Combinatorial libraries of chiral ligands for enantioselective catalysis

Since achieving 95% ee only involves energy difference of about 2 kcal, which is no more than the barrier encountered in a simple rotation of ethane, it is unlikely that before the fact one can predict what kind of ligand structures will be effective. With Knowles, people can look forward to the time when computational methods and mechanistic knowledge will permit the prediction of the optimum catalyst for new applications. Until that day, combinatorial methodologies will remain an invaluable tool for catalyst discovery and optimization

Computer‐Assisted Design and Synthetic Applications of Chiral Enol Borinates: Novel, Highly Enantioselective Aldol Reagents

We have recently described the development of a quantitative transition state model for the prediction of stereoselectivity in the boron-mediated aldol reaction. This model provides qualitative insights into the factors contributing to the stereochemical outcome of a variety of reactions of synthetic importance. The force field model was used to assist the design and preparation of new chiral boron ligands derived from menthone. The chiral boron enolates were employed in various stereoselective processes, including the addition to chiral aldehydes and the reagent-controlled total synthesis of (3S,4S)-statine. The chiral enolates derived from alpha-halo and alpha-oxysubstituted thioacetates were added to aldehydes and imines. Addition to imines leads to the enantioselective synthesis of chiral aziridines, a formal total synthesis of (+)-thiamphenicol, and a new highly efficient synthesis of the paclitaxel (taxol®) C-13 side-chain and taxol semisynthesis from baccatin III. The stereochemical outcome of the addition to imines was rationalised with the aid of computational studies. Enantioselective addition reactions of the chiral boron enolate derived from thioacetate have successfully been applied to solid phase bound aldehydes to give aldol products in comparable yields and enantioselectivities to the usual solution conditions. Descrevemos recentemente o desenvolvimento de um modelo quantitativo de estados de transição para a previsão da estereosseletividade em condensações aldólicas mediadas por boro. Este modelo fornece percepções qualitativas sobre os fatores, contribuindo para o resultado estereoquímico de uma variedade de reações de importância sintética. O modelo de campo de força foi utilizado para auxiliar na elaboração e preparação de novos ligantes de boro quirais derivados da mentona. Os enolatos de boro quirais foram empregados em vários processos estereosseletivos, incluindo a adição a aldeídos quirais e a síntese total, controlada pelo reagente, da (3S,4S)-estatina. Os enolatos quirais derivados a partir de tioacetatos alfa-halo e alfa-oxisubstituídos foram adicionados a aldeídos e iminas. A adição de iminas leva à síntese enantiosseletiva de aziridinas quirais, a síntese total formal da (+)-tioamfenicol, a uma nova e altamente eficiente síntese da cadeia lateral em C-13 do paclitaxel (taxol®) e a semi-síntese do taxol a aprtir da bacatina III. O resultado estereoquímico da adição das iminas foi racionalizado com o auxílio de estudos computacionais. Reações de adição enantiosseletiva de enolatos de boro quirais derivados do tioacetato foram empregados com sucesso a aldeídos ligados à fase sólida, fornecendo produtos aldólicos em rendimentose enantiosseletividades comparáveis às condições usuais em solução

A Library Approach to the Development of BenzaPhos, Highly Efficient Chiral Supramolecular Ligands for Asymmetric Hydrogenation

A library of chiral supramolecular ligands named BenzaPhos, of straightforward preparation (two steps from commercial or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search of new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins such as enamide S4 and beta-dehydroamino ester S5 (> 99% ee: best value ever reported in both cases). A series of control experiments were undertaken in order to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen and the substrate amide NH

Acceleration of hemiacetal cleavage through hydrogen bonding : a new synthetic catalyst with balanced conformational flexibility and preorganization

Hemiacetal cleavage catalyst 1 was designed, synthesized, and shown to be effective in promoting glycolaldehyde dimer dissociation and tetramethylglucose mutarotation

Solid-phase synthesis of peptides containing reverse-turn mimetic bicyclic lactams

The solid-phase synthesis and characterization of a series of peptides (4-15) containing reverse-turn mimetic bicyclic lactams is reported. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a Pturn. Amino acid conjugates of these bicyclic lactams were synthesized on solid supports following a g-fluorenylmethoxycarbonyl (FMOC) protection strategy on WangMerrifield resin. Coupling between amino acids was accomplished by means of diisopropylcarbodiimide (DIC)/ hydroxyazabenzotriazole (HOAt). Coupling between amino acids and the mimics was performed with the potent Carpino's reagent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramelhyluronium hexafluorophosphate (HATU). The final compounds were cleaved from the resin and obtained as N-acetylated methyl esters or benzyl amides