Α-chiral Center Research Articles

Recent Advances in the Asymmetric Catalytic Synthesis of Phosphonates with an α-Chiral Center

AbstractPhosphonates and derivatives with an α-chiral center are of great importance and they are widely distributed in many natural products, pharmaceuticals, and agrochemicals with various bioactive features. Great effort has been made toward the development of efficient methods for their synthesis. In this short review, recent advances in the asymmetric catalytic synthesis of phosphonates with an α-chiral center are summarized, including asymmetric hydrogenation of α,β-unsaturated phosphonates, asymmetric addition of phosphonates to unsaturated electrophiles, and asymmetric addition of nucleophiles to α,β-unsaturated phosphonates. In addition, continuous development of enantioselective catalytic synthetic methods and the application of phosphonates and derivatives with α-chiral center are future prospects.1 Introduction2 Asymmetric Hydrogenation of α,β-Unsaturated Phosphonates3 Asymmetric Addition of Phosphonates to Unsaturated Electrophiles4 Asymmetric Addition of Nucleophiles to α,β-Unsaturated Phosphonates5 Conclusion

Ynamide-Mediated Thioester Synthesis.

A novel ynamide-mediated thioester synthesis strategy was developed. Importantly, no detectable racemization was observed for the thioesterifications of carboxylic acids containing an α-chiral center, enabling it to be useful for the synthesis of peptide thioester, which is the key component of native chemical ligation. It is worth mentioning that amino acid side chain functional groups such as -OH and indole -NH are compatible with the reaction conditions, rendering their protection unnecessary. Moreover, this method was also amenable to selenoesters.

Synergistic Catalysis of Tandem Michael Addition/Enantioselective Protonation Reactions by an Artificial Enzyme.

Enantioselective protonation is conceptually one of the most attractive methods to generate an α-chiral center. However, enantioselective protonation presents major challenges, especially in water. Herein, we report a tandem Michael addition/enantioselective protonation reaction catalyzed by an artificial enzyme employing two abiological catalytic sites in a synergistic fashion: a genetically encoded noncanonical p-aminophenylalanine residue and a Lewis acid Cu(II) complex. The exquisite stereocontrol achieved in the protonation of the transient enamine intermediate is illustrated by up to >20:1 dr and >99% ee of the product. These results illustrate the potential of exploiting synergistic catalysis in artificial enzymes for challenging reactions.

Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems.

We have the investigated base mediated asymmetric intramolecular oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane core. Intramolecular cycloaddition constructed two new rings, three new stereogenic centers, and provided a tricyclic cycloadduct with high diastereoselectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene tether on the substrates and examined the effect of the size of alkyl groups and alkene tether length on diastereoselectivity. The requisite substrates for the oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for the degree of stereoselectivity of the cycloadduct.

Ynamide-Mediated Intermolecular Esterification.

An ynamide-mediated one-pot, two-step intermolecular esterification via the condensation of carboxylic acids with nucleophilic hydroxyl species was reported. A broad substrate scope with respect to carboxylic acids, alcohols, and phenols was observed. The α-acyloxyenamide intermediates formed by the addition of carboxylic acids to ynamides proved to be effective acylating reagents for the esterification of alcohol and phenol derivatives with the assistance of base catalysis. Notably, the racemization of the α-chiral center of carboxylic acids can be avoided.

Chiral Spiro Phosphoric Acid-Catalyzed Friedel–Crafts Conjugate Addition/Enantioselective Protonation Reactions

Asymmetric Friedel–Crafts conjugate addition reactions that generate an α-chiral center are challenging because the configuration-determining step is a proton-transfer reaction of a highly active e...

Formation of α-chiral centers by asymmetric β-C(sp3)-H arylation, alkenylation, and alkynylation.

The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

Highly diastereoselective synthesis of tertiary alcohols via intramolecular Baylis-Hillman reaction using less reactive acrylamides as activated alkenes and ketones as electrophiles

A simple and convenient protocol for highly diastereoselective intramolecular Baylis-Hillman (IBH) reaction of substrates containing less reactive acrylamides as activated alkene and ketones with α-chiral center (racemic) as electrophile components, thus producing α-methylene-γ-lactam frameworks having β-tertiary alcoholic functional group, has been developed.

Pd-Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for Synthesis of (S)-N-Boc-2,6-dimethyltyrosine and Its Analogues.

A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible α-chiral centers.

Monoselective o-C-H Functionalizations of Mandelic Acid and α-Phenylglycine.

Pd-catalyzed C–H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd(II)/Pd(IV) and Pd(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers.

Lipase-catalyzed enantioselective resolution of (R,S)-N-2-methylalkanoyl-3-(2-pyridyl)pyrazoles in organic solvents

Abstract The lipase - catalyzed resolution of ( R , S )-pyrazolides containing a 2-aryl substituent to the α-chiral center has been successfully extended to ( R , S )-N-2-methylalkanoyl-3-(2-pyridyl)pyrazoles ( 1 – 4 ) containing different alkanoyl-chain lengths. The best reaction condition for CALB-catalyzed hydrolysis of ( R , S )-N-2-methylheptanoyl-3-(2-pyridyl)pyrazole ( 1 ) in water-saturated MTBE at 35 °C is selected, leading to an excellent enantioselectivity ( V R / V S > 100) with improved initial specific activities in comparison with that of ( R , S )-N-2-phenylpropionyl-3-(2-pyridyl)pyrazole. The thermodynamic analysis for the hydrolysis of 1 demonstrates great influences of water content and solvent hydrophobicity on varying the ehthalpic and entropic contributions in water-saturated and anhydrous MTBE and IPE, and leads to an excellent enthalpy–entropy compensation relationship ΔΔ S = 3.113ΔΔ H + 33.86 ( r 2 = 0.999). Moreover, a thorough kinetic analysis for all substrates indicates that a critical valeroyl-chain length for obtaining the enantiomer discrimination and improved lipase activity for the fast-reacting ( R )-pyrazolide is needed.

An asymmetric route to total synthesis of the furano lignan (+)-veraguensin

Total synthesis of the furano lignan (+)-veraguensin is described. The key steps involve a diastereoselective aldol-type condensation of an ester enolate having an α-chiral center with an aromatic aldehyde and a novel isomerization of the syn vicinal substituents on the furan ring via a ring opening–ring closing protocol.

Kinetic resolution of (R,S)-pyrazolides containing substituents in the leaving pyrazole for increased lipase enantioselectivity

Abstract With hydrolysis of ( R , S )-azolides in water-saturated methyl tert -butyl ether (MTBE) via Candida antarctica lipase B (CALB) as the model system, ( R , S )-pyrazolides containing a leaving 3-, 4- or 3,4-substituted-pyrazole moiety are selected as the best substrates for preparing various optically pure carboxylic acids containing an α-chiral center. Great improvements of enzyme activity for the ( R )-enantiomers with excellent enantioselectivity ( V R / V S > 100) are obtainable, if ( R , S )-pyrazolides containing a leaving 3- or 3,4-substituted-pyrazole moiety are employed for the hydrolysis or alcoholysis by methanol in anhydrous MTBE. A detailed kinetic analysis for ( R , S )- N -2-phenylpropionylpyrazoles indicates that a bulky 3-substituent such as 3-(3-bromophenyl) or 3-(2-pyridyl) in the leaving pyrazole moiety has profound effects on decreasing the nucleophilic attack and proton transfer of catalytic serine for the slow-reacting enantiomer in anhydrous MTBE, as well as that and substrate affinity for both enantiomers in water-saturated MTBE. The resolution platform is also successfully applied to the hydrolysis of ( R , S )-pyrazolides in water-saturated cyclohexane via Candida rugosa lipase (Lipase MY) having opposite enantioselectivity to CALB.

Enantiodivergent synthesis of (−)-methylenolactocin and (+)-methylenolactocin from d-mannitol

An enantiodivergent synthesis of both enantiomers of methylenolactocin is described through stereocontrolled addition of n-pentyl magnesium bromide to two d-mannitol-derived diastereomerically related aldehydes having an α-chiral center with a β hetero atom.

Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric arylamide functionality

Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-one and 4,5-dihydroxy-1 H-isoindole-1,3(2 H)-dione integrase inhibitors, we report differential effects on inhibitory potency induced by introduction of an α-chiral center into a key aryl substituent. We show that introduction of the chiral center is uniformly deleterious to binding, with the ( R)-enantiomer being more deleterious than the ( S)-enantiomer. A greater enantiomeric difference in potency is shown by inhibitors that have restricted rotation of the aryl ring, with the larger difference being due to poorer potency of the ( R)-enantiomer rather than higher potency of the ( S)-enantiomer. The potency difference for enantiomers based on the isoindoline-1,3-dione ring system is less than for those derived from the isoindol-1-one ring system. Our findings provide useful information that should aid in understanding molecular binding interactions of DKA-derived IN inhibitors.

A stereocontrolled approach for the synthesis of 2,5-diaryl-3,4-disubstituted furano lignans through a highly diastereoselective aldol condensation of an ester enolate with an α-chiral center: total syntheses of (−)-talaumidin and (−)-virgatusin

A general stereocontrolled approach for entry into a family of highly biologically active 2,5-diaryl-3,4-disubstituted furano lignans has been developed. The key step involves a diastereoselective aldol-type condensation of an ester enolate having an α-chiral center with an aromatic aldehyde. The methodology has been illustrated with the total syntheses of (−)-talaumidin and (−)-virgatusin.

Highly Diastereoselective Preparation of (E)‐Alkenylsilanes Bearing an α‐Chiral Center.

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Highly Diastereoselective Preparation of (E)-Alkenylsilanes Bearing an α-Chiral Center

The copper(I)-mediated anti-S(N)2' allylic substitution allows a highly stereoselective preparation of alkenylsilanes bearing a chiral center in the alpha-position with high transfer of chirality. These alkenylsilanes were converted into alpha,beta-unsaturated ketones or into the corresponding boronic esters without loss of the chiral information. [reaction: see text]

Stereoselective dimerization of chiral α-bromoamides promoted by Fe(CO)5

Organic α-bromocarboxylates react with aldehydes and ketones in the presence of Fe(CO)5 (the Reformatsky-type reactions). Unlike them, N-oxazolidinone derivatives of the same acids undergo diastereoselective reductive dimerization to give (2S,3S)-dimers, regardless of the configuration of the α-chiral center in the starting reagent.

Double Stereocontrol in α-Alkylation of Chiral Lithium Dienolates Generated from (E)-α,β-Olefinic Amides and Esters

Abstract The methylation of the lithium dienolate generated from (E)-α,β-olefinic amide with Katsuki’s chiral auxiliary affords the α-methylated β,γ-enamide in an exceptionally high Z-selectivity (99%) over the terminal olefinic bond along with 99% de at the α-chiral center. The origin of the high Z-selectivity is discussed.