A Concise Building Block Approach to a Diverse Multi-Arrayed Library of the Circumdatin Family of Natural Products

Abstract

Using a polymer-supported phosphine-mediated intramolecular aza-Wittig reaction in a key step of a reaction sequence a diverse library of benzodiazepine-quinazolinone alkaloids (Circumdatins) has been prepared using a novel modified Eguchi protocol. The multi-arrayed library generation strategy commenced from readily accessible benzodiazepinedione derivatives (and anthranilic acids) and all library members were purified by reverse phase preparative HPLC.

Key words

aza-Wittig reaction - polymer supported triphenylphosphine - natural product libraries - privileged scaffolds

References

• 1 Dai J.-R. Carte BK. Sidebottom PJ. Yew ALS. Ng S.-W. Huang Y. Butler MS. J. Nat. Prod.  2001,  64:  125 
• 2 Raebaek L. Breinholt J. J. Nat. Prod.  1999,  62:  904 
• 3 Raebaek L. Breinholt J. Frisvald JC. Christopherson C. J. Org. Chem.  1999,  64:  1689 
• 4 Sun HH. Barrow CJ. Sedlock DM. Gillum AM. Cooper R. J. Antibiotics  1994,  47:  515 
• 5a Sugimori T. Okawa T. Eguchi S. Yashima E. Kakehi A. Okamoto Y. Tetrahedron  1998,  54:  7997 
• 5b Sugimori T. Okawa T. Eguchi S. Yashima E. Okamoto Y. Chem. Lett.  1997,  869 
• 6 He F. Foxman BM. Snider BB. J. Am. Chem. Soc.  1998,  120:  6417 
• 7a Joshi BK. Gloer JB. Wicklow DT. Dowd PF. J. Nat. Prod.  1999,  62:  650 
• 7b Total synthesis of Circumdatin F and Sclerotigenin: Snider BB. Busuyek MN. Tetrahedron  2001,  57:  3301 
• 8 Herpin TF. Van Kirk KG. Salvino JM. Yu ST. Labaudiniere RF. J. Comb. Chem.  2000,  2:  513 
• 9 Thomas AW. Bioorg. Med. Chem. Lett.  2002,  12:  1881 
• 10 Masciadri R, Thomas AW, and Wichmann J. inventors; PCT WO  200240487. 
• 11 For a more detailed discussion of workflow procedures and automation technology utilized for synthetic arrays, see: Nettekoven M. Thomas AW. Curr. Med. Chem.  2002,  9:  2179