Development of New Reactions Driven by N-O Bond Cleavage: from O-Acyl Hydroxylamines to Tetrodotoxin.

This Account describes new reactions that have been developed in the Johnson laboratories at UNC Chapel Hill enabled by considerations of N-O bond cleavage. Three main case studies are highlighted: the metal-catalyzed electrophilic amination of O-acyl hydroxyl amines, multihetero-Cope rearrangements driven by O-N bond breakage, and merged dearomatization/N=O cycloadditions for the synthesis of complex 4-aminocyclohexanols such as those found in the natural product tetrodotoxin.

Rhodium-Catalyzed Asymmetric Arylation-Induced Glycolate Aldol Additions of Silyl Glyoxylates.

(Diene)Rh(I) complexes catalyze the stereoselective three-component coupling of silyl glyoxylates, arylboronic acids, and aldehydes to give glycolate aldol products. The participation of Rh-alkoxides in the requisite Brook rearrangement was established through two component Rh-catalyzed couplings of silyl glyoxylates with ArB(OH)2 to give silyl-protected mandelate derivatives. The intermediacy of a chiral Rh-enolate was inferred through enantioselective protonation using a chiral Rh-catalyst. Diastereoselective three-component couplings with aldehydes as terminating electrophiles to give racemic products were best achieved with a bulky aryl ester on the silyl glyoxylate reagent. Optimal enantioselective couplings were carried out with the tert-butyl ester variant using an anisole-derived enantiopure tricyclo[3.2.2.02,4 ]nonadiene ligand.

Psoriasis in the transplant population.

Solid organ and stem cell transplants are increasingly common, and dermatologists will more frequently encounter and need to manage common skin diseases, such as psoriasis, in transplant patients. This review explores psoriasis remission and occurrence in recipients of solid organ and stem cell transplants. Hematopoietic and mesenchymal stem cell transplants may show potential for treating psoriasis in patients with leukemia or who have other medical conditions requiring stem cell transplant. The effects of solid organ transplant are less clear, partly due to limitations in the breadth of the literature. De novo psoriasis has been reported in recipients of solid organ transplants, but the reasons for this development have yet to be fully understood. Overall, the literature on this subject is limited to primarily case reports. Feasibility of studies on the subject may be a considerable barrier to further research assessing the use of transplant for treating psoriasis, but there is potential benefit from transplant for psoriasis patients. This subject should receive further exploration to fully understand these benefits.

An Oxidative Dearomatization Approach to Tetrodotoxin via a Masked ortho-Benzoquinone.

Progress toward a stereoselective synthesis of tetrodotoxin (TTX) is presented. Oxidative dearomatization of a tetrasubstituted guaiacol arene yielded a masked ortho-benzoquinone that intercepted an acyl nitroso species generated in situ by the copper-catalyzed aerobic oxidation of an acyl hydroxylamine. The subsequent alkene dihydroxylation and reduction of a bis-neopentylic ketone proceeded with perfect diastereoselectivity to reveal advanced intermediates toward the synthesis of TTX.

De Novo Synthesis of the DEF-Ring Stereotriad Core of the Veratrum Alkaloids.

The synthesis of the stereotriad core in the eastern portion of the Veratrum alkaloids jervine (1), cyclopamine (2), and veratramine (3) is reported. Starting from a known ß-methyltyrosine derivative (8), the route utilizes a diastereoselective substrate-controlled 1,2-reduction to establish the stereochemistry of the vicinal amino alcohol motif embedded within the targets. Oxidative dearomatization is demonstrated to be a viable approach for the synthesis of the spirocyclic DE ring junction found in jervine and cyclopamine.

Intermolecular Diels-Alder Cycloaddition for the Construction of Bicyclo[2.2.2]diazaoctane Structures: Formal Synthesis of Brevianamide B and Premalbrancheamide.

A stereoselective intermolecular Diels-Alder cycloaddition of an intermediate pyrazinone with both achiral and chiral acrylate-derived dienophiles provides rapid access to the bicyclo[2.2.2]diazaoctane core shared among several prenylated indole alkaloids. The product derived from cycloaddition with 2-nitroacrylate required an additional five to six synthetic operations to intercept established precursors to premalbrancheamide and brevianamide B. The chemistry detailed in this manuscript constitutes a formal total synthesis (12 steps each) of these [2.2.2]diazabicyclic natural products from proline methyl ester.