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Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at MerckCo. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.

The first highly enantioselective iridium-catalyzed allylic alkylation that provides access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This Account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary stereocenter, to our most recent discovery that allows for the synthesis of vicinal quaternary centers.1 Introduction2 Synthesis of Vicinal Tertiary and All-Carbon Quaternary Stereocenters via Enantio- and Diastereoselective Iridium-Catalyzed Allylic Alkylation2.1 Cyclic Nucleophiles2.2 Acyclic Nucleophiles2.3 Alkyl-Substituted Electrophiles3 Umpoled Iridium-Catalyzed Allylic Alkylation Reactions3.1 Tertiary Allylic Stereocenters3.2 Quaternary Allylic Stereocenters4 Synthesis of Vicinal All-Carbon Quaternary Centers via Enantio­selective Iridium-Catalyzed Allylic Alkylation5 Summary and Future Outlook

Transition-metal-catalyzed asymmetric allylic alkylation of enolates is a powerful method for the formation of carbon− carbon bonds. Within this field, palladium-catalyzed allylic alkylation reactions have undoubtedly been the most studied. Aside from limited cases, palladium catalysts preferentially form the linear substitution product through alkylation at the less-substituted terminus of the allylic electrophile (Scheme 1). However, in contrast to palladium, most other transition metals (e.g., Mo, W, Fe, Ru, Co, Rh, Ni, Pt, and Ir) have been shown to favor the construction of the branched product, with iridium catalysts being some of the most efficient and selective. The potential application of these chiral, branched products to the synthesis of natural products and biologically active compounds has motivated the development of practical and reliable transition-metal-catalyzed methods for their construction.

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.

A catalytic, enantioselective formal synthesis of (+)-dichroanone and (+)-taiwaniaquinone H is reported. The all-carbon quaternary stereocenter was constructed by asymmetric conjugate addition catalyzed by a palladium(II) (S)-tert-butylpyridinooxazoline complex. The unexpected formation of a [3.2.1] bicyclic intermediate required the identification of a new route. Analysis of the Hammett constants for para-substituted arenes enabled the rational design of a highly enantioselective conjugate addition substrate that led to the completion of the formal synthesis.

Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities.

The development of the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form an all-carbon quaternary stereogenic center with an aliphatic-substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone-derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.

Transition-metal-catalyzed asymmetric allylic alkylation of enolates is a powerful method for the formation of carbon− carbon bonds. Within this field, palladium-catalyzed allylic alkylation reactions have undoubtedly been the most studied. Aside from limited cases, palladium catalysts preferentially form the linear substitution product through alkylation at the less-substituted terminus of the allylic electrophile (Scheme 1). However, in contrast to palladium, most other transition metals (e.g., Mo, W, Fe, Ru, Co, Rh, Ni, Pt, and Ir) have been shown to favor the construction of the branched product, with iridium catalysts being some of the most efficient and selective. The potential application of these chiral, branched products to the synthesis of natural products and biologically active compounds has motivated the development of practical and reliable transition-metal-catalyzed methods for their construction.

This account describes our laboratory’s efforts in the development of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic conjugate acceptors. Specifically, we highlight the study of this transformation in the following areas: (a) construction of all-carbon quaternary stereocenters, (b) elucidation of the reaction mechanism, (c) addition to heterocyclic acceptors to generate tertiary stereocenters, and (d) application in the synthesis of natural products.

This account describes our laboratory’s efforts in the development of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic conjugate acceptors. Specifically, we highlight the study of this transformation in the following areas: (a) construction of all-carbon quaternary stereocenters, (b) elucidation of the reaction mechanism, (c) addition to heterocyclic acceptors to generate tertiary stereocenters, and (d) application in the synthesis of natural products.

A. (S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2). A 1 L one-necked round-bottomed flask equipped with a 3.0 cm x 1.4 cm, egg-shaped, Teflon-coated magnetic stirring bar is sealed with a septum and connected via needle adapter to a two-tap Schlenk adapter attached to an oil bubbler and a nitrogen/vacuum manifold (Note 1). The flask is dried with a heat gun under vacuum and cooled under a stream of nitrogen. The flask is charged with 2-picolinic acid (1) (6.15 g, 50.0 mmol, 1.00 equiv) (Note 2), evacuated and back-filled with nitrogen three times, then charged with dichloromethane (300 mL, 0.17 M) (Note 3) and N-methylmorpholine (7.59 g, 8.25 mL, 75.0 mmol, 1.50 equiv). The flask is cooled in an ice/water bath and iso-butylchloroformate (6.86 mL, 7.17 g, 52.5 mmol, 1.05 equiv) is added dropwise over 30 min by syringe pump. The reaction mixture is stirred for an additional 30 min while remaining submerged in the ice/water bath. A separate 100 mL one-necked round-bottomed flask is sealed with a septum and connected via needle adapter to the two-tap Schlenk adapter and manifold, dried with a heat gun under vacuum, and allowed to cool under a stream of nitrogen. This flask is charged with (S)-tert-leucinol (6.45 g, 55.0 mmol, 1.10 equiv), dichloromethane (40 mL), and N-methylmorpholine (6.07 mL, 5.56 g, 55.0 mmol, 1.10 equiv). The resulting clear solution is taken up in a syringe and transferred dropwise using a syringe pump over the course of 1 h to the stirring reaction mixture in the ice/water bath. The cooling bath is removed, and the pale gold colored reaction mixture is stirred for an additional 6 h at 23 °C. Upon consumption of starting material (Note 4), the mixture is quenched at ambient temperature with a single addition of an aqueous solution of saturated NH_4Cl (50 mL), diluted with additional H_2O (25 mL), and transferred into a 1 L separatory funnel. The phases are separated, and the aqueous phase is extracted with CH_2Cl_2 (3 x 100 mL). The combined organic phases are washed with an aqueous solution of saturated NaHCO_3 (1 x 50 mL) and brine (1 x 50 mL). The combined organic phases are dried over Na_2SO_4 (10 g, 15 min while agitating), filtered through a M pore glass frit, and concentrated by rotary evaporation (28 °C, 15 mmHg). Excess N-methylmorpholine is further removed by placing the crude residue under high vacuum (< 12 mmHg, 12 h) to provide a pale red solid (Note 5). The crude residue is dissolved in 10 mL of acetone and purified via silica gel flash chromatography (Note 6). The combined product-containing fractions are concentrated by rotary evaporation (40 °C, 15 mmHg) to yield a solid, which is dried under high vacuum (< 12 mmHg, 12 h) to afford (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2) as a white amorphous solid (9.88-9.95 g, 44.4-44.8 mmol, 89-90% yield) (Note 7).