Scheme 42 Synthesis of N-acetylchondrosine.

vi O

prior to sulfation of the axial 4-OH. However, glycosylation of diol IV.5 with methyl (2,3,4-tri-O-acetyl-a-l-idopyranosyl bromide) uronate [94] (IV.27) was reported to produce a low yield (16%) of desired disaccharide IV.28 (Scheme 43). The major product isolated (66%) was the intermediate orthoester IV.29 [95]. The presence of the vicinal 4-OH appeared to complicate the rearrangement of orthoester IV.29 into IV.28. All attempts to effect this rearrangement with tin tetrachloride were unsuccessful, and an alternate strategy was then employed.

Glycosyl acceptor IV.30, obtained by benzylidenation of IV.1 with a,a-dime-thoxytoluene and camphorsulfonic acid in nitromethane, was used instead. Silver triflate mediated glycosylation of IV.30 with IV.27 in the absence of 2,3,4-trimethyl-pyridine afforded the disaccharide IV.31 in 54% yield. Alternatively, trimethylsilyl triflate promoted glycosylation of IV.30 with the a-trichloroacetimidate IV.32 (obtained from glycosyl bromide IV.27) gave an improved yield of the disaccharide IV.31 (68%). The 4-OH of the galactopyranoside unit was selectively unmasked [96] to give 70% of IV.28, and then O-sulfated to produce disaccharide IV.33 in 94% yield. Saponification of IV.33 with sodium hydroxide followed by catalytic hydro-genolysis and N-acetylation provided the target disaccharide (IV.22) as the disodium salt.

Using the same synthetic approach, Sinay and coworkers also reported the synthesis of the second repeating copolymer of dermatan sulfate, N-acetylchondro-sine (IV.37) (Scheme 44). Silver triflate mediated glycosylation of IV.30 with methyl(2,3,4-tri-O-acetyl-a-d-glucopyranosyl bromide)uronate (IV.34) gave the corresponding disaccharide IV.35. Compound IV.35 was then converted to the target disaccharide (IV.37) as described above, in 60% overall yield.

Ogawa and Goto reported the synthesis of a dermatan sulfate hexasaccharide (IV.38) that utilized trichloroacetimidate glycosylations in a regio- and stereocon-trolled manner according to the retrosynthetic route shown in Scheme 45 [97]. The target hexasaccharide IV.38 is derived from benzyl-protected precursor IV.39, which is in turn derived from IV.40 through oxidation, N-acetylation, and sulfation. The central tetrasaccharide was constructed by the repeated use of the imidate disaccha-ride IV.42, and the nonreducing end and reducing end units utilized monosaccharides IV.41 and IV.43 [98], respectively. The preparation of glycosyl donors IV.41 and IV.42 is detailed in the corresponding reference. The linear synthesis of the hexa-saccharide started at the reducing end by the TMSOTf-promoted glycosylation of IV.43 with trichloroacetimidate IV.42 to produce trisaccharide IV.44 in 86% yield (Scheme 46). Removal of the levulinoyl group with hydrazine acetate and coupling of the resultant glycosyl acceptor IV.45 with another unit of IV.42 in the presence of ferf-butyldimethylsilyl triflate afforded the pentasaccharide IV.46 in 87% yield. Following de-levulinoylation of IV.46 to IV.47, the terminal l-idose moiety was installed by glycosylation of IV.47 with IV.41 in the presence of ferf-butyldi-methylsilyl triflate to afford 99% of the hexasaccharide IV.48. Regioselective ring opening of the benzylidene followed by acetylation gave precursor IV.40 in 64% overall yield. Transformation of IV.40 to IV.49 was achieved sequentially by treatment with thioacetic acid [99], deprotection [100], and subsequent Swern oxidation and esterification. Deacetylation and saponification of the methyl esters with sodium hydroxide afforded IV.50. Finally, sulfation with sulfur trioxide-triethylamine complex gave IV.39, which upon hydrogenolysis (Pd/C) produced the target hexasac-charide IV.38.

Reverse Testicular Atrophy
iv.32, R = OC(NH)CCI3

Scheme 43 The Sinay synthesis of sulfated N-acetyldermosine.

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