Pd-catalyzed asymmetric prenylation of oxindoles to afford selectively either the prenyl or reverse-prenyl product has been demonstrated. Control of the regioselectivity in this transformation is ...governed by the choice of ligand, solvent, and halide additive. The resulting prenylated and reverse-prenylated products were transformed into ent-flustramides and ent-flustramines A and B. Additionally, control of the regio- and diastereoselectivity was obtained using π-geranylpalladium complexes.
A novel synthetic strategy toward the asymmetric synthesis of vicinal diols bearing a tertiary center is presented. The method encompasses the dinuclear Mg-catalyzed asymmetric addition of ethyl ...diazoacetate into several aldehydes, oxidation of the diazo functionality, and diastereoselective alkyl transfer of various organometallics into the resulting chiral β-hydroxy-α-ketoesters to afford a diverse range of 1,2-diols in high yield, diastereoselectivity, and chirality transfer.
Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of ...such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRAS
stabilized by covalent inhibitors. One CLAMP enables the visualization of KRAS
covalent modification in vivo and can be used to investigate response heterogeneity to KRAS
inhibitors in patient tumors. A second CLAMP enhances the affinity of weak ligands binding to the KRAS
switch II region (SWII) by stabilizing a specific conformation of KRAS
, thereby enabling the discovery of such ligands that could serve as leads for the development of drugs in a high-throughput screen. We show that combining the complementary properties of antibodies and small molecules facilitates the study and drugging of dynamic proteins.
The use of a bifunctional nitrogen nucleophile and an allyl carbonate starting material in successive enantioselective palladium- and diastereoselective rhodium-catalyzed reactions enables the rapid ...assembly of unique amino aziridine products. Further elaboration of these materials affords complex, stereodefined polyamine architectures, thus demonstrating the power of these combined methods for simplifying asymmetric C−N bond construction.
A convergent synthetic route toward cytotoxic agent peloruside A that hinges on the use of an alkyne linchpin to assemble the natural product is described. Other highlights of this synthesis include ...an asymmetric desymmetrization reaction of a 1,3-diol, a one-pot conversion of a dibromoolefin to a stereodefined enone, and a diastereoselective aldol condensation. Misassignment of the absolute stereochemistry of the C18 stereocenter in our synthesis provided the natural product epimeric at the C18 ethyl stereocenter.
Rhodium-catalyzed oxidative cyclization of allylic hydroxylamine-derived sulfamate esters furnishes a novel family of bicyclic aziridines that serve as functional precursors to substituted diamines. ...Investigations with the N4-Troc form of these heterocycles have led to manifold improvements in reaction performance and scope and have revealed unique differences in the stability and reactivity of such compounds dictated by the choice of N4-protecting group.
The chemoselective functionalization of a range of dihaloaromatics with methyl, cyclopropyl, and higher alkyl Grignard reagents via iron-catalyzed cross-coupling is described. The site selectivity of ...C-X (X = halogen) activation is determined by factors such as the position of the halogen on the ring, the solvent, and the nucleophile. A one-pot protocol for the chemoselective synthesis of mixed dialkyl heterocycles is achieved solely employing iron catalysis.
This paper describes our efforts to design a Pd‐catalyzed asymmetric prenylation of 3‐substituted oxindoles that affords access to both the linear and reverse‐prenylated products. Both 3‐alkyl‐ and ...3‐aryloxindoles performed well under our optimized reaction conditions. The regiodivergent alkylation of monoterpene‐derived electrophiles using this methodology was also investigated. The utility of this methodology in natural product synthesis was demonstrated through the efficient total syntheses of four Flustra alkaloids, which also allowed the absolute stereochemistry of the prenylated oxindole products to be assigned. Surprisingly, the same enantiomer of ligand produced linear and branched regioisomers of opposite chirality.
An orthogonal set of reaction conditions has been developed for the asymmetric Pd‐catalyzed prenylation of 3‐alkyl‐ and 3‐aryloxindoles, allowing for selective formation of both the prenyl and reverse‐prenyl oxindoles. The subtle factors that guide regioselectivity are applied to reactions using hemi‐ and monoterpenoid electrophiles. The absolute stereochemistry of the products was determined through the asymmetric synthesis of flustramines A and B.
Chromium(II) chloride catalyzes the chemoselective cross‐coupling reaction of dichloropyridines with a range of functionalized (hetero)aromatic Grignard reagents at room temperature. Functional ...groups, such as esters and acetals, are well tolerated in this transformation. Previously challenging substrates, quinolines and isoquinolines, participate in the selective Cr‐catalyzed cross‐coupling in cyclopentyl methyl ether (CPME) as the solvent. The effective purging of Cr salts is demonstrated by using various solid supports.
Low‐toxicity CrCl2 was shown to be an efficient catalyst for regio‐ and chemoselective cross‐coupling reactions of various dichlorinated heteroaromatics with functionalized aryl Grignard reagents. The reactions proceed fast within minutes at room temperature to give exclusively the α‐arylated heterocycles without the formation of significant homocoupled side‐products. Solid supports are proven to be effective in removing chromium salts prior to subsequent transformations (see scheme).
The development of a highly stereospecific process for the C–O to C–N exchange with retention of configuration is described. This transformation enables access to optically enriched ...β-amido-α-diazoesters. These products are transformed to β-amino acids not readily accessible using known methods.
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