Scheme 15 The Ogawa synthesis of the HA tetrasaccharide.
conditions, acceptor II.53 and imidate II.42 were coupled to produce the fully protected tetrasaccharide II.54 in 87% yield. De-isopropylidenation, acetylation, and de-levulinoylation provided the diol II.55. Conversion of II.55 into target tetrasaccharide II.41 was performed as described for the di- and trisaccharides.
As demonstrated by Ogawa and coworkers, the preparation of HA oligosaccharides can be achieved in a stereocontrolled and high-yielding manner (80-90% yield). Although requiring two steps, the Swern oxidation is consistently high yielding, thereby demonstrating its utility over other types of oxidation that occasionally lead to low yields and mixtures of products.
Danishefsky's iodosulfonamidation methodology offers an alternate route to 2-deoxy-2-amino functionalized sugars, although the reported use of N-protecting groups is limited to benzenesulfonamides. Carter and coworkers demonstrated the use of this methodology in the construction of the protected ¡(1,4)-HA disaccharide (Scheme 16) . Glycosylation of iodosulfonamide II.56 and II.57 in the presence of lithium tetramethylpiperidide (LTMP) and silver triflate (AgOTf) afforded disac-charide II.58 in 51% yield. Subsequent removal of the 4-methoxybenzyl ether with CAN followed by Jones oxidation of C6 and esterification with CH2N2 produced II.59 in 43% overall yield. However, all attempts to remove the benzenesulfonyl and benzyl protecting groups to yield the target disaccharide resulted in incomplete de-protection and/or decomposition.
The problems associated with the deprotection of II.59 prompted the use of an alternate glycosyl donor, II.60 . The use of II.61 eliminates the need to oxidize C6 after glycosylation. Moreover, II.61 incorporates a phthalamide as the N-pro-tecting group, which is more easily removed. Glycosylation of II.60 and II.61 was carried out in the presence of AgOTf and sym-collidine  at — 30°C and, upon warming to room temperature, provided the protected disaccharide II.62 in 94% yield. Hydrogenolysis with 30% Pd/C afforded 75% of diol II.63. Unfortunately, removal of the tert-butyl ester with formic acid produced, in addition to II.64, an unidentified side product that could not be removed. Glycosylation of II.60 with alternate acceptor II.57 via AgOTf and sym-collidine afforded the corresponding
Scheme 16 The Carter synthesis of the ^(1,4)-HA disaccharide.
Scheme 16 The Carter synthesis of the ^(1,4)-HA disaccharide.
disaccharide that could be purified only after removal of the 4-methoxybenzyl ether to give II.65 (Scheme 17). Jones oxidation followed by esterification with diazo-methane provided II.66 in 58% yield. Complete deprotection and N-acetylation were achieved in four steps and 52% overall yield to give the target disaccharide II.67.
Although the final published route of II.67 by Carter and coworkers utilized classic glycosylation methodology, their prior synthetic approach involving the io-dosulfonamidation methodology demonstrates its own utility in effecting glycosidic bond formation. Unfortunately, the subsequent deprotection of the aromatic sulfonamides usually requires strongly reducing conditions that are incompatible with other functionalities on the GAG backbone. Deprotection of II.59 with Na0/NH3 led to less than 10% of the amine, while the majority of the resulting mass balance consisted of decomposed monomer fragments.
It is apparent that the success of Danishefsky's iodosulfonamidation methodology in GAG synthesis depends on the ability to remove the benzenesulfonamide group under mild conditions. Vedejs and Lin reported the use of SmI2 for the de-protection of arenesulfonamides, citing excellent yields without epimerization . Based on these results, Hill and coworkers investigated the application of SmI2-mediated deprotection of arylsulfonamides in the N-tosyl-2-deoxy-2-amino- and N-sulfonyl-2-deoxy-2-amino-glycosides, II.68 and II.58, made by the iodosulfonidation methodology (Scheme 18) . Synthesis of the protected ^(1,4)-hyaluronan disac-charide II.58 was achieved as previously reported in 38% yield and the protected ^(1,3)-hyaluronan disaccharide II.68 was prepared by condensation of II.56 and II.69 in the presence of LTMP and AgOTf in 82% yield. Cleavage of the N-sulfonyl bond to the corresponding free amines (II.70 and II.71), achieved by using SmI2 and 1,3-dimethylpropyleneurea (DMPU), occurred in 48 and 60% yield, respectively. These reductions took longer than those reported by Vedejs (2-3 days vs. 24 h) and, in general, the phenyl sulfonamides are reduced more quickly than the corresponding tosylamides. Fukuyama and coworkers have found 2- and 4-nitrobenzenesulfonam-ides to be efficient N-protecting groups for both primary and secondary amines, undergoing facile deprotection with thiophenol or mercaptoacetic acid . These sulfonamides may find utility in GAG synthesis as N-protecting groups.
The preparation of the largest synthesized fragments of HA was reported by Blatter and Jacquinet . The tetra- (II.72), hexa- (II.73), and octasaccharides (II.74) were prepared, with each fragment containing a methyl ^-d-glucopyranosi-
duronic acid residue at the reducing end. The approach differs from the earlier preparations of HA in that a direct coupling at C4 of d-glucuronic acid derivatives was used. The poor nucleophilicity of the coupling units was offset by the efficiency of the trichloroacetimidate glycosylation methodology.
The synthesis of targets II.72, II.73, and II.74 was achieved from precursors II.75, II.76, and II.77, which were, in turn, constructed from disaccharide units II.78 and II.79 (Scheme 19). The key to this strategy was the synthesis of a common dimeric building block, II.80, which could be converted into both the glycosyl donor (II.78) and the acceptor (II.79). Disaccharide II.80 was obtained by coupling glycosyl donor (II.81) and acceptor (II.82) in the presence of TMSOTf (89% yield). Conversion of II.80 into imidate II.78 was achieved by removal of the 4-methoxy-phenyl group with CAN to form the hemiacetal, followed by treatment with trichloro-acetonitrile and DBU. Disaccharide II.78 was converted into the corresponding methyl glycoside (II.83) by condensation with methanol; however, the reaction proved to be irreproducible (60-90% yield). Consequently, an alternate acceptor (II.84) was employed and glycosylated with imidate II.81 to give disaccharide II.83 in 91% yield (Scheme 20). Removal of the chloroacetate (ClAc) group with thiourea provided acceptor II.79 in 96% yield. With II.78 and II.79 in hand, condensation in the presence of TMSOTf produced the tetrasaccharide II.75 in 87% yield. Removal of the trichloroacetyl group gave tetrasaccharide II.85. Further glycosylation of II.85 with imidate II.78, as described for the preparation of II.75, afforded the hexasac-charide derivative II.76 in 93% yield. Subsequent deprotection of II.76 gave alcohol II.86, which could be further condensed with imidate II.78 to afford octasaccharide II.77 in 93% yield, which upon dechloroacetylation gave II.87.
Deprotection of II.85, II.86, and II.87 was carried out as follows. Conversion of the ^-trichloroacetyl groups to the corresponding ^-acetyl groups was achieved by treatment with tributylstannane and azoisobutylnitrile (AIBN) to give the corre-
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