Enantioselective Total Synthesis of (–)-TAN-67
5 affiliations
- 1Borch Department of Medicinal Chemistry and Molecular Pharmacology
- 2Purdue University
- 3Department of Molecular Chemistry
- 4Universite de Bourgogne Europe
- 5Department of Chemistry
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.
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BibTeX
@misc{mahgoub2026enantioselective,
title = {{Enantioselective Total Synthesis of (–)-TAN-67}},
author = {Abdulrahman A. Mahgoub and Jagadish Khamrai and Omos Obakpolor and Ryan A. Altman},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008288/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008288/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Enantioselective Total Synthesis of (–)-TAN-67
AU - Abdulrahman A. Mahgoub
AU - Jagadish Khamrai
AU - Omos Obakpolor
AU - Ryan A. Altman
PY - 2026
DA - 2026/09/04
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008288/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008288/v1
AB - (–)-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.
ER -