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Au(I)착물은 파이결합에 대한 높은 루이스산성을 가지며, 온화한 조건에서 다양한 C-C, C-X결합 형성을 유도한다. COSLab은 금촉매 반응의 난제로 남아있는 분자간 반응, 다중촉매(multi-modal)반응, 비대칭 반응 등의 분야에서 독창적인 반응설계와 리간드 설계를 통해 기여하고 있다.
N-O Bond Redox via Gold Catalysis
Angew. Chem. Int. Ed. 2008, 47, 7040; Angew. Chem. Int. Ed. 2010, 49, 1611; Acc. Chem. Res. 2014, 47, 966.
Traditional oxidation commonly involves reagents having toxic metals (Cr, Mn, & Os) or stoichiometric waste. Towards green oxidation, we initiated N-O bond redox chemistry catalyzed by gold(I) complex. In general, reagents having N-O bonds (~55 kcal/mol) is much less reactive than peroxy reagents (O-O, 36 kcal/mol), and thus are difficult to activate. Here alkyne-activating power of Au-catalysis may be exploited.
We have chosen nitrones as N-O reagents and employed them as nucleophiles attacking Au-activated alkyne. This results in OAT (O-atom transfer), forming gold carbene intermediates. We designed reactions that use the 'gold carbene' to form an azomethine ylide dipole for [3+2] cycloaddition (ACIE, 2008), and to initiate a the pinacol-type 1,2-shift to transform it into a Au-enolate for Mannich reaction (ACIE, 2010). Succeeding developments are summarized in our perspective (ACR, 2014).
[4+2] Cycloaddition and Enyne Metathesis
J. Am. Chem. Soc. 2012, 134, 208.
Olefin metathesis with a controlled Z stereochemistry has been challenging, because of the reversible mechanism of Ru-based metathesis. Au-catalyst may engender a related metathesis between alkenes and alkynes, and in this case, we discovered a stereospecific metathesis reaction. We obtained (E,Z)- or (E,E)-1,3-dienes, respectively, starting from Z- and E-olefins, which is due to the diotropic mechanism of Au-catalyzed enyne metathesis. On the other hand, a more polarized olefin leads to [4+2] cycloaddition, furnishing α,β-unsaturated-δ-lactones that are core structures of anti-cancer agents, such as fostriecin and leustroducin.
Enantioselective [4+2] Cycloaddition and thioallylation
Angew. Chem. Int. Ed. 2018, 57, 13130; J. Am. Chem. Soc. 2020, 143, 20788.
Due to the coordination geometry of Au(I)-complexes, development of enantioselective Au(I)-catalysis has been a challenging goal. Chiral ligands are positioned opposite (180 o) to the active site where addition to alkyne occurs. Yet, the first asymmetric gold catalysis came out from Echavarren's group on asymmetric [2+2] cycloaddition in 2017.
In 2018, we reported our own study on the enantioselective [4+2] cycloaddition, leading to optically active α,β-unsaturated-δ-lactones in up to 85% ee. We found that addition of surfactants (SDS) enhance the chemoselectivity between [4+2] cycloaddition and metathesis, and interpreted this observation as an example of entropy control.
We continued to come up with an enantioselective version of our Au-catalyzed alkoxyallylation (OL, 2013). We noted that alkoxyallylation results in a low yield and %ee, due to a premature dissociation of the allyl groups in the TS of Claisen rearrangement. Converting allylethers into allylthioethers was a huge success, leading to a highly enantioselective up to 99% ee. The thioallylation has remarkablely diverse scope of allyl groups, and products with a quaternary center can be obtained in high yield and %ee. The thioethers can be used to our advantage in the subsequent cross-coupling chemistry.
Enantioselective CPA Catalysis: 1) N,O-Acetal Formation, 2) Allenamide Activation
Org. Lett. 2019, 21, 9009; Adv. Synth. Catal. 2020, 362, 1841
In 2003, Akiyama and Terada discovered organocatalytic asymmetric Mannich reaction, employing chiral phosphoric acids (CPAs) that can activate imines. Since then, CPA-mediated Brønsted acid catalysis has become a mainstay of organocatalysis.
We have discovered that ynamides can be oxidized by mCPBA into N,O-acetals. We noted that they may be used as precursors to catioinic N-imminium salts and developed unprecedented CPA-catalyzed trans-acetalization. Allenamides can be activated by gold-complex or CPA to form an iminium salts, leading to various cationic cyclization. We developed an enantioselective route to indolo[2,3-b]quinolines by CPA-catalyzed cyclization of homotryptamine derivatives.
Enantioselective Umpolung Alkylation
In 2017, we have developed an umpolung alkylation leading to α-indolyl carbonyl compounds. We continued to develop an enantioselective version of this reaction. Ynamides can be activated by Brønsted acid (HNTf2) to induce the addition of pyridine-N-oxides. Subsequent SN2’ reaction may occur in an enantioselective fashion when an axially chiral N,N'-dioxides were used. This process can be employed to prepare α-indolyl sulfonimides, UK-350,926 in an optically active form. We recently developed a related alkylation in the preparation of α-azidocarbonyl compounds, which will be reported in due course.
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