Using Directing Groups For Stereocontrol

Although several improved glycosyl donors have been developed to accomplish "direct'' sialylations of acceptors, elimination reactions of the sialyl oxocarbenium ion intermediate often are significant competing nonproductive reaction pathways. Additionally, control of the stereochemistry at the NeuAc anomeric center is difficult and nontrivial. To alleviate these problems, several laboratories have investigated the use of stereodirecting auxiliaries at C3 of NeuAc. The postulate is that this group Y in 63 (Scheme 20) could, after activation, assist in stabilizing the positive charge of the oxocarbenium intermediate 64. In doing so, an intermediate such as 65 would be formed. Not only would this suppress elimination reactions, but one could imagine that the trajectory of attack of the glycosyl acceptor would be guided anti to the three-membered onium ion. As a result, the anomeric configuration might be assembled in a more predictable and a-selective fashion.

Goto and coworkers, who were early contributors, synthesized compounds of this nature from the 2,3-dehydro sialic acid 21 [22]. The Goto group initially investigated hydroxyl groups at C3 as directors and used the reliable Koenigs-Knorr method for glycosylation (Scheme 21) [22]. The prototypical donor was the bromide 67. As a means of examining the versatility of this sialyl donor, the a-2,9 and a-2,8 NeuAc dimers were chosen as the synthetic targets. Treatment of 67 with silver triflate and a selectively protected sialic acid glycal 68 afforded 42% of the a-2,9 dimer 69 along with a 21% of the /3 anomer. The secondary alcohol 70 was also glycosylated with 67 to give 26% of disaccharide 71. Although the yield of the glycosylation was rather modest, the stereoselectivity was good (3:1 a:fi). The Goto lab later found that bromides at C3 could also be used as directing groups [23]. This prompted a great deal of research into more convenient C3 substituents that would provide higher stereocontrol.

C02CH3

AcO OAc

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