Authors: Varvara Alexandrovna Morozova
Source: Electronic Theses of LMU Munich (Ludwig-Maximilians-Universität München) (article, 2018-01-01)
Field: Chemistry — Organic Chemistry

Stereoselective preparation of chiral polyfunctional secondary alkyllithiums and alkylcoppers and their application towards natural product synthesis Scheme 1. Structures of carvone and thalidomide.Thus, the synthesis and isolation of enantiopure compounds is a very important task in organic synthesis.There are two fundamental approaches to access stereodefined molecules: the first and the oldest one is the separation of racemic mixtures.The second one is enantioselective synthesis. [7]Each approach has several advantages and disadvantages and both strategies will be discussed in detail further. Access to chiral molecules Separation of racemic mixturesIn a chiral separation the racemate is placed into an unsymmetrical environment and as a result the enantiomers have different behaviour and can be separated.An unsymmetrical environment can be, for example, a chemical transformation, involving a reaction with a chiral agent, or a chiral material, which interacts differently with enantiomers, or a biological system. [7]Here the mostly used chiral resolution methods will be discussed. Chiral derivatizationIf both enantiomers react with an optically active compound with similar rates, the 1:1 mixture of diastereomers is formed.The obtained diastereomers have different physical properties and therefore they can be separated during purification, for example, by recrystallization or column chromatography.This method is called chiral derivatization. [7,8]After the separation, the diastereomers are usually converted back to the original substances and used further as enantiopure compounds.For example, racemic ibuprofen (1) reacts with (S)-(-)-1phenylethylamine (S)-2 to produce corresponding mixture of salts (3), whereas (R,S)diastereoisomer is soluble in water and (S,S)-diastereomers precipitates (Scheme 2). [9]As soon as the salts are separated, they are treated with acid to obtain the starting ibuprofen as two single enantiomers.Scheme 2. Chiral resolution of ibuprofen (1) using (S)-(-)-1phenylethylamine (2) as derivatizing agent.This method is reasonable to use for the compounds which can be quantitatively derivatized as well as quantitatively converted back to the starting materials.The advantages of this type of chiral resolution are the broad substrate scope, relative ease of use and access to both enantiomers after all manipulations in very high enantiomeric purity.However, if only one enantiomer is of interest, which is usually the case, the maximum yield of isolated product is 50%. Kinetic resolutionIn kinetic resolution, one of the enantiomers reacts much faster with a chiral catalyst or reagent than the other one, resulting in an enantioenriched sample of the less reactive enantiomer. [7,10]e enantiomeric excess (ee) of the starting material as well as the ee of the formed product is directly dependent on the differences in the rate of the reaction between the enantiomers and the resolving agent.Thus, the higher the difference the higher the ee.Nowadays a lot of various transformations are used for the kinetic resolution, employing transition metal catalysis, organocatalysis, etc., [10][11][12][13] since it allows to obtain both the products and starting materials in high optical purity from racemates.For example, Sharpless epoxidation is a very reliable method for the kinetic resolution of variety of secondary allylic alcohols (Scheme 3). [14]plementation of the reaction with (+)-diisopropyl L-tartrate (L-5) as a ligand for the titanium catalyst allows to epoxidize selectively only (S)-4 to the give corresponding epoxide (S)-6, without affecting (R)-enantiomer.Both compounds (R)-4 and (S)-6 are obtained in high ee of >96%.Scheme 3. Kinetic resolution of 1-(1-cyclohexen-1-yl)ethanol (4) by Sharpless epoxidation with (+)-diisopropyl Ltartrate (L-5).Despite the broad usage, the specificity of these reactions to certain class of substrates and the use of sophisticated catalysts or reagents limit the scope of application. [10,15]In contrast to chiral derivatization, kinetic resolution often allows to obtain only one enantiomer, but there 1 Since most of the examples of the dynamic kinetic resolution are performed with an asymmetric catalyst, it was decided to classify it here. Chiral auxiliariesA chiral auxiliary is a chiral group or a unit that is temporarily installed into an organic compound to control the stereochemical outcome of the synthesis. [7,8]The present chirality in the auxiliary directs the stereoselectivity of one or more subsequent reactions.As soon as all chiral transformations are performed, the auxiliary is removed from the target molecule and can be recovered for future use.The most famous examples are the Evans oxazolidinone auxiliaries, that are widely used for the enantioselective aldol reactions, [26,[31][32][33] alkylation reactions, [34,35] Diels-Alder reactions [36,37] and others [33] .In the shown example below, compound 14 reacted with Bu2BOTf in the presence of base Et3N to give Z-enolate 15 (Scheme 6). [38] The generated enolate 15 was treated with benzaldehyde to exclusively produce syn-aldol (2S,3S)-16, which was isolated as a single diastereomer in 97% ee and 72% yield.The reaction is proposed to proceed via a Zimmerman-Traxler-type cyclic transition state. [39]The corresponding transition state 17a is more energetically favorable than 17b due to steric hindrance of the chiral auxiliary, and as a result only syn-(2S,3S)-16 was obtained. Chiral poolAnother approach towards enantiopure targets is a chemical modification of readily available optically active compounds. [7,8]This method is called chiral pool and it is the oldest concept in asymmetric synthesis.In this strategy various stereodefined starting materials are used as building blocks to create more complex molecules.Usually, the available chiral units are Scheme 7. Total synthesis of (+)-artemone ( 22) from (-)-linalool (18) by Vosburg.Due to the availability of many optically active sources (thanks to Mother Nature and modern synthetic chemistry!),chiral pool approach has found a great application in enantioselective synthesis.Nowadays various synthetic methods allow to convert almost every functionality into another one.This fact encourages synthetic chemists to use chiral pool strategy, since the majority of these reactions do not require a substrate specific optimization of the process.Scheme 9. Generation of alkyllithiums anti-and syn-24 via reductive lithiation of thioacetal 23 and subsequent reactions with acetone, leading to the corresponding alcohols anti-and syn-25. DeprotonationAnother way to synthesize an organometallic compound is a deprotonationa reaction between a C-H acid and a metallic base.This method is based on an acid-base equilibrium.Coordinating groups like amines, ethers, and others, as well as electron-withdrawing substituents, like halogens, carbonyls, etc., can increase the stability of the formed carbonmetal bond and therefore shift the equilibrium towards the metalated species. [7,50,[60][61]][62] Various organometallics can be used as a base, for example, n BuLi or i PrMgBr, however, aminoderived bases like LDA and TMP bases, [63] are applied more frequently.Scheme 11. (-)-Sparteine-controlled deprotonation of N-Boc-pyrrolidine (29) and subsequent trapping with (MeO)2SO2 to obtain 31. Halogen-metal exchangeHalogen-metal exchange is a common way to synthesize many organometallic reagents. [7,50]e driving force of this process is a formation of a more stable organometallic.The Scheme 12. Iodide-lithium exchange of (R)-32 using s BuLi and following trapping with CO2 to obtain carboxylic acid (R)-34.Recently, Knochel and co-workers developed a new procedure of the iodine-lithium exchange of chiral secondary species. [72][73][74] An addition of a solution of an alkyl iodide to a solution of t BuLi at -100 C in the mixture of hexane:ether allowed to decrease the elimination and deprotonation side reactions and to generate corresponding alkyllithiums in high yield with a high retention of configuration.For example, alkyl iodide syn-35 was converted to the corresponding lithium reagent syn-36 with the retention of configuration using t BuLi and an inverse addition of the iodide (Scheme 13). [73]The subsequent trapping of the alkyllithium syn-36 with Me2S2 provided thioether syn-37 in 75% yield and dr = 94:6.The stereochemical outcome of the reaction was confirmed by a reaction of the iodide anti-35 with MeSNa, which proceeds with the inversion of configuration and provides the thioether syn-37. [73]cheme 14. Stereoconvergent generation of alkyllithium 39 and subsequent alkylation to yield syn-40. TransmetalationProbably, transmetalation is the most common way to synthesize various organometallic reagents.This method requires a use of two metal-containing compounds, resulting in the exchange of the metal atoms.The exchange can be achieved by an elemental metal, a salt or another organometallic reagent (Scheme 15). [7,50] Natural product ; Stereoselectivity ; Chemistry ; Product (mathematics) ; Organic chemistry ; Combinatorial chemistry ; Catalysis ; Mathematics Coordination Chemistry and Organometallics ; Asymmetric Synthesis and Catalysis ; Chemical Reactions and Isotopes