General approach for the chromatographic determination of 2-hydroxypyridine-1-oxide (HOPO) in pharmaceutically relevant materials utilizing a high pH ion-pairing strategy.

2-Hydroxypyridine-1-oxide (HOPO) is utilized in the pharmaceutical sector to facilitate the formation of amide bonds. This present work describes the development of a HPLC high pH ion-pairing method for the trace analysis of HOPO in pharmaceutically relevant materials. Several method development aspects are discussed and the application of this method to several late-stage programs is presented.

Sequential rhodium-, silver-, and gold-catalyzed synthesis of fused dihydrofurans.

A triple cascade process was developed for the rapid synthesis of polycyclic benzo-fused dihydrofurans. The first step is a rhodium-catalyzed cyclopropanation of α-aryldiazoketones with alkenes. This is followed by a silver-catalyzed ring expansion to dihydrofurans, which then undergo a gold-catalyzed cyclization to form benzo-fused dihydrofurans.

Application of donor/acceptor-carbenoids to the synthesis of natural products.

The metal catalyzed reactions of diazo compounds have been broadly used in organic synthesis. The resulting metal-carbenoid intermediates are capable of undergoing a range of unconventional reactions, and due to their high energy, they are ideal for initiating cascade sequences leading to the rapid generation of structural complexity. This tutorial review will give an overview of the most versatile reactions of donor/acceptor carbenoids, an exciting class of intermediates capable of highly selective reactions. This will include cyclopropanation, [4 + 3] cycloaddition, and C-H functionalization methodologies. The application of this chemistry to the synthesis of a range of natural products will be described.

Asymmetric [4 + 3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (-)-5-epi-vibsanin E.

The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).

Enantioselective reactions of donor/acceptor carbenoids derived from alpha-aryl-alpha-diazoketones.

The reaction of a variety of alpha-aryl-alpha-diazo ketones with activated olefins, catalyzed by the adamantyl glycine-derived dirhodium complex Rh(2)(S-PTAD)(4), generates cyclopropyl ketones with high diastereoselectivity (up to >95:5 dr) and enantioselectivity (up to 98% ee). Intermolecular C-H functionalization of 1,4-cyclohexadiene by means of carbenoid-induced C-H insertion was also possible with this type of carbenoid.

Stereoselective construction of nitrile-substituted cyclopropanes.

Nitrile-substituted cyclopropanes are readily synthesized in a stereocontrolled fashion from the intermolecular cyclopropanation between 2-diazo-2-phenylacetonitrile and electron-rich olefins, catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).

Enantioselective synthesis of trifluoromethyl-substituted cyclopropanes.

The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh2(R-PTAD)4, generates trifluoromethyl-substituted cyclopropanes with high diastereoselectivity (>94%) and enantioselectivity (88->98%).