Chiral compounds of varying conformational rigidity and methods of synthesis

Abstract

Synthesis of compounds having varying degrees of conformational rigidity is obtained via a low cost, high yield and efficient synthetic reactions. The library of compounds is structurally diverse, having at least one or more chiral centers and providing large numbers of compounds having building block diversity and substantial scaffold diversity. The compounds further provide a novel method for obtaining candidate therapeutic agents for prevention, treatment or diagnosis of diseases.

What is claimed: 
     
         1 . A method of synthesizing a chiral monomer comprising:
 obtaining a stereodefined allylic alcohol via a stereoselective aldol reaction or a related transformation reaction and proceeding via stereoselective allylic transposition of the resulting allylic alcohol; and   converting the resulting rearranged product to a chiral acid having a general structure of Formula I′:   
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein R 1  and R 2  comprise a molecular architecture compatible with the synthesis of Formula I′ or introduced after synthesis of a central pentenoic acid of Formula I′. 
     
     
         3 . The method of  claim 1 , wherein two or more monomers of Formula I′ are optionally oligomerized, the oligomerization of Formula I′ proceeding via a 1- or 2-directional homologation or functionalization of Formula I′. 
     
     
         4 . The method of  claim 3 , wherein X and Y comprise any molecule compatible with the oligomerization of Formula I′. 
     
     
         5 . The method of  claim 2 , wherein an oligomer or polymer of Formula I′ comprises homogeneous monomers, heterogeneous monomers or combinations thereof. 
     
     
         6 . A compound comprising a monomer set forth in Formula I: 
       
         
           
           
               
               
           
         
         wherein, X and Y comprise any molecular motifs or functional groups compatible with oligomerization of two or more monomers of Formula I. 
       
     
     
         7 . The compound of  claim 6 , wherein an oligomeric compound comprises at least two or more monomers represented by Formula I comprising a chiral center in an R configuration, an S configuration or multiple combinations thereof. 
     
     
         8 . The compound of  claim 6 , wherein the monomer of Formula I is a pentenoic amide. 
     
     
         9 . The compound of  claim 8 , wherein the pentenoic amide is a central N-substituted 5-amino-2, 4-dialkyl-3-pentenoic amide. 
     
     
         10 . The compound of  claim 6 , wherein a monomer of Formula I comprises substitutions which maintain conformational control about a β, γ-unsaturated carbonyl and minimize allylic strain. 
     
     
         11 . The compound of  claim 6 , wherein monomers or oligomers of Formula I comprise substitutions having varying degrees of flexibility imparted by monomers comprising the backbone. 
     
     
         12 . The compound of  claim 6 , wherein uni- or bidirectional functionalization of Formula I produces a higher molecular weight compound comprising Formula I having a structure whereby conformation is controlled by minimization of A-1,3 strain inherent to a substituted β,γ-unsaturated carbonyl. 
     
     
         13 . The compound of  claim 12 , wherein the higher molecular weight compound of Formula I comprises oligomers having repeating units of Formula I and/or repeating monomers of Formula I having different substitutions R 1  and R 2 , wherein R 1  and R 2  comprise any molecular architecture capable of forming a bond with the monomers or oligomers of Formula I. 
     
     
         14 . The compound of  claim 13 , wherein R 1  and R 2  independently comprise OR 3 , NHR 4 , NR 4 R 5 , halide, alkyl, linear alkyl, branched alkyl, heteroatom-substituted alkyl, unsaturated and polyunsaturated linear and branched hydrocarbons, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl, heteroatom-substituted unsaturated and polyunsaturated linear and branched hydrocarbons, cycloalkyl, heteroatom-substituted cycloalkyl, saturated and unsaturated heterocycles, substituted cycloalkyl, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic; R 3  independently comprises H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; and, R 4  independently comprises H, OR 3 , alkyl, aryl, or heteroaryl. 
     
     
         15 . The compound of  claim 6 , wherein X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3  independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4  independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1  independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2  independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X. 
     
     
         16 . A method of identifying a candidate therapeutic agent, comprising:
 screening a library comprising one or more monomers, oligomers, or polymers of Formula I:   
       
         
           
           
               
               
           
         
         contacting a biological sample, cell, tissue, or molecule in solution or attached to a solid or semi-solid support, with a compound of Formula I; 
         assaying for any desired therapeutic effects; and, 
         identifying a candidate therapeutic agent. 
       
     
     
         17 . The method of  claim 16 , wherein for Formula I: X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3  independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4  independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1  independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2  independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X. 
     
     
         18 . The method of  claim 16 , wherein desired therapeutic effects comprise: tumor cell death, inhibition of viral replication, cytolysis of virally infected cells, modulation of receptors, modulation of growth factors, modulation of cytokines, modulation of cellular factors, modulation of immune cells, anti-bacterial effects, anti-parasitic effects or combinations thereof. 
     
     
         19 . A pharmaceutical composition comprising a compound having a structure of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein X and Y comprise any molecular motif or functional group compatible with oligomerization of two or more monomers of Formula I. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein R 1  and R 2  comprise any molecular architecture capable of forming a bond with monomers or oligomers of Formula I. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein R 1  and R 2  independently comprise OR 3 , NHR 4 , NR 4 R 5 , halide, alkyl, linear alkyl, branched alkyl, heteroatom-substituted alkyl, unsaturated and polyunsaturated linear and branched hydrocarbons, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl, heteroatom-substituted unsaturated and polyunsaturated linear and branched hydrocarbons, cycloalkyl, heteroatom-substituted cycloalkyl, saturated and unsaturated heterocycles, substituted cycloalkyl, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic; R 3  independently comprises H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; and, R 4  independently comprises H, OR 3 , alkyl, aryl, or heteroaryl. 
     
     
         23 . The pharmaceutical composition of  claim 19 , wherein X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3  independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4  independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1  independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2  independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X. 
     
     
         24 . A compound comprising: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A compound of Formula I comprising a monomer set forth in Formula I: 
       
         
           
           
               
               
           
         
         wherein, X and Y comprise any molecular motif or functional group compatible with oligomerization of monomers of Formula I.; and, one or more monomers of an oligomer of Formula I are conjugated to a cytotoxic agent or detectable label. 
       
     
     
         26 . The compound of  claim 25 , wherein R 1  and R 2  comprise any molecular architecture capable of forming a bond with monomers or oligomers of Formula I. 
     
     
         27 . The compound of  claim 26 , wherein R 1  and R 2  independently comprise OR 3 , NHR 4 , NR 4 R 5 , halide, alkyl, linear alkyl, branched alkyl, heteroatom-substituted alkyl, unsaturated and polyunsaturated linear and branched hydrocarbons, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl, heteroatom-substituted unsaturated and polyunsaturated linear and branched hydrocarbons, cycloalkyl, heteroatom-substituted cycloalkyl, saturated and unsaturated heterocycles, substituted cycloalkyl, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic; R 3  independently comprises H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; and, R 4  independently comprises H, OR 3 , alkyl, aryl, or heteroaryl. 
     
     
         28 . The compound of  claim 25 , wherein X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3  independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4  independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1  independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2  independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X. 
     
     
         29 . The compound of  claim 25 , wherein a cytotoxic agent comprises: a toxin, radioactive molecule, chemotherapeutic agent, an inhibitor of replication, or combinations thereof. 
     
     
         30 . The compound of  claim 25 , wherein the detectable label comprises: a fluorescent molecule, radioactive molecule, a metal, or dye. 
     
     
         31 . A method of treating a hematopoietic malignancy in vivo, comprising: administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising at least one compound of  claims 6 ,  24  or  25 , wherein the compound is conjugated to one or more cytotoxic agents and specifically binds to a hematopoietic malignant cell; and, treating the hematopoietic malignancy 
     
     
         32 . The method of  claim 31 , wherein the hematopoietic malignancy comprises: B cell malignancies or neoplasms, chronic myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, acute myeloid leukemias, B cell neoplasms, T-cell and NK-cell neoplasms, Hodgkin's lymphoma, histiocytic and dendritic cell neoplasms or mastocytosis. 
     
     
         33 . The method of  claim 32 , wherein the B cell malignancy comprises: B cell chronic lymphocytic leukemia (B-CLL), B cell lymphomas, aggressive B-cell lymphoma, Hodgkin's disease, B cell non-Hodgkin's lymphoma (NHL), lymphomas, Waldenstrom's macroglobulinaemia (lymphoplasmacytic lymphoma or immunocytoma), central nervous system lymphomas, leukemias, acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myoblastic leukemia), myelomas, multiple myeloma), small lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extra-nodal marginal zone B cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, grey zone lymphoma, B cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder. 
     
     
         34 . The method of  claim 31 , whereby the B cell malignancy is B-CLL. 
     
     
         35 . The method of  claim 31 , further comprising administering to a patient a chemotherapeutic agent or radiotherapy. 
     
     
         36 . A method of diagnosing a hematopoietic malignancy comprising administering to a patient, or contacting a biological sample in vitro with a compound of  claims 6 ,  24  or  25 , wherein the compound is conjugated to a detectable label and the compound specifically binds to a hematopoietic malignant cell in vivo or in vitro; and, diagnosing a hematopoietic malignancy. 
     
     
         37 . The method of  claim 36 , wherein the hematopoietic malignancy is B cell chronic lymphocytic leukemia (B-CLL). 
     
     
         38 . A method of modulating an immune cell disease or disorder comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising at least one compound of  claims 6 ,  24  or  25 , wherein the compound is conjugated to one or more agents and specifically binds to an immune cell receptor or ligand and modulates the immune cell mediated disease or disorder. 
     
     
         39 . The method of  claim 38 , wherein the immune cell disease or disorder comprises: autoimmune diseases, inflammatory diseases, transplantation rejection, lymphoproliferative diseases, allergies, neuroinflammatory diseases and disorders thereof.