Absolute Configuration Of Products Research Articles

Ligand cooperativity enables highly enantioselective C–C σ-bond hydroboration of cyclopropanes

<h2>Summary</h2> Given the utility of enantioenriched alkylboronates, asymmetric borylation has attracted substantial research interest in recent decades. Herein, a catalytic enantioselective hydroboration through desymmetrization of enantiotopic carbons in cyclopropanes involving C–C bond activation is reported. Treatment of cyclopropanes bearing an amide directing group in the presence of rhodium catalysis using HBpin as a boron source allows the construction of a series of alkyl boronates containing γ-stereogenic amines. The key to high enantioselectivity relies on two distinct ligands that act cooperatively: an exogenous monodentate chiral phosphite that induces enantioselectivity and an endogenous acetylacetonate that exerts a remarkably positive influence on the enhancement of enantioselectivity. Detailed experimental and computational studies elucidate the effect of ligand cooperativity and the key steps involving σ-bond activation process, C–B bond formation, and the absolute configuration of products.

A Dipolar Cyclization/Fragmentation Strategy for the Catalytic Asymmetric Synthesis of Chiral Eight-Membered Lactams

A Dipolar Cyclization/Fragmentation Strategy for the Catalytic Asymmetric Synthesis of Chiral Eight-Membered Lactams

Dinuclear Zinc Catalyzed Enantioselective Dearomatization [3+2] Annulation of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes.

The application of dinuclear zinc catalysts in a dearomatization reaction has been developed. Catalytic asymmetric dearomatization [3+2] annulations of 2-nitrobenzofurans or 2-nitrobenzothiophenes with CF3 -containing N-unprotected isatin-derived azomethine ylides catalyzed by dinuclear zinc catalysts are realized with excellent diastereomer ratios (dr) of >20 : 1 and enantiomeric excess (ee) of up to 99 %. This protocol provides a practical, straightforward access to structurally diverse pyrrolidinyl spirooxindoles containing a 2,3-fused-dihydrobenzofuran (or dihydrobenzothiphene) moiety, and four contiguous stereocenters. Reactions can be performed on a gram scale. The absolute configuration of products is confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed.

Catalytic Asymmetric Synthesis of Tetrahydrofuran Spirooxindoles via a Dinuclear Zinc Catalyst.

An asymmetric Michael/hemiketalization and Fridel-Crafts reaction has been reported through a one-pot reaction. A number of structurally novel tetrahydrofuran spirooxindoles are synthesized in the presence of a 10 mol % dinuclear zinc catalyst with diastereomer ratios (dr) of 3:1-13:1 and an enantiomeric excess (ee) of 75-99%. The reaction can be performed on a gram scale without impacting its efficiency. The absolute configuration of products is confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed.

Synthesis of a 4‐Vinyltetrahydrocarbazole by Palladium‐Catalyzed Asymmetric Allylic Alkylation of Indole‐Containing Allylic Carbonates

AbstractPalladium‐catalyzed intramolecular asymmetric allylic alkylation was used for the first time to prepare 4‐vinyltetrahydrocarbazole 3. Suitable indole‐containing allylic carbonates were synthesized and cyclized in the presence of a chiral catalyst formed in situ from Pd(OAc)2 and members of the PhthalaPhos ligand library (i.e., 1,1′‐bi‐2‐naphthol‐monophosphites possessing a phthalic acid diamide group). The use of a stable and readily available palladium source such as Pd(OAc)2―reduced in situ by the phosphite to form the Pd0 catalyst―allowed better and more reproducible results to be obtained relative to the results achieved by using [Pd2(dba)3·CHCl3] (dba = dibenzylideneacetone) and [Pd(allyl)Cl]2. A ligand screening led to identification of the best ligand [(S)‐L1], which, after optimization of the reaction parameters, gave product 3 with 75 % ee. Remarkably, the reaction turned out to be stereodivergent: by using ligand (S)‐L1, the absolute configuration of product 3 was found to depend on the geometry of the substrate's double bond [(E)‐substrate → (S)‐3, (Z)‐substrate → (R)‐3].

Machine learning induction of chemically intuitive rules for the prediction of enantioselectivity in the asymmetric syntheses of alcohols

In an asymmetric catalytic reaction involving a specific catalyst, the prediction/determination of the absolute configuration of the major product is one of the essential issues. Some encouraging results of enantioselectivity prediction in asymmetric reactions have been achieved by chemoinformatics methods. However, intuitive empirical rules of enantioselectivity are to be preferred by chemists. This investigation attempted to combine chemoinformatics methods with the empirical rules of experts, i.e., to build chemoinformatics models on the basis of intuitive descriptors to derive interpretable empirical rules. In order to implement this, chiral substituent codes were specially developed, and Fisher linear discriminant analysis was used to construct the relationship between chiral substituent codes and the absolute configurations of the products in asymmetric reactions. The method was successfully applied to two data sets of reactions, namely to the products of the reaction – chiral alcohols. On the basis of the excellent results of structure–enantioselectivity relationships (SER), several empirical rules were extracted from the constructed mathematical models, which highlighted aspects of the mechanism and can almost entirely replace the analytical expressions. This investigation extends the application of chemoinfomatics methods to the area of generation of empirical rules, and the idea has the potential to be generally applied with enantioselective reactions by using different codes and different machine learning methods.

Enantioselective C-C bond formation as a result of the oriented prochirality of an achiral aldehyde at the single-crystal face upon treatment with a dialkyl zinc vapor.

Enantioselective C-C bond formation as a result of the oriented prochirality of an achiral aldehyde at the single-crystal face upon treatment with a dialkyl zinc vapor.

Gold(I)-Catalyzed Synthesis of Furo[3,4-d]-[1,2]oxazines

A previous regio- and diastereo­selective tandem cyclization-[3+3] cycloaddition of 2-(1-allynyl)-2-alken-1-ones 1 with nitrones 2 lead to furo[3,4-d][1,2]oxazines 3 with moderate enantioselectivity using AuCl2 as catalyst and (R)-MeO-biphep as ligand (F. Liu, Y. Yu, J. Zhang Angew. Chem. Int. Ed. 2009, 48, 5505). In this report, the replacement of L3 by L1 (modification of the bite angle) or L2 (bulkier substituents on the phosphorous aryl moieties) allowed the synthesis of optically active furo[3,4-d][1,2]oxazines 3 in high yield and excellent diastereoselectivities. The choice of solvent was also crucial to keep high dia­stereoselectivity. The absolute configuration of products 3 was confirmed by single-crystal X-ray analysis.

Chemoenzymatic synthesis of 2-oxabicyclo[3.3.1]nonan-3-one enantiomers via microbial reduction by Absidia coerulea AM 93

Microbial enantioselective reduction of (±)-diethyl 2-(3-oxocyclohexyl)malonate ( 1) has been described. A screening test on twenty-four fungi strains was carried out. Most of the microorganisms preferred bioreduction of (+)-isomer of δ-ketoester ( 1) to (+)- trans δ-hydroxy ester ( 2) with the anti-Prelog selectivity. Biotransformation conditions using Absidia coerulea AM 93 were optimized with respect to the growth medium, temperature and pH. An effect of 48 chemical additives on the course of biotransformation was checked. (−)-Diethyl 2-(( S)-3-oxocyclohexyl)malonate ((−)- 1) (ee = 98%) and (+)-diethyl 2-((1 R, 3 R)-3-hydroxycyclohexyl)malonate ((+)- 2) (ee = 99%) were isolated and subjected to chemical lactonization, leading to (+)-(1 R, 5 S)-2-oxabicyclo[3.3.1]nonan-3-one ((+)- 3) and (−)-(1 S, 5 R)-2-oxabicyclo[3.3.1]nonan-3-one ((−)- 3). The absolute configuration of product (−)- 1 was confirmed by comparison of its optical rotation with the literature data. The absolute configuration the carbon atom bearing hydroxyl group in product (+)- 2 was determined using the Mosher's ester.

Palladium-catalysed allylic alkylations and aminations with hetero- and homoannularly bridged bidentate ferrocene ligands

Sets of hetero- and homoannularly bridged ferrocenyl aminophosphine and diphosphine ligands were investigated in palladium-catalysed allylic alkylation and amination reactions ([1-PPh 2-2,1′-(α-R-CH(CH 2) 2)-ferrocene]: ( R c , R p )- 1: R = N(CH 3) 2; ( R c , R p )- 4: R = PPh 2; ( R c , R p )- 5: R = PCy 2; ([1-PPh 2-2,3-(α-R-CH(CH 2) 3)-ferrocene]: ( R c , R p )- 2: R = N(CH 3) 2; ( S c , R p )- 3: R = N(CH 3) 2; ( S c , R p )- 6: R = PPh 2; ( S c , R p )- 7: R = PCy 2). Diphenylprop-2-en-1-yl acetate and pent-3-en-2-yl acetate were used as the substrates and dimethyl malonate or benzylamine as the nucleophiles. Catalytic data were analysed and compared to those of PPFA ( 8) and Josiphos-type ( 9, 10) ligands ([1-PPh 2-2-(α-R-CHCH 3)-ferrocene]: ( S c , R p )- 8: R = N(CH 3) 2; ( S c , R p )- 9: R = PPh 2; ( S c , R p )- 10: R = PCy 2). Correlations between changes in enantioselectivity or absolute configuration of product and changes in ligand backbones or functional groups were assessed. Cationic palladium(II) diphenylallyl complexes of ligands 1, 4, 5 and 7 were isolated and their conformational behaviour in solution was analysed both as the isolated complexes and under catalytic conditions. The molecular structure of complex 7C ( endo syn/ syn form) was determined by X-ray diffraction.

Synthesis of novel norephedrine-based chiral ligands with multiple stereogenic centers and their application in enantioselective addition of diethylzinc to aldehyde and chalcone

Novel norephedrine-based chiral ligands with multiple stereogenic centers were conveniently prepared from norephedrine and N-substituted pyrrole. These novel chiral ligands were used to catalyze the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. The absolute configuration of products was found to be affected by the stereogenic centers on the norephedrine part of the novel chiral ligands.

Asymmetric Catalysis on the Intramolecular Cyclopropanation of α‐Diazo‐β‐keto Sulfones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric catalysis on the intramolecular cyclopropanation of alpha-diazo-beta-keto sulfones.

This work describes the development of a highly enantioselective asymmetric catalysis on the intramolecular cyclopropanation of alpha-diazo-beta-keto sulfones. We have found that the catalytic asymmetric intramolecular reactions of alpha-diazo-beta-keto sulfones generally proceed with high enantioselectivity when the alpha-diazo-beta-keto mesityl sulfone is used with the newly prepared ligand 2e. The absolute configuration of products has been determined by X-ray crystallographic analysis, and the outcome of the enantioselectivities is explained well by our proposed models A and B. The products possess great potential for natural product synthesis because (1) many different chemistries of cyclopropane, ketone, and sulfone are available, and (2) the products are generally highly crystalline, facilitating the supplies of enantiomerically pure synthetic intermediates.

Asymmetric synthesis of β-hydroxyesters by aldol type condensation of enantiomerically pure t-butyl p-tolyl sulfinyl acetate: unexpected substituent effect on the absolute configuration of the product

Aldol type condensation of enantiomerically pure t-butyl p-tolyl sulfinyl acetate was shown to give the opposite configuration at the hydroxylic center in the case of an α,β-unsaturated aldehyde, a result which is in sharp contrast with literature results. The absolute configurations of the aldol products were determined by X-ray crystallography.

Conversion of Various Aromatic Compounds by Resting Cells of Fusarium moniliforme Strain MS31.

Resting cells of Fusarium moniliforme strain MS31 convert propylbenzene to 1-phenylpropanol with high regio- and stereospecificity. To elucidate the scope of substrate acceptability by the fungus, we used various aromatic compounds for the bioconversion. The fungus hydroxylated various alkylbenzenes at the benzylic position to produce optically active alcohols. Butylbenzene was converted to nonbenzylic alcohols. In all cases, the R absolute configuration of products was more abundant. Aromatic compounds with linear side chains and (1-methylethyl)benzene were converted to their corresponding alcohols with an enantiomeric excess of 94% to 100%. Further oxidation of the alcohols was detected, but it was weak.

Conversion of various aromatic compounds by resting cells of Fusarium moniliforme strain MS31

Resting cells of Fusarium moniliforme strain MS31 convert propylbenzene to 1-phenylpropanol with high regio- and stereospecificity. To elucidate the scope of substrate acceptability by the fungus, we used various aromatic compounds for the bioconversion. The fungus hydroxylated various alkylbenzenes at the benzylic position to produce optically active alcohols. Butylbenzene was converted to nonbenzylic alcohols. In all cases, the R absolute configuration of products was more abundant. Aromatic compounds with linear side chains and (1-methylethyl)benzene were converted to their corresponding alcohols with an enantiomeric excess of 94% to 100%. Further oxidation of the alcohols was detected, but it was weak.

An efficient synthesis of bicyclic β-turn dipeptides via a photochemical key step

A novel synthetic route to bicyclic β-turn dipeptides (BTD) is described. It starts with L-β-benzoylalanine 1, which is N-protected and coupled with proline esters yielding the dipeptides 3. Upon irradiation 3a-c undergo a cyclization to the indolizinones 4 in a highly stereoselective manner. 4a and 4c were converted into the N-protected BTD derivatives suited for the peptide synthesis. The absolute configuration of products 4 and 5 were unambiguously elucidated from NOE results.

Biotransformations of γ-methyl-β-ketosulfones: stereoselectivity of 3-methyl-1-(phenylsulfonyl)hexan-2-one reductions by various yeasts

Abstract The stereoselectivity of the reduction of rac-3-methyl-1-(phenylsulfonyl)hexan-2-one (1) to 3-methyl-1-(phenylsulfonyl)hexan-2-ol (2) diastereomers by more than 20 yeasts was studied. Reduction of carbonyl group in 1 proceeds with a high Re-face enantioselectivity: Candida guillermondii (989% e.e.), C. zeylanoides (>99.9%) and Kloeckera apiculata (99.6%), respectively and the (R)- 1 enantiomer usually reacted faster. The enantioselectivity was determined by GC on chiral cyclodextrine phases and absolute configurations of products were assigned by NMR spectroscopy and a chemical correlation.

Resolution of the diols of bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.1]octane by enzymic hydrolysis, and their absolute configurations

Enzyme (pig liver esterase and lipase from Aspergillus niger)-catalysed enantioselective hydrolyses of racemic diacetates, (1R*,2S*,4R*,5S*)- and (1R*,2R*,4R*,5R*)-2,5-diacetoxybicyclo[2.2.1]heptanes, (1R*,2S*,4R*,5S*)-, (1R*,2R*,4R*,5R*)- and (1R*,2R*,4R*,5S*)-2,5-diacetoxybicyclo[2.2.2]-octanes, (2R*,3R*)-2,3-diacetoxybicyclo[2.2.2]octane and (1R*,2S*,6S*,8R*)- and (1R*,2S*,6S*,8S*)-2,8-diacetoxybicyclo[3.2.1]octanes gave the corresponding monoacetates and the recovered diacetates in an optically active form. The absolute configurations of products were unequivocally determined by chemical correlation to the corresponding known monoacetates, (2S)-(+)-2-acetoxybicyclo[2.2.1]heptane, (2S)-(+)-2-acetoxybicyclo[2.2.2]octane and (2S)-(+)-2-acetoxybicyclo[3.2.1 ]octane, and circular dichroism spectra of keto acetates and diketones derived from the hydrolysis products were examined.

Enantioselective synthesis of cyclohexene nitroaldehydes

An enantioselective synthesis of cyclohexene nitroaldehydes 2e–5e has been effected, via Diels-Alder reaction with sugar nitroolefins as chiral dienophiles. Absolute configuration of products has been determined by X-ray crystallographic analysis and chemical correlation.