Synthesis of Tunicaminyluracil Derivatives

Abstract

A tunicaminyluracil derivative, which is a key component of the tunicamycin nucleoside antibiotics, was synthesized using a samarium diiodide (SmI₂) mediated aldol reaction and intramolecular Pummerer reaction as the key steps. The α‐phenylthio ketone 11, the precursor of the samarium enolate, was prepared from d‐galactose. Treatment of 11 with SmI₂ at − 40°C resulted in complete conversion to the corresponding samarium enolate, and subsequent addition of uridine 5′‐aldehyde 12 afforded the desired aldol products 13a,b. Compound 13a was converted to the sulfoxide 15 by a sequential diastereoselective reduction of the ketone and an oxidation with mCPBA. Activation of 15 with Tf₂O provided the desired cyclized compound 17. In this reaction, the aldol product 13a was also obtained as a consequence of a competitive intramolecular version of DMSO‐oxidation via a 7‐membered ring intermediate. Compound 18 or 19 are ready for use as a glycosyl donor in glycosylations to provide a range of analogues as potential glycosyltransferase inhibitors as well as related natural products.

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

^#This paper constitutes Part 225 of Nucleosides and Nucleotides: Shuto, S.; Fukuoka, M.; Kudoh, T.; Garnham, C.; Galione, A.; Potter, B. V. L.; Matsuda, A. J. Med. Chem. 2003, 46, 4741.

Keywords:

• Tumicamycins
• Tunicaminyluracil
• Antibiotics
• Samarium diiodide
• Aldol reaction
• Pummerer reaction

Notes

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

^#This paper constitutes Part 225 of Nucleosides and Nucleotides: Shuto, S.; Fukuoka, M.; Kudoh, T.; Garnham, C.; Galione, A.; Potter, B. V. L.; Matsuda, A. J. Med. Chem. 2003, 46, 4741.

³The uridine 5′‐aldehyde derivative 12 was prepared by Dess–Martin periodinane oxidation of 2′,3′‐di‐O‐TBS uridine.