Syn Relationship Research Articles

Palladium-Mediated CO2 Extrusion Followed by Insertion of Allenes: Translating Mechanistic Studies to Develop a One-Pot Method for the Synthesis of Alkenes

A palladium-mediated one-pot synthesis of alkenes from aromatic carboxylic acids and allene substrates (R1R2C═C═CH2, where either: R1 = Ph, R2 = H; R1 = Ph, R2 = Me or R1 = nPe, R2 = H) is reported. This is an isoelectronic variant of CO2 extrusion–insertion (ExIn) reactions previously developed using heterocumulenes for the synthesis of thioamides (from isothiocyanates, RNCS), amidines (from carbodiimides, RNCNR), and amides (from isocyanates, RNCO). Evidence that the key aryl-palladium intermediate reacts to form a stable allyl-palladium product via insertion of the allene at the C2 position that enables the synthesis of alkenes was provided by a combination of gas-phase multistage mass spectrometry (MSn) experiments and condensed-phase monitoring using 1H NMR spectroscopy as well as theoretical computational data. Isolation and X-ray crystallographic analysis of the salt [(phen)Pd(CH2CH(Ar)CHPh)]+(CF3CO2–) (where Ar = 2,6-dimethoxyphenyl) confirmed insertion of the allene at the C2 position and revealed a syn relationship between the two aryl groups. A survey of different hydrogen sources to promote the removal of palladium from the alkene product revealed that NaBH4 provides the highest yield and with the Z-alkene as the major isomer.

Determination of the Absolute Configuration of the Male-Produced Sex Pheromone of the Stink Bug Pellaea stictica, (2R,4R,8R)-2,4,8,13-Tetramethyltetradecan-1-ol by Stereoselective Synthesis Coupled with Enantiomeric Resolution.

In a previous study, we reported the identification and synthesis of a male-specific sex pheromone component of the stink bug, Pellaea stictica, as the alcohol 2,4,8,13-tetramethyltetradecan-1-ol (1). To establish the correlation between the stereochemistry of the pheromone and its bioactivity, it first was necessary to determine its absolute configuration. For this purpose, a series of syntheses were designed to: (a) furnish a mixture of all possible stereoisomers; (b) a narrowed down group of diastereomers, and (c) one specific enantiomer. A crucial step in the syntheses involved a coupling reaction between two key intermediates: a phosphonium salt and an aldehyde, through a Wittig olefination. Nuclear magnetic resonance data of a mixture of the synthetic pheromone diastereomers and further comparison of GC retention times with that of the natural product by gas chromatography suggested that the methyl branches at C2 and C4 were in a syn relationship, reducing the possibilities to only four of the eight possible stereoisomers. Employing GC analysis, chiral derivatization reagents and synthetic (8R)-2,4-syn-1 it was possible to confirm the configuration of the methyl branch at C8 as R, reducing the number of possible stereoisomers to two. After enantioselective synthesis of (2R,4R,8R)-1, the absolute configurations of all methyl branches of the natural compound were confirmed as R, fully identifying the male-produced sex pheromone of P. stictica as (2R,4R,8R)-2,4,8,13-tetramethyltetradecan-1-ol.

Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization.

The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.

Mild stereoselective formation of tri- and tetrasubstituted olefins by regioselective ring opening of 1,1-disubstituted vinyl oxiranes with dialkyl dithiophosphates

Presented in this Letter is a mild new method to stereoselectively ring open 1,1-disubstituted vinyl oxiranes using dialkyl dithiophosphate nucleophiles. This new reaction proceeds in toluene at room temperature to afford tri- and tetrasubstituted allylic alcohols with high Z-selectivity. The syn relationship between the alcohol and the newly incorporated dithiophosphate moiety presented an opportunity to evaluate the anionic hopping properties of the ring opening product. Treatment of the ring opening product with base results in a facile phosphate hopping followed by a selective thiolate 3-exo-trig instead of a 5-exo-tet cyclization.

The Influence of Anionic Ligands on Stereoisomerism of Ru Carbenes and Their Importance to Efficiency and Selectivity of Catalytic Olefin Metathesis Reactions

Investigations detailed herein provide insight regarding the mechanism of stereochemical inversion of stereogenic-at-Ru carbene complexes through a nonolefin metathesis-based polytopal rearrangement pathway. Computational analyses (DFT) reveal that there are two key factors that generate sufficient energy barriers that are responsible for the possibility of isolation and characterization of high-energy, but kinetically stable, intermediates: (1) donor-donor interactions that involve the anionic ligands and the strongly electron donating carbene groups and (2) dipolar effects arising from the syn relationship between the anionic groups (iodide and phenoxide). We demonstrate that a Brønsted acid lowers barriers to facilitate isomerization, and that the positive influence of a proton source is the result of its ability to diminish the repulsive electronic interactions originating from the anionic ligands. The implications of the present studies regarding a more sophisticated knowledge of the role of anionic units on the efficiency of Ru-catalyzed olefin metathesis reactions are discussed. The electronic basis for the increased facility with which allylic alcohols participate in olefin metathesis processes will be presented as well. Finally, we illustrate how a better understanding of the role of anionic ligands has served as the basis for successful design of Ru-based Z-selective catalysts for alkene metathesis.

2,3-Anhydrosugars in Glycoside Bond Synthesis. Application to 2,6-Dideoxypyranosides

We describe here the first use of 2,3-anhydrosugars as glycosylating agents for the preparation of 2-deoxypyranosides. In particular, the methodology was used to assemble 2,6-dideoxysugar glycosides. Glycosylation of a panel of alcohols with one of two 6-deoxy-2,3-anhydrosugar thioglycosides (8 and 9) in the presence of a Lewis acid afforded 2,6-dideoxy-2-thiotolyl glycoside products in generally excellent yields with an exclusively syn relationship between the aglycon and the C-3 hydroxyl group. Removal of the 2-thiotolyl group can be achieved upon reaction with tri-n-butyltin hydride and AIBN to give the corresponding 2,6-dideoxy pyranosides. Once developed, the method was applied to the synthesis of oligosaccharide moieties in the natural products apoptolidin and olivomycin A.

Asymmetric Induction in Methyl Ketone Aldol Additions to α-Alkoxy and α,β-Bisalkoxy Aldehydes: A Model for Acyclic Stereocontrol

A systematic study of methyl ketone aldol additions under nonchelating conditions with alpha-alkoxy and alpha,beta-bisalkoxy aldehydes is described. Additions to aldehydes containing a single alpha-alkoxy stereocenter generally provide the product diastereomers in accord with the Cornforth/polar Felkin-Anh models for carbonyl addition. Vicinal asymmetric induction is sensitive to the aldehyde alpha-alkyl substituent, but is relatively insensitive to the nature of the alkoxy protecting group. Aldehyde pi-facial selectivity in additions to substrates containing an additional beta-alkoxy-substituted stereocenter exhibits a striking dependence on the relative configuration of the alpha- and beta-stereocenters. Aldehydes with the alpha- and beta-alkoxy substituents in an anti relationship in most cases exhibit good diastereoselectivity, while aldehydes with the alpha- and beta-alkoxy substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on Cornforth-like transition-state arrangements is proposed.

Evolution of a Strategy for the Synthesis of Structurally Complex Batzelladine Alkaloids. Enantioselective Total Synthesis of the Proposed Structure of Batzelladine F and Structural Revision

Stereoselective synthesis of octahydro-5,6,6a-triazaacenaphthalenes 29 and 34 having the anti-relationship of the angular hydrogens flanking the pyrrolidine nitrogen confirmed suspicions that the relative configuration of the left-hand tricyclic guanidine fragment of batzelladine F should be revised to have the syn relationship of these hydrogens. Several strategies were examined for coupling tricyclic guanidine fragments to prepare potential structures for batzelladine F. Eventually, a convergent synthesis strategy was devised, whose central step was a fragment-coupling tethered-Biginelli reaction (Scheme 17). Using this approach we synthesized four potential structures of batzelladine F, 35-38. None of these compounds, nor their enantiomers, were identical to natural batzelladine F. Reinvestigation of mass spectra of natural batzelladine F, and fragments 88 and 89 obtained upon saponification of batzelladine F, demonstrated that the originally proposed connectivity of this alkaloid was also incorrect. The revised connectivity, 90, of natural batzelladine F depicted in Scheme 21 is proposed.

A Dipyridoimidazolium Salt from Phenylchlorocarbene and 2,2'‐Bipyridyl: Synthesis, Reaction Mechanism, and Effect of Rotamerism

AbstractPhenylchlorocarbene, generated by photolysis or thermolysis of the phenylchlorodiazirine, reacts with 2,2'‐bipyridyl to give, in alkane solvents, the 6‐phenyldipyrido[1,2‐c:2',1'‐e]imidazolium chloride. We investigated the mechanism of the reaction by flash photolysis. Like the mechanism of formation of 3‐phenylindolizine from phenylchlorocarbene + 2‐vinylpyridine, the process involves generation of the carbene, formation of a pyridinium ylide, and cyclization of the syn rotamer of this ylide, with the two N atoms of the bipyridyl in a syn relationship. The cyclization product then eliminates Cl– to give a stable aromatic cation. We observed and identified all the intermediate species and measured the rate constants for the successive elementary reactions. This enabled us to define experimental conditions under which the reaction is nearly quantitative (the chemical yield of isolated product is >90 %). By contrast, use of a polar solvent such as dichloromethane yields a mixture of the products resulting from the cyclization of both the syn‐ and the anti‐bipyridylium ylide rotamers. Semiempirical calculations qualitatively account for the effect of solvent polarity on the relative rates of cyclization of the syn‐ and anti‐bipyridylium ylide rotamers and thus on the nature of the products. These calculations predict that, in the presence of o‐phenanthroline, a model for the syn bipyridyl rotamer, phenylchlorocarbene should not give the expected diazacyclopentaphenanthrene, in agreement with the experiment findings. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

1,3-Polyol arrays via the stereoselective rearrangement of vinyl acetals

A series of 1,3-dioxanyl vinyl acetals were readily synthesized from the corresponding dioxanone by a reduction and in situ acylation followed by Petasis olefination. Treatment of these vinyl acetals with BF 3·OEt 2 results in an O to C rearrangement to form anti-3,5-dihydroxyketones while a mixture of Me 3Al and BF 3·OEt 2 provides the corresponding syn relationship via a stereoretentive rearrangement.

Asymmetric alternating copolymerization of cyclohexene oxide and CO2 with dimeric zinc complexes.

Dimeric zinc complex 2a [ = Et(2)Zn(2)(1a)(2)] has been synthesized by the reaction of Et(2)Zn and (S)-diphenyl(pyrrolidin-2-yl)methanol (1a-H). X-ray crystallography revealed that the alkoxide ligand replaced one of the two ethyl groups of Et(2)Zn and formed a five-membered chelate ring through a Zn-N dative bond. Two zinc centers were bridged by oxygen atoms to form a Zn(2)O(2) four-membered ring with a syn relationship between the two ethyl groups on the zinc centers. Dimeric zinc complex 2a was an active catalyst for asymmetric alternating copolymerization of cyclohexene oxide and CO(2). An MALDI-TOF mass spectrum of the obtained copolymer showed that the copolymerization was initiated by the insertion of CO(2) into Zn-alkoxide to give [(S)-diphenyl(pyrroridin-2-ly)methoxy]-[C(=O)O-(1,2-cyclohexylene)-O](n)-H (copolymer I), including chiral ligand 1a as an initiating group. Complex 3a-OEt ( = EtZn(1a)(2)ZnOEt), in which an ethoxy group replaced one of the two ethyl groups in 2a, also polymerized cyclohexene oxide and CO(2) with higher catalytic activity and enantioselectivity than 2a and afforded EtO-[C(=O)O-(1,2-cyclohexylene)-O](n)-H ( = copolymer III), including an ethoxy group as an initiating group. Throughout the studies, dimeric zinc species are indicated to be the active species for the copolymerization. It is also depicted that the substituent on the aryl moiety in diaryl(pyrrolidin-2-yl)methanol 2b-e influenced the polymerization activity.

Relative stereochemical determination of β‐hydroxycarbonyl compounds (aldol products) utilizing the J‐based configuration analysis method

Abstractβ‐Hydroxycarbonyl moieties (aldol products) are common features in a variety of molecular structures. Whether this structural motif is synthetically prepared or incorporated into a natural product, the determination of the anti or syn (threo and erythro, respectively) relationship between the α and β centers using previously reported NMR methods has, up to this point, been unreliable. Here, we report a method to determine the relative configuration of aldol products through the combined use of 3JHH homonuclear and, nJCH long‐range heteronuclear coupling constants in tandem with dipolar couplings in a manner related to the previously described J‐based configuration analysis method. Copyright © 2003 John Wiley & Sons, Ltd.

Synthesis and characterization of a new binuclear cobalt complex containing μ- acetamidino- μ- amido- μ- nitrito-bridged groups via an intramolecular condensation

Condensation of coordinated acetonitrile and one of the amine ligands in [(NH 3) 4Co·μ(NH 2,NO 2)·Co(NH 3) 4](CF 3SO 3) 4. H 2O ( 2c) results in the formation of a bridging acetamidino group. It is assumed that an intramolecular reaction occurred in which a coordinated amido ligand attack the substituted acetonitrile group to yield the third bridge. In this process the amido and acetonitrile groups which are coordinated to adjacent cobalt centers should bear a syn relationship. Synthesis and characterization of [(NH 3) 3Co·μ(CH 3C(NH) 2,NH 2,NO 2)·Co(NH 3) 3](CF 3SO 3) 3 ( 5) is reported here.

The molecular structure of acyclic aralkyl compounds studied by a crystallographic database survey. Relevance of the intramolecular CH/? hydrogen bond to conformation

A database study was carried out, by the use of the Cambridge Structural Database, to investigate the conformation of aralkyl compounds ArCH2XCH2Y 1 and ArCHCH3XCH 2 in crystals. The structure bearing R (R: any group) and Ar in the syn relationship has often been found in these compounds. The proportion of crystal structures bearing R and Ar in the syn relationship relative to the anti conformation (rsyn/anti) varied from 0.55 for 1 to 3.68 for 2. The logarithm of rsyn/anti was plotted against the difference in Gibbs energy ΔGsyn − anti obtained by MO calculations of model compounds at the MP2/6-311G(d,p)//MP2/6-31G(d) level: C6H5CH2XCH3 and C6H5CHCH3XCH3. A linear correlation has been shown between lnrsyn/anti and ΔGsyn − anti. The CH/π interaction is suggested to operate in controlling the R/Ar-folded crystal structure of these aralkyl compounds.

Conformational studies by dynamic NMR. 90. Structure and stereodynamics of the rotamers of di- and tri-alpha-naphthylphenyl derivatives.

The crystal structure of 1,3,5-tris(4-methylnaphth-1-yl)benzene, 1, shows one naphthyl substituent in an anti relationship to the other two. On the other hand, low temperature (-70 degrees C) (1)H NMR spectra in solution show the presence of a second rotational conformer (rotamer) having all the three naphthyl substituents in a syn relationship. The interconversion barrier between the anti (77%) and syn (23%) rotamers of 1 was determined by line shape simulation of the temperature-dependent NMR spectra (Delta G(++) = 12.1 kcal mol(-1)). In the analogous disubstituted meta and paraderivatives, that is, 1,3- and 1,4-bis(4-methylnaphth-1-yl)benzene (2 and 3, respectively), the presence of both the anti and syn rotamers was also detected by low-temperature NMR spectroscopy. In the latter compounds, the proportions of the anti and syn forms are nearly equal, and the corresponding anti to syn interconversion barriers were found to be lower (11.4 and 11.1(5) kcal mol(-1), respectively) than those of the trisubstituted derivative 1.

2-[3-Furyl(hydroxy)methyl]-2,3-dimethylcyclohexanone.

Contribution No. 1750 of the Instituto de Quimica, UNAM, Mexico. In the molecule of the title compound, C(13)H(18)O(3), there is a syn relationship between the two vicinal methyl groups. The six-membered ring adopts a chair conformation, with one equatorial and two axial groups, and the furyl group is almost parallel to the ketone group. Intermolecular hydrogen bonds [O[bond]H...O[double bond]C 2.814 (3) A] form chains along [100].

1,3-Bis(3-pyridylmethyl)-2-thiourea

The mol­ecule of 1,3-bis(3-pyridyl­methyl)-2-thio­urea, C13H14N4S, has approximate C2 symmetry, implying a syn relationship between the two N—H groups. The mol­ecules associate via N—H⋯Npyridyl interactions to form a two-dimensional arrangement with adjacent layers connected via C—H⋯π contacts.

Benzamides derived from 1,2-diaminocyclopropane as novel ligands for human D2 and D3 dopamine receptors

Benzamides (3a–f ) derived from 4-amino-5-chloro-2-methoxybenzoic acid and either cis or trans 1,2-diaminocyclopropane were synthesised and were evaluated in binding assays employing, bovine striatal D2 receptors, recombinant human hD2 and hD3 receptors expressed in CHO cells and rat, cortical 5-HT3 and striatal 5-HT4 receptors. The cis and trans isomers of the derivatives were isolated and characterised. The results demonstrated the superiority of the cis conformers over the trans conformers in dopamine receptor binding assays (Ki hD2=13.4 and 6.9nM and Ki hD3=17.7 and 4.5nM for the cis-3b and cis-3f compounds, respectively; Ki hD2=816 and >1000nM and Ki hD3=469 and >1000nM for the corresponding trans-3b and trans-3f compounds respectively). The cis compounds are folded: the benzamide group and the basic nitrogen atom were in a syn relationship. Compound 3f can be superimposed with a conformation of the tropane derivative, BRL 25594, having the benzyl group in an axial position to give a suitable fit, indicating that both compounds may have a common binding site in the dopamine receptor.

Application of the Tethered Biginelli Reaction for Enantioselective Synthesis of Batzelladine Alkaloids. Absolute Configuration of the Tricyclic Guanidine Portion of Batzelladine B.

Tethered Biginelli condensation of enantioenriched hexahydropyrrolopyrimidines 8 with beta-ketoesters provides efficient asymmetric access to tricyclic guanidines 9 having a syn relationship of the angular C2a and C8a hydrogens. This reaction was employed to realize the first practical enantioselective access to this fragment of batzelladine alkaloids B (2) and E (5). The efficiency of this strategy is illustrated in the synthesis of the dextrorotatory enantiomer of batzelladine B methanolysis product 10 in 10 steps and 25% overall yield from 2-nonanone and methyl acetoacetate. The asymmetric synthesis of 10 establishes that the absolute configuration of the tricyclic portion of batzelladine B (2) is 25aR,28S,30R. The 4-methyl-7-alkyl-1,2,2a,3,4,5,6,7,8,8a-decahydro-5,6,8b-triazaacenaphthalene-3-carboxylic acid subunit, e.g., 29, of batzelladine alkaloids A (1), D (4), F (6), and G was also prepared for the first time by catalytic hydrogenation of tricyclic guanidines 26 having the 2a,8a-anti stereochemistry.

Regiochemistry of Wacker-type oxidation of vinyl group in the presence of neighboring oxygen functions. Part 1

Palladium(II) oxidation of (±)-17α-vinyl-1,3,5(10)-gonatriene derivatives 1 bearing a lactonic bridge on the β-face affords the expected acetyl derivatives. In contrast, when the lactonic bridge or a hydroxy group is present on the α-face (syn relationship), aldehydes resulting from an anti-Markovnikov hydroxypalladation are obtained in appreciable yields.