Chiral Imide Research Articles

ChemInform Abstract: Catalytic Enantioselective Protonation of Lithium Enolates with Chiral Imides.

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton so...

Enantioselective Addition of Simple Hydrazines to Unsaturated Imides

This is the first example of enantio­selective conjugate addition of monosubstituted hydrazines to α,β-unsaturated imides. Although diastereoselective alternatives to this method (additions of hydrazines to chiral imides and additions of chiral hydrazines to achiral imides) are known, no enantioselective reaction has been reported so far. The attempts to establish a general and efficient protocol for addition of bisnucleophiles have been plagued with chemoselectivity issues. Here, using catalytic amounts of Lewis acid, products of great biological importance and chemical potential are obtained through a novel enantioselective and chemoselective reaction.

Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents

The Ni(acac) 2 catalytic ZnEt 2-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various acetophenones was studied. The chiral imido zinc enolate, which was formed through the metal–halogen exchange reaction of chiral α-bromopropionyl-2-oxazolidinones 2 with diethyl zinc under the catalysis of Ni(acac) 2, performed the asymmetric zinc-Reformatsky reaction with activated α-haloacetophenones 3 to give the chiral β-hydroxyamide 4 in good yields and high ratios of syn-(2 R,3 R)-isomers (up to >97%). This new asymmetric synthesis technology affords a practical method to synthesize the versatile chiral building block 5 for triazole antifungal agents, such as Voriconazole, Ravuconazole, TAK-187, and RO-0094815.

Stereoselective Preparation of a Cyclopentane-Based NK1 Receptor Antagonist Bearing an Unsymmetrically Substituted Sec−Sec Ether

A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions.

Facile Synthesis of 3‐Hydroxyglutamic Acids via Cyanation of Chiral N‐Acyliminium Cation Derived From (S)‐Malic Acid

Facile synthesis of 3‐hydroxyglutamic acids via cyanation of an N‐acyliminium intermediate derived from (S)‐malic acid is described. The chiral cyclic imide derived from (S)‐malic acid was converted to an acetoxylactam by reduction with sodium borohydride followed by acetylation. The obtained acetoxylactam was treated with trimethylsilyl cyanide in the presence of boron trifluoride etherate to give the corresponding cyanolactam in high yield, even though the diastereoselectivity of the cyanation reaction was moderate. The diastereomers of the cyanolactam were chromatographically separable and were independently converted to (2R,3S)‐ and (2S,3S)‐3‐hydroxyglutamic acids.

Chiral imides as potential chiroptical switches: synthesis and optical properties

A series of chiral aromatic imides and diimides were synthesized and their electrochemical, absorption, fluorescent, and chiroptical properties were examined for their potential application as molecular chiroptical switches. These compounds exhibit strong UV–vis absorptions, and can be electrochemically reduced to radical anions that absorb in the near infrared (NIR) region. Further reduction to the dianionic states results in new absorptions in the visible region. The changes in circular dichroism upon redox switching were apparent in the UV–vis region but were absent in the NIR region.

Highly diastereoselective conjugate additions of monoorganocopper reagents to chiral imides

Stereoselective conjugate additions to chiral N-enoyl amides employing various monoorganocuprate reagents, Li[RCuI], are described. The presence of TMSI in the addition of Li[RCuI] in THF provided the highest stereoselectivities. Reversed major diastereomeric ratios were obtained employing Li[RCuI] in ether or conventional copper-promoted Grignard reagents. The results presented support the favored anti- s- cis conformation of the substrates using Li[RCuI]/TMSI in THF, while the copper-promoted Grignard reagents or the Li[RCuI] reagents in ether favor the opposite syn- s- cis conformation. Influence of lithium ions on the stereoselective conjugate addition of the monoorganocuprate reagent, Li[BuCuI], has been investigated and two different mechanistic pathways are presented. The results show that iodotrimethylsilane (TMSI) is crucial for the asymmetric conjugate addition of the copper reagent, but only in THF or when 12-crown-4 is used. The reaction is thought not to involve any halosilane in any critical steps in the organocopper mechanisms conducted in ether. The (CuI) 4(SMe 2) 3 complex precursor plays an instrumental role for the conjugate addition using monoorganocopper reagents.

Recent Advances in Asymmetric Synthesis with Chiral Imide Auxiliaries

AbstractFor Abstract see ChemInform Abstract in Full Text.

Optically Active Telluronium Imides: Optical Resolution, Absolute Configuration, and Mechanism of Racemization.

Thermodynamically and kinetically stabilized asymmetric diaryltelluronium imides were synthesized and optically resolved into their enantiomers on an optically active column using medium-pressure column chromatography. The relationship between the absolute configuration and the optical properties of the chiral telluronium imides was clarified. The mechanism of the racemization, which involves the formation of telluroxides by the hydrolysis of the telluronium imides, was proposed. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:523–529, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10185

An asymmetric synthesis of aza analogues of the tricyclic skeleton of daphnane and the ABC ring system of phorbol.

An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds containing the 5-7-6-fused framework of daphnane involved construction of the central seven-membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethanesulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions of the phorbol skeleton.

Highly Enantioselective Synthesis of Chiral Imides and Derived Products via Chiral Base Desymmetrization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly enantioselective synthesis of chiral imides and derived products via chiral base desymmetrisation

The enantioselective deprotonation of several ring-fused imides with a chiral base, followed by electrophilic quenching, gives a range of chiral products in good yield and in ≥91% ee. The absolute stereochemistry of two of the products was determined by X-ray crystallography. A number of the imide products were subjected to further, highly regioselective, transformations, including enolate substitution, reduction and thionation.

A Novel Chiral Base Mediated Glutarimide Desymmetrisation: Application to the Asymmetric Synthesis of (-)-Paroxetine

The asymmetric desymmetrisation of certain 4-aryl substituted glutarimides has been accomplished with high levels of selectivity (up to 97% ee) by enolisation with a chiral bis-lithium amide base. The selectivity of the reaction is shown to be the result of asymmetric enolisation, followed by a kinetic resolution. One of the chiral imides synthesised was converted into the selective seratonin reuptake inhibitor (-)-paroxetine.

Highly selective asymmetric synthesis of 2‐hydroxy fatty acid methyl esters through chiral oxazolidinone carboximides

AbstractHighly selective asymmetric synthesis of 2‐hydroxy fatty acid methyl esters has been accomplioshed through chiral imide enolates. Five chiral oleic acid imides were prepared by reaction of oleioc acid with pivaloyl chloride followed by reaction with five different lithiated chiral oxazolidinones including (R)‐(+)‐4‐benzyl‐2‐, (S)‐(‐)‐4‐benzyl‐2‐, (4R,5S)‐(+)‐4‐methyl‐5‐phenyl‐2‐, (4S,5R)‐(‐)‐4‐methyl‐5‐phenyl‐2‐, and (R)‐(+)‐4‐isopropyl‐2‐oxazolidinones in 88–92% yileds. The chiral imides were reacted with NaN(Me3Si)2 at −78°C to give enolates, which subsequently reacted with 2‐(phenylsulfonyl)‐3‐phenyloxaziridine to give hydroxylated products in 78–83% yields. Methanolysis of the hydroxylated products with magnesium methoxide gave methyl 2‐hydroxyoleate. Enantiomeric excesses (ee) of the products were determined to be very high (98–99% ee) by 1H nuclear magnetic resonance study after esterification of the hydroxy group with (S)‐(+)‐O‐acetylmandelic acid. Enantioselective hydroxylation of other fatty acids including elaidic, petroselinic, vaccenic, and linoleic was evaluated under the similar conditions using (4R, 5S)‐(+)‐4‐methyl‐5‐phenyl‐2‐oxazolidinone as a chiral auxiliary to give 98% ee values for all cases.

Catalytic enantioselective protonation of lithium enolates with chiral imides

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton sources examined in the protonation of the lithium enolate of 2,2,6-trimethylcyclohexanone catalyzed by (S,S)-imide 1, 2, 6-di-tert-butyl-p-cresol (BHT) and its derivatives gave the highest enantiomeric excess. For example, 90% ee of (R)-enriched ketone was obtained when (S,S)-imide 1 (0.1 equiv) and BHT (1 equiv) were used. Use of 0.01 equiv of the chiral catalyst still caused a high level of asymmetric induction. For catalytic protonation of the lithium enolate of 2-methylcyclohexanone, chiral imide 6 possessing a chiral amide portion was superior to (S,S)-imide 1 as a chiral proton source and the enolate was effectively protonated with up to 82% ee.

Enantioselective Protonation of Lithium Enolates with Chiral Imides Possessing a Chiral Amide

Abstract New chiral imides possessing a chiral amide can be prepared from 1,3,5-trimethyl-r-1,c-3,c-5-cyclohexanetricarboxylic acid or related triacids and optically active amines. These imides are superior to 1,3,5-trimethyl-c-5-[(4S,5S)-4,5-diphenyl-2-oxazolin-2-yl]-r-1,c-3-cyclohexanedicarboximide reported previously as a chiral proton source for enantioselective protonation of lithium enolates of 2-alkylcycloalkanones.

Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-Deoxyhapalosin

Hapalosin ( 2), a 12-membered cyclic depsipeptide possessing MDR-reversing activity, and analogues ( 3) and ( 4) have been synthesized using macrolactamization as an important ring-forming step. Three building blocks: (2 S, 3 R)-3-( tert-butyldimethylsilyloxy)-2-methyl-decanoic acid ( 13), benzyl ( S)-2-hydroxy-3-methylbutanate ( 14), and (4 S,3 R)-4-(benzyloxycarbonyl-methylamino)-3-methoxymethoxy-5-phenyl-pentanoic acid ( 28) were prepared from Evans’s chiral imide ( 9), l-valine, and l- N-Boc phenylalanine ( 17), respectively, and were assembled together by applying twice Yamaguchi’s coupling methodology. A new and efficient selective N-methylation of γ-hydroxy-β-amino ester taking advantage of the vicinal amino alcohol function was uncovered in the course of this study. Thus, treatment of compound 19 with HCHO in the presence of catalytic amount of pTsOH followed by reduction (NaBH 3CN, TFA, CH 2Cl 2) of the so-formed oxazolidine 24 gave the N-methylated product 25. Furthermore, a dual role of oxazolidine as protecting group of vicinal amino alcohol and latent N-methyl function was established which allowed synthesizing both hapalosin ( 2) and N-desmethylhapalosin ( 3) from the same linear precursor 32 in a step-efficient and atom economic way. In contrast to hapalosin ( 2) and N-desmethyl analogue ( 3), the amide bond of 8-deoxy hapalosin ( 4) exists at room temperature (CDCl 3) exclusively in s-cis conformation as evidenced by NOE studies. This observation has been explained on the basis of computational studies. No significant MDR reversing activity of 8-deoxy hapalosin ( 4) was observed in K562 R and S/Adriblastine against human erythroleucemic cell lines indicating thus the important contribution of hydroxy group to the bioactivity of hapalosin.

Pyramidal inversion energies and conformational analysis of chalcogen-onium imides based on ab initio MO calculations †

Ab initio MO calculations of sulfonium, selenonium and telluronium imides R12X→NR2 (X = S, Se, Te) have been performed to obtain their pyramidal inversion (vertex inversion) barriers and rotation barriers around the chalcogen–nitrogen bonds. The activation energies for the pyramidal inversion reaction, which is an important pathway for racemization of the chiral chalcogen-onium imides when the two R1 groups are different, depend on the substituents, R1 and R2, on the chalcogen and nitrogen atoms. The computations indicated that the telluronium imides require larger activation energies for the pyramidal inversion reaction than those of corresponding sulfonium and selenonium imides. The rotation barriers around the chalcogen–nitrogen bonds, which is the conformational exchange pathway between two local minima of the chalcogen-onium imides, showed the opposite trend.

Biosynthesis of porphyrins and related macrocycles. Part 52. Synthesis of (11-S )-[11-2H1]porphobilinogen and the (11R)-enantiomer for stereochemical studies on hydroxymethylbilane synthase (porphobilinogen deaminase)

A synthetic route is devised for the synthesis of (11S)-[11-2H1]porphobilinogen 1a and of the (11R)-enantiomer 1b. Their absolute configurations and enantiomeric purity are established by degradation to a derivative of [2-2H1]glycine of known stereochemistry. Methods are then developed, based on the synthesis of chiral imidate esters, for determination of the configuration of [2H1]-labelled aminomethylpyrroles by converting them into [2H1]-labelled amidines followed by analysis using 1H-NMR. The labelled samples of PBG 1a and 1b serve as substrates for hydroxymethylbilane synthase and the products are trapped as [2H1]-labelled aminomethylbilanes 7c and 7d. Their configurations are determined by the NMR assay to demonstrate that as PBG 1 is enzymically converted into the aminomethylbilane 7, there is overall retention of configuration at the aminomethyl carbon.

Enantioselective protonation of prochiral enolates with chiral imides

New chiral proton sources possessing an asymmetric 2-oxazoline ring, ( S, S)-imide 1 and related imides, were synthesized from Kemp's triacid and optically active 2-amino alcohols. With these chiral imides, various lithium enolates of α-monoalkylated cycloalkanones were effectively protonated with excellent to moderate enantioselectivity. An increase in enantioselectivity was observed in the asymmetric protonation of prochiral enolates with ( S, S)-imide 1 using lithium salt as an additive. For example, ( R)-enriched 2- n-pentylcyclopentanone 35 was obtained in high yield with 90% ee when the silyl enol ether 33 was treated with n-BuLi in the presence of 5 equiv of LiBr in Et 2O, and the resulting lithium enolate 34 was then protonated by a solution of ( S, S)-imide 1 in THF. In contrast, the product 35 obtained without LiBr exhibited a lower enantiomeric excess (74% ee).