Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the “click reaction”, serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)...

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry

Beyond a doubt organocatalysis belongs to the most exciting and innovative chapters of organic chemistry today. Organocatalysis has emerged not only as a complement to metal-catalyzed reactions and to biocatalysis over the last decade, but also provides new asymmetric organocatalyzed reactions that cannot be accomplished by metal- or biocatalyzed reactions so far. A large number of organocatalytic processes are already well established in organic synthesis. Nevertheless, the number of publications in this field is still on the increase; new important results are produced constantly. This review gives a detailed overview of the latest developments and main streams in organocatalyzed asymmetric CC bond formation processes of the last three years. It is intended to outline the most important current findings focused on especially new synthetic methodologies.

Recent Advances in Organocatalytic Methods for Asymmetric C ? C Bond Formation

A Direct Metal-Free Decarboxylative Sulfono Functionalization (DSF) of Cinnamic Acids to α,β-Unsaturated Phenyl Sulfones

The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry

Catalytic decarboxylative reactions are attractive as biomimetic reactions and environmentally friendly reaction processes. In this review, the origin and recent development of organocatalytic enantioselective decarboxylative reactions of malonic acid half oxy- or thioesters, or β-ketoacids are summarized.

Catalytic enantioselective decarboxylative reactions using organocatalysts.

This is the first hydrogen-bond-directed enantioselective decarboxylative Mannich reaction of β-ketoacids with ketimines affording quinazolinone derivatives with quaternary stereocenters in high yields and with excellent enantioselectivities using saccharide-based amino-thiourea organocatalysts.

Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich Reaction of β-Ketoacids with Ketimines: Application to the Synthesis of Anti-HIV Drug DPC 083

Optically active b-amino esters are an important class of molecules in biological systems and organic synthesis. Direct asymmetric Mannich reaction of simple esters with imines provides an ideal approach toward the construction of these useful building-blocks. However, such transformation remains a great challenge due to the high pKa value of the a-proton in carboxylic acid derivatives. In this context, the enantioselective decarboxylative Mannich reaction of malonic acid half esters with imines has emerged as a very important tool for the asymmetric synthesis of optically active b-amino esters. For example, this process generally employs an ester equivalent, such as a malonic acid half oxyester or thioester, to participate in the reaction under very mild conditions and thereby circumvent the problems with strong bases and self-condensation. Catalytic asymmetric decarboxylative Mannich reactions with a wide range of aldimine-based electrophiles have proven to be highly effective. However, expansion of the electrophilic acceptors to ketimines for the synthesis of b-amino esters with a quaternary stereogenic center seems to be more challenging, since controlling the ketimine geometry in combination with the p-facial selectivity of electrophilic attack is critical for the stereochemical outcome. Only one recent report by Shibata and co-workers has addressed a decarboxylative addition of malonic acid half thioesters (MAHTs) to ketimines derived from isatins to offer the b-amino thioesters with a maximum of 83 % ee. Obviously, there is still plenty of room for the development of efficient protocols for the enantioselective decarboxylative Mannich reactions with ketimines. Moreover, the asymmetric decarboxylative Mannich reaction using the less reactive malonic acid half oxyesters (MAHOs), which directly leading to b-amino oxyesters, has not been documented yet. Herein, we demonstrate that cyclic trifluoromethylketimines are highly effective substrates for organocatalytic asymmetric decarboxylative Mannich reaction of MAHOs, providing products in excellent yields and enantioselectivities. The cyclic structure of these ketimines, in which the C=N bond is constrained in the E geometry, appears to be important for the success of the reactions. Furthermore, the potential application of this catalytic asymmetric decarboxyl ACHTUNGTRENNUNGative Mannich reaction was further exemplified in a highly enantioselective synthesis of the anti-HIV drug DPC 083. We initiated our study from the decarboxylative Mannich condensation of 3-oxo-3-phenoxypropanoic acid (1 a) with cyclic trifluoromethylketimine 2 a in THF at room temperature. The reaction hardly occurs without the use of a catalyst (Table 1, entry 1). Then we focused on the catalytic performance of the saccharide-derived amino-thioureas, developed previously in our laboratory (Figure 1). The amine moiety of the catalyst was found to have a significant effect on the catalytic activity as well as the enantioselectivity: a poor result was attained with catalyst (d, S, S)-Aa bearing a primary amine function (entry 2), whereas remarkable improvement in the yields and enantioselectivities of the Mannich adduct 3 a could be observed when tertiary amine-thiourea catalysts were employed (entries 3–10). Among them, catalyst (d, S, S)-Bd exhibited the best catalytic activity and chiral induction ability (entry 8). Solvent screening revealed that THF remains to be the solvent of choice, and other solvents such as chloroform, dichloromethane, toluene, and 1,4-dioxane diminish the yield and/or enantioselectivity (entries 11–14). The catalyst loading can be reduced to as low as 1 mol% without a significant decrease in the product yield and enantioselectivity, although a prolonged time was required (entries 15 and 16). Reducing the amount of MAHO to 1.5 or even 1.2 equivalents gave comparable results under standard reaction conditions (entries 17 and 18). Interestingly, the catalyst (d, R, R)-C, a diastereoisomer of (d, S, S)-Bd with the opposite configuration on the diamine moiety, could give the Mannich adduct 3 a with the retained configuration in high enantioselectivity as well (entry 19). There is no doubt that the use of catalyst (l, R, R)-D led to the other enantiomer of the b-amino oxyester in comparable yield and ee value (entry 20). These results demonstrated that the reversal of enantioselectivity is directly related to the saccharide moiety of organocatalysts. Under the optimal conditions, the scope of the reaction was explored with a variety of MAHOs 1 and cyclic keti[a] H.-N. Yuan, Dr. S. Li, Dr. J. Nie, Dr. Y. Zheng, Prof. J.-A. Ma Department of Chemistry, Key Laboratory of Systems Bioengineering (The Ministry of Education), State Synergetic Innovation Center of Chemical Science and Engineering Tianjin University, Tianjin 300072 (P. R. of China) Fax: (+ 86) 22-2740-3475 E-mail : majun_an68@tju.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303307.

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β‐Amino Esters and Anti‐HIV Drug DPC 083

Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich Reaction of β-Ketoacids with Ketimines: Application to the Synthesis of anti-HIV Drug DPC 083.

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β-Amino Esters and anti-HIV Drug DPC 083.

Hai-Na Yuan

Papers

Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich Reaction of β-Ketoacids with Ketimines: Application to the Synthesis of Anti-HIV Drug DPC 083

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β‐Amino Esters and Anti‐HIV Drug DPC 083

Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich Reaction of β-Ketoacids with Ketimines: Application to the Synthesis of anti-HIV Drug DPC 083.

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β-Amino Esters and anti-HIV Drug DPC 083.