Silvia Catalan

Gold-Catalyzed Intramolecular Hydroamination of o-Alkynylbenzyl Carbamates: A Route to Chiral Fluorinated Isoindoline and Isoquinoline Derivatives

Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellmans N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group.

Anionic–Anionic Asymmetric Tandem Reactions: One-Pot Synthesis of Optically Pure Fluorinated Indolines from 2-p-Tolylsulfinyl Alkylbenzenes†

The indoline skeleton is a ubiquitous scaffold found in the structures of several alkaloids and other natural products which have diverse biological activity. Indolines are considered to be “privileged structures” which accounts for their widespread use not only as building blocks in the total synthesis of natural products, but also as a common motif in the design of new biologically significant compounds. Indolines have also been successfully employed as chiral auxiliaries in asymmetric synthesis. Consequently, a number of multistep strategies have been developed for synthesizing these compounds. However, no short and efficient methods for the preparation of enantiomerically pure substituted indolines have been developed to date, therefore the search for new methods for synthesizing them remains a challenge. Surprisingly, no examples of fluorinated indolines have been reported despite the fact that the inclusion of fluorinated fragments, such as the trifluoromethyl group, in organic molecules has contributed significantly to the development of new pharmaceuticals. Our research group has recently reported that reactions of 2-(p-tolylsulfinyl) benzylcarbanions with different electrophiles take place with almost complete control of the configuration at the benzylic position, thus providing one of the best methods for creating optically pure benzylic carbon centers. In particular, the use of imines as electrophiles has allowed us to synthesize 2-phenylethyl (and propyl) amines with complete control of the configuration at the two stereogenic centers that are created simultaneously. [9] We hypothesized that amines resulting from nucleophilic addition (AN) could serve as substrates for the synthesis of optically pure indolines—once the optimal reaction conditions for the displacement of the sulfinyl group by the nitrogen center are determined, an intramolecular nucleophilic aromatic substitution (SNAr) could take place (Scheme 1). [10] We also felt that

Tandem asymmetric Michael reaction-intramolecular Michael addition. An easy entry to chiral fluorinated 1,4-dihydropyridines.

A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.

Asymmetric synthesis of indolines through intramolecular shifting of aromatic sulfinyl groups. Role of the pi,pi-stacking interactions in these unusual S(N)Ar processes.

Cyclization of N-aryl substituted 1-aryl-2[2-p-tolylsulfinyl]phenyl propylamines under LDA, LHMDS, or KHMDS provides a new approach for synthesizing optically pure 2,3-disubstituted indolines. Both the scope and the limitations of this method have been investigated. The pi,pi-stacking interactions are crucial for these unprecedented intramolecular S(N)Ar processes, in which a sulfinyl group located on a slightly deactivated ring is substituted by amide anions under mild conditions. X-ray and NMR proofs supporting these pi,pi-stacking interactions are presented.

A new strategy for the synthesis of optically pure beta-fluoroalkyl beta-amino acid derivatives.

The first general approach for the diastereoselective formation of a variety of optically pure anti-beta-fluoroalkyl beta-amino acid derivatives is described. The process relies on the stereocontrolled reaction, mediated by a remote sulfoxide, of fluorinated imines with sulfinylated benzyl carbanions, which are used as synthetic equivalents of chiral ester enolates.

Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium‐Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding α-fluoroalkyl o-iodobenzylamines. A base-mediated anti β-hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pKa of the base.

Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

Numerous antibiotics bind to ribosomal RNA, and many functional RNA motifs have considerable therapeutic potential. However, the development of small RNA-binding agents has been hampered by the difficulties posed by these structures, which have limited physicochemical diversity and are often flexible. In order for this approach to be successful, it is essential to identify new chemical scaffolds recognizing RNA. The Rev response element (RRE) is a strongly conserved 350-nucleotide structure located in the env gene of human immunodeficiency virus type-1 (HIV-1) RNA. Within subdomain IIB of the RRE, the unusually widened major groove of a 4:6 internal loop forms a high-affinity complex with the arginine-rich a-helix of Rev, a virally encoded 116 amino acid protein that adopts a helix-turn-helix conformation (Figure 1). This interaction between internal loop IIB and the RNA-binding a-helix of Rev (Rev34-50) is essential for virus viability because it triggers a cascade of events that allow the transport of unspliced or incompletely spliced viral RNA molecules into the cytoplasm of the infected cell in the late phase of the viral infectious cycle. These events include the cooperative incorporation of additional Rev molecules into the complex through interactions with further sites on the RRE and protein–protein contacts, and the tethering of the RRE–Rev ribonucleoprotein to the Crm1 host export factor. In addition to RNA nuclear export, Rev has been shown to

Synthetic and Biological Applications of Fluorous Reagents as Phase Tags

The search for new and better techniques for the purification of organic compounds has made the recent emergence of fluorous chemistry in the field of organic synthesis possible. Using fluorous reagents as phase tags allows for the access of different synthetic routes, and this has been translated into a time reduction and higher simplicity compared to standard, nonfluorous procedures. The synthesis in fluorous phase of target molecules can be pursued in a parallel or combinatorial manner in order to access chemical libraries with structural and/or stereochemical diversity. The preparation of radiolabeled molecules also benefits from the advantages of fluorous synthesis. Finally, biochemical tools such as microarrays or proteomic techniques are improved by means of fluorous-tagged compounds.

Unique reactivity of fluorinated molecules with transition metals.

Organofluorine and organometallic chemistry by themselves constitute two potent areas in organic synthesis. Thus, the combination of both offers many chemical possibilities and represents a powerful tool for the design and development of new synthetic methodologies leading to diverse molecular structures in an efficient manner. Given the importance of the selective introduction of fluorine atoms into organic molecules and the effectiveness of transition metals in C-C and C-heteroatom bond formation, this review represents an interesting read for this aim.

Selective Formal Transesterification of Fluorinated 2-(Trimethylsilyl)ethyl α-Imino Esters Mediated by TBAF

The scope of the transesterification reaction between beta-fluorinated alpha-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated alpha-imino esters.