Zhiyong Jiang

Synthesis of a Chiral Quaternary Carbon Center Bearing a Fluorine Atom: Enantio‐ and Diastereoselective Guanidine‐Catalyzed Addition of Fluorocarbon Nucleophiles

The perfect combination: The title reaction provides adducts having quaternary carbon centers bearing a fluorine atom with high ee and d.r. values (see scheme). The mechanism and origin of stereoselectivity were elucidated by DFT calculations. The bifunctional mode of the guanidine catalysis was demonstrated in the transition states resulting from the DFT results.

Highly enantio- and diastereoselective reactions of γ-substituted butenolides through direct vinylogous conjugate additions

The g,g-disubstituted butenolide unit, which bears a quaternary stereogenic center, has been recognized as a crucial fragment in a number of natural products and medicinally important agents. The stereocontrolled synthesis of g,gdisubstituted butenolide derivatives has thus been the subject of enormous interest in the past few decades. Protocols for asymmetric synthesis focused on utilizing Mukaiyama-type additions, which were limited to preformed silyloxyfurans. With regard to atom economy and efficiency, natural nonactivated g-substituted butenolides gained attention because of their potential in the direct construction of g,g-disubstituted butenolides. The first breakthrough was reported by Chen and co-workers, who developed a highly enantioand diastereoselective allylic alkylation of Morita-Baylis–Hillman carbonates with g-aryl-substituted butenolides using (DHQD)2PYR as the Lewis base catalyst. [4] Subsequently, Alexakis and co-workers described the addition of g-alkylsubstituted butenolides (a-angelica lactone) to enals using aminal–pyrrolidine (APY) as catalyst. In both reactions, stereoselectivity was achieved through the formation of a covalent intermediate and/or transition state of the catalyst and the substrate. Recently, Feng and co-workers presented the first Lewis acid catalyzed asymmetric vinylogous Mannich-type reaction of aldimines with g-alkyl-substituted butenolides. It is worth noting that reports on the use of hydrogen-bonding catalysis to afford g,g-disubstituted butenolides are rare, and reactions involving g-aryland alkylsubstituted butenolides as nucleophiles have not yet been reported. Therefore, it is highly desirable to develop an efficient catalyst to allow easy access to diverse g,g-disubstituted butenolides from both g-aryland alkyl-substituted butenolides. Amides with a-stereogenic centers are useful building blocks for the synthesis of biologically active compounds. Our groups have recently disclosed a wide range of asymmetric organocatalytic conjugate addition reactions that employ (E)-4-oxo-4-arylbutenamides as electrophiles. In particular, the 2-oxazolidinone amide moiety allows the substrate to positively interact with bifunctional catalysts, such as C2-symmetric bicyclic guanidine [11a,b, 12] and Cinchona alkaloid thiourea, 11c] thus often resulting in much improved reactivity and stereoselectivity. Therefore we rationalized that direct vinylogous Michael addition of g-substituted butenolides to (E)-4-oxo-4-arylbutenamides can be achieved with bifunctional catalysts. We selected the addition of g-phenyl-substituted butenolide 1a to (E)-4-oxo-4-phenylbutenamide 2a as the model reaction, and examined various bifunctional catalysts (Figure 1, Table 1). First, in the presence of C2-symmetric bicyclic guanidine A (5 mol %), the reaction was completed in four hours, affording adduct 3a in good yield, but poor enantioselectivity (19% ee ; Table 1, entry 1). Subsequently, we screened chiral pyrrolidinyl sulfonamide (CPS) catalysts B and C (Table 1, entries 2 and 3), which were previously studied in our group to promote tandem conjugate addition– elimination reactions. Product 3 a was obtained with promising 49% ee (entry 2), thus indicating that an l-amino acid is the preferred framework for a catalyst. In an attempt to improve the catalyst, we replaced the sulfonamide group with thiourea and prepared a series of amine–thiourea catalysts (D–H). We anticipated an improvement to the enantioselectivity through additional H-bond interactions. The survey

Expanding the Utility of Brønsted Base Catalysis: Biomimetic Enantioselective Decarboxylative Reactions

As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond-formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations.

Highly Enantio‐ and Diastereoselective Synthesis of β‐Methyl‐γ‐monofluoromethyl‐Substituted Alcohols

Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.

Controllable Chemoselectivity in Visible-Light Photoredox Catalysis: Four Diverse Aerobic Radical Cascade Reactions†

Reported is the controllable selectivity syntheses of four distinct products from the same starting materials by visible-light photoredox catalysis. By employing a dicyanopyrazine-derived chromophore (DPZ) as photoredox catalyst, an aerobic radical mechanism has been developed, and allows the reactions of N-tetrahydroisoquinolines (THIQs) with N-itaconimides to through four different pathways, including addition-cyclization, addition-elimination, addition-coupling, and addition-protonation, with satisfactory chemoselectivity. The current strategy provide straightforward access to four different but valuable N-heterocyclic adducts in moderate to excellent yields.

Organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins.

The first organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins has been developed. In the presence of easily prepared L-tert-leucine-derived tertiary amine/thiourea catalyst, the Michael addition of 5H-oxazol-4-ones to nitroolefins proceeded in an excellent diastereo- and enantioselective manner (up to 99% ee and >19:1 dr). The Michael adducts obtained are valuable precursors for the synthesis of chiral α-alkyl-α-hydroxy carboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds.

Highly Enantioselective Organocatalytic Sulfenylation of 3-Aryloxindoles

An organocatalytic asymmetric sulfenylation of 3-aryloxindoles with N-(sulfanyl)succinimides has been developed by using commercially available (DHQD)(2)PHAL as catalyst. Various chiral 3-benzylthio-, alkylthio-, and arylthio-substituted oxindoles, containing 3,3-disubstituted quarternary carbon stereocenters, could be obtained in high enantioselectivities (85-97% ee). Furthermore, the opposite enantiomers of the sulfenylated products were readily accessible with equal excellent enantioselectivities (86-95% ee) by replacing the catalyst with (DHQ)(2)PHAL.

Fluorinated Aromatic Ketones as Nucleophiles in the Asymmetric Organocatalytic Formation of CC and CN Bonds: A Facile Route to the Construction of Fluorinated Quaternary Stereogenic Centers.

The development of a broadly useful platform for the organocatalytic nucleophilic addition of carbonyl compounds represents a major research field in asymmetric catalysis. Recent research efforts have mainly focused on dicarbonyl compounds such as b-ketoesters and b-ketosulfones, which are easily activated and widely used in many conjugated addition reactions. Most of the aliphatic ketones and acetophenone nucleophiles used in organocatalytic asymmetric transformations rely on the formation of highly reactive enamine intermediates. On the other hand, Brønsted bases are seldom used as catalysts in reactions of simple carbonyls because of to the rather low basicity of most organobases, and thus their inability to activate the carbonyl group through enolization. Successful strategies are those that try to increase the acidity of the a-proton. For example, activated esters, such as trifluoroethyl thioesters, acyanothioacetates, a-substituted cyanoacetates, and anitroacetates, are valuable nucleophiles for organic basecatalyzed reactions because of their enhanced acidity. In contrast, fused cyclic aromatic ketones are still challenging substrates to activate as a result of the difficulty in forming the enamine intermediate and their poor reactivity. To our knowledge, the use of activated aromatic ketones as nucleophiles for Brønsted base-catalyzed reactions is restricted to several reports which focused on a-cyano ketones. Organofluorine compounds are important in medicinal and bioorganic chemistry. Enantiopure compounds containing a fluorine atom directly connected to a quaternary carbon center are nontrivial to prepare. The most common approach thus far is to generate such compounds through an enantioselective fluorination of tertiary carbon nucleophiles using chiral transition-metal complexes or organocatalysts. The less explored route is the asymmetric formation of C C bonds by using fluorocarbon nucleophiles. Recently, a-fluoro-b-ketoesters have been employed as fluorocarbon nucleophiles in organocatalytic processes, asymmetric Michael, amination, and Mannich reactions. The asymmetric alkylation of a-fluoro-b-ketoACHTUNGTRENNUNGesters under phase-transfer conditions, and asymmetric Robinson annulations have been carried out using fluorocarbon nucleophiles. Other fluorocarbon nucleophiles such as 1-fluoro-bis(phenylsulfonyl)methane (FBSM) and 1fluoro-1-nitro(phenylsulfonyl)methane (FNSM) were also developed. We have also shown that the a-fluoro-b-ketoACHTUNGTRENNUNGester and the a-fluoro-b-keto ACHTUNGTRENNUNGacyloxazolidinone underwent guanidine-catalyzed enantioselective Michael and Mannich reactions, which resulted in high enantioselectivities. The use of simple a-fluorinated aromatic ketones as nucleophiles has been less studied. However, there were two independent reports on the use of phase-transfer catalysts for asymmetric alkylation reactions of a-fluorotetralone that resulted in unsatisfactory enantioselectivities and yields. Herein, we present the highly enantioselective formation of C N and C C bonds using a-fluorinated aromatic ketones as nucleophiles. Our initial efforts focused on the aamination reaction of a-fluorinated aromatic ketones catalyzed by a bicyclic chiral guanidine. To the best of our knowledge, there are no reports on enantioselective synthesis of nitrogen-substituted fluorinated stereogenic carbons from a-fluorinated ketones using organocatalytic processes. However, successful examples using a-fluoro-b-ketoesters and catalyzed with copper and nickel complexes of Cinchona alkaloid derivatives have been reported. Direct a-amination of a-fluorinated aromatic cyclic ketones 1 d catalyzed by chiral guanidine 2 with azodicarboxylates 3 led to optically active a-hydrozino-a-fluorinated aromatic cyclic ketones 4 and 5 d. When di-tert-butyl azodicarboxylate 3 a was used as the nitrogen source (Table 1, entries 1–7), the best result obtained was 84 % ee in THF (Table 1, entry 7). A bulkier version of azodicarboxylate, di3-ethylpentan-3-yl azodicarboxylate 3 b (EocN=NEoc), was designed as we are aware that bicyclic guanidine catalyst responds positively to an increase in the steric demand of the [a] Y. Zhao, Y. Pan, H. Liu, Y. Yang, Prof. Dr. C.-H. Tan Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore) Fax: (+65) 6779-1691 E-mail : chmtanch@nus.edu.sg [b] Prof. Dr. Z. Jiang Provincial Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University Jinming Campus, Kaifeng, Henan, 475004 (P.R. China) Fax: (+86) 0378-2864665 E-mail : chmjzy@henu.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201003761.

Highly enantioselective organocatalytic α-sulfenylation of azlactones.

The first asymmetric α-sulfenylation of azlactones with N-(sulfanyl)succinimides has been developed by using cinchona alkaloid-derived squaramide as a catalyst and 4 Å molecular sieves as an additive. The reaction conditions were suitable to 4-alkyl and benzyl-substituted azlactones as well as N-(benzyl/alkyl/arylthio)succinimides, affording adducts with high enantioselectivities (81-94% ee).

Synthesis of α‐Stereogenic Amides and Ketones by Enantioselective Conjugate Addition of 1,4‐Dicarbonyl But‐2‐enes

In the conjugate addition reaction of a alpha,beta-unsaturated compound, the new stereogenic center is created in the beta-position. In contrast, conjugate addition to 1,4-dicarbonyl but-2-enes will generate an alpha-stereogenic center with respect to one of the carbonyl groups, which informally, can be considered as an inversion of normal reactivity patterns or Umpolung. In this paper, we demonstrate that chiral bicyclic guanidine can catalyze the addition of 1,3-dicarbonyl compounds to 1,4-dicarbonyl but-2-enes [(E)-4-oxo-4-arylbutenamides and (E)-4-oxo-4-arylbutenones] with high regioselectivity and enantioselectivity (ee values up to 97%).