2 research outputs found
Monoamine Oxidase (MAO-N) Catalyzed Deracemization of Tetrahydro-β-carbolines: Substrate Dependent Switch in Enantioselectivity
The tetrahydro-β-carboline
(THBC) ring system is an important
structural motif found in a large number of bioactive alkaloid natural
products. Herein we report a broadly applicable method for the synthesis
of enantiomerically pure β-carbolines via a deracemization procedure
employing the D9 and D11 variants of monoamine oxidase from <i>Aspergillus niger</i> (MAO-N) in combination with a nonselective
chemical reducing agent. Biotransformations were performed on a preparative
scale, leading to the synthesis of optically enriched products in
excellent enantiomeric excess (e.e.; up to 99%) and isolated yield
(up to 93%). Interestingly, a switch in enantioselectivity associated
with the MAO-N variants is observed as the nature of the C-1 substituent
of the THBC is varied. Molecular modeling provided an explanation
for this observation and highlighted key active site residues which
were modified, resulting in an increase in (<i>R</i>)-selectivity
associated with the enzyme. These results provide insight into the
factors which influence the selectivity of the MAO-N variants, and
may offer a platform for future directed evolution projects aimed
toward the challenge of engineering (<i>R</i>)-selective
amine oxidase biocatalysts
Chemoenzymatic Synthesis of <i>O</i>-Mannosylpeptides in Solution and on Solid Phase
<i>O</i>-Mannosyl glycans are known to play
an important
role in regulating the function of α-dystroglycan (α-DG),
as defective glycosylation is associated with various phenotypes of
congenital muscular dystrophy. Despite the well-established biological
significance of these glycans, questions regarding their precise molecular
function remain unanswered. Further biological investigation will
require synthetic methods for the generation of pure samples of homogeneous
glycopeptides with diverse sequences. Here we describe the first total
syntheses of glycopeptides containing the tetrasaccharide NeuNAcα2-3Galβ1-4GlcNAcβ1-2Manα,
which is reported to be the most abundant <i>O</i>-mannosyl
glycan on α-DG. Our approach is based on biomimetic stepwise
assembly from the reducing end and also gives access to the naturally
occurring mono-, di-, and trisaccharide substructures. In addition
to the total synthesis, we have developed a “one-pot”
enzymatic cascade leading to the rapid synthesis of the target tetrasaccharide.
Finally, solid-phase synthesis of the desired glycopeptides directly
on a gold microarray platform is described