Chain-Extension of Carbohydrates. 5. Synthesis of the C-Glycosyl Amino Acid Moiety of Miharamycins Involving Stereocontrolled Ethynylation of Methyl 2,3,4-Tri-O-benzyl-.alpha.-D-gluco-hexodialdo-1,5-pyranoside

• Published in: Journal of organic chemistry Vol. 60; no. 3; pp. 650 - 655
• Main Authors: Czernecki, Stanislas, Horns, Stefan, Valery, Jean-Marc
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.02.1995; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; NUCLEOSIDE; ANTIBIOTICS; STEREOSPECIFIC ETHYNYLATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo00108a030

A multistep synthesis of the C-glycosyl amino acid moiety of miharamycins from methyl 2,3,4-tri-O-benzyl-alpha-D-gluco-hexodialdo-1,5-pyranoside (1) is described, The ethynyl group was employed as a synthetic equivalent of the carboxylic acid function, In the key step, highly diastereoselective ethynylation of compound 1 with the Grignard reagent of (trimethylsilyl)acetylene in the presence of magnesium bromide followed by desilylation afforded acetylenic alcohols 4 and 5 (19:1). The L-glycero configuration at C(6) of the major isomer 4 was unambiguously proven by H-1 NMR of the 4,6-benzylidene derivative 9. The amino function was introduced at C(6) by reaction of 4 with zinc azide in the presence of triphenylphosphine and diisopropyl azodicarboxylate. Transformation of the resulting methyl 6-azido-2,3,4-tri-O-benzyl-6,7,8-trideoxy side (10) into methyl 6-(N-acetylamino)-2,3,4-tri-O-benzyl-6-deoxy-D-glycero-alpha-D-gluco-heptopyranosiduronic acid (17) was achieved by two different sequences of reactions: (1) oxidative cleavage of the triple bond, benzylation, reduction of the azido group, and N-acetylation or (2) reduction of the azido group, N-acetylation, oxidative cleavage of the triple bond, and treatment with phenyldiazomethane. The overall yield of the two sequences was different (41% versus 50%), showing the second method to be superior. Final debenzylation afforded methyl 6-(N-acetylamino)6-deoxy-L-glycero-alpha-D-gluco-heptopyranisoduronic acid (18). To prepare the epimeric amino acid derivative 28, the configuration at C(6) of 4 was inverted by a Mitsunobu reaction. The same sequence of reactions was applied to the so-obtained D-glycero isomer 5 and methyl 6-(N-acetyl-amino)-6-deoxy-L-glycero-alpha-D-gluco-heptopyranosiduronic acid (28) was obtained. In this case almost identical overall yields were obtained for the two different transformations of the azidoalkyne 20 to compound 28 (62% versus 63%).