A Nine-Step Formal Synthesis of (±)-Morphine

Abstract

A nine-step stereoselective formal synthesis of (±)-morphine from readily available o-vanillin is presented. The carbocyclic structure of morphine was quickly assembled through an orchestration of the intermolecular Diels−Alder/ Claisen/Friedel−Crafts sequential reaction. This approach involves many one-pot procedures and no protecting groups, and only a few chromatographic purifications are required.

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine

“…Over the past 60 years, extensive synthetic studies of morphine-type alkaloids and derivatives (Fig. 1) have been conducted 4–12 , resulting in both the discovery of numerous structurally related drugs to solve its undesired side effects 13,14 and the creative development of more than 30 total as well as formal syntheses based on the design of various strategies to address its potential problems of source supplies from nature. However, catalytic asymmetric total synthesis of (‒)-morphine has seldom been reported 15–19 , and moreover, the lack of efficient asymmetric synthetic approach is still an unsolved issue.…”

Dearomative logic in natural product total synthesis

“…Of note, even though dearomatization is not involved in the key transformation, substrates like 292 are oen synthesized from corresponding aromatic counterparts. While other elegant strategies towards morphinans have emerged over the years, [313][314][315][316] considering the tremendous success of dearomative methods, it is not surprising that, even aer 35 years, these approaches still dominate the eld.…”

Interpol Review of Drug Analysis 2019-2022

“…2019 novel and sensitive sensor for morphine based on electrochemically synthesized poly(p-aminobenzenesulfonicacid)/reduced grapheneoxide (poly(p-ABSA)/RGO) composite modified glassy carbon electrode [ 212 ]; nine step method to synthesize morphine from o-vanillin [ 213 ]; immunochromatographic lateral flow strip with gold nanoparticles labeling was developed for monitoring of morphine [ 214 ]; electrochemical sensor for detection of morphine [ 215 ]; 2020 Review of electrochemical detection methods of differeent moodified electrodes for deteection of morphine [ 216 ]; synthesis and use of poly(cetyltrimethylammoniumbromide)/graphene oxide (poly(CTAB)/GO) composite as novel sensor for morphine detection [ 217 ]; sensor for determination of morphine and diclofenac via differential pulse voltammetric, cyclic voltammetric, and chronoamperometry [ 218 ]; fluorescence immunoassay method for detection of morphine [ 219 ]; 2021 surface ionization mass spectrometry method for the direct detection and analysis of morphine [ 220 ]; a quantitative lateral flow immunoassay instrument that uses magnetic resistance sensors for quantitative measurement of morphine [ 221 ]; comparison of two different sensing platforms (electrochemical impedance spectroscopy and a quartz crystal microbalance) for the detection of morphine [ 222 ]; evaluation of the use of plant extracts and herbal products as a SPME sorbet for use with RP-HPLC and LC-MS/MS for detection of Morphine and Codeine [ 223 ]; electrochemical sensor for DPV determination of morphine [ 224 ]; utilization of a gas-phase chloride attachment with IMS for selective detection of morphine in a morphine/codeine mixture [ 225 ]; N,Cl-doped deep eutectic solvents-based carbon dots as a selective fluorescent probe for determination of morphine in food [ 226 ]; electrochemical sensor for detection of morphine in drug samples [ 227 ]; 2022 electrochemical sensor for simultaneous detection of Diclofenac and Morphine [ 228 ]; sensor for detection of morphine [ 229 , 230 ]; methodology to isolate morphine from opium and heroin (deacetylated to morphine) for isotopic analysis and regional analysis of submissions from Mexico, South America, Southwest Asia, and Southeast Asia [ 231 ]; electrochemical sensors for detection of morphine in unprocessed coffee and milk [ 232 ].…”