Major Diastereomer Research Articles

Chirality and diastereoselection of Δ/Λ-configured tetrahedral zinc(II) complexes with enantiopure or racemic Schiff base ligands

Diastereoselection of enantiopure (S or R)-2-{(E)-(2-hydroxy-1-phenylethylimino)methyl}phenol (S- or R-HL1) with zinc(II)acetate leads to Δ-bis[(S)-2-{(E)-(2-hydroxy-1-phenylethylimino)methyl}phenoxide-κ2N,O]zinc(II) (Δ-Zn-S-L1) or Λ-bis[(R)-2-{(E)-(2-hydroxy-1-phenylethylimino)methyl}phenoxide-κ2N,O]zinc(II) (Λ-Zn-R-L1) as major products while racemic (R/S)-2-{(E)-(2-hydroxy-2-phenylethylimino)methyl}phenol (R/S-HL2) yields racemic Δ/Λ-bis[(R/S)-2-{(E)-(2-hydroxy-2-phenylethylimino)methyl}phenoxide-κ2N,O]zinc(II) (Δ/Λ-Zn-R/S-L2), respectively. The complexes are characterized by IR, UV–Vis, 1H NMR, mass spectrometry, circular dichroism (CD), and polarimetry. The bidentate N,O-chelation of two chiral enantiopure or racemic Schiff base ligands to four-coordinated, non-planar Zn(N^O)2 complexes leads to the preferential formation of one diastereomer or enantiomeric pair, respectively, in the solid state. Freshly prepared (30min) chloroform solutions from the solid product indicate a major diastereomeric component (ca. 67%) and a minor component (ca. 33%) by 1H NMR. The compound Zn-R/S-L2 crystallizes in the non-centrosymmetric polar space group Iba2 with formation of the enantiomeric pair Λ-Zn-S-L2 and Δ-Zn-R-L2 as a racemic mixture in the solid state. Time-dependent 1H NMR studies indicate that a single enantionmeric pair is still present in chloroform solution within 10min. In solution diastereomerization takes place, and the other diastereomers re-form within 40min (36h) to yield a diastereomeric ratio of 67:33% (54:46%) with the enantiomeric pair Λ-Zn-S-L2 and Δ-Zn-R-L2 as major diastereomers and Δ-Zn-S-L2 and Λ-Zn-R-L2 as minor diastereomers. The non-unity ratio of the different-energy enantiomeric pairs Λ-S/Δ-R (54%) versus Δ-S/Λ-R (46%) can be the basis for observed preferential crystallization of Λ-Zn-S-L2 and Δ-Zn-R-L2 with concomitant slow enantiomerization in solution as one component is removed from the solution equilibrium.

Diastereoselectiveortho-Metalation of a Chiral Ferrocenylphosphonic Diamide and Its Organotin Derivatives

The syntheses of the enantiopure ferrocenylphosphonic diamide (3aR,7aR)-2-ferrocenyl-3a,4,5,6,7,7a-octahydro-1,3-dimethyl-1,3,2-benzodiazaphosphole 2-oxide ((R,R)-FcP(O)(DMCDA), (R,R)-1) and its enantiomer (S,S)-FcP(O)(DMCDA) ((S,S)-1) are reported. Their ortho lithiation and subsequent treatment with Ph3SnCl selectively provided the corresponding tetraorganotin derivatives FcP(O)(DMCDA)SnPh3 ((R,R,RP)-2 and (S,S,SP)-2) in a diastereoselective ratio of 88:12. The absolute configuration of the major diastereomer was confirmed by single-crystal X-ray diffraction analysis. DFT calculations revealed that kinetic effects of the lithiation step cause the high diastereoselectivity of the formation of (R,R,RP)-2. Further functionalization of (R,R,RP)-2 with elemental iodine gave the enantiopure organotin iodide derivatives FcP(O)(DMCDA)SnInPh3–n ((R,R,RP)-3:, n = 1; (R,R,RP)-4, n = 2, (R,R,RP)-5, n = 3). The triorganotin fluoride FcP(O)(DMCDA)SnFPh2 ((R,R,RP)-6) was obtained by the reaction of (R,R,RP)-3 in dichloromethane with aqueous KF solution. The reaction of the compound (R,R,RP)-3 with silver triflate gave the R,R,RP-configurated triorganotin triflate FcP(O)(DMCDA)SnPh2(OTf) (7), which exists as a contact ion pair in the solid state and shows dynamic behavior in solution. The reaction of 7 with Ph3PO afforded the corresponding organotin salt [FcP(O)(DMCDA)SnPh2(OPPh3)][OTf] ((R,R,RP)-8).

Stereoselective reduction, methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (131R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (131S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 131-stereogenic center as in the reduced product. All of the anion species (H−, CH3−, and C6H5−) favorably attacked the 131-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.

Tertiary amine functionalized polyacrylonitrile fiber catalyst for the synthesis of tetrahydrothiophenes

A tertiary amine immobilized fiber was prepared and used to efficiently catalyze tandem Michael–intramolecular Henry reactions between 1,4-dithiane-2,5-diol and trans-β-nitrostyrenes to form the corresponding tetrahydrothiophene derivatives. This newly developed fiber catalyst is applicable to a wide range of trans-β-nitroalkenes and affords good to excellent yields (75–93%) under mild conditions (with 2.5 mol % fiber catalyst at 50 °C in ethanol for 5 h). The fiber catalyst exhibits excellent recyclability and reusability (up to 10 times) after simple workup procedure with only a slight loss in catalytic activity. It is noteworthy that the major diastereomers have r-R, trans-nitro, trans-hydroxy configurations with diastereoselectivities of up to 15:1. This differs from the results obtained when the same reaction is catalyzed by a homogeneous catalyst. This is the first example of a fiber catalyst exhibiting excellent diastereoselectivity.

Synthesis of Six-Membered Spirocyclic Oxindoles with Five Consecutive Stereocenters in an Asymmetric Organocatalytic One-Pot Michael/Michael/Aldol Addition Sequence

An asymmetric organocatalytic one-pot synthesis of six-membered spirocyclic oxindoles has been successfully developed through a relay Michael/Michael/aldol addition reaction catalyzed by the combination of readily available diphenylprolinol silyl ether and bifunctional quinine thiourea. The one-pot protocol affords the highly substituted spirocyclic oxindoles in high yields and perfect enantioselectivities. More importantly, through judicious choice of the organocatalysts employed, this reaction could be readily adapted to predominantly afford an alternative major diastereomer of the product.

Synthesis and stereochemical analysis of β-nitromethane substituted γ-amino acids and peptides

The high diastereoselectivity in the Michael addition of nitromethane to α,β-unsaturated γ-amino esters, crystal conformations of β-nitromethane substituted γ-amino acids and peptides are studied. Results suggest that the N-Boc protected amide NH, conformations of α,β-unsaturated γ-amino esters and alkyl side chains play a crucial role in dictating the high diastereoselectivity of nitromethane addition to E-vinylogous amino esters. Investigation of the crystal conformations of both α,β-unsaturated γ-amino esters and the Michael addition products suggests that an H-C(γ)-C(β)=C(α) eclipsed conformer of the unsaturated amino ester leads to the major (anti) product compared to that of an N-C(γ)-C(β)=C(α) eclipsed conformer. The major diastereomers were separated and subjected to the peptide synthesis. The single crystal analysis of the dipeptide containing β-nitromethane substituted γ-amino acids reveals a helical type of folded conformation with an isolated H-bond involving a nine-atom pseudocycle.

Asymmetric Michael additions of α-cyanoacetates by soft Lewis acid/hard Brønsted acid catalysis: stereodivergency with bi- vs. monometallic catalysts

The direct asymmetric conjugate addition of α-cyanoacetates to enones generating densely functionalized α-amino acid precursors with adjacent quaternary and tertiary stereocenters is described comparing mono- and bis-palladacycle catalysts. This edge article features the complementary value of mono- and bimetallic catalysis in a case study using related catalyst systems. Different major diastereomers of the 1,4-addition products are formed by the use of the planar chiral mono- and bimetallic catalyst systems and provide access to epimeric amino acid derivatives. Both catalyst types require the use of a Brønsted acid (HOAc) as a co-catalyst to avoid an undesired β-hydride elimination. Kinetic studies show that the C–C bond forming step takes place almost instantaneously with the bis-palladium complex after productive substrate coordination. This extraordinarily high reactivity for an elementary step generating a sterically demanding linkage of a quaternary and a tertiary stereocenter stresses the cooperativity of both metal centers.

Insights into the spontaneous emergence of enantioselectivity in an asymmetric Mannich reaction carried out without external catalyst

ESI-MS, chiral HPLC, time-resolved 1H NMR and optical rotation measurements were performed to gain insights into the nature of spontaneous mirror symmetry breaking in the catalyst-free Mannich reaction of PMP protected α-iminoethylglyoxylate with hydroxyacetone. Spontaneous temporary generation of enantiomeric excesses of up to 7.4% in the major syn diastereomer is reproducibly observed in aqueous phosphate buffers, starting from achiral conditions. The syn-product ee values for both enantiomers [(2S,3S) and (2R,3R)], although not with stochastic distribution, have been observed with no clear preference for either enantiomer.

Investigation of the Electronic Origin of Asymmetric Induction in Palladium-Catalyzed Allylic Substitutions with Phosphinooxazoline (PHOX) Ligands by Hammett and Swain–Lupton Analysis of the13C NMR Chemical Shifts of the (π-Allyl)palladium Intermediates

Isomeric 4′- and 5′-substituted phosphinooxazoline (PHOX) ligands are used to probe the electronic origins of enantioselective nucleophilic additions to (1,3-diphenylallyl)palladium PHOX ligand complexes. Hammett analysis of the 13C NMR chemical shifts of the allyl C-1 and C-3 carbons shows that the major exo diastereomer is less susceptible to differential changes at C-1 and C-3 and that the location of the substituent has a smaller impact on these changes. In contrast, the minor endo diastereomer is more susceptible to differential 13C NMR changes at C-1 and C-3 and the location of the substituent has a greater impact on these changes. The endo diastereomer exhibits a pronounced “cis effect” by the ligating nitrogen and phosphorus atoms across the palladium center that explains its lower reactivity and, therefore, how the enantioselectivity typically obtained with PHOX ligands exceeds the approximately 8/1 ratio of exo to endo intermediates. Swain–Lupton analysis reveals the importance of both resonance and field effects by the substituents regardless of their location and supports the overall electronic control model for enantioselection by PHOX ligands. For rational chiral ligand design and electronic tuning of ligand properties, these results suggest that the overall electronic impact of a remote substituent generally depends more on its identity than on its location within the ligand.

ChemInform Abstract: A Reusable TNF‐Tagged Chiral Bis(oxazoline)—Copper Catalyst for Diels—Alder Transformations.

AbstractBOA is applied to Diels—Alder reactions between N‐acyloxazolidinones and cyclopentadiene to give bicyclic products (III) as major diastereomers.

One-pot three-step thioconjugate addition-oxidation-Diels–Alder reactions of ethyl propiolate

Ethyl propiolate undergoes one-pot three-step thioconjugate addition-oxidation-Diels–Alder cycloaddition when treated with a variety of thiols in the presence of catalytic base, meta-chloroperbenzoic acid, lithium perchlorate, and cyclopentadiene. The reaction of S-aryl thiols is catalyzed by trialkylamines, and the reaction of aliphatic thiols requires catalytic alkoxide base. Yields of the major diastereomer of the conveniently functionalized bicyclic products range from 47% to 81% depending upon the thiol reactant, which compares favorably to yields observed when the entire synthesis is performed step-by-step.

Understanding Reactivity and Stereoselectivity in Palladium-Catalyzed Diastereoselective sp3 C–H Bond Activation: Intermediate Characterization and Computational Studies

The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd(II)-catalyzed sp(3) C-H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C-H insertion intermediate by X-ray paved the way for further investigations into C-H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C-H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C-H activation occurs at the monomeric Pd center and that the most preferred transition state for C-H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C-H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C-H bonds and Pd-OAc bonds is crucial for C-H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr-substituted oxazolines.

Distinct biological effects of golgicide a derivatives on larval and adult mosquitoes

A collection of Golgicide A (GCA) analogs has been synthesized and evaluated in larval and adult mosquito assays. Commercially available GCA is a mixture of four compounds. One enantiomer (GCA-2) of the major diastereomer in this mixture was shown to be responsible for the unique activity of GCA. Structure–activity studies (SAR) of the GCA architecture suggested that the pyridine ring was most easily manipulated without loss or gain in new activity. Eighteen GCA analogs were synthesized of which five displayed distinct behavior between larval and adult mosquitos, resulting in complete mortality of both Aedes aegypti and Anopheles stephensi larvae. Two analogs from the collection were shown to be distinct from the rest in displaying high selectivity and efficiency in killing An. stephensi larvae.

Stereochemical assignments of aldol products of 2‐arylimino‐3‐aryl‐thiazolidine‐4‐ones by 1H NMR

The aldol reactions of 2-arylimino-3-aryl-thiazolidine-4-ones with benzaldehyde carried out at -78 °C were found to produce sec-carbinols. Intramolecular hydrogen bonding within the aldol products forming a six-membered ring enabled the assignment of stereochemistries of the major and minor diastereomers via analysis of the syn and anti (3)J(H,H) (1)H NMR coupling constants.

New multicomponent domino reaction on water: highly diastereoselective synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridines] catalyzed by NaCl

A direct and efficient approach for the preparation of medicinally promising pyrazolopyridinyl spirooxindoles has been developed through a sequential one-pot, three-component reaction of easily available isatin, α-cyanoacetic ester or malononitrile, and 5-amino-3-methylpyrazole catalyzed by sodium chloride in water. Desired products were obtained in high to excellent yields using a simple workup procedure. The product synthesized using α-cyanoacetic ester showed high diastereoselectivity in which the stereochemistry of major diastereomer was confirmed by X-ray diffraction analysis. The present green synthesis shows attractive characteristics such as the use of water as the reaction medium, one pot conditions, short reaction period, easy workup/purification, and reduced waste production, without use of any acid or metal promoters.

Passerini reactions for the efficient synthesis of 3,3-disubstituted oxetanes

Three-component reactions of oxetan-3-ones with isocyanides and carboxylic acids produce 3,3-disubstituted oxetanes in good yields. Good levels of diastereocontrol (dr=4:1) can be achieved in these Passerini reactions when the oxetane nucleus possesses a bulky cyclohexyl substituent at C–2. The (2S∗,3R∗)-stereochemistry of the major diastereomer was confirmed by X-ray crystallography after ester hydrolysis, and a possible mechanism to account for the diastereofacial selectivity is presented.

Levels, isomer profiles and chiral signatures of particle-bound hexabromocyclododecanes in ambient air around Shanghai, China

Hexabromocyclododecanes (HBCDs) have been considered candidate persistent organic pollutants, however, environmental data on their presence in China, a major world market, are limited. In this study, airborne particle-bound HBCDs in Shanghai, China were quantified with liquid chromatography–tandem mass spectrometry, and their total concentrations varied from 3.21 to 123 pg/m3. The industrial area showed about three times higher HBCD levels than the urban areas. Gamma-HBCD dominated in particle-associated HBCDs in the industrial area, while α-HBCD was the major diastereomer of the urban areas, which is quite different from the pattern of technical products. Besides α-, β- and γ-HBCDs, δ-HBCD was also detected in all samples (0.09–6.31 pg/m3), while no ɛ-HBCD was found. Airborne β- and γ-HBCDs were racemic in most studied areas due to their chiral signatures showing no significant difference from commercial mixture. Fractions of (+)-α-HBCD (0.417–0.467), however, suggested the enrichment of (−)-α-HBCD and the involvement of enantioselective bioprocesses.

Three-Component Glycolate Michael Reactions of Enolates, Silyl Glyoxylates, and α,β-Enones

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.

Enhancement of Diastereoselectivity in Photodimerization of Alkyl 2-Naphthoates with Chiral Auxiliaries via Inclusion within γ-Cyclodextrin Cavities

Irradiations of alkyl 2-naphthoates are known to result in four isomeric "cubane-like" photodimers: anti(HH)-2, syn(HH)-2, anti(HT)-2, and syn(HT)-2 where the anti(HH)-2, anti(HT)-2, and syn(HT)-2 consist of pairs of diastereomers. Here, chiral auxiliary and chiral microreactor strategies have been combined to achieve high diastereoselectivity in photodimerizations of an enantiomeric pair of 2-naphthoates with (R)- and (S)-1-methoxycarbonylethyl esters as chiral auxiliaries (1R and 1S). Thus, irradiations of their γ-cyclodextrin (γ-CD) complexes have been conducted. Fluorescence, IR, and NMR spectra of both enantiomers of 1 demonstrate that their γ-CD complexes are mainly 2:2 with the molecules of 1 in head-to-head orientations. Irradiation of the complexes in the solid state mainly resulted in anti(HH)-2. The absolute configuration of each diastereomer of anti(HH)-2 has been established for the first time here. The diastereomeric excesses (de's) of anti(HH)-2 from 1R and 1S were 94% and 86%, respectively. These de's are much higher than those found from irradiations in solution (55% for 1R and 1S), where the opposite diastereomeric form is in excess! Calculations of the energies of various conformations of the head-to-head 2:2 inclusion complexes were performed using the PM3 approach. The predicted major diastereomers based on the calculation are consistent with those found experimentally.

Synthesis of α-fluoro-β-hydroxy esters by an enantioselective Reformatsky-type reaction

The first enantioselective Reformatsky-type reaction of ethyl iodofluoroacetate has been accomplished with alkyl aryl ketones. High diastereoselectivities and excellent enantioselectivities for the major diastereomer (93-95% ee) were achieved with large alkyl groups. For smaller alkyl groups the diastereoselectivities were moderate, but excellent enantioselectivities were obtained for both diastereomers (79-94% ee).