Process for making arylomycin ring analogs

1. A method of making an arylomycin ring of formula o:

or a salt or solvate thereof,

wherein:

R is: hydrogen; or C 1-4 alkyl;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; cyano-C 1-6 alkyl; or nitro, wherein the amino and hydroxyl moieties may each optionally include a protecting group;

R 7 is: hydrogen; or C 1-4 alkyl;

R 8 is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; or cyano-C 1-6 alkyl, wherein the amino and hydroxyl moieties may each optionally include a protecting group;

Pg 1 is an optional amine protecting group; and

Pg 2 is an optional hydroxyl protecting group;

the method comprising:

reacting a phenyl boronate compound of formula l:

or a salt or solvate thereof,

wherein:

R a is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R a groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring; and

R, R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined in the arylomycin ring of formula o;

with a phenyl halide compound of formula e:

or a salt or solvate thereof,

wherein:

Y is halogen; and

R 1 , R 2 , R 3 , and Pg 1 are as defined in the arylomycin ring of formula o;

in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II), and after said reacting removing one amine protecting group Pg 1 , to form a compound of formula y:

or a salt or solvate thereof,

wherein:

R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 , and Pg 2 are as defined in the arylomycin ring of formula o; and

cyclizing the compound of formula y, or a salt or solvate thereof, by forming an amide bond to make the arylomycin ring of formula o, or a salt or solvate thereof.

2. The method of claim 1 , further comprising reacting a compound of formula k:

or a salt or solvate thereof,

wherein:

Y, R, R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 , and Pg 2 are as defined in claim 1 ;

with a boronating agent to form the compound of formula l, or a salt or solvate thereof.

3. The method of claim 2 , further comprising:

reacting a compound of formula h:

or a salt or solvate thereof,

wherein:

Y, R, R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

with an amino acid of formula i:

or a salt or solvate thereof,

wherein:

R 8 and Pg 1 are as defined in claim 1 ;

to form a compound of formula j:

or a salt or solvate thereof,

wherein:

Y, R, R 4 , R 5 , R 6 , R 7 , R 8 , and Pg 1 are as defined in claim 1 ; and

introducing a hydroxyl protecting group Pg 2 to the compound of formula j, or a salt or solvate thereof, to form the compound of formula k, or a salt or solvate thereof.

4. The method of claim 3 , further comprising:

esterifying a compound of formula g:

or a salt or solvate thereof,

wherein:

Y, R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

to form the compound of formula h, or a salt or solvate thereof.

5. The method of claim 4 , further comprising:

halogenating a compound of formula f:

or a salt or solvate thereof,

wherein:

R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

to form the compound of formula g, or a salt or solvate thereof.

6. The method of claim 1 , further comprising:

reducing a compound of formula d:

or a salt or solvate thereof,

wherein:

Y, R 1 , R 2 , R 3 , and Pg 1 are as defined in claim 1 ;

to form the compound of formula e, or a salt or solvate thereof.

7. The method of claim 6 , further comprising:

reacting a compound of formula c:

or a salt or solvate thereof,

wherein:

Y, R 1 , R 2 , R 3 , and Pg 1 are as defined in claim 1 ;

with trioxane to form the compound of formula d, or a salt or solvate thereof.

8. The method of claim 7 , further comprising:

halogenating a compound of formula a:

or a salt or solvate thereof,

wherein:

R 1 , R 2 , and R 3 are as defined in claim 1 ;

to form a compound of formula b:

or a salt or solvate thereof,

wherein:

Y, R 1 , R 2 , and R 3 are as defined in claim 1 ; and

introducing an amine protecting group Pg 1 to the compound of formula b, or a salt or solvate thereof, to form the compound of formula c, or a salt or solvate thereof.