Diastereoselective synthesis of 3,3-disubstituted oxindoles from atropisomeric N-aryl oxindole derivatives

Diastereoselective synthesis of 3,3-disubstituted oxindoles has been examined by transformations involving nucleophilic addition, alkylation, and cycloaddition using chiral racemic N-aryl oxindoles bearing C–N axial chirality. The most striking features of this approach are high diastereoselectivities (up to >95:<5) when using ortho-monosubstituted N-aryl oxindoles and easy removal of the p-(benzyloxy)aryl moiety in the axially twisted amides by a mild two-step sequence.     

Asymmetric construction of quaternary stereocenters by direct conjugate addition of oxindoles to enone

Chiral cinchona-based primary amine A was found to catalyze the asymmetric direct conjugate addition of prochiral 3-oxindoles with enones to afford 3,3-disubstituted oxindoles in good yields, moderate to high diastereoselectivities, and excellent enantioselectivities.     

Molybdenum-catalyzed asymmetric allylation of 3-alkyloxindoles: application to the formal total synthesis of (-)-physostigmine

The first example of Mo-catalyzed asymmetric allylation for the generation of quaternary stereocenters at a prochiral nucleophile is reported. A variety of 3-alkyl oxindoles can be alkylated with high yields and enantioselectivity. This method provides expedited access to (-)-physostigmine and its analogues.     

Stereoselective oxidative rearrangement of 2-aryl tryptamine derivatives

The oxidation of 2-aryl tryptamines followed by a stereoselective rearrangement provides a versatile strategy for the synthesis of C3-quaternary oxindoles bearing a C3-aryl group. Treatment of optically active 2-aryl hydroxyindolenines with scandium trifluoromethanesulfonate in toluene at 110 degrees C leads to complete and stereoselective isomerization to the corresponding C3-aryl oxindoles which represent versatile intermediates for the synthesis of C3a-aryl hexahydropyrroloindoles.     

Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita-Baylis-Hillman carbonates

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.     

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.     

高分子支载的金鸡纳生物碱催化剂在不对称催化反应中的应用进展

综述了近年来高分子支载的金鸡纳生物碱催化剂在不对称双羟基化反应、不对称Michael加成反应、活性亚胺的不对称烷基化反应以及潜手性酮的不对称还原反应中的应用及最新进展。     

Cross-dehydrogenative coupling of secondary benzylic ethers with indoles and pyrroles

Current studies on cross-dehydrogenative coupling of benzylic ethers for new C–C bond construction predominantly focus on primary ether moieties. Oxidative cross-coupling of secondary benzylic ethers remains elusive. Herein, we describe the first cross-dehydrogenative coupling of secondary benzylic ethers with indoles and pyrroles for tertiary ether construction. A broad range of α-aryl substituted isochromans react with a variety of electronically varied indoles and pyrroles smoothly under mild metal-free conditions in high efficiency. In addition, the catalytic asymmetric variant was preliminarily explored, and corresponding tertiary ether was obtained in 69% ee.     

Organocatalytic Friedel–Crafts Alkylation/Lactonization Reaction of Naphthols with 3‐Trifluoroethylidene Oxindoles: The Asymmetric Synthesis of Dihydrocoumarins

Naphthols and 3‐trifluoroethylidene oxindoles were found to undergo an asymmetric Friedel–Crafts alkylation/lactonization reaction, catalyzed by only 2.5 mol % of a quinine‐derived squaramide catalyst, to afford the corresponding α‐aryl‐β‐trifluoromethyl dihydrocoumarin derivatives in high yields (up to 99 %) with excellent enantio‐ and diastereoselectivities (up to 98 % ee , >20:1 d.r.). Importantly, the lactonization proceeded by nucleophilic attack of the naphthol hydroxy group at the amide motif of the oxindoles under mild reaction conditions. This protocol represents a new strategy for the formation of dihydrocoumarins by an efficient intramolecular amide C−N bond‐cleavage and esterification process.     

Synthesis of new N-aryl oxindoles as intermediates for pharmacologically active compounds

Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active 2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles.     

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr＞95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.     

Remote Construction of Chiral Vicinal Tertiary and Quaternary Centers by Catalytic Asymmetric 1,6‐Conjugate Addition of Prochiral Carbon Nucleophiles to Cyclic Dienones

An unprecedented remote construction of chiral vicinal tertiary and quaternary centers by a catalytic asymmetric 1,6‐conjugate addition of prochiral carbon nucleophiles to cyclic dienones has been developed. Both 5H‐oxazol‐4‐ones and 2‐oxindoles were found to be very efficient carbon nucleophiles in this reaction at a remote position, giving products with excellent enantio‐ and diastereoselectivities (up to 99 % ee and >19:1 d.r. for 5H‐oxazol‐4‐ones and up to 97 % ee and >19:1 d.r. for 2‐oxindoles).     

New chiral diamino-bis(tert-thiophene): an effective ligand for Pd- and Zn-catalyzed asymmetric transformations

Enantiomerically pure diamino-bis(tert-thiophene) proved to be a valuable and flexible chiral ligand for Pd- and Zn-catalyzed transformations, allowing for high levels of stereocontrol in asymmetric allylic alkylation (ee up to 99%) and hydrosilylations of prochiral carbonyls (ee up to 97%).     

应用手性高分子试剂和催化剂的不对称有机合成反应

不对称有机合成是有机化学的前沿课题之一.本文综述了应用手性高分子试剂和催化剂对潜手性化合物通过不对称氧化、还原、烷基化、加成反应进行不对称合成的进展情况.     

Palladium‐Catalyzed Asymmetric Benzylic Alkylation of Active Methylene Compounds with α‐Naphthylbenzyl Carbonates and Pivalates

A Pd/(R)‐H₈‐BINAP‐catalyzed asymmetric benzylic alkylation of active methylene compounds has been developed. The reaction proceeds without the use of an external base, and the starting racemic diarylmethyl carbonates are converted into the optically active coupling products which contain the benzylic chiral stereocenter by a dynamic kinetic asymmetric transformation (DYKAT). Additionally, with suitable carbonates bases, the same palladium catalysis allows the corresponding pivalates to be adopted in the same DYKAT process.     

Highly enantioselective Friedel-Crafts alkylation of indole and pyrrole with β,γ-unsaturated α-ketoester catalyzed by chiral dicationic palladium complex

The chiral dicationic Pd complexes, bearing sterically demanding diphosphine ligands as Lewis acid catalysts, are shown to catalyze the asymmetric Friedel-Crafts (F-C) alkylations of indoles and pyrroles with β,γ-unsaturated α-ketoesters, to provide the F-C alkylation products with benzylic stereocenters in high yields and enantioselectivities. The reactive chelated structure, formed by the chiral dicationic Pd complex and the electrophile, would be important to gain a high level of asymmetric induction in the F-C alkylation. The F-C products can be readily functionalized to give α-hydroxy esters via catalytic asymmetric ene sequences.     

Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a.     

Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3‐Fluorinated and All‐Carbon Quaternary Oxindoles

Synthetically versatile 3,3‐disubstituted fluorooxindoles exhibiting vicinal chirality centers were obtained in high yields and with excellent enantio‐, diastereo‐, and regioselectivity through catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be scaled up without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted by the incorporation of additional functionalities and the formation of 3‐fluorinated oxindoles exhibiting an array of four adjacent centers of chirality. A new C−F bond functionalization path that provides unprecedented possibilities for the stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced.     

Palladium‐Catalyzed Asymmetric Benzylation of Azlactones

Asymmetric benzylation of prochiral azlactone nucleophiles enables the catalytic introduction of a benzyl group towards the synthesis of α,α‐disubstituted amino acids. Herein, we report an enantioselective palladium‐catalyzed process using chiral bis(diphenylphosphinobenzoyl)diamine (dppba) ligands. Naphthalene‐ and heterocycle‐based methyl carbonates react with a number of azlactones derived from both natural and unnatural amino acids. Monocyclic benzylic electrophiles, for which the barrier to ionization is higher, must employ a phosphate leaving group in order to react. Reaction conditions for electron‐rich and ‐neutral benzylic electrophiles have been developed, and the scope of the reaction has been explored with respect to both reaction partners. The high levels of asymmetric induction, as well as the reactivity pattern of the electrophiles, suggest an η³‐benzyl intermediate that arises through two distinct pathways.     

Catalytic enantioselective allylation at the activated benzylic position of prochiral aryl cyano esters: access to quaternary stereogenic centers

Palladium catalyzed asymmetric allylic alkylation of prochiral aryl cyano esters has been carried out in the presence of various chiral ligands. The base and additives have been varied and allowed to produce the allyl derivative presenting a highly functionalized quaternary stereogenic center. The chiral pocket ligands of Trost appears the most appropriate to produce the desired chiral derivative.