compounds of Formula I wherein R₅ is represented by linear C₁-C₄ alkyl, or phenylalkyl can be prepared as set forth in Scheme H by substituting the appropriate N-(9-phenylfluorenyl)piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3(R)-methyl ester for the appropriate N-(9-phenylfluorenyl)piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (35). The appropriate N-(9-phenylfluorenyl)piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3(R)-methyl ester can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). Starting materials for use in Scheme H are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme H. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 11 3(S)-(Phosphonoacetyl)piperidine-3(R)-methyl-2(R)-carboxylic acid Step a: N-(9-Phenylfluorenyl)piperidine-3(R)-methyl-2(R)- tert -butyl ester-3(S)-methyl ester Dissolve diisopropylamine (0.73mL) in anhydrous tetrahydrofuran (10mL), cool to 0°C and place under an inert atmosphere. Add, by dropwise addition, n-butyllithium (3.11mL of a 1.6M solution in hexane) and stir for 15 minutes at 0°C then at -78°C for 15 minutes. Add, by dropwise addition, a solution of α- tert -butyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate (1.22g) in anhydrous tetrahydrofuran (10mL). Stir for 1 hour at -78°C then at -38°C for 3 hours. Cool to -78°C and add via cannula to a solution of iodomethane (3mL) in tetrahydrofuran (10mL). Stir at -78°C for 3 hours, quench with acetic acid and warm to room temperature. Evaporate to a residue and purify by silica gel chromatography (methylene chloride) to give impure title compound. Dissolve diisopropylamine (0.35mL, 2.5mmol) in anhydrous tetrahydrofuran, cool to 0°C and place under an inert atmosphere. Add, by dropwise addition, n-butyllithium (1.4mL of a 1.6M solution in hexane, 2.5mmol) and stir for 1/2 hour at 0°C. Cool to -78°C and add hexamethylphosphoramide (0.43mL, 2.5mmol) followed by a solution of N-(9-phenylfluorenyl)piperidine-2(S)- tert -butyl ester-3(S)-methyl ester (0.8g, 1.7mmol) in anhydrous tetrahydrofuran (5mL). Stir for 1/2 hour and add iodomethane (0.42mL, 6.8mmol). Stir at -78°C overnight, quench with actic acid and warm to room temperature. Evaporate to a residue and purify by silica gel chromatography (80:20/methylene chloride/hexane) to give the title compound (0.56g). ¹H NMR (300MHz, CDCl₃) ppm 7.18-7.75 (m, 13), 3.93 (s, 1), 3.88 (s, 3), 3.82 (m, 1), 3.08 (m, 1), 2.59 (m, 1), 2.14 (m, 1), 1.98 (m, 1), 1.78 (m, 1), 1.62 (m, 1), 1.08 (s, 9). Step b: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-3(R)-methyl-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosponate (1.14g, 7.5mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an inert atmosphere. Add n-butyllithium (4.68mL of a 1.6M solution in hexane, 7.5mmol) and stir for 20 minutes. Add, by dropwise addition, a solution of N-(9-phenylfluorenyl)piperidine-3(R)-methyl-2(R)- tert -butyl ester-3(S)-methyl ester (0.55g, 1.1mmol) in anhydrous tetrahydrofuran (10mL). Stir for 4 hours at -48°C and add acetic acid (2mL). Warm to room temperature, evaporate to a residue and purify by silica gel chromatography (ethyl acetate) to give the title compound (0.33g). ¹H NMR (300MHz, CDCl₃) ppm 7.18-8.75 (m, 13), 4.10 (m, 4), 3.54 (m, 1), 3.51 (s, 1), 3.15 (m, 1), 2.99 (m, 2), 2.48 (m, 1), 1.98 (m, 1), 1.29 (m, 6), 0.92 (s, 9). Step c: 3(S)-(Phosphonoacetyl)piperidine-3(R)-methyl-2(R)-carboxylic acid Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-3(R)-methyl-2(R)-carboxylic acid, tert -butyl ester (0.35g) in acetonitrile and cool to 0°C. Stir vigorously and add, by dropwise addition, a solution of trifluoroacetic acid (20mL) in water (2mL). Stir for 15 minutes, warm to room temperature and stir for 3 hours. Evaporate to a solid residue, take up in water (100mL) and wash with toluene (100mL). Freeze dry the aqueous phase to give a white solid. Take up the white solid in acetonitrile (10mL) and methylene chloride (10mL). Pass a gentle stream of nitrogen through the solution and add trimethylsilyliodide (2mL). Stir for 6 hours, quench with water and wash with toluene (5X100mL). Freeze dry the aqueous phase and dissolve the resulting yellow solid in methanol (5mL) and isopropanol (2.5mL). Add propylene oxide (2.0mL) and stir for 2 hours. Filter to give the title compound. ¹H NMR (300MHz, D₂O) ppm, 3.69 (s, 1), 3.32 (m, 1), 2.9 (m, 1), 2.28 (m, 1), 1.4-1.8 (m, 3), 1.53 (s, 3). The following compound can be prepared in a similar fashion to that described above in Example 11 : 3(S)-(Phosphonoacetyl)piperidine-5-benzyl-3(R)-methyl-2(R)-carboxylic acid. The 2(R)-3-unsaturated piperidine compounds of Formula I can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme I. In Scheme I all substituents unless otherwise indicated are as previously defined. X = I, -SeC₆H₅ R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl Scheme I provides a general synthetic procedure for preparing the 2(R)-3-unsaturated piperidine compounds of Formula I. In step a, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is cyclized and either iodinated or selenated to give the corresponding N-(9-phenylfluorenyl)piperidine-3(R)-iodo-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) or N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44). For example, the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34) is contacted with an appropriate base such as lithium diisopropylamine. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 2-20 hours and at a temperature range of from -78°C to -20°C. The N-(9-phenylfluorenyl)piperidine-3(R)-iodo-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) or N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) is recovered from the reaction zone by a low-temperature quench into iodine or diphenyldiselenide, followed by acidification and extraction as is known in the art. It may be purified by silica gel chromatography. When N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) is prepared in step a, the selenyl functionality must be subsequently oxidized by techniques well known in the art to give the corresponding N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenoxyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester before continuing with step b. In step b, the appropriate N-(9-phenylfluorenyl)piperidine-3(R)-iodo-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) or N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenoxyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester is eliminated to give the corresponding N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45). For example, the appropriate N-(9-phenylfluorenyl)piperidine-3(R)-iodo-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester of structure (44) or N-(9-phenylfluorenyl)piperidine-3(R)-phenylselenoxyl-2(R)-C₁-C₄ alkyl or benzyl ester-3(S)-methyl ester is contacted with a molar excess of a strong base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reactants are typically contacted in a suitable organic solvent such as benzene. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to 80°C. The N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography. In step c, the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (46) as described previously in Scheme A, step d. In step d, the appropriate N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (46) is deprotected to give the corresponding 3-[(dialkoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (47) as described previously in Scheme A, step f. The appropriate 3-[(dialkoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (47) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3-[(functionalized phosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid derivatives of Formula I prepared as described above in Scheme H may also be further functionalized into the corresponding 3-[1-imino-2-phosponoethyl]-Δ3-piperidine-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Alternatively, the enantiomerically pure 2(S)-3-unsaturated piperidine compounds of Formula I can be prepared as set forth in Scheme I by substituting the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate for the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34). The appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). Starting materials for use in Scheme I are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme I. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 12 3-(Phosphonoacetyl)-3-piperidene-2(R)-carboxylic acid Step a: N-(9-Phenylfluorenyl)piperidine-3(R)-iodo-2(R)- t ert -butyl ester-3(S)-methyl ester Dissolve diisopropylamine (2.4mL, 17.12mmol) in anhydrous tetrahydrofuran (80mL), cool to 0-5°C and place under an inert atmosphere. Add n-butyllithium (10.5mL of a 1.6M solution in hexane, 16.8mmol) and cool to -70 to -75°C. Add a solution of α- tert -butyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate (4.0g, 6.54mmol) in tetrahydrofuran (10mL). Stir at -78°C for 1 hour, then warm to -35°C and stir for 3-4 hours to give the enolate. Dissolve iodine (2.5g, 9.85mmol) in tetrahydrofuran (30mL) and cool to -78°C. Add the -40°C solution of the enolate and stir overnight, slowly warming to room temperature. Add phosphoric acid (20mL of a 0.5M solution) and extract into ethyl ether (3X20mL). Combine the organic phases and wash with saturated sodium thiosulfate (10mL) and saturated sodium hydrogen carbonate (20mL). Dry (MgSO₄/Na₂SO₄) and evaporate the solvent in vacuo to give the title compound (3.99g). ¹H NMR (300MHz, CDCl₃) ppm 7.1-1.9 (m, 13), 4.01 (s, 1), 3.75 (m, 1), 3.65 (s, 3), 3.28 (m, 1), 3.18 (m, 1), 2.2-2.4 (m, 1), 1.8 (m, 1), 1.3 (m, 1), 0.9 (s, 9). Step b: N-(9-Phenylfluorenyl)-Δ3-piperidine-2(R)- tert -butyl ester-3-methyl ester Mix N-(9-phenylfluorenyl)piperidine-3(R)-iodo-2(R)- tert -butyl ester-3(S)-methyl ester (3.99g, 6.55mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.9mL, 19.62mmol) and benzene (8.5mL). Heat to 65°C fo several hours. Add phosphoric acid (50mL of a 0.5M solution) and extract into ethyl ether (4X20mL). Dry (MgSO₄/Na₂SO₄), evaporate the solvent in vacuo and purify by silica gel chromatography (30/70 ethyl ether/hexane) to give the title compound. ¹H NMR (300MHz, CDCl₃) ppm 7.15-7.75 (m, 13), 6.98 (m, 1), 4.51 (s, 1), 3.68 (s, 3), 3.38 (m, 1), 3.05 (m, 1), 1.89 (m, 2), 1.2 (s, 9). Step c: N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (1.14g, 7.5mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an inert atmosphere. Add n-butyllithium (4.68mL of a 1.6M solution in hexane, 7.5mmol) and stir for 20 minutes. Add, by dropwise addition, a solution of N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)- tert -butyl ester-3-methyl ester (545mg, 1.1mmol) in anhydrous tetrahydrofuran (10mL). Stir for 4 hours at -48°C and add acetic acid (2mL). Warm to room temperature, evaporate to a residue and purify by silica gel chromatography (ethyl acetate) to give the title compound. Step d: 3-(Phosphonoacetyl)-Δ3-piperidine-2(R)-carboxylic acid Dissolve N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]-Δ3-piperidine-2(R)-carboxylic acid, tert -butyl ester (0.35g) in acetonitrile and cool to 0°C. Stir vigorously and add, by dropwise addition, a solution of trifluoroacetic acid (20mL) in water (2mL). Stir for 15 minutes, warm to room temperature and stir for 3 hours. Evaporate to a solid residue, take up in water (100mL) and wash with toluene (100mL). Freeze dry the aqueous phase to give a residue. Take up the residue in acetonitrile (10mL) and methylene chloride (10mL). Pass a gentle stream of nitrogen through the solution and add trimethylsilyliodide (2mL). Stir for 6 hours, quench with water and wash with toluene (5X100mL). Freeze dry the aqueous phase and dissolve the resulting residue in methanol (5mL) and isopropanol (2.5mL). Add propylene oxide (2.0mL) and stir for 2 hours. Filter to give the title compound. The following compound can be prepared in a similar fashion to that described above in Example 12 : 3-(Phosphonoacetyl)-Δ3-piperidine-5-methyl-2(R)-carboxylic acid. The 2(R), 3(S)-4-unsaturated piperidine compounds of Formula I can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme J. In Scheme J all substituents unless otherwise indicated are as previously defined. Scheme J provides a general synthetic scheme for preparing the 2(R), 3(S)-4-unsaturated piperidine compounds of Formula I. In step a, the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) undergoes a deconjugative alkylation to give the corresponding N-(9-phenylfluorenyl)-Δ4-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (48). For example, the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) is contacted with a strong base, such as n-butyllithium. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 1-10 hours and at a temperature range of from -78°C to -20°C. The N-(9-phenylfluorenyl)-Δ4-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (48) is recovered from the reaction zone by a low-temperature quench into an appropriate alkylating agent of the formula R₅-Hal or a proton source such as diisopropyl phenol, followed by acidification and extraction as is known in the art. It may be purified by silica gel chromatography. In step b, the appropriate N-(9-phenylfluorenyl)-Δ4-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (48) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (49) as described previously in Scheme A, step d. In step c, the appropriate N-(9-phenylfluorenyl)-3(S)-[(dialkoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (49) is deprotected to give the corresponding 3(S)-[(dialkoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (50) as described previously in Scheme A, step f. The appropriate 3(S)-[(dialkoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, benzyl or C₁-C₄ alkyl ester of structure (50) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3(S)-[(functionalized phosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid derivatives of Formula I prepared as described above in Scheme J may also be further functionalized into the corresponding 3(S)-[1-imino-2-phosponoethyl]-Δ4-piperidine-2(R)-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Alternatively, the enantiomerically pure the 2(S), 3(R)-4-unsaturated piperidine compounds of Formula I can be prepared as set forth in Scheme J by substituting the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3-methyl ester for the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45). The appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3-methyl ester can be prepared as set forth in Scheme I by substituting the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate for the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34). The appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-L-aspartate can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). In addition, the enantiomerically pure 2(R), 3(R)-4-unsaturated piperidine compounds of Formula I can be prepared as set forth in Scheme J by substituting the appropriate N-(benzyloxycarbonyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester for the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) followed by an HPLC separation as set forth in Scheme B. Alternatively, the enantiomerically pure 2(S), 3(S)-4-unsaturated piperidine compounds of Formula I can be prepared as set forth in Scheme J by substituting the appropriate N-(benzyloxycarbonyl)-Δ3-piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3-methyl ester for the appropriate N-(9-phenylfluorenyl)-Δ3-piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3-methyl ester of structure (45) followed by an HPLC separation as set forth in Scheme B. The appropriate N-(benzyloxycarbonyl)-Δ3-piperidine-2(S)-C₁-C₄ alkyl or benzyl ester-3-methyl ester can be prepared as set forth in Scheme I by substituting the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(benzyloxycarbonyl)-L-aspartate for the appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(9-phenylfluorenyl)-D-aspartate of structure (34). The appropriate α-C₁-C₄ alkyl or benzyl-β-methyl-N-(3-iodopropyl)-N-(benzyloxycarbonyl)-L-aspartate can be prepared as set forth in Scheme F by substituting L-aspartic acid for the D-aspartic acid (28). Starting materials for use in Scheme J are readily available to one of ordinary skill in the art. The following examples present typical syntheses as described in Scheme J. These examples are intended to be illustrative only and are not intended to limit the scope of the present invention in any way. Example 13 3(S)-(Phosphonoacetyl)-Δ4-piperidine-2(R)-carboxylic acid Step a: N-(9-Phenylfluorenyl)-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diisopropylamine (12mL, 85.6mmol) in anhydrous tetrahydrofuran, cool to -78°C and place under an inert atmosphere. Add n-butyllithium (52mL of a 1.6M solution in hexane, 83.2mmol) and stir at -78°C for 20 minutes. Add hexamethylphosphoramide and add, by dropwise addition, a solution of N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)- tert -butyl ester-3-methyl ester (16.2g, 32.7mmol) in anhydrous tetrahydrofuran (50mL). Stir at -78°C for 1 hour, warm to - 48°C and stir for 3 hours. Cool to -78°C and transfer via cannula to a -78°C solution of diisopropyl phenol (30.8g, 0.17mol) in tetrahydrofuran. (200mL). Stir for 1 hour and add acetic acid (5.2mL). Warm to room temperature and quench with water (100mL). Partition between methylene chloride (500mL) and water (300mL). Separate the organic phase, dry (Na₂SO₄) and evaporate to a residue. Purify by silica gel chromatography to give the title compound. Step b: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (1.14g, 7.5mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an inert atmosphere. Add n-butyllithium (4.68mL of a 1.6M solution in hexane, 7.5mmol) and stir for 20 minutes. Add, by dropwise addition, a solution of N-(9-phenylfluorenyl)-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester (529mg, 1.1mmol) in anhydrous tetrahydrofuran (10mL). Stir for 4 hours at -48°C and add acetic acid (2mL). Warm to room temperature, evaporate to a residue and purify by silica gel chromatography (ethyl acetate) to give the title compound. Step c: 3(S)-(Phosphonoacetyl)-Δ4-piperidine-2(R)-carboxylic acid Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester (0.35g) in acetonitrile and cool to 0°C. Stir vigorously and add, by dropwise addition, a solution of trifluoroacetic acid (20mL) in water (2mL). Stir for 15 minutes, warm to room temperature and stir for 3 hours. Evaporate to a solid residue, take up in water (100mL) and wash with toluene (100mL). Freeze dry the aqueous phase to give a residue. Take up the residue in acetonitrile (10mL) and methylene chloride (10mL). Pass a gentle stream of nitrogen through the solution and add trimethylsilyliodide (2mL). Stir for 6 hours, quench with water and wash with toluene (5X100mL). Freeze dry the aqueous phase and dissolve the resulting residue in methanol (5mL) and isopropanol (2.5mL). Add propylene oxide (2.0mL) and stir for 2 hours. Filter to give the title compound. Example 14 3(S)-(Phosphonoacetyl)-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid Step a: N-(9-Phenylfluorenyl)-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diisopropylamine (0.17mL, 0.79mmol) in anhydrous tetrahydrofuran (4.8mL), cool to 0°C and place under an inert atmosphere. Add n-butyllithium (0.75mL of a 1.6M solution in hexane, 1.20mmol) and cool to -78°C. Add, by dropwise addition, hexamethylphosphoramide (0.22mL, 1.26mmol), keeping the temperature below -60°C. Stir at -78°C for 30 minutes and add, by dropwise addition, a solution of N-(9-phenylfluorenyl)-Δ3-piperidine-2(R)- tert -butyl ester-3-methyl ester (380mg, 0.79mmol) in anhydrous tetrahydrofuran (5mL). Warm to -50°C to -45°C and stir for 1 hour, maintaining a temperature of -50°C to -38°C. Cool to -78°C and transfer via cannula to a -78°C solution of iodomethane (0.21mL, 3.37mmol). Stir at -78°C overnight and add add methanol (2mL) and phosphoric acid (15mL of a 0.5M solution). Extract into ether ether (3X10mL), dry (Na₂SO₄/MgSO₄) and evaporate the solvent in vacuo to give a dark yellow oil. Purify by silica gel chromatography (25/75 ethyl acetate/hexane) to give the title compound (170mg, 43%). ¹H NMR (300MHz, CDCl₃) ppm 7.15-7.8 (m, 13), 6.12 (m, 1), 5.80 (m, 1), 3.84 (m, 1), 3.68 (s, 1), 3.52 (s, 3), 2.69 (s, 3), 1.25 (m, 1), 0.92 (s, 9). Step b: N-(9-Phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosponate (1.14g, 7.5mmol) in anhydrous tetrahydrofuran (10mL), cool to -78°C and place under an inert atmosphere. Add n-butyllithium (4.68mL of a 1.6M solution in hexane, 7.5mmol) and stir for 20 minutes. Add, by dropwise addition, a solution of N-(9-Phenylfluorenyl)-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester (560mg, 1.1mmol) in anhydrous tetrahydrofuran (10mL). Stir for 4 hours at -48°C and add acetic acid (2mL). Warm to room temperature, evaporate to a residue and purify by silica gel chromatography (ethyl acetate) to give the title compound. Step c: 3(S)-(Phosphonoacetyl]-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]-3(R)-methyl-Δ4-piperidine-2(R)-carboxylic acid, tert -butyl ester (0.35g) in acetonitrile and cool to 0°C. Stir vigorously and add, by dropwise addition, a solution of trifluoroacetic acid (20mL) in water (2mL). Stir for 15 minutes, warm to room temperature and stir for 3 hours. Evaporate to a solid residue, take up in water (100mL) and wash with toluene (100mL). Freeze dry the aqueous phase to give a residue. Take up the residue in acetonitrile (10mL) and methylene chloride (10mL). Pass a gentle stream of nitrogen through the solution and add trimethylsilyliodide (2mL). Stir for 6 hours, quench with water and wash with toluene (5X100mL). Freeze dry the aqueous phase and dissolve the resulting residue in methanol (5mL) and isopropanol (2.5mL). Add propylene oxide (2.0mL) and stir for 2 hours. Filter to give the title compound. The following compounds can be prepared in a similar fashion to that described above in Examples 13 and 14 : 3(S)-(Phosphonoacetyl)-3(R)-methyl-5-methyl-Δ4-piperidine-2(R)-carboxylic acid; 3(S)-(Phosphonoacetyl)-3(R)-methyl-5-benzyl-Δ4-piperidine-2(R)-carboxylic acid. The pyrrolidine compounds of Formula I wherein R₅ is hydrogen can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme K. In Scheme K all substituents unless otherwise indicated are as previously defined. Bz = CH₂-C₆H₅ R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl R₇ = Et or t-Bu Scheme K provides a general synthetic procedure for preparing the pyrrolidine compounds of Formula I wherein R₅ is hydrogen. In step a, the 4-chloro functionality of the appropriate ethyl 4-chlorobutyrate of structure (51) is exchanged to give the corresponding ethyl 4-iodobutyrate of structure (52) as described previously in Scheme F, step e. In step b, the 4-iodo functionality of the appropriate ethyl 4-iodobutyrate of structure (52) is displaced with dibenzylamine to give the corresponding 4-dibenzylaminobutyric acid, ethyl ester of structure (53). For example, the appropriate ethyl 4-iodobutyrate of structure (52) is contacted with a molar equivalent of dibenzylamine and a molar equivalent of a suitable base, such as potassium carbonate. The reactants are typically contacted in a suitable organic solvent such as ethanol. The reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours. The 4-dibenzylaminobutyric acid, ethyl ester of structure (53) is recovered from the reaction zone by evaporation of the solvent. It may be purified by silica gel chromatography. In step c, the appropriate 4-dibenzylaminobutyric acid, ethyl ester of structure (53) is alkylated with an appropriate dialkyl oxylate of structure (54) to give the corresponding 4-dibenzylamino-2-alkyloxylyl-butyric acid, ethyl ester of structure (55). For example, the appropriate 4-dibenzylaminobutyric acid, ethyl ester of structure (53) is contacted with a molar equivalent of the appropriate dialkyl oxylate of structure (54) and a molar equivalent of a base such as potassium carbonate. The reactants are typically contacted in a suitable organic solvent mixture such as ethanol/benzene. The reactants are typically stirred together at a temperature range of from room temperature to reflux for a period of time of from 2-24 hours. The 4-dibenzylamino-2-alkyloxylyl-butyric acid, ethyl ester of structure (55) is recovered from the reaction zone by acidification and evaporation of the solvent. It may be purified by silica gel chromatography. In step d, the appropriate 4-dibenzylamino-2-alkyloxylyl-butyric acid, ethyl ester of structure (55) is cyclyzed to give the corresponding d,l-cis -pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (56). For example, the appropriate 4-dibenzylamino-2-alkyloxylyl-butyric acid, ethyl ester of structure (55) is contacted with a catalytic amount of a hydrogenation catyalyst such as palladium hydroxide. The reactants are typically contacted in a suitable organic solvent such as ethanol. The reactants are typically shaken at room temperature in the presence of hydrogen at a pressure of 30-50psi for a period of time ranging from 2-16 hours. The d,l-cis -pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (56) is recovered from the reaction zone by filtration and evaporation of the solvent. It may be purified by silica gel chromatography. In step e, the appropriate d,l-cis -pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (56) is protected to give the corresponding d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (57) as described previously in Scheme A, step b. In step f, the appropriate d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (57) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding d,l-cis -N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (58) as described previously in Scheme A, step d. In step g, the appropriate d,l-cis -N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (58) is deprotected to give the corresponding d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59a) and the d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59b) as described previously in Scheme A, step f. The appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59a) and the d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59b) can be separated into their diastereomeric pairs as shown previously in Scheme B. Alternatively the enantiomericaly pure 3(S)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(R)-carboxylic acid, ester and enantiomericaly pure 3(R)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(S)-carboxylic acid, ester can be prepared as set forth in Scheme K by subjecting the appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59a) and the d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59b) to an enzymatic hydrolysis as described previously in Scheme D, step c and Scheme E, optional step d. In addition, the enantiomericaly pure 3(S)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(R)-carboxylic acid, ester and enantiomericaly pure 3(R)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(S)-carboxylic acid, ester can be prepared as set forth in Scheme K by subjecting the appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59a) to an enzymatic hydrolysis as described previously in Scheme D, step c and Scheme E, optional step d. Similarly, the enantiomericaly pure 3(S)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(S)-carboxylic acid, ester and enantiomericaly pure 3(R)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2(R)-carboxylic acid, ester can be prepared as set forth in Scheme K by subjecting the appropriate d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of structure (59b) to an enzymatic hydrolysis as described previously in Scheme D, step c and Scheme E, optional step d. The appropriate 3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, ester of Formula I described above in Scheme K can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3-[(functionalized phosphinyl)acetyl]pyrrolidine-2-carboxylic acid derivatives of Formula I prepared as described above in Scheme K may also be further functionalized into the corresponding 3-[1-imino-2-phosponoethyl]pyrrolidine-2-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Starting materials for use in Scheme K are readily available to one of ordinary skill in the art. The following examples present typical syntheses as described in Scheme K. These examples are intended to be illustrative only and are not intended to limit the scope of the present invention in any way. Example 15 d , l - cis -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid and d , l - trans -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid Step a: Ethyl 4-iodo-3-methylbutyrate Mix ethyl 4-chloro-3-methylbutyrate (80g), acetone (400mL) and sodium iodide (100g). Reflux for 8 hours, cool and add methylene chloride (400mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200mL) and water (200mL). Separate the organic phase, dry (MgSO₄) and evaporate to an oil. Purify by distillation to give the title compound. Step b: 4-Dibenzylamino-3-methylbutyric acid, ethyl ester Mix ethyl 4-iodo-3-methylbutyrate (46,1 g, 0.18mol), dibenzylamine (35.5g, 0.18mol), potassium carbonate (24.9g, 0.18mol) and ethanol (114mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography to give the title compound. Step c: 4-Dibenzylamino-3-methyl-2- tert -butyloxylyl-butyric acid, ethyl ester Mix 4-dibenzylamino-3-methylbutyric acid, ethyl ester (20.5g, 63mmol), tert -butyl methyl oxylate (10g, 63mmol), potassium carbonate (9.3g), ethanol (5mL) and benzene (150mL). Stir overnight at room temperature under a nitrogen atmosphere. Add ethanol (10mL) and stir for an additional hour. Quench with acetic acid until the dark color clears to a light yellow, filter through celite and evaporate the filtrate to an oil. Purify by silica gel chromatography to give the title compound. Step d: d , l - cis -Pyrrolidine-4-methyl-2- tert -butylcarboxylate-3 ethylcarboxylate Mix 4-dibenzylamino-3-methyl-2- tert -butyloxylyl-butyric acid, ethyl ester (10g), 20% palladium hydroxide on carbon (1g) and ethanol. Place on a Paar Hydrogenation apparatus and hydrogenate at 30psi for 3 hours. Filter and evaporate to an oil. Purify by silica gel chromatography to give the title compound. Step e: d , l - cis -N-(9-Phenylfluorenyl)pyrrolidine-4-methyl-2- tert -butylcarboxylate-3-ethylcarboxylate Mix d , l - cis -pyrrolidine-4-methyl-2- tert -butylcarboxylate-3-ethylcarboxylate (5g), 9-phenylfluorenyl bromide (8.39g, 26mmol), lead nitrate (3.9g, 24mmol), diisopropylethylamine (5mL, 28mmol) and acetonitrile (100mL). Stir at room temperature for 4 hours and add methylene chloride (200ml). Filter through silica gel and evaporate the filtrate to an oil. Purify by silica gel chromatography to give the title compound. Step f: d,l -cis -N-(9-Phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-4-methyl-2-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (9.25g, 60mmol) in anhydrous tetrahydrofuran (50mL), cool to -78°C and place under a nitrogen atmsophere. Add n-butyllithium (37.5mL of a 1.6M solution in hexane, 60mmol) and stir for 1/2 hour. Add a solution of d , l - cis -N-(9-phenylfluorenyl)pyrrolidine-4-methyl-2- tert -butylcarboxylate-3-ethylcarboxylate (10.2g, 20mmol) in tetrahydrofuran (50mL) and stir at -78°C for 1 hour. Quench with acetic acid and pour into saturated sodium chloride (100mL). Extract with ethyl acetate (2X100mL) and dry. Purify by silica gel chromatography to give the title compound. Step g: d , l - cis -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid and d , l - trans -3-(Phosphonoacetyl)pyrrolidine-4-methyl-2-carboxylic acid Stir d , l - cis -N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-4-methyl-2-carboxylic acid, tert -butyl ester (3g) with trifluoroacetic acid (30mL) and water (1mL). Blow to a residue with a stream of nitrogen, take up the residue in water (120mL) and wash with ethyl acetate (75mL). Freeze dry the aqueous phase to give a yellow oil. Dissolve the yellow oil in acetonitrile (20mL) and methylene chloride (20mL). Add trimethylsilyl iodide (3.5mL, 24mmol) and stir for 5 hours. Pour into water (250mL) and wash with toluene (3X250mL). Freeze dry the aqueous phase to give a solid residue. Take up the solid residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (2mL) and stir for 1 hour. Filter and dry to give the title compounds. Separate by High Performance Liquid Chromatography on a P/10 SAX M/20-24 (Whatman) Column with 0.025M hydrochloric acid/acetonitrile to give the separate title compounds. Example 16 d , l - cis -3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid and d , l - trans -3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid Step a: Ethyl 4-iodobutyrate Mix ethyl 4-chlorobutyrate (80g), acetone (400mL) and sodium iodide (100g). Reflux for 8 hours, cool and add methylene chloride (400mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200mL) and water (200mL). Separate the organic phase, dry (MgSO₄) and evaporate to an oil. Purify by distillation to give the title compound (89g); bp 64°C @ 0.5mm Hg. Step b: 4-Dibenzylaminobutyric acid, ethyl ester Mix ethyl 4-iodobutyrate (43.5g, 0.18mol), dibenzylamine (35.5g, 0.18mol), potassium carbonate (24.9g, 0.18mol) and ethanol (114mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography (methylene chloride) to give the title compound (47g). ¹H NMR (90MHz, CDCl₃) ppm 3.95 (q, 2), 4.35 (s, 4), 2.40 (t, 2), 2.25 (t, 2), 1.75 (q, 2), 1.1 (t, 3). Step c: 4-Dibenzylamino-2- tert -butyloxylyl-butyric acid, ethyl ester Mix 4-dibenzylaminobutyric acid, ethyl ester (19.5g, 63mmol), tert -butyl methyl oxylate (10g, 63mmol), potassium carbonate (9.3g), ethanol (5mL) and benzene (150mL). Stir overnight at room temperature under a nitrogen atmosphere. Add ethanol (10mL) and stir for an additional hour. Quench with acetic acid until the dark color clears to a light yellow, filter through celite and evaporate the filtrate to an oil. Purify by silica gel chromatography (ethyl acetate/hexane) to give the title compound. Step d: d,l-cis -Pyrrolidine-2- tert -butylcarboxylate-3-ethylcarboxylate Mix 4-dibenzylamino-2- tert -butyloxylyl-butyric acid, ethyl ester (10g), 20% palladium hydroxide on carbon (1g) and ethanol. Place on a Paar Hydrogenation apparatus and hydrogenate at 30psi for 3 hours. Filter and evaporate to an oil. Purify by silica gel chromatography (90:10 ethyl acetate/hexane) to give the title compound (5.2g). Step e: d,l-cis -N-(9-Phenylfluorenyl)pyrrolidine-2- tert -butylcarboxylate-3-ethylcarboxylate Mix d,l-cis -pyrrolidine-2- tert -butylcarboxylate-3-ethylcarboxylate (5g), 9-phenylfluorenyl bromide (8. 39g, 26mmol), lead nitrate (3.9g, 24mmol), diisopropylethylamine (5mL, 28mmol) and acetonitrile (100mL). Stir at room temperature for 4 hours and add methylene chloride (200ml). Fitler through silica gel and evaporate the filtrate to an oil. Purify by silica gel chromatography (70% ethyl acetate/hexane) to give the title compound (9.5g). Step f: d , l - cis -N-(9-Phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (9.25g, 60mmol) in anhydrous tetrahydrofuran (50mL), cool to -78°C and place under a nitrogen atmsophere. Add n-butyllithium (37.5mL of a 1.6M solution in hexane, 60mmol) and stir for 1/2 hour. Add a solution of d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2- tert -butylcarboxylate-3-ethylcarboxylate (9.5g, 20mmol) in tetrahydrofuran (50mL) and stir at -78°C for 1 hour. Quench with acetic acid and pour into saturated sodium chloride (100mL). Extract with ethyl acetate (2X100mL) and dry. Purify by silica gel chromatography (70:30 ethyl acetate/hexane) to give the title compound (3.2g). ¹H NMR (300MHz, CDCl₃) ppm 7.2-7.75 (m, 13), 4.05 (m, 4), 3.64 (d, 1), 3.32 (t, 1), 3.15 (m, 2), 2.92 (dd, 1), 2.79 (m, 1), 2.35 ( m, 1), 1.8 (m, 1), 1.29 (s, 9), 1.22 (m, 6). Step g: d , l - cis -3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid and d,l-trans-3-(Phosphonoacetyl)pyrrolidine-2-carboxylic acid Stir d , l - cis -N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-2-carboxylic acid, tert -butyl ester (3g) with trifluoroacetic acid (30mL) and water (1mL). Blow to a residue with a stream of nitrogen, take up the residue in water (120mL) and wash with ethyl acetate (75mL). Freeze dry the aqueous phase to give a yellow oil. Dissolve the yellow oil in acetonitrile (20mL) and methylene chloride (20mL). Add trimethylsilyl iodide (3.5mL, 24mmol) and stir for 5 hours. Pour into water (250mL) and wash with toluene (3X250mL). Freeze dry the aqueous phase to give a solid residue. Take up the solid residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (2mL) and stir for 1 hour. Filter and dry to give the title compounds (1.0g). Separate by High Performance Liguid Chromatography on a P/10 SAX M/20-24 (Whatman) Column with 0.025M hydrochloric acid/acetonitrile to give the separate title compounds with the trans eluting first. trans ¹H NMR (300MHz, D₂O) ppm 4.8 (d, 1), 3.95 (m, 1), 3.55 (m, 1), 3.2-3.5 (m, 3), 2.51 (m, 1), 2.28 (m, 1). cis ¹H NMR (300MHz, D₂0) ppm 4.59 (d, 1), 4.19 (m, 1), 3.51 (m, 1), 3.2-3.5 (m, 3), 2.49 (m, 1), 2.41 (m, 1). The pyrrolidine compounds of Formula I wherein R₅ is linear C₁-C₄ alkyl or alkylphenyl can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme L. In Scheme L all substituents unless otherwise indicated are as previously defined. R₁' = C₁-C₄ alkyl or CF₃ R₂'' = CH₂C₆H₅ or C₁-C₄ alkyl R₅' = linear C₁-C₄ alkyl or alkylphenyl Scheme L provides a general synthetic procedure for preparing the pyrrolidine compounds of Formula I wherein R₅ is linear C₁-C₄ alkyl or alkylphenyl. In step a, the appropriate d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (57) is alkylated with an appropriate alkylating agent of the formula R₅'-Hal to give the corresponding d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-alkyl-3-ethylcarboxylate of structure (60). For example, the appropriate d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-ethylcarboxylate of structure (57) is contacted with a molar equivalent of a suitable non-nucleophilic base, such as lithium diisopropylamide. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from -78°C to 0°C. The d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-alkyl-3-ethylcarboxylate of structure (60) is recovered from the reaction zone by a low-temperature quench into the appropriate alkylating agent of the formula R₅'-Hal, followed by extraction by methods known in the art. It may be purified by silica gel chromatography. In step b, the appropriate d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2-alkylcarboxylate-3-alkyl-3-ethylcarboxylate of structure (60) is coupled with the appropriate phosphonate ester of structure (5) to give the corresponding d,l-cis -N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (61) as described previously in Scheme A, step d. In step c, the appropriate d,l-cis -N-(9-phenylfluorenyl)-3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (61) is deprotected to give the corresponding d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62a) and d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62b) as described previously in Scheme A, step f. The appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62a) and d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62b) can be separated into their diastereomeric pairs as shown previously in Scheme B. In addition, the enantiomericaly pure 3(S)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2(R)-carboxylic acid, ester and enantiomericaly pure 3(R)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2(S)-carboxylic acid, ester can be prepared as set forth in Scheme K by subjecting the appropriate d,l-cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62a) to an enzymatic hydrolysis as described previously in Scheme D, step c and Scheme E, optional step d. Similarly, the enantiomericaly pure 3(S)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2(S)-carboxylic acid, ester and enantiomericaly pure 3(R)-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2(R)-carboxylic acid, ester can be prepared as set forth in Scheme K by subjecting the appropriate d,l-trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62b) to an enzymatic hydrolysis as described previously in Scheme D, step c and Scheme E, optional step d. The appropriate 3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of Formula I described above in Scheme L can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate d , l - cis -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62a) and d , l - trans -3-[(dialkoxyphosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid, ester of structure (62b) can be further functionalized as described previously in Scheme A, steps g₁-i. The appropriate 3-[(functionalized phosphinyl)acetyl]pyrrolidine-3-alkyl-2-carboxylic acid derivatives of Formula I prepared as described above in Scheme L may also be further functionalized into the corresponding 3-[1-imino-2-phosponoethyl]pyrrolidine-3-alkyl-2-carboxylic acid derivatives of Formula I as described previously in Scheme C, step a. Starting materials for use in Scheme L are readily available to one of ordinary skill in the art. The following example presents typical syntheses as described in Scheme L. This example is intended to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 17 d , l - cis -3-(Phosphonoacetyl)pyrrolidine-3-methyl-2-carboxylic acid and d , l - trans -3-(Phosphonoacetyl)pyrrolidine-3-methyl-2-carboxylic acid Step a: d , l - cis -N-(9-Phenylfluorenyl)pyrrolidine-2- tert -butylcarboxylate-3-methyl-3-ethylcarboxylate Dissolve diisopropylamine (0.6mL, 4.3mmol) in tetrahydrofuran (10mL) and cool to 0°C. Add, by dropwise addition, n-butyllithium (2.7mL of a 1.6M solution, 4.3mmol). Stir for 1/2 hour, cool to -78°C and add, by dropwise addition, a solution of d,l-cis -N-(9-phenylfluorenyl)pyrrolidine-2- tert -butylcarboxylate-3-ethylcarboxylate (795mg, 1.6mmol) in tetrahydrofuran (10mL) Stir for 1 hour at -78°C and then for 3 hours at -30°C. Transfer rapidly, via water heated cannula, to a -78°C solution of iodomethane (426mg, 3mmol) in tetrahydrofuran (10mL). Allow to warm to room temperature overnight. Add ethyl acetate and wash with brine. Evaporate to a residue and purify by silica gel chromatography to give the title compound. Step b: d,l - cis -N-(9-Phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-3-methyl-2-carboxylic acid, tert -butyl ester Dissolve diethyl methylphosphonate (9.25g, 60mmol) in anhydrous tetrahydrofuran (50mL), cool to -78°C and place under a nitrogen atmsophere. Add n-butyllithium (37.5mL of a 1.6M solution in hexane, 60mmol) and stir for 1/2 hour. Add a solution of d , l - cis -N-(9-phenylfluorenyl)pyrrolidine-3-methyl-2- tert -butylcarboxylate-3-ethylcarboxylate (10.2g, 20mmol) in tetrahydrofuran (50mL) and stir at -78°C for 1 hour. Quench with acetic acid and pour into saturated sodium chloride (100mL). Extract with ethyl acetate (2X100mL) and dry. Purify by silica gel chromatography (70:30 ethyl acetate/hexane) to give the title compound. Step c: d , l - cis -3-(Phosphonoacetyl]pyrrolidine-3-methyl-2-carboxylic acid and d , l - trans -3-(Phosphonoacetyl]pyrrolidine-3-methyl-2-carboxylic acid Stir d , l - cis -N-(9-phenylfluorenyl)-3-[(diethoxyphosphinyl)acetyl]pyrrolidine-3-methyl-2-carboxylic acid, tert -butyl ester (3g) with trifluoroacetic acid (30mL) and water (1mL). Blow to a residue with a stream of nitrogen, take up the residue in water (120mL) and wash with ethyl acetate (75mL). Freeze dry the aqueous phase to give a yellow oil. Dissolve the yellow oil in acetonitrile (20mL) and methylene chloride (20mL). Add trimethylsilyl iodide (3.5mL, 24mmol) and stir for 5 hours. Pour into water (250mL) and wash with toluene (3X250mL). Freeze dry the aqueous phase to give a solid residue. Take up the solid residue in methanol (10mL) and isopropanol (5mL). Add propylene oxide (2mL) and stir for 1 hour. Filter and dry to give the title compounds (1.0g). Separate by High Performance Liquid Chromatography on a P/10 SAX M/20-24 (Whatman) Column with 0.025M hydrochloric acid/acetonitrile to give the separate title compounds. The compounds of Formula I are excitatory amino acid antagonists. They antagonize the effects which excitatory amino acids have upon the NMDA receptor complex. They preferentially bind to the glutamate binding site located on the NMDA receptor complex. They are useful in the treatment of a number of disease states. The compounds exhibit anti-convulsant properties and are useful in the treatment of epilepsy. They are useful in the treatment of grand mal seizures, petit mal seizures, psychomotor seizures, and autonomic seizures. One method of demonstrating their anti-epileptic properties is by the compounds ability to inhibit audiogenic convulsions in DBA/2 mice. This test can be conducted in the following manner. Typically one group of from 6-8 male DBA/2J audiogenic susceptible mice are administered from about 0.01 µg to about 100 µg of the test compound. The test compound is administered intracerebrally into the lateral ventricle of the brain. A second group of mice are administered an equal volume of a saline control by the same route. Five minutes later the mice are placed individually in glass jars and are exposed to a sound stimulus of 110 decibels for 30 seconds. Each mouse is observed during the sound exposure for signs of seizure activity. The control group will have a statistically higher incidence of seizures than the group which receives the test compound. Another method for demonstrating the anti-epileptic properties of these compounds is by their ability to inhibit the seizures that are caused by the administration of quinolinic acid. This test can be conducted in the following manner. One group containing ten mice are administered 0.01 - 100 µg of test compound intracerebroventricularly in a volume of 5 microliter of saline. A second control group containing an equal number of mice are administered an equal volume of saline as a control. Approximately 5 minutes later, both groups are administered 7.7 micrograms of quinolinic acid intracerebroventricularly in a volume of 5 microliters of saline. The animals are observed for 15 minutes thereafter for signs of clonic seizures. The control group will have a statistically higher rate of clonic seizures than will the test group. The compounds of Formula I are useful for preventing or minimizing the damage which nervous tissues contained within the CNS suffer upon exposure to either ischemic, hypoxic, or hypoglycemic conditions. Representative examples of such ischemic, hypoxic, or hypoglycemic conditions include strokes or cerebrovascular accidents, carbon monoxide poisoning, hyperinsulinemia, cardiac arrest, drownings, physical trauma, suffocation, and neonatal anoxic trauma. The compounds should be administered to the patient within 24 hours of the onset of the hypoxic, ischemic, or hypoglycemic condition in order for the compounds to effectively minimize the CNS damage which the patient will experience. The compounds are also useful in the treatment of neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, multi-infarct dementia, Parkinson's disease and neuronal damage associated with uncontrolled seizures. The administration of these compounds to a patient experiencing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or it will decrease the rate at which the neurodegeneration occurs. As is apparent to those skilled in the art, the compounds will not correct any CNS damage that has already occurred as the result of either disease or a lack of oxygen or sugar. As used in this application, the term "treat" refers to the ability of the compounds to prevent further damage or delay the rate at which any further damage occurs. The compounds exhibit an anxiolytic effect and are thus useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability to block distress vocalizations in rat pups. This test is based upon the phenomenon that when a rat pup is removed from its litter, it will emit an ultrasonic vocalization. it was discovered that anxiolytic agents block these vocalizations. The testing methods have been described by Gardner, C.R., Distress vocalization in rat pups: a simple screening method for anxiolytic drugs. J. Pharmacol. Methods, 14 : 181-187 (1985) and Insel et al., Rat pup ultrasonic isolation calls: Possible mediation by the benzodiapine receptor complex, Pharmacol. Biochem. Behav., 24 : 1263-1267 (1986). The compounds also exhibit an analgesic effect and are useful in controlling pain. The compounds may also be utilized to prophylacticaly prevent migraines or to terminate a migraine episode. In order to exhibit any of these therapeutic properties, the compounds need to be administered in a quantity sufficient to inhibit the effect which the excitatory amino acids have upon the NMDA receptor complex. The dosage range at which these compounds exhibit this antagonistic effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. Typically the compounds exhibit their therapeutic effect at a dosage range of from about 0.01 mg/kg/day to about 500 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above. The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally). Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically acceptable carrier. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art. For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art. As used in this application: a) the term patient refers to warm blooded animals such as, for example, guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and humans; b) the term treat refers to the ability of the compounds to either relieve, alleviate, prevent or slow the progression of the patient's disease; c) the term neurodegeneration refers to a progressive death and disappearance of a population of nerve cells occurring in a manner characteristic of a particular disease state and leading to brain damage. The compounds may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art. Neurodegenerative diseases are typically associated with a loss of NMDA receptors. Thus, the compounds of Formula I may be utilized in diagnostic procedures to aid physicians with the diagnosis of neurodegenerative diseases. The compounds may be labeled with isotopic agents by techniques known in the art and utilized as imaging agents. They may then be administered to a patient in order to determine whether the patient is exhibiting a decreased number of NMDA receptors and the rate at which that loss is occurring.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A compound of the formula (I) in which R₁ is represented by hydrogen, C₁₋₄ alkyl or CF₃; M is represented by O, N-O-R₄ or in which R₄ is represented by hydrogen, C₁₋₄ alkyl or alkylphenyl; A is represented by one of the following substituents: R₂ is represented by hydrogen, C₁₋₄ alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, substituted phenyl, or trifluoromethyl; R₃ is represented by hydrogen, C₁₋₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; R₅ is represented by hydrogen, linear C₁₋₄ alkyl, or alkylphenyl; R₆ is represented by hydrogen, C₁₋₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 wherein M is O. A compound according to claim 1 wherein M is N-O-R₄. A compound according to claim 1 wherein M is A compound according to any of claims 1 to 4, wherein R₃ is hydrogen. A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to claim 8 in which R₅ and R₃ are hydrogen. A compound according to claim 1, namely 3-(Phosphonoacetyl)piperidine-2-carboxylic acid. A compound according to claim 1, namely 3(S)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid. A process for producing a compound of the formula (I) according to any of claims 1 to 12 comprising: a) carrying out a coupling reaction between a phosphonate ester as described by structure 5 below, in which R₁ is as defined in claim 1, and; b) an appropriate heterocyclic moiety selected from the group consisting of in which Z is represented by -C(O)O-alk, in which alk is a C₁₋₄ linear alkyl, Pg is a suitable protecting group or H, and R₂, R₃, R₅ and R₆ are as defined in claim 1, and; c) subjecting the resulting product to an optional deprotection, protection and subsequent deprotection, condensation, esterification or separation reaction. Use of a compound of the formula (I) according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in antagonizing the effects of excitatory amino acids upon the NMDA receptor complex. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in the treatment of epilepsy. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in the treatment of neurodegenerative diseases. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in preventing ischemic/hypoxic/hypoglycemic damage to cerebral tissue. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in the treatment of anxiety. Use according to claim 14 wherein the pharmaceutical composition prepared is useful in producing an analgesic effect. A pharmaceutical composition containing a compound of the formula (I) according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and optionally a pharmceutically acceptable carrier and/or diluent. The pharmaceutical composition of claim 21 for antagonizing the effects of excitatory amino acids upon the NMDA receptor complex. Claims for the following Contracting States : ES, GR A compound of the formula (I) in which R₁ is represented by hydrogen, C₁₋₄ alkyl or CF₃; M is represented by O, N-O-R₄ or in which R₄ is represented by hydrogen, C₁₋₄ alkyl or alkylphenyl; A is represented by one of the following substituents: R₂ is represented by hydrogen, C₁₋₄ alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, substituted phenyl, or trifluoromethyl; R₃ is represented by hydrogen, C₁₋₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; R₅ is represented by hydrogen, linear C₁₋₄ alkyl, or alkylphenyl; R₆ is represented by hydrogen, C₁₋₄ alkyl, phenyl, alkylphenyl, or cyclohexylmethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 wherein M is O. A compound according to claim 1 wherein M is N-O-R₄. A compound according to claim 1 wherein M is A compound according to any of claims 1 to 4, wherein R₃ is hydrogen. A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to any of claims 1 to 4, in which A is A compound according to claim 8 in which R₅ and R₃ are hydrogen. A compound according to claim 1, namely 3-(Phosphonoacetyl)piperidine-2-carboxylic acid. A compound according to claim 1, namely 3(S)-(Phosphonoacetyl)piperidine-2(R)-carboxylic acid. A process for producing a compound of the formula (I) according to any of claims 1 to 12 comprising: a) carrying out a coupling reaction between a phosphonate ester as described by structure 5 below, in which R₁ is as defined in claim 1, and; b) an appropriate heterocyclic moiety selected from the group consisting of in which Z is represented by -C(O)O-alk, in which alk is a C₁₋₄ linear alkyl, Pg is a suitable protecting group or H, and R₂, R₃, R₅ and R₆ are as defined in claim 1, and; c) subjecting the resulting product to an optional deprotection, protection and subsequent deprotection, condensation, esterification or separation reaction. A method for the preparation of a pharmaceutical composition comprising combing a compound of the formula (I) according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. The method according to claim 14 wherein the pharmaceutical prepared is useful in antagonizing the effects of excitatory amino acids upon the NMDA receptor complex. The method according to claim 14 wherein the pharmaceutical prepared is useful in the treatment of epilepsy. The method according to claim 14 wherein the pharmaceutical prepared is useful in the treatment of neurodegenerative diseases. The method according to claim 14 wherein the pharmaceutical prepared is useful in preventing ischemic/hypoxic/hypoglycemic damage to cerebral tissue. The method according to claim 14 wherein the pharmaceutical prepared is useful in the treatment of anxiety. The method according to claim 14 wherein the pharmaceutical prepared is useful in producing an analgesic affect.

Inventors: WHITTEN JEFFREY P, WHITTEN, JEFFREY P.
Applicants: MERRELL DOW PHARMA, MERRELL DOW PHARMACEUTICALS INC.
Application year: 1991
Main classification: C07F9
IPC codes: A61P25, A61P43, A61K31, C07F9, A61P29