Anti Products Research Articles

Diastereodivergent Asymmetric Sulfa-Michael Additions of α-Branched Enones using a Single Chiral Organic Catalyst

A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,β-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalyst's diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

Effect of Buffer General Acid−Base Catalysis on the Stereoselectivity of Ester and Thioester H/D Exchange in D2O

As part of a comprehensive investigation on the stereochemistry of base-catalyzed 1,2-elimination and H/D exchange reactions of carbonyl compounds, we have found that the stereoselectivity of H/D exchange of 3-hydroxybutyryl N-acetylcysteamine (3) in D(2)O is strongly influenced by the presence of buffers. This buffer effect is also operative with a simple acyclic ester, ethyl 3-methoxybutanoate (7). Buffers whose general-acid components are cyclic tertiary ammonium ions are particularly effective in changing the stereoselectivity. (2)H NMR analysis showed that without buffer, H/D exchange of 3 produces 81-82% of the 2R*, 3R* diastereomer of 2-deuterio 3 (the anti product). In the presence of 0.33 M 3-quinuclidinone buffer, only 44% of the 2R*, 3R* diastereomer was formed. With ester 7, the stereoselectivity went from 93-94% in DO(-)/D(2)O to 60% in the presence of buffer. Phosphate buffer, as well as others, also showed substantial effects. The results are put into the context of what is known about the mechanism of H/D exchange of esters and thioesters, and the relevance of the buffer effect on the mechanism of the enoyl-CoA hydratase reaction is discussed. It is likely that hydrogen bonding in the enolate-buffer acid encounter complex is an important stereochemical determinant in producing a greater amount of the 2R*, 3S* diastereomer (the syn product). Studies that involve the protonation of enolate anions in D(2)O need to include the buffer general acid in any understanding of the stereoselectivity.

Investigation of the stereochemistry of intermolecular conjugate additions of nucleophiles to acyclic nitrosoalkenes.

Michael-type conjugate additions of γ-chiral aldehyde-derived acyclic nitrosoalkenes have been explored using a series of carbon and hetero nucleophiles. In all cases examined, these reactions are stereoselective, leading exclusively to the anti products.

Stereoselective synthesis of syn and anti 1,2-hydroxyalkyl moieties by Cu-catalyzed asymmetric allylic alkylation

A stereoselective synthesis of 1,2-hydroxyalkyl moieties is described herein. These valuable building blocks are obtained with complete regiocontrol and excellent stereocontrol both for the syn or the anti products, by choosing the appropriate enantiomer of the ligand in a copper-catalyzed asymmetric allylic alkylation of δ-alkoxy-substituted allyl bromides.

Direct Synthesis of anti-1,3-Diols through Nonclassical Reaction of Aryl Grignard Reagents with Isopropenyl Acetate

A series of symmetrical aromatic 1,3-diols were efficiently synthesized from substituted aryl Grignard reagents and isopropenyl acetate in a one-step reaction that formed anti products as the major species. Both experimental and theoretical studies suggested that the reaction involves the formation of a relatively stable intermediate E containing a six-membered ring from intermediate A. The stereoselectivity of the reactions and the molecular structure of the products were confirmed by NMR spectroscopy, X-ray diffraction, and gas chromatography.

Asymmetric Aldol Reaction in Water Catalyzed by Chitosan Aerogel

Aerogel microspheres of chitosan catalyzed the direct aldol reaction of para-nitro­benzaldehyde (1) or isatin (2) with ketones in water to afford the corresponding products 3 or 4 in 76-97% yield with up to 93% ee. When 2,4-dinitrophenol (DNP) or stearic acid was used as an additive, the enantiomeric excess of 3c was increased (DNP; anti/syn = 76:24, 92% ee for the anti product, stearic acid; anti/syn = 76:24, 93% ee for the anti product).

ChemInform Abstract: Photooxygenation of α-Ionone and Oxygen Transfer Reactions of the Resulting Allylic Hydroperoxides.

The photooxygenation of α-ionone (4) in different solvents leads, with higher than 90% regioselectivity, to a mixture of two diastereomeric allylic hydroperoxides 5a and 5b (diastereomeric ratio 77:23). These compounds are transformed in the presence of Ti(OiPr)4 into the corresponding epoxy alcohols 8a and 8b (cis selectivity) and the allylic alcohols 7a and 7b with high diastereoselectivity. In these cases the substrate configuration exhibits a pronounced control of type selectivity: the cis allylic hydroperoxide 5a is preferentially reduced to the allylic alcohol 7a, whereas the diastereomeric trans compound 5b is preferentially (syn selectivity) converted to the epoxy alcohol 8b. Epoxidation of the allylic alcohol 7a with meta-chloroperbenzoic acid leads, in contrast to the Ti(IV)-catalyzed reaction, to a mixture of diastereomeric epoxy alcohols 8a and 8c, with the anti product 8c as major diastereomer (diastereomeric ratio 28:72). These reactions serve as a route to three of the four possible diastereomeric epoxides of 3-hydroxy-γ-ionone.

ChemInform Abstract: Stereoselective Production of β-Amino Alcohols and β-Thioacyl Alcohols via an Application of the Non-Aldol Aldol Process.

Abstract The mesylates used as protecting groups to permit the formation of bis(polypropionates) via the non-aldol aldol process can be easily displaced with good nucleophiles, e.g., azide, thioacetate, acetate, to generate β-azido (and β-amino) alcohols, β-thioacyl alcohols, and aldols of the opposite chirality, e.g., syn isomers afford anti products. Thus the anti mesylate 15 affords the all-anti mzido aldol system 16 in good yield.

ChemInform Abstract: Diastereoselective Addition Reactions of Racemic Chiral Vinyl Sulfimides.

S-Aryl S-vinyl sulfimides are prepared by a new method via Horner–Wadsworth–Emmons reagents generated in situ. Lewis acid-catalysed Diels–Alder reaction of S-ethenyl-S-phenyl-N-tosylsulfimide with cyclopentadiene leads to the endo anti product with good diastereofacial and endo–exo selectivities. A range of alcohols and amines, with the limitation that they be practically usable in large excess, add to β-aryl vinyl sulfimides with modest diastereoselectivity. The major products of both the cycloaddition and the nucleophilic additions are rationalised by a model invoking addition to the least-hindered face of the s-cisconformation of the vinyl sulfimide.

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives ( S)- 2c and ( S)- 2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener ( R)- 2a as well as its O-protected derivatives ( R)- 2b– d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2 R,4 R)- and (2 S,4 R)- 3a– d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2 R,4 R)- 3a was favored.

Synthesis and theoretical studies on energetics of novel N- and O- perfluoroalkyl triazole tagged thienopyrimidines – Their potential as adenosine receptor ligands

A series of novel N- and O- perfluoroalkyl triazole tagged thienopyrimidines 6a– c and 7a– d was synthesized in two steps from thienopyrimidin-4-ones 2 through O- and N-propargylated regioisomers 3a– i and 4a– i respectively. Compound 2 was reacted with propargyl bromide to form O- and N-propargylated regioisomers 3 and 4 in definite proportions. Each regioisomer was separated and independently subjected to [3 + 2] cycloaddition using perfluoroalkyl azides through Click reaction under Sharpless conditions and obtained exclusively anti product in each case. The formation of two regioisomers in the first step and single anti addition product in the next step could be explained based on computational studies carried out at B3LYP/6-31G(d) level of theory. Results of Fukui function indices at the reactive centers are in accordance with the observations. On evaluation of the synthesized molecules for their binding affinities towards adenosine receptors, 4 d and 4 f were found to be selective to A 1 over A 2A receptors.

Chiral Lithium(I) Binaphtholate Salts for the Enantioselective Direct Mannich-Type Reaction with a Change of Syn/Anti and Absolute Stereochemistry

A highly diastereo- and enantioselective direct Mannich-type reaction of aldimines with 1,3-dicarbonyl compounds using Li(I) BINOLate salts as effective Lewis acid-Brønsted base catalysts has been developed. Li(I) BINOLate salts offered high catalytic activity toward 1,3-dicarbonyl compounds such as diketone, ketoester, ketothioester, ketoamide, and ketolactone. The reactions proceeded at -78 degrees C within 1-2 h in the presence of 1-10 mol % catalyst, which showed a catalytic activity (turnover frequency = 284 h(-1)) quite unlike those of other previous catalysts. Anti products were selectively obtained from acyclic ketoesters without epimerization at an alpha-tertiary-carbon center, and these are valuable since previous catalysts often gave syn/anti mixtures or the stereochemistry has not yet been determined.

One-Pot Stereoselective Synthesis of Furanoid Amino Acids

Reported is the synthesis of furanoid amino acids through a one-pot Michael addition-aldol reaction sequence. The addition of DMPU after the aldol addition, but before warming to room temperature was essential to achieve the desired cyclization. Only two of the possible dia­stereomers are observed as products. Previous work has shown that this Michael addition proceeds to give almost exclusively anti products (98% de). Therefore, the syn/anti ratio is a result of selectivity within the aldol addition step. Unfortunately, this ratio could not be increased through the use of more sterically demanding aldehydes as this decreased the rate of the aldol addition, thus favoring cyclopropanation to give A.

Metal-dependent modulation of diastereoselectivity in the Barbier-type crotylation of ( R)-cyclohexylideneglyceraldehyde

The diastereoselectivity of the Barbier-type crotylation of ( R)-cyclohexylideneglyceraldehyde could be tuned by changing the metal atom and solvent. The Ga-mediated reaction in [bmim][Br] produced the best diastereoselectivity, furnishing the all- anti product in good yield.

N-Primary-Amine-Terminal β-Turn Tetrapeptides as Organocatalysts for Highly Enantioselective Aldol Reaction

Tetrapeptides, containing a terminated primary amine and conformationally restricted D-Pro-Gly or D-Pro-Aib (2-aminoisobutanoic acid) segment as a strongly beta-turn-nucleating element, were designed and synthesized with condensation of N-module dipeptides with C-module dipeptides in solution. They were first applied to catalyze aldol reactions, and were found to be effective catalysts for the transformations. The tetrapeptide Val-D-Pro-Gly-Leu-OH (1g) was the optimal organocatalyst. It was shown that the intensive beta-turn conformation, indicated by CD and NOESY spectra, contributed to the (R)-aldol and high enantioselectivity of the reaction of acetone in MeOH, whereas the sharply varied conformation should contribute to the low enantioselectivity and (S)-product of the reaction in 1,2-dichloroethane (DCE). The asymmetric induction in the reaction of hydroxyacetone was not affected by solvents, and predominant anti products were achieved by 1g in MeCN with the additive (S)-BINOL.

Anti-Selective Epoxidation of Methyl α-Methylene-β-tert-butyldimethylsilyloxycarboxylate Esters. Evidence for Stereospecific Oxygen Atom Transfer in a Nucleophilic Epoxidation Process

Methyl alpha-methylene-beta-tert-butyldimethylsilyloxycarboxylate esters are found to undergo diastereoselective epoxidation in the presence of potassium tert-butoxide-tert-butyl hydroperoxide to form anti products. In an effort to better understand mechanistic details of the transformation and the basis of diastereoselectivities observed, we studied the epoxidation of substrates with alpha-methylene groups containing (trans) deuterium labels and discovered that oxygen-atom transfer proceeds with > or = 95% stereospecificity in all cases examined. These and other experiments suggest that the mechanism of epoxidation is not distinguishable from a concerted process.

2,4-Dinitrophenol as an Effective Cocatalyst: Greatly Improving the Activities and Enantioselectivities of Primary Amine Organocatalysts for Asymmetric Aldol Reactions

Seven primary amine organocatalysts 1a-g were readily prepared from natural primary amino acids via two steps and then were used to catalyze the direct asymmetric aldol reaction, but they showed very poor enantioselectivities and activities. As an effective cocatalyst, 2,4-dinitrophenol (DNP) dramatically elevated the activities and enantioselectivities of these very inefficient primary amine organocatalysts. This remedial course to the very inefficient organocatalysts by selection and employment of the optimal cocatalyst was particularly cost-effective and environment-beneficial compared with de novo development of catalysts. The highest efficient organocatalytic system that was composed of 1f and DNP showed high enantioselectivities and good to high diastereoselectivities with a broad spectrum of seven ketones. The linear ketones and cyclopentanone got predominant syn products whereas cyclohexanone mainly gave anti products.

The Domino Multicomponent Allylation Reaction for the Stereoselective Synthesis of Homoallylic Alcohols

Stereoselective allylations of carbonyl compounds such as aldehydes and ketones are useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks in the synthesis of biologically active natural compounds and pharmaceuticals. Although researchers have developed several methods for the facially selective allylation of aldehydes, the stereoselective allylation of ketones still poses a severe problem. We have developed a highly diastereoselective domino multicomponent allylation reaction of a ketone and allyltrimethyl silane using the trimethylsilyl ether of a norpseudoephedrine or mandelic acid derivative as an auxiliary with a diastereoselectivity of up to 98:2. The reaction is performed at -78 degrees C in the presence of a catalytic amount of trifluoromethanesulfonic acid and leads to the corresponding tertiary ethers. The procedure can also be used for the allylation of aliphatic aldehydes with a diastereomeric ratio >99:1. Ketones give the 4,1'-syn product while the aldehydes give the reversed selectivity to yield a 4,1'-anti product. In addition, the reaction of gamma-substituted allyl silanes with ketones yields a product with two stereogenic centers and an anti diastereoselectivity of >99:1. The homoallylic ethers formed in the domino multicomponent process can be used in further synthetic transformations: the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. Based on a number of both experimental and theoretical studies of the reaction mechanism, we conclude that an intermediate oxocarbenium ion is formed in the reaction of ketones. The oxocarbenium ion is attacked by the allyl silane during the stereogenic step. Using density functional theory methods, we could trace the observed stereoselectivity phenomena back to open transition states (TSs) where there is no interaction between the silane's trimethylsilyl group and the former carbonyl oxygen. On the contrary, the reaction with aldehydes forms an intermediate oxazolidinium salt, which explains the opposite selectivity. We have used the new allylation procedure in several total syntheses of natural products such as vitamin E, (+)-hydroxymyoporone, 5,6-dihydrocineromycin B, and polyoxygenated cembrenes.

Bi(OTf)3‐Catalyzed Diastereoselective SN1‐Type Reactions of Chiral Propargylic Acetates

Stereoelectronic factors are apparently responsible for the high selectivity observed in the title SN1-type reaction of acetates 1 in favor of the anti products 2. The preferred conformation of the intermediate propargylic cations would lead to the syn product; however, a second conformation exists, in which the tert-butyl group adopts an antiperiplanar orientation with respect to the incoming nucleophile. Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.

One-Pot Synthesis of Tetrahydroquinolines by an Imino-Diels-Alder Reaction

Reported is a synthesis of 1,2,3,4-tetrahydroquinolines by the Diels-Alder reaction of alkenes with iminium salts formed in situ from N-methylaniline and different sources of formaldehyde. The influence of the source of formaldehyde, Lewis acid and alkene structure on yield and stereochemistry of the products obtained was moderately investigated. The formation of both syn and anti products suggests the competition of pericyclic [4+2] cycloaddition with a stepwise mechanism involving cationic species.