Prochiral Carbon Research Articles

Tuning the Reactivity of Difluoromethyl Sulfoximines from Electrophilic to Nucleophilic: Stereoselective Nucleophilic Difluoromethylation of Aryl Ketones

A stereoselective synthesis of enantiomerically enriched difluoromethyl tertiary alcohols by tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic difluoromethylating agents is reported. The key feature of this chemistry is the diastereoselective addition of the difluoromethyl sulfoximine to the prochiral carbon of the ketone. The present method was used to prepare enantiomerically enriched difluoromethyl secondary alcohols and difluorinated analogues of the natural products gossonorol and boivinian B, demonstrating the potency of the method.

Highly Enantioselective Iridium‐Catalyzed Hydrogenation of α,β‐Unsaturated Esters

α,β-Unsaturated esters have been employed as substrates in iridium-catalyzed asymmetric hydrogenation. Full conversions and good to excellent enantioselectivities (up to 99 % ee) were obtained for a broad range of substrates with both aromatic- and aliphatic substituents on the prochiral carbon. The hydrogenated products are highly useful as building blocks in the synthesis of a variety of natural products and pharmaceuticals.

Iridium-Catalyzed Asymmetric Hydrogenation Yielding Chiral Diarylmethines with Weakly Coordinating or Noncoordinating Substituents

Diarylmethine-containing stereocenters are present in pharmaceuticals and natural products, making the synthetic methods that form these chiral centers are important in industry. We have applied iridium complexes with novel N,P-chelating ligands to the asymmetric hydrogenation of trisubstituted olefins, forming diarylmethine chiral centers in high conversions and excellent enantioselectivities (up to 99% ee) for a broad range of substrates. Our results support the hypothesis that steric hindrance in one specific area of the catalyst is playing a key role in stereoselection, as the hydrogenation of substrates differing little at the prochiral carbon occurred with high enantioselectivity. As a result, excellent stereodiscrimination was obtained even when the prochiral carbon bore, for example, phenyl and p-tolyl groups.

Iridium-N,P-Ligand-Catalyzed Enantioselective Hydrogenation of Diphenylvinylphosphine Oxides and Vinylphosphonates

Diphenylvinylphosphine oxides and di- and trisubstituted vinylphosphonates have been employed as substrates in iridium-catalyzed asymmetric hydrogenations. Complete conversions and excellent enantioselectivities (up to and above 99% ee) were observed for a range of substrates with both aromatic and aliphatic groups at the prochiral carbon. We have also hydrogenated electron-deficient carboxyethylvinylphosphonates with excellent stereoselectivity (up to and above 99% ee). The hydrogenated products of both classes of substrates are synthetically useful intermediates.

Rational Design of a Novel Chiral Palladacycle: Synthesis, Optical Resolution, and Stereochemical Evaluation

AbstractA novel palladacycle was designed and prepared by direct cyclopalladation of the ligand 1‐(3,6‐dimethylnaphthalen‐1‐yl)‐N,N‐dimethylethanamine, which was synthesized by a multistep sequence starting from 2,7‐dimethylnaphthalene. The palladacycle structure and ring conformations of its triphenylphosphane derivative was investigated by X‐ray structural analysis in the solid state and 2D 1H–1H ROESY NMR spectroscopy in solution. The ortho‐palladated ring is stereochemically rigid, and the five‐membered ring conformation is locked by repulsive interactions between the methyl group on the prochiral carbon atom and its neighboring naphthylene proton. The racemic cyclopalladated complex could be efficiently resolved through the formation of its (S)‐prolinato derivatives, and efficient separation of the resulting diastereomeric complexes was achieved by simple silica‐gel chromatography. The structures and absolute configurations of the two optically resolved palladium complexes were determined by X‐ray crystallography. Both the (R,R)‐ and (S,S)‐di‐μ‐chloride dimeric palladium complexes could be obtained chemoselectively by treating the corresponding prolinato derivatives with 1 M hydrochloric acid. Despite the severe interchelate steric constraints within this new organopalladium complex, the bulky monodentate ligand 3,4‐dimethyl‐1‐phenylphosphole (dmpp) was coordinated regiospecifically to the ortho‐palladated amine unit trans to the NMe2 group. In comparison to its naphthylamine analogue, the new palladacycle showed a much higher stereoselectivity in the chiral template‐promoted asymmetric Diels–Alder reaction of coordinated dmpp and N,N‐dimethylacrylamide.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Carbon-fate maps for metabolic reactions

Stable isotope labeling of small-molecule metabolites (e.g. (13)C-labeling of glucose) is a powerful tool for characterizing pathways and reaction fluxes in a metabolic network. Analysis of isotope labeling patterns requires knowledge of the fates of individual atoms and moieties in reactions, which can be difficult to collect in a useful form when considering a large number of enzymatic reactions. We report carbon-fate maps for 4605 enzyme-catalyzed reactions documented in the KEGG database. Every fate map has been manually checked for consistency with known reaction mechanisms. A map includes a standardized structure-based identifier for each reactant (namely, an InChI string); indices for carbon atoms that are uniquely derived from the metabolite identifiers; structural data, including an identification of homotopic and prochiral carbon atoms; and a bijective map relating the corresponding carbon atoms in substrates and products. Fate maps are defined using the BioNetGen language (BNGL), a formal model-specification language, which allows a set of maps to be automatically translated into isotopomer mass-balance equations. The carbon-fate maps and software for visualizing the maps are freely available (http://cellsignaling.lanl.gov/FateMaps/).

One Pot Synthesis of Biodynamic Bisamidothiophosphonates Incorporating Asymmetric Phosphorus Atom

N-alkyl-2-pyridinylidenamido(phenyl)chlorothiophosphonates have been generated in situ by oxidative phosphorylation of N-alkyl-2-aminopyridinium halides through the intermediacy of functionalized halophosphines. As evident from the proton NMR spectroscopy, the generated chiral system had induced diastereotopicity in the geminal protons attached to a prochiral carbon atom. Due to the presence of an active chlorine atom, they have been used as precursors for the synthesis of novel bisamidothiophosphonates. The bioactive nature of these compounds has been established after bioassay against the fungi Alternaria alternata, Aspergillus flavus, Aspergillus niger, and Fusarium oxysporum and the insect Holotrichea Consanguinea.

Selectivity in the Self-Assembly of Organometallic Gold(I) Rings and [2]Catenanes

The selectivity of formation of organometallic rings or [2]catenanes [{X(4-C 6 H 4 OCH 2 -C≡CAu) 2 (μ-Ph2PZPPh2)} n ], n =1 or 2, respectively, has been studied as a function of the hinge group X and the diphosphine ligand [X = O, S, SO 2 , CH 2 , CMe 2 , CPh 2 , C(CF 3 ) 2 , C 6 H 1 0 ; Z = (CH 2 ) m with m = 2-5]. When Z = (CH 2 ) 3 , mixing of pairs of compounds with different C 2 v -symmetrical hinge groups (X, X' = SO 2 , CH 2 , CMe 2 , CPh 2 , C(CF 3 ) 2 , C 6 H 1 0 ) led to formation of an equilibrium mixture containing the unsymmetrical [2]catenanes [{X(4-C 6 H 4 OCH 2 -C≡CAu) 2 (μ-Ph2PZPPh2)}{X'(4-C 6 H 4 OCH 2 C≡CAu)2(μ-Ph2PZPPh2)], as identified by NMR spectroscopy. The complexes with Z = (CH 2 ) 4 exist in solution predominantly as the macrocycles and so do not form analogous mixed diacetylide complexes. When the hinge group contained a prochiral carbon center (X = CHMe, CMePh, 1,1-indanylidene), only achiral macrocycles [X(4-C 6 H 4 OCH 2 C≡CAu) 2 (μ-Ph 2 PZPPh 2 )] were formed in solution when Z = (CH 2 ) 4 , but mixtures containing both achiral macrocycles and chiral [2]catenane were formed when Z = (CH 2 ) 3 . In several cases, the solid-state structures of the isolated complexes were not representative of the structures in solution, with macrocycles being dominant in solution and [2]catenanes formed preferentially during crystallization.

Efficient Stereoselective Alkenylation Through a Homolytic Domino Reaction Involving a 1,5 Sulfur‐to‐Carbon Translocation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient stereoselective alkenylation through a homolytic domino reaction involving a 1,5 sulfur-to-carbon translocation.

An effective method for cis-stereoselective attachment of functionalized alkenyl appendages to sp3 carbon is reported. This method is based on a free-radical process, involving a sequence of addition-elimination steps, resulting in alkenyl group transposition from divalent sulfur to a prochiral carbon radical. Absolute stereoselectivity is secured since the new carbon-carbon bond is formed in a ring-closure reaction leading to a bridged bicyclic carbon-centered radical intermediate. The latter undergoes beta-scission of the C-S bond, leaving the alkenyl side chain in its predetermined position while releasing a thiyl radical. This thiyl radical is trapped by tri-n-butylstyryltin, affording a (styrylsulfanyl)methyl side chain and a tri-n-butyltin radical that continues the chain. When 2-(alkenylsulfanyl)methyl-4-bromo(or iodo)pyrrolidines were used as starting materials 2,4-cis-disubstituted 4-alkenyl-2-(styrylsulfanyl)methylpyrrolidines were obtained as products (70-90% yield). Tri-n-butylstyryltin was used rather then the more common n-Bu3SnH as tin radicals sources because the latter led predominantly to bridged bicyclic 3-thia-6-azabicyclo[3.2.1]octanes (up to 77% yield). An additional advantage of using tri-n-butylstyryltin derives from the discovery that the resulting styrylsulfide functionality is an excellent synthetic equivalent to the formyl group. Thus, using a Pummerer-type oxidative desulfurization, 4-cis-alkenyl-proline aldehydes were obtained.

Stereoselective free radical phenylsulfenylation of a nonactivated δ-carbon atom

A stereoselective free radical introduction of a phenylthio group onto a nonactivated methyl group in the ?-position, adjacent to a prochiral carbon atom, was achieved by photolysis of (-)-menthyl benzenesulfenate in the presence of hexabutylditin and (1R, 3R, 4S, 8S)-9-phenylthiomenthol (4) was obtained with 91%optical purity. High stereoselectivity of the reaction was calculated (ab initio MP2/6-31G**) to be the consequence of the difference in the transition state eneregies (??G# = 5.08 kJ/mol) favouring 4 relative to (1R,3R,4S,8R)-9-phenylthiomenthol (5). The absolute configuration of a the new chiral carbon atom was confirmed by its correlation with the corresponding menthane-3,9-diol of known stereochemistry.

New phosphino-oxazoline and related phosphino-iminolate palladium complexes; structure of an unusual zwitterionic dinuclear Pd(ii) complex

Reaction of the phosphino-oxazoline chiral ligand (4-(R)-phenyl-2-oxazoline-2-ylmethyl)diphenylphosphine) (abbreviated (R)-PCH2oxPh) with [Pd(dmba-C,N)(μ-Cl)]2 or [PdCl2(cod)] (cod = 1,5-cyclooctadiene) led to the formation of [Pd(dmba-C,N){(R)-PCH2oxPh-κ2P,N}]Cl 1 and [PdCl2{(R)-PCH2oxPh-κ2P,N}] 5, respectively. Deprotonation of the palladium phosphino-oxazoline complex 1 occurred at the PCH2 group and resulted in the formation of an anionic P,N chelate with a prochiral carbon atom in [Pd(dmba-C,N){(R)-PCHoxPh-κ2P,N}] 2. Reaction of 2 with [Pd(dmba-C,N)(μ-Cl)]2 led to the unexpected and diastereoselective formation of the dinuclear complex [{Pd(dmba-C,N)Cl}-(R)-{CHPPh2-(R)-oxPh}Pd(dmba-C,N)] 4 in which a Pd(dmba-C,N)Cl moiety is directly bonded to the carbon α to the P atom of the anionic P,N chelate of 2. This results in an unsual zwitterionic structure. In the course of this work, crystals of [(dmba-C,N)Pd(μ-OH)(μ-Cl)Pd(dmba-C,N)]·1/2[Pd(dmba-C,N)(μ-Cl)]27 were obtained and the single crystal X-ray analyses of complexes 2, 4·2THF, 5·CH2Cl2, [PdCl(Me){(R)-PCH2oxPh-κ2P,N}] 6 and 7 are presented.

Preparation and properties of dinuclear dioxomolybdenum(VI) complexes with ONO–ONO-type hexadentate Schiff base ligands

Preparation and properties of dinuclear cis-dioxomolybdenum(VI) complexes containing ONO–ONO-type hexadentate Schiff bases derived from 2,5-dihydroxyterephthalaldehyde and aminoalcohols in a 1:2 molar ratio are reported. When 2-amino-2-methyl-1,3-propanediol was used as the aminoalcohol, the 1H NMR spectrum of the complex showed two sets of resonances, indicating the presence of two isomers. The origin of the isomerism was elucidated by variable-temperature 1H NMR spectroscopy and by comparing the 1H NMR spectrum with those of the analogous dinuclear complexes derived from (1 R,2 S)- and (1 S,2 R)-norephedrine and with those of the corresponding mononuclear complexes. The Schiff base ligand derived from 2,5-dihydroxyterephthalaldehyde and 2-amino-2-methyl-1,3-propanediol contains two prochiral carbon atoms, which become chiral ( R and S) upon coordination. The combination of these two chiral centers generates three stereoisomers, RR, SS, and RS (= SR), and the NMR characteristics were accounted for by these isomers.

Studies in the stereoselective trapping of prochiral carbon radicals by optically active camphoxyl nitroxides

Optically active camphoxyl nitroxides derived from camphene react with prochiral carbon radicals to give diastereomeric coupling products. The diastereomeric ratio can be conveniently measured by 1H-NMR spectroscopy, in contrast to previous work employing steroidal nitroxides. The structure of the camphoxyl radical was modified; all couplings resulted in modest diastereoselectivity.

Intramolecular Regioselective Insertion into Unactivated Prochiral Carbon−Hydrogen Bonds with Diazoacetates of Primary Alcohols Catalyzed by Chiral Dirhodium(II) Carboxamidates. Highly Enantioselective Total Synthesis of Natural Lignan Lactones

Intramolecular insertion into unactivated prochiral C−H bonds of 3-aryl-1-propyl diazoacetates catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-carboxylate], Rh2(4R-MPPIM)4 or Rh2(4S-MPPIM)4, occurs in 91−96% ee and with virtually complete regiocontrol for the formation of β-benzyl-γ-butyrolactones. This methodology has been applied to the total synthesis of dibenzylbutyrolactone lignans (−)- and (+)-enterolactone, (−)- and (+)-hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19−27% overall yields. Aryltetralin lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee and 23% yield overall. Applications of the chiral Rh2(MPPIM)4 catalysts to fully aliphatic systems resulting in the formation of β-substituted-γ-butyrolactones with high regiocontrol and with 93−96% ee have demonstrated the generality of this met...

Asymmetrische Synthesen mit chiralen 1,4‐Oxazin‐2,5‐dionen: Darstellung enantiomerenreiner 2‐substituierter Pipecolinsäurederivate

Asymmetric Synthesis with Chiral 1,4‐Oxazine‐2,5‐diones: Preparation of Enantiomerically Pure 2‐Substituted Pipecolic Acid Derivatives Herrn Prof. Dr. H.‐D. Stachel mit den besten Wünschen zum 65. Geburtstag gewidmet. A new asymmetric synthesis of α‐amino acids is presented. This synthesis is based on the chiral 1,4‐oxazine‐2,5‐diones 5 and 14 relying on the α‐hydroxy acid 12 as a chiral auxiliary. A base‐mediated alkylation of these chiral amino acid building blocks (5, 12) with different alkyl halides proceeds, after deprotonation with sec‐butyllithium, with high yields and excellent d.s. (up to 99.5/0.5). As exemplified by the synthesis of 15 (in comparison to that of 7a) the absolute configuration of the stereocenter in the amino acid unit is determined by the sequence the substituents are introduced. In the enolate 6 and in that of 14 the electrophile adds consistently to the re face of the prochiral carbon. From the alkylation products the corresponding 2‐substituted pipecolic acid derivatives are obtained in good yields upon hydrolysis under basic or acidic conditions.

Stereoselectivity of enzymic and chemical oxygenation of sulfur atoms in 2-methyl-1,3-benzodithiole

S-Monooxygenation of 2-methyl-1,3-benzodithiole, to yield cis- and trans-2-methyl-1,3-benzodithiole 1-oxide, has been studied as a new stereochemical probe using achiral and chiral chemical oxidants and enzymes from microbial and animal sources. Chemical oxidants showed a preference for trans S-oxide formation, and this preference was enhanced in the presence of a chiral matrix. The ability of pure enzymes to stereodifferentiate between geminal lone pairs on a prochiral sulfur atom, or geminal sulfur atoms on a prochiral carbon atom, has been observed

Stereoselective free-radical cyclization on a sugar template the sulphonyl radical as a synthetic tool for functionalized glycosides

The addition of a sulphonyl radical to the external double bond of an allyl glycal generates a pro-chiral carbon radical which adds to the glycal double bond with a high diastereoselectivity. Through three consecutive radical steps, the configurations of three new asymmetric centers are controlled.

ChemInform Abstract: Asymmetric Functionalization at a Prochiral Carbon Center by the Aid of Sulfinyl Chirality: A Selective Formation of 6‐Substituted (3R,Ss)and (3S,Ss)‐3‐Hydroxymethyl‐3,4‐dihydro‐5‐(p‐tolyl)sulfinyl‐2H‐pyrans.

AbstractThe iodomethyl‐1,3‐dioxane (IV) and the chiral sulfones (VII), prepared as shown in the reaction scheme, are coupled and then cyclized to form the bicyclic sulfinyldioxanes (IX).

Diastereotopic selectivity at prochiral carbon centers: functionalization of differentiated hydroxymethyl groups provides access to either stereoisomeric configuration

Application de la spiroacetalisation a la synthese de (±)-invictolide et a la synthese non racemique du fragment C 1 -C 9 de l'ionomycine