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The stereoselective addition of ethyl acetate enolate to the C═N bond of N-tert-butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N-sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative. Ministerio de Ciencia e Innovación PID2019-104767RB-I00 Junta de Andalucía US- 1381590, FQM-106

We thank Prof. Anthony Linden (University of Zurich) for solving the crystal structure of 8 and Ms. Christina Wronna for carrying out the elemental analyses. Financial support by Friedrich–Alexander University and King Abdullah University of Science and Technology (KAUST) is acknowledged. For computer time, this research used the resources of the Supercomputing Laboratory (KSL) at KAUST.

A stereodivergent synthesis using inexpensive reagents, i.e., dibenzazepine and glucose-derived t-Bu-sulfinate diastereomers (RS)-6 or (SS)-6, affords respective S(O)-alkene hybrid ligands (S)-7 and (R)-7 on gram scales and in excellent optical purity (ee > 99%). Phenyl substitution of the dibenzoazepine backbone generates planar chirality to give epimerization-resistant (pS,RS)-10 diastereoisomer in high isomeric purity. Furthermore, the crystal structure of widely used sulfinate (RS)-6 is disclosed for the first time since its discovery a quarter of a century ago. Ligands 7 and 10 coordinate Rh(I) in a bidentate fashion through the S atoms and the alkene functions as evidenced by the crystal structures of complexes (R)-11 and (SN,SS)-12. (R)-11 catalyzes the conjugate addition of arylboronic acids to enones with enantioselectivities of up to 77% ee. The reaction proceeds smoothly also under base-free conditions at 40 °C. The planar chirality in ligand (pS,RS)-10 is shown to override and invert the sense...

Quinine-based (R)-tert-butylsulfinate 3 reacts with tris-lithiated bis-arylamide 2 to afford gram-quantities of optically pure (S*O)N(S*O) sulfoxide pincer ligand (R,R)-4. Deprotonation of (R,R)-4 and p-Tol-substituted analogue (S,S)-5 with MgPh2 and BnK yields respective Mg and K amido-bis-sulfoxides 6–9. In Mg complexes 6 and 7, the sulfoxide functions are O-coordinated, thereby imparting a pronounced helicity to the ligand backbone. Transmetalation of 6 and 7 with [PdCl2(NCPh)2] affords the S,S-coordinated C2-symmetric and the O,S-coordinated C1-symmetric chlorido complexes 10 and 11, respectively, and reaction of potassium amides 8 and 9 with [PdCl(CH3)(COD)] leads to methyl-palladium pincer complexes 12 and 13, respectively. The crystal structures of 6, 7, 12, and 13 reveal a chameleonic ligand system with predictable behavior: (R)-configured 4 induces pronounced λ backbone helicity in the O-coordinated Mg-complex and weaker δ helicity in S-coordinated Pd-complexes, while (S)-configured ligand 5 mirr...

10-Phenyl-5H-dibenz[b,f]azepine (5) is synthesized by Suzuki cross coupling of the protected bromo alkene 4 with PhB(OH)2. 5 reacts with PCl3 to afford the dichlorophosphanyl-azepine 6 in >90% yield. Alkylation of 6 with 1 equiv of t-BuMgBr leads, after recrystallization in Et2O, to the diastereomerically enriched (dr > 98:2) chloride rac-7, which the crystal structure reveals to be the (pS,RP)/(pR,SP) pair. The fact that rac-7 crystallizes in the Sohncke space group P212121 opens up the possibility of a mechanical separation of the enantiomers. Methylation of rac-7 is perfectly stereoselective with inversion of configuration at the P atom to yield the new ligand rac-8 as the (R,R)/(S,S) pair. The corresponding BH3-protected diastereomer rac-9 (i.e., the (R,S)/(S,R) pair), is isolated after flash column chromatography in 73% yield. Compounds 5–9 are accessible in multigram quantities. X-ray crystal structures of Ru(II) complexes demonstrate the ambidentate nature of ligand rac-8: Complex 10 is exclusively...

A number of P-stereogenic N-phosphinyl compounds were stereoselectively prepared in good yields by a straightforward approach, thanks to the diversified and, up until now, unexplored reactivity of (R)- and (S)-dicyclohexylidene-D-glucose methyl phenyl phosphinates toward metal amides. Under adequate conditions, structurally different phosphinamides with one or two P-chiral centers were obtained.

An improved method for the tert-butanesulfinylation of diacetone glucose with tert-butanesulfinyl chloride is reported. The method is based on a beneficial effect of catalytic DMAP, which enhances both the rate of the reaction and the enantioselectivity of the process to give (RS)-diastereomer 2RS with a 94 % de and in quantitative yield. (RS)-DAG sulfinate ester 2RS is an excellent intermediate for the synthesis of enantiopure tert-butyl sulfoxides. Grignard agents and organolithium reagents can displace smoothly the diacetone glucose moiety to give synthetically relevant enantiopure sulfoxides, including highly functionalized derivatives, in high yields and with high enantioselectivities. (RS)-DAG sulfinate ester 2RS is also an excellent N-sulfinylating agent; simple addition of LiHMDS (lithium hexamethyldisilazide) in THF gives (SS)-tert-butanesulfinamide, and N-tert-butanesulfinylimines are then formed in a two-step one-pot manner. N-Alkylated tert-butanesulfinamides are formed by the condensation of 2RS with lithium amides.

A number of P-stereogenic N-phosphinyl compounds were stereoselectively prepared in good yields by a straightforward approach, thanks to the diversified and, up until now, unexplored reactivity of (R)- and (S)-dicyclohexylidene-D-glucose methyl phenyl phosphinates toward metal amides. Under adequate conditions, structurally different phosphinamides with one or two P-chiral centers were obtained.

A new type of chiral sulfinamide phosphinate catalysts with up to three stereogenic centers, readily accessible from commercially available starting materials, is reported. The naphthyl derivative SulPhos proved to be highly efficient in the organocatalytic asymmetric imine reduction, leading to a wide range of arylmethylamines in high yields with up to 99% ee under 10% catalyst loading. The synthetic utility of this method was demonstrated by the expeditious enantioselective synthesis of the calcimimetic NPS-R568., This work was supported by the “Ministerio de Economía y Competitividad” (CTQ2013-49066-C2-2-R) and the Junta de Andalucía (P11-FQM-08046).

A number of P-stereogenic N-phosphinyl compounds were stereoselectively prepared in good yields by a straightforward approach, thanks to the diversified and, up until now, unexplored reactivity of (R)- and (S)-dicyclohexylidene-D-glucose methyl phenyl phosphinates toward metal amides. Under adequate conditions, structurally different phosphinamides with one or two P-chiral centers were obtained., We are grateful to the Spanish Ministerio de Economía y Competitividad (MEC) (grant number CTQ2013‐49066‐C2‐2‐R) and the Junta de Andalucía (grant number P11‐FQM‐08046) for financial support.

Motivación: La utilización de compuestos estereoquímicamente puros presenta numerosas ventajas frente al uso de racematos en la industria farmacéutica, debido principalmente a la estrecha e importante relación existente entre quiralidad y actividad biológica. En este sentido, el trabajo que se presenta en esta comunicación se enmarca dentro de un proyecto más amplio encaminado al desarrollo de nuevas estrategias para el diseño y la síntesis estereoselectiva de compuestos quirales con actividad biológica de interés. En concreto, nos centramos en la síntesis enantioselectiva de compuestros derivados de hidroxi-ésteres y de sus correspondientes lactonas, con estructura de 4-aminocroman-2-ona, asi como sus análogos fosoforados. Estos compuestos conctituyen la estrcutura básica de una familia de inhibidores de la agregación plaquetaria, modulador de la formación de trombos (1), cuya síntesis hasta la fecha, no ha podido ser realizada en forma ópticamente pura. Métodos: La metodología aplicada se basa en la capacidad que presenta el grupo sulfinilo como inductor quiral en las adiciones nucleofílicas a N-sulfiniliminas quirales (2). Por una parte, la adición del anión de acetato de etilo permite obtener las correspondientes 2-aminocromanonas ópticamente puras. Y por otra parte, la adición del metil carbanión del fenilfosfinato de metilo da lugar a los correspondientes bioisósteros derivados de fósforo. Resultados: Las adiciones de ambos aniones resultan ser estereoselectivas y nos permiten acceder a una amplia quimioteca de derivados quirales cuya síntesis se ha llevado a cabo por vez primera en forma ópticamente pura, lo que permite el estudio de la actividad de ambos enantiómeros por separado. Conclusiones: Se ha desarrollado una nueva metodología general, fácil, eficaz y modulable para la síntesis estereoselectiva de ambos enantiómeros de una amplia gama de ésteres de diferente naturaleza, que constituyen una nueva familia de compuestos de interés para su posterior apliación en farmacología.

El trabajo presentado en esta Tesis Doctoral forma parte de un proyecto de investigación más amplio desarrollado a lo largo de los últimos años por nuestro grupo de investigación, que tiene por objeto la síntesis estereoselectiva de compuestos quirales de azufre de interés sintético y/o farmacológico. En concreto, en esta Tesis Doctoral nos hemos propuesto extender el uso de diversos sulfinilderivados quirales a aquellos campos en los que su aplicación ha sido menos explorada, como es la catálisis asimétrica y especialmente la organocatálisis, y hacer extensivo este estudio a los derivados análogos con un átomo de fósforo quiral, los fosfinilderivados, aprovechando la similitud que existe entre la química de ambos tipos de derivados. En el primer capítulo se describe la preparación de terc-butanosulfinatos de DAG y metil fenilfosfinatos de DCG, a gran escala y de forma diastereoselectiva, utilizando la metodología de la DAG desarrollada previamente por nuestro grupo de investigación. Esto ha sido posible gracias al efecto catalítico, hasta ahora inexplorado y determinante, que ejerce la DMAP sobre el curso estereoquímico del proceso. Ambos ésteres han demostrado ser unos excelentes agentes de sulfinilación y fosfinilación, respectivamente, y mediante su reacción con diferentes nucleófilos tanto carbonados como nitrogenados se han obtenido una gran variedad de compuestos quirales de azufre y de fósforo. Por otra parte, aprovechando el carácter ácido de los protones metílicos de los metilfosfinatos, se han aplicado los correspondientes carbaniones como nucleófilos en procesos de sustitución, sobre sulfinatos y fosfinatos, para obtener de forma estereoselectiva diferentes ligandos bidentados. El capítulo II se dedica exclusivamente al estudio de la adición de los metilcarbaniones de los (R) y (S)-metil fenilfosfinatos de DCG a doble enlaces imínicos de diferentes N-terc-butilsulfiniliminas enantiopuras, prestando especial atención a la estereoselectividad del proceso. Las reacciones transcurren en general de forma estereoselectiva, siendo el azufre sulfinílico quien controla la estereoquímica del nuevo centro quiral en el producto final. De esta forma se ha obtenido una amplia quimioteca de productos quirales diferentemente sustituidos, entre los que cabe destacar algunos derivados bifuncionales con estructura de 2-(terc-butilsulfinamido)etil fosfinatos. En el capítulo III se describe el estudio de la reactividad de estos derivados y su transformación en productos de interés biológico (isósteros de ¿-aminoácidos) o sintético (organocatalizadores bifuncionales). Por último, como fruto de nuestro interés por la catálisis asimétrica y aprovechando la modularidad de los métodos desarrollados a lo largo de la Tesis, el capítulo IV se ha consagrado a la optimización de la estructura de los derivados obtenidos en los apartados anteriores para su aplicación como ligandos quirales en diferentes procesos de catálisis, tanto orgánica como organometálica. En este sentido, los 2-(terc-butilsulfinamido)etil fosfinilderivados han demostrado ser unos excelentes organocatalizadores quirales en la reacción de hidrosililación de iminas, permitiendo la síntesis de aminas quirales con altas enantioselectividades y altos rendimientos químicos, compitiendo así favorablemente con los mejores catalizadores descritos hasta la fecha en la literatura. La efectividad de estos organocatalizadores ha sido demostrada mediante la síntesis enantioselectiva de un calciomimético de nueva generación el NPS R-568, en tan solo cuatro etapas y 58% de rendimiento global. En cuanto a la catálisis asimétrica promovida por metales de transición, se han sintetizado y estudiado dos tipo de ligandos, los bis-sulfóxidos C2-simétricos y unos nuevos ligandos bidentados llamados sulfolefinas con un azufre de tipo sulfinamida y una olefina coordinante. Este estudio nos ha permitido encontrar nuevos sistemas catalíticos efectivos y altamente enantioselectivos tanto en la adición 1,4 como en la adición 1,2 de ácidos arilborónicos a cetonas activadas, catalizada por rodio, y desarrollar una versión de este sistema más respetuosa con el medio ambiente en ausencia de disolventes orgánicos.

© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. An improved method for the tert-butanesulfinylation of diacetone glucose with tert-butanesulfinyl chloride is reported. The method is based on a beneficial effect of catalytic DMAP, which enhances both the rate of the reaction and the enantioselectivity of the process to give (RS)-diastereomer 2RS with a 94%de and in quantitative yield. (RS)-DAG sulfinate ester 2RS is an excellent intermediate for the synthesis of enantiopure tert-butyl sulfoxides. Grignard agents and organolithium reagents can displace smoothly the diacetone glucose moiety to give synthetically relevant enantiopure sulfoxides, including highly functionalized derivatives, in high yields and with high enantioselectivities. (RS)-DAG sulfinate ester 2RS is also an excellent N-sulfinylating agent; simple addition of LiHMDS (lithium hexamethyldisilazide) in THF gives (SS)-tert-butanesulfinamide, and N-tert-butanesulfinylimines are then formed in a two-step one-pot manner. N-Alkylated tert-butanesulfinamides are formed by the condensation of 2RS with lithium amides.

The application of acyclic C2-symmetric chelating bis-sulfoxide ligands in the Rh(I)-catalyzed enantioselective 1,4-addition of boronic acids to electron-deficient alkenes is reported. Among the acyclic ethane-bridged bis-sulfoxides tested, the ligand Ferbisox (11), bearing ferrocenyl moieties as substituents at the sulfinyl sulfurs, has exhibited the best results in terms of chemical yield (up to 96%) and enantioselectivity (up to 97% ee). The conjugate addition takes place smoothly in toluene at room temperature in short reaction times (typically 2 h). The reaction scope, including the use of different boronic acids, five-, six-, and seven-membered cyclic enones, an unsaturated lactone, and the most challenging acyclic ketones, is reported. An X-ray diffraction study of the [Ferbisox·RhCl]2 precatalyst clearly exhibits a dimeric structure with an S coordination of the sulfoxide to rhodium. On the basis of the X-ray data and on structural studies conducted in solution by 1H NMR, a model explaining the hi...

An efficient micellar catalytic approach for the 1,4-addition of boronic acids to cyclic ketones (I) and lactone (IV), which permits the preparation of chiral ketones (III) and ester (V), resp., in high enantioselectivities is described.

The application of acyclic C2-symmetric chelating bis-sulfoxide ligands in the Rh(I)-catalyzed enantioselective 1,4-addition of boronic acids to electron-deficient alkenes is reported. Among the acyclic ethane-bridged bis-sulfoxides tested, the ligand Ferbisox (11), bearing ferrocenyl moieties as substituents at the sulfinyl sulfurs, has exhibited the best results in terms of chemical yield (up to 96%) and enantioselectivity (up to 97% ee). The conjugate addition takes place smoothly in toluene at room temperature in short reaction times (typically 2 h). The reaction scope, including the use of different boronic acids, five-, six-, and seven-membered cyclic enones, an unsaturated lactone, and the most challenging acyclic ketones, is reported. An X-ray diffraction study of the [Ferbisox·RhCl]2 precatalyst clearly exhibits a dimeric structure with an S coordination of the sulfoxide to rhodium. On the basis of the X-ray data and on structural studies conducted in solution by (1)H NMR, a model explaining the high enantioselection observed is proposed.

The sulfinamide is efficient for the asymmetric 1,4-addition of boronic acids to both cyclic and acyclic enones.

Reported is a single high yielding step approximation to mixed olefin/sulfinamide ligands enclosing a chiral sulfur atom as the sole chiral center. The synthetic design is validated by a rapid optimization of the substituent at the sulfinyl sulfur, and by the synthesis of an efficient, highly enantioselective catalyst for the Rh-catalyzed 1,4-addition of boronic acids to both, cyclic and acyclic olefins.

Reported is a single high yielding step approximation to mixed olefin/sulfinamide ligands enclosing a chiral sulfur atom as the sole chiral center. The synthetic design is validated by a rapid optimization of the substituent at the sulfinyl sulfur, and by the synthesis of an efficient, highly enantioselective catalyst for the Rh-catalyzed 1,4-addition of boronic acids to both, cyclic and acyclic olefins. Ministerio de Ciencia e Innovación CTQ2010-21755-CO2-00 Junta de Andalucía P07-FQM-2774

8 páginas, 3 figuras, 1 tabla, 5 esquemas., Reported herein is a straightforward and enantiodivergent synthesis of both enantiomers of trifluoromethylated analogues of calcimimetic NPS R-569 in a highly estereoselective manner. The synthesis features a diastereoselective synthesis of the N-(isopropylsulfinyl)imine unit by the “DAG methodology” and a diastereoselective addition of Ruppert–Prakash's reagent to the imine as the key steps. No protecting groups were necessary, permitting an atom economic synthesis in only six steps. Further addition reactions of the CF3 anion to different N-(isopropylsulfinyl)imines were performed to demonstrate the suitability of the sulfinyl substituent to balance perfectly reactivity and diastereoselectivity., The authors thank the Spanish Ministerio de Ciencia e Innovación (MICINN), the European Regional Development Fund (grant numbers CTQ2007-61185 and CTQ2006-15515) and the Junta de Andalucía (grant numbers P06-FQM-01852 and P07-FQM-2774) for financial support. A. A. thanks the Ministerio de Educación y Ciencia (MEC) for a Ramón y Cajal Contract, V. V. thanks the Consejo Superior de Investigaciones Científicas (CSIC) for a predoctoral I3P grant. The authors thank the Spanish Ministerio de Ciencia e Innovación (MICINN), the European Regional Development Fund (grant numbers CTQ2007-61185 and CTQ2006-15515) and the Junta de Andalucía (grant numbers P06-FQM-01852 and P07-FQM-2774) for financial support. A. A. thanks the Ministerio de Educación y Ciencia (MEC) for a Ramón y Cajal Contract, V. V. thanks the Consejo Superior de Investigaciones Científicas (CSIC) for a predoctoral I3P grant.