A

Scheme 12

Scheme 13

a "onium'' isomers, 41 and 42, respectively (Scheme 14). The authors predicted that the ^-onium species 41 would preferentially undergo attack to afford the a-glycoside 44.

Preliminary experiments revealed that a sialyl donor containing a methyl sulfide and a 2-carbon spacer within the ester was the optimum substrate for these studies. This sialyl donor 48 was synthesized as an approximately 1:1 mixture of anomers and was activated with V-iodosuccinimide and trifluoromethanesulfonic acid. Gly-cosylations of compound 48 were compared with the methyl ester control 45 in various solvents to determine the extent of the enhancement of stereoselectivity (Scheme 15). Interestingly, glycosylations of 2-[2-(2-azidoethoxy)ethoxy]ethanol with donor 45 in acetonitrile or dichloromethane gave the same product ratios (entries 1 and 2), suggesting that for this system acetonitrile does not provide an increase in stereoselectivity. However, the tethered donor 48 predominantly favored formation of the a-glycosides (entrites 3, 4, and 5), with the solvent dimethoxyethane (DME) providing the highest a:/3 ratios. Next, the sialyl donor 48 was utilized in the synthesis of a-2,6- and a-2,3-linked disaccharides under the optimal reaction conditions (entires 6 and 7). The selectivities observed were similar to those in the earlier

AcHN

Ac0 OAc 43

Scheme 14

examples, although increased formation of products derived from elimination caused the reaction yields to drop significantly.

A useful and powerful method that has been developed independently by Wong [16] and by Schmidt [17] and their colleagues utilizes sialyl phosphites as glycosyl donors. Phosphites are synthesized from the corresponding anomeric alcohols by reacting the latter with a phosphoramidite. This greatly shortens the reaction sequence needed to obtain the sialyl donors because many transformations that ordinarily would be needed to install a nonoxygen atom at the anomeric carbon are precluded, and several phosphoramidite reagents are readily available. An additional and significant advantage of these donors is that they are activated by many commonly used Lewis acids such as TMSOTf. Lewis acid activation is now a standard for glycoside synthesis, thus making these methods compatible with the most commonly used protecting group patterns and assembly strategies. Furthermore, sialyl phosphites are activated at low temperatures, and as a result generally provide products in high stereoselectivity. Some typical examples of the use of phosphites for

AcO J C02R'

AcO OAc

45 R'=CH3 48 R'=CH2CH2SCH3

-40°C-rt Solvent

AcO.

AcO OAc

49 R'=CH2CH2SCH3

AcO.

AcO OAc

49 R'=CH2CH2SCH3

AcHN

AcO OAc

50 R'=CH2CH2SCH3

MBnO

OMBn b

50 R'=CH2CH2SCH3

och3

OMBn och3

OMBn

MBn=4-methylbenzyl

Entrv

Donor (R1)

Acceptor (R)

Solvent

Glycoside

Yield (%)

0 0

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