Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the ...pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.
A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that ...tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to C
sp
3
─C
sp
3
cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides. Moreover, the union of two secondary aliphatic carbon centers, a long-standing challenge for organic molecule construction, has been accomplished with a wide array of structural formats. Last, this technology can be selectively merged with C
sp
2
─C
sp
3
aryl–alkyl couplings to build drug-like systems in a highly modular fashion.
Cluster excision of polymeric {Mo3S7Cl4}n phases with chiral phosphane (+)‐1,2‐bis(2R,5R)‐2,5‐(dimethylphospholan‐1‐yl)ethane ((R,R)‐Me‐BPE) or with its enantiomer ((S,S)‐Me‐BPE) yields the ...stereoselective formation of the trinuclear cluster complexes Mo3S4{(R,R)‐Me‐BPE}3Cl3+ ((P)‐1+) and Mo3S4{(S,S)‐Me‐BPE}3Cl3+ ((M)‐1+), respectively. These complexes posses an incomplete cuboidal structure with the metal atoms defining an equilateral triangle and one capping and three bridging sulfur atoms. The P and M symbols refer to the rotation of the chlorine atoms around the C3 axis, with the capping sulphur atom pointing towards the viewer. Incorporation of copper into these trinuclear complexes affords heterodimetallic cubane‐type compounds of formula Mo3CuS4{(R,R)‐Me‐BPE}3Cl4+ ((P)‐2+) or Mo3CuS4{(S,S)‐Me‐BPE}3Cl4+ ((M)‐2+), respectively, for which the chirality of the trinuclear precursor is preserved in the final product. Cationic complexes (P)‐1+, (M)‐1+, (P)‐2+, and (M)‐2+ combine the chirality of the metal cluster framework with that of the optically active diphosphane ligands. The known racemic Mo3CuS4(dmpe)3Cl4+ cluster (dmpe=1,2‐bis(dimethylphosphanyl)ethane) as well as the new enantiomerically pure Mo3CuS4 (P)‐2+ and (M)‐2+ complexes are efficient catalysts for the intramolecular cyclopropanation of 1‐diazo‐5‐hexen‐2‐one (3) and for the intermolecular cyclopropanation of alkenes, such as styrene and 2‐phenylpropene, with ethyl diazoacetate. In all cases, the cyclopropanation products were obtained in high yields. The diastereoselectivity in the intermolecular cyclopropanation of the alkenes and the enantioselectivity in the inter‐ or intramolecular processes are only moderate.
La reacción de escisión de la fase polimérica {Mo3S7Cl4}n con la fosfina quiral (+)‐1,2‐bis(2R,5R)‐2,5‐(dimetilfosfolan‐1‐il)etano, (R,R)‐Me‐BPE, o con su enantiómero, (S,S)‐Me‐BPE, conduce a la formación estereoselectiva de los complejos clúster trinucleares Mo3S4(R,R‐Me‐BPE)3Cl3+ ((P)‐1+) y Mo3S4(S,S‐Me‐BPE)3Cl3+ ((M)‐1+), respectivamente. Estos complejos poseen una estructura de cubo incompleto, dónde los átomos metálicos definen un triángulo equilátero, con un azufre unido a tres átomos de molibdeno y tres azufres puente. Los símbolos P y M hacen referencia a la rotación de los átomos de cloro alrededor del eje C3, con el azufre apuntado dirigido hacia el observador. La incorporación de cobre a estos complejos trinucleares conduce a compuestos heterodimetálicos con estructura tipo cubano de fórmula Mo3CuS4(R,R‐Me‐BPE)3Cl4+ ((P)‐2+) y Mo3CuS4(S,S‐Me‐BPE)3Cl4+ ((M)‐2+) donde la quiralidad del precursor trinuclear se mantiene en el producto final. Los complejos catiónicos (P)‐1+, (M)‐1+, (P)‐2+ y (M)‐2+ combinan la quiralidad del esqueleto clúster con la de los ligandos difosfina. El clúster racémico Mo3CuS4(dmpe)3Cl4+ (dmpe=1,2‐bis(dimetilfosfino)etano), así como los complejos Mo3CuS4 enantioméricamente puros (P)‐2+ o (M)‐2+ son catalizadores eficaces para la reacción de ciclopropanación intramolecular de 1‐diazo‐5‐hexen‐2‐ona (3) y para la ciclopropanación intermolecular de alquenos, estireno y 2‐fenilpropeno, con etil diazoacetato. En todos los casos los productos de ciclopropanación se obtienen con rendimientos elevados. La diastereoselectividad en la ciclopropanación intermolecular de alquenos y la enantioselectividad en los procesos tanto inter‐ como intramoleculares son únicamente moderadas.
Chiral catalysts: An efficient strategy for preparing enantiomerically pure heterodimetallic cubane‐type clusters of the general formula Mo3CuS4(diphosphane)3Cl4+ has been developed. NMR spectroscopy, X‐ray crystallography, and circular dichroism analyses (see figure) confirmed their chiral purity. Catalytic activity/selectivity performance of the clusters was also investigated.
High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has ...also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry’s commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.
We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a ...bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and ...apolipoprotein(a) (apo(a))
. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K
) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs.
). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K
7-8. We identify compounds that bind to apo(a) K
7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that ...tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to C
-C
cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides. Moreover, the union of two secondary aliphatic carbon centers, a long-standing challenge for organic molecule construction, has been accomplished with a wide array of structural formats. Last, this technology can be selectively merged with C
-C
aryl-alkyl couplings to build drug-like systems in a highly modular fashion.
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Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer’s disease. We previously reported the ...fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.
Here we report an optimized protocol for the asymmetric introduction of a fluorine atom into a quaternary center facilitated by d-proline, Selectfluor®, and trifluoroethanol. The synthesis proceeds ...over four steps starting from a chiral amino alcohol precursor and provides the desired enantiomer with no erosion of chiral purity and good diastereoselectivity. The process optimization allowed diastereoselective preparation of the key intermediate on a multigram scale.
The p38 MAP kinase activity of two series of trisubstituted imidazoles (X
=
C, N) is reported, leading to compounds with highly potent cellular and in vivo activity.
Herein we report investigations ...into the p38α MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
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