Catalysis of diazoalkane-carbonyl homologation. How new developments in hydrazone oxidation enable the carbon insertion strategy for synthesis.

Diazo compounds continue both to challenge and to fascinate practitioners of chemical synthesis. The most strategically powerful and unique type of reactivity observed with these reagents is a formal insertion of the donor-acceptor carbon into C-C or C-H bonds alpha to carbonyl groups. Although the reaction does not involve discrete carbon-metal bonds, it can be catalyzed by metal-based Lewis acids. This chapter investigates both classical and modern developments in diazoalkyl carbon insertion with a special emphasis on nonstabilized nucleophiles.

Enantioselective total synthesis of hyperforin.

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.

Catalytic homologation of cycloalkanones with substituted diazomethanes. Mild and efficient single-step access to alpha-tertiary and alpha-quaternary carbonyl compounds.

Though volatile, toxic, and unstable, diazomethane is an indispensable one-carbon reagent with manifold uses in chemical synthesis. In this work, known protocols for hydrazone oxidation were adapted to permit facile access to a range of mono- and disubstituted aryl- or alkyldiazomethanes in pure form in solution; such procedures proceed in 30-60% overall yield starting from inexpensive carbonyl compounds. More important is the discovery that commercial Sc(III) salts are efficient catalysts for net insertion of the diazoalkyl carbon in these nucleophiles into the carbonyl C-C bond of simple cycloalkanones. In a single step, these reactions (1) forge two new C-C bonds under mild conditions, (2) produce molecular nitrogen as the sole stoichiometric byproduct, and (3) afford high yields of complex alpha-tertiary and -quaternary cyclic ketones that are typically accessible only through multistep procedures.

Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide).

Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor KZR-504 (12).

Total Synthesis of (-)-Nemorosone and (+)-Secohyperforin.

A general strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols is described in which a scalable, Lewis acid catalyzed epoxide-opening cascade cyclization is used to furnish common intermediate 4. The utility of this approach is exemplified by the total syntheses of both ent-nemorosone and (+)-secohyperforin, which were each accomplished in four steps from this intermediate.

An enantioselective synthesis of 2-aryl cycloalkanones by Sc-catalyzed carbon insertion.

Current methods for asymmetric α-arylation require blocking groups to prevent reaction at the α'-carbon, basic conditions that promote racemization, or multistep synthesis. This work records the first catalytic enantioselective examples of the diazoalkane-carbonyl homologation reaction. Medium ring 2-aryl ketones are prepared in one step in up to 98:2 er and 99% yield from the unsubstituted lower homologue by Sc-catalyzed aryldiazomethyl insertion with simple bis- and tris(oxazoline) ligands.

Catalytic and regioselective ring expansion of arylcyclobutanones with trimethylsilyldiazomethane. Ligand-dependent entry to beta-ketosilane or enolsilane adducts.

Divergent reactivity is uncovered in the homologation of arylcyclobutanones with trimethylsilyldiazomethane. With Sc(OTf)(3) as catalyst, enolsilanes are obtained with a high preference for methylene migration. By contrast, Sc(hfac)(3) gives beta-ketosilanes with both regio- and diastereocontrol. Each adduct affords the cyclopentanone upon hydrolysis.

Diverse alkanones by catalytic carbon insertion into the formyl C-H bond. Concise access to the natural precursor of achyrofuran.

Over a century ago, the first reactions of diazomethane with aldehydes delivered methyl ketones. In the interim, aldehydes have been homologated with trimethylsilyldiazomethane, diazoacetates, and aryldiazomethanes, on rare occasion with catalysis. This work describes a mild procedure for convergent ketone assembly from nonstabilized diazoalkanes, including examples of chiral ketone synthesis with disubstituted (internal) nucleophiles. The method's remarkable tolerance to steric crowding is showcased in a simple approach to achyrofuran, a complex dibenzofuran.

Enantioselective synthesis of cyclic amides and amines through mo-catalyzed asymmetric ring-closing metathesis.

First, an efficient method for the synthesis of optically enriched N-fused bicyclic structures is reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-, 5,7-, and 5,8-bicyclic amides can be synthesized in up to >98% ee. The effects of catalyst structure, olefin substitution, positioning of Lewis basic functional groups and ring size are examined and discussed in detail. In the second phase of investigations, a catalytic asymmetric method for highly enantioselective (up to 97% ee) synthesis of small- and medium-ring unsaturated cyclic amines is reported; optically enriched products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereoselective functionalizations of olefins within the optically enriched amine products have been carried out. Both catalytic asymmetric methods include transformations that lead to the formation of trisubstituted as well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high optical purity; such products are not easily accessed by alternative protocols and can be used in enantioselective total syntheses of biologically active molecules.