13 research outputs found
2,2-Dimethyl-4-(4-methoxy-phenoxy) butanoate and 2,2-Dimethyl-4-azido Butanoate: Two New Pivaloate-ester-like Protecting Groups
The title compounds were developed to extend the available orthogonalities within the class of protecting groups removed by assisted cleavage. The mild, complementary (oxidative vs reductive) reaction conditions for the removal, together with their pivaloate-like character, were exploited, in combination with a levulinoyl-ester functioning as a third orthogonal protecting group, in the assembly of a <i>Streptococcus mutans</i> hexasaccharide built up from a oligorhamnose backbone featuring Ī²-glucosyl appendages
Reagent Controlled Stereoselective Synthesis of Ī±āGlucans
The development of a general glycosylation
method that allows for
the stereoselective construction of glycosidic linkages is a tremendous
challenge. Because of the differences in steric and electronic properties
of the building blocks used, the outcome of a glycosylation reaction
can vary greatly when switching form one glycosyl donorāacceptor
pair to another. We here report a strategy to install <i>cis</i>-glucosidic linkages in a fully stereoselective fashion that is under
direct control of the reagents used to activate a single type of donor
building block. The activating reagents are tuned to the intrinsic
reactivity of the acceptor alcohol to match the reactivity of the
glycosylating agent with the reactivity of the incoming nucleophile.
A protecting group strategy is introduced that is based on the sole
use of benzyl-ether type protecting groups to circumvent changes in
reactivity as a result of the protecting groups. For the stereoselective
construction of the Ī±-glucosyl linkages to a secondary alcohol,
a per-benzylated glusosyl imidate donor is activated with a combination
of trimethylsilyltriflate and DMF, while activation of the same imidate
donor with trimethylsilyl iodide in the presence of triphenylphosphine
oxide allows for the stereoselective <i>cis</i>-glucosylation
of primary alcohols. The effectiveness of the strategy is illustrated
in the modular synthesis of a <i>Mycobacterium tuberculosis</i> nonasaccharide, composed of an Ī±-(1ā4)-oligoglucose
backbone bearing different Ī±-glucosyl branches
Reagent Controlled Stereoselective Synthesis of Ī±āGlucans
The development of a general glycosylation
method that allows for
the stereoselective construction of glycosidic linkages is a tremendous
challenge. Because of the differences in steric and electronic properties
of the building blocks used, the outcome of a glycosylation reaction
can vary greatly when switching form one glycosyl donorāacceptor
pair to another. We here report a strategy to install <i>cis</i>-glucosidic linkages in a fully stereoselective fashion that is under
direct control of the reagents used to activate a single type of donor
building block. The activating reagents are tuned to the intrinsic
reactivity of the acceptor alcohol to match the reactivity of the
glycosylating agent with the reactivity of the incoming nucleophile.
A protecting group strategy is introduced that is based on the sole
use of benzyl-ether type protecting groups to circumvent changes in
reactivity as a result of the protecting groups. For the stereoselective
construction of the Ī±-glucosyl linkages to a secondary alcohol,
a per-benzylated glusosyl imidate donor is activated with a combination
of trimethylsilyltriflate and DMF, while activation of the same imidate
donor with trimethylsilyl iodide in the presence of triphenylphosphine
oxide allows for the stereoselective <i>cis</i>-glucosylation
of primary alcohols. The effectiveness of the strategy is illustrated
in the modular synthesis of a <i>Mycobacterium tuberculosis</i> nonasaccharide, composed of an Ī±-(1ā4)-oligoglucose
backbone bearing different Ī±-glucosyl branches
Stereoselectivity of Conformationally Restricted Glucosazide Donors
Glycosylations of 4,6-tethered glucosazide
donors with a panel
of model acceptors revealed the effect of acceptor nucleophilicity
on the stereoselectivity of these donors. The differences in reactivity
among the donors were evaluated in competitive glycosylation reactions,
and their relative reactivities were found to be reflected in the
stereoselectivity in glycosylations with a set of fluorinated alcohols
as well as carbohydrate acceptors. We found that the 2-azido-2-deoxy
moiety is more Ī²-directing than its C-2-<i>O</i>-benzyl
counterpart, as a consequence of increased destabilization of anomeric
charge development by the electron-withdrawing azide. Additional disarming
groups further decreased the Ī±-selectivity of the studied donors,
whereas substitution of the 4,6-benzylidene acetal with a 4,6-di-<i>tert</i>-butyl silylidene led to a slight increase in Ī±-selectivity.
The C-2-dinitropyridone group was also explored as an alternative
for the nonparticipating azide group, but this protecting group significantly
increased Ī²-selectivity. All studied donors exhibited the same
acceptor-dependent selectivity trend, and good Ī±-selectivity
could be obtained with the weakest acceptors and most reactive donors
Mapping the Reactivity and Selectivity of 2āAzidofucosyl Donors for the Assembly of <i>N</i>āAcetylfucosamine-Containing Bacterial Oligosaccharides
The synthesis of complex oligosaccharides
is often hindered by
a lack of knowledge on the reactivity and selectivity of their constituent
building blocks. We investigated the reactivity and selectivity of
2-azidofucosyl (FucN<sub>3</sub>) donors, valuable synthons in the
synthesis of 2-acetamido-2-deoxyfucose (FucNAc) containing oligosaccharides.
Six FucN<sub>3</sub> donors, bearing benzyl, benzoyl, or <i>tert</i>-butyldimethylsilyl protecting groups at the C3-<i>O</i> and C4-<i>O</i> positions, were synthesized, and their
reactivity was assessed in a series of glycosylations using acceptors
of varying nucleophilicity and size. It was found that more reactive
nucleophiles and electron-withdrawing benzoyl groups on the donor
favor the formation of Ī²-glycosides, while poorly reactive nucleophiles
and electron-donating protecting groups on the donor favor Ī±-glycosidic
bond formation. Low-temperature NMR activation studies of Bn- and
Bz-protected donors revealed the formation of covalent FucN<sub>3</sub> triflates and oxosulfonium triflates. From these results, a mechanistic
explanation is offered in which more reactive acceptors preferentially
react via an S<sub>N</sub>2-like pathway, while less reactive acceptors
react via an S<sub>N</sub>1-like pathway. The knowledge obtained in
this reactivity study was then applied in the construction of Ī±-FucN<sub>3</sub> linkages relevant to bacterial saccharides. Finally, a modular
synthesis of the <i>Staphylococcus aureus</i> type 5 capsular
polysaccharide repeating unit, a trisaccharide consisting of two FucNAc
units, is described
Influence of O6 in Mannosylations Using Benzylidene Protected Donors: Stereoelectronic or Conformational Effects?
The stereoselective synthesis of Ī²-mannosides and
the underlying
reaction mechanism have been thoroughly studied, and especially the
benzylidene-protected mannosides have gained a lot of attention since
the corresponding mannosyl triflates often give excellent selectivity.
The hypothesis for the enhanced stereoselectivity has been that the
benzylidene locks the molecule in a less reactive conformation with
the O6 trans to the ring oxygen (O5), which would stabilize the formed
Ī±-triflate and subsequent give Ī²-selectivity. In this
work, the hypothesis is challenged by using the carbon analogue (C7)
of the benzylidene-protected mannosyl donor, which is investigated
in terms of diastereoselectivity and reactivity and by low-temperature
NMR. In terms of diastereoselectivity, the C-7-analogue behaves similarly
to the benzylidene-protected donor, but its low-temperature NMR reveals
the formation of several reactive intermediate. One of the intermediates
was found to be the Ī²-oxosulfonium ion. The reactivity of the
donor was found to be in between that of the ātorsionalā
disarmed and an armed donor
Cyanopivaloyl Ester in the Automated Solid-Phase Synthesis of Oligorhamnans
The development of
effective protecting group chemistry is an important
driving force behind the progress in the synthesis of complex oligosaccharides.
Automated solid-phase synthesis is an attractive technique for the
rapid assembly of oligosaccharides, built up of repetitive elements.
The fact that (harsh) reagents are used in excess in multiple reaction
cycles makes this technique extra demanding on the protecting groups
used. Here, the synthesis of a set of oligorhamnan fragments is reported
using the cyanopivaloyl (PivCN) ester to ensure effective neighboring
group participation during the glycosylation events. The PivCN group
combines the favorable characteristics of the parent pivaloyl (Piv)
ester, stability, minimal migratory aptitude, minimal orthoester formation,
while it can be cleaved under mild conditions. We show that the remote
CN group in the PivCN renders the PivCN carbonyl more electropositive
and thus susceptible to nucleophilic cleavage. This feature is built
upon in the automated solid-phase assembly of the oligorhamnan fragments.
Where the use of a Piv-protected building block failed because of
incomplete cleavage, PivCN-protected synthons performed well and allowed
the generation of oligorhamnans, up to 16 monosaccharides in length
Chiral Pyrroline-Based Ugi-Three-Component Reactions Are under Kinetic Control
Although it is often assumed that the stereochemistry in Ugi multicomponent reactions is determined in the final Mumm rearrangement step, experimental and computational evidence that Ugi reactions on hydroxylated pyrrolines proceed under kinetic control is reported. The stereochemistry of the reaction is established with the addition of the isocyanide to the intermediate iminium ion, whose conformation is determined by its substitution pattern
Exploring and Exploiting the Reactivity of Glucuronic Acid Donors
The relative reactivity of glucuronic acid esters was
established
in a series of competition experiments, in which two thioglucoside
and/or thioglucuronic acid ester donors competed for a limited amount
of activator (NIS-TfOH). Although glucuronic acid esters are often
considered to be of very low reactivity, the series of competition
reactions revealed that the reactivity of the glucuronic acid esters
studied is sufficient to provide productive glycosylation reactions.
The latter is illustrated in the synthesis of two <i>Streptococcus
pneumoniae</i> trisaccharides, in which the applicability of
the two similarly protected frame-shifted thiodisaccharide donors,
Glc-GlcA and GlcA-Glc, were compared. The Glc-GlcA disaccharide, featuring
the glucuronic acid donor moiety, proved to be the most productive
in the assembly of a protected <i>S. pneumoniae</i> trisaccharide
Automated Solid-Phase Synthesis of Hyaluronan Oligosaccharides
Well-defined fragments of hyaluronic acid (HA) have been obtained through a fully automated solid-phase oligosaccharide synthesis. Disaccharide building blocks, featuring a disarmed glucuronic acid donor moiety and a di-<i>tert</i>-butylsilylidene-protected glucosamine part, were used in the rapid and efficient assembly of HA fragments up to the pentadecamer level, equipped with a conjugation-ready anomeric allyl function