Practical syntheses of a CXCR3 antagonist.

Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.

Iodide-catalyzed reductions: development of a synthesis of phenylacetic acids.

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.

Asymmetric synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor.

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

An efficient and scalable Ritter reaction for the synthesis of tert-butyl amides.

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.

Pd-catalyzed deoxygenation of mandelate esters.

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

A case of remote asymmetric induction in the peptide-catalyzed desymmetrization of a bis(phenol).

We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.

Highly selective cascade couplings for the syntheses of functionalized piperidinones and bispidines.

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.

An efficient and scalable synthesis of substituted phenanthrenequinones by intramolecular Friedel-Crafts reaction of imidazolides.

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).

Novel intramolecular reactivity of oximes: synthesis of cyclic and spiro-fused imines.

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]

Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947.

[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.

Direct N-acetyl enamine formation: lithium bromide mediated addition of methyllithium to nitriles.

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.

Synthetic methodology utilized to prepare substituted imidazole p38 MAP kinase inhibitors.

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.

An expedient synthesis of highly functionalized naphthyridones and quinolines from a common N-aryl pyridinone template.

[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.

Efficient and general protocol for the copper-free sonogashira coupling of aryl bromides at room temperature.

[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.

Improved carbonylation of heterocyclic chlorides and electronically challenging aryl bromides.

[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.

Synthesis of substituted imidazoles via organocatalysis.

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]

Pseudoephedrine as a chiral auxiliary for asymmetric Michael reactions: synthesis of 3-aryl-delta-lactones.

[reaction: see text] The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-delta-lactones in a two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones.

Human therapies as a successful liaison between chemistry and biology.

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.

Chlorination/cyclodehydration of amino alcohols with SOCl2: an old reaction revisited.

A simple, one-pot preparation of cyclic amines via efficient chlorination of amino alcohols with use of SOCl(2) has been developed. This approach obviates the need for the classical N-protection/O-activation/cyclization/deprotection sequence commonly employed for this type of transformation. The reaction pathways and the general scope of this method have also been investigated.

Discovery of a stable molecular complex of an API with HCl: a long journey to a conventional salt.

We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 140 degrees C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development.