Krishna P. Kaliappan

Recent Trends in Copper‐Catalyzed C−H Amination Routes to Biologically Important Nitrogen Scaffolds

Nitrogen-containing heterocycles have found remarkable applications in natural product research, material sciences, and pharmaceuticals. Although the synthesis of this interesting class of compounds attracted the interest of generations of organic chemists, simple and straightforward assembly methods based on transition-metal catalysis have regularly been elusive. The recent advancements in the development of C-H functionalization have helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. This Focus Review summarizes the recent advances in one particular field: the copper-catalyzed C-N bond formation reactions via C-H bond functionalization to furnish a comprehensive range of nitrogen heterocycles. Applicability and synthetic feasibility of a particular reaction represent major requirements for the inclusion in this review.

Discovery and Syntheses of “Superbug Challengers”—Platensimycin and Platencin

Bacteria have developed resistance to almost all existing antibiotics known today and this has been a major issue over the last few decades. The search for a new class of antibiotics with a new mode of action to fight these multiply-drug-resistant strains, or superbugs, allowed a team of scientists at Merck to discover two novel antibiotics, platensimycin and platencin using advanced screening strategies, as inhibitors of bacterial fatty acid biosynthesis, which is essential for the survival of bacteria. Though both these antibiotics are structurally related, they work by slightly different mechanisms and target different enzymes conserved in the bacterial fatty acid biosynthesis. This Focus Review summarizes the synthetic and biological aspects of these natural products and their analogues and congeners.

Application of an Enyne Metathesis/Diels―Alder Cycloaddition Sequence: A New Versatile Approach to the Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides

An efficient approach for the synthesis of a variety of C-aryl and spiro-C-aryl glycosides is described. This diversity-oriented strategy employed here relies on a sequential enyne metathesis to generate the 1,3-diene moiety and Diels-Alder reaction with different dienophiles followed by aromatisation. Whereas cross-enyne metathesis with ethylene gas is used to install the 1,3-diene moiety at the anomeric centre for the synthesis of C-aryl glycosides, an intramolecular enyne metathesis on the sugar enyne is performed to generate the 1,3-diene moiety for the synthesis of spiro-C-aryl glycosides. Efforts to extend this strategy to the synthesis of the core structure of natural C-aryl glycoside gilvocarcin are also described. A combination of both C-aryl and spiro-C-aryl glycosides in the same moiety to combine the features thereof has also been accomplished. A tandem enyne metathesis/Diels-Alder reaction/aromatisation has also been attempted to directly access the C-aryl glycosides in one pot albeit in low yield.

A versatile access to calystegine analogues as potential glycosidases inhibitors.

An efficient metathetic strategy and nitrone chemistry have been suitably tethered to construct 8-azabicyclo[3.2.1]octanes as versatile precursors for the synthesis of several calystegine analogues. This synthetic strategy relies on the ability of mannose-derived nitrone to undergo a highly stereoselective nucleophilic addition of various Grignard reagents to access syn orientation of alkenes, which then smoothly undergo ring-closing metathesis (RCM) to provide this framework. These RCM products 18 and 20 have been successfully used as advance precursors to synthesize many calystegine analogues (27, 36, 38, 40, 43, and 44) either by syn-dihydroxylation or by hydrogenation and followed by global deprotection. Interestingly, both compounds 36 and 40 exhibited significant noncompetitive inhibition against alpha-mannosidase and N-acetyl-beta-D-glucosaminidase.

A formal total synthesis of palmerolide A.

An efficient formal total synthesis of the marine natural product palmerolideu2005A is reported herein, involving 24 longest linear steps. The key features of our synthesis involve a combination of Sharpless epoxidation and Shimizu reaction to construct the syn aldol moiety, a Julia–Kocienski reaction to construct the diene, and ring-closing metathesis to form the macrocycle.

A ring-closing metathesis approach to a synthesis of the B ring of eleutherobin

A short and efficient RCM route is reported for the construction of the key nine-membered B ring of eleutherobin starting from the readily available 1,2,5,6-diisopropylidene-D-glucose.

A one-pot copper catalyzed biomimetic route to N-heterocyclic amides from methyl ketones via oxidative C-C bond cleavage.

A direct one-pot Cu-catalyzed biomimetic oxidation of methyl ketones to pharmaceutically important N-heterocyclic amides is reported. The scope of the method is broad, scalable, and mild, and the reaction is tolerant with various acid, base sensitive functionalities with multiple heteroatoms and aryl halides. The extensive mechanistic studies suggest that this reaction follows the Luciferin-Luciferase-like pathway.

A Shimizu Non‐Aldol Approach to the Formal Total Synthesis of Palmerolide A

A formal total synthesis of palmerolide A has been accomplished by assembling three fragments by means of successive Julia-Kocienski olefination, Yamaguchi esterification, and ring-closing metathesis (RCM). Our initial efforts to combine the first two fragments through a Julia-Kocienski reaction between a secondary sulfone and a ketone were not successful; nevertheless, it was feasible between a primary sulfone and aldehyde. Yamaguchi esterification with the third fragment then set the stage for a RCM reaction. Initial failure of the RCM with a PMB-ether adjacent to the olefins and the difficulty in cleaving the PMB-ether prompted us to change the choice of protecting groups, which then paved the way to the macrocyclic core of palmerolide A.

Combinatorial discovery of two-photon photoremovable protecting groups

A design principle for a two-photon photochemically removable protecting group based on sequential one-photon processes has been established. The expected performance of such groups in spatially directed photoactivation/photodeprotection has been shown by a kinetic analysis. One particular molecular class fitting into this design, the nitrobenzyl ethers of o-hydroxycinnamates, has been presented. An initial demonstration of two-photon deprotection of one such group prompted further optimization with respect to photochemical deprotection rate. This was accomplished by the preparation and screening of a 135-member indexed combinatorial library. Optimum performance for λ >350 nm deprotection in organic solvent was found with 4,5-dialkoxy and α-cyano substitution in the nitrobenzyl group and 4-methoxy substitution in the cinnamate.

A tandem enyne/ring closing metathesis approach to 4-methylene-2-cyclohexenols: an efficient entry to otteliones and loloanolides.

A short and efficient approach to a 4-methylene-2-cyclohexenone substructure present in otteliones and loloanolides is described. This strategy involves a tandem enyne/ring closing metathesis as the key reaction to construct this labile core unit.