R

Transferase 1

Transferase 2

Transferase 3

Figure 2.84. Two general approaches for immobilized solid-phase oligosaccharide synthesis.

126 2. O-Glycoside Formation „OH

HOHO

126 2. O-Glycoside Formation „OH

OH O

HOHO

UDO-Gal Gal-T

OH O

UDO-Gal Gal-T

CMP-NeuAc Sialyl-T

Linker

CO2H OH OH O

OH O

linker -

OH OH

Figure 2.85. Enzymatic-solid phase glycosylation reaction.

OH O

linker -

OH OH

Figure 2.85. Enzymatic-solid phase glycosylation reaction.

4. the ring opening of cyclodextrins followed by oligosaccharide chain elongation and cycloglycosylation (Figure 2.86).

Despite the significant advances observed in cyclic oligosaccharide synthesis, their preparation is time-consuming, producing the target compounds with low regio- and stereoselective in low yields. The total synthesis of a-CD and y-CD was described according to Figure 2.87.9192

AG = acceptor linearoligosaccharide GD = donor g cyclic oligosaccharide o-

disaccharide cyclo-oligomerization enzymatic degradation or cyclo-oligomerization

smaller cyclic oligosaccharide polysaccharide or disaccharide (n = 0)

Figure 2.86. The four suggested approaches to the synthesis of cyclic oligosaccharides.

In 1990 it was reported the chemical synthesis of (3-(1—>3) linked hexasaccha-ride. The chemical approach involved the glycosidic reaction between benzylidene acceptor and protected glucosyl bromide as glycosyl donor, under silver triflate-promoter conditions. As can be seen in Figure 2.88, the construction of the linear oligosaccharide and its final cycloglycosylation was performed by using glycosyl bromides, which were prepared by photolytic brominolysis of 1,2-O-benzylidene glucose with BrCCl3(Figure 2.88).93

The formation of (1—6)-glycopyranosidic linkages might produce cyclic di-tri- and tetrasaccharides. An early synthesis of |3-(1—6)-glucopyranan under Helferich conditions, generated along with the linear oligomer, a cyclic di- and tetrasaccharide in 12 and 6%, respectively (Figure 2.89).94

An improved synthesis of cyclotetraoside was described by the same group 10 years later, consisting in the preparation from the peracetylated tetrasaccharide into the tetrasaccharide derivative having both the acceptor and the donor components. The final cyclization was performed under Helferich conditions providing a mixture of tri- and tetrasaccharide in 22% and 25% yield, respectively (Figure 2.90).95

2.2.1 Chemoenzymatic and Enzymatic Synthesis

The use of enzyme is as mentioned for many O- or N-glycosides the parallel possibility for preparing cyclic oligosaccharides. The limitation continues to be

Figure 2.87. Chemical synthesis of cyclic a(1—4)-oligosaccharide y-CD.

i) SnCl2/AgOTf. ii) PdCl2/AcOH. iii) SO2Cl2/DMF. iv) AgF/MeCN. v) NaOMe/MeOH/THF. vi) H2, Pd-C, THF-MeOH/H2O.

Figure 2.87. (continued)

i) SnCl2/AgOTf. ii) PdCl2/AcOH. iii) SO2Cl2/DMF. iv) AgF/MeCN. v) NaOMe/MeOH/THF. vi) H2, Pd-C, THF-MeOH/H2O.

Figure 2.87. (continued)

v the availability and affordability, however. Some enzymes such as glycosidases and cycloglycosyltransferases (CGTases) that are involved in the preparation of cyclodextrins from starch and other a-(1^4)-glucans are accessible and more versatile.95

The feasibility of the chemoenzymatic approach was established in the preparation of cyclic (3(1^4) hexa-, hepta- and octasaccharides, from 6-O-methylmaltosyl fluoride when incubated with CGTase. Thus, a mixture of 6\ 6m, 6V-tri-O-methyl-a-CD (42%), 6\ 6m, 6V-tetra-O-methyl-y-CD (16 %) and in less proportion 6I, 6m, 6V-tri-O-methyl-(-CD was obtained (Figure 2.91).96

Me^O OHO

Me^O OHO

Me^O

Me^O

Me^O

Me^O

Figure 2.88. Synthesis of cyclic ß-(1—3)-linked oligosaccharide.

Figure 2.88. (continued)

AcO AcO

AcO AcO

AcO AcO

AcO AcO

O OAc

OAc OAc

OAc i) Hg(CN)2, HgBr2, MeCN. Figure 2.89. Preparation of linear and cyclic |3(1^6) di- and tetrasaccharides.

AcO

AcO AcO

AcO AcO

i) Cl2CHOMe, BF3.Et2O/DCE. ii) HgBr2/DCE, MS. Figure 2.90. Improved synthesis of cyclic |3(1^6) tri- and tetrasacharides.

Furthermore, under the same conditions it was possible to prepare from the maltotriosyl fluoride the cyclic a(1^4) hexasaccharide (6I, 6n-dideoxy-6\6n-diiodo-a-CD) in 38% (Figure 2.92).97

An alternative option for the enzymatic preparation of cyclic oligosaccharides besides CGTases are glycosidases, which exert their action on polysaccharides. This possibility was exploited in the preparation of cyclic fructins by conversion of |3-(1^2)-fructofuranan by bacterial fructotransferases isolated from Bacillus circulans (Figure 2.93).98

i

Figure 2.91. Synthesis of of 6', 6m, 6V-tri-O-methyl-a-CD, 6', 6m, 6V-tetra-O-methyl-y-CD and 6\ 6nI, 6V-tri-O-methyl-P-CD.

i) CGTase phosphate buffer pH 6.5

Figure 2.91. Synthesis of of 6', 6m, 6V-tri-O-methyl-a-CD, 6', 6m, 6V-tetra-O-methyl-y-CD and 6\ 6nI, 6V-tri-O-methyl-P-CD.

i) CGTase phosphate buffer pH 6.5

Figure 2.92. Enzymatic synthesis of 61, 6II-dideoxy-6I,6II-diiodo-a-CD. °H

Figure 2.92. Enzymatic synthesis of 61, 6II-dideoxy-6I,6II-diiodo-a-CD. °H

i) CFTase phosphate buffer pH 7.0 Figure 2.93. Enzymatic synthesis of cycloinulooligosaccharides.

Summary of Preparation of the Main Glycosyl Donors

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N-Glycosides

These types of glycosides are generated when a sugar component is attached to an aglycon, through a nitrogen atom, establishing as a result a C-N-C linkage. Nucleosides are among the most relevant N-glycosides since they are essential components of DNA, RNA, cofactors, and a variety of antiviral and anti-neoplasic drugs.

Usually for nucleosides, a pyrimidine or purine base is linked to the anomeric carbon of a furanoside ring. The nucleosides responsible for the formation of the genetic material DNA and RNA are adenine, guanine, cytidine, and thymine, the latter exchanged by uracil in the case of RNA (Figure 3.1). Nucleosides can be classified in natural nucleosides such as those involved in the genetic storage of information, naturally modified nucleosides, and synthetic nucleosides.

Naturally modified nucleosides include a significant and diverse number of compounds, some of them with slight changes mostly at the base, or major structural modifications done by enzymes. So far most of them have unknown biochemical function;1 nonetheless they have been strongly associated with antiviral, antitumoral, and growth regulation processes (Figure 3.2).

Representative examples of natural modified nucleosides includes queuosine (Q) and Wye base (W), which have been found in the tRNA of some plants and bacteria, and it plays an important rule in the inhibition of tumor processes. Derived from this relevant biological function the total synthesis of these unique nucleosides have been reported for Q2-4 and W.5

Moreover, the synthesis of complex nucleoside antibiotics has been reviewed.6 The analysis was focused on the challenging synthetic methods for carbohydrate and nucleoside chain elaboration, glycosidation, and methods for controlling stereochemistry and for joining subunits. As a result, the total synthesis of Polyoxin J,7 sinefungin,8 thuringiensin,9 tunicamycin V,10 nikkomycin B,11 octosyl acid A,12 hikizimycin,13 and capuramycin14 was completed (Figure 3.3).

Important cofactors playing a key rule as biological catalysts required by the enzymes for the optimal performance of biochemical transformations are nucleotides. Such is the case of adenosine triphosphate ATP and nicotinic acid adenine dinu-cleotide NAD that are constituted by an adenosine nucleoside combined with phosphate for the former, and phosphate and nicotinamide for the latter (Figure 3.4).

OH R

HO HO

OH R

OH R

Heterocyclic base = cytosine DNA nucleoside = 2' deoxycytidine RNA nucleoside = cytidine

thymine thymidine

/q5 61N

3 jJ

OH R

OH R

OH R

OH R

OH R

uracil uridine

N "NH2

Heterocyclic base = adenine DNA nucleoside = 2' deoxyadenosine RNA nucleoside = adenosine guanine 2' deoxyguanosine guanosine

Figure 3.1. DNA and RNA nucleosides.

3.1 Nucleoside Formation

Considering a disconnection analysis, there are two major general routes for nucleoside syntheses.15 The first is based on the attachment between the aglycon base and the protected sugar activated with a good leaving group at the anomeric position. Under these conditions, the stereoselectivity is conditioned by the protecting group attached at position 2. The second general procedure considers the coupling reaction between a base precursor and the sugar derivative, which contains the free amine linked to the anomeric carbon. The ring closure generally takes place after the glycosidation reaction and the configuration is predetermined by the nitrogen attached to the anomeric carbon. The latter approach has been most efficiently used for preparing carbocyclic nucleosides (Figure 3.5).

dihydrouridine h3chnh2c

5-methylaminomethyl-2-tiouridine (mmm5s2U)

ribothymidine (T)

MeO^

NH if N

co2h nh2

ho2ch2co.

ho2ch2co.

5-methoxyuridine 3-(3-amio-3-carboxypropyl)uridine

uridine-5-oxyacetic acid

(acp3U)

CH2CO2CH3

NO R

5-(methoxycarbonylmethyl)uridine 3-methylcytidine

(mcm5U)

,CH3 H3C

,CH3 H3C

NO R

5-methylcytidine

NO R

0 NHCOCH3 NH2 0

5-methy|thiouridine N 4-cety|cytidine thiocytidine 5-(methoxycarbonylmethyl)-2-thiouridine

(m5s2U) (mcm5s2U)

Figure 3.2. Naturally modified nucleosides.

3.2 Protecting Groups

It has been mentioned in the previous chapter that protecting groups are important components for most of the general methodologies designed for establishing glyco-sidic bonds. Usually the methods for glycoside formation require prior protection of those elements (usually heteroatoms) within the molecule that are needed

0 0

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