Syntheses of Morphine

Maier, Martin A.

doi:10.1002/9783527619948.ch38

Cited by 14 publications

(1 citation statement)

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“…The compact, functional-group-rich structures of this class continue to provoke the interest and effort of synthetic chemists. Among many imaginative approaches which have been explored, a number have led to total syntheses or formal total syntheses …”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Parker

Fokas

2005

J. Org. Chem.

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[reaction: see text] The radical cyclization approach to the morphine alkaloids has been applied in an asymmetric synthesis of (-)-dihydrocodeinone. A chiral cyclohexenol (R-32), from the CBS reduction of the enone, is the source of chirality. The first key step, tandem closure in which stereochemistry is controlled by geometric constraints, (-)-15b --> (+)-16, was followed by an unprecedented reductive hydroamination, completing the synthesis of (-)-dihydroisocodeine ((-)-17) in 13 steps from commercially available materials.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Parker

Fokas

2005

J. Org. Chem.

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Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

Hanessian

Mauduit

2001

Angew. Chem.

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This paper is dedicated to Professor A. I. Meyers in recognition of his seminal contributions to organic synthesisThe isopavine alkaloids of the Papaveraceae family were first recognized as a novel heterocyclic framework following intensive studies on their isolation and structure elucidation four decades ago. [1] Isopavines and pavines have been associated with varying pharmacological properties [2, 3] pertaining to Alzheimers disease, Parkinsons disease, and Downs syndrome. The traditional syntheses of the isopavines [4] have relied on intramolecular cyclizations of a-aryl-abenzylamino acetaldehydes, proceeding first to 1-benzyl-4hydroxy-1,2,3,4-tetrahydroisoquinolines, followed by a second cyclization. Syntheses of enantiomerically pure or enriched isopavine alkaloids have traditionally resorted to optical resolution, or starting with naturally occurring compounds. [5] Other syntheses of racemic isopavines are also known. [6] Natural O-methylthalisopavine was first prepared by Meyers and co-workers, [7] by utilizing chiral nonracemic formamidines as substrates in an asymmetric synthesis. Dominguez and co-workers [8] relied on b-amino alcohols as chiral auxiliaries in their synthesis of the same alkaloid.In view of the pharmacological importance of the isopavines, and the paucity of methods to access enantiopure analogues that would be useful to study selective interactions with designated receptors, we investigated various routes to their stereocontrolled synthesis. We report herein examples of highly stereocontrolled, diastereoselective [1,2]-Stevens rearrangements [9, 10] of 13-substituted dihydro methanodiarylazocines, which are readily available from a-amino acids, [11] to give 6-substituted enantiopure isopavines.Scheme 1 illustrates the sequence and the generality of the [1,2]-Stevens rearrangement. Methylation of the individual azocine analogues 1 a ± h afforded the corresponding quaternary ammonium salts 2 a ± h. Treatment with a solution of potassium tert-butoxide in 1,4-dioxane [2b] at 80 8C for 1 h, and chromatographic purification gave the corresponding 6-substituted isopavines 3 a ± h in excellent yields. The structures of 3 a and 3 e were ascertained by means of singlecrystal X-ray analysis (Figure 1) The facile construction of the 6R-methyl-O-methylthalisopavine 6 skeleton from the N,N-dibenzylamino alcohol 4 via the azocine 5 is shown in Scheme 2.The highly stereoselective [1,2]-Stevens rearrangement in this series is unprecedented [12,13] and can be rationalized by considering two reaction pathways (Scheme 3). Abstraction of a C-7 benzylic proton in the azocinium ion intermediate (pathway a) leads to ylide A, which fragments to the iminium anion A or its diradical equivalent. [10] This is in a favorable alignment for an intramolecular attack (recombination), which leads to the observed isopavine 3 a. On the other hand, abstraction of the C-5 benzylic proton generates ylide B, which upon fragmentation results in an anion or diradical that is destabilized by allylic 1,2-strain in the incip...

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Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

Hanessian

Mauduit

2001

Angew. Chem. Int. Ed.

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Syntheses of Morphine

Abstract: Morphine (1) M e o / 0 qBNW 0 H Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995 4 5 6 8 J J -/ J arategk bonds in morphine I I 7 8 9 1 0 g U 15 J J 7 J J -Scheme 1. Retrosynthetic analysis of the morphine skeleton.

Cited by 14 publications

References 27 publications

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

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Syntheses of Morphine

Abstract: Morphine (1) M e o / 0 qBNW 0 H Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995 4 5 6 8 J J -/ J arategk bonds in morphine I I 7 8 9 1 0 g U 15 J J 7 J J -Scheme 1. Retrosynthetic analysis of the morphine skeleton.

Cited by 14 publications

References 27 publications

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine1,

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine1,

Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

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Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,