Bridged macrocyclic compounds and processes for the preparation thereof

1. A process comprising the step of reacting a macrocyclic compound characterized by at least two nucleophilic moieties with a bifunctional bridging component characterized by its ability to form π-allyl metal complex in the presence of catalyst, whereby each of two nucleophilic moieties of the macrocyclic compound reacts with said bifunctional bridging component, thereby achieving a bridged macrocyclic product.

2. The process of claim 1 , wherein the macrocyclic compound is a macrolide antibiotic.

3. The process of claim 1 , wherein the macrocyclic compound is an erythromycin derivative.

4. The process of claim 3 , wherein the erythromycin derivative is azithromycin, desmethyl azithromycin, roxithromycin, clarithromycin, telithromycin, or cethromycin.

5. The process of claim 1 , wherein the macrocyclic compound is selected from:

wherein

D is selected from —NHCH 2 —, —NHCHR 1 —, —NHCR 3 R 4 —, —NR 1 CH 2 —, —NHC(O)—, —NR 1 C(O)—, —NHC(S)—, or —NR 1 C(S)—;

Each R 1 is independently selected from hydrogen, deuterium, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group;

R 3 and R 4 is independently selected from the group consisting of hydrogen, acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group; or can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring;

L is selected from hydrogen, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group;

one of U or V is hydrogen and the other is independently selected from the group consisting of: R 1 , OR 1 , OC(O)R 1 , OC(O)NR 3 R 4 , S(O) n R 1 ,

or other carbohydrate or sugar moiety;

or U and V, taken together with the carbon atom to which they are attached, are C═O;

or UV and R e R f , taken together with the carbon atoms to which they are attached, are —C(R 1 )═CH—;

one of J or G is hydrogen and the other is selected from: R 1 , OR 1 , or NR 3 R 4 ;

or J and G, taken together with the carbon atom to which they are attached, are selected from: C═O, C═NR 1 , C═NOR 1 , C═NO(CH 2 ) m R 1 , C═NNHR 1 , C═NNHCOR 1 , C═NNHCONR 3 R 4 , C═NNHS(O) n R 1 , or C═N—N═CHR 1 ;

R a , R b , R c , and R d are independently selected from —R 1 , —OR 1 , —S(O) n R 1 , —C(O)OR 1 , —OC(O)R 1 , —OC(O)OR 1 , —C(O)R 1 , —C(O)NH—R 1 , —NHC(O)—R 1 , —N(R 3 )(R 4 ), —NHC(O)—OR 1 , —NHC(O)NH—R 1 , or —OC(O)NH—R 1 ;

or R a and R b , R a and R c , R a and R d , R b and R c , R b and R d , or R c and R d , taken together with the carbon atom or atoms to which they are attached, are selected from substituted or unsubstituted alicyclic or substituted or unsubstituted heterocyclic;

one of R e and R f is selected from hydrogen or methyl, and the other is independently selected from halogen, deuterium, or R 1 ;

R h is hydroxy;

R g is selected from hydrogen, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group;

or R g and R h , taken together with the carbon atom to which they are attached, are selected from an epoxide, a carbonyl, a substituted or unsubstituted olefin, a substituted or unsubstituted alicyclic, a substituted or unsubstituted heterocyclic;

W is NR 3 R 4 ;

one of X and Y is hydrogen, substituted or unsubstituted aliphatic, and the other is independently selected from: hydroxy, —SH, —NH 2 , or —NR 1 H;

or X and Y, taken together with the carbon atom to which they are attached, are selected from: C═O, C═NR 1 , C═NOR 1 , C═NO(CH 2 ) m R 1 , C═NNHR 1 , C═NNHCOR 1 , C═NNHCONR 3 R 4 , C═NNHS(O) n R 1 , or C═N—N═CHR 1 ;

R p is selected from hydrogen, acyl, silane, or a hydroxy protecting group;

X H is selected from hydrogen or halogen;

m is an integer; and

n is 0, 1, or 2.

6. The process of claim 5 , wherein, for the macrocylic compound, L is ethyl.

7. The process of claim 5 , wherein, for the macrocylic compound, one of X and Y is hydrogen and the other is selected from hydroxy or amino.

8. The process of claim 5 , wherein, for the macrocylic compound, X and Y, taken together with the carbon atom to which they are attached, are selected from the group consisting of: C═O, C═NH, C═N—OH, or C═N—NH 2 .

9. The process of claim 5 , wherein, for the macrocylic compound, R g is methyl.

10. The process of claim 5 , wherein, for the macrocylic compound, R e is hydrogen and R f is selected from methyl, allyl, or propargyl.

11. The process of claim 5 , wherein, for the macrocyclic compound, one of U and V is hydrogen and the other is selected from —OH or —O-cladinose.

12. The process of claim 5 , wherein, for the macrocylic compound, U and V, taken together with the carbon atom to which they are attached, are C═O.

13. The process of claim 1 wherein each of the two nucleophilic moieties is alkylated by a functional group of the bridging component.