Cristina

Water-Freezing Regiocontrol An efficient modular and regioselective synthesis of deuterated cyclic enones has been achieved by successive coupling of three simple starting materials and a deuterium source. Dialkoxy 2-cyclopentenones were generated under anhydrous conditions, whereas dialkoxy 2-cyclohexenones were formed under water-promoted solidification of the reaction mixture. This unprecedented water-freezing effect induced a total inversion of the regioselectivity in the intramolecular cyclization of allenyl-substituted alkylchromate intermediates. For more details, see the Communication by J. Flórez et al. on page 1854 ff.

A Rh^III-catalyzed C–H activation/cyclative capture approach, involving a nucleophilic addition of C(sp³)–Rh species to polarized double bonds is reported. This constitutes the first intermolecular catalytic method to directly access 1-aminoindolines with a broad substituent scope under mild conditions.

Buckle up! The nucleophilic addition of C(sp³)–Rh species to polarized double bonds is the key step in a Rh^III-catalyzed C–H activation/cyclative capture reaction. This constitutes the first intermolecular catalytic method to directly access the 1-aminoindoline core with a broad substituent scope under mild conditions (Boc=tert-butoxycarbonyl, DG=directing group).

A careful interplay between the π electrophilicity of a cationic Au^I center and the basicity of the corresponding counterion allowed for the chemo- and regioselective inter- as well as intramolecular de-aromatization of 2,3-disubstituted indoles with allenamides. The silver-free bifunctional Lewis acid/Brønsted base complex [{2,4-(tBu)₂C₆H₃O}₃PAuTFA] assisted the formation of a range of densely functionalized indolenines under mild conditions.

Power balance: The regioselective gold-catalyzed de-aromatization of indoles is shown through inter- as well as intramolecular condensations with allenamides. Densely functionalized 3,3-disubstituted indolines and indolenines were obtained under mild conditions in a highly diastereoselective manner by using [{2,4-(tBu)₂C₆H₃O}₃PAuTFA] as catalyst (see scheme; TFAH=trifluoroacetic acid; EWG=electron-withdrawing group, Ts=p-toluenesulfonyl).

A wide range of alkynyldimethylaluminum reagents, which were derived from terminal alkynes and trimethylaluminum, underwent a double addition to N,N-disubstituted formamides and their acetals to provide the corresponding N,N-disubstituted 3-amino-1,4-diynes in moderate to excellent yields. Also, these reagents smoothly underwent the addition to N,O-acetals to give the corresponding N,N-disubstituted 3-amino-1-ynes in excellent yields.

A range of alkynyldimethylaluminum reagents were added to N,N-disubstituted formamides and the their acetals to provide the corresponding N,N-disubstituted 3-amino-1,4-diynes. Also, these reagents smoothly underwent the addition to N,O-acetals to give the corresponding N,N-disubstituted 3-amino-1-ynes.

A highly efficient gold(I)-catalyzed cascade reaction for the synthesis of fully substituted 3-formyl-4-iodofurans has been developed. Mechanistic investigations indicate a reaction pathway that involves a direct iodination reaction of the organogold intermediate via functionalization of the AuC(sp²) bond, instead of a direct iodination of the 3-formylfurans.

A new family of cationic ligands, N-alkyl/aryl pyridiniophosphines, has been synthesized through a short, scalable, and highly modular route. Evaluation of their electronic properties evidenced weak σ-donor and quite strong π-acceptor character when used as ancillary ligands. These attributes confer a substantially enhanced π-acidity to the Pt^II and Au^I complexes thereof derived and, as result, they depict an improved ability to activate alkynes towards nucleophilic attack. This superior performance has been demonstrated along several mechanistically diverse Pt^II- and Au^I-catalyzed transformations.

Be positive! Pyridinium-substituted phosphines carry a positive charge directly attached to the phosphorus atom. This makes them weak σ-donor but excellent π-acceptor ligands. Their synthesis and their remarkable effect in Pt and Au catalysis are described.

A number of saturated abnormal N-heterocyclic carbene (NHC) complexes of gold, in combination with KBAr^F₄ as activator, were successfully applied in the chemoselective addition of hydrazine to alkynes. The reaction proceeds even at room temperature, which was not possible to date with gold catalysts. The reaction can be applied to a number of substituted arylalkynes. With alkylalkynes the yields are low. The saturated abnormal NHC ligands are resistant to isomerization to the saturated normal NHC coordination mode under basic reaction conditions. Under acidic conditions, a simple protonation at the nitrogen atom not neighboring the carbene center was observed and unambiguously characterized by an X-ray crystal-structure analysis. Computational studies confirm that such an isomerization would be highly exothermic, the observed kinetic stability probably results from the need to shift two protons in such a process.

Golden boy: A saturated abnormal N-heterocyclic carbene (NHC) ligand allows room-temperature hydrohydrazination of alkynes. The mild conditions avoid reduction of the noble-metal center and competitive azine formation. The catalyst is thermodynamically instable but kinetically stable against isomerization to the saturated normal NHC even under strong basic or acidic conditions (see scheme).

Dibenzocycloheptatrienes are obtained by a gold-catalyzed 7-exo-dig hydroarylation protocol in a highly efficient manner. The gold-catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and efficient access to dibenzocycloheptanoids, which are an interesting and unique class of natural products. This was underlined by the first total synthesis of reticuol.

Going for gold: A methodology for the selective formation of seven-membered dibenzocycloheptatrienes by a gold-catalyzed hydroarylation reaction was developed (see scheme). As a proof of the synthetic versatility, the natural product reticuol was synthesized in an efficient sequence involving the new method as a key step.

We highlight the versatility of non-heteroatom-stabilized tungsten–carbene complexes 3 synthesized in situ, which have been used in a modular approach to access 2-benzazepinium isolable intermediates 5. By employing very mild conditions, benzazepinium derivatives 5 have been obtained in high yield from simple compounds, such as acetylides 2, Fischer-type alkoxycarbenes 1, and phenylimines 4. The process, involving a formal [4+3] heterocycloaddition, occurs in a totally regioselective manner, which differs from the approach previously observed in similar procedures for other carbene analogues. This work, which involves three components, reveals a control of the reactivity of non-heteroatom-stabilized carbene complexes 3 ([4+3] vs. [2+2]-heterocycloaddition reactions) depending on the acetylide substitution pattern. The influence of the substitution pattern in the behavior of the complexes has been computationally analyzed and rationalized. Finally, elaboration of the 2-benzazepinium intermediates allows access to 3H-benzo[c]azepines 6 and 3H-1,2-dihydrobenzo[c]azepines 7–9 with high control of the substitution of the nine positions of the heterocycle.

Choose your substitution pattern: Non-heteroatom-stabilized tungsten–carbene complexes synthesized in situ have been used in a modular approach to provide access to 2-benzazepinium isolable intermediates as a starting point to fully substituted 2-benzazepine derivatives (see figure). These intermediates were obtained under very mild conditions from simple compounds, such as acetylides, Fischer-type alkoxycarbenes, and phenylimines. An acetylide substitution pattern controls the reaction.

The one-pot sequential synthesis of (−)-oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO₂H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E–Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone.

(−)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E–Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine.

Matching catalyst and substrate: Organocatalytic cycloaddition between dienamines and 1,4-benzo- or 1,4-naphthoquinones affords biologically interesting dihydronaphtho- and dihydroanthraquinone core structures. The enantioselectivity of this new reaction is ensured by a steric shielding catalyst and carefully selecting substrates that greatly favor the endo approach (see scheme) due to electrostatic interactions in the zwitterionic intermediate.

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α-chiral carbonyls. We describe herein chiral primary-amine-catalyzed conjugate additions of indoles to both α-substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate-limiting in iminium formation and they all involve a uniform H₂O/acid-bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α-branched acroleins, facial selections on H₂O-bridged protonation determine the enantioselectivity, which is enhanced by an OH⋅⋅⋅π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the CC bond-formation step, which precedes a highly stereospecific enamine protonation.

Two modes diverged: A chiral vicinal primary–tertiary diamine was found to catalyze the asymmetric Friedel–Crafts reaction of α-substituted acroleins and vinyl ketones with indoles. Divergent stereocontrol modes on enamine protonation between α-substituted acroleins and vinyl ketones have been uncovered (see scheme).