SYNTHETIC APPROACHES TO BIOACTIVE CARBOHYDRATES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 407

TBSO OTBS

O

TBSO

NIS, TfOH
CH 2 Cl 2 , MS 4 Å

OH OBn BnO

TBSO

OBn O

O
OBn

O

O + +

BnO HO

SPh SPh

O
BnO

BnO AcO -88 to -50°C

64%

BnO

TBSO

SPh OAc OBn

BnO

TBSO

O

O

SPh

AcO

Donor 1
“super-armed”

Donor 2
armed

Donor 3
disarmed

OAc

SCHEME 12.22 “Superarmed”-based one-pot synthesis of a trisaccharide.

The p -nitrophenylthioglycoside required harsher conditions for activation, employing a
combination of p -TolSCl and AgOTf to enable the isolation of tetrasaccharide. This
one-pot sequential synthesis of a valuable

-(1 ! 6)-galactan was accomplished in an

b

excellent 39% overall yield.
Seeking to extend further the reactivities of glycosyl donors available for use
in one-pot sequences, Bols and coworkers [80] prepared 2,3,4-tri- O- TBDMS
thioglycoside donor (Scheme 12.22) with the anticipation that it would adopt an
inverted conformation. They demonstrated that this new “superarmed” donor has
reactivity beyond that of more conventional armed donors. This phenomenon
originates from the maximization of axial or pseudoaxial C-O bonds in the
predominant conformation of the donor, which renders them less destabilizing
toward the electron-deficient transition state [81] and is a logical extrapolation of
the galactose effect (see below). An important stereochemical consequence of the
inverted conformation of the superarmed donor is that pseudoaxial attack on
the presumed intermediate glycosyl oxocarbenium ion delivers the -glycoside.

This superarmed donor, therefore, provides a further alternative means of entry into
1,2- trans -equatorial glycosides, avoiding the use of neighboring group participa-
tion and acetonitrile as solvent. Taking advantage of the reactivity of the superarmed
system, the authors completed a one-pot synthesis of a trisaccharide by the use of
three donors in the presence of NIS/TfOH at low temperature. The final trisaccha-
ride was obtained with 64% yield and is ready to be used as a donor for a new
glycosylation reaction.

b

12.3.6. Solid-Phase Synthesis of Globo-H
Taking a different approach to the problem, Seeberger and coworkers elaborated
an automated polymer-supported synthesis of the Globo-H hexasaccharide
(Scheme 12.23) that made use of six different donors, all of which carried one
temporary protecting group—a Fmoc carbonate [82]. A critical step in this automated
synthesis was the installation of the

-galactosidic linkage, for which it was observed

a

that the use of a -galactosyl phosphate donor gave high selectivity compared to

that of trichloroacetimidate-based systems. This synthesis also features the use
of N -phenyl trifluoroacetamidate type of donor, which is more stable than the
classical trichloroacetamidate [83]. The protected hexasaccharide was assembled
on the octenediol-functionalized polystyrene resin by successive glycosylation/
deprotection steps and was finally released by olefin cross-metathesis with an overall
yield of 30%.

b