IP Library › Granted Patent US 9,365,493

Granted Patent B2

US 9,365,493 · App. 14/063,868 · Granted Jun 14, 2016

Synthesis of tetracyclines and analogues thereof

Inventors: Andrew G. Myers (Boston, MA); Mark G. Charest (Belle Mead, NJ); Christian D. Lerner (Binningen, CH); Jason D. Brubaker (Cheshire, CT); Dionicio R. Siegel (New York, NY)

Assignee: President and Fellows of Harvard College

C07C231/10 C07C237/26 C07D209/56 C07D209/58 C07D213/56 C07D221/18 C07D235/02 C07D237/26 C07D239/70 C07D241/38 C07D261/20 C07D263/52 C07D277/30 C07D277/56 C07D277/64 C07D277/66 C07D307/77

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Quick Facts

Patent No.: US 9,365,493
App. No.: 14/063,868
Granted: Jun 14, 2016
Kind: B2

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Abstract

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.

Claims (194)

1. A method of synthesizing a compound of formula:

or 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;

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; 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; and

n is 0 or an integer in the range of 1 to 3, inclusive;

the method comprising:

reacting an anion of a toluate, wherein the toluate is of formula:

wherein the anion is formed by deprotonation of a toluate under basic conditions, and

wherein:

R 9 is —OR I , —CN, —SCN, —SR I , or —N(R I ) 2 ; and each R I is independently hydrogen; a protecting group; a cyclic or acyclic, substituted or unsubstituted aliphatic; a cyclic or acyclic, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; or a substituted or unsubstituted heteroaryl; and

P is hydrogen, lower (C 1 -C 6 ) alkyl, acyl, or a protecting group;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group;

to provide a compound of formula:

or a salt, isomer, or tautomer thereof.

2. The method of claim 1 , wherein each instance of R 1 , R 2 , R 3 , and R 4 is hydrogen.

3. The method of claim 1 , wherein R 5 is —N(R E ) 2 , and wherein each occurrence of R E is independently hydrogen, a protecting group, or lower (C 1 -C 6 ) alkyl.

4. The method of claim 1 , wherein R 5 is —N(R E ) 2 and both R E are methyl.

5. The method 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 method of claim 5 , wherein at least one instance of R 7 is —NHC(O)R G .

7. The method of claim 5 , wherein at least one instance of R 7 is —OR G .

8. The method of claim 5 , wherein at least one instance of R 7 is halogen.

9. The method of claim 5 , wherein at least one instance of R 7 is cyclic substituted or unsubstituted heteroaliphatic.

10. The method of claim 1 , wherein P is a protecting group.

11. The method of claim 1 , wherein each occurrence of P′ is a protecting group.

12. A method of synthesizing a compound of formula:

or salt, isomer, or tautomer thereof;

wherein:

R 2 is hydrogen;

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;

n is 0 or an integer in the range of 1 to 3, inclusive;

the method comprising:

reacting an anion of a toluate, wherein the toluate is of formula:

wherein the anion is formed by deprotonation of a toluate under basic conditions, and

wherein:

R 9 is —OR I ; —CN; —SCN; —SR I ; or —N(R I ) 2 ; and each R I is independently hydrogen; a protecting group; a cyclic or acyclic, substituted or unsubstituted aliphatic; a cyclic or acyclic, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; or a substituted or unsubstituted heteroaryl; and

P is hydrogen, lower (C 1 -C 6 ) alkyl, acyl, or a protecting group;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group;

to provide a compound of formula:

or a salt, isomer, or tautomer thereof, wherein R 5 is —N(R E ) 2 ; and

deprotecting the compound of formula:

or a salt, isomer, or tautomer thereof, wherein R 5 is —N(R E ) 2 ,

to provide a tetracycline of formula:

or a salt, isomer, or tautomer thereof.

13. A method of synthesizing a compound of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 2 is hydrogen;

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; 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;

n is 0 or an integer in the range of 1 to 3, inclusive;

by reacting an anion of a toluate, wherein the toluate has the formula:

wherein the anion is produced by metallation of the toluate, and

wherein:

R 9 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

Y is a halogen or Sn(R Y ) 3 , wherein R Y is alkyl;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group;

to provide a compound of formula:

or a salt, isomer, or tautomer thereof.

14. A method of synthesizing a compound of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 2 is hydrogen;

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; 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;

n is 0 or an integer in the range of 1 to 3, inclusive;

by reacting an anion of a toluate, wherein the toluate has the formula:

wherein the anion is produced by metallation of the toluate, and

wherein:

R 9 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

Y is a halogen or Sn(R Y ) 3 wherein R Y is alkyl;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group;

to provide a compound of formula:

or a salt, isomer, or tautomer thereof; and

deprotecting the compound of formula:

or a salt, isomer, or tautomer thereof,

to provide a tetracycline of formula:

or a salt, isomer, or tautomer thereof.

15. A method of synthesizing 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;

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;

represents a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic moiety, in which each occurrence of X is selected from the group consisting of —O—, —S—, —NR 8 —, and —C(R 8 ) 2 —;

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; 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;

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;

by reacting an anion of a toluate, wherein the toluate has the formula:

wherein the anion is formed by deprotonation of a toluate under basic conditions, and wherein R 9 is selected from the group consisting of substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group; and

deprotecting to provide a compound of formula:

or a salt, isomer, or tautomer thereof.

16. The method of claim 15 , wherein

represents a substituted or unsubstituted heterocyclic.

17. The method of claim 15 , wherein

represents a substituted or unsubstituted carbocyclic.

18. The method of claim 15 , wherein

represents a substituted or unsubstituted heteroaryl.

19. The method of claim 15 , wherein

represents a substituted or unsubstituted aryl.

20. A method of synthesizing 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;

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;

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;

by reacting an anion of a toluate, wherein the toluate has the formula:

and wherein the anion is formed by metalation of the toluate,

wherein:

R 9 is selected from the group consisting of substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

Y is a halogen or Sn(R Y ) 3 , wherein R Y is alkyl;

with an enone of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 6 is hydrogen; and

each P′ is independently hydrogen or a protecting group; and

deprotecting to provide a compound of formula:

or a salt, isomer, or tautomer thereof.

21. A method of synthesizing a compound of formula:

or salt, isomer, or tautomer thereof;

the method comprising deprotecting the compound of formula:

or a salt, isomer, or tautomer thereof, wherein R 5 is —N(R E ) 2 ,

to provide a tetracycline of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 2 is hydrogen;

n is 0 or an integer in the range of 1 to 3, inclusive;

P is hydrogen, lower (C 1 -C 6 ) alkyl, acyl, or a protecting group; and

each P′ is independently hydrogen or a protecting group.

22. A method of synthesizing a compound of formula:

or a salt, isomer, or tautomer thereof;

the method comprising deprotecting the compound of formula:

or a salt, isomer, or tautomer thereof,

to provide a tetracycline of formula:

or a salt, isomer, or tautomer thereof;

wherein:

R 2 is hydrogen;

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; 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;

n is 0 or an integer in the range of 1 to 3, inclusive; and

each P′ is independently hydrogen or a protecting group.

Assignments (2)

CONFIRMATORY LICENSE Recorded Jan 13, 2021

From: HARVARD UNIVERSITY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 054978/0442 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 13, 2013

From: BRUBAKER, JASON D.; CHAREST, MARK G.; LERNER, CHRISTIAN D.; MYERS, ANDREW G.; SIEGEL, DIONICIO R.

To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE

Reel/Frame 031591/0878 →

Continuity (5)

Continuation 12778797 · May 12, 2010

Division 11133789 · May 20, 2005

Provisional Application 60573623 · May 21, 2004

Provisional Application 60660947 · Mar 11, 2005

Related Publication 20140163238A1 · Jun 12, 2014