GLUCOSIDATION AVEC CONTROLE DE LA STEREOSPECIFICITE

STEREOCONTROLLED GLYCOSIDATION

Abrégé anglais

Novel glycosides containing novel leaving
groups, pyridyloxy, pyrimidyloxy, methoxypyridyloxy,
pyridyl carbonate and pyridyl thiocarbonate are utilized
in many fertile syntheses of glycosides, disaccharides,
trisaccharides, oligosaccharides, nucleosides and the
like. These synthetic schemes are superior in
stereospecificity, yield and speed of preparation of
numerous novel compounds. Polymer supported syntheses
may be utilized within the general scheme to provide
enhanced product purity.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. In a process of glycoside or nucleotide synthesis involving the reaction of
a
donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor
selected from alcoholic hydroxyl containing acceptors and trialkylsilyl ethers
of a
pyrimidine acceptors, in which the reaction is carried out in the presence of
a
promoter or solvent, the improvement wherein said donor is substituted by
leaving
groups X of formula I, or related heterocyclic bases,
<IMG>
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms,.
2. The process of claim 1 wherein said promoter is selected from the group
consisting
of MeOTf, TfnH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals.

3. The process of claim 1 or 2, wherein said solvent is
selected from the group consisting of CH3NO2, and CH2Cl2, Et2O,
CH3CN, DMF, THF and mixtures thereof.
4. The process of claim 1, wherein the promoter is TMSOTf,
Lewis acids and chelating metals.
5. The process of claim 1 or 4, wherein said solvent is
selected from the group consisting of toluene, benzene,
dioxane, CH2Cl2, Et2O, THF and mixtures thereof .
6. The process of claim 1, wherein the promoter is
selected from the group consisting of MeOTf, TfOH, BF3,
Cu(OTf)2, ZnCl2, Lewis acids and chelating metals; said solvent
is selected from the group consisting of CH3NO2, and CH2Cl2,
Et2O, CH3CN, DMF, THF, and mixtures thereof; and wherein the
glycoside is coupled to a supporting resin by a coupling group
integral to said resin, and a linking element bonded to
coupling group and said glycoside.
7. In a process of glycoside synthesis comprising reaction
of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with an alcoholic hydroxyl acceptor, in the
presence of a promoter and a solvent, the improvement
comprising said donor is selected from the group consisting of
glycosides substituted by leaving groups X of formula I and
related heterocyclic bases:
<IMG>

where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon
atoms,
said promoter is selected from the group consisting of
MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating
metals,
said solvent is selected from the group consisting of
CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
8. A process of claim 7 wherein said donor is an
O-pyranosyl glycoside,
said promoter is selected from the group consisting of
MeOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2,
said solvent is selected from the group consisting of
CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
9. A process of claim 7 wherein said donor is selected
from the group consisting of glycosides of formula RX wherein
X has formula I, and R has the formula II

<IMG>
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms,
acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,
or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
independently hydroxy, acyloxy of 2 to 6 carbon atoms,
arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is
independently hydroxy, acyloxy of 2 to 6 carbon atoms,
arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
10 carbon atoms, alkoxy of 1 to 10 carbon atoms,
trialkylsiloxy wherein the alkyls are independently of 1
to 5 carbon atoms, or R2, R3, R4, R5, may be R,
said promoter is selected from the group consisting
of MeOTf, TMSOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2,
said solvent is selected from the group consisting
of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures
thereof.
10. A process of claim 9, wherein said acceptor is
selected from the group consisting of R'OH, wherein R' is
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1
to 27 carbon atoms, N-substituted amino-alcohols
and S-substituted thio-alcohols, esters of
alkanols of 1 to 10 carbon atoms with hydroxyalkanoic
acids of 2 to 6 carbon atoms, esters of alkanols of 1 to
10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6
carbon atoms having the amino function acylated by an
acid of 2 to 10 carbon atoms, and glycosides of formula
R"Y, wherein R" has formula III,

<IMG>
containing at least one unprotected alcoholic hydroxyl,
where Y is selected from the group consisting of alkoxy
of 1 to 5 carbon atoms and X, R7 is azido, hydroxyl,
acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of
2 to 10 carbon atoms, R8 is hydrogen, hydroxyl,
alkenyloxy of 1 to 5 carbon atoms, acyloxy of 2 to 6
carbon atoms, arylcarboxy of 7 to 10 carbon atoms,
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10
carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon
atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may
together be alkylidenyldioxy of 3 to 9 carbon atoms, or
cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and
R9 may together be alkylidenyldioxy of 3 to 9 carbon
atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms
or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon
atoms or R7, R8, R9, R10 may be R or R".
11. A process of claim 9 wherein X is
3-methoxy-pyridyl-2-oxy.
12. A process of claim 9 wherein R has formula IV

<IMG>
and wherein R2, R3, R4, R5 and X are as defined in claim 9.
13. A process of claim 9 wherein R has formula V
<IMG>
where R2, is azido, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R3, R4 and R5 are arylalkoxy
of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms,
said promoter is Cu(OTf)2
said solvent is selected from the group consisting of
CH2Cl2, Et2O and mixtures thereof,
said acceptor is selected from the group consisting of
glycosides of formula R"Y, containing at least one unprotected
alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms,
R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of
7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or
aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen,
hydroxyl, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to
carbon atoms or alkoxy of 1 to 10 carbon atoms, R9 is
hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon
atoms, R9 and R10 may togeher be aralkylidenyldioxy of 7 to 10
carbon atoms.
14. A process of claim 10 wherein R2, R3 and R4 are
independently hydroxy, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R5 is

independently hydroxy, arylalkoxy of 7 to 10 carbon
atoms, alkoxy of 1 to 10 carbon atoms or trialkylsiloxy
wherein the alkyls are independently of 1 to 5 carbon
atoms, or R2, R3, R4, R5 may be R, and at least one of
R2, R3, R4 and R5 is hydroxyl,
selecting said promoter from the group consisting of
MeOTf, TMSOTf, BF3, Cu(OTf)2, and ZnCl2,
selecting said solvent from the group consisting of
CH3NO2, CH2Cl2, CH3CN, and THF and mixtures thereof.
15. A process of claim 14 wherein said acceptor is
selected from the group consisting of alkanols, alkenols
and cycloalkanols of 1 to 6 carbon atoms and glycosides
of formula R"Y, containing at least one unprotected
alcoholic hydroxyl, wherein Y and R7 together are
alkylidenyldioxy of 3 to 9 carbon atoms, R8 and R9
together are alkylidenyldioxy of 3 to 9 carbon atoms.
16. A process of claim 14 wherein R2, R3, R4 and R5 are
hydroxyl.
17. A process of claim 11 wherein R2, R3, R4 and R5 are
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10
carbon atoms,
said promoter is selected from the group consisting
of MeOTf, and Cu(OTf)2,
said solvent is selected from the group consisting
of CH3NO2, CH2Cl2, Et2O, and CH3CN and mixtures thereof.
18. A process of claim 17 wherein said acceptor is
selected from the group consisting of alkanols of 1 to 5
carbon atoms and glycosides of formula R"Y, containing at
least one unprotected alcoholic hydroxyl, wherein Y is
selected from the group consisting of alkoxy of 1 to 5
carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is azido,
hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,

alkoxy of 1 to 10 carbon atoms, hydrogen, or
aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydroxyl,
acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to l0
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl,
arylcarboxy of 7 to 10 carbon atoms, or acyloxy of 2 to 6
carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7
may together be alkylidenyldioxy of 3 to 9 carbon atoms,
or R8 and R9 may together be alkylidenyldioxy of 3 to 9
carbon atoms, or R9 and R10 may together
aralkylidenyldioxy of 7 to 10 carbon atoms.
19. A process of claim 11 wherein R2, R3, and R4 are
independently acyloxy of 2 to 6 carbon atoms, or
arylcarboxy of 7 to 10 carbon atoms, R5 is independently
acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10
carbon atoms, and trialkylsiloxy wherein the alkyls are
independently of 1 to 5 carbon atoms, or R,
said promoter is Cu(OTf)2,
said solvent is CH2Cl2.
20. A process of claim 19 wherein said acceptor is a
glycoside of formula R"Y, containing at least one
unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1
to 5 carbon atoms, R7 is arylalkoxy of 7 to 10 carbon
atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy
of 2 to 10 carbon atoms, R8 is alkenyloxy of 1 to 5
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl,
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10
carbon atoms, R10 is hydroxyl, arylalkoxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms.
21. the process of claim 11 wherein R2 is acylamino of 2
to 5 carbon atoms, R3, R4 and R5 are hydroxyl,
said promoter is selected from the group consisting

of MeOTf, and TfOH,
said solvent is selected from the group consisting
of CH3NO2 and DMF and mixtures thereof.
22. A process of claim 21 wherein said acceptor is
selected from the group consisting of alkanols of 1 to 5
carbon atoms and glycosides of formula R"Y, containing at
least one unprotected alcoholic hydroxyl, wherein Y is
3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2 to
6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms, R10
is hydroxyl, Y and R7 may together be alkylidenyldioxy of
3 to 9 carbon atoms, or R8 and R9 may together be
alkylidenyldioxy of 3 to 9 carbon atoms.
23. A process of claim 11 wherein R2 is azido, R3, is
arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10
carbon atoms or R wherein R2, R3, R4, and R5 are acyloxy
of 2 to 6 carbon atoms, R4 and R5 are arylalkoxy of 7 to
carbon atoms, or alkoxy of 1 to 10 carbon atoms, or R4
and R5 together are alkylidenyldioxy of 3 to 9 carbon
atoms,
said promoter is Cu(OTf)2,
said solvent is selected from the group consisting
of CH2Cl2, and CH3CN and mixtures thereof.
24. A process of claim 23 wherein said acceptor is
selected from the group consisting of esters of alkanols
of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids
of 2 to 6 carbon atoms having the amino function acylated
by an acid of 2 to 10 carbon atoms, and glycosides of
formula R"Y, containing at least one unprotected
alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon
atoms, R7 is acyloxy of 2 to 6 carbon atoms, arylalkoxy
of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms,
hydroxyl, or aminocarbalkoxy of 2 to 10 carbon atoms, R8
is hydrogen, acyloxy of 2 to 6 carbon atoms, arylalkoxy
of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms,

or hydroxyl, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon
atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10
carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is
hydroxyl or acyloxy of 2 to 6 carbon atoms, or R9 and R10
aralkylidenyldioxy of 7 to 10 carbon atoms.
25. In a process of nucleoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with an acceptor of trialkylsilyl ether of a
pyrimidine, in the presence of a promoter and a solvent, the
improvement comprising said donor is selected from the group
consisting of glycosides substituted by leaving groups X of
formula I:
<IMG>
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon
atoms,
said promoter is TMSOTf, Lewis acids and chelating metals,
said solvent is selected from the group consisting of
toluene, benzene, dioxane, CH2Cl2, Et2O, THF, and mixtures
thereof.
26. A process of claim 25 wherein said donor is an
O-pyranosyl or O-furanosyl glycoside, of formulae II or VI, and
said trialkyl silyl pyrimidine ether has formula VII
<IMG>

<IMGS>
wherein R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon
atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein
the alkyls are independently of 1 to 5 carbon atoms, R14 is
trialkylsiloxy wherein the alkyls are independently of 1 to 5
carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is
hydrogen, or alkyl of 1 to 5 carbon atoms.
27. A process of claim 26 wherein R2, R3, R4, R5, R11, R12
are benzyloxy, R11 is hydrogen or benzyloxy, R13 is
trimethylsiloxy, R14 is trimethylsiloxy or benzamido, R15 is
hydrogen or methyl.
28. In a process of glycoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with an alcoholic hydroxy acceptor, in the presence
of a promoter and a solvent, the improvement comprising said
donor is selected from the group consisting of glycosides
substituted by leaving groups X of formula I:

<IMG>
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon
atoms,
said promoter is selected from the group consisting of
MeOTf, TfOH, BF3 Cu(OTf)2, ZnCl2, Lewis acids and chelating
metals,
said solvent is selected from the group consisting of
CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof
and said glycoside is coupled to a supporting resin by a
coupling group integral to said resin, and a linking element
bonded to coupling group and said glycoside.
29. A process of claim 28, wherein said coupling group is
phenylenemethylamine, said linking element is a dicarboxylic
acid residue forming an amido bond with said coupling group and
an ester bond with said glycoside.
30. A process of claim 29, wherein said glycoside
comprises a plurality of saccharide units.
31. A novel glycoside wherein the glycoside has a
substituent selected from the group consisting of
<IMG>
wherein R1 and A are as defined in claim 1;

<IMG>
wherein R2 R3, R4 and R5 are as defined in claim 9;
<IMG>
wherein R7, R8, R9, R10 and Y are as defined in claim 10;
<IMG>
wherein R2, R3, R4 and R5 are as defined in claim 9;
<IMG>
wherein R2, R3, R4 and R5 areas defined in claim 13;

<IMG>
wherein R10, R11 and R12 are as defined in claim 26;
or
<IMG>
wherein R13, R14 and R15 are as defined in claim 26.

32. In a process of glycoside or nucleoside synthesis involving the reaction
of a
donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor
selected from alcoholic hydroxyl, trialkylsilyl pyrimidine ether and acylated
purine, in
which the reaction is carried out in the presence of a promotor or oxidizer
and a
solvent, the improvement wherein said donor is selected from the group
consisting of
glycosides substituted by leaving groups of formula VIII:
<IMG>
where B is O or S.
33. The process of claim 32 wherein said promoter is selected from the goup
consisting of MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating
metals.

34. The process of claim 32 or 33 wherein said solvent is
selected from the group consisting of CH3NO2, and CH2Cl2, Et2O,
CH3CN, DMF, THF, and mixtures thereof.
35. The process of claim 32 wherein said promoter is
selected from the group consisting of TMSOTf, MeOTf, TfOH, BF3,
AgOTf, Cu(OTf)2 ZnCl2, Lewis acids and chelating metals.
36. The process of claim 32 or 35 wherein said solvent is
selected from the group consisting of toluene, THF, and
mixtures thereof.
37. The process of claim 32 wherein said solvent is DMF,
and said oxidizer is bromine.
38. In a process of glycoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with an alcoholic hydroxy acceptor, in the presence
of a promoter and a solvent, the improvement wherein said donor
is selected from the group consisting of glycosides substituted
by leaving groups of formula VIII:
<IMG>

where B is O or S,
said promoter is selected from the group consisting of
MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids and
chelating metals,
said solvent is selected from the group consisting of
CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
39. A process of claim 38 wherein said donor is an
O-pyranosyl glycoside,
said promoter is selected from the group consisting of
AgOTf and Cu(OTf)2,
said solvent is selected from the group consisting of
CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
40. A process of claim 39 wherein said donor is selected
from the group consisting of glycosides of formula IX wherein
Z has formula VIII,
<IMG>
wherein R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently
acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon
atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to
carbon atoms, R5 is independently acyloxy of 2 to 6 carbon
atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy
wherein the alkyls are independently of 1 to 5 carbon atoms,
or R2, R3, R4, R5, may be R,

said promoter is selected from the group consisting
of AgOTf, and Cu(OTf)2,
said solvent is selected from the group consisting
of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures
thereof.
41. A process of claim 39 wherein said donor is selected
from the group consisting of glycosides of formula X
wherein Z has formula VIII,
<IMG>
wherein R2, R3 and R4 are independently acyloxy of 2 to 6
carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5
is alkyl of 1 to 5 carbon atoms,
said promoter is selected from the group consisting
of AgOTf, and Cu(OTf)2,
said solvent is selected from the group consisting
of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures
thereof.
42. A process of claim 38 wherein said acceptor is
selected from the group consisting of glycosides of
formula RX wherein X has formula I, and R has the formula
II
<IMG>

<IMG>
wherein A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon
atoms, R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy
of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,
or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently
hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy
of 1 to 10 carbon atoms, R5 is independently hydroxy.
43. In a process of nucleoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with a trialkysilyl pyrimidine ether acceptor, in
the presence of a promoter and a solvent, the improvement
comprising said donor is selected from the group consisting of
glycosides substituted by leaving groups of formula VIII:
<IMG>
where B is O or S,
said promoter is selected from the group consisting of
TMSOTf, MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids
and chelating metals,
said solvent is selected from the group consisting of
toluene, THF, and mixtures thereof.

44. A process of claim 43 wherein said donor is an
O-pyranosyl or O-furanosyl glycoside, of formulae IX, X, or
XI, and said trialkyl silyl pyrimidine ether has formula
VII
<IMGS>
wherein R2, R3, R4, and R5 are arylalkoxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is
hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy
of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7
to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms,
R13 is trialkylsiloxy wherein the alkyls are
independently of 1 to 5 carbon atoms, R14 is
trialkylsiloxy wherein the alkyls are independently of 1
to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms,
R15 is hydrogen, or alkyl of 1 to 5 carbon atoms, and Z

has formula VIII.
45. In a process of nucleoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-furanosyl
glycosides, with an acceptor of an acylated purine in the
presence of bromine, and a solvent, the improvement comprising
said donor is selected from the group consisting of glycosides
substituted by leaving groups of formula VIII:
<IMG>
where B is O or S,
said solvent is DMF.
46. A process of claim 45, wherein said purine is
6-benzoyl adenine.
47. A novel glycoside wherein the glycoside has a
substituent selected from the group consisting of
<IMG>
wherein B is 0 or S:

<IMG>
wherein R2, R3, R4 and R5 are as defined in claim 40;
<IMG>
wherein R2, R3, R4 and R5 are as defined in claim 41;
or
<IMG>
wherein R10, R11 and R12 are as defined in claim 44.

Description

rr.! ~"tølf'~~~
"~ .iy ~~; a
STEREOCONTROLLED GLYCOSIDATION
The requirement to produce pure stereospeci.fic
products is the core, pith and marrow of carbohydrate
chemistry. Particularly essential is> the requirement to
produce purer) alpha and beta anomers (C-1 anomers ire D-
and L-sugars). Optimized yield of the compound and
proportion of alpha anomer are both highly desirable, as
those skilled in the art would appreciate, fox- practical
and commercial reasons.
The present invention primarily relates to a. process
of providing pure, or significantly higher proportion of
alpha anomers in significantly improved yield. Specific
donors, acceptors, promoters, and solvents are combined
to produce specific anomers. The present invention
secondarily provides novel compounds prepared by the
process. Although the invention wil_L be described and
referred to as it relates to processes of preparation of
anomers from specific donors, acceptors, promoters, and
solvents, and the resulting anomers, it will be
understood that the principles of this invention are
equally applicable to similar proces:~es and anomers and
accordingly, it will be understood that the invention is
not limited to such processes and anomers.
BACKGROUND AND PRIOR ART
The literature teaches the use of various glycosyl
donors (sugar residues with a leaving group) with
anomeric bromide and other functional groups to build an
ultimate di-, tri-, or oligosaccharide.
O-protected beta bromo anomer is converted to the
alpha disaccharide in 42% and 65% yield (Lemieux, J. Am.
Chem. Soc. 1975, 97, 4056), Table I.
1

~a ~ ~, fl !~ s3
_~ r,~
Similarly the alpha bromo 1,2-trans peracetyl
glycoside anomer is converted to the equivalent beta
(1,2-trans) glycoside in 47%, 64%, and 72% yield while
the beta acetyl anomer was similarly converted in 71%,
72% and 80% yield (Hanessian, Carbohdr. Res., 53, C13
(1977) and 59, 261 (1977), Table II.
Activation of various anomeric donors has been
heavily studied, using a variety of promoters, Table III.
Particularly of interest are those where the alpha: beta
product ratio is known and can be improved, and where the
overall yield is high, Table IV.
Previous work from applicant's laboratories has
shown that glycosides can be prepared form glycosyl
heterocyclic donors without protection of OH groups (S.
Hanessian et al. Carbohydrate Res. 80, C17 (1980)).
Speculation as to reaction mechanisms suggests metal
complex formation with beta 2-pyridylthio donor leaving
group, that is the activation is remote to the anomeric
carbon, Table V, which applicant has termed "remote
activation."
Extension of experimentation to a beta perbenzylated
glycosyl 2-pyridinecarboxylate donor showed solvent
dependence of anomeri.c product - ether-CHzCl2 giving
primarily alpha while CH3CN gave primarily beta, Table VI.
Other extension based on applicant's original work can be
found in Tetrahedron, 47, 6435, (1991).
It is a broad object of the invention to prepare
specific anomeric compounds in improved yield and
proportion, by selection of specific donors, selection of
specific acceptors, ~~election of specific solvents, and
selection of specific: promoters, in combination
underselected specific process conditions. It is an
2

rmst,r: t
~? (~ '~ ii
i>r ~_ ~ i.~ ,_~ ~ ,r =:>
OBn Odn OBn
Et~N-' Br- -~~ ROH Bno. o
E3n0 ~ an0 pr ;,
pit0 E3n0 BnO
ODn dr OBn OBn OR
O / \O
O O
O O
1 65% 42%
0
~o O
R. U. Len~icux, et al, J. Arn. Cf~em. Soc., 97, X1056(1975)
onnt,r I z
one
ngOTr OAc
nc0 O Ac0 -O
f~011
o'
nc0 + nco
(Me2N)zC0 . CF12C1zAc0
nc0 Br O
c
n
Ph~O O _
O--CI IZ-C-Me , Q Bn0''
~ Bn0 '' I
l-
~ Bn0 OMe
Me
OMe
6~
47% 72%
S. I-inNESSIAN el al. C13 (1977)
, Carbolrydr. rtes.
, 5~ ,
.ono
ono
O SnCI,, nc0~~0
nco one + not-t ~-- nco-~-~~o~
nco or I2clz nco
Aco
n= Meu,yl (ao i ) , 2-r~ronyl (7 r i ) , Cyclonexyl (72'/ )
S. IInNESSIAN el al. , Carbohydr. files. , :59 . 261 (1977)
3

~i ~3 ~l ;'~ %'1 . a
F: a. a,a (~ ;~_ .~
-D Cn 'T1 z ~ n ~ ~ ~ ~ O
a O °_' C7 c w
z~
O w \ m cn o
a ~.W ~ o ~ ~ o
a~
c~ o ~ ~ ~" ---y- n
(Q OD ~D C n .-~ ~ ~ ~' z
C_7 cD -~-t~. r~ -~ COO D Z
O ~ "~ ~(D
_ ~ ZJ ''--. Cn
D Z:
O \ ~ ~ ~ ~ ~ cn ~ cn Z O \
o \ O. C~~ ~ o
p w~ O T ~' o
o ~ ~ ~ = Cy ~
_..~ cn ~<
o~ ~ ~ ~ ~ N y~
o ;~ z a~ ~, _-- ~ \
N ~ O ~ ~ -s
< ~ --.
CD
(D c~D W H
o~ ~ a
cn
-- r
H
1-J
H
~
m cn ~ G) 'o~ n o \
cn ~ ~, ono m o \ -i ~. ~n ~ ~~ z ~ o
o~ ~, " o ~o~< O w
~_ ~ ~o z ~° o c~ ~ ~~ s~ _
° '~ ~ \ /
O m _ -J -. -.
°- cfl cn
w
o ~_ ~~ > o O
o 'D '~ ~~~
~
~i ~ n
w O ~ c
--icn
'c ~' ~ w =- cn
rv O z Q7 ~ m
Sv
O
o CJ~ ~'
O
cn
~
\
-I
~
~O
4

'I'AllI,l: I V
~ ~ r"1 ~~'9 ~ l C~ a
I-a . a'. ~..~ i_~ I~ iu
Of3n OE3n OBn
ODn O
O I10 O Bn0 O
E3n0'=~ X -~ BnO~ '-- E3n0-~r~pn0
f3n0 OBr' OMe OBn~ Me
Of3n
Activator «~ ~ I~ Yield(°/~)
O 3 : 1 88
~~O~NII ( Scllmidt ) TfOSiMe3
on
oci3
TBPq 1 : 2.1 84
~~o~oEt ( Sinay )
on
( Nicolaou ) I3F3.E120 -- 65
on
O ( Fraser-f3eid ) NDS 3 : 1 95
on
S N
( Mereyala ) _ Mel major ~ 85
i
TAISI,I: V
Activation -° ~ or dimes
_os~~ -os.
I-I _ O~ N S
O f l ~.._ ' r
O~N <)Fi ML
Oli R OI1
OI-i OI 1
I-IO o s N -ROf-1, Ng(ONOz)z Ino_ o ort
rio
oli \ PJIeCN, (ew min. rt lio oIi
35 - 95%
S. Hanessian, et al, Carbohydr. Res., 80, C17(1980)

TAlrLls VI
t~ 1 ~1 !~ ~ .r
w d.
!b ~. ,. _ 'J ~~.f -L
Otln OBn
Of3n / CU(Ur()?, -50'~C ~ ~ ~ ~,
f3n0'~ C~n0~0~
~ ~
+ ROI-I ---- -- onc> ''~ ~n
ono~o ~rl or Sn(Ol!)2 ~1 o
t3n0 Oftn O~ OOn
OC!n p
Eno r ci ce~cN
lZci2
cc : (1 a. : (i
(Yield) (Yield)
R = -(3111 71 : 29 19 : 81
(C>7 % (89 % )
)
OtW IO_
_.Mr.n
f!n0 Oa
~ 83 : 17 9 : 91 (77
(97 % ) % )
Cln
oo~~ rnP
otJn
!)np ~O 9~ : 8 (70%)13 : 87
(92~)
X
OOn
OMo
S. Kobayashi, et al., Telratiedron Lelt., 32, 7065(1991 )
!'Af)L1; VII
one
OEI
I10 O 1. Promoter, rt Q
r! O N CI I.jNO~ / iso-PrOV-i (1:1 ) ~ ~ ~~~ -t- ~ - anOtllel~
one
onl ~ , 2. Py / nc~0
Promoter (equiv.) Time a : (1 Yield(%)
Hg(N03)? (1.0) 1 day No Reaction
TMSOTf (1.0) 3.5hrs 6 ; 1 81
Me07 f (i. 1) 45rnin g ; f 7
6

t~-~ ~Y~~~s~-~
I-J _w. ~.: _ ~._I .I .:1.
ancillary object of the invention to identify specific
donors, suitable for use in the invention. It is another
ancillary object of the invention to identify specific
acceptors, suitable for use in the invention. 7.t is
another ancillary object of the invention to identify
specific promoters, suitable for use in the invention.
It is another ancillary object of the: invention to
identify specific solvents, suitable for use in the
invention. It is a subsidiary object: of the invention to
prepare novel anomeric compounds, utilizing unprotected
and O-protected glycosyl donors. It is a fur_thebx~
subsidiary object of the invention to develc7p ~,ynt:hc~tic
methods for the synthesis of glycosides, disaccharides,
oligosaccharides and nucleosides, using glycosides
including but not restricted to pyriclyloxy,
methoxypyridyloxy, pyrimidyloxy, pyri.dylcarbonate, and
pyridylthiocarbonate leaving groups, to provide said
glycosides, disaccharides, oligosaccharides and
nucleosides, including polymer supported oligosaccharide
syntheses, in superior yield and stereospecificity,
faster reaction times and shorter syntheses.
DESCRIPTION OF THE INVENTION
The appended summary tables after the general
disclosure but before the claims are integral to the
description of the present invention.
GLYCOSIDE SYNTHESIS WITH UNPROTECTED GLYCOSYL DONORS
2-PYRIDYLOXYGLYCOSYL DONORS AND VARIANTS
Unprotected 2-pyridyloxy beta-D--glycosyl donor was
treated with iPrOH (acceptor):CH3N02 (solvent) 1:1, at
room temperature with Hg(NO3)Z, TMSOT:f and MeOTf
(promoter), Table VII, followed by acetylation :in
pyridine, Hg(N03)2 gave no reaction, TMSOTf 6:1
alpha:beta, 81%, MeOTf 9:1 alpha:beta, 78%.
7

lAllll: VI11
~-,, ,~ :-y !', ~
F.. ~.. . 'n ;-
,Onc
~. Maori, a - ~L,o
Ilo- 1~~ so~~e~,n iso-o~o~ i ( ~ : I) n~oS-~ -~ (3 - anorner
nco ' ~ I
I10 ,O N~ 2. Py/ nc~0 On ()
OI-1
Solvent MeOTf (equiv.)rime a : Yield(/
(l )
ICS' Ct-1~N0~ 1.1 ~l5min 9 : 75
1
CI-1 CI t .0 ~l5min 5 : ~0
2 2 1
CH~CN 1.0 ~l5min 4 : a't
1
~ t-y 1 .o ~t5n
lln
/
~1,~
iso-Pr01-I 1.0 l5min 11 : B5
1
TAIll,l; IX
OI 1 ~OAc
1. MeOTI, tl
~O X CFi3N02/ iso-PrOli ( t : i) nc0~ -t- ~3 - anomer
Ilo-~ --~ nco
of I 2. r~y F nc2o one o~
~O I N~ 45 min, 7E3% ~O N 1 15 min, Ei!I%
a : (3 9 : 1 I i N cr. : (l 5 : 1
UNREACTIVE TO MeOTf:
~O ~S ~ ~S N~ .,-O fJ\ V~ ~'S N' N~
I / I / ' /
8

C~ISLF, x W .j
~. t; s~ ~ T,. -2.
one
oFt t. Meort, ri
CF13NOZ/ iso-fn Of i ( 1 : 1 ) nc0 '~
no-~X - nco ;-1 + (3 - anomer
eo of t 2. f~y i nczo one o l
MeOTf (equiv.) Tine a Yield(
: (3 % )
Ii t.1 45rnin 9 : 1 7El
~O
N 0 <5rnin F3 : 1 79
1
ICS I .
~i'
MeO
,O N~
1.0 2.5h a : 1 F3E3
OMe '
I'AFSI,Ii X1
OMe
~ ~OMe
tJ~ OMe N~ N~
N
i
pKa = 5.20 ~ 3.2n 4.8~~ 6.62
Reactivity:
.,
~~ O N > ~~- O ~ > ~~ p N
OH O I ~ OH I OI-I
/ / /
Me OMe
few min. 45 min >I2h
j3CNMR(ppm) 97.81 (C-1 ) 98.21 (C-1 ) 98.71 (C-1 )
9

~-~ ~~ C' :~: s
E: _i t; Li l.1 ,~ ~.
Variation of solvent in the same process using MeOTf
promoter, Table VIII, CH3N02, CH2Clz, CH3CN, THF, iPrOH (as
solvent and acceptor) gave good yields (78-85%) and
ratios (11:1 to 6:4).
Variation of leaving groups in t:he same process,
Table IX, demonstrated that 2-pyridyloxy and 6-
pyrimidinyloxy gave satisfactory yields and z°at.ios, while
phenoxy, thiophenyl, 2-pyridylthio, .?-napht:hyrid.inyloxy,
and 2-2-bipyridyl-2-thio were not reactive, under these
conditions.
3-METHOXYPYRIDYL-2-OXY (MOP) GLYCOSYL DONORS
Further testing of 3- and 4-methoxypyridyl-2-oxy
leaving groups, in the same process, Table X, grave
excellent yields (78-88%) and ratios (8 to 9:1 or
higher). The time factor was significantly less for the
3-methoxy radical (hereafter MOP) <5 minutes, as opposed
to 2.5 hours for the 4-methoxy radical, while the 2-
pyridyloxy radical took 45 minutes.
The donor results so far can be convincingly
partially correlated with basicity (hKa) of the
equivalent pyridine, the reactivity time, and the ~3CNMR
(ppm) of the anomeric carbon atom, Table XI.
Having established the superiority of the MOP donor,
it was tested in the same process against a variety of
promoters, Table XII. Time considerations militated
against ZnClz, yields against ZnClz, PTS, ratios against
NBS, PTS. ZnCl2, and especially Cu(OTf)z, BF3, and even
more so MeOTf gave excellent results.
The proportion of MeOTf was varied in the same
process, Tab7_e XIII, 1.0, 0.2 and 0.016 eq. gave closely
similar results 76 to 79% yield ratio 8:1. Only 0.016
10

I'AI11,1: XIV ~'I ~ ~ ~' .w
-~1
!., .~. 1.i ;~ ;~
On 1. MeOT(, rl one
I 10 o Cf-1nN02 / 8011 ( 1 : 1 ) O
LI - _ n~o
O ~ Nw ' nc0
oy~ ~?. Ac20 / Py one
o r~
0
t
Me
ROH MeOTf (equiv.)Time a (3Yield(%)
MeOH 0.2 <5lnin 10: 1 B2
Iso-PrOH 0.2 <5rnin 8 1 76
:
Mew/-doll 0.1 l0min 16: 1 77
Cyclohexanol0.2 30rnin 5 1 G2
:
IAI1LI: XV
I-10 OFI I Ip '
o MeOTI (0.2 eduiv.) OI 1 + ~_-W~OR
I10~~0 N yo~~o
~ CI-L RT
NO
, N N3
Z,
~
N~ Ori
/
O
Me
ROIH (equiv.) Time ~, : ij Yield(%)
iso-PrOFi / CII~NO? (1 3 i~rs 12 : 1
: 1)
O
IIO~o~ (34) 211rs 17: 1 70
NI-If~oc
IIO~Or3n (30) 4 hrs 8 1 65
Me~OIi (2.1) 3 hrs 6 : 1
11

f~ '1 :'~) ~.P -"
TAlli,l; X I I 4r -n- Rv '~ :. .~'
OAc
OI i 1. Promoter, rt
CI f 3N0z/ iso-PrOf f ( 1 : 1 ) nc0~ O
Flo- ° o N ,- -_~ n~~~ -~ (1 - anomer
! to '~ ~ a. r y / n~~o one
ofi p
M Je
Promoter (equiv.)Tirne cx Yieid(~o)
:
()
MeOTf (1.0) <5rnin 8 : 79
1
PTS ( 1.0) 5min 1 : 65
1
BFI (1.0) 5rnin 8 : 77
1
Cu(OT()Z ( 1.0) 5rnin 7 : 82
1
ZnCl2 (1.0) 3days 4 : 61
1
NDS ( 1.0) <5min 6 : 78
4
I'AI?Lf; XI II
ono
OF-I t. MeOTI, rt
O CI-i3N0~1 iso-Pr01-1 ( 1 : t) ~ n O~=
eo-~ + (3 - anomer
r i0 Ov N 1 2. Py / nc~0 C>nc O
Ofl
O /
Me
MeOT( (equiv.) Time a : (3 Yieid(°~o)
1 <5 min 8 : 1 79
0.2 < 5min 8 : 1 76
0.016 40min 8 : 1 78
12

~ .g ~ ~, i' , ~ ;,
~~ '_i ~~,~ ..
eq. gave a longer time 40 min. as opposed to <5 min,
which was felt to indicate catalytic rather than reactant
nature of the MeOTf promoter.
The process was repeated using beta MOP D-
glucopyranoside donor, with methanol,, isopropanol,
transbut-2-en-1-ol, and cyclohexanol as acceptors, and
0.2 or 0.1 eq. of MeOTf, gave yields (62 to 820) and
ratios (5 to 16:1) Table XIV.
A similar process was modified using beta MOP 2-
azido-2-deoxy-D-galactopyranoside donor, iPrOH acceptor,
benzyl glycolate, benzyl N-t-butoxycarbonylserine
transbut-2-en-1-of in heavy equivalent excess gave
reaction times of 2 to 4 hours with yields of 6.5 to 86%
and ratios of 6 to 17:1, Table XV, which are important as
glycosides of 2-amino-2-deoxysugar derivatives.
In summary thus far superiority of yield, ratio,
time, temperature, and promoter effectiveness has been
conclusively demonstrated, with the MOP group. The
effective application of the process to donors including
unprotected hydroxyl groups has also been shown.
The MOP gluco- and galactopyranoside donors of
Tables XIV and XV were prepared following Schemes I and
II, which would be instantly intelligible to those
skilled in the art of sugar or organic chemistry.
A tentative possible hypothetical mechanism is
developed in Scheme III although thia is neither
scientifically binding nor substantiated by kinetic
experimentation.
The same process was applied to 2-acetamido-2-deoxy-
beta-D-hexopyranoside MOP donors, with 0.1 eq. MeOTf in
the gluco case and 0.2 eq. in the galacto case. Pure
13

SOIII:Mfi 1
cz ~ k ~ 1~ :~i ;:r
E.d .~:. .. ?. 1 .. . .. _ ._
nyo N
Onc O I ~ Onc .OII
nc0~ M° -~ ~1c0~ NaOMe tl0~ ~LO
nc0 TOIueno,110"C nc0~'O rJ fI~T~O ~ N\
MeOII / CFI?Ch ~ oll
Onc ~, l5min, ?Il5'.o Onc ~ puant. yield /
O ~ O
M° Me
! IgDr2, Xylene
130"C, 5hrs, 4~
ono ~ol I
0
nc0 NaOMe FI o ~
nco ~-
Onc o N MeOF-1 / CIi2Clz OL l o N
puant. yield
O O
Mo Me
IIO N
Onc ~ I / Onc .OII
~ (7 oqniv ) ~
nco~ t'~° _' nco-N-OJ,o N NaOMe / MeOFi tlii0
n~;o ~ nc ~o
tJl me E3u~NE3r / Na01 I NI Inc ~ gC~ ~ rJl Inc
I CIlzClz, rl, 30min O o
M° M°
S(:IIEMP; II
ngo N
o ~ ~ n~o one Fro ol-I
nc0 Onc r (1.5 equiv.) ~, O NaOMe L O
O lute nc0~~0 N~ _
nc0 I-10~~0 N\
toluene, 11o~C N~ ~~ / Me0F1 N
N3 Br 45min p' J 3 O
Me Me
63"/
LiCI
ng0 N\
n~o ono ~ ~ n~o ono t-to olo
O ~ (1.5 equiv.) nc0 O NaOMe FIO
nc0 CI Me -_
N3 O N
MeOFi
Na toluene, 110"C N3 O N~
I r, r
poi o I ~
r Me
Me
14

SCIII:!,lli II I
t1 ~ ~, '~ ', ::) '
~4 i ~ rd -y-
_o rt0! f, -rI'slfp pn
11p
s~ pT
pl TIOr1
MeOTI + n 1 ,2 -
ROI-1 1 bans
p'
'r''
o
w
T(Qr1 Me
Tf011 li
f O N
O l .-O +
N 11p
_._ Tlip
~~l
'
pl1
~
~
~ IZOIf
p ~ sr~2 - iike pn ,
- Me
' Me
Me
1,2 - cis
nNOMCmznTioN
-riot-I
p ~r~o ~ p
~ ~ - on
rlp-
-fl~
~ s T so
I1 S
_ __ rT O I-1
_ OI1 5~~2 _ olT
o O N like
N ~~ ~
1 Jl
ip
~J
p p 1,2
. - traps
Me Me
rnm.I: xv1
OEi OAc
h-10'_~~ 1. MaOTf ( 0.1 equiv.) O
Ii0 O N\ , ~ ~ ~~~0
NI-IAc /~ CI-I~N02/ Iso-Pr01-t ~lyAc
O / rt, 5min
2. Ac:zO / Py
o~~ly ~3, 83%
Llo or I Ago one
1. NIeOTf ( 0.2 equiv.) ~ O
HO O N~ . Aco~~--o
rreAc ~ c~yNO2/ISO-r~rol-~ Ne-IAA
't, 5min
2. Ac?o / Py only (3, 88%

I'nlll,l: XIX
l''p -~ :'1 ;'3 i'7 w3 y
,i
f~ .~_ 5." ',.' ~~ :.F .SL
OII ~OAc (' OII ~OA_c
to nc0-'N-", MeOTf (0.2 e<lulv.) IIO--r1-O nco~
110 LO N nc0-'~'~O N -s I10~-?~ ~- Ac0-~7~0
of o~ ~ Onc O~~ Cll,rlOz/lso-f rOli(1:1) 0l1 ~ one
rt, 5mln
M" ht" not observed
Reactive Unreactive
oll on~
rlo~ o~ n~o-~.~ 0
IWo rl n~o~-~-~-o F!
0l1 ~ ono
/ o /
0
Me Mo
f10 OII Ac0 Onc
~O~ ~- O
I10~0 N AcO~'~O N
011 i Onc
/ /
(7~ O
Mo A1e
IIO Ofl nc0 Onc
I~< O' '< ,O
FIO~O N~ At0~7~~0Y N
F!~ I N~ 1I '1J
O
n
Mn F.lc
1'n111,F: XX
TfOi-i (2.0 equiv.)
DMF, rt, 15 - 20rniy
on n~o ol-I ,~ one
o do ° o
tlh0'-'~O~ Nw -y nc0~~~0 N\ - I10 Nlinc nc0~~0 N\
NI inc ~ / N3 ~ / t'Ic
O O O
Me Me Me
1.0 equiv. 10 equiv. 65 - 70°0
TfOi-I (2.0 equiv.)
DMF, rt, 30min
ola Ino on one
flo oll nco
0 0
O O N F nc0~~.0 N\ - - FiO~~ncO ~O
f 10 ~~ ~ ~ ~t I NHnc ' ~O N\
Nlinc ~ / ~ N
O O O
Me Me Me
1.0 equiv, 10 equ v. 61
16

TAIiI,rv XV I I '
~~~ ~~~~114~
-r .,9. ;,~ xlt L~ .~,'~
Of I Onc
.O
I IOC~O N MeOTf (0.2 equiv.) ' n~20~ / I'Y ~ ~~~ 19%
Nllnc I ~ C;I1~NOZ,r1,10min N O
p ~., f 13
i
Me
II tit
O~ N
OI-I
O
Me MeOTf ( 0.2 equiv.) E 10 O nc2O / f'y
II -
IIN+ O
1'
C rl3
R
R~-O ~OI-) ono R~
O R-t-O
o~,o n o~~ o ~0 0
/ I i. Nllnc
R, R = Cycloliexylidene I~IX~ , then nc?o / r'y
R R
( 14 equiv.) 6d°~o
1AI1I,1~. XVIII
--t- 0 Ol i
O~ O
(10 equiv.)
O O
or-t ~ Necover the excess
O f-1
HO O NO~.-O
FIC~O N\ I10 ~ O -~- ~ - anomer
oIJ ~~ 1 MeOTf(0.2 equiv.) ce o
CI-13N0?, rt, l5min o o
M a 61 % ~O
4~ : ~1
17

~° ~~ d~~ :'~ ~;~ :.n ,rt
, ~ '~ !.
b. _u. ~,, ~! ;.i ~ a . .
beta products were obtained in 83 and 88o yield
respectively, Table XVI.
DISACCHARIDE SYNTHESIS
The 2-acetamido-2-deoxy-beta-D-glucopyranosyJ. MOP
donor was treated first with MeOTf ( c) . 2 eq. ) in CH3NOz, at
room temperature for 10 minutes, fol_Lowed addit.i.on of 14
eq, of 1,2-3,4 di-O-cyclohexylidenyl-D- galactopyranose
acceptor with a free 6-hydroxyl, then acetic anhydride-
pyridine, which gave 68% of the peracetylated ra~at~.a
disaccharide, Table XVII. When the perhydr.~c~xy nluc:osyl
beta MOP donor was similarly treated, with -the equivalent
1,2-3,4 di-O-isopropylidene-D- galactopyranose acceptor
without subsequent peracetylation, t)ze reaction gave 610
yield of the disaccharide with 4:1 a_Lpha:beta ratio,
Table XVIII.
In the absence of the acceptor -the oxazoline
derivative can be isolated, Table XV:III.
Treating unprotected and peracetylated beta MOP
acceptors in the presence of MeOTf (~0.2 eq.) in
CH3N02/iPrOH for 5 minutes, Table XIX, showed the
unprotected gluco-, galacto- and 2-azido-2-deoxygalacto
donors gave alpha products, while peracetylated donors
gave no observable products, and were considered
unreactive.
Gluco- and galacto- 2-acetamido-2-deoxypyranosyl
beta MOP donors were each treated with 10 eq. of beta
MOP, 2-azido-2-deoxy, 3,4, di-O-acetyl galacto-pyranoside
acceptor with a free 6-hydroxyl, in the presence of 2.0
eq. TfOH, in DMF. 15-20 minutes at room temperature in
the gluco case gave E.5-70% yield of pure beta 1,6-
disaccharide, while 30 minutes in the galacto case gave
610 of pure beta 1,6-disaccharide, Table XX.
18

.., ,e -~ r ; :~ 1 ~ .c
A a t,' v ~. ~ ;u -'.
Consideration of the results so far led to three
proposed schemes for iterative oligosaccharide synthesis,
Scheme IV, in which an active donor is coupled with an
inactive donor as acceptor to give a disaccharide. The
latent donor is then activated either by change c~f
leaving group (1), activation of leaving group (3), or
change of substituent (2), and the process repeated with
another acceptor. As shown only beta linkages a-re
present, although as those skilled in the az°t would
understand alpha linkages can be generated routinely in
such syntheses.
One such synthesis is indicated, Table XXI starting
using the 2-acetamido--2-deoxy-D-glucopyranosyl MOP donor
of Table XX, and forming the same beta disaccharide in
70% yield, which is then reduced peracetylated to its
diacetamidohomolog, deprotected to form an active donor
and coupled with l0 eq. of the same acceptor, in the
presence of 2 eq. TfOH in DMF, for 20 minutes at room
temperature, then peracetylated to give the beta
trisaccharide in 34% yield, which can be further
optimized.
In a close variation on the immediately preceding
synthesis, the identi<~al disaccharide is prepared,
deprotected and treated with 0.5 eq..MeOTf, CH3NOZ/iPrOH,
at room temperature for 9 hours followed by
peracetylation, to gi~,re the isopropyl derivative of the
disaccharide in 66% yield, alpha: beta. 17:1, Table XXII.
ACTIVATION OF O-ACYL PROTECTED GLYCO~~YL MOP DONORS FOR
BETA-GLYCOSIDE SYNTHESIS - COPPER TRI:FLATE ACTIVATOR
O-acyl protected 1,2-trans MOP c~lycosyl donors are
coupled with glycoside acceptors containing a single free
hydroxyl, using Cu(OTf)z (2 eq.), CHZClz solvent at room
temperature for 2 to 8 h, gave beta 1_inked D-glyco-
19

w:af:n~e tv
c~ .q t, r-3 ~) :~ .~
i .~. ~,. ~'~._7 ;j/ i J .~
n'livm° x ~n:,n9° Y la x ,.,..o ~~-o
.r-o , o _
1. no :.--~x no ~.% ~r -a._ '~~° o ~r _ no"~--,1~°'~'~-l,x
no
oorron nccEpron
.v o
FiO~~~Y ncllvnle X
E.'tC. ~_ _ _ _ _ _ _ _ nO ~O~--~O ~Y
ncllvoln donor ~O chsngo n' Io n ~O ~~ ~O~ ~
~.O ~O ~-O ~ --~- nD v~0 ~X
2. no :fix -F no ~-~-x --~ no :~-~° or"~'x ~ on
o n'
ooNOn nccsr~ron
.v o
Ilow~-~.'x ~ ocllvnledonor
On
O O O
BtC. -y- _ _ _ _ _ _ _ nOW.~ ~-x
On OR
O ncllvnle X ~O oelivale Y O y0
110 ~Y nO v-~ y~0 ~Z
3. no ~ x ~ ~ w no :~°''~Y '~ i.- ~ o
." o
ooNOn nccenTOn llo~'.--J-z
etc.
I'nfll,fi XXI
TIOH(2.0 oquiv.)
pM'', It, 15 - 20min
of l nco of /of 1. tlZ, Pd / C. EtOF1
I10~ ~O' 'O'~ 2. ncp0 / Py
~~ O nc0
I O~O~ rJ ~~ O W 10 rJl Jnc nc0 '~O N
-' MTInc~ O I / N~ I / rJ~ O I /
O
Me ~I° Me
1.0 equiv. 10 equiv.
nc0 JFI
nc0~ O
~O~
Ns II
O /
Onc OI I 01.1 10 AqnIW Ma
Onc O
nco~o- NaOMo l Me0li l~~p~/~o~,o N
nco Nllnc nco o N ~ Nnn' ~J -
rJl Inc NI Inc ~I 1 TIOI-1 (2 equlv.)
O ( / O/v DMf-, rl, 20m1n
r.>, a
rrt n
74
one «nc
ncO~o-~O Onc
nc O / r nc ~ '~0
Y Nllnc n'(7. O
Nli~nc0 J) O rJ
N~
O /
M°

f
~rnnl,I: x x r W' ''~
~.r .S. ',J 1.' ~ i-J ..~
TtOH (2.0 equiv.) 011 Onc
or{ nco on
DMF, ri, 15 - 20rnin 11p-~I)-
-< n O
HO~O~ N + ncO~~p N\ -~- F-i0 NHnc n"O~O N
F 1 --~~ ~/ ''''''0
Nhinc ~ \ Na ~ / 70% N~
O / O O /
Me hfe Me
1.0 equiv. 10 equiv.
pr1 0~1 1. MeOTf (0.5 equiv.), rt ~~Onc Onc
NaOMe / Me01-I h ~O~IiO CI-l3NOz/iso-PrOH, 9h nc02'~o o-
~O nc0 T~
h1o Nhlnc h~o Lo - ~- iut~nc nco
N~ ~ 2. n~?o / r~y N3
U
pY
rvie 66%
cx:(3=17:1
Tnllt,l: XXII I
Bz0' OBz Bz0 OBz ~ODn
~~O N Cu(OTf)z (2 equiv.)
Bz0 w Bz0
OBz ~ / ROf! / CHZC12, rt E3h OBz BO~
O «?B~ COI Me
Me E35%
Bz0 OBz Bz0 OBz
O Cu(OTI)2 (2 equiv.) O ~OBn
Bz0 ~~O N~ Bz0 ~~0~"O
flOf 1 / Ct hClz, rl, 2h OBz nll0 NI
OBz ~
~ OMe
O
r
Me
69%
OTBDMS OTBDMS
B O N Cu(OT()? (2 equiv.) ~d
_ O
OBz ~ / f101i / CtI?CIz, rt, 2h OBzBBO~ O
r
O OB~ Me
Me
60%
21

lAlil.l? XXI\1
c3 ~ ~ ~~ ~ ;.a
;
h
W
j
, i
~ a
l
on on
n0 ~n 2 edniv nO
) ~n
rt
Me0 i I (0
~ rr . ~
, + (1- anorner
. ~ on
on C11~N0~/iso-i'r011() <y
U i ~ 1 : 1
ht~
ol, Time a ; (1 Yield(%)
o n
oll ~ <5rnin 8 : 1
o
hire
,01F,C)MS
_~~
-oa
I~
~
~ 20rT~in 9 : 1 84
u'
~'
I ~
0
rr,
<o~rm
r'
~
(~r
o rr. 1 h 5 : 1 88
on I ~
0
M
<O~II
~~oo~o N 2h only a 95
on.,
'
o
M r~
<O,D~n
"~o~o 5h only a 85
rr'
IT
~'
o '
rae
CAIILI: XXV
OBn OBn
O gn0 ~O~
Oli
gn0 O O N~ -t- ~ I O _ rvteOTt (0.2 equiV.)r pgn0~0 -t- ~) - anomer
gn
Oen ~~ , \~ Et?O, rt, 2hh O
O' J ° ° G6%
r ~ OXO
Me
1.5 equiv.
5.7 : 1
OBn
OBn
OI-I Bn0 O
Bno ° o ~~ o MeoTt (0.2 equiv.) osn~ .,. ~ - anomer
BnC-'~ I N~ -F ~~ Et7O, rt, 20h O O
Ogn O~ O~c OMe 64%
Me O~c C)Me
1.5 equiv.
5.1 : 1
22

a
~i g~l''~:
i'-. _~_ ~J 1.~ ~~ ;.~ _?
rnnl.e xxvt
,oo~,
on., nc of I ' u~,o X1.,-0
~~,os
B~~o~o N + n~o~~o N M~OTf (0.5 equiv.) _ o~n _ n~ -a- (~ - anorner
E120.JrtQ 151t nc0(~O tJ
r tJ 7
Mo Mo (11
Me
1.5 eqnid.
4.5 : 1
OOn
OI I ~n0 L
O~n
ezoyo N MeOTf (0.5 equiv.) ,~o" + (3 - anomer
r3no~o N ~ ~
Bn0 ~ + ~'o Opr I / EIzO / CF-IzCIZ(4:1 ) aio~0 N
OBn / rt, 3h ezo-~7'''
47% 013z
Mo ' p
Mo
0.5 equiv
rnnt,e xxvtt
6 : 1
OEIn
onn of I nno~C~
O o N + ~O Cu(OTf)2 (1.0 ecluiv.) t3n0- p~
0
o~,o~~~ ~ n':o~ 121, nro~'o + ~ - anorner
Itno n,.o ~ EtzO, rt,
OUn ~ / Onc OMo 75% n ~ Mo
Mo
5.a : 1
or3n orm
of
O o N , c~(o-tf)2 (t.o ocJui~.) r~~,o"~o -+- cx - anomer
~ ~ r ono-
B~~o~ , ncoy o~n n~o~~
r7n0 Onn I nc0~ ~ ~ ~ CFI~CN, ri, t5 rain nc0
Onc. OMo 67 % Onc OMo
Mo
2.6 : i
Of3n
Of3i,
Cu(orf), (t.o e~uiv.) ,~ , + (3 - anorner
a"o o N -~- ~no
en~ ~ E1~0, cl,oloslorol Bn0
OOn
Br' ~ rt, 3.5h O
7E3'o
Me 4 . 1
~OBn
OBn BnO~~''O
OI I Bn0
Br,o-~ ° + n~o ~° CrJ(oTf)2 (i.o e~ufv.) _ oe~ + (3 -
anomer
eno~T~ ~ ~
OBn nc nc0' ' =
O N one oMA ElzO, 4l1 MS, rt, 2larnln nc --''~~ ~_o
73% Onc~ Me
i
4.3 : 1
Me
23

~ ~i 61 i~ C ~ P
(.J .k. ~.: ._~ v_i ~,t _...
pyranosyl disaccharides in 60-85o yie)_d, Table XXIII.
A number of D-glucopyranoside beta MOP donors
unprotected, protected by 6-O-TBDMS, 3,4,6-O-benzyl,
2,3,4-O-benzyl and 2,3,4,6-O-benzyl were treated with
MeOTf (0.2 eq) in CH3N02/iPrOH, at room temperature, the
yields varied from 76-95%. with alpha: beta ratios from
5:1 to 1000 alpha. Reaction time and alpha proportion
tended to increase with total bulk of protecting groups,
Table XXIV.
GLYCOSIDE SYNTHESIS WITH O-ETHER PROTECTED GLYCOSYL MOP
DONORS
Perbenzylated glucopyranosyl beta MOP donor was
treated in the presence MeOTf 0.2 eq., in ether at room
temperature with 1.5 eq. of 6-hydroxy acceptors protected
with isopropylidene, and acetyl groups, for 24 and 20
hours respectively to give 66% yield of 5.7:1 alpha: beta
and 64% yield of 5:1 alpha: beta Table XXV.
Perbenzylated glucopyranosyl beta MOP donor was
treated in the presence of MeOTf 0.5 eq., in ether at
room temperature, 15 h, with 1.5 eq. of 6-hydrox.y
diacetyl azidodeoxy glucopyranosyl beta MOP latent donor
as acceptor, to give 55% yield of 4.5:1 alpha:beta. The
same donor was treated in the presence MeOTf 0.5 eq., in
ether/CHzCl2 at room temperature, 3 h, with 1.5 eq. of 6-
hydroxy tribenzyl glucopyranosyl beta MOP latent donor as
acceptor, to give 47% unoptimized yield of disaccharide
alpha: beta 6:1 Table XXVI.
Perbenzylated glucopyranosyl beta MOP donor was
treated in the presence of Cu(OTf)2 1.0 eq., in ether at
room temperature, 12 h, with methyl 2;,3,4, tri-O-acetyl
beta-D-glucopyranoside as acceptor, t:o give 75o yield of
disaccharide, alpha:beta 5.8:1. The same reaction in
24

a W ~ 'O
., .~ J ~J .~
CH3CN in 7_5 minutes gay%e 67% yield alpha: beta 1:2.6,
favoring a beta-glycosidic linkage in this solvent.
Perbenzylated glucopyranosvl beta P~"IOl? donor was treated
with Cu(OTt)2 1.0 eq., in ether at room temperal.ure, 3.5
h, with cholesterol acceptor, to givf= 78% yield,
alpha : beta 4 : 1 . Perbenzylated gl_ucopyrano.sy7_ a.l.pha MOP
donor was treated with Cu(OTf)z 1.0 e~q., in ether at room
temperature, 20 min, 4A MS , wi L:h methyl 2 , 3 , ~1-wt:zv. - U-
acetyl-a1_pha-D-glucopyranoside as acceptor, to ~_l~_ve 73
yield of disaccharide alpha: beta 4.3:1, TaJal~ X:XV1I.
Perbenzylated 2-az ido-2-deoxy-galactopyrarr.!:»;y7_ beta
MOP donor was treated with Cu (O'ff) 2 1.. 2 eq. , in C~3ZClz at
room temperature, 6 h, with methyl 2,3,4--tri-O-acetyl-
alpha-D-glucopyranoside acceptor, to give 90% yield of
disaccharide, alpha: beta 3.2:1. The same reaction with
Cu (OTf ) 2 2 . 2 eq. , in CH~CN i.n 12 h gave 60 0 ~,ri_eld c~f
disaccharide, alpha: beta 1:2.6 Tab~.e XXZ'III.
Perbenzylated 2-azido-2.-deoxy-g:3lactopyranosyl alpha
MOP donor was treated with Cu (OTf ) 2 1_ . 2 eq. , in CHzr~7.2 at
room temperature, 30 min, with the following: 6-hydroxy,
3-hydroxy, 4-hydroxy, and 2-hydroxy methyl glycoside
acceptors combining a variety of O a:nd N protective
groups, Table XXIX, u.>hich gave respe~~tively 85% yield of
disaccharide (alpha:~~eta 3:1), 53% yield (100% a~.ph~),
63o yield (alpha:bata. 6:i), and 48% yield (alpha: beta
4.2:7_) .
Per_benzylated glucopyranosyl beta MOP donor (1.5
eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room
temperature, 8 h, with r:~,ethyl 3-O-ac«tyl--4,6-O-
benzylidene-alpha-D-glucapyranoside as acceptor to give
yield 45% of disaccharide, alpha: beta 2.4:1.
Per_benzylated glucopyra.r,osyl beta MOP donor ( 1.. 5 e;~ . ) was
treated wi th Cu (OTf ) 2 1 eq. , in CH,C7.~/~ther ( I. : 4 ) at room
temperature, 15 h, and methyl 2-O--Gcetyl-4,6-O-

r
benzylidene-alpha-D-glucopyranoside acceptor to give
yield 60% of disaccharide, alpha: beta 10:1.
Perbenzylated glucopyranosyl beta MoP donor (1.5 eq.) was
treated with Cu(OTf)2 1 eq., in CHzCl2 at room
temperature, 9 h, with methyl 2,3,6 tri-O-benzyl alpha-D-
glucopyranoside acceptor to give yield 50% of
disaccharide, alpha:beta 2:1, Table X:~X.
Perbenzylated galactopyranosyl b<~ta MOP donor (1.5
eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room
temperature, 6 h, with 3-0-acetyl 4,6-O-benzylidene-
alpha-D-glucopyranoside acceptor to give yield 85% of
disaccharide, alpha 1000. Perbenzylated galactopyranosyl
beta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq.,
in CHZClz at room temperature, 7 h, and methyl 2-O-acetyl-
4,6-benzylidene-alpha-D-glucopyranoside acceptor to give
yield 600 of disaccharide, alpha 100%. Perbenzylated
galactopyranosyl beta MOP donor (1.5 ~eq.) was treated
with Cu(OTf)z 1 eq., in CHZC12 at room temperature, 24 h,
with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside as
acceptor to give yield 60% of disaccharide, alpha 100%
Table XXXI. Perbenzylated galactopyranosyl beta MOP
donor (1.5 eq.) was treated with Cu(O'Tf)z 1 eq., in CHZCIz
at room temperature, 9 h, and methyl 4,6-O-benzylidene-2-
benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside
acceptor to give yield 45% of disaccharide, alpha 100%.
Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.)
was treated with Cu(OTf)z 1 eq., in CHZC12 at room
temperature, 15 h, and methyl 2,3,4-tri-O-acetyl alpha-~D°-
glucopyranoside acceptor to give yield 85% of the
disaccharide, alpha: beta 3:1, Table XXXII. In the same
table is shown treatment of the MOP 1,4 2,3,4,6-O-
tetracetyl-beta-D-galactopyranosyl-4,6-O-isopropylidenyl-
2-azido-2-deoxy-alpha-galactopyranoside with benzyl-N-
benzoylserine, in CHzClz, 4A MS, in the presence of
Cu(OTf)z to give 82% yield, alpha: beta 4:1.
2b

i'~ '~ 3~i s !
r n a r, n x x v r 1 t s, :;. .. L, t.~ f"r .
~np .OBn
ril,o or3n ~o
olr
O C - Cu(OTf)z (t.2 Bc)uiv.) C~nO
/° N~ v n~o~ __ ~ ry O -+- (3 - anorner
nc0 Onc CHzCl7; rt, 6h nco'~'~' O
On ~~''110
° OMe 90 % ncO
Me Onc Orvte
3.2 : t
ftn0 OE3n ~n0 .OE3n
Cn(OTr)2 (2.2 ec~uiv.)
ono ° N + ° - ono ~°~ + a - anorner
nco O
nc0 Oncl CH3CN, ri, 12h N, A OO
p OMe EO % ~ Me
Ma
2.6 : 1
vnnLr; xxtx
Bn0 OBn
~
Bn0 OBn OII Cn(OTI)z Bn0-'-N
O y (1.2 eynlv.)o i. ~i - ~norner
~
~ O '~ CI-lzClz, nc0~
tJ., Onc r1.30min !
OS" 0
o
O~ pr~n , w
/ O!\c OMe
O 3 . 1
hr"
Bn0 OBn f'h~O FI, OO
p ~ Cu(OTI)z
O v (1.2 eqniv.)rJ
l
NL
Bn0 to -- - O
I ItJL OMq CIiyClp, H
fl, 53 OMo
% Bn0-
rJ f -O
o O N Z
OnC
OBn
/
only (7
MS
Bn0 OOn
~
~
B"O OBn /OBn Crl(Tr)? -
O O (1.2 E?ytliv.)BnO
l 00
' j ~ i- (~ - anomer
~ 0 0~-1 cl ycl,,
u, sa %
No OBnOMo OBnOMe
rr
/ 6 t
0
Me
Bn0 OBn
Bn0 OBn
of r Cn(Oli)z OBn
B Ph~O~ O (1.2 eyniv.)
O~ -E O'~ ~ r!
---
n ~ o
~ , cl I,c:lz, F,,-~-O ~ +~ (3 - anomer
'T~1~ uMo rf. ~o~o
rlo
/ ~ Mn
0
Me 4.2 t
27

t~ ~ 1~, I~ r1 a E .~
TnItI.I, XXx (.~ -~. ~ ~x E... ~:
Ph O
Ac0
Cu(0E1)z (1 equiv.) OgnO OMe
Bn0 O N PI~~ ~ ~ Bn0 J
DoC~ ~ r. ~O 1 CII~CI~ , Ell. , r.l. B"~ O + ~- anomer
ODn ~ / OII C,Me ~5°~ OBn
O
Me 2.~1 : 1
(1.5 equiv.)
OBn PrW ~ O
O
BnU'='~O N PIWO'~O Cu(OTI)Z (t equiv.) Bn0 OBnO Ac~
ar,o ~ F o~ oMe
ogn ~ ~ Elo Aco ~ cn~Cl~m~o (l:n) Bno_l
G GMA ,~h. , r.t. + (3- anomer
ogn
Me 60
(1.5 equiv.) l(~' 1 ~ : 1
OBn
< ~ OBn
Bn0'~~~O~N\ fi0~0 Cu(OTf)~ (1.5 equiv.~_ OBn
Bno ''~ ''' ~ + y-- anomer
Bno'~~
Ogn I / r Bn0 ~ CI IzCi~ , 91~. , r.l. pn0 go
O Bn0 OMe 50 % OBn O O
i
Me . gn
(1.5 equiv.) E3nG OMe
2 : 1
rnm,l: xxxE
Phi ~O
Bn0 ODn Ac0
O Cu(OTr)z (tequiv.)~ Ogn~~OMe
~~~ r'Iy0 O - Bn0
Bn0 ~~O N~ r. O O
oBn I n~~~ Cr IzCh , sh. , r.L
0 0l f on>le °5'° Bno ogn
Mo ONLY Ct
(1.5 equiv.)
Bn0 OBn Phi'
l_< - p
~~O N PIyO'~O Cu(OTf)2 (1 ~quiv.) Ogre Ac0
Bn0 ~~ ''' ~ U --i.- BnO 7 OMe
ODn O~~ v FIO-/1~~1 CrhCh , 7h. , r.t.
OMe 60 % Bn0 Ogn
(1.5 equiv.) Me
ONLY OC
Dn0 ODn
O N OBn Cu(OT-I)~ (1.5 ec,uiv.) Bn0 ODn
Bn0 I ~ l-f0-~ -w-
ODn
r- Bn0 Cr-IzCh , 2~1~. , r.l. Bn0 ~ OBn
Dn0
OMe 60 % OBn O O
Me
(1.5 equiv.) Dn0
Bn0 OMo
ONLY (7:
28

4') ~! r'R t1 "'r . v a
r: .J a
1'~.UI,I' XXXII
an0 Oan Ph''~O
O ---''~''// ''\~~'
O O N Ph O Cu 01( 1 ecuiv. OanO~
an0 ~~ ~ ~ O ( )z ( I ),.- an0 1-INZ OMe
OBn O ~ / r I-IC'~ CrIzClz , 9h. , r.t. an0
I INZ OMo 45'o Oan
(1.5 ecJuiv.) M~
ONL',' a'
an0 Oan
Oan
O N ~ OI-f Cn(OTI)z (J.2 equiv.)
ano ~ n~o~~ -~ ,~~ + (3- anomer
oar, ' , I eno
nCo CI IzCIZ , IJ11. , f.l, anp
O ~ ~~O OMe F35 ~ Oan
(1.5 equiv.) Mo nc0 O
AcC
nc0 OMe
3 : 1 '
29

c-r .i ~ (l r) :::
E~~ !. ~,.' ~j ~. I~J
In summary the 2-(3-methoxy)-pyridyl MOP beta-D-
hexopyranosides, exemplified by analogs in the D-gluco-,
D-galacto- and their 2-azido-2-deoxy variants (~L,2-trans
MOP glycosides) with hydroxyl acceptors, (alcohols and
carbohydrates) in suitable solvents dive primarily alpha
products (1,2-cis products) in the presence of MeOTf as
promoter, in catalytic proportion, five other related
leaving groups did not. MOP (3-methoxypyridyl-2-oxy) was
shown superior (shorter) in reaction time to 2-
oxypyridyl, and 4-methoxypyridyl-2-o}:y, although closely
similar in yield and alpha proportion. The unprotected
beta 2-acetamido MOP glycosides gave exclusively beta
products under similar conditions. The peracetylated MOP
glycosides were unreactive as glycosyl donors. Ether
protected equivalents were reactive as donors to give
alpha products, in the presence of Cu(OTf)Z. Increasing
degree of protection lengthened reaction time and
increased alpha proportion. Perbenzylated beta MOP
glycosides gave alpha disaccharide products. Solvent
dependency was noted, water miscible alcohols may be used
as solvent and donor with excellent results, apart from
this coincidence, the solvent is fairly critical CH3N02,
CHzCl2, and ether, gave satisfactory to excellent results
for alpha glycosides while CH3CN, favored the formation of
beta-glycosides.
NUCLEOSIDE SYNTHESIS USING MOP GLYCOS YL DONORS
In a further development MOP leaving group? have
been utilized to prepare nucleosides.. Clinically
relevant nucleosides including AZT, used in the treatment
of AIDS are shown in Table XXXIII. prior syntheses of
1,2 cis-pyrimidine nucleosides in Table XXXIV, using
hemiacetal sugar acetates with trimei~hylsilyl substituted
ethyl and butyl uracils, and of 1,2 i~rans-pyrimidine
nucleosides in Table XXXV, where thymine derivatives are
similarly prepared from thiophenyl hc~miacetals.

c3 ~ !.1 r ,! ,,~, : ~ '~
GN ~ l.° .r ~;~ ra .~
Perbenzylated galactopyranosyl beta MOP donor is allowed
to react with trimethylsilyl uracil, thymine and cytosine
in THF and toluene at room temperature using TMSOTf
promoter, Table XXXVI, to give the expected beta-D-
galactopyranosyl nucleosides in 55 to 95% yield with
alpha: beta ratios of 6 to 9:91 to 94, showing excellent
stereocontrol. Perbenzylated furanosyl nucleosides were
prepared from trimethylsilyl thymine, Table XXXVII,
uracil, Table XXXVIII, and cytosine, Table XXXIX, and MOP
perbenzylated furanosides, from inspection generally best
yields and highest alpha proportion are obtained using
toluene. Table XL shows a synthetic route to thymidines.
In a related development solid state
oligosaccharides can prepared via MOP glycosides. The
iterative process involves bonding of a MOP glycoside to
a benzyl moiety on a resin support, the fixed glycoside
is then allowed to react with an acetylated (inactive)
MOP glycoside forming a stereospecific linkage. The
acetate is then saponified and the process repeated,
Table XLI. Details of the base strategy, Table XLII,
first experiment, Table XLIII, and test recovery of
unchanged MOP glycoside, Table XLIV are shown. Test
effects using coupled glucopyranosyl MOP donor,
CH3N02/iPrOH acceptor and MeOTf promoi~er, and changing the
solvent are shown in Table XLV, yields vary from 40 to
100%, while alpha: beta ratios vary from 7.6 to 5:1.
Preparation of a disaccharide using a similar process is
shown, Table XLVI. An enhanced coupling procedure using
S-pyridyl thioester, is demonstrated, Table XLVII, while
preparation of the resin-sugar linking precursor' is
indicated, Table XLVIII.
2-PYRIDYL CARBONATE DONORS
The idea of using 2-pyridyl carbonate as donor, was
tested, showing reasonable yields and. alpha-beta ratios,
31

G~ -~ ~'3 ~ r? :" y q
.i ~J v.' i J ..~.
while the equivalent phenyl carbonate was inactive under
similar conditions, Table XLIX.
2-PYRIDYL THIOCARBONATE DONORS
The concept of using the equivalent thiocarbonate is
shown, Table L, the preparation of a number of such
syntheses thiocarbonate donors, hereinafter TOPCAT, is
shown, Table LI, these compounds are all crystalline,
stable, 1,2 - trans isomers. TOPCAT perbenzyl alpha-D-
glucopyranoside donor was tested with. methyl 2,3,4-tri-O-
acetyl alpha-d-glucopyranose, using as promoters 1.2 eq.
Cu(OTf)2 and 2 eq. AgOTf in ether and CHZC12, and then
reacted in excess (1.5 eq.) with various glycosides and
AgOTf (3 eq.), Table LII, yields of 40 to 80% with
alpha:beta ratios of 4:1 to 1.5:1 were noted. The
concept was further explored using TOPCAT alpha--D-
galactopyranosyl, alpha-L-fucopyrano~,yl, and 1,2-trans
glycosyl donors, the promoter was AgOTf, the solvent
CHZC12, effectuated by 4 A MS, yields from 46 to 83% were
obtained with alpha: beta ratios of 8:1 to 100% alpha,
Table LIII.
Pursuing the concept further, it: was demonstrated
that it was possible to couple TOPCAT glycosyl donors, to
a variety of MOP glycosyl donors, as acceptors, to
produce potential disaccharide MOP donors, with AgOTf
promoter, and either CHzCl2 or CHzClZ-~ather, yields from 54
to 74%, with alpha-beta ratios of 3:1. to 11:1, Table LIV.
The products can obviously be utilized both as themselves
and as precursors in later syntheses.
A scheme for such synthetic is indicated, wherein PG
means protecting group, showing coupling of TOPCAT donor
with MOP acceptor, and further reactions, specific
details of oligosaccharides of interest are also shown,
Table LV.
32

~a .~ ~ ~ , ". ; ~
,,
Practical employment of such approaches are shown
indicating preparation of TN-antigen type O-serine
glycoside using TOPCAT and a related MOP synthesis,
preparation of T-antigen type O-serine glycoside via a
TOPCAT disaccharide, and a similar but different MOP
approach, for comparison the conventional approach is
also shown, with its inferior qualitative yield, of alpha
stereoisomer, Table LVI.
An additional development reacting trimethylsilyl
pyrimidine acceptors with TOPCAT pyranosyl donors
produces pyranosyl nucleosides, in good yield and
alpha: beta ratios of 1:1 or better, Table LVII, and with
a purine acceptor, Table LVIII. Arabinofuranosyl
nucleoside preparation is detailed, Table LIX, while
ribofuranosyl nucleoside preparation. is similarly
detailed, Table LX. By inspection those skilled in the
art can appreciate that both yields and stereospecificity
are more than satisfactory.
A further demonstration of MOP and TOPCAT
versatility and elegance, is shown by the syntheses of Lex
structures by MOP, Table LXI, and TOPCAT, Table LXII,
both showing excellent yield and stE:reospecific:ity.
The overall synthetic scope of the invention is
generally indicated, without such indication being
restrictive or limiting in scope or application, Table
LXIII.
In one broad aspect the invention is directed to an
improved process of glycoside synthesis comprising
reaction of a donor selected from O--pyranosyl <~nd O-
furanosyl glycosides, with an acceptor including an
alcoholic hydroxyl, in the presence of a promoter and a
solvent. The improvement provides a donor is selected
from the group consisting of glycosides substituted by
33

y .~ G 1, 11 . 1 ~~
i
_e_ 1J 0.r ~.r~ ld . ~?,.
leaving groups X of formula I and re7_ated heterocyclic
bases:
., y
(.1
!~ J
FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5
carbon atoms. The promoter is selected from t~.he group
consisting of MeOTf, TfOH, BF3, Cu(OTf)Z, ZnCl.?, and other
acids, Lewis acids and chelating metals. ~rhE~ :~alvent a.s
selected from the group consisting of CH3N02, and CHzCl2,
EtzO, CH3CN, DMF, THF, and other solvents of like polarity
and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl gl.yc:ostde,
the promoter is selected from the group consisting of
MeOTf, TfOH, BF3, Cu(OTf)Z, and ZnClz, and trio solvent is
selected from the group consisting of CH3NOZ, and CHzClz,
EtzO, CH3CN, DMF and THF, and mixture~> thereof .
More preferably the donor is selected from the group
consisting of glycosides of formula R.X wherein x: has
formula I and related heterocyclic structures, and R has
formula II,
-~~,r--\~.
~~1- ~ ;.y, y
FORMULA II
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms,
acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,
or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
independently hydroxy, acyloxy of 2 to 6 carbon atoms,
arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
34

~'V .~ F ~ ,.7 ,:~ >
G. _',_ ~..~.._i ~_= .,a .:
carbon atoms, or a_Lkoxy of 1 to 10 carbon atoms, R5 is
independently hydroxy, acyloxy of 2 to 6 carbon atoms,
arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
10 carbon atoms, alkoxy of 1 to 10 carbon atoms,
trialkylsiloxy wherein the alkyls are: independently of 1
to 5 carbon atoms, or R2, R3, R4, R5, may be R. The
promoter is selected from the group consisting of MeOTf,
TMSOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2, while the solvent
is selected from the group consisting~~ of CH3N02, CHZClz,
Et20, CH3CN, DMF, and THF and mixture; thereof .
Conveniently the the acceptor i~, selected i.'rom the
group consisting of R'OH, wherein R' is alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon
atoms, including N-substituted amino-~alcohols and S-
substituted thio-alcohols, esters of alkanols of. 1 to 10
carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon
atoms, esters of alkanols of 1 to 10 carbon atoms with
hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having
the amino function acylated by an acid of 2 to 7_0 carbon
atoms, and glycosides of formula R"Y, wherein R" has
formula III,
~cS
FORMULA III
containing at least one unprotected alcoholic hydroxyl,
where Y is selected from the group cons~_st:ing of: alkoxy
of 1 to 5 carbon atoms and X, R7 is a.zido, hydroxyl,
acyloxy of 2 to 6 carbon atoms, arylc:arboxy of i' to 10
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of
2 to 10 carbon atoms, R8 is hydrogen, hydroxyl,
alkenyloxy of 1 to 5 carbon atoms, ac:yloxy of 2 to 6
carbon atoms, arylcarboxy of 7 to 10 carbon atoms,
arylalkoxy of 7 to 10 carbon atoms, or alkoxy of: 1 to 10

spy ~~;9~e
I-. .; ~,.~ v_~ .r i..~
carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, or acyloxy o:~ 2 to 6 carbon
atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, Y and :R7 may
together be alkylidenyldioxy of 3 to ~3 carbon atoms, or
cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and
R9 may together be alkylidenyldioxy o:f 3 to 9 carbon
atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms
or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon
atoms or R7, R8, R9, R.10 may be R or )2".
Most preferably X is 3-methoxy-pyridyl-2-oxy. The
process may be considered as two distinct groups
depending on whether the X group is alpha or beta on the
pyranosyl ring. In the beta case R has formula IV, while
in the alpha case R has the formula V.
v~ )
FORMULA IV (BETA)
i ~ ~'
;,
I': ~~ ' ~ /
r
:-
FORMULA V (ALPHA)
In the alpha case, R2, is azido, arylalkoxy of 7 to
carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3,
R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms. The :promoter is Cu(OTf)z.
The solvent is selected from the group consisting of
CHZClz, Et20, and mixtures thereof . The acceptor is
selected from the group consisting of glycosides of
formula R"Y, containing at least one unprotected
36

:, ~9, .~
I~~mY ~ V ~ ~ YJ _~.
alcoholic hydroxyl, wherein Y is alko:xy of 1 to 5 carbon
atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms,
arylalkoxy of 7 to 10 carbon atoms, alkoxy of. 1 to 10
carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms,
R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms
arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10
carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon
atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may
together be aralkylidenyldioxy of 7 to 10 carbon atoms.
In another aspect the process may be applied to
unprotected donors wherein R2, R3, and R4 are
independently hydroxy, arylalkoxy of '7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, R5 is
independently hydroxy, arylalkoxy of '7 to 10 carbon
atoms, alkoxy of 1 to 10 carbon atoms or trialkylsiJ.oxy
wherein the alkyls are independently of 1 to 5 carbon
atoms, or R2, R3, R4, R5 may be R, and at least one of
R2, R3, R4 and R5 is hydroxyl. The promoter is selected
from the group consisting of MeOTf, T1!~SOTf, BF3, Cu(OTf)Z,
and ZnClz. The solvent is selected from the group
consisting of CH3NOZ, CHzCl2, CH3CN, and THF and mixtures
thereof. The acceptor may be selected from the group
consisting of alkanols, alkenols and ~~ycloalkanols of 1
to 6 carbon atoms and glycosides of formula R"Y,
containing at least one unprotected alcoholic hydroxyl,
wherein Y and R7 together are alkylid~snyldioxy of 3 to 9
carbon atoms, R8 and R9 together are alkylidenyldioxy of
3 to 9 carbon atoms. More preferably wherein R2, R3, R4
and R5 are hydroxyl, that it is the donor is unprotected.
In a further aspect protecting groups may be
provided by ethers, in which case R2, R3, R4 and R5 are
arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10
carbon atoms. The promoter is selected from the group
consisting of MeOTf, and Cu(OTf)2. The solvent is
37

~~~ IAl~ll~~'a
F. r_ ,. ,_ ;_3 a:~ n
selected from the group consisting of CH3NOz, CHzCl2, EtZO,
and CH3CN and mixtures thereof. PrefE:rably the acceptor
is selected from the group consisting of alkanols of 1 to
carbon atoms and glycosides of formula R"Y, containing
at least one unprotected alcoholic hydroxyl, wherein Y is
selected from the group consisting of alkoxy of 1 to 5
carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is ,azido,
hydroxyl, acyloxy of 2 to 6 carbon atoms, arylca:rboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,
alkoxy of 1 to 10 carbon atoms, hydrogen, or
aminocarbalkoxy of 2 t.o l0 carbon atoms, R8 is hydroxyl,
acyloxy of 2 to 6 carbon atoms, arylcarboxy of 'i to 10
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or
alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl,
arylcarboxy of 7 to 10 carbon atoms, or acyloxy of 2 to 6
carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7
may together be alkylidenyldioxy of 3 to 9 carbon atoms,
or R8 and R9 may together be alkylidenyldioxy of 3 to 9
carbon atoms, or R9 and R10 may together
aralkylidenyldioxy of 7 to 10 carbon atoms.
In a further aspect the protecting groups may be
esters, here R2, R3, and R4 are independently acyloxy of
2 to 6 carbon atoms, or arylcarboxy o:f 7 to 10 carbon
atoms, R5 is independently acyloxy of 2 to 6 carbon
atoms, arylcarboxy of 7 to 10 carbon atoms, and
trialkylsiloxy wherein the alkyls are independently of 1
to 5 carbon atoms, or R. The promoter is Cu(OTf)2, and
the solvent is CHzClz. In this case the acceptor is
preferably a glycoside of formula R"Y, containing at
least one unprotected alcoholic hydro:icyl, wherein Y is
alkoxy of 1 to 5 carbon atoms, R7 is arylalkoxy of 7 to
carbon atoms, alkoxy of 1 to 10 carbon atoms, or
aminocarbalkoxy of 2 to 10 carbon atoms, R8 is alkenyloxy
of 1 to 5 carbon atoms, arylalkoxy of 7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, R9 is :hydroxyl,
38

~l s S > n, 'o s~
;.") ;,~
arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10
carbon atoms, R10 is hydroxyl, arylal:koxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms.
In a further aspect when an aminosugar or precursor
is being prepared when the precursor function is
acylamino, then R2 is acylamino of 2 to 5 carbon atoms,
R3, R4 and R5 are hydroxyl. The promoter is selected
from the group consisting of MeOTf, and TfOH. The
solvent is selected from the group consisting of CH3NOz
and DMF and mixtures thereof. Preferably the acceptor
is selected from the group consisting of alkanols of 1 to
carbon atoms and glycosides of formula R"Y, containing
at least one unprotected alcoholic hydroxyl, wherein Y is
3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2
to 6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms,
R10 is hydroxyl, Y and R7 may together be
alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may
together be alkylidenyldioxy of 3 to 9 carbon atoms.
In a further aspect when an aminosugar or precursor
is being prepared when the precursor function is azido,
then R2 is azido, R3, is arylalkoxy of 7 to 10 carbon
atoms, alkoxy of 1 to 10 carbon atoms or R wherein R2,
R3, R4, and R5 are acyloxy of 2 to 6 carbon atoms, R4 and
R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1
to 10 carbon atoms, or R4 and R5 together are
alkylidenyldioxy of 3 to 9 carbon atoms. The promoter is
Cu(OTf)2, while the solvent is selected from the group
consisting of CHZC12, and CH3CN and mixtures thereof.
Preferably the acceptor is selected from the group
consisting of esters of alkanols of 1 to 10 carbon atoms
with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms
having the amino function acylated by an acid of 2 to 10
carbon atoms, and glycosides of formula R"Y, containing
at least one unprotected alcoholic hydroxyl, wherein Y is
alkoxy of 1 to 5 carbon atoms, R7 is acyloxy of 2 to 6
39

i.. a. '_: a '_~% ~ r
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, hydroxyl, or aminocarbalkoxy of
2 to 10 carbon atoms, R8 is hydrogen, acyloxy of 2 to 6
carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy
of 1 to 10 carbon atoms, or hydroxyl, R9 is hydroxyl,
arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
carbon atoms, alkoxy of 1 to 10 carbon atoms, or
acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl or
acyloxy of 2 to 6 carbon atoms, or R9 and R10
aralkylidenyldioxy of 7 to 10 carbon atoms.
The invention additionally encompasses an improved a
process of nucleoside synthesis comprising reaction of a
donor selected from O-pyranosyl and O-furanosyl
glycosides, with an acceptor including a trialkylsilyl
ether of a pyrimidine, in the presence of a promoter and
a solvent. The improvement lies in selecting the donor
from the group consisting of glycosides substituted by
leaving groups X of formula I and related heterocyclic
bases:
~~~~.n
FORMULA I
where A is N, or CH, and Rl is H or alkoxy of 1 to 5
carbon atoms. The promoter is TMSOTf, and other acids,
Lewis acids and chelating metals. The solvent i.s
selected from the group consisting of toluene, benzene,
dioxane, CHZClz, Et20, THF, and other solvents of like
polarity and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl or O-furanosyl
glycoside, of formulae II or VI, and the trialkyl silyl
pyrimidine ether has formula VII.

~~ ~~ LT ~ J
n r7
/ l_, )
i
~ ,I.
IO ,_
FORMULA II
i,~~
s./
\ ,,.,v~~ ~'~
\\ /
,.T
~, ~~ I 0
~I~
FORMULA VI
~ ~ ~\
,c~~
;; _~~ v ~a_~~~
\- \ , /.___
FORMULA VII
wherein R2, R3, R4, and R5 are arylal.koxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is
hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy
of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7
to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms,
R13 is trialkylsiloxy wherein the alkyls are
independently of 1 to 5 carbon atoms, R14 is
trialkylsiloxy wherein the alkyls are independently of 1
to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms,
R15 is hydrogen, or alkyl of 1 to 5 carbon atoms. Most
preferably R2, R3, R4, R5, R11, R12 are benzyloxy, R11 is
hydrogen or benzyloxy, R13 is trimethylsiloxy, R14 is
trimethylsiloxy or benzamido, R15 is hydrogen or methyl.
The invention is further directed to an improved
process of glycoside synthesis comprising reaction of a
donor selected from O-pyranosyl and O-furanosyl
glycosides, with an acceptor including an alcoholic
hydroxyl, in the presence of a promoter and a solvent.
The improvement lies in selecting the donor from the
group consisting of glycosides substituted by leaving
groups X of formula I and related heterocyclic bases:
41

'~''~ 4~ra'>"~
x
Gr _d. ~~ "~,' '~ G,f
~J ..., i vl \
i, v
'\ 1
FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5
carbon atoms. The prcmoter is selectcad from the group
consisting of MeOTf, 'ffOH, BF3, Cu(OTf)z, ZnClz, and other
acids, Lewis acids and chelating meta:Ls. The solvent is
selected from the group consisting of CH3NOZ, and CHzCl2,
Et20, CH3CN, DMF, THF, and other solvents of like polarity
and dipole moment and mixtures thereof. The glycoside is
coupled to a supporting resin by a coupling group
integral to the resin, and a linking ~=_lement bonded to
coupling group and the glycoside. Pr~=_ferably the
coupling group is phenylenemethylamine, the linking
element is a dicarboxylic acid residua forming an amido
bond with the coupling group and an eater bond with the
glycoside. More preferably the glycoside comprises a
plurality of saccharide units.
In a further aspect the invention is directed to an
improved process of glycoside synthesis comprising
reaction of a donor selected from 0-pyranosyl and O-
furanosyl glycosides, with an acceptor including an
lcoholic hydroxyl, in the presence of a promoter and a
solvent. The improvement comprising selecting the donor
from the group consisting of glycosides substituted by
leaving groups of formula VIII:
-iC~.~ ~~~ \
~J~
FORMULA VIII
where B is O or S. The promoter is selected from the
group consisting of MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2,
42

~~ ~~t ~ ! 1 G'
't i , k
f.i .a. '~ ': ._
ZnClz, and other acids, Lewis acids and chelating metals,
The solvent is selected from the group consisting of
CH3NOZ, and CHZC12, EtzO, CH3CN, DMF, THF, and other
solvents of like polarity and dipole :moment and mixtures
thereof. When the donor is an O-pyra:nosyl glycoside,
the promoter is selected from the group consisting of
AgOTf and Cu(OTf)z, the solvent is selected from the group
consisting of CH3NOz, and CHzCl2, Et20, CH3CN, DMF and THF,
and mixtures thereof. When the donor is selected from
the group consisting of glycosides of formula IX wherein
Z has formula VIII,
T
3 w__~
i\ .~ L
FORMULA IX
then R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of
7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms,
or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
independently acyloxy of 2 to 6 carbon atoms, arylcarboxy
of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon
atoms, or alkoxy of 1 to 10 carbon atoms, R5 is
independently acyloxy of 2 to 6 carbon atoms, arylcarboxy
of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon
atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy
wherein the alkyls are independently of 1 to 5 carbon
atoms, or R2, R3, R4, R5, may be R. 'The promoter, is
selected from the group consisting of AgOTf, and Cu(OTf)2.
The solvent is selected from the group consisting of
CH3NOz, CHzClz, EtzO, CH3CN, DMF, and TF-(F and mixtures
thereof.
When the donor is selected from the group consisting
of glycosides of formula X wherein Z has formula VIII,
43

c'~ .~ r'~ n :'o
~2 S / '
~%'~~'L~-2;t
y
'~
FORMULA X
then R2, R3 and R4 are independently acyloxy of 2 to 6
carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5
is alkyl of 1 to 5 carbon atoms. Then the promoter is
selected from the group consisting of AgOTf, and Cu(OTf)z,
the solvent is selected from the group consisting of
CH3NOz, CH2C12, Et20, CH3CN, DMF, and THh and mixtures
thereof.
When the acceptor is selected from the group
consisting of glycosides of formula RX wherein X has
formula I and related heterocyclic structure, and R has
the formula II
~,_n/.
U
i ~ , v,~i
I
/ \ / ~,
1~ ~ , ,;
,w
FORMULA I
/ /, c,,
i;~v ~2? '
FORMULA II
then A is N, or CH, and R1 is H or alk.oxy of 1 to 5
carbon atoms, R2 is azido, acyloxy of 2 to 6 carbon
atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of
7 to 10 carbon atoms, or alkoxy of 1 t.o 10 carbon atoms,
R3, and R4 are independently ydroxy, a.cyloxy of 2, to 6
carbon atoms, arylcarboxy of 7 to 10 carbon atom~~,
arylalkoxy of 7 to 10 carbon atoms, or' alkoxy of 1 to 10
carbon atoms, R5 is independently hydroxy.
44

~ ; ~~.'1,~~~
~.. ~. a ~ :J .~
In a further development the invention is directed
to an improved process of nucleoside synthesis comprising
reaction of a donor selected from O-pyranosyl and O-
furanosyl glycosides, with an acceptor including a
trialkysilyl pyrimidine ether, in the presence of a
promoter and a solvent, the improvement lies in selecting
the donor from the group consisting of glycosides
substituted by leaving groups of formula VIII:
'7
,% ~J \
(I
FORMULA VIII
where B is O or S. The promoter is selected from the
group consisting of TriSOTf, MeOTf, TfOH, BF3, AgcJTf,
Cu(OTf)2, ZnCl2, and other acids, Lewis acids and
chelating metals. The solvent is selected from the group
consisting of toluene, THF, and other solvents of like
polarity and dipole moment and mixtures thereof. When
the donor is an O-pyranosyl or O-furanosyl glycoside, of
formulae IX, X, or XI, and the trialkyl silyl pyrimidine
ether has formula VII
-.,1
C _~; /~ __ t ~ /'
11 ,-~ ~ __ 1 ~...1~;,
FORMULA VII
/y
LZ ~~,,,~~.,;r:~~~ ° ~~\
P~-,
FORMULA IX

,_ \\ ,i~~~Li.jLil
i / L.-_
_i'
__ /; ~ o
LG
FORMULA X
,~~., ,~ -~~=
_.,
r: . ,
~'- ~~~ i ~ i
,.,,
FORMULA XI
wherein R2, R3, R4, and R5 are arylalk:oxy of 7 to 10
carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is
hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy
of 1 to 10 carbon atom:, R11 and R12 are arylal~:oxy of 7
to 10 carbon atoms, or alkoxy of 1 to .LO carbon atoms,
R13 is trialkylsiloxy wherein the alkyls are
independently of 1 to 5 carbon atoms, R14 is
trialkylsiloxy wherein the alkyls are independent=ly of 1
to 5 carbon atoms, or acylamino of 7 t;o 10 carbon atoms,
R15 is hydrogen, or alkyl of 1 to 5 carbon atoms,, and Z
has formula VIII.
In a further development the invention is directed
to an improved process of nucleoside :synthesis comprising
reaction of a donor: selected from O-pyranosyl and O-
furanosyl glycosides, with an acceptor including an
acylated purine in the presence of bromine or a :like
oxidiser, and a solvent, the improvement comprising the
donor is selected from the group consisting of glycosides
substituted by leaving groups of formula VIII:
__ ( ~ ., - , _,
' ~~ U l,
~ ~i
0
FORMULA VIII
where B is O or S. The solvent is selected from the
group consisting of DMF and other solvents of_ like
46

polarity and dipole moment and mixtures thereof.
Preferably the purine is 6-benzoyl adenine.
EXPERIMENTAL DETAILS
The above noted examples and il7_ustrations are
illustrative only in nature and not limiting.
The novel compounds of the present invention have utility as
intermediates in the production of other compounds and as well have
utility to those known glycosides but with improved results.
As those skilled in the art would realize these
preferred illustrated details can be subjected to
substantial variation, modification, change, alteration,
and substitution without affecting o:r modifying the
function of the illustrated embodiments.
This invention is not limited to the embodiments
described above, and it will be apparent to persons
skilled in the art that numerous modifications and
variations form part of the present invention insofar as
they do not depart from the spirit, nature and scope of
the claimed and described invention.
47