Synthesis of tetracyclines and analogues thereof
The tetracycline class of antibiotics has played a major role in the treatment of infectious diseases for the past 50 years. However, the increased use of the tetracyclines in human and veterinary medicine has led to resistance among many organisms previously susceptible to tetracycline antibiotics. The modular synthesis of tetracyclines and tetracycline analogs described provides an efficient and enantioselective route to a variety of tetracycline analogs and polycyclines previously inaccessible via earlier tetracycline syntheses and semi-synthetic methods. These analogs may be used as anti-microbial agents or anti-proliferative agents in the treatment of diseases of humans or other animals.
1. A compound of Formula:
or a salt, isomer, or tautomer thereof;
wherein:
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
R 4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR D ; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N(R D ) 2 ; —NHC(O)R D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
R 5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR E ; —CN; —SCN; —SR E ; or —N(R E ) 2 ; wherein each occurrence of R E is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
each occurrence of R 7 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR G ; —C(═O)R G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; —NO 2 ; —N(R G ) 2 ; —NHC(O)R G ; or —C(R G ) 3 ; wherein each occurrence of R G is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
each occurrence of P′ is independently hydrogen or a protecting group; and
n is an integer in the range of 0 to 3, inclusive.
2. The compound of claim 1 , wherein each instance of R 1 , R 2 , R 3 , and R 4 is hydrogen.
3. The compound of claim 1 , wherein R 5 is —N(R E ) 2 , wherein each occurrence of R E is independently hydrogen, a protecting group, or lower (C 1 -C 6 ) alkyl.
4. The compound of claim 3 , wherein R 5 is —N(CH 3 ) 2 .
5. The compound of claim 1 , wherein each occurrence of R 7 is independently halogen; cyclic substituted or unsubstituted heteroaliphatic; substituted or unsubstituted heteroaryl; —OR G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; or —NHC(O)R G ; wherein each occurrence of R G is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio.
6. The compound of claim 5 , wherein at least one instance of R 7 is —NHC(O)R G .
7. The compound of claim 5 , wherein at least one instance of R 7 is halogen.
8. The compound of claim 7 , wherein halogen is —F.
9. The compound of claim 5 , wherein at least one instance of R 7 is —OR G .
10. The compound of claim 5 , wherein at least one instance of R 7 is cyclic substituted or unsubstituted heteroaliphatic.
11. The compound of claim 5 , wherein one instance of R 7 is —OR G and one instance of R 7 is cyclic substituted or unsubstituted heteroaliphatic.
12. The compound of claim 5 , wherein one instance of R 7 is halogen and one instance of R 7 is —NHC(O)R G .
13. The compound of claim 12 , wherein halogen is —F.
14. The compound of claim 5 , wherein one instance of R 7 is —OR G and one instance of R 7 is halogen.
15. The compound of claim 14 , wherein halogen is —F.
16. The compound of claim 1 , wherein n is 0.
17. The compound of claim 1 , wherein n is 1.
18. The compound of claim 1 , wherein n is 2.
19. The compound of claim 1 , wherein n is 3.
20. The compound of claim 1 , wherein the compound is:
or a salt, isomer, or tautomer thereof;
wherein:
n is 0, 1, or 2; and
P is hydrogen, lower alkyl group, acyl group, or a protecting group.