Asymmetric synthesis of fluorinated β-hydroxy esters via ruthenium-mediated hydrogenation

Blanc, Delphine; Ratovelomanana‐Vidal, Virginie; Gillet, J. P.; Genêt, Jean‐Pierre

doi:10.1016/s0022-328x(00)00174-1

Cited by 34 publications

(13 citation statements)

References 21 publications

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“…The catalytic system based on SYNPHOS  ligand gave high enantiomeric excesses for the reduction of β-keto esters (7aϪe) under 4 bar of hydrogen at 50°C, providing the correspond- Ligand configuration Solvent ing substituted β-hydroxy esters with enantiomeric excesses ranging from 97%, for the aromatic compound 7e, to Ͼ 99% for aliphatic compounds 7aϪd. Ruthenium-mediated hydrogenation is known to give poor values of ee for fluorous substrates 7f and 7g, even at high temperature (99°C ), [20] but SYNPHOS  ligand displayed higher enantioselectivities (49% and 63%, respectively) than BINAP ligand (23% and 44%, respectively) under the same conditions. [20] Enantioselectivities for the reduction of other ketone substrates also turned out to be very high.…”

Section: Asymmetric Hydrogenationmentioning

confidence: 99%

“…Ruthenium-mediated hydrogenation is known to give poor values of ee for fluorous substrates 7f and 7g, even at high temperature (99°C ), [20] but SYNPHOS  ligand displayed higher enantioselectivities (49% and 63%, respectively) than BINAP ligand (23% and 44%, respectively) under the same conditions. [20] Enantioselectivities for the reduction of other ketone substrates also turned out to be very high. α-Hydroxy esters, resulting from the asymmetric hydrogenation of compounds 8, were obtained with enantiomeric purities of 92Ϫ94% under 20 bar of hydrogen at 50°C, except for thienyl compound 8c, which gave a moderate 71% ee, under 10 bar of hydrogen at 80°C.…”

Section: Asymmetric Hydrogenationmentioning

confidence: 99%

“…For several years now, chemists at Hoffmann-La Roche [26] and in our group [20,27] have found that MeO-BI-PHEP ligand is sometimes more efficient than BINAP ligand in the ruthenium-mediated asymmetric hydrogenation of functionalized prochiral ketones. Having in hand molecular modeling information about three atropisomeric diphosphane ligands, BINAP, MeO-BIPHEP, and SYNPHOS  , we decided to determine the influence that the dihedral angles have on the enantioselectivities of the asymmetric hydrogenations of several substrates.…”

Section: Correlation Between Molecular Modeling and Enantioselectivitiesmentioning

confidence: 99%

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Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

et al. 2003

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A new, optically active, atropisomeric diphosphane ligand, (2,3,2Ј,3Ј-tetrahydro-5,5Ј-bi(1,4-benzodioxin)-6,6Ј-diyl)bis-(diphenylphosphane) (SYNPHOS  ), has been synthesized, characterized, and used in ruthenium-catalyzed asymmetric hydrogenations. This new ligand has been compared with other atropisomeric diphosphanes (BINAP and MeO-BI- [a] 1931 PHEP) with respect to their dihedral angles calculated by molecular modeling and the enantioselectivity of their ruthenium-mediated hydrogenation reactions.The first aim was to achieve ortholithiation of compound 3. The lithiated intermediate could be oxidized by FeCl 3 to provide bis(phosphane oxide) 5, or transformed into an iodide derivative 4 suitable for Ullmann coupling. As outlined in Table 1, we tried several conditions for the difficult ortholithiation/oxidative coupling sequence. Best results were obtained with tBuLi at low temperature (Ϫ100°C then Ϫ70°C) under thermodynamically controlled conditions, [12] and compound 5, hereafter named SYNPHOSO 2 , was obtained in 50% yield by using FeCl 3 as the coupling agent.

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Section: Asymmetric Hydrogenationmentioning

confidence: 99%

Section: Asymmetric Hydrogenationmentioning

confidence: 99%

Section: Correlation Between Molecular Modeling and Enantioselectivitiesmentioning

confidence: 99%

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Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

et al. 2003

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“…Os atropoisômeros enantiomericamente puros são amplamente utilizados em sínteses assimétricas catalisadas por metais [31][32][33][34] , promovendo a formação de complexos organometálicos quirais, através da indução de quiralidade por diferenciação termodinâmica do sítio reativo dos substratos durante a catálise [35][36][37] . Os principais atropoisômeros comercializados com esta finalidade são apresentados na Figura 11, com destaque para os enantiômeros do bifenilnaftol (BINOL) 32 e da bifenilfosfina (BINAP) 33,34 , que estão entre os ligantes quirais mais utilizados em síntese assimétrica.…”

Section: Uso Do Atropoisomerismo Em Reações Assimétricasunclassified

“…Dentre os exemplos disponíveis podemos destacar os compostos atropoisoméricos apresentando grupos amida, onde o eixo de quiralidade geralmente se forma em torno de uma ligação C-N, favorecendo a remoção do grupo indutor de quiralidade ao final do processo sintético, devido à relativa labilidade química da ligação peptídica. Como exemplo, pode-se destacar o trabalho de Simpkins e colaboradores 35 , onde foi possível notar o efeito do atropoisomerismo na estereosseletividade de adição nucleofílica a intermediários do tipo acilimínio 29 (Figura 12). Observou-se que apesar da rápida interconversão do intermediário atropoisomérico 30, o uso de substratos enantiomericamente puros, como o intermediário 28, garante a obtenção do produto final em excessos enantioméricos maiores que 99% após remoção do anel arila orto-funcionalizado.…”

Section: Uso Do Atropoisomerismo Em Reações Assimétricasunclassified

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Santos¹,

Pinheiro²,

Sodero³

et al. 2007

Quím. Nova

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Recebido em 26/9/05; aceito em 30/3/06; publicado na web em 26/9/06 ATROPISOMERISM: THE EFFECT OF THE AXIAL CHIRALITY IN BIOACTIVE COMPOUNDS. Atropisomerism is a special kind of stereoisomeric relationship that arises from the freezing of a certain conformation of an organic molecule, associated with a high rotational barrier about a single covalent bond. Atropisomerism has been originally described in orto-functionalyzed biphenyl derivatives, but a lot of other organic functionalities can present this structural phenomenon, characterized by the presence of chiral properties in compounds that don't present classical stereogenic centers. Atropisomeric compounds, intermediates and catalysts have well-know importance in organic synthesis, but the influence of the axial chirality in substances able to modulate biological systems is still not very exploited in drug design and development. In this context, the present account describes the importance of this structural property in the medicinal chemistry of different classes of bioactive compounds or therapeutic agents, emphasizing how atropisomerism could affect the molecular recognition of a ligand or a prototype by the target bioreceptor.Keywords: atropisomerism; atropisomerism of drugs; stereoselective molecular recognition. INTRODUÇÃOO fenômeno conhecido como atropoisomerismo, denominação oriunda da palavra grega atropos (i.e. sem rotação), é atribuído a um tipo de estereoisomerismo característico de sistemas onde a rotação livre em torno de uma ligação simples é impedida, produzindo uma barreira energética suficientemente elevada, de modo a permitir o isolamento ou simplesmente a detecção dos diferentes rotâmeros, chamados atropoisômeros 1,2 . Este tipo de isomeria axial é caracterizada pela atividade ótica promovida por um eixo de ligação, não necessitando que a substância apresente carbono estereogênico como elemento de quiralidade. O fenômeno foi observado pela primeira vez por Christie e Kenner 3 , após a resolução dos atropoisômeros do ácido 6,6'-dinitro-2,2'-difênico 1, os quais não se mostraram interconversíveis à temperatura ambiente (Figura 1).A nomenclatura de substâncias que apresentam quiralidade axial pode ser atribuída como R ou S pela aplicação das regras de prioridade de Cahn-Ingold-Prelog 4,5 , conforme exemplificado na Figura 2. A partir da projeção da estrutura vista na direção do eixo de ligação do sistema bifenílico, deve-se definir a ordem de prioridade dos grupos funcionais, iniciando por aqueles mais próximos ao observador e, em seguida, atribuir a configuração absoluta R ou S com base no sentido da rotação produzida quando se caminha do substituinte de maior prioridade para o de menor prioridade. Apesar de ser opcional, a descrição da configuração absoluta de estereoisômeros atropoisoméricos deve ser acompanhada pela introdução do prefixo a, i.e. aR ou aS, visando distinguí-los de outros tipos de compostos oticamente ativos. De maneira alternativa, os compostos atropoisoméricos podem ser vistos como hélices e suas configurações descritas...

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Enantioselective Ketone and β‐Keto Ester Hydrogenations (Including Mechanisms)

Ohkuma¹,

Noyori²

2006

The Handbook of Homogeneous Hydrogenation

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Enantioselective hydrogenation of b-keto esters is a well-established procedure to produce chiral b-hydroxy esters in high optical purity [1][2][3][4]. Many important biologically active compounds have been synthesized through this procedure, even on a commercial scale [1][2][3][4]. Ru complexes [5] bearing appropriate chiral phosphine ligands [6][7][8] provide excellent catalytic efficiency for this reaction. Certain chiral Rh catalysts [3,4] and heterogeneous Ni catalysts [9] are also utilized. The recent development of the chiral diphosphine/diamine-Ru catalyst enables rapid and stereoselective hydrogenation of simple ketones without a hetero-atom functionality close to the carbonyl group [2,4]. These enantioselective transformations are summarized in the present chapter. Chiral LigandsIn enantioselective hydrogenation of ketonic substrates, the excellent catalytic performance such as high turnover number (TON), turnover frequency (TOF = -TON h -1 or s -1 ), and enantioselectivity is achievable only when (pre)catalysts are prepared by the appropriate combination of metal species and chiral ligands [6-8, 10, 11]. Stereo-repulsive interaction between substituents of ligands and substrates is normally utilized for the regulation of stereochemistry. The metal and ligand must be carefully selected because of the diversity of substrate structures [1][2][3][4][5]. Chiral diphosphine ligands with a C 2 symmetry (see Fig. 32.1) have played a main role in this respect. Recently, however, various effective C 1 phosphine ligands as well as phosphinite ligands have been developed, the structures of which are illustrated in Figures 32.2 and 32.3, respectively. Chiral amine and imine ligands (Fig. 32.4) are also useful, particularly when they are coupled with a chiral diphosphine ligand in the hydrogenation of simple ketones [2,4,5]. Immobilized BINAPs are detailed in Figure 32.5.

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Asymmetric synthesis of fluorinated β-hydroxy esters via ruthenium-mediated hydrogenation

Cited by 34 publications

References 21 publications

Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Enantioselective Ketone and β‐Keto Ester Hydrogenations (Including Mechanisms)

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Asymmetric synthesis of fluorinated β-hydroxy esters via ruthenium-mediated hydrogenation

Cited by 34 publications

References 21 publications

Synthesis and Molecular Modeling Studies of SYNPHOS®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

Synthesis and Molecular Modeling Studies of SYNPHOS®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Enantioselective Ketone and β‐Keto Ester Hydrogenations (Including Mechanisms)

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Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation

Synthesis and Molecular Modeling Studies of SYNPHOS^®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation