The rational design of highly stereoselective boron enolates using transition-state computer modeling: a novel, asymmetric anti aldol reaction for ketones

Gennari, Cesare; Hewkin, C. T.; Molinari, Francesco; Bernardi, Anna; Comotti, Angiolina; Goodman, Jonathan M.; Paterson, Ian

doi:10.1021/jo00045a033

Cited by 57 publications

(10 citation statements)

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“…[46] We preferred this two-step route to the method reported in the literature, [42] since reproducing the in situ epimerization under the basic conditions of the Wittig reaction was troublesome.…”

Section: Introductionmentioning

confidence: 99%

Microbial Baeyer–Villiger Oxidation of Prochiral Polysubstituted Cyclohexanones by Recombinant Whole‐Cells Expressing Two Bacterial Monooxygenases

Mihovilovic¹,

Rudroff²,

Grötzl³

et al. 2005

Eur J Org Chem

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The microbial Baeyer-Villiger oxidation of prochiral 3,5-dimethylcyclohexanones bearing various functionalities with recombinant E. coli cells overexpressing cyclohexanone monooxygenase from Acinetobacter sp. NCIMB 9871 and cyclopentanone monooxygenase from Comamonas sp. NCIMB 9872 has been investigated. A distinct difference in substrate specificity and stereoselectivity of the two enzymes was observed, and enantiocomplementary products were obtained in some cases. The biocatalytic systems enabled ac-

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Section: Introductionmentioning

confidence: 99%

Microbial Baeyer–Villiger Oxidation of Prochiral Polysubstituted Cyclohexanones by Recombinant Whole‐Cells Expressing Two Bacterial Monooxygenases

Mihovilovic¹,

Rudroff²,

Grötzl³

et al. 2005

Eur J Org Chem

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“…3) leading to an anti aldol, we were delighted to discover that the new chiral enolates showed a distinct stereoselectivity in the computational run, surpassing by far Ipc (isopinocampheyl) or any other designed reagent 4 .…”

Section: Transition State Modeling and Design Of New Boron Ligandsmentioning

confidence: 99%

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

Gennari¹,

Ceccarelli²,

Piarulli³

et al. 1998

J. Braz. Chem. Soc.

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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 α-halo e α-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.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 α-halo and α-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.

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“…[13,29,30] In fact, one major shortcoming of force fields is the lack of accurate parameters for metal complexes, which are necessary to model metal-catalyzed reactions and need to be specifically developed. [31] ACE is a molecular-mechanics-based independent program that has been developed from simple organic chemistry principles.…”

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confidence: 99%

Toward a Computational Tool Predicting the Stereochemical Outcome of Asymmetric Reactions: Development and Application of a Rapid and Accurate Program Based on Organic Principles

et al. 2008

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Asymmetric catalyst discovery as currently practiced often relies on expensive, and sometimes serendipitous, stepwise optimization and/or library screening.[1] We believe that this paradigm is poised to change, as computational predictive methods have reached a level of accuracy that obviates many steps now done manually. We report herein the early version of a new program, ACE (asymmetric catalyst evaluation), its underlying concepts, and the assessment of its applicability and accuracy in distinguishing efficient asymmetric catalysts or chiral auxiliaries from inferior ones.Although much effort has been directed toward the development of computer-aided drug design tools, there has been little investigation into computational tools for asymmetric catalyst design. Nowadays, the fields of quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) [2] are highly developed and have yielded accurate predictions of asymmetric reaction stereoselectivities. [3][4][5][6] However, QM methods would require months of computation to screen a library of potential catalysts in the search for new ones. To address this issue, other methods were developed, which include reverse docking [7,8] and quantitative structure-selectivity relationships [9][10][11] and more specifically the use of quantum mechanics interaction fields. [12,13] As another alternative to QM techniques, molecular mechanics applied to ground-state structures have been used. [14] Advanced MM-based transition-state (TS) techniques, which accurately predict TS structures and their relative potential energies, have also been reported.[15] Although these methods (e.g., Q2MM (QM-guided MM), [16] using TSFF (transition-state force fields), [17] SEAM (seam of two potential-energy functions), [18,19] EVB (empirical valence bond), [20,21] and MCMM (multiconfiguration MM) [22] ) have shown great potential in locating and investigating TSs, only a very few studies were reported that attempted to predict the stereochemical outcome of reactions, [7,8,14,[23][24][25][26][27][28] with even fewer applications to the design of new asymmetric catalysts. [13,29,30] In fact, one major shortcoming of force fields is the lack of accurate parameters for metal complexes, which are necessary to model metal-catalyzed reactions and need to be specifically developed. [31] ACE is a molecular-mechanics-based independent program that has been developed from simple organic chemistry principles. For example, the Hammond-Leffler postulate states that the TS is most similar to the species (reactants or products) which it is closest to in energy. Following this principle, ACE constructs TSs from a linear combination of reactants and products, including a factor l describing the position of the TS on the potential-energy surface [Eq. (1),A similar approach is used to locate transition states by the EVB method mentioned above, in which l is changed stepwise from 0 to 1 to find the maximum energy corresponding to the TS. EVB has indeed been used successfully in the study of several enzy...

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The rational design of highly stereoselective boron enolates using transition-state computer modeling: a novel, asymmetric anti aldol reaction for ketones

Cited by 57 publications

References 0 publications

Microbial Baeyer–Villiger Oxidation of Prochiral Polysubstituted Cyclohexanones by Recombinant Whole‐Cells Expressing Two Bacterial Monooxygenases

Microbial Baeyer–Villiger Oxidation of Prochiral Polysubstituted Cyclohexanones by Recombinant Whole‐Cells Expressing Two Bacterial Monooxygenases

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

Toward a Computational Tool Predicting the Stereochemical Outcome of Asymmetric Reactions: Development and Application of a Rapid and Accurate Program Based on Organic Principles

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