Arecoline synthesis

Recently, Jankowski et al. [80] reported the application of MW to the Diels-Alder synthesis of N-methyloctahydroisoquinoline adducts, which are important intermediates in the synthesis of medicinally important compounds, such as HIV protease inhibitor isoquinoline carboxylate pharmaceuticals. The reaction of the arecoline 67 or its isomer 70 with Danishefsky s diene 68 in toluene (Scheme 4.32) was studied under both conventional and MW heating in sealed tubes, i. e. at elevated pressure. 

Jeng JH, Hahn U, Lin BR, Hsieh CC, Chan CP, Chang MC. (1999). Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med. 28(2) 64-71. 

Wolf-Pflugmann M, Lambrecht G, Wess J, Mutschler E. (1989). Synthesis and muscarinic activity of a series of tertiary and quaternary N-substituted guvacine esters structurally related to arecoline and arecaidine propargyl ester. Arzneimittelforschung. 39(5) 539-44. 

A synthesis of arecoline (17) from acetaldehyde has been described.17 Sederine (18) is a minor base occurring in Sedum acre-, its structure has been settled by spectral and chemical study, but its stereochemistry has yet to be established.18 A new total synthesis of racemic solenopsin A (19) (fire-ant venom) has been published the pathway is outlined in Scheme 2.19... 

In fact, it isn t necessary to make 57 as, when R=Me, it is the natural alkaloid arecoline. However, when the synthesis was continued by attempted conjugate addition of the enolate of methyl acetoacetate to 57 only very low yields (12-18%) of products could be found. The problem turned out to be the base-catalysed rearrangement of 57 into the aromatic pyridone 71. 

This procedure for the partial reduction of the pyridine ring has been applied to the synthesis of arecoline,8,21,44,45 l-substituted-3-... 

The two-step one-pot total synthesis of Ro 22-1319, an antipsychotic agent featuring a rigid pyrrolo[2,3-g]isoquinoline skeleton, was accomplished by D.L. Coffen and co-workers. The cyclic 1,3-diketone precursor was prepared from arecoline and dimethyl malonate, and in the same reaction vessel an amino ketone hydrochloride was added. The pH of the reaction mixture was adjusted to 4 in order to initiate the formation of the pyrrole. 

Arecoline is prepared from bis(2-cyanoethyl)amine (174) which is a by-product of the alanine synthesis [125] (Scheme 23). 

The cytotoxic and genotoxic effects of arecoline continue to be investigated. Arecoline was cytotoxic to Hep 2 cells in an acidic medium, and decreased DNA and protein synthesis [350]. The observed cytotoxicity increased on addition of sodium nitrite [350]. Arecoline was found to be clastogenic and genotoxic by observation of chromosome aberrations and sister-chromatid exchanges in Chinese hamster ovary cells [351], It induced unscheduled DNA synthesis in Hep 2 cells [352], Arecoline decreased the survival and proliferation of cultured oral mucosal fibroblasts [353]. Glutathione and cysteine prevented this cytotoxicity, suggesting that thiol depletion could play a role in the toxicity of 117 [353],... 

Rapid access to the chiral azabicyclo[2.2. Ijheptane backbone has been exploited in the synthesis of rigid enantiomorphic conformations (e.g. 75) of arecoline (74), a natural achiral alkaloid with muscarinic agonist activity [25] ... 

The synthesis of isoquinolinone carboxylates by Diels-Alder reaction was carried out by using arecoline (or its isomer methyl tetrahydropyridine carboxylate) with Danishefsky s diene under thermal and microwave conditions. It was found that with microwave technique, higher yields of the adduct were achieved as well as a new a, P-unsaturated pyridyl ketone was also formed (Jankowski et al., 2001). 

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