Recent Progress in the Synthesis of Morphine Alkaloids

Abstract

Recent accomplishments in the field of total synthesis of morphine alkaloids are reviewed. Approaches to the skeleton of morphine are included as are various efforts towards related medicinally important agents. The literature coverage begins after the publication of our last update in 2000 and continues mid-way through 2004.

A Total Synthesis of (±)‐Codeine by 1,3‐Dipolar Cycloaddition

“…After correction of the oxidation state in the side chain, morphinane core 3 would be completed by transannular alkylation of the secondary amine liberated by reductive N À O bond cleavage. [9] Allylic substitution [10] could yield allopseudocodeine and another allylic transposition in which the hydroxy group is shifted from C8 to C6 would finally yield codeine (2). With allopseudocodeine in hand, a formal synthesis is already completed.…”

“…In the search for morphine derivatives with reduced side effects, total synthesis offers an attractive opportunity although an economical route competitive to isolation is currently not within reach. [1,2] Several efforts in the recent past, for example, the elegant synthesis by Magnus, [3] the improved strategy of Fukuyama, [4] the chemoenzymatic approach of Hudlicky, [5] and the innovative route of Stork, [6] express the permanent interest of the scientific community. Among the numerous strategies for construction of the phenanthrene skeleton, an approach based on intramolecular nitrone cycloaddition starting from a suitably substituted aldehyde seems powerful enough for this challenging task.…”

Enantioselective Total Synthesis of (−)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones

“…The 2-azabicyclo[3.3.1]nonane motif, known as the morphan core, 1 is found in over 300 natural products across a variety of families, including the Strychnos, 2 Morphine, 3 Madangamine, 4 and Daphniphyllum alkaloids 5 (Scheme 1A). Many of these compounds, such as strychnine 6 and morphine, exhibit potent biological effects.…”

Eine Totalsynthese von (±)‐Codein durch 1,3‐dipolare Cycloaddition

“…Bei der Suche nach Morphinderivaten mit reduzierten Nebenwirkungen bietet die Totalsynthese attraktive Möglichkeiten, allerdings ist eine ökonomische Route, die konkurrenzfähig zur Isolierung ist, bis heute nicht in Reichweite. [1,2] Etliche Anstrengungen in der jüngeren Vergangenheit, wie die elegante Synthese von Magnus, [3] die verbesserte Strategie von Fukuyama, [4] der chemoenzymatische Ansatz von Hudlicky [5] und die innovative Route von Stork, [6] zeugen vom andauernden Interesse der Forschung. Unter den zahlreichen Strategien zum Aufbau des Phenanthrengerüsts scheint ein Ansatz basierend auf einer intramolekularen Nitron-Cycloaddition ausgehend von einem geeignet substituierten Aldehyd dieser Herausforderung gewachsen zu sein.…”

“…Die SuzukiKupplung mit A [3] nach dem Protokoll von Magnus lieferte nach basischer Hydrolyse des TBS-Ethers das Biaryl 8 in hervorragender Ausbeute. [14] Eine Phenoloxidation [15] mit PhI(OAc) 2 [19] Der gebräuchlichere Einsatz von Superhydrid [20] schlug wegen der möglicherweise begleitend auftretenden Reduktion des Isoxazolidins fehl. Tosylierung des resultierenden Alkohols und Hydrogenolyse des Isoxazolidins mit Raney-Nickel [9] induzierten eine spontane intramolekulare Alkylierung, welche das korrekt überbrückte Isochinolin 3 …”