(529f) Stereoconvergent Tandem Systems Combining Photocatalyzed Isomerization and Enzymatic Reduction for Chiral Building Blocks Synthesis

Zhao, H., University of Illinois at Urbana-Champaign
Hartwig, J. F., University of California, Berkeley


increasing demand for chiral building blocks, especially those used for the
preparation of biologically active compounds, has motivated the development of
novel strategies for enantioselective synthesis. Particularly, there is a
growing interest in the development of one-pot tandem catalytic systems
combining the reactivity of a chemical catalyst with the selectivity engendered
by an enzyme. Such tandem systems can achieve levels of chemo-, regio- and
stereo-selectivity that are unattainable with a small molecule catalyst. Here,
we report the development of a conceptually distinct cooperative chemoenzymatic
system by coupling a photosensitizer-catalyzed alkene isomerization in tandem
with an enantioselective ene-reductase that selectively reduces one of the isomers
for the synthesis of various chiral building blocks of drugs and biologically
active compounds. With this system, we can stereoconvergently reduce the isomer
mixtures of 2-substitued 1,4-dicarbonyl alkenes, cyano-substituted acrylate
esters or ketones, cyano- or ester-substituted acrylamides to corresponding
enantiopure reduced products at high yield (>80%) and excellent enantiomeric
excess (>95%). These products can be used to easily synthesize ɣ-butyrolactones,
ɣ-lactams, β-amino acids, ɣ-amino acids,
amines and diamines, a structural motif found in many bioactive compounds, such
as Phenibut and Baclofen. Importantly, this is the first example of
combining photoisomerization with enzymes for enantiopure product synthesis
rather than photocatalyst-directed co-factor regeneration in an oxidoreduction
reaction. In addition, we show for the first time, that flavin mononucleotide
(FMN) can catalyzes two different reactions, alkene isomerization and hydride
transfer, in a single system, making our tandem reaction potentially metal-free. 
We anticipate our system to be a starting point for more synthetic applications
when coupled with different enzymes.