Process for making arylomycin ring analogs

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

wherein:

Y is halogen;

R is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence;

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 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 optionally include a protecting group;

R a is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R 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;

Pg 1 is an optional amine protecting group and may be the same or different on each occurrence; and

Pg 2 is an optional hydroxyl protecting group and may be the same or different on each occurrence;

the method comprising:

reacting a phenyl boronate compound of formula m:

or a salt or solvate thereof,

with a phenyl halide compound of formula e;

or a salt or solvate thereof,

to form a compound of formula n;

or a salt or solvate thereof; and

treating the compound of formula n with chloro(crotyl)(tri-tert-butylphosphine)palladium(II), to make the compound 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,

with a boronating agent to form a compound of formula 1:

or a salt or solvate thereof; and

removing the protecting group Pg′ from compound 1 to form the compound of formula m;

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,

with an amino acid of formula i:

or a salt or solvate thereof,

to forma compound of formula i:

or a salt or solvate thereof; and

introducing a hydroxyl protecting group Pg 2 to compound j 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,

to form the compound of formula h;

or a salt or solvate thereof.

5. The method of claim 4 , further comprising:

halogenating of a compound formula f:

or a salt or solvate thereof,

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:

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,

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,

to form a compound of formula b:

or a salt or solvate thereof; and

introducing an amine protecting group to compound b to form the compound of formula c;

or a salt or solvate thereof.

9. The method of claim 1 , further comprising:

reacting the compound of formula o, or a salt or solvate thereof;

with an alkylating reagent of formula p:

R 9 —X p ,

or a salt or solvate thereof,

to form a compound of formula q:

or a salt or solvate thereof;

wherein:

X is a leaving group; and

R 9 is: C 1-4 alkyl; halo-C 1-4 alky; hydroxyl-C 1-4 alkyl; amino-C 1-4 alkyl, aminosulfonyl-C 1-4 alkyl; or C 1-4 alkoxy-C 1-4 alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group.

10. The method of claim 9 , further comprising:

removing the amine protecting group Pg 1 , and optionally removing the hydroxyl protecting group Pg 2 from the compound of formula q, or a salt or solvate thereof, to form a compound of formula r:

or a salt or solvate thereof.

11. The method of claim 10 , further comprising:

reacting the compound of formula r, or a salt or solvate thereof;

with an amino acid reagent of formula s:

or a salt or solvate thereof;

to form a compound of formula t:

or a salt or solvate thereof.