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Organic Synthesis workbook li - Bittner C.

Bittner C. Organic Synthesis workbook li - John Wiley & Sons, 2001. - 292 p.
ISBN: 3-527-30415-0
Download (direct link): bittnerorganicsynthesisworkbook2001.pdf
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Finally a good leaving group has to be introduced to transform 39 into the glycosyl donor 7. It has been shown that glycosyl phosphite donors can easily be synthesized and are more stable than some other common glycosyl donors. Within a few minutes stirring at room temperature in the presence of /V- e t h I d i i s p ropy 1 arn i n 41 (lliinig's base) you get 7 in good yields.19
15 GM2
253
How can an acetal be sustained? Hints
What kinds of silylating reagent are used to protect a secondary alcohol as TDS ether?
1. Me2CO, H+ (ion-exchange resin), r. t., 24 h Solution
2. TDSC1, imidazole, DMF, r. t., 3 h
Lactose is transformed into a glycosyl acceptor finally. A view on the oligosaccharide moiety of the GM2 shows the connection of the two already built glycosyl donors to the hydroxy groups at C-3b and C-4b of the lactose. To get the free OH functionalities later, in due time they have to be deprotected selectively.
First the isopropylidene ketal at C-3b and C-4b is generated using acetone and an ion-exchange resin at first. There is no further ketal formation at other positions of the lactose. It is also possible to use 2,2-dimethoxypropane (Me)2C(OMe)2 instead of acetone. The problem in this step is the partial formation of hemi-ketals with the other hydroxy groups which lower the yield. They are destroyed by heating to 100 C in glacial acetic acid.20
Hereafter the anomeric center is protected. When the ceramide building block has to be connected to the oligosaccharide, normally selectively deprotection of the C-l a position of the lactose is necessary. The thexyldimethylsilyl (TDS) group is a less common trialkylsilyl protecting group in carbohydrate synthesis. Advantageously it survives some rather harsh conditions. The liquid TDSC1 42 with imidazole 43 or DMAP as basic activator in a dipolar aprotic solvent like DMF forms the C-l protected compound 8 as a mixture of anomers.21

Discussion
6a^-OH
SiMe2CI
42
TDSCI
N
W V
I
H
43
imidazole
254
15 GM2
Problem
Hints
Solution
Discussion
OTDS
9
Which method is used to benzylate an alcohol?
The exocyclic -atoms of the sugar have to be activated before the benzyl ether is formed.
1. NaH, BnBr, DMF, r. t 15 h 65 % (over three steps)
Deprotection of the hydroxy groups at C-3b and C-4b will take place under acidic conditions later in the synthesis. Therefore a protecting group, which is stable during the cleavage of the isopropylidene ketal, is needed. The benzyl group is an often used protecting group and is suitable for this purpose. Also it increases the reactivity of the lactose acceptor. It can be removed by hydrogenolysis for instance.
During the benzylation of an alcohol the hydroxy functionalities are turned into alkoxides. Therefore NaH is necessary. Next benzyl bromide is added. For an efficient alkylation using sodium hydride as base dipolar aprotic solvents like DMF or DMSO are necessary.22 During the benzylation a reversible TDS rearrangement between C-l a and C-2a of the lactose occurs.23 First deprotonation with NaH leads to C-2a-oxide 44 formation and then to the rearrangement.
15 GM2
255
-
HO^V-"T--^OTDS

44

----SiR3
45
^
LoV^\
^-^--'
TDSO 46
^
---\
^^
0 OTDS
49
^
> -1^---^
TDSO I 47 00
--
^^^
TDSO
^
',
R3Si,
0
48
50
As displayed above there is an anomerization of 44 to 49 due to trans-(2l)-0- (44>46) and ensuring cis-(2>l)-0- (47>49) silyl group migration, presumably via pentacovalent silicon intermediates or transition states 45 and 48.
Because of the high nucleophilicity 46 is trapped by means of fast irreversible anomeric O-alkylation and leads to 50.3 23 In general the equatorial oxygen bears the highest nucleophilicity under these reaction conditions. Accompanying the -silyl group rearrangement and the anomeric benzylation excess NaH and benzyl bromide provides fully benzyl protected lactose derivative 9.
256
15 GM2
Problem
OTDS
1. TBAF, THF,-20 C,
30 min, 94 %
2. PivCI, pyridine,
0 C - r. t., 5 d, quant.
.OBn
10
Hints
Solution
Protecting groups are changed.
3. TFA/ H20, CH2C12, 100 C, 1 h, 85 %
HO
--OBn
^OBn
0^ܰ^0
OPiv
10
Discussion
OBn
^OBn
\^0
BnO--X
OH
51
VCI
52
pivaloyl chloride
In the first step tetrabutylammonium fluoride (TBAF) cleaves the silyl protecting group at C-2a (51). Secondly the pivaloate ester 53 is formed.24 In the last step the ketal was removed under acidic conditions by using trifluoroacetic acid (TFA) in water and CH2C12.
,OBn
.
v
+ H20
U
HO
54
55
HO
56

.OBn
After proton ation of the ketal 54 and additi on of
water hemi-ketal 56 is formed and leads after proton migration to the deprotected diol 57 and acetone 58.
Although acetic acid is less acidic than TFA, with acetic acid (80 %) at 100 C the same result is reached.
HO
Hokii
58
57
OPiv
53
15 GM2
257
OAc
7 10
1.Sn(OTf)2, MeCN, -40 'C, 61 %, ot: (J = 9 :1
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