Consecutive Intermolecular Reductive Amination/Asymmetric Hydrogenation: Facile Access to Sterically Tunable Chiral Vicinal Diamines and N‐Heterocyclic Carbenes

A highly enantioselective iridium‐ or ruthenium‐catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2‐quinoline aldehydes and aromatic amines has been developed. A broad range of sterically tunable chiral N,N′‐diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N‐heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition‐metal‐catalyzed asymmetric Suzuki–Miyaura cross‐coupling reaction and asymmetric ring‐opening cross‐metathesis, respectively.     

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

A Ru-catalyzed direct asymmetric reductive amination of ortho-OH-substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible -OH group.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Asymmetric Proline‐Catalyzed Addition of Aldehydes to 3H‐Indol‐3‐ones: Enantioselective Synthesis of 2,3‐Dihydro‐1H‐indol‐3‐ones with Quaternary Stereogenic Centers

The proline‐catalyzed addition of various aliphatic aldehydes to sterically hindered 2‐aryl‐substituted 3H‐indol‐3‐ones affords 2,2‐disubstituted 2,3‐dihydro‐1H‐indol‐3‐one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)‐2‐(2‐bromophenyl)‐2,3‐dihydro‐2‐(2‐hydroxyethyl)‐1H‐indol‐3‐one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.     

Asymmetric oxidation of sulfides with H2O2 catalyzed by titanium complexes of Schiff bases bearing a dicumenyl salicylidenyl unit

The sterically hindered Schiff bases (L³–L⁵), prepared from 3,5‐dicumenyl salicylaldehyde and chiral amino alcohols, were used in combination with Ti(OiPr)₄ for asymmetric oxidation of aryl methyl sulfides with H₂O₂ as terminal oxidant. Among the ligands L³–L⁵, L⁴ with a tert‐butyl group in the chiral carbon of the amino alcohol moiety gave the best result with 89% yield and 73% ee for the sulfoxidation of thioanisole under optimal conditions [with 1 mol% of Ti(OiPr)₄ in a molar ratio of 100:1:1.2:120 for sulfide:Ti(OiPr)₄:ligand:H₂O₂ in CH₂Cl₂ at 0 °C for 3 h]. The reaction afforded good yield (84%) with a moderate enantioselectivity (62% ee) even with a lower catalyst loading from 1.0 to 0.5 mol%. The oxidations of methyl 4‐bromophenyl sulfide and methyl 4‐methoxyphenyl sulfide with H₂O₂ catalyzed by the Ti(OiPr)₄–L⁴ system gave 79–84% yields and 54–59% ee of the corresponding sulfoxides in CH₂Cl₂ at 20 °C. The chiral induction capability of the cumenyl‐modified sterically hindered Schiff bases for sulfoxidation was compared with the conventional Schiff bases bearing tert‐butyl groups at the 3,5‐positions of the salicylidenyl unit. Copyright © 2011 John Wiley & Sons, Ltd.     

Asymmetric,regio‐ and stereo‐selective alternating copolymerization of CO2 and propylene oxide catalyzed by chiral chromium Salan complexes

Chiral chromium complexes of tetradentate N,N′‐disubstituted bis(aminophenoxide) (designated as Salan, a saturated version of Schiff‐base Salen ligand) in conjunction with an ionic quaternary ammonium salt can efficiently catalyze the copolymerization of CO₂ with racemic propylene oxide (rac‐PO) at mild conditions to selectively afford completely alternating poly(propylene carbonate) (PPC) with ～ 95% head‐to‐tail linkages and moderate enantioselectivity. These new catalyst systems predominantly exceed the previously much‐studied SalenCr(III) systems in catalytic activity, polymer enantioselectivity, and stereochemistry control. The chiral diamine backbone, sterically hindered substitute groups on the aromatic rings, and the presence of sp³‐hydridized amino donors and its N,N′‐disubstituted groups in chiral SalanCr(III) complexes all play significant roles in controlling polymer stereochemistry and enantioselectivity. Furthermore, a relationship between polycarbonate enantioselectivity and its head‐to‐tail linkages in relation to regioselective ring‐opening of the epoxide was also discussed on the basis of stereochemical studies of PPCs derived from the copolymerization of CO₂ with chiral PO at various conditions. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6102–6113, 2008     

Catalyst‐Free Enantiospecific Olefination with In Situ Generated Organocerium Species

Described is the in situ formation of triorganocerium reagents and their application in catalyst‐free Zweifel olefinations. These unique cerium species were generated through novel exchange reactions of organohalides with n‐Bu₃Ce reagents. The adequate electronegativity of cerium allowed for compensating the disadvantages of both usually functional‐group‐sensitive organolithium species and less reactive organomagnesium reagents. Exchange reactions were performed on aryl and alkenyl bromides, enabling enantiospecific transformations of chiral boron pinacol esters. Finally, these new organocerium species were engaged in selective 1,2‐additions onto enolisable and sterically hindered ketones.     

Enantioselective Synthesis of 3,4‐Dihydropyran‐2‐ones by Domino Michael Addition and Lactonization with New Asymmetric Organocatalysts: Cinchona‐Alkaloid‐Derived Chiral Quaternary Ammonium Phenoxides

Chiral quaternary ammonium phenoxides were readily prepared from commercially available cinchona alkaloids and proved to be useful new asymmetric organocatalysts. Among various chiral quaternary ammonium phenoxides, a cinchonidine‐derived catalyst that bears both a sterically hindered N1‐9‐anthracenylmethyl group and a strongly electron withdrawing 9‐O‐3,5‐bis(trifluoromethyl)benzyl group were found to be highly effective for the Michael addition of ketene silyl acetals (derived from phenyl carboxylates) and α,β‐unsaturated ketones followed by lactonization. Optically active 3,4‐dihydropyran‐2‐one derivatives were obtained in high yields with excellent control of enantio‐ and diastereoselectivity. This catalyst can be handled in air and stored at room temperature in a sealed bottle without decomposition for at least one month.     

Stereoregular polycarbonate synthesis: Alternating copolymerization of CO2 with aliphatic terminal epoxides catalyzed by multichiral cobalt(III) complexes

Completely stereoregular polycarbonate synthesis was achieved with the use of unsymmetric multichiral cobalt‐based complexes bearing a derived chiral BINOL and an appended 1,5,7‐triabicyclo[4.4.0] dec‐5‐ene as catalyst for the copolymerization of CO₂ and aliphatic terminal epoxides at mild conditions. The (S,S,S)‐Co(III) complex 1c with sterically hindered substituent group is more stereoregular catalyst for the copolymerization of CO₂ and racemic propylene oxide to afford a perfectly regioregular poly(propylene carbonate) (PPC), with >99% head‐to‐tail linkages, >99% carbonate linkages, and a K_rel of 24.4 for the enchainment of (R)‐epoxide over (S)‐epoxide. The isotactic PPC exhibits an enhanced glass transition temperature of 47 °C, which is 10–12 °C higher than that of the corresponding irregular polycarbonate. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011.     

Novel benzoferrocenyl chiral ligands: Synthesis and evaluation of their suitability for asymmetric catalysis

Four benzoferrocenyl phosphorus chiral ligands were conveniently prepared in good overall yields. These ligands were found to be stable in solid form and in solution. Two of the four ligands were resolved by chiral HPLC. Unlike a reported bis(phosphino-η⁵-indenyl)iron(II) complex, in which the indenyl ligands undergo ring flipping through an η¹-intermediate, these two ligands were found to be configurationally stable in solution and in solid state. The suitability of these ligands for enantioselective catalysis was assessed in studies on allylic alkylation reactions. When the two less sterically hindered ligands were used, excellent chemical yields were obtained, but the other two more sterically hindered ones gave lower yields. When the two enantiopure ligands were used, enantioselectivity of up to 51% ee was observed. These findings suggest that benzoferrocene derivatives may be used as chiral ligands for asymmetric catalysis.     

Regioselective Arylation and Alkynylation of 2,3‐Dibromo‐1H‐inden‐1‐one by Suzuki?Miyaura and Sonogashira Cross‐Coupling Reactions

Suzuki? Miyaura reactions of 2,3‐dibromo‐1H‐inden‐1‐one afforded a wide range of arylated 1H‐inden‐1‐ones. Sonogashira cross‐coupling reactions gave alkynylated indenones. The reactions proceeded with very good regioselectivity in the less sterically hindered and more electron‐deficient position 3.     

Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)‐2‐aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring‐opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P?O bond. Interestingly, the use of a P^III phosphine precursor afforded a P‐epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.     

Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions at sp3‐Hybridized Carbon Atoms: Kinetic Resolution of β‐Amino Alcohols by p‐Methoxybenzylation

A catalytic strategy was developed for asymmetric substitution reactions at sp³‐hybridized carbon atoms by using a chiral alkylating agent generated in situ from trichloroacetimidate and a chiral phosphoric acid. The resulting chiral p‐methoxybenzyl phosphate selectively reacts with β‐amino alcohols rather than those without a β‐NH functionality. The use of an electronically and sterically tuned chiral phosphoric acid enables the kinetic resolution of amino alcohols through p‐methoxybenzylation with good enantioselectivity.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

Total Synthesis of (−)‐Apratoxin A, 34‐Epimer,and Its Oxazoline Analogue

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18‐step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β‐hydroxyl group at the C35‐position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7‐dihydroxy‐2,5,8,8‐tetramethylnonanoic acid (Dtena), the three reagent‐controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically‐unfavorable N‐methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf₂O and Ph₃PO‐mediated dehydrative cyclization, and final macrocyclization was achieved between N‐methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.     

Facile Synthesis and Unusual Methanesulfonylation Reaction of (2R,3R)‐1,4‐Dimethoxy‐1,1,4,4‐tetrasubstituted‐2,3‐butanediols

A facile method for the synthesis of (2R,3R)‐1,4‐dimethoxy‐1,1,4,4‐tetrasubstituted‐2,3‐butanediols involving oxidative cleavage of benzylidene acetal as a key step is described. These sterically hindered diols unusually formed cyclic sulfites as the major product under methanesulfonylation reaction conditions.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

New strategies for the synthesis of N-alkylated indoles (Review)

New data, mostly published in the last five years, on methods for the synthesis of N-alkylated indoles both as a result of direct introduction of the alkyl substituent at the nitrogen atom and by construction of the indole heterocyclic system are reviewed. Only examples of indole derivatives containing branched, sterically hindered, and chiral alkyl substituents at the nitrogen atom are discussed.     

Toward the Total Synthesis of Onchidin,a Cytotoxic Cyclic Depsipeptide from a Mollusc

The total synthesis of onchidin ( 1 ), a cytotoxic, C₂‐symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel β‐amino acid, (2S,3S)‐3‐amino‐2‐methyl‐7‐octynoic acid (AMO), was efficiently prepared in high yield with high diastereo‐ and enantioselectivity based on a catalytic asymmetric three‐component Mannich‐type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N‐methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary‐amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid‐phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid‐phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.