Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
J Org Chem. 2017 Oct 20;82(20):11157-11165. doi: 10.1021/acs.joc.7b02179. Epub 2017 Oct 11.
β-Ketosulfonamides derived from Boc or Cbz-protected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating N-allyl, N-alkyl methanesulfonamides with n-BuLi, followed by reaction of the resulting carbanion with methyl esters of N-protected l-amino acids. The analogous reaction using the dianion derived from an N-alkyl methanesulfonamide proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15-60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be removed in good yield using cat. Pd(PPh)) and dimethyl barbituric acid. When the fluorination reaction was performed with CsCO as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while β-ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides.
β-酮基磺酰胺是由 Boc 或 Cbz 保护的带有疏水侧链的氨基酸衍生而来的，通过用 n-BuLi 处理 N-烯丙基、N-烷基甲磺酰胺，然后使所得碳负离子与 N-保护的 l-氨基酸甲酯反应，可以很好到优异的收率得到。使用 N-烷基甲磺酰胺的二负离子进行类似的反应，产率要低得多。在室温下，在 DMF 中使用 Selectfluor 和 CsF 对β-酮基磺酰胺进行亲电氟化 15-60 分钟，可以得到良好到优异收率的β-酮-α，α-二氟磺酰胺。使用 cat. Pd(PPh)) 和二甲巴比妥酸可以很好的收率脱除烯丙基保护基。当用 CsCO 作为碱进行氟化反应时，来自 Val、Leu 或 Ile 的β-酮基磺酰胺得到了预期的β-酮-α，α-二氟磺酰胺，而来自 Ala、Phe 或 hPhe 的β-酮基磺酰胺得到了亚氨基β-酮-α，α-二氟磺酰胺的水合物。
