METHODS FOR SYNTHESIZING SUBSTITUTED TETRACYCLINE COMPOUNDS

1 . A method for synthesizing a carboxaldehyde substituted tetracycline compound comprising reacting a tetracycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base, such that said carboxaldehyde substituted tetracycline compound is synthesized.

2 . The method of claim 1 , wherein said carboxaldehyde substituted tetracycline compound is a 7-, 9- and/or 10-carboxaldehyde substituted tetracycline compound.

3 . The method of claim 1 , wherein said tetracycline reactive intermediate is a halogenated tetracycline intermediate or a triflate substituted tetracycline intermediate.

4 . The method of claim 3 , wherein said halogenated tetracycline intermediate is an iodine substituted tetracycline intermediate, a chlorine substituted tetracycline intermediate, a bromine substituted tetracycline intermediate, a iodine and chlorine substituted tetracycline intermediate or a bromine and iodine substituted tetracycline intermediate.

5 . The method of claim 4 , wherein said halogenated tetracycline intermediate is 7-iodosancycline, 9-iododoxycycline, 7-chloro-9-iodosancycline or 7-bromo-9-iodosancycline.

6 . A method of synthesizing a substituted tetracycline compound comprising reacting the carboxaldehyde substituted tetracycline compound of claim 1 under palladium catalyzed coupling conditions, hydrogenolysis conditions or reductive amination conditions.

7 . The method of claim 1 , wherein said reactive tetracycline intermediate is substituted at a first position with a first reactive moiety and at a second position with a second reactive moiety, such that the first reactive moiety is replaced with a carboxaldehyde substituent and the second reactive moiety is unreacted.

8 . The method of claim 7 , further comprising the step of reacting the second reactive moiety under hydrogenolysis conditions or palladium catalyzed coupling conditions.

9 . The method of claim 7 , wherein said first and second reactive moieties are selected from halogens and triflates.

10 . The method of claim 7 , wherein said carboxaldehyde substituent is further reacted under reductive amination conditions to produce an aminomethyl substituted tetracycline compound; and the second reactive moiety is further reacted under palladium coupling conditions or under hydrogenolysis conditions.

11 . The method of claim 10 , wherein said aminomethyl substituted tetracycline compound is a 7- or 9-aminomethyl substituted tetracycline compound.

12 . The method of claim 7 , wherein said first reactive moiety is iodine and said second reactive moiety is bromine.

13 . The method of claim 7 , wherein said reactive tetracycline intermediate is 7-bromo-9-iodosancycline.

14 . A method for synthesizing a carboxaldehyde substituted minocycline compound comprising reacting a minocycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a silane and a base, such that said carboxaldehyde substituted minocycline compound is synthesized.

15 . The method of claim 14 , wherein said minocycline reactive intermediate is a 9-halogenated minocycline intermediate.

16 . The method of claim 15 , wherein said halogenated minocycline intermediate is an iodine substituted minocycline intermediate, a chlorine substituted minocycline intermediate, or a bromine substituted minocycline intermediate.

17 . The method of claim 14 , wherein said palladium catalyst is PdCl 2 (tBu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].

18 . A method of synthesizing a substituted minocycline compound comprising reacting the carboxaldehyde substituted minocycline compound of claim 14 under palladium catalyzed coupling conditions, hydrogenolysis conditions or reductive amination conditions.

19 . A method for synthesizing an aminomethyl substituted minocycline compound comprising the steps of reacting the carboxaldehyde minocycline of claim 14 under reductive amination conditions.

20 . The method of claim 19 , wherein said aminomethyl substituted minocycline compound is a 9-aminomethyl substituted minocycline compound.