High Syn Selectivity Research Articles

Synthesis and transformations of 2-(phenylhydroxymethyl)cyclohexylamines

Diastereomeric 2-(phenylhydroxymethyl)cyclohexylamines were synthesised by reduction of 2-benzoylcyclohexylamines. (1S∗,2R∗)-2-Benzoylcyclohexylamine can be reduced diastereoselectively to the corresponding γ-amino alcohol with sodium borohydride; for the trans counterpart (1R∗,2R∗)-2-benzoylcyclohexylamine, lithium aluminium hydride was found to be a selective reducing agent. In both cases, high syn selectivities were observed. The amino alcohols were transformed to the corresponding cyclohexane-fused tetrahydro-1,3-oxazin-2-ones and -2-thiones. The γ-amino alcohols reacted with arylimidates to afford 4,5-dihydro-6H-1,3-oxazines. Their cyclization with phenyl isothiocyanate yielded 2-phenyliminotetrahydro-1,3-oxazines.

Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: stereoselective synthesis of alpha-methyl-beta-hydroxy acids, esters, ketones, and 1,3-Syn and 1,3-anti diols

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.

Highly Stereoselective Coupling Reaction of Acrolein or Vinyl Ketone with Aldehydes

Treatment of acrolein with a TiCl4−n-Bu4NI mixed reagent in the presence of 2 equiv of aldehydes provided 4-hydroxy-1,3-dioxane derivatives in good yields with high stereoselectivities. The use of vinyl ketones instead of acrolein afforded aldol-type adducts with high syn selectivities.

Highly diastereoselective nucleophilic addition of organometallic reagents to 2-pyrrolidinyl nitrones: a semiempirical approach

2-Pyrrolidinyl nitrones 1 and 2 derived from l-proline and trans-4-hydroxy- l-proline, respectively, undergo nucleophilic additions of Grignard reagents and organolithium compounds with high syn selectivity, to yield enantiomerically pure pyrrolidinyl benzyl hydroxylamines. A rationale for the observed stereoselectivity based on semiempirical calculations is presented.

Efficient 1,2-asymmetric induction in radical reactions: Addition of acyl radicals to 3-hydroxy-1-(methylthio)-1-( p-tolylsulfonyl)-1-alkenes and their acetates

Irradiation of aliphatic and aromatic aldehydes in the presence of benzophenone produces the corresponding acyl radicals which add to 3-hydroxy-1-(methylthio)-1-( p-tolylsulfonyl)-1-alkenes and their acetates with high syn selectivity.

Studies towards total synthesis of antillatoxin: Synthesis of C1C11 fragment

Synthesis of the key intermediate ( 5) of Antillatoxin ( 1) is presented. The synthesis is based on the indium-mediated allylation of 2,4,6,6-tetramethyl-2,4-heptadienal ( 3) and methyl (Z)-2-(bromomethyl)-2-butenoate ( 4) in saturated ammonium chloride catalyzed by lanthanide triflate which afforded the corresponding product 2 in good yield and high syn selectivity.

Stereoselective Aldol Reaction of α-Phenylseleno Esters

The TiCl4-catalyzed reaction of a-phenylseleno esters with aldehydes in the presence of Ph3P or Ph3P=O gives aldol products with high syn selectivity.

Stereoselective Michael/aldol tandem reaction triggered by thiolate anion or analogues

A combination of a tert-butyl α,β-unsaturated ester, an aldehyde and lithium thiophenolate in CH2Cl2 undergoes a one-pot Michael/aldol tandem reaction to give a condensation adduct of the three components, an α-phenylthiomethyl-β-hydroxy ester, in good yield with high syn-selectivity.

Reactivity of ( E)-1-( tert-Butyldimethyl)silyloxy-3,3-bis(tributylstannyl)-Propene : Syn Selective S E′ Addition to Aldehydes

The reactivity of ( E)-1-( tert-butyldimethyl)silyloxy-3,3-bis(tributylstannyl)propene 1 as potential 1,3 dianion equivalent has been investigated. Condensation with aldehydes 4a–h, in presence of BF 3·OEt 2, afforded in high yields the mono-protected diols 5a–h exhibiting an exclusive E configuration of the vinyltin residue. Good to high syn selectivities have been measured, in agreement with an S E′ addition mechanism. Further transformation of the resulting vinyltin moiety of these diols into various functionalities has been successfully tested. © 1997 Elsevier Science Ltd.

Highly stereoselective radical addition to 3-hydroxy-1-(methylthio)-1-( p-tolylsulfonyl)-1-alkenes and its application to the preparation of optically active compounds

Efficient 1,2-asymmetric induction was realized in the addition of a 1-hydroxyalkyl radical (R 2C-OH) to 3-hydroxy-1-(methylthio)-1-( p-tolylsulfonyl)-1-alkenes and their acetates ( 1): Irradiation of 1 and benzophenone in an alcohol (R 2CHOH) gave an adduct ( 2) with a high syn selectivity. Optically active 1 is easily obtainable by means of Lipase PS-catalyzed transesterification and, therefore, the present radical asymmetric induction provides a synthetic route leading to various chiral compounds.

Chemistry of Aziridine Carboxylic Acids, 7. Synthesis of Ethyl (2R,3S)‐N‐Boc‐ and ‐N‐Benzyl‐3‐vinylaziridine‐2‐carboxylates: New Potential Building Blocks for Enantiomerically Pure Unsaturated Amino Acids

AbstractEnantiomerically pure cis‐ and trans‐1H‐aziridine‐carboxylic acid derivatives 2a, b and 3a, b have been prepared by asymmetric Michael‐type addition of ammonia to chiral acrylates 1a, b with high syn selectivity. The title compounds were obtained from the diols 8a, b by Corey‐Winter olefination.

π-Facial diastereoselectivity in electrophilic additions and 1,3-dipolar cycloadditions to bicyclo[2.2.2]oct-2-enes 5,6-cis,exo-disubstituted with electron withdrawing groups

The high syn selectivity (e.g., synlanti ⩾ 83:17) observed in epoxidation of the torsionally and sterically unbiased 5,6-cis,exo-disubstitutedbicyclo[2.2.2]oct-2-enes (bearing electron withdrawing groups) progressively decreases on going to dihydroxylation and 1,3-dipolar cycloadditions, with practically no selectivity in the case of nitrones and dominance of anti attack in the reactions of diazomethane (synlanti ⩽ 32:68), in contrast with predictions based on Cieplak's theory.

Chelate‐Controlled Additions of Titanium and Lithium Enolates to Chiral β‐Formyl Esters – Diastereofacial and Simple Diastereoselectivity

AbstractThe aldol‐type additions of metal enolates 2‐Met derived from pinacolone to the chiral β‐formyl carboxylate 1a were optimized. The highest trans:cis ratio (86:14) of the products 3 was obtained when the trichlorotitanium enolate 2‐TiCl3 was combined with 1a precomplexed with one equivalent of TiCl4. The lithium enolate 2‐Li is rather unselective. The simple diastereoselectivity of prochiral enolates 4‐Met was first examined with achiral β‐formyl carboxylates 1b and 1c. Appropriate reagents made products with high anti or with high syn selectivity available when the unbranched aldehyde 1b was the electrophile. In contrast, the sterically more hindered aldehyde 1c provided syn products with all enolates 4‐Met employed. Finally, chiral aldehyde 1a was combined with prochiral enolates 4‐Met. Conditions could be found which furnished either the trans/anti or the trans/syn product 7 with good selectivity. The results are discussed and compared with reactions of related metal enolates with aldehydes capable of chelate formation.

Asymmetric [2,3]-sigmatropic wittig rearrangement of chiral α-allyloxy-hydrazones

The asymmetric [2,3]-Wittig rearrangement of chiral α-allyloxy-hydrazones ( S)-3 and ( S)-7 proceeds with very good yields (72 – 100%) together with high syn-selectivities (87 – 97%) and asymmetric inductions (63 – 92%) to give the corresponding α-hydroxyhydrazones 4 and 8. Depending on the substitution patterns of the starting material, optically active aliphatic and aromatic α-hydroxyketones 5 or protected cyanohydrins 10 and α-hydroxyaldehydes 11 respectively, can be generated in high enantiomeric excesses (92 – 98%) and syn-selectivities (88 – > 99%) after chromatographic purification and removal of the auxiliary.

Asymmetric syn‐Selective Michael Addition of Enolates to Chiral 8‐Phenylmenthyloxy Vinyl Chromium Carbene Complexes

AbstractMichael addition reactions of ketone and ester lithium enolates to optically active Fischer vinylcarbene complexes derived from (‐)‐8‐phenylmenthol take place with high syn selectivity and high levels of asymmetric induction. The initial Michael adducts can be further elaborated through diastereoselective addition of organometallic reagents to ketones and aldol reactions. Removal of the metal fragment and chiral auxiliary group leads to cyclic enol ethers with three or five contiguous stereogenic centers and of high enantiomeric purity.

1,2-Asymmetric induction in reactions of nonconjugated acyclic radicals: a new model for highly selective atom-transfer reactions of alkyl-substituted radicals

The iodine-transfer addition of methyliodomalonodinitrile (1) to several dialkyl-substituted olefins is reported. The iodine-transfer reaction to the acyclic nonconjugated radical intermediates often results in selective product formation due to 1,2-asymmetric induction. The level of diasterselectivity depends on the size of the alkyl substituent on the radical. Tertiary alkyl groups give high syn selectivity, secondary groups lead to a moderate syn selectivity, and primary groups show completely unselective reactions. To explain the stereochemical outcome, a new steric model of the 1 Bu-substituted radical 5e is introduced on the basis of AM1 calculations and EPR data

Lewis acid-mediated reaction with silyl ketene acetals and allylstannane of the aluminum acetals generated by DIBALH reduction of α-amino acid esters

The intermediates generated by DIBALH reduction of α-amino acid esters undergo condensation without racemization with silyl ketene acetals and allylstannane in the presence of Lewis acid to afford the corresponding β-hydroxy esters and homoallylic alcohols in good yields while achieving high syn selectivity via an aluminum-assisted chelation control.

The origin of the stereoselectivity in the aldol reactions of β-boronate carbonyl derivatives.

β-Boronate carbonyl derivatives can be readily deprotonated using LDA and reaction of the resulting enolates with aldehydes gives the corresponding aldol products, with high syn-selectivity for Z-enolates with both benzaldehyde and pivaldehyde. Moderate to good syn-selectivity is observed for E-enolates. These results are consistent with chelation enhanced stabilisation of the enolate geometry via the boronate moiety and chelation enhanced locking of the resulting aldolate stereochemistry.

Chemistry of silylketenes: a simple preparation of α-silyl-α-stannylacetic esters and their stereoselective Reformatsky-type reaction with aldehydes or aldimines

Silylketenes 1a, b reacted smoothly with alkoxystannanes 3 to give the corresponding α-silyl-α-stannylacetates 4 almost quantitatively. Treatment of 4 with TiCl4 caused selective cleavage of the C–Sn bond to bring about Reformatsky-type reaction with aldehydes 6 giving β-hydroxy-α-silyl esters 7. These two steps were carried out by one-pot operation, and variously substituted compounds 7 were obtained with high syn-selectivity (52–96% d.e.) in 41–89% yields. A similar one-pot procedure starting from 1a–c, 3, and aldimines 11 also provided the corresponding β-amino-α-silyl esters 12 with excellent syn-selectivity (96% d.e.) in 64–94% yields. Stereocontrolled preparation of both (E)- and (Z)-α,β-unsaturated esters 8 and a syn-amino diol derivative 17 from syn-7 and syn-12, respectively, is also described.

High diastereofacial selectivity in the reaction of silyl enol ethers with chlorosulfides

The chlorosulfides 1 or 2 react with silyl enol ethers in presence of anhydrous zinc bromide to give mainly the corresponding syn products 4 or 6 respectively. The high syn selectivity of these reaction is explained by nucleophilic addition to a Chelated Chiral thioniun ion.