Intramolecular N-Acyliminium Ion-Olefin Cyclization in the Synthesis of Optically Pure Isoquinoline Derivatives: Control of Stereochemistry and Application to Synthesis of Morphine Alkaloids

Abstract

The 3-[2-(cyclohex-1-eneyl)ethyl]-[1,3]oxazoline-2,4-dione derivatives 9, 14 and 16 were subjected to hydride reduction followed by acid-catalyzed olefin-N-acyliminium ion cyclization to afford a series of perhydroisoquinolines 10, 11a, 11b, 19a-19c, 20a, 20b and 21. A mechanism was proposed that accounts for the observed stereoselectivity of the cyclization reactions based on the neighboring group participation by a benzoate group.

Comparison of Approaches to ent-Morphine via Radical, Cationic, and Heck-Type Cyclizations

“…9 ) by a simple Mitsunobu inversion. It cyclized smoothly to pentacycle 13, which contains some of the structural elements of neopine-type alkaloids.…”

“…The closure of 9 to 8 followed by further elaboration led to the complete morphine skeleton (in the ent-series) 8 . The synthesis of isoquinoline derivatives 9 in both enantiomeric series has been improved subsequently by the use of acid-catalyzed iminium-ion closures 9 and electrochemical methods 10 for the synthesis of precursors.…”

Chemoenzymatic synthesis of complex natural and unnatural products: morphine, pancratistatin, and their analogs

“…Morphine. Several approaches to this alkaloid have been pursued in the groups over the last 15 years and have been published [21][22][23][24][25][26] and reviewed. [1][2][3] In 1997 we reported an approach to morphine based on the recognition that the biphenyl-like compound 33 could be derived from the aminoacid 34 by combination of Suzuki coupling and Kazmaier-Claisen rearrangement of glycinate enter 36 to acid 35 as shown in Scheme 7.…”

Elucidation of the stereochemistry of octahydroisoquinoline derivatives by NMR spectroscopy

“…8 Proof of the structure was the coupling of the OH proton (the one which was bound to no carbon in the HSQC spectrum) to the proton at position 7. The ortho protons on the benzoate group at position 6a presented NOEs with the axial protons at positions 8 and 10 and to the adjacent protons, the hydroxyl one and that in position 10a.…”

“…For 17, the cis relationship of the substituents in positions 7 and 8 was demonstrated by x-ray crystallography. 8 The stereochemistry of the epoxy ring was assigned based on the pattern of NOEs between relevant protons. First, 15 and 17 were assigned as theˇ-and the˛-epoxide, respectively.…”