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; substituted or unsubstituted 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; substituted or unsubstituted 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 aliphatic; cyclic or acyclic, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted 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; substituted or unsubstituted 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; substituted or unsubstituted 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; substituted or unsubstituted 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, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
represents a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic moiety, wherein each occurrence of X is independently selected from the group consisting of O, S, NR 8 , C(R 8 ) 2 , C(R 8 ), and N, n is an integer in the range of 1 to 5, inclusive, and the bonds between adjacent X moieties are either single or double bonds; and
each occurrence of R 8 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR H ; ═O; —C(═O)R H ; —CO 2 R H ; —CN; —SCN; —SR H ; —SOR H ; —SO 2 R H ; —NO 2 ; —N(R H ) 2 ; —NHC(O)R H ; or —C(R H ) 3 ; wherein each occurrence of R H is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio.
2. The compound of claim 1 , wherein each occurrence of P is hydrogen.
3. The compound of claim 1 , wherein R 1 is hydrogen.
4. The compound of claim 1 , wherein R 2 is hydrogen.
5. The compound of claim 1 , wherein R 3 is hydrogen.
6. The compound of claim 1 , wherein R 4 is hydrogen.
7. The compound of claim 1 , wherein each occurrence of R 1 , R 2 , R 3 , and R 4 is hydrogen.
8. The compound of claim 1 , wherein R 5 is —N(R E ) 2 .
9. The compound of claim 1 , wherein R 5 is —N(CH 3 ) 2 .
10. The compound of claim 1 , wherein each occurrence of R 7 is independently hydrogen, halogen, —OR G , —SR G , or —N(R G ) 2 .
11. The compound of claim 1 , wherein
represents a substituted or unsubstituted phenyl moiety.
12. The compound of claim 1 , wherein
represents a substituted or unsubstituted heteroaryl moiety.
13. The compound of claim 12 , wherein
represents a substituted or unsubstituted heteroaryl moiety selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, and isoquinolinyl.
14. The compound of claim 1 , wherein
represents a substituted or unsubstituted heterocyclic moiety.
15. The compound of claim 14 , wherein
represents a substituted or unsubstituted heterocyclic moiety selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
16. The compound of claim 1 , wherein
is selected from the group consisting of:
17. The compound of claim 1 , wherein
is selected from the group consisting of:
18. The compound of claim 1 , wherein
is selected from the group consisting of:
19. The compound of claim 1 of formula:
or a salt, isomer, or tautomer thereof.
20. The compound of claim 1 of formula:
or a salt, isomer, or tautomer thereof.
21. The compound of claim 1 selected from the group consisting of:
and salts, isomers, and tautomers thereof.
22. A pharmaceutical composition comprising a compound of claim 1 , or a salt, isomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
23. A method of treating a bacterial infection, the method comprising administering an amount of the compound of claim 1 effective to kill or inhibit the growth of the bacteria.
24. The method of claim 23 , wherein the infection is caused by a Gram-positive organism.
25. The method of claim 23 , wherein the infection is caused by a Gram-negative organism.