Anthony R. Lingham

Studies towards the synthesis of Salvinorin A

Salvinorin A 1, a psychoactive neoclerodane diterpenoid from the Mexican sage S. divinorum, has gained interest as a selective κ-opioid receptor agonist. Non-racemic 3-furylamines 9a and 9b have been prepared from (+)-pseudoephedrine and (–)-ephedrine for application in the stereoselective synthesis of the ketone ring of 1. Diels–Alder reaction of 9b with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, has allowed access to the cyclohexenone 17 with preservation of stereochemistry at C2. A model route to the lactone ring has also been achieved through a one-pot deconjugation/esterification procedure of 2-bromocrotonyl chloride 20 to the furyl alcohol 19 followed by Reformatski-mediated ring closure.

Alternative synthesis of the anti-baldness compound RU58841

RU58841 is active against baldness and is commercially available. The previously reported synthesis uses phosgene, three discrete inert atmosphere steps and three steps that require flash chromatography. Our synthesis uses no phosgene, only one inert atmosphere step and does not require flash chromatography. This is achieved by stepwise construction of the hydantoin moiety around the amino group of 3-trifluoromethyl-4-cyanoaniline and ring closure to give a 2-nitropropane leaving group. On a small scale we achieved an overall yield of 33%.

Synthesis of Some 3-Furylamine Derivatives

A general and efficient method for the synthesis of 3-furylamines via Michael addition of amines to acyclic keto alkynol precursors has been achieved. The preparation of various 3-furylamines has been carried out using a flexible methodology which also allows modification of the substituent at the 5-position.

Marine Fragrance Chemistry

The main marine message in perfumery is projected by Calone 1951® (7‐methyl‐2H‐1,5‐benzodioxepin‐3(4H)‐one). Kraft (Givaudan) and Gaudin (Firmenich) further maximized the marine fragrance molecular membership by extending the carbon chain of the 7‐Me group. Our research targeted the polar group of the benzodioxepinone parent compound to investigate how this region of molecular makeup resonates with the dominant marine fragrance of the Calone 1951® structure. The olfactory evaluation of analogues prepared by chemical modification or removal of the CO group resulted in the introduction of aldehydic, sweet and floral‐fruity notes with a diluted/diminished potency of the marine odor. To further analyze the olfactory properties of benzodioxepinones containing a diverse range of aromatic ring substituents, a novel synthesis route was developed. We found that a 7‐alkyl group in Calone 1951® was essential for the maintenance of the significant marine odor characteristic, and our studies support the concept that the odorant structure occupying the hydrophobic binding pocket adjacent to the aromatic ring‐binding site of the olfactory receptor is pivotal in the design and discovery of more potent and characteristic marine fragrances. How the structure of benzodioxepinones connects to marine sea‐breeze fragrances is our continuing challenging research focus at the chemistry‐biology interface.

Diels-Alder reactions of 3-furylamines in organic and aqueous solvents

Various 5-methyl-3-aminofurans have been shown to undergo facile Diels-Alder reactions with methyl acrylate in aqueous media. Reactions proceeded with exclusive regiochemistry, and enamine cycloadducts were readily hydrolyzed to afford 7-oxabicyclo[2.2.1]heptanones in high yields.

Dietary Directions Against Dementia Disorders

Since human health benefits are influenced by diets and lifestyle, the dietary intake and body–brain interactions of phytochemicals which are abundant in fruits, berries, vegetables, herbs, and in beverages are a promising avenue and resource that can provide dietary intervention and protection strategies against Alzheimer’s disease, Parkinson disease, Huntington disease, and Amyotrophic Lateral Sclerosis dementia diseases. The manipulation of the molecular mechanisms and metabolic processes of food consumption occurring in body and brain can direct, determine, and provide new strategies of how to optimize and select dietary constituents that may sustainably provide generic benefits for neurons to defend against insults and damage, and sustain mental fitness against all neurodegenerative diseases. This chapter provides a perspective of the molecular episodes of dietary phytochemicals including polyphenols, brain foods/beverages, and herbs that can be used and directed towards providing health-sustaining interventions against protein misfolding-neurodegenerative and dementia disorders.

Bromo–nitro substitution on a tertiary α carbon—a previously uncharacterized facet of the Kornblum substitution

Sodium nitrite in dimethylformamide substitutes nitro for bromine alpha to an amide carbonyl in high yield at a tertiary site. Hammett plots show a strongly positive ρ value (+0.67), indicating a negatively-charged transition state, in contrast to the typical SN1/SN2 mechanism domain for Kornblum substitutions.