Chain Extension of Carbohydrates VI. Synthesis of the Two C-6 Epimers of the 6-Acetylamino-4,6-dideoxyheptopyranosiduronic Acid Present in Amipurimycin by Means of Stereocontrolled Ethynylation of Methyl 2,3-Di-O-benzyl-4-deoxy-α-d-xylo-hexodialdo-1,5-pyranoside

Abstract

The two C-6 epimers of 6-acetylamino-4,6-dideoxy-heptopyranosiduronic acid present in amipurimycin were prepared by selective reactions from methyl 2,3-di-O-benzyl-4,6,7,8-tetradeoxy-α-l-ido-7-ynopyranoside (4) in which the ethynyl group was employed as a precursor of the carboxylic acid function. The masked amino group was introduced at C-6 by reaction of 4 with zinc azide in the presence of triphenylphosphine and diisopropyl azodicarboxylate. The resulting methyl 6-azido-2,3-di-O-benzyl-4,6,7,8-tetradeoxy-α-d-gluco-oct-7-ynopyranoside (5) was transformed into benzyl[6-(acetylamino)-2,3-di-O-benzyl-4,6-dideoxy-α-d-gluco-heptopyranosid]uronate (7) by two different sequences of reactions: (1) oxidative cleavage of the triple bond, benzylation, reduction of the azido group, N-acetylation or (2) reduction of the azido group, N-acetylation, oxidative cleavage of the triple bond and treatment with phenyldiazomethane. The second sequence of reactions was found to be more efficient (33% overall yield versus 13%). The configuration at C-6 was unambiguously confirmed by X-ray diffraction with a single crystal of 7. Final hydrogenolysis of benzyl groups afforded methyl 6-(acetylamino)-4,6-dideoxy-α-d-gluco-heptopyranosiduronic acid (9). A Mitsunobu reaction on acetylenic alcohol 4 followed by saponification afforded the C-6 epimer 11. The same sequences of reactions was applied to 11 and methyl 6-(acetylamino)-4,6-dideoxy-α-l-ido-heptopyranosiduronic acid (16) was obtained.

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

“…Tremendous efforts toward the chemical synthesis of amipurimycin are described. [3][4][5][6][7][8][9] Thus,anumber of the advanced precursors and analogues of amipurimycin have been synthesized, including at hymine analogue by Datta et al, [7] al inear analogue by Czernecki et al, [6a] peptidyl glycoside fragments by Garner et al, [3c] and thymine nucleoside fragments by Dhavale et al [9] However, none of those synthetic approaches could lead to the target amipurimycin. Herein, we report the first total synthesis of the proposed amipurimycin, including all the four possible diastereoisomers (1a-d)and their 8'R antipodes (1e-h).…”

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

“…[1b] However,i ts structure was not determined until 1982. [3][4][5][6][7][8][9] Thus,anumber of the advanced precursors and analogues of amipurimycin have been synthesized, including at hymine analogue by Datta et al, [7] al inear analogue by Czernecki et al,[6a] peptidyl glycoside fragments by Garner et al, [3c] and thymine nucleoside fragments by Dhavale et al [9] However, none of those synthetic approaches could lead to the target amipurimycin. [2] Nevertheless,t he absolute configuration including,t he cis-cyclopentanyl amino acid residue (at C2'' and C3'')a nd the stereochemistry at C6',w ere undetermined.…”

Further Study toward Amipurimycin: Synthesis of the Northern Part

“…As parts of a program devoted to the synthesis of 1 , we have already studied the stereocontrolled transformation of the primary alcohol into the α-amino acid and the construction of the hydroxylated chain at C-3 on methyl 4-deoxy-α- d - xylo -hexopyranoside derivatives.…”

“…In our previous work, compound 6 was obtained efficiently by stereocontrolled ethynylation of methyl 2,3-di- O -benzyl-4-deoxy-α- d - xylo -hexadialdo-1,5-pyranoside followed by azidation. For convenience and efficiency, we decided to try to preserve the azido group along the whole sequence of reactions and introduce the cis -cyclopentylamino acid at the end of the synthesis.…”

“…Furthermore, a participating group at C-2 is necessary to control the formation of the desired β-anomer. Since, in our previous work, the oxidative cleavage of the triple bond of 6 to a carboxylic ester was not very efficient,the benzyl ethers of 6 were replaced before oxidation. Hydrogenolysis was not possible in the presence of a triple bond and an azido group, so they were cleaved by boron trichloride at low temperature .…”