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<p>A novel synthetic approach to the key pentacyclic phenol intermediate <b>1</b>, common to Trabectedin <b>3</b> and Lurbinectedin <b>4</b>, is described. This manuscript presents a convergent synthetic strategy involving aryl di-triflates <b>13</b> and <b>14</b> as efficient alternatives to the previously reported aryl mono-triflate <b>6</b>. The study focuses on the selective mono-deprotection of bis(triflate) <b>14</b> to a mono-triflate <b>8</b>, followed by hydroxyl group protection to obtain aryl O-MOM mono-triflate <b>9</b>. Optimal conditions were identified and applied for the efficient synthesis of the key intermediate <b>9</b>. Further synthetic advancement involved a Kumada coupling reaction, facilitating the C-methylation of <b>9</b> to the corresponding alkane <b>15</b>. This strategy ultimately delivers the key pentacyclic phenol <b>1</b> with controlled desmethyl impurity <b>12</b>, a significant improvement in overall yield (68% vs. 51%), use of cost-effective reagents, and adherence to green chemistry principles. The method demonstrates operational simplicity and scalability, suitable for multigram-scale synthesis.</p> Graphical abstract <p></p>

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Selective mono-deprotection strategy for efficient synthesis of Trabectedin, Lurbinectedin key intermediate

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Chandrasekhar Byravakunta,
  • Ramesh Kola,
  • Nareshkumar Reddy Kondampally,
  • Subba Narasimhulu Porala,
  • Sathishkumar Rajkumar

摘要

A novel synthetic approach to the key pentacyclic phenol intermediate 1, common to Trabectedin 3 and Lurbinectedin 4, is described. This manuscript presents a convergent synthetic strategy involving aryl di-triflates 13 and 14 as efficient alternatives to the previously reported aryl mono-triflate 6. The study focuses on the selective mono-deprotection of bis(triflate) 14 to a mono-triflate 8, followed by hydroxyl group protection to obtain aryl O-MOM mono-triflate 9. Optimal conditions were identified and applied for the efficient synthesis of the key intermediate 9. Further synthetic advancement involved a Kumada coupling reaction, facilitating the C-methylation of 9 to the corresponding alkane 15. This strategy ultimately delivers the key pentacyclic phenol 1 with controlled desmethyl impurity 12, a significant improvement in overall yield (68% vs. 51%), use of cost-effective reagents, and adherence to green chemistry principles. The method demonstrates operational simplicity and scalability, suitable for multigram-scale synthesis.

Graphical abstract