Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers

Enzymes
are Nature’s polyfunctional catalysts tailor-made
for specific biochemical synthetic transformations, which often proceed
with almost perfect stereocontrol. From a synthetic point of view,
artificial catalysts usually offer the advantage of much broader substrate
scopes, but stereocontrol is often inferior to that possible with
natural enzymes. A particularly difficult synthetic task in asymmetric
catalysis is to overwrite a pronounced preference for the formation
of an inherently favored diastereomer; this requires a high level
of stereocontrol. In this Article, the development of a novel artificial
polyfunctional catalyst type is described, in which an imidazolium–aryloxide
betaine moiety cooperates with a Lewis acidic metal center (here Cu­(II))
within a chiral catalyst framework. This strategy permits for the
first time a general, highly enantio­selective access to the
otherwise rare diastereomer in the direct 1,4-addition of various
1,3-dicarbonyl substrates to β-substituted nitro­olefins.
The unique stereocontrol by the polyfunctional catalyst system is
also demonstrated with the highly stereo­selective formation
of a third contiguous stereocenter making use of a diastereo­selective
nitronate protonation employing α,β-disubstituted nitro­olefin
substrates. Asymmetric 1,4-additions of β-ketoesters to α,β-disubstituted
nitro­olefins have never been reported before in literature.
Combined mechanistic investigations including detailed spectroscopic
and density functional theory (DFT) studies suggest that the aryloxide
acts as a base to form a Cu­(II)-bound enolate, whereas the nitro­olefin
is activated by H-bonds to the imidazolium unit and the phenolic OH
generated during the proton transfer. Detailed kinetic analyses (RPKA,
VTNA) suggest that (a) the catalyst is stable during the catalytic
reaction, (b) not inhibited by product and (c) the rate-limiting step
is most likely the C–C bond formation in agreement with the
DFT calculations of the catalytic cycle. The robust catalyst is readily
synthesized and recyclable and could also be applied to a cascade
cyclization.

酶（Enzymes）是自然界中为特定生化合成转化量身打造的多官能催化剂（polyfunctional catalysts），此类转化通常能以近乎完美的立体调控（stereocontrol）进行。从合成化学的视角来看，人工催化剂通常具备底物范围更广的优势，但其立体调控能力往往不及天然酶。不对称催化领域中一项极具挑战性的合成任务，是逆转底物对生成固有优势非对映异构体（diastereomer）的强烈偏好，这需要极高水平的立体调控能力。本文报道了一种新型人工多官能催化剂体系：在手性催化剂框架内，咪唑鎓-芳氧化物甜菜碱（imidazolium–aryloxide betaine）结构单元与路易斯酸性金属中心（此处为Cu(II)）协同发挥作用。该策略首次实现了通用且高对映选择性地获取各类1,3-二羰基底物与β-取代硝基烯烃直接发生1,4-加成反应时原本难以得到的罕见非对映异构体。通过使用α,β-二取代硝基烯烃底物进行非对映选择性硝基质子化反应，高立体选择性构建第三个连续手性中心，进一步验证了该多官能催化剂体系独特的立体调控能力。此前文献中从未报道过β-酮酸酯与α,β-二取代硝基烯烃的不对称1,4-加成反应。联合机理研究涵盖详细的光谱学分析与密度泛函理论（DFT）计算，结果表明芳氧化物作为碱，可形成与Cu(II)结合的烯醇负离子；而硝基烯烃则通过与咪唑鎓单元以及质子转移过程中生成的酚羟基形成氢键而被活化。详细的动力学分析（速率进度动力学分析RPKA、变温动力学分析VTNA）显示：其一，催化剂在催化反应过程中保持稳定；其二，不受产物抑制；其三，限速步骤极有可能为C-C键形成，这与催化循环的DFT计算结果相符。该稳定性优异的催化剂易于合成且可回收利用，还可应用于级联环化反应。