Gerrit J. Meuzelaar

Heteropoly acid-catalyzed Diels-Alder reactions

Tungstophosphoric acid supported on silica gel has been shown to catalyze Diels-Alder reactions of quinones. The catalyst is active under mild conditions and can be easily recovered and re- used.

Improvements in the Total Synthesis of Morphine

The chiral 1,2,3,4-tetrahydroisoquinoline intermediates in the Rice and Beyerman routes to morphine, (+)-(R)-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (6) and (+)-(R)-1-(3,5-dibenzyloxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (5), were prepared in high ee by ruthenium-catalyzed asymmetric transfer hydrogenation of the corresponding imine precursors (Noyori method). The yield of the key raw material in the Beyerman route, 3,5-dibenzyloxy-4-methoxyphenylacetic acid (1), starting from gallic acid methyl ester (7) was improved by a factor of 5 over previously described syntheses. Key steps in the new procedure are the selective formation of methyl 3,5-dihydroxy-4-methoxybenzoate (9) via the 3,5-diacetate and an improved benzylation of the hydroxyl groups in 9.

Chemistry of opium alkaloids. Part 44: synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans.

7- and 8-substituted 6alpha,14alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morphinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7alpha- and 7beta-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5Beta-alkyl substitution of 6alpha,14alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5beta-methyl series the affinity for the mu and delta receptors increased from 7alpha-dimethylmethanol to 7alpha-methylhexylmethanol. In the 5beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6beta,14beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments.

A Novel Synthesis of Substituted 1-Benzyloctahydroisoquinolines by Acid-Catalyzed Cyclization of N-[2-(Cyclohex-1-enyl)ethyl]-N-styrylformamides

The acid-catalyzed cyclization of N-[2-(cyclohex-1-enyl)ethyl]-N-styrylformamides 1–5 gave access to 1-benzyl-2-formyloctahydroisoquinolines 6–10. The reactions were performed in the presence of the Lewis acid 9-borabicyclo[3.3.1]non-9-yl triflate. The cyclization of enamide 1 was also studied with Bronsted acid catalysts, such as triflic acid and the heterogeneous catalyst tungstophosphoric acid supported on silica gel. In all cases the 1,2,3,4,5,6,7,8-octahydroisoquinoline formed was accompanied by minor concentrations of one, two, or three isomeric octahydroisoquinolines. 1-Benzyl-2-formyloctahydroisoquinoline (6) could also be prepared from N-[2-(cyclohex-1-enyl)ethyl]formamide (11) by reaction with phenylacetaldehyde in a mixture of acetic acid and trifluoroacetic acid. The octahydroisoquinolines 6, 8, 10 as model compounds, were converted into the corresponding N-formylmorphinans.

Diels–Alder reactions of carbonyl-containing dienophiles catalyzed by tungstophosphoric acid supported on silica gel

Tungstophosphoric acid (H3PW12O40) supported on silica gel proved to be an active heterogeneous catalyst for Diels–Alder reactions of enones with various dienes. The Diels–Alder adducts were formed in high regio- and/or stereoselectivity. In some cases the Diels–Alder reactions were accompanied by competing polymerization of the starting compounds. We also found that trifluoromethanesulfonic acid (triflic acid) is an effective homogeneous catalyst for the reaction of unprotected but-3-en-2-one (methyl vinyl ketone) with 1,3-cyclohexadiene, albeit with a lower activity than tungstophosphoric acid.

Synthesis of benzyl substituted tetrahydropyridines and 1,2,3,4-tetrahydroisoquinolines via acid catalyzed cyclization of γ,δ-unsaturated N-formyl-N-styryl amines

Abstract Acid-catalyzed cyclization of N-(3-methylbut-3-enyl)-N-styrylformamides 1–3 in the presence of 9-BBN triflate gave access to 2-benzyl-1-formyl-4-methyl-1,2,5,6-tetrahydropyridines 4a–6a and minor amounts of the isomeric 1,2,3,6-tetrahydropyridines 4b–6b. Triflic acid catalyzed cyclization of N-2-(arylethyl)-N-styrylformamides 7, 8 gave the corresponding 1-benzyl-2-formyl-1,2,3,4-tetrahydroisoquinolines 9 and 10.