IP Library › Granted Patent US 8,921,599

Granted Patent B2

US 8,921,599 · App. 13/280,991 · Granted Dec 30, 2014

Processes for forming amide bonds and compositions related thereto

Inventors: Lanny S. Liebeskind (Atlanta, GA); Wenting Wu (Decatur, GA); Zhihui Zhang (Downers Grove, IL); Hao Li (Decatur, GA); Angus A. Lamar (Atlanta, GA)

Assignee: Emory University

C07H1/00 C07D213/82 C07D233/90 C07D295/192 C07D307/52 C07F7/1852 C07F7/1856 C07H21/02 C07K1/003 C07K1/02 C07K5/06026 C07K5/06034 C07K5/0606 C07K5/06078 C07K5/06086 C07K5/06104 C07K5/0812

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Quick Facts

Patent No.: US 8,921,599
App. No.: 13/280,991
Granted: Dec 30, 2014
Kind: B2

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Abstract

The disclosure relates to methods for producing amide bonds and reagents related thereto. In some embodiments, the disclosure relates to methods of producing an amide comprising mixing an O-silylated thionoester and an amine under conditions such that an amide is formed. In another embodiment, the disclosure relates to mixing a thiolacid, a silylating agent, and an amine under conditions such that an amide is formed.

Claims (199)

1. A compound comprising the following formula:

wherein,

Prot is a protecting group, wherein Prot is tert-butoxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc), peptide, or linker to a substrate or biological material, or R 13 ;

n is 1, 2, 3, 4, 5, or 6;

each R 5 is independently selected from hydrogen, alkyl, hydroxyalkyl, thiolalkyl, aminoalkyl, selenoalkyl, carboxylalkyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more R 11 ;

each R 6 is independently selected from hydrogen, alkyl, aryl, and heterocyclyl, wherein R 6 is optionally substituted by one or more substituents independently selected from halogen, alkyl, and alkoxy;

R 10 is hydrogen, alkyl, or acyl, or

R 10 and Prot and the attached atoms form a protecting group comprising a 4 to 7 member heterocyclic ring, wherein the heterocyclyl is optionally substituted with one or more R 11 or

or R 10 and R 5 and the atoms to which they are attached to form a 4-7 membered heterocyclic ring optionally substituted with one or more R 11 ;

R 11 is independently selected from alkyl, alkenyl, alkanoyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl wherein R 11 is optionally substituted with R 12 ;

R 12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl;

R 13 is alkyl, alkanoyl, formyl, alkylcarboxy, alkylcarbamoyl wherein R 13 is optionally substituted with R 14

R 14 is independently selected from alkyl, alkenyl, alkanoyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl wherein R 14 is optionally substituted with R 15 ;

R 15 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.

2. The composition of claim 1 , wherein n is 1 or 2.

3. The composition of claim 1 , where the biological material is a polypeptide, enzyme, receptor, nucleic acid, cell, antibody, saccharide, or glycopeptide.

4. The composition of claim 1 , wherein the linker is an peptide, a nucleic acid, hydrocarbon, polyethylene glycol, polysaccharide, acrylate polymer, or other polymer.

5. A compound selected from N-alpha-Boc-alanine-O-trimethylsilylthionoester,

N-beta-Boc-beta-alanine-O-trimethylsilylthionoester,

N-alpha-Boc-N-alpha-methyl-alanine-O-trimethylsilylthionoester,

N-alpha-Boc-alpha-aminobutyric acid O-trimethylsilylthionoester,

N-Boc-4-aminobutanoic acid O-trimethylsilylthionoester,

N-alpha-Boc-alpha-aminoisobutyric acid O-trimethylsilylthionoester,

N-alpha-Boc-N G -(4-Methoxy-2,3,6 trimethylbenzenesulfonyl)-arginine-O-trimethylsilylthionoester,

N-alpha-Boc-N G -nitro-arginine-O-trimethylsilylthionoester,

N-alpha-Boc-N G -tosyl-arginine-O-trimethylsilylthionoester,

N-alpha-Boc-N G ,N G -bis-CBZ-arginine-O-trimethylsilylthionoester,

N-alpha-Boc-asparagine-O-trimethylsilylthionoester,

N-alpha-Boc-beta-trityl-asparagine-O-trimethylsilylthionoester,

N-alpha-Boc-N-beta-xanthyl-asparagine-O-trimethylsilylthionoester,

N-alpha-Boc-isoasparagine-O-trimethylsilylthionoester,

N-alpha-Boc-aspartic acid alpha-O-trimethylsilylthionoester beta-1-adamantyl ester,

N-alpha-Boc-aspartic acid alpha-O-trimethylsilylthionoester beta-2-adamantyl ester,

N-alpha-Boc-aspartic acid alpha-benzyl ester beta-O-trimethylsilylthionoester,

N-alpha-Boc-N-alpha-methyl-valine-O-trimethylsilylthionoester,

N-alpha-Boc-valine-O-trimethylsilylthionoester,

Boc-6-aminohexanoic acid O-trimethylsilylthionoester,

N-alpha-Boc-tert-leucine-O-trimethylsilylthionoester,

N-alpha-Boc-S-acetamidomethyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Boc-S-benzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Boc-S-p-methylbenzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Boc-S-p-methoxybenzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Boc-S-trityl-cysteine-O-trimethylsilylthionoester,

N-alpha-Boc-beta-cyclohexyl-alanine-O-trimethylsilylthionoester,

N-alpha-Boc-glutamic acid gama-O-trimethylsilylthionoester alpha-benzyl ester,

N-alpha-Boc-glutamic acid gama-benzyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Boc-glutamic acid gama-cyclohexyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Boc-glutamic acid gama-tert-butyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Boc-gama-trityl-glutamine-O-trimethylsilylthionoester,

N-alpha-Boc-gama-xanthyl-glutamine-O-trimethylsilylthionoester,

N-alpha-N-im-di-Boc-histidine-O-trimethylsilylthionoester,

N-alpha-Boc-N-im-tosyl-histidine-O-trimethylsilylthionoester,

N-alpha-Boc-N-im-dinitrophenyl-histidine-O-trimethylsilylthionoester,

N-alpha-Boc-N-im-trityl-histidine-O-trimethylsilylthionoester,

N-alpha-Boc-trans-4-hydroxyproline-O-trimethylsilylthionoester,

N-alpha-Boc-glycine-O-trimethylsilylthionoester,

N-alpha-Boc-isoleucine-O-trimethylsilylthionoester,

N-alpha-Boc-N-epsilon-acetyl-lysine-O-trimethylsilylthionoester,

N-alpha,epsilon-di-Boc-lysine-O-trimethylsilylthionoester,

N-alpha-Boc-N-epsilon-2-chloro-CBZ-lysine-O-trimethylsilylthionoester,

N-alpha-Boc-N-epsilon-trifluoroacetyl-lysine-O-trimethylsilylthionoester,

N-alpha-Boc-leucine-O-trimethylsilylthionoester,

N-alpha-Boc-methionine-sulfone-O-trimethylsilylthionoester,

N-alpha-Boc-methionine-O-trimethylsilylthionoester,

N-alpha-Boc-methionine-sulfoxide-O-trimethylsilylthionoester,

N-alpha-Boc-N-alpha-methyl-norleucine-O-trimethylsilylthionoester,

N-alpha-Boc-norleucine-O-trimethylsilylthionoester,

N-alpha-Boc-norvaline-O-trimethylsilylthionoester,

N-alpha-Boc-3,4-dehydro-proline-O-trimethylsilylthionoester,

N-alpha-Boc-proline-O-trimethylsilylthionoester,

N-alpha-Boc-N-alpha-methyl-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Boc-4-chloro-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Boc-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Boc-phenylglycine-O-trimethylsilylthionoester,

N-alpha-Boc-N-δ-benzyloxycarbonyl-ornithine-O-trimethylsilylthionoester,

N-alpha-Boc-sarcosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-benzyl-serine-O-trimethylsilylthionoester,

N-alpha-Boc-O-methyl-serine-O-trimethylsilylthionoester,

N-alpha-Boc-O-tert-butyl-serine-O-trimethylsilylthionoester,

N-1-Boc-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid alpha-O-trimethylsilylthionoester,

N-alpha-Boc-N-in-Boc-trypophan-O-trimethylsilylthionoester,

N-alpha-Boc-N-in-formyl-tryptophan-O-trimethylsilylthionoester,

N-alpha-Boc-N-in-mesitylene-2-sulfonyl-tryptophan-O-trimethylsilylthionoester,

N-alpha-Boc-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-N-alpha-methyl-O-benzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-2-bromobenzyloxycarbonyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-benzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-2,6-dichlorobenzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-ethyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-methyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-tert-butyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Boc-O-benzyl-threonine-O-trimethylsilylthionoester,

N-alpha-Boc-threonine-O-trimethylsilylthionoester,

N-alpha-Fmoc-alanine-O-trimethylsilylthionoester,

N-beta-Fmoc-beta-alanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-alpha-methyl-alanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-alpha-aminobutyric acid O-trimethylsilylthionoester,

N-Fmoc-4-aminobutanoic acid O-trimethylsilylthionoester,

N-alpha-Fmoc-alpha-aminoisobutyric acid O-trimethylsilylthionoester,

N-alpha-Fmoc-N G -(4-Methoxy-2,3,6 trimethylbenzenesulfonyl)-arginine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N G -nitro-arginine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N G -tosyl-arginine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N G ,N G -bis-CBZ-arginine-O-trimethylsilylthionoester,

N-alpha-Fmoc-asparagine-O-trimethylsilylthionoester,

N-alpha-Fmoc-beta-trityl-asparagine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-beta-xanthyl-asparagine-O-trimethylsilylthionoester,

N-alpha-Fmoc-isoasparagine-O-trimethylsilylthionoester,

N-alpha-Fmoc-aspartic acid alpha-O-trimethylsilylthionoester beta-1-adamantyl ester,

N-alpha-Fmoc-aspartic acid alpha-O-trimethylsilylthionoester beta-2-adamantyl ester,

N-alpha-Fmoc-aspartic acid alpha-benzyl ester beta-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-alpha-methyl-valine-O-trimethylsilylthionoester,

N-alpha-Fmoc-valine-O-trimethylsilylthionoester,

Fmoc-6-aminohexanoic acid 0 -trimethylsilylthionoester,

N-alpha-Fmoc-tert-leucine-O-trimethylsilylthionoester,

N-alpha-Fmoc-S-acetamidomethyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Fmoc-S-benzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Fmoc-S-p-methylbenzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Fmoc-S-p-methoxybenzyl-cysteine-O-trimethylsilylthionoester,

N-alpha-Fmoc-S-trityl-cysteine-O-trimethylsilylthionoester,

N-alpha-Fmoc-beta-cyclohexyl-alanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-glutamic acid gama-O-trimethylsilylthionoester alpha-benzyl ester,

N-alpha-Fmoc-glutamic acid gama-benzyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Fmoc-glutamic acid gama-cyclohexyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Fmoc-glutamic acid gama-tert-butyl ester alpha-O-trimethylsilylthionoester,

N-alpha-Fmoc-gama-trityl-glutamine-O-trimethylsilylthionoester,

N-alpha-Fmoc-gama-xanthyl-glutamine-O-trimethylsilylthionoester,

N-alpha-N-im-di-Fmoc-histidine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-im-tosyl-histidine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-im-dinitrophenyl-histidine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-im-trityl-histidine-O-trimethylsilylthionoester,

N-alpha-Fmoc-trans-4-hydroxyproline-O-trimethylsilylthionoester,

N-alpha-Fmoc-glycine-O-trimethylsilylthionoester,

N-alpha-Fmoc-isoleucine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-epsilon-acetyl-lysine-O-trimethylsilylthionoester,

N-alpha,epsilon-di-Fmoc-lysine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-epsilon-2-chloro-CBZ-lysine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-epsilon-trifluoroacetyl-lysine-O-trimethylsilylthionoester,

N-alpha-Fmoc-leucine-O-trimethylsilylthionoester,

N-alpha-Fmoc-methionine-sulfone-O-trimethylsilylthionoester,

N-alpha-Fmoc-methionine-O-trimethylsilylthionoester,

N-alpha-Fmoc-methionine-sulfoxide-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-alpha-methyl-norleucine-O-trimethylsilylthionoester,

N-alpha-Fmoc-norleucine-O-trimethylsilylthionoester,

N-alpha-Fmoc-norvaline-O-trimethylsilylthionoester,

N-alpha-Fmoc-3,4-dehydro-proline-O-trimethylsilylthionoester,

N-alpha-Fmoc-proline-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-alpha-methyl-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-4-chloro-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-phenylalanine-O-trimethylsilylthionoester,

N-alpha-Fmoc-phenylglycine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-δ-benzyloxycarbonyl-omithine-O-trimethylsilylthionoester,

N-alpha-Fmoc-sarcosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-benzyl-serine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-methyl-serine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-tert-butyl-serine-O-trimethylsilylthionoester,

N-1-Fmoc-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid alpha-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-in-Fmoc-trypophan-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-in-formyl-tryptophan-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-in-mesitylene-2-sulfonyl-tryptophan-O-trimethylsilylthionoester,

N-alpha-Fmoc-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-N-alpha-methyl-O-benzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-2-bromobenzyloxycarbonyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-benzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-2,6-dichlorobenzyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-ethyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-methyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-tert-butyl-tyrosine-O-trimethylsilylthionoester,

N-alpha-Fmoc-O-benzyl-threonine-O-trimethylsilylthionoester, and

N-alpha-Fmoc-threonine-O-trimethylsilylthionoester.

6. A compound comprising the following formula:

wherein,

Prot is a protecting group, wherein Prot is 4-methoxy-2,3,6-trimethylphenyl)sulfonyl (Mtr), 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pmc), tosyl (Tos), mesitylenesulfonyl (Mts), 4,4′-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), tripheylmethyl (Trt), tert-buty (tBu), benzyl (Bzl), t-Butoxymethyl ether (Bum), (2,4-dinitrophenol) Dnp, benzyloxymethyl (Bom), benzyloxycarbonyl (Z), 2-chloro-benzyloxycarbonyl (CIZ), formyl (CHO) or 2-bromobenzyloxycarbonyl (BrZ);

n is 1, 2, 3, 4, 5, or 6;

R 10 is hydrogen, alkyl, or acyl, or

R 10 and Prot and the attached atoms form a protecting group comprising a 4 to 7 member heterocyclic ring, wherein the heterocyclyl is optionally substituted with one or more R 11 or

or R 10 and R 5 and the atoms to which they are attached to form a 4-7 membered heterocyclic ring optionally substituted with one or more R 11 ;

R 13 is alkyl, alkanoyl, formyl, alkylcarboxy, alkylcarbamoyl wherein R 13 is optionally substituted with R 14

R 15 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N- methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.

7. A compound comprising the following formula:

wherein,

Prot is a protecting group, peptide, or linker to a substrate or biological material, or R 13 ;

n is 1, 2, 3, 4, 5, or 6;

R 10 is hydrogen or

R 10 and Prot and the attached atoms form a protecting group comprising a 4 to 7 member heterocyclic ring, wherein the heterocyclyl is optionally substituted with one or more R 11 or

or R 10 and R 5 and the atoms to which they are attached to form a 4-7 membered heterocyclic ring optionally substituted with one or more R 11 ;

R 13 is alkyl, alkanoyl, formyl, alkylcarboxy, alkylcarbamoyl wherein R 13 is optionally substituted with R 14

Assignments (3)

CONFIRMATORY LICENSE Recorded Jan 5, 2015

From: EMORY UNIVERSITY

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

Reel/Frame 034722/0432 →

CONFIRMATORY LICENSE Recorded Feb 21, 2012

From: EMORY UNIVERSITY

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

Reel/Frame 027736/0323 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2011

From: LIEBESKIND, LANNY S.; WU, WENTING; ZHANG, ZHIHUI; LAMAR, ANGUS A.; LI, HAO

To: EMORY UNIVERSITY

Reel/Frame 027315/0409 →

Continuity (2)

Provisional Application 61407089 · Oct 27, 2010

Related Publication 20120107902A1 · May 3, 2012