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1.
Chem Biol ; 21(9): 1046-54, 2014 Sep 18.
Article in English | MEDLINE | ID: mdl-25237852

ABSTRACT

The development of novel therapies is arguably one of the most important roles of modern chemistry and biology. Here, we shed light on a particular class of human therapies in which synthetic chemical entities are attached to expressed biologicals (proteins) with the goal to enhance clinical activity. We focus our discussion on three key categories of these derivatized biologicals: proteins conjugated with biologically inert molecules, proteins conjugated with biologically active small molecules and peptides (e.g., antibody drug conjugates [ADCs]), and proteins conjugated with radio isotopes. Overall, it is apparent by the impact on clinical activity as well as the commercial success that chemical modification of recombinant proteins is becoming of increasing importance. Therefore, we argue that deeper understanding of the chemical reactions between large proteinaceous molecules and small molecule reagents will allow for more precise and elegant solutions to existing limitations in this field.


Subject(s)
Pharmaceutical Preparations/metabolism , Proteins/metabolism , Antibodies/chemistry , Antibodies/metabolism , Humans , Immunoconjugates/chemistry , Immunoconjugates/therapeutic use , Immunotoxins/chemistry , Immunotoxins/therapeutic use , Neoplasms/drug therapy , Peptides/chemistry , Peptides/metabolism , Pharmaceutical Preparations/chemistry , Polyethylene Glycols/chemistry , Proteins/chemistry , Proteins/genetics , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/therapeutic use , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/therapeutic use
2.
J Org Chem ; 76(22): 9519-24, 2011 Nov 18.
Article in English | MEDLINE | ID: mdl-21988471

ABSTRACT

A new convenient and scalable synthesis of phenylacetic acids has been developed via the iodide catalyzed reduction of mandelic acids. The procedure relies on in situ generation of hydroiodic acid from catalytic sodium iodide, employing phosphorus acid as the stoichiometric reductant.


Subject(s)
Iodides/chemistry , Phenylacetates/chemical synthesis , Acids/chemistry , Catalysis , Iodine Compounds/chemistry , Mandelic Acids/chemistry , Molecular Structure , Oxidation-Reduction , Phenylacetates/chemistry , Stereoisomerism
3.
J Org Chem ; 74(5): 2207-9, 2009 Mar 06.
Article in English | MEDLINE | ID: mdl-19245267

ABSTRACT

A scalable procedure for the conversion of nitriles to N-tert-butyl amides via the Ritter reaction was optimized employing tert-butyl acetate and acetic acid. The reaction has a broad scope for aromatic, alkyl, and alpha,beta-unsaturated nitriles.


Subject(s)
Amides/chemical synthesis , Amides/chemistry , Molecular Structure , Nitriles/chemistry , Stereoisomerism
4.
J Org Chem ; 74(1): 445-7, 2009 Jan 02.
Article in English | MEDLINE | ID: mdl-19053601

ABSTRACT

A new approach to the synthesis of phenylacetic acids and esters has been developed via the palladium-catalyzed deoxygenation of mandelate esters.


Subject(s)
Esters/chemistry , Mandelic Acids/chemistry , Organometallic Compounds/chemistry , Oxygen/chemistry , Palladium/chemistry , Catalysis , Esters/chemical synthesis , Molecular Structure , Phenylacetates/chemical synthesis , Phenylacetates/chemistry , Stereoisomerism
6.
Org Lett ; 9(21): 4103-6, 2007 Oct 11.
Article in English | MEDLINE | ID: mdl-17880225

ABSTRACT

An efficient synthesis of 9,10-phenanthrenequinones is described. The two carbonyl groups were introduced by an orthoselective intermolecular Friedel-Crafts reaction of 3-methoxyphenol with ethyl chlorooxoacetate. The formation of a biaryl bond by Suzuki-Miyaura coupling reaction, followed by the hydrolysis of the ester, gave a biaryloxoacetic acid. Treatment of this acid with CDI gave the corresponding imidazolide. The ring closure to the desired phenanthrenequinone was accomplished by intramolecular Friedel-Crafts reaction of the imidazolide promoted by TiCl(4).


Subject(s)
Imidazoles/chemistry , Phenanthrenes/chemical synthesis , Quinones/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Phenanthrenes/chemistry , Quinones/chemistry
7.
Org Lett ; 9(14): 2669-72, 2007 Jul 05.
Article in English | MEDLINE | ID: mdl-17579445

ABSTRACT

Efficient cascade couplings to synthesize functionalized piperidinones 1 and bispidines 2 and 3 have been developed. Simple modifications to the reaction conditions allow for the highly controlled and selective formation of each compound. In addition, the cis isomer of 1 can be selectively obtained under acidic conditions, while the preparation of the corresponding trans isomer can also be readily realized through a base-catalyzed, dynamic crystallization-driven process.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Piperidines/chemical synthesis , Crystallization , Indicators and Reagents , Molecular Conformation , Pharmaceutical Preparations/chemical synthesis , Stereoisomerism
8.
Org Lett ; 9(6): 981-3, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17319674

ABSTRACT

Under conventional heat (135-145 degrees C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a novel sp3 C-H activated cyclization to produce the corresponding isoindoles, and aliphatic oximes afford the corresponding dihydropyrroles. The cyclization occurs with various substrates in good yield (46-82%) leading to unique spiro-fused and cyclic imines. An initial mechanistic investigation suggests the reaction occurs via a nitrenium or vinyl nitrene intermediate. [reaction: see text]


Subject(s)
Combinatorial Chemistry Techniques , Imines/chemical synthesis , Oximes/chemistry , Spiro Compounds/chemical synthesis , Acetic Anhydrides/chemistry , Cyclization , Hot Temperature , Imines/chemistry , Indoles/chemistry , Microwaves , Models, Chemical , Pyrroles/chemistry , Vinyl Compounds/chemistry
9.
Org Lett ; 8(17): 3885-8, 2006 Aug 17.
Article in English | MEDLINE | ID: mdl-16898842

ABSTRACT

[reaction: see text] An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.


Subject(s)
Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cyclopropanes/chemical synthesis , Aza Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclopropanes/chemistry , Molecular Structure , Nitriles/chemistry , Stereoisomerism
10.
Org Lett ; 8(18): 3903-6, 2006 Aug 31.
Article in English | MEDLINE | ID: mdl-16928034

ABSTRACT

An improved protocol for N-acetyl enamine formation is disclosed which involves LiBr-mediated addition of MeLi to substituted nitriles. The resulting enamides are isolated in high yields and excellent purity which permits subsequent hydrogenation at very low catalyst loading.

11.
J Org Chem ; 69(15): 5120-3, 2004 Jul 23.
Article in English | MEDLINE | ID: mdl-15255748

ABSTRACT

A general procedure for the synthesis of 4-arylpiperidines via the coupling of 4-(N-BOC-piperidyl)zinc iodide with aryl halides and triflates is presented. The reaction requires cocatalysis with both Cl(2)Pd(dppf) and a copper(I) species. An improved, safer procedure for the activation of zinc dust is also presented.

12.
Org Lett ; 6(13): 2097-100, 2004 Jun 24.
Article in English | MEDLINE | ID: mdl-15200294

ABSTRACT

[reaction: see text] Optimized conditions are described that effect the carbonylation of diverse heterocyclic chlorides to yield the desired alkyl esters. In addition, bromoanilines and bromoanisoles, which normally are poor substrates under standard carbonylation protocols, were efficiently converted to the desired products under these new conditions. The nature of the metal bidentate ligand complex was found to be critical. Specifically, a correlation between ligand bite angle and catalytic efficiency is documented.

13.
Org Lett ; 6(5): 843-6, 2004 Mar 04.
Article in English | MEDLINE | ID: mdl-14986989

ABSTRACT

A one-pot synthesis of substituted imidazoles is described. The cornerstone of this methodology involves the thiazolium-catalyzed addition of an aldehyde to an acyl imine to generate the corresponding alpha-ketoamide in situ followed by ring closure to the imidazole in a one-pot sequence. The extension of this methodology to the one-pot synthesis of substituted oxazoles and thiazoles is also described. [reaction: see text]

14.
Org Lett ; 5(22): 4191-4, 2003 Oct 30.
Article in English | MEDLINE | ID: mdl-14572282

ABSTRACT

[reaction: see text]. A mild and general protocol for the copper-free Sonogashira coupling of aryl bromides with acetylenes has been developed. The use of (AllylPdCl)2 and P(t-Bu)3 provides the active Pd(0) catalyst that allows subsequent coupling of various alkynes at room temperature with good to excellent yields.

15.
J Org Chem ; 68(11): 4598-9, 2003 May 30.
Article in English | MEDLINE | ID: mdl-12762782

ABSTRACT

In this paper, we disclose an efficient one-pot procedure for the preparation of substituted 1,8-naphthyridin-4-one analogues. Previous efforts to effect this type of transformation were complicated by the formation of benzene tricarboxylate. Via the use of excess base, the impurity formation was completely inhibited. This allowed for the clean preparation of the desired intermediate and subsequent formation of naphthyridone analogues in a single flask, which could then be crystallized directly from the reaction mixture in good yield and high purity.

16.
Curr Opin Drug Discov Devel ; 6(6): 945-65, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14758763

ABSTRACT

In this manuscript, we review the synthetic methods utilized to prepare a variety of imidazole p38 MAP kinase inhibitors. Several methods have been used to prepare the key templates that are discussed; manipulation of the heterocycles around the imidazole core are also considered in the context of their biological activity. Finally, we discuss new synthetic methodologies discovered in our laboratories, which are useful for the preparation of a member of this class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves the thiazolium-catalyzed cross-benzoin condensation of a pyridine aldehyde with an N-acylimine. The pyridine aldehyde was prepared in three steps and 68% yield from 2-chloro-4-cyanopyridine. The tosylamide precursor to the N-acylimine was prepared in two steps and 93% yield from isonipecotic acid. We demonstrate the scope and some preliminary mechanistic studies concerning this new reaction. The resulting alpha-ketoamide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in six steps and 38% overall yield.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Chemistry, Pharmaceutical , p38 Mitogen-Activated Protein Kinases
17.
Org Lett ; 4(12): 2071-4, 2002 Jun 13.
Article in English | MEDLINE | ID: mdl-12049520

ABSTRACT

[reaction: see text] We describe herein a new base-mediated process for the formation of N-arylpyridinones 2 and their use for the preparation of naphthyridones and quinolines. The cyclization of various hindered enamines with methyl propiolate proceeds efficiently in the presence of NaOH to afford the corresponding N-arylpyridinones. These substrates were then found to undergo subsequent cyclizations to afford highly functionalized naphthyridones and quinolines.

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