Pedro Ramírez-López

On the Mechanism of Asymmetric Allylation of Aldehydes with Allyltrichlorosilanes Catalyzed by QUINOX, a Chiral Isoquinoline N-Oxide

Allylation of aromatic aldehydes 1a-m with allyl- and crotyl-trichlorosilanes 2- 4, catalyzed by the chiral N-oxide QUINOX (9), has been found to exhibit a significant dependence on the electronics of the aldehyde, with p-(trifluoromethyl)benzaldehyde 1g and its p-methoxy counterpart 1h affording the corresponding homoallylic alcohols 6g, h in 96 and 16% ee, respectively, at -40 degrees C. The kinetic and computational data indicate that the reaction is likely to proceed via an associative pathway involving neutral, octahedral silicon complex 22 with only one molecule of the catalyst involved in the rate- and selectivity-determining step. The crotylation with (E) and (Z)-crotyltrichlorosilanes 3 and 4 is highly diastereoselective, suggesting the chairlike transition state 5, which is supported by computational data. High-level quantum chemical calculations further suggest that attractive aromatic interactions between the catalyst 9 and the aldehyde 1 contribute to the enantiodifferentiation and that the dramatic drop in enantioselectivity, observed with the electron-rich aldehyde 1h, originates from narrowing the energy gap between the (R)- and (S)-reaction channels in the associative mechanism (22). Overall, a good agreement between the theoretically predicted enantioselectivities for 1a and 1h and the experimental data allowed to understand the specific aspects of the reaction mechanism.

A straightforward synthesis of tetrameric estrone-based macrocycles.

A straightforward approach to macrocycles having four estrone-derived nuclei by the sequential Cu-catalyzed Huisgen azide-alkyne cycloaddition-Glaser-Eglington Cu homocoupling has been developed. Due to its efficiency and simplicity, this sequence is useful for application to different natural product scaffolds.

Two Versatile and Parallel Approaches to Highly Symmetrical Open and Closed Natural Product-Based Structures

Two parallel approaches for preparing diverse and highly symmetrical homohybrids derived from a series of mono- and diterpenes, steroids, and alkaloids are reported. Both procedures are based on the mono-addition of bis(alkynyl) dilithium reagents to natural products having a carbonyl group to produce the corresponding alkynyl derivatives. The Glaser-Hay Cu-promoted homocoupling of these alkynyl natural product mono-adducts as well as the Huisgen Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction resulted in the synthesis of steroid-, terpene-, and alkaloid-based homohybrid derivatives incorporating diverse spacers to join the natural product scaffolds. Straightforward entries to novel closed highly symmetrical and complex estrone-based macrocyclic and cage architectures by means of the Glaser-Eglinton homocoupling and the CuAAC reaction have been devised.

The Assembly of Macrocyclic Bis- and Tetra-β-lactams with Embedded Platinum or Palladium Square-Planar Centers

The synthesis, isolation, and full characterization of different types of stable, metal-assembled macrocyclic beta-lactams are reported. By using adequately functionalized bis-beta-lactams with defined stereochemistry as building blocks, a series of mono- and bimetallic Pd and Pt macrocycles has been prepared in good to quantitative yields. These novel structures combine the beta-lactam moiety with transition-metal fragments with cis-square-planar geometry and constitute a new class of metal-assembled cavities involving molecules with biological relevance as building blocks. By combining the adequate ligands, metallic fragments, and tuning the reaction conditions, different mono- and bimetallic macrocyclic beta-lactam cavities can be selectively obtained. Macrocycles with Pt-ethynyl groups are suitable to form host-silver triflate guest complexes in a tweezer fashion.

Mechanistic Dichotomy in the Asymmetric Allylation of Aldehydes with Allyltrichlorosilanes Catalyzed by Chiral Pyridine N‐Oxides

Detailed kinetic and computational investigation of the enantio- and diastereoselective allylation of aldehydes 1 with allyltrichlorosilanes 5, employing the pyridine N-oxides METHOX (9) and QUINOX (10) as chiral organocatalysts, indicate that the reaction can proceed through a dissociative (cationic) or associative (neutral) mechanism: METHOX apparently favors a pentacoordinate cationic transition state, while the less sterically demanding QUINOX is likely to operate via a hexacoordinate neutral complex. In both pathways, only one molecule of the catalyst is involved in the rate- and selectivity-determining step, which is supported by both experimental and computational data.

Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald-Hartwig Amination.

The Pd(0)-catalyzed coupling of racemic heterobiaryl bromides, triflates, or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter and suggest that coordination of the amine to the Pd center is the stereodetermining step.

The Sequential Building of Chiral Macrocyclic Bis‐β‐Lactams by Double Staudinger–Cu‐Catalyzed Azide–Alkyne Cycloadditions

A novel approach for the synthesis of macrocyclic bis-beta-lactams based on the Cu-catalyzed alkyne-azide cycloaddition (CuAAC) is reported. The procedure is general and allows access to a full range of diastereomerically or enantiomerically pure macrocyclic cavities in good yields. The incorporation of chiral oxazolidinone fragments at C3 in the beta-lactam rings allows the total enantiocontrol of the process.

Synthesis of axially chiral heterobiaryl alkynes via dynamic kinetic asymmetric alkynylation

The dynamic kinetic Pd0-catalyzed alkynylation of racemic heterobiaryl sulfonates was used for the asymmetric synthesis of axially chiral heterobiaryl alkynes with a broad scope. The use of Pd(OAc)2/(S)-QUINAP as the precatalyst provides products in excellent yields and enantioselectivities under mild conditions (DMSO, 40 °C). Semireduction, 1,3-dipolar cycladdition or N-oxidation served to illustrate the synthetic potential of the methodology.

Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality

A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl α-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N, N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a β-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.