High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries.
The Vorbrüggen glycosylation reaction was adapted into a one-step 5 min/130 degrees C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl triflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield +/- SD was 26 +/- 16%, and the average purity +/- SD was 95 +/- 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
Bookser
Brett C
BC
Metabasis Therapeutics, Incorporated, 11119 North Torrey Pines Road, La Jolla, California 92037, USA. bookser@mbasis.com
Raffaele
Nicholas B
NB
D030541:Databases, Genetic; D006031:Glycosylation; D008872:Microwaves; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry* / Q000235:genetics*; D013997:Time Factors
D009705:Nucleosides