Production of novel isoquinoline-containing functional reagents and new developmet

• Project/Area Number: 15590019
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Tohoku Pharmaceutical University
• Principal Investigator: TAKAHATA Hiroki Tohoku Pharmacuetical University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00109109)
• Co-Investigator(Kenkyū-buntansha): SAITO Yukako Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Reseach Associate, 薬学部, 助手 (30364409)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: condensing reagent / isoquinoline / esterification / amidation / catalyzed reaction / アシル活性化体 / Boc化 / アミノ酸エステル / EEDQ

Research Abstract

We reported a novel and chemoselective tert-butoxycarbonylation reagent, 1-tert-butoxy-2-tert-butoxycarbonyl-1, 2-dihydroisoquinoline (BBDI), which was easily prepared in quantitative yield by the reaction of isoquinoline with Boc_2O. BBDI effected easily the tert-butoxycarbonylation for acidic substrates in the absence of bases rather than basic ones, while that for acidic compounds such as phenols, carboxylic acids using Boc_2O required some base. The synthesis of carboxylic esters is one of the most fundamental and pivotal protocols for producing natural and synthetically useful compounds in organic chemistry. The coupling reactions between activated derivatives of carboxylic acids and alcohols have been employed. These procedures are of considerable interest, especially as relate to the manipulation of peptides or complicated biologically active compounds such as macrolides. A simple and mild esterification of N-protected amino acids using BBDI as a novel condensing reagent in a on e-pot method was developed. This protocol has several advantages including the use of nearly equimolar amounts of alcohols, no requirement for additives, and no racemization occurs. Next, we developed a novel BBDI-catalyzed esterification of N-protected amino acids in the presence of Boc_2O under simple and mild conditions. Although a variety of methods for acid-catalyzed esterification reactions have been reported, the use of a nearly neutral catalyst such as BBDI has not been extensively investigated. Further, it was found that catalytic esterification using BBDI typed reagent derived from electron-rich isoquinoline such as 6-methoxyisoquinoline shortened a reaction time. The synthesis of carboxylic amide is one of the most fundamental and pivotal protocols for producing natural and synthetically useful compounds such as peptides in organic chemistry. We succeeded a simple and mild amidation that uses nearly equimolar amounts of a variety of carboxylic acids and amines and BBDI without the need for any additives.

Research Products

• [Journal Article] A novel 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline(BBDI)-catalyzed esterification of N-protected amino acids with nearly equimolar amounts of alcohols in the presence of Boc_2O (2006)
  • Author(s): Saity, Y., Watanabe, T., Takahata, H.
  • Journal Title: Tetrahedron Letters 47 Pages: 3099-3102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline(BBDI)-catalyzed esterification of N-protected amino acids with nearly equimolar amounts of alcohols in the presence of Boc_2O (2006)
  • Author(s): Saito, Y., Watanabe, T., Takahata, H
  • Journal Title: Tetrahedron Letters 47 Pages: 3099-3102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI)-catalyed esterification of N-protected amino acids with nearly equimolar amounts of alcohols in the presence of Boc_2O (2006)
  • Author(s): Saito, Y., Watanabe, T., Takahata, H.
  • Journal Title: Tetrahedron Letters 47
• [Journal Article] Simple and mild esterification of N-protected amino acids with nearly equimolar amounts of aldohols usig 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (2005)
  • Author(s): Saito, Y., Yamaki, T, Kohashi, F., Watanabe, T., Ouchi, H., Takahata, H.
  • Journal Title: Tetrahedron Letters 46 Pages: 1277-1279
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Simple and mild esterification of N-protected amino acids with nearly equimolar amounts of alcohols using 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (2005)
  • Author(s): Saito, Y., Yamaki, T., Kohashi, F., Watanabe, T., Ouchi, H., Takahata, H.
  • Journal Title: Tetrahedron Letters 46 Pages: 1277-1279
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Simple and mild esterification of N-protected amino acids with nealy equimolar amounts of alcohols using 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (2005)
  • Author(s): Saito, Y., Yamaki, T., Kohashi, F., Watanabe, T., Ouchi, H, Takahata, H.
  • Journal Title: Tetrahedron Letterts 46/8 Pages: 1277-1279
• [Patent(Industrial Property Rights)] 公開特許公報(A) (2004)
  • Inventor(s): 高畑廣紀
  • Industrial Property Rights Holder: 高畑廣紀
  • Patent Publication Number: 2006-063035
  • Filing Date: 2004-08-27
  • Acquisition Date: 2006-03-06
  • Description: 「研究成果報告書概要(和文)」より