Jimmy Wu

Gallium(III)‐Catalyzed Three‐Component (4+3) Cycloaddition Reactions

(IC50 = 63 nm) of SIRT1, a member of the class III histone deacetylases (HDAC). SIRT1 can effectively deacetylate p53 and has also been implicated in the regulation of apoptosis. With an IC50 of 100 nm, compound 3 inhibits the production of leukotriene B4 (LTB4) which is involved in various inflammatory responses. A third molecule, 4, inhibits the adipocyte fatty-acid binding protein (A-FABP) with an IC50 of 450 nm. [3] The biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopentaand cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics. In the last decade alone, nearly two dozen patents have been issued on the basis of these structural motifs. At issue is the synthesis of cyclohepta[b]indoles. 4] They are most often prepared by means of the Fischer indole synthesis which, while quite useful, possesses certain limitations. These limitations include the need to make the requisite hydrazine and ketone starting materials. Regioselectivity with unsymmetrical ketones can also sometimes be problematic. Finally, electron-withdrawing groups on the aromatic hydrazine can substantially attenuate reactivity. Other methods for preparing cyclohepta[b]indoles are known but have not been extensively explored, and are in fact quite different from the work described herein. We report herein that gallium(III) salts effectively mediate regioand diastereoselective three-component (4+3) cycloaddition reactions to furnish cyclohepta[b]indoles in high yields (Scheme 1). These reactions occur in a single step

Dearomative Indole (3 + 2) Cycloaddition Reactions

A diastereoselective (3 + 2) dearomative annulation of 3-substituted indoles with α-haloketones has been developed. Significant regiochemical control was observed. This methodology provides easy access to highly functionalized cyclopenta- or cyclohexa-fused indoline compounds, which are common structures of many natural products. The synthetic potential of this reaction was demonstrated in the concise syntheses of the core structures of vincorine, isocorymine, and aspidophylline A. DFT studies (B3LYP-D3/6-311++G**/MeOH) on cyclization mechanisms involving the 2-hydroxyallyl cation and its deprotonated oxyallyl cation have been performed. Under the reaction conditions, with a sparingly soluble Na2CO3 base, both species may be present and both pathways are viable. Both pathways support the formation of the experimentally observed O-bound intermediate, its transformation to the final product, the regiochemical and eventual stereochemical outcome of the kinetic cyclization product, and the thermodynamic preference for formation of the final stereoisomer.

Dearomative Indole (3 + 2) Reactions with Azaoxyallyl Cations--New Method for the Synthesis of Pyrroloindolines.

Herein, we report the first examples of the synthesis of pyrroloindolines by means of (3 + 2) dearomative annulation reactions between 3-substituted indoles and highly reactive azaoxyallyl cations. Computational studies using density functional theory (DFT) (B3LYP-D3/6-311G**++) support a stepwise reaction pathway in which initial C–C bond formation takes place at C3 of indole, followed by ring closure to give the observed products. Insights gleaned from these calculations indicate that the solvent, either TFE or HFIP, can stabilize the transition state through H-bonding interactions with oxygen of the azaoxyallyl cation and other relevant intermediates, thereby increasing the rates of these reactions.

Cu(I)-catalyzed, α-selective, allylic alkylation reactions between phosphorothioate esters and organomagnesium reagents.

Regiocontrol of allylic alkylation reactions involving hard nucleophiles remains a significant challenge and continues to be an active area of research. The lack of general methods in which α-alkylation is favored underscores the need for the development of new processes for achieving this type of selectivity. We report that Cu(I) catalyzes the allylic substitution of phosphorothioate esters with excellent α-regioselectivity, regardless of the nature of the Grignard reagent that is used. To the best of our knowledge, the Cu-catalyzed allylic alkylation of phosphorothioate esters has never been described. We have also developed a simple protocol for inducing high α selectivity starting from secondary allylic halides. This is accomplished by using sodium phosphorothioates as an additive.

Ga(OTf)3-Catalyzed Direct Substitution of Alcohols with Sulfur Nucleophiles

It is reported that Ga(OTf)(3) catalyzes the direct displacement of alcohols with sulfur nucleophiles. The products are versatile intermediates that can be utilized in carbon-carbon, carbon-sulfur bond formation or used in modified Julia olefination reactions. The only byproduct generated is water.

Palladium-Catalyzed Allylic Fluorination of Cinnamyl Phosphorothioate Esters

A highly regioselective, Pd-catalyzed allylic fluorination of phosphorothioate esters is reported. This chemistry addresses several limitations of previously reported methods in which elimination and lack of reactivity were problematic. Preliminary mechanistic investigations reveal that these reactions are stereospecific and provide fluorinated products with net retention of stereochemical configuration. In analogy to other Pd-catalyzed allylic substitution reactions, this process likely proceeds through a palladium π-allyl intermediate.

Mild Two-Step Process for the Transition-Metal-Free Synthesis of Carbon−Carbon Bonds from Allylic Alcohols/Ethers and Grignard Reagents

A mild two-step process for the regioselective, transition-metal-free preparation of carbon-carbon bonds from allylic alcohols/ethers and Grignard reagents is described. This process obviates the need for the harsh deprotection conditions usually required for removal of methyl ethers. The synthesis is accomplished by photochemically promoted allylic substitution reactions of allylic alcohols and ethers with diethylphosphorothioic acid followed by sp(3)-sp(3) or sp(2)-sp(3) bond formation with various Grignard reagents under transition-metal-free conditions. Depending on the nature of the nucleophile, the regioselectivity of the carbon-carbon bond-forming event can be controlled to furnish either quaternary or tertiary carbon centers.

Redox Chain Reaction—Indole and Pyrrole Alkylation with Unactivated Secondary Alcohols

Secondary role: Indole and pyrrole derivatives are alkylated with unactivated secondary aliphatic alcohols by a Brønsted acid-catalyzed redox chain reaction mechanism. Broad functional-group tolerance has been demonstrated and preliminary studies suggest that 1,4-reduction of a putative indolyl carbocation is the dominant mechanistic pathway.

Phosphorothioic Acids and Related Compounds as Surrogates for H2S—Synthesis of Chiral Tetrahydrothiophenes

The convenient preparation of chiral tetrahydrothiophenes (THTs) in high enantiopurity via phosphorothioic acids and related compounds is reported. We consider these to be safer alternatives to the use of H(2)S which is a highly toxic gas. Each of the THTs is derived from a common intermediate, thereby greatly enhancing the flexibility of the synthesis. The key transformation is a base-promoted, intramolecular, carbon-sulfur bond-forming event. These reactions are highly stereospecific as they operate through a double S(N)2 displacement mechanism. The methodology is amenable to a broad array of functional groups and heterocycles. The tetrahydrothiophene motif is important because it is present in a number of bioactive natural products. They have also been utilized to promote various asymmetric transformations including hydrogenation, epoxidation, cyclopropanation, and aziridination reactions.

Convenient synthesis of allylic thioethers from phosphorothioate esters and alcohols.

The synthesis of allylic thioethers arising from the reaction between phosphorothioate esters and alcohols is described. The synthesis is accomplished in one step by the addition of an exogenous alkoxide to the corresponding allylic phosphorothioate ester. It is demonstrated that this process is amenable to various functional groups and a wide variety of heterocycles. In contrast to conventional methods for thioether synthesis, no malodorous sulfur compounds such as thioacetic acid or thiols are required.