Stereogenic Carbon Research Articles

Organocatalytic Asymmetric Tandem Michael−Henry Reactions: A Highly Stereoselective Synthesis of Multifunctionalized Cyclohexanes with Two Quaternary Stereocenters

A novel organocatalytic asymmetric tandem Michael-Henry reaction catalyzed by 9-amino-9-deoxyepiquinine (VI) has been developed. The reaction was efficiently catalyzed by catalyst VI to give highly functionalized cyclohexanes with four stereogenic carbons including two quaternary stereocenters in excellent enantioselectivities (97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr). Thus, the first organocatalytic asymmetric Henry reaction of common ketones as acceptors is shown.

Gold(III) Chloride‐Catalyzed Diastereoselective Alkylation Reactions with Chiral Benzylic Acetates

AbstractGold(III) chloride was shown to be an efficient catalyst for the diastereoselective CC bond formation of various chiral para‐methoxybenzylic acetates and different nucleophiles. All electrophilic acetates carried next to the reacting center a stereogenic carbon center bound to a functional group (FG), a methyl substituent and a proton. Selectivities were good (dr>80/20) in favor of the anti‐product for FG=COOMe, NO2, CN and in favor of the syn‐product for FG=SO2Et, PO(OEt)2. The reactions proceed most likely via a free carbocation, in which a face differentation is facilitated by a preferred conformation. Several arene nucleophiles were shown to be compatible with the catalysis conditions providing the corresponding substitution products in high yields (13 examples, 62–98%). Moreover, other nucleophiles (allyltrimethylsilane, trimethylsilyl cyanide, 2,2‐dimethyl‐3‐(trimethylsilyloxy)butane, p‐toluenesulfonamide, and acetylacetone) reacted with a representative chiral electrophile in a high yielding and diastereoselective fashion.

ChemInform Abstract: Enantioselective Construction of Quaternary Stereogenic Carbons by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An asymmetric synthesis of esters and γ-lactones with simultaneous construction of vicinal stereogenic carbons at the α- and β-position starting from optically active 1-chlorovinyl p-tolyl sulfoxides

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides with two different substituents at the 2-position, which were synthesized from aldehydes or unsymmetrical ketones and ( R)-(−)-chloromethyl p-tolyl sulfoxide in two or three steps, with the lithium enolate of carboxylic acid tert-butyl esters gave the adducts with substituents at the α- and β-position with high 1,3- and 1,4-chiral induction from the stereogenic sulfur center in high yields. The adducts were converted to optically active esters and γ-lactones having stereogenic centers at the α- and β-position in good to high yields. This procedure offers a new method for a synthesis of optically active carboxylic acid derivatives with stereogenic centers at the α- and β-position.

Novel Catalytic Synthetic Route to Protected α-Methyl Threonine and the First Asymmetric Acetyl Migration in a Steglich Rearrangement Reaction

A short synthetic route to protected a-methyl threonine 5 as a representative example for (protected) a-methylated a-amino-b-hydroxy acids bearing a stereogenic quaternary carbon center in a-position was developed. This multistep synthesis is based on the use of an easily accessible prochiral starting material in the presence of an organocatalyst, and allows the access to all four types of stereoisomers. In addition, the first enantioselective acetyl migration in a Steglich rearrangement reaction as a key step in this multistep synthesis of 5 was achieved. The heterocycle 12, which was used in Steglich rearrangement reaction for the first time, turned out to be an efficient organocatalyst leading to an enantioselectivity of up to 63% ee.

The role of chemical synthesis in structure elucidation of oxasqualenoids

Recently, highly oxidized and structurally diverse triterpene polyethers, which are thought to be biogenetically squalene-derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial organisms. However, it is often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic quaternary carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, we report total assignments of the previously incomplete stereostructures of an epoxy tri-THF diol, intricatetraol and enshuol, members of the oxasqualenoids, through the first asymmetric total syntheses of the natural products, the configurations of which are difficult to determine by other means. Since this article is basically written as a communication without detailed experimental procedures and spectroscopic data, original papers with full data should follow.

パラジウム錯体触媒による置換アレン類の立体選択的合成法の開発とその応用

A novel Pd-catalyzed reaction of a 2-halo- or 2-trifloxy-l, 3-butadiene derivative with a soft nucleophile is developed. The reaction proceeds via an exo-alkylidene-π-allylpalladium intermedi-ate in a formal SN2' fashion to give an allenic compound exclusively. A variety of soft nucleophiles, such as malonates, phenoxides, and imides, are applicable to the reaction, and thus a wide range of functionality can be introduced to the products. The reaction is extended into an asymmetric counterpart and axially chiral allenes are prepared with up to 93% ee by the use of chiral palladium catalysts. A formal total synthesis of an insect pheromone is achieved using the Pd-catalyzed asymmetric reaction as a key step. The Pd-catalyzed reaction also enables to prepare axially chiral (allenylmethyl) silanes and allenylsilanes in optically active forms. Reactions of these silylallenes with appropriate electrophiles proceed via SE', pathways and the allenic axial chirality is efficiently transferred to stereogenic carbon centers in the SE', products.

Catalytic Asymmetric Fluorination of α-Chloro-β-ketoesters in the Presence of Chiral Palladium Complexes

The chemistry of organic fluorine compounds is a rapidly developing area of research because of their importance in biochemical and medicinal applications and material science. Introduction of fluorine atom into biologically active compounds often leads to improvement of chemical and physical properties of the parent compounds due to unique properties of the fluorine atom. Chiral organofluorine compounds containing a fluorine atom bonded directly to a stereogenic center have been utilized in studies of enzyme mechanisms and as intermediates in asymmetric syntheses. The development of effective methodologies for the preparation of stereoselectively fluorinated compounds having a fluorine atom at a stereogenic carbon center is critical in order to further advances of fluorine chemistry. Until now, a number of enantioselective fluorinations have been achieved by reagent-controlled and catalytic enantioseletive fluorination. Recently, several groups have been reported the catalytic enantioselective fluorination of active methine derivatives using chiral Lewis acids such as Binap-Pd(II) and transition metal-bis(oxazoline) complexes and organocatalysts such as cinchonine-derived quaternary ammonium salt, imidazolidinone, and proline derivatives. A few synthetic methods for the preparation of α-chloroα-fluoro-β-ketoesters have been reported. In general, αchloro-α-fluoro-β-ketoesters were prepared by the electrophilic fluorination of α-chloro-β-ketoesters using NFSI or F2 in the presence of formic acid. Togni has recently reported the first catalytic enantioselective synthesis of α-chloro-αfluoro-β-ketoesters using chiral titanium complexes with up to 65% selectivity. As part of research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we reported the catalytic enantioselective α-fluorination and α-amination of β-ketoesters with excellent enantioselectivity which promoted by chiral ammonium salts and chiral palladium complexes. In this letter, we wish to report the catalytic enantioseletive electrophilic α-fluorination of α-chloro-β-ketoesters using chiral palladium complexes 3 which are airand moisturestable. To determine suitable reaction condition for the catalytic enantioselcetive fluorination of α-chloro-β-ketoesters 1, we first examined electrophilic fluorination of 1-chloro benzoylacetate 1a with N-fluorobenzenesulfonimide (NFSI) in the presence of 5 mol% of 3a in MeOH at room temperature (Table 1). As can be seen from Table 1, the fluorinated

Towards Configurationally Stable [4]Helicenes: Enantioselective Synthesis of 12‐Substituted 7,8‐Dihydro[4]helicene Quinones

The synthesis of enantiopure C-12 methoxy- or alkyl-substituted 5,7,8,12b-tetrahydro[4]helicene quinones 16 and 17 and the 7,8-dihydroaromatic analogues 4 and 5 has been achieved from (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone. In the first series, with a structure containing both central and helical chiralities, the R absolute configuration of the stereogenic carbon atom was defined after the asymmetric cycloaddition step, whereas the P or M helicity was shown to be dependent on the nature of the C-12 substituent. The size of this group was also defining the configurational stability of the final (P)-7,8-dihydro[4]helicene quinones 4 and 5. The interconversion barriers between the P and M helimers in the latter, computed with a DFT B3LYP method, matched well with the experimentally observed stability. Our study provided evidence that, in addition to steric effects, a small but significant role of electronic effects is governing the configurational stability of such helical quinones.

Recent Progress on the Lipase‐Catalyzed Asymmetric Syntheses

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Enantioselective Construction of Quaternary Stereogenic Carbons by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes

Silyl ketene imines derived from a variety of alpha-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl4 and the catalytic action of chiral phosphoramide (R,R)-5, silyl ketene imines undergo extremely rapid and high yielding addition to a wide variety of aromatic aldehydes with excellent diastereo- and enantioselectivity. Of particular note is the high yields and selectivities obtained from electron-rich, electron-poor, and hindered aldehydes. The nitrile function serves as a useful precursor for further synthetic manipulation.

Carbene Activation of P4 and Subsequent Derivatization

Broken down and added onto: An enantiomerically pure cyclic (alkyl)(amino)carbene cleanly activates P4, affording highly reactive products that can be further used for the diastereoselective construction of P4-containing molecules that feature phosphorus–carbon bonds (see scheme; DMB=2,3-dimethylbutadiene; portions of the products have been omitted, * denotes a stereogenic carbon center).

Lanthanide Complexes of the Chiral Hexaaza Macrocycle and Its meso-Type Isomer: Solvent-Controlled Helicity Inversion

Lanthanide(III) complexes of the enantiopure chiral hexaaza tetraamine macrocycle L, 2(R),7(R),18(R),23(R)-1,8,15,17,24,31-hexaazatricyclo[25.3.1.1.0.0]-dotriaconta-10,12,14,26,28,30-hexaene, as well as of its meso-type 2(R),7(R),18(S),23(S)-isomeric macrocycle L1, have been synthesized and characterized by spectroscopic methods. The 2D NMR spectra confirm the identity of these complexes and indicate C2 symmetry of the [LnL]3+ and Cs symmetry of the [LnL1]3+ complexes. The crystal structures of the [PrL(NO3)(H2O)2](NO3)2, [EuL(NO3)(H2O)2](NO3)2, [DyL(NO3)2]2[Dy(NO3)5] x 5CH3CN, [YbL(NO3)2]2[Yb(NO3)5] x 5CH3CN, [YbL(H2O)2](NO3)3 x H2O, and [EuL1(NO3)(H2O)2]0.52[EuL1(NO3)2]0.48(NO3)1.52 x 0.48H2O complexes have been determined by single-crystal X-ray diffraction. In all complexes, the lanthanide(III) ions are coordinated by six nitrogen atoms of the macrocycle L or L1, but for each type of complex, the conformation of the macrocycle and the axial ligation are different. The crystallographic, NMR, and CD data show that the [YbL]3+ complex exists in two stable forms. Both forms of the Yb(III) complex have been isolated, and their interconversion was studied in various solvents. The two forms of [YbL]3+ complex correspond to two diastereomers of ligand L, which differ in the sense of the helical twist and the configuration at the stereogenic amine nitrogen atoms. In one of the stereoisomers, the macrocycle L of (RRRR) configuration at the stereogenic cyclohexane carbon atoms adopts the (RSRS) configuration at the amine nitrogen atoms, while in the other stereoisomer, the macrocycle L of (RRRR) configuration at the stereogenic cyclohexane carbon atoms adopts the (SSSS) configuration at the amine nitrogen atoms. The (RRRR)(RSRS) isomer is quantitatively converting to the (RRRR)(SSSS) isomer in water solution, while the reverse process is observed for an acetonitrile solution, thus representing the rare case of helicity inversion controlled by the solvent.

Organocatalytic asymmetric aldol reaction of ketones with isatins: straightforward stereoselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones

An efficient asymmetric aldol condensation of ketones with isatins has been developed using an l-proline-derived bifunctional organocatalyst. This strategy allows the enantioselective synthesis of a variety of 3-alkyl-3-hydroxyindolin-2-ones with a stereogenic quaternary carbon center in excellent yields with good to excellent enantiomeric excess. The method has been applied to the enatioselective synthesis of ( S)-convolutamydine A successfully.

Stereospecific Synthesis, Structural Characterisation and Resolution of 2‐Phospha[3]ferrocenophane Derivatives – a New Chiral Scaffold

AbstractThe first 2‐phospha[3]ferrocenophanes containing stereogenic carbon atoms in the three‐atom bridge have been synthesised from phenylphosphane by stereospecific ring‐closing phosphanation reactions. Either α‐substituted 1,1′‐bis(hydroxymethyl)ferrocenes or the corresponding 2‐oxa‐[3]ferrocenophanes have been used as diastereomerically pure starting materials. The resolution of 1,2,3‐triphenyl[2]phosphaferrocenophane has been achieved by chromatographic separation of the diastereomeric adducts of a chiral cyclopalladate complex. The X‐ray crystal structures of two 2‐phospha[3]ferrocenophane‐borane complexes are also reported. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Total Synthesis of (±)-Terpestacin and (±)-11-epi-Terpestacin

The total synthesis of racemic terpestacin and 11-epi-terpestacin using the allene ether Nazarov reaction as the key step is described. All stereochemistry is derived from the stereogenic carbon atom that is formed during the Nazarov reaction.

An Allylpalladium(IV) Intermediate in the Synthesis of Highly Substituted Benzoxepines and Benzopyrans via Reactions of Stable Pallada(II)cycles with Allyl Bromides

Stable pallada(II)cycles L2Pd-1-C6H5-2-OCHCO2Et, featuring a Pd-bonded sp3-hybridized stereogenic carbon and bipyridine or bis(imine) auxiliary ligands (L-L), reacted with allyl bromides via a Pd(II)−Pd(IV)-mediated process involving a direct C(sp2)−H functionalization to afford highly substituted benzoxepines or benzopyrans. An allylpalladium(IV) complex, which was detected by low-temperature 1H NMR analysis and characterized by X-ray crystallography, was shown to operate as an intermediate in the reaction sequence.

Synthesis of novel chiral 1,3-aminophenols and application for the enantioselective addition of diethylzinc to aldehydes

Novel chiral 1,3-aminophenols were efficiently synthesized by applying a Friedel–Crafts reaction and optical resolution. The catalytic activity of the aminophenols was studied for the addition of diethylzinc to benzaldehyde. The results showed that ( S)- 5a with bulky tert-butyl groups on the stereogenic carbon atom and 4,6-positions of phenol favored higher enantioselectivity (94% ee). The same ligand was also used with other aldehydes, to give optically active alcohols in good chemical yields and ee values (up to 99%).

Computational prediction of the regio- and diastereoselectivity in a rhodium-catalyzed hydroformylation/cyclization domino process

The regioselectivity of the hydroformylation reaction of 2-methyl-3-(3-acetylpyrrol-1-yl)prop-1-ene catalyzed by an unmodified Rh catalyst has been investigated at the B3LYP/6-31G* level with Rh described by effective core potentials in the LANL2DZ valence basis set. Considering the population of all the H-Rh(CO)3-olefin transition state complexes, a regioselectivity ratio (B:L) of 12:88 has been obtained, in satisfactory agreement with the experiment producing the chiral linear aldehyde as the only product. The aldehyde, after complete diastereoselective cyclization, yields a 1:1 mixture of 1-acetyl-6R(S)-methyl-8R(S)-hydroxy-5,6,7,8-tetrahydroindolizine (having the same configuration on both stereogenic carbon atoms) and 2-acetyl-6-methyl-5,6-dihydroindolizine [Lett Org Chem (2006) 3:10-12]. The reason for such a high degree of diastereoselectivity has been elucidated examining the B3LYP/6-31G* potential energy surface for the reactions leading to the RR and RS diastereomers on a model system (without the acetyl substituent) and the actual compound. In the absence of a catalyst, a very high barrier is found along the reaction pathway, whereas spontaneous annulation occurs to a protonated pentahydroindolizine in the presence of H+. When a counterion (F-) is added, the proton on the newly formed tetrahedral carbon is abstracted, obtaining a structure closer to the final product (tetrahydroindolizine). Replacing H+ with Rh+, an initial adduct along the RS path much more favorable than any of those computed along the RR one is located because of the presence of the acetyl group. Tentative approaching paths obtained using [Rh(CO)3]+, bound to the aldehyde O, feature a higher barrier along the RS one, and offer a convincing explanation for the observed diastereoselectivity.

Synthesis of P-chiral phosphines via chiral metal template promoted asymmetric furan Diels–Alder reaction

The organoplatinum complex containing ortho-metalated ( S)-(1-(dimethylamino)ethyl)-naphthalene as the chiral auxiliary has been used to promote the asymmetric [4+2] Diels–Alder reaction between phenyldivinylphosphine and 2-diphenylphosphinofuran. The reaction was complete in 6 days at room temperature, with the formation of four isomeric diphosphino-substituted oxanorbornene metal complexes in the ratio of 4:2:2:1. Only the exo-cycloaddition products were formed. The formation of stereogenic carbon centers within the oxanorbornene skeleton are highly stereoselective, with all four cycloadducts adopting the same absolute configurations. However, the stereocontrol at the external phosphorus stereogenic center is less efficient ( S p: R p = 2:1 for the template cycloadducts). The chiral naphthylamine auxiliary could be removed chemoselectively by treatment with concentrated hydrochloric acid, and further ligand liberation of the dichloro complexes with aqueous cyanide gave the diphosphino-substituted oxanorbornene ligands. Hydrogenation of the double bonds in the cycloadduct stabilizes the phosphorus stereogenic center of the free diphosphine ligand which otherwise undergoes inversion of absolute configuration.