Sulfoxides as ‘traceless’ resolving agents for the synthesis of atropisomers by dynamic or classical resolution

Clayden, Jonathan; Kubinski, Przemyslaw; Sammiceli, Federica; Helliwell, Madeleine; Diorazio, Louis J.

doi:10.1016/j.tet.2004.01.099

Cited by 41 publications

(27 citation statements)

References 35 publications

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“…We have previously employed sulfoxides for both purposes: we showed that sulfoxide-containing intermediates could be used in the classical resolution of binaphthyls 13 or in the dynamic resolution of atropisomeric amides or ethers. 11,13,14 Accordingly we took the crude reaction mixture containing the unseparated diastereoisomeric sulfoxides 13 from the synthesis shown in Scheme 4 and heated them in cumene to 120°C for 2 h. Under these conditions, equilibration gave a 4:1 mixture of diastereoisomers ( 1 H NMR spectroscopy or HPLC) from which (R,M)-13 could be isolated in 77% yield after column chromatography (Scheme 10). Knochel and coworkers coverted (R,M)-13 to (R)-QUINAP in two steps and 60% yield.…”

Section: Enantioselective Synthesis Of Biaryl Atropisomers Bymentioning

confidence: 99%

“…2,[6][7][8] Interactions between the dipoles associated with the two functional groups allow the conformation of atropisomeric and near-atropisomeric molecules to be controlled. 5,9 Such strategies have been used in the asymmetric synthesis (by dynamic resolution under thermodynamic control, or "dynamic thermodynamic resolution" 10 ) of atropisomeric amides [11][12][13] and diaryl ethers. 14 The most effective controlling groups have been those with the greatest associated dipoles, 6 with sulfoxides reigning supreme in applicability: 7,11,14 not only are the conformational selectivities provided generally high, but they are also easy to introduce in enantiomerically pure form and easy to displace by a variety of substitution or oxidation methods.…”

Section: Introductionmentioning

confidence: 99%

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Controlling Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines: Application to the Asymmetric Synthesis of QUINAP by Dynamic Thermodynamic Resolution

et al. 2009

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Unlike related biphenyl compounds, 2-arylpyridines and 1-arylisoquinolines can be induced to adopt preferentially one of two axial conformations by the presence of a sulfinyl substituent adjacent to the Ar-Ar bond. In the case of more substituted biaryls, the compounds are atropisomeric, and thermodynamic selectivities of about 4:1 may be attained on heating. In the case of less hindered compounds, conformer ratios of up to 20:1 may be achieved. Preferred conformations are deduced by comparison of experimental CD spectra with those derived from theory. The conformational preferences induced by the sulfoxides may be exploited in the asymmetric synthesis of atropisomers, including the ligand QUINAP, by dynamic resolution under thermodynamic control.

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Section: Enantioselective Synthesis Of Biaryl Atropisomers Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Controlling Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines: Application to the Asymmetric Synthesis of QUINAP by Dynamic Thermodynamic Resolution

et al. 2009

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“…A resolução de misturas atropoisoméricas pode ser comumente realizada através da derivatização da mistura enantiomérica em mistura diastereoisomérica, através da reação com um derivado com quiralidade definida, geralmente favorecendo a separação por processos simples de cromatografia em coluna 13,14 . Entretanto, a separação do par enantiomérico de misturas atropoisoméricas nem sempre é viável, principalmente devido à baixa energia necessária para a interconversão dos rotâmeros.…”

Section: Métodos De Determinação E Resolução De Atropoisômerosunclassified

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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“…[8][9][10][11][12][13][14][15][16][17] The absolute configuration of sulfoxides can be determined in the solid state by means of the anomalous dispersion of X-ray crystallography [18][19][20] and in solution by means of the theoretical interpretation of electron circular dicroism (ECD) [21][22][23][24][25] or vibrational circular dicroism (VCD) [25][26][27] spectra. In particular, DFT computations yield quite reliable prediction of ECD and VCD spectra, allowing a meaningful comparison with the experimental CD traces to be performed.…”

Section: Introductionmentioning

confidence: 99%

Conformation and absolute configuration of 2‐naphthylalkylsulfoxides by combined use of dynamic NMR, ECD spectroscopy, DFT computations, and X‐ray diffraction

et al. 2008

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The E/Z conformer ratios of five 2-naphtylalkylsulfoxides were determined by means of dynamic NMR spectroscopy at very low temperatures and this information was used to predict, by means of DFT calculations, the ECD spectra of the R and S enantiomers. The latter were separated by enantioselective HPLC technique and the comparison of theoretical and experimental ECD spectra allowed the absolute configurations to be determined. In the case of 2-naphtyl tert-butylsulfoxide (1), the assignment was independently confirmed by anomalous dispersion using single crystal X-ray crystallography.

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Sulfoxides as ‘traceless’ resolving agents for the synthesis of atropisomers by dynamic or classical resolution

Cited by 41 publications

References 35 publications

Controlling Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines: Application to the Asymmetric Synthesis of QUINAP by Dynamic Thermodynamic Resolution

Controlling Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines: Application to the Asymmetric Synthesis of QUINAP by Dynamic Thermodynamic Resolution

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Conformation and absolute configuration of 2‐naphthylalkylsulfoxides by combined use of dynamic NMR, ECD spectroscopy, DFT computations, and X‐ray diffraction

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