Optically active aminoalcohol derivatives and method of producing same

Abstract

An object of the present invention is to provide a safe method of commercially producing optically active aminoalcohol derivatives, which serve as intermediates for the synthesis of medicinal chemicals such as the immunopotentiating anticancer agent bestatin, in a simple and easy manner in high yields and with high levels of selectivity. The present invention consists in a method of producing 3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (1) ##STR1## wherein R 1 and R 2 each independently represents a hydrogen atom or an amino group protecting group, and a method of producing 3-amino-2-hydroxy-4-phenylbutyric acid derivatives derivable therefrom.

We claim: 
     
       1. An 3-amino-1-nitro-4-phenyl-2-butanol derivative of the general formula (1) ##STR8## wherein R 1  and R 2  each independently represents a hydrogen atom or an amino group protecting group and R 3  represents a hydrogen atom or a hydroxy group protecting group. 
     
     
       2. A compound as claimed in claim 1, wherein, in general formula (1), R 3  is a hydrogen atom and the amino group protecting group is a phthaloyl group. 
     
     
       3. A compound as claimed in claim 1, wherein, in general formula (1), R 3  is a hydrogen atom and the amino group protecting group is a t-butoxycarbonyl group. 
     
     
       4. A compound as claimed in claim 1, wherein the general formula (1) has the .[.(2S,3S).]. .Iadd.(2R,3S).Iaddend.-erythro form configuration. 
     
     
       5. A compound as claimed in claim 1, wherein the general formula (1) has the .[.(2S,3R).]. .Iadd.(2R,3S).Iaddend.-threo form configuration. 
     
     
       6. A method of producing 3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (1) ##STR9## wherein R 1  and R 2  each independently represents a hydrogen atom or an amino group protecting group and R 3  represents a hydrogen atom or a hydroxy group protecting group, which comprises reacting an amine aldehyde of the general formula (2) ##STR10## wherein R 1  and R 2  are as defined above, with nitromethane in the presence of a base. 
     
     
       7. A method of stereoselectively producing .[.(2S,3S).]. .Iadd.(2R,3S).Iaddend.-3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (4) ##STR11## wherein R 1  in combination with R 2  represents a phthaloyl group and R 3  is a hydrogen atom, which comprises reacting an (S)-aminoaldehyde derivative of the general formula (3) ##STR12## wherein R 1  and R 2  are as defied above, with nitromethane in the presence of a base. 
     
     
       8. A method of stereoselectively producing .[.(2S,3R).]. .Iadd.(2R,3R).Iaddend.-3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (6) ##STR13## wherein R 1  is a hydrogen atom and R 2  represents a t-butoxycarbonyl group and R 3  is a hydrogen atom, which comprises reacting an (R)-aminoaldehyde derivative of the general formula (5) ##STR14## wherein R 1  and R 2  are as defined above, with nitromethane in the presence of a base. 
     
     
       9. A method as claimed in claim 6 wherein the base is an alkali metal alkoxide. 
     
     
       10. A method as claimed in claim 9, wherein the alkali metal alkoxide is a compound of the general formula (7) ##STR15## wherein R 4  and R 5  each represents an alkyl group containing 1 to 6 carbon atoms. 
     
     
       11. A method as claimed in claim 6 wherein the base is a compound of the general formula (8)   R.sup.7 Li                                                 (8)     wherein R 7  represents an aryl group or an alkyl group containing 1 to 6 carbon atoms.   
     
     
       12. A method as claimed in claim 6 wherein the base is a complex prepared from a compound of the general formula (9)   MX.sub.3                                                   ( 9)     wherein M represents a rare earth atom and X represents a halogen atom, and 1,1'-bi-2-naphthol or the lithium salt thereof.   
     
     
       13. A method as claimed in claim 12, wherein the complex is one prepared from lanthanum trichloride and (R)-1,1'-bi-2-naphthol. 
     
     
       14. A method as claimed in claim 6 wherein the base is a complex prepared from a compound of the general formula (10)   M(OR.sup.8).sub.3                                          ( 10)     wherein M represents a rare earth atom and R8 represents a substituted alkyl group containing 1 to 8 carbon atoms, and 1,1'-bi-2-naphthol or the lithium salt thereof.   
     
     
       15. A method as claimed in claim 14, wherein the complex is one prepared from lanthanum triisopropoxide and the lithium salt of (R)-1,1'-bi-2-naphthol. 
     
     
       16. A method of producing compounds of the general formula (11) ##STR16## wherein R 1  and R 2  each independently represents a hydrogen atom or an amino group protecting group, R 3  represents a hydrogen atom or a hydroxy group protecting group and R 6  represents a hydrogen atom or an alkyl group containing 1 to carbon atoms, or salts thereof which comprises treating an 3-amino-1-nitro-4-phenyl-2-butanol derivative of the general formula (1) ##STR17## wherein R 1 , R 2  and R 3  are as defined above, with an acid. 
     
     
       17. A method as claimed in claim 16, wherein the general .[.formulas.]. .Iadd.formula .Iaddend.(1) .[.and.]. .Iadd.has the (2R,3S)-erythro form configuration and the compound of general formula .Iaddend.(11) .[.each.]. has the (2S,3S)-erythro form configuration and the amino group protecting group is a phthaloyl group. 
     
     
       18. A method as claimed in claim 16, wherein the general .[.formulas.]. .Iadd.formula .Iaddend.(1) .[.and.]. .Iadd.has the (2R,3S)-threo form configuration and the compound of general formula .Iaddend.(11) .[.each.]. has the (2S,3R)-threo form configuration and .[.tile.]. .Iadd.the .Iaddend.amino group protecting group is a t-butoxycarbonyl group. 
     
     
       19. A method of producing compounds of the general formula (11) ##STR18## wherein R 1  and R 2  each independently represents a hydrogen atom or an amino group protecting group, R 3  represents a hydrogen atom or a hydroxy group protecting group and R 6  represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or salts thereof which comprises reacting an aminoaldehyde derivative of the general formula (2) ##STR19## wherein R 1  and R 2  are as defined above, with nitromethane in the presence of a base and treating the resulting 3-amino-1nitro-4-phenyl-2-butanol derivative of the general formula (1) ##STR20## wherein R 1 , R 2  and R 3  are as defined above, with an acid. 
     
     
       20. The method as claimed in claim 19, wherein said base is a complex prepared from a compound of the general formula (9)   MX.sub.3                                                   ( 9)     wherein M represents a rare earth atom and X represents a halogen atom, or a compound of the general formula (10)     M(OR.sup.8).sub.3                                          ( 10)     wherein M is as defined above and R 8  represents a substituted alkyl group containing 1 to 8 carbon atoms, and 1,1'-bi-2-naphthol or the lithium salt thereof.   
     
     
       21. The method as claimed in claim 20, wherein said derivative of the general formula (1) is 1-nitro-4-phenyl-3-phthaloylamino-2-butanol having the erythro configuration or phenylnorstatine having the erythro configuration from optically active 3-phenyl-2-phthaloylamino propanol. 
     
     
       22. The method as claimed in claim 21, wherein the optically active 3-phenyl-2-phthaloylaminopropanal is the (2S) form, the 1-nitro-4-phenyl-3-phthaloylamino-2-butanol having the erythro configuration is the .[.(2S,3S).]. .Iadd.(2R,3S) .Iaddend.form and the phenylnorstatine having the erythro configuration is the (2S,3S) form. 
     
     
       23. The method as claimed in claim 20, wherein said derivative of the general formula (1) is 3-t-butoxycarbonyl amino-1-nitro-4-phenyl-2-butanol having the threo configuration or phenylnorstatine having the threo configuration from optically active 2-t-butoxycarbonyl amino-3-phenylpropanal. 
     
     
       24. The method as claimed in claim 23, wherein the optically active 2-t-butoxycarbonylamino-3-phenylpropanal is the (2R) form, the 3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol having the threo configuration is the .[.(2S,3R).]. .Iadd.(2R,3R) .Iaddend.form and the phenylnorstatine having the threo configuration is the (2S,3R) form.