{
  "abstract": "(–)-TAN-67 is a synthetic opioid alkaloid that acts as a selective δ-opioid receptor (δ-OR) agonist and shares structural similarity to µ-opioid ligands, such as morphine, naltrexone, and many clinically employed derivatives. Previously, the synthesis of (–)-TAN-67 required preparing trans-fused (±)octahydroisoquinoline 1 followed by chiral resolution. The existing routes to access this key intermediate require 7–9 steps, produce 2–20% overall yield, produce racemic material, and have reproducibility issues. Herein, we disclose the first enantioselective synthesis of (–)-TAN-67, which was enabled by the synthesis of a distinct cis-fused (+)-octahydroisoquinoline intermediate, which was synthesized in 10 steps and 15% overall yield. This synthesis features an enantioselective conjugate addition step to establish the all-carbon quaternary stereocenter, a γ-selective Mukaiyama-Mannich reaction to form the isoquinolinone core, a Friedlander’s quinoline synthesis, and a substrate-controlled diastereospecific reduction to establish the tertiary stereocenter delivering (–)-TAN-67 in 13 steps, 8% yield, and 95% ee. This synthesis enables access to (–)-TAN-67 and analogs thereof, which could accelerate medicinal chemistry efforts.",
  "abstract_shown": true,
  "affiliations": [
    "Borch Department of Medicinal Chemistry and Molecular Pharmacology",
    "Purdue University",
    "Department of Molecular Chemistry",
    "Universite de Bourgogne Europe",
    "Department of Chemistry"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Abdulrahman A. Mahgoub"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jagadish Khamrai"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Omos Obakpolor"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Ryan A. Altman",
      "orcid": "0000-0002-8724-1098"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/axv1pca04bhhx.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15008288/v1",
  "fulltext_url": null,
  "id": "axv1pca04bhhx",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008288/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Advanced Synthetic Organic Chemistry"
    ]
  ],
  "openalex": "W7208760982",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15008288/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-04",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/axv1pca04bhhx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.26434/chemrxiv.15008288",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008288/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Advanced Synthetic Organic Chemistry",
      "subfield": "organic"
    }
  ],
  "title": "Enantioselective Total Synthesis of (–)-TAN-67",
  "title_text": "Enantioselective Total Synthesis of (–)-TAN-67",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:17Z",
  "url": "https://research.draconitic.com/paper/axv1pca04bhhx",
  "venue": "ChemRxiv",
  "versions": []
}