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The first step, protection of the NH2 group, is performed in order to deactivate this reaction center for later glycosylation to the tetrasaccharide. Using 2,2,2-trichloroethoxycarbonyl chloride (TrocCl) 17 is a standard procedure to protect amino groups.7 The acetyl group is not suitable because of its strong neighbor group effect, stabilizing the intermediate oxonium ion 20. During the subsequent glycosylation the stable oxazoline 21 would be formed.
, , x
The Troc group has a weaker neighbor group effect than the acetyl group. (Ether protected trichloroacetimidates are more reactive than
ester protected ones.) Furthermore the Troc group can be removed easily and stereoselectively.
There are different methodologies known to peracetylate a carbohydrate. An acetic anhydride / pyridine mixture (2:1) with catalytic amounts of 4-dimethylaminopyridine (DMAP) to speed up the reaction is very common.8'9
First /V- ac e ty Ip ó ri d i n i u m acetate (24) is formed, which is the acetylating species during this step. This is a relatively mild method and leads to 25.
To get the desired trichloroacetimidate at C-l you have to deprotect this position selectively. With hydrazine acetate (N2Ft4-HOAc) in DMF there is a possibility to do this.10 This reaction is non-catalytic; you have to take equivalent amounts of hydrazine acetate. Generally, trichloroacetimidates are stable and represent good glycosyl donors.11 Non-participating protecting groups like benzyl ethers in non-polar solvents, with weak Lewis acids as catalysts, lead to the opposite stereochemistry of the utilized trichloroacetimidate. This is comparable with Sn2 reactions. Participating neighbor groups with a strong catalyst in a polar solvent lead to 1,2-trans glycosides in a subsequent glycosylation.12
One can manage the formation of the kinetical Ä- or the thermodynamical «-anomer by means of different reaction protocols.
Application of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (30) as base will exclusively yield the a formation; using Ê2ÑÎç you will get the /Ç-anomer. After abstraction of a proton at the anomeric center you get an equilibrium 26 27. The interactions of the electron pairs of
26 lead to a bigger nucleophilicity than 27. Compound 26 is stabilized 1,8-diazabicycio[5.4.o]undec-7-ene by the anomeric effect. <DBU>
The anomeric effect, a stereoelectronic effect, is explained in terms of lone pair-lone pair repulsion, dipole-dipole interactions and by M.O. theory. The equatorial positions of a carbohydrate are favored by sterically demanding substituents. However, electronegative groups at the anomeric center prefer the axial position because of the stereoelectronic effects. This fact is known as the anomeric effect.13 If there is a positive charge at the anomer substituent of a carbohydrate, the equatorial conformation is preferred. To explain this result a reverse anomeric effect was proposed and first detected at /V-(a-glycopyranosyl)pyridinium ions 31 and 32.14
AcO ,N© Br
The existence of the reverse anomeric effect is controversial and RO
seems to be rebuttet for pyranoses by NMR titration studies with 4'-N(H+)
yV-(D-glucopyranosyl)imidazole (33). Nitrogen-protonation of the or
imidazole should increase the proportion of the /?-anomer if there is a r = h, Ac
reverse anomeric effect. During and after titration no shift of the a .fi- 33
equilibrium to the /J-anomer was observed.15
1. ÀßÐ| OP(OEt)2
Neu5Ac -> Ã/ 0'^/^C02Me
• This time the COOH group is protected first.
• Selective protection of all other functionalities except the OH group at C-2 of the neuraminic acid is performed.
• Finally sialic acid is transformed into the shown glycosyl donor.
1. CH2N2, Et20,0°C^r. t„ 12 h
2. Ac20, HC104, 20 °C, 2 h
3. ClP(OEt)2, CH2C12, EtN7Pr2, r. t„ 10 min 97 % (over three steps)
The methylester 38 of the carboxylic acid 34 is formed by using diazomethane 35.16
34 35 36 37 38
The 1,3 dipole diazomethane is a mild reagent to furnish methyl esters (see Chapter 13), but it has some disadvantages, too: it is volatile, toxic and furthermore explosive. For this reason it has to be prepared by reaction of KOH with N - m e t h ó 1 - /V- n i t ro s î -p a ra -1 î I uc n e s u I fî n -amide (carcinogenic!) or in situ}1 Another simple method to protect the COOH functionality of the neuraminic acid is the esterification with methanol as solvent and reactand under H+ catalysis e. g. ion exchanger.
In the following, all alcohol functionalities besides the C-2 of the neuraminic acid have to be protected. Kuhn et al. describe a simple method to get product 39 in good yields.18 By means of the different reactivities of the OH-groups the peracetylated neuraminic acid or 39 is obtained by carrying out the reaction at 20 °C for 2 h in acetic anhydride with catalytic amounts of perchloric acid (ÍÑÞ4). If the temperature or the reaction time is rising you get the completely peracetylated product. The advantage of perchloric acid is the low basicity of the anion C104~. Instead, the use of sulfuric acid as catalyst yields the peracetylated glycal 40.