Preparation and Diastereoselective Birch Reduction−Alkylation of Chiral 3,4-Dihydro-1(2H)-isoquinolinones. Enantiospecific Syntheses and Opioid Receptor Affinities of Several Hydro-2,3- dimethyl-1H-7,12a-methanobenzo[6,7]cycloocta[1,2-c]pyridine-9-ols

Abstract

Synthetic procedures have been developed to provide 2,3-disubstituted-3,4-dihydro-1(2H)-isoquinolinones 6, 10, and 15 from (1R,2S)-ephedrine, (1R,2R)-pseudoephedrine, and l-phenylalanine. Birch reduction of 6 and 10 gave enantiomerically related lactam enolates that were alkylated with methyl iodide, allyl bromide, benzyl bromide, p-benzyloxybenzyl bromide, and p-methoxybenzyl bromide to give 7a−7e, 11a, and 11b with diastereoselectivities > 20:1. Birch reduction−methylation of 15 gave 19 with a diastereoselectivity of >35:1. Selective reduction of the disubstituted double bond in 19 with diimide and cleavage of the tert-butyldimethylsilyl ether gave 20b, from which iodoetherification under thermodynamic control gave the iodopyran 21a; iodoetherification of 20b under kinetic control gave the iodotetrahydrofuran 22. Enantiospecific syntheses of analogues of 24 (Schultz, A. G.; Kirincich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551−4554) have been developed. Tetracycle 24 is isomeric with the potent analgesic agent levorphanol, but the bridging of the hydroisoquinoline ring by the hydroxybenzyl unit in 24 is at C(7, isoquinoline numbering) and C(8a) rather than at C(1) and C(4a) as in levorphanol. The key step in the transformation of 7d and 7e to tetracyclic phenolic amines (−)-26 and (+)-28 is the Grewe-type cyclization of 7d to 25b and 7e to 25c. K i values for the inhibition of binding to the μ-, δ-, and κ-opioid receptors by (−)-26, (+)-26, (+)-28, (−)-28, and (+)-32 are reported.

Stereoselective Synthesis of β‐Proline Derivatives from Allylamines via Domino Hydroformylation/Wittig Olefination and Aza‐Michael Addition

“…This is remarkable, because olefins with a chirality center in an allylic position are prone to partial racemization or epimerization in transition metal-catalyzed reactions. [22] …”

Determination of the Configuration of an Archaea Membrane Lipid Containing Cyclopentane Rings by Total Synthesis

“…De Rosa et al obtained various pure diols with five-membered rings, among them 1, by degradation of natural etherlipids and determined their constitution by mass spectrometry and NMR spectroscopy. [7] Important features, revealed by 13 C NMR spectroscopy, are the C 2 symmetry of the structure of 1 and the trans configuration of the rings which was deduced by comparison of the 13 C NMR spectroscopy data with those of cis-and trans-1,3-dimethylcyclopentane. [8] Herein we report the determination of the complete relative and absolute configuration of the diol 1 by a stereoselective synthesis.…”

Bestimmung der Konfiguration eines Cyclopentanringe enthaltenden Archaea‐Membranlipids durch Totalsynthese

“…De Rosa et al konnten verschiedene Diole mit Cyclopentanringen, unter ihnen 1, durch Abbau von natürlichen Etherlipiden erhalten und bestimmten ihre Konstitution durch Massenspektrometrie und NMR-Spektroskopie. [7] Wesentliche Aspekte, aus den 13 C-NMR-Daten ermittelt, sind die C 2 -Symmetrie der Struktur von 1 und die trans-Konfiguration der Ringe, welche durch Vergleich der 13 C-NMR-Daten mit denen von cis-und trans-1,3-Dimethylcyclopentan abgeleitet wurde. [8] Wir berichten nun über die Bestimmung der vollständigen relativen und der absoluten Konfiguration des Diols 1 durch dessen stereoselektive Synthese.…”

“…Proben des synthetischen C 40 -Diols 1 und des aus Archaea-Lipiden hergestellten Diols 1 lieferten identische 13 …”