Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors.

The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations.

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

An Enantioselective Synthesis of an 11-ß-HSD-1 Inhibitor via an Asymmetric Methallylation Catalyzed by (S)-3,3'-F2-BINOL.

An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon-14 and stable isotopes.

Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-(14)C]pyrimidine [(14)C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [(14)C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [(14)C]-carbon dioxide. A chiral auxiliary (S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [(14)C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [(14)C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [(14)C]-(18) and finally removal of the chiral auxiliary gave [(14)C]-(2) in 7% overall yield. For stable isotope syntheses, [(13)C6]-(1) was obtained in three steps using [(13)C4]-(6) and trimethylsilylacetylene-[(13)C2] in 26% yield, while [(2)H5]-(2) was obtained by first preparing the iodopyridine [(2)H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [(2)H5]-(2) in 42% overall yield.

Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate.

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

Asymmetric methallylation of ketones catalyzed by a highly active organocatalyst 3,3'-F2-BINOL.

(S)-3,3'-F2-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (S)-3,3'-F2-BINOL could be easily recovered and reused.

A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

Room temperature palladium-catalyzed cross coupling of aryltrimethylammonium triflates with aryl Grignard reagents.

Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe(3)OTf relative to PhCl, PhBr, PhI, and PhOTf.

Mild and general zinc-alkoxide-catalyzed allylations of ketones with allyl pinacol boronates.

A general and efficient zinc-alkoxide-catalyzed allylation of a diverse array of ketones with allyl boronates is presented. The methodology is effective with 2 mol % of catalyst and with relatively short reaction times. Studies of the key exchange process are presented, which support a cyclic transition state for the boron to zinc exchange.

Copper catalyzed asymmetric propargylation of aldehydes.

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes.

In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.

Highly diastereoselective zinc-catalyzed propargylation of tert-butanesulfinyl imines.

A zinc-catalyzed diastereoselective propargylation of t-butanesulfinyl imines is presented. The methodology provided both aliphatic and aryl homopropargylic amines in up to 98:2 and 99.8:0.2 dr, respectively. The utility of the homopropargylic amines was demonstrated by the application to the synthesis of a cis-substituted pyrido-indole through a diastereoselective Pictet-Spengler cyclization.

Zinc catalyzed and mediated propargylations with propargyl boronates.

The utility of allenyl and propargyl boronates for the propargylation of aldehydes and ketones mediated by zinc is presented. The reaction is catalytic in zinc with allenyl or propargyl borolanes. The propargylation with crystalline and air-stable propargyl diethanolamine boronates was also achieved. A catalytic cycle is proposed, and preliminary mechanistic studies are discussed.

Regioselective allene synthesis and propargylations with propargyl diethanolamine boronates.

The utility of propargyl diethanolamine boronates as reagents for the preparation of allenes and homopropargylic alcohols is presented. Protonolysis with TFA and electrophilic substitution with N-halosuccinimides proceeded with inversion to provide the corresponding allene in high yield and regioselectivity. Alternatively, the propargylation of aldehydes was achieved with use of the in situ generated lithiated complex.

Trifluoromethyl ketones from enolizable carboxylic acids via enediolate trifluoroacetylation/decarboxylation.

Primary and secondary (enolizable) carboxylic acids were converted in a single step to trifluoromethyl ketones. Treatment of the acid with 2.2 equiv of LDA generated an enediolate that was trifluoroacetylated with EtO(2)CCF(3). Quenching the reaction mixture with aqueous HCl resulted in rapid decarboxylation and provided the trifluoromethyl ketone product in good yield. The process may be performed at -20 degrees C with a slight reduction in yield. The reaction was extended to the preparation of pentafluoroethyl and chlorodifluoromethyl ketones.

N-heterocyclic carbene-catalyzed silyl enol ether formation.

N-Heterocyclic carbenes (NHCs) were found to catalyze the silyl transfer from trialkylsilyl ketene acetals to ketones. In the presence of a catalytic amount of NHC 3 (IAd, 0.1 to 5 mol %), a series of enolizable ketones as well as cyclohexanecarboxaldehyde were efficiently converted into the corresponding silyl enol ethers at 23 degrees C in THF.