Asymmetric lithiation

It should be noted that the sense of asymmetric induction in the lithiation/ rearrangement of aziridines 274, 276, and 279 by treatment with s-butyllithium/ (-)-sparteine is opposite to that observed for the corresponding epoxides (i.e. removal of the proton occurs at the (S)-stereocenter) [102], If one accepts the proposed model to explain the selective abstraction of the proton at the (R) -stereo-center of an epoxide (Figure 5.1), then, from the large difference in steric bulk (and Lewis basicity) between an oxygen atom and a tosyl-protected nitrogen atom, it is obvious that this model cannot be applied to the analogous aziridines. 

Cycloalkenyl sulphones, reactions of 646 Cycloalkyl aryl sulphones, lithiated 641 Cyclodextrins 59, 72 in asymmetric synthesis of sulphoxides 292... 

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

Chuzel O, Riant O (2005) Sparteine as a Chiral Ligand for Asymmetric Catalysis. 15 59-92 Clayden J (2003) Enantioselective Synthesis by Lithiation to Generate Planar or Axial Chirality. 5 251-286... 

Thus, a reversal of the diastereoseleetivity of the reaetion was observed if the enolate was prepared in the presenee of a lithiated base. The different behaviour of the base could be attributable to the geometry of the enolate. It was assumed that the use of KOH as a base would give predominantly the E enolate, whereas the Z enolate would be formed with a lithiated base such as LiN(TMS)2- This methodology was applied to the asymmetric synthesis of quaternary a-amino acids starting from an imino alaninate compound. 

This ligand has also been used by the same authors to promote the addition of ZnMe2 to a functionalised a,(3-unsaturated ketone in the asymmetric key step of the first enantioselective synthesis of (-)-frontalin. This synthesis started with the naphthalene-catalysed lithiation of a chlorinated ketal (Scheme 4.15) that, after several transmetalation processes, was trapped by reaction... 

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

Lithiated chiral oxazolines have been shown to react with various electrophiles, generating a new asymmetric center with considerable bias. This process has led to the synthesis of optically active a-alkylalkanoic acids,47 n-hydroxy(methoxy)alkanoic acids,48 / -hydroxy(methoxy)alkanoic acids,49 n-substituted y-butyrolactones,50 and 2-substituted-l,4-butanediols (Fig. 2-4).50... 

The stannepins which encompass the 2,2 -positions of 1,1 -binaphthyl are interesting because, in their enantiomeric forms, they can bring about stereoselective reactions. Scheme 14 shows the synthesis of the methyltin hydride, which has been used in asymmetric reduction,172 and of the dimethyltin compound, which, via lithiation, can act as the precursor for further derivatives such as the silepins.327... 

Figure 70. Asymmetrical behavior of toward lithiation and delithiation. Comparison between the Nyquist plots of the anode and cathode symmetrical cells at different states-of-charge (a) graphite/graphite (b) cathode/cathode. (Reproduced with permission from ref 512 (Figure 5). Copyright 2003 Elsevier.)...

A review entitled a-heteroatom-substituted 1-alkenyllithium regents carbanions and carbenoids for C-C bond formation has addressed the methods of generation of such species, illustrated the carbenoid reactivity of a-lithiated vinyl halides and vinyl ethers, and emphasized the synthetic potential of the carbanion species in asymmetric synthesis of a-hydroxy- and a-amino-carbonyl compounds. ... 

The bis(oxazoline) S, 5)-(115) has been used as an external chiral ligand to induce asymmetric diastereoselective lithiation by r-BuLi during [2,3]-Wittig rearrangement of achiral substrates, (fj-crotyl propargylic ethers.It is believed that the enantios-electivity is determined predominantly at the lithiation step. 

The resolution required for the synthesis of 288 or 291 can be avoided by making them by asymmetric reduction or by asymmetric alkylation of an aldehyde . The amines 291 (R = Et or w-Bu) formed in this way are lithiated with diastereoselectivity similar to, or greater than, that achieved with 288. a-Ethyl and a-butylphosphines 294 incidentally may show even higher selectivity than the more widely used a-methylphosphine ligand PPEA 283. 

Bis-oxazoline ligands can also be produced by oxidative coupling of the copper derivative of diastereoisomerically pure 306 (Scheme 145) . Further lithiations of the product 317, which was produced as single diastereoisomer, occur (as in Scheme 143) at the second site adjacent to the oxazoline, giving, for example, 318, despite the (presumably) less favourable stereochemistry of the lithiation step. Bisoxazolines 318 direct the asymmetric copper-catalysed cyclopropanation of styrene using diazoacetate. 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

Couplings can also be carried out by simple nucleophilic substitution reactions of arenechromium tricarbonyls . For example, in the synthesis of biaryl 469, asymmetric lithiation of 463 using in situ silylation provides the complex 466 via 464 and 465. Nucleophilic substitution by the tolyl Grignard 467 yields 468 as a single atropisomer in 68% yield, and decomplexation gives the biaryl 469 in 92% yield (Scheme 184). 

Wilhelm and Widdowson have exploited the asymmetric deprotonation of 470 in a synthesis of a protected version 478 of the biaryl component of vancomycin, actinoidinic acid (Scheme 185) " . One of the rings derives from an arenechromium tricarbonyl with stereochemistry controlled by asymmetric lithiation. The most readily lithiated position of 470, between the two methoxy groups, first needed blocking. Enantioselective... 

Enantioselective reactions of laterally lithiated amides and anilides have been reported by Beak and coworkers but these are properly asymmetric transformations in which stereoselectivity arises subsequent to the lateral lithiation step they are not enantioselective lithiations. 

Asymmetric deprotonation of the achiral oxazolidine iV-Boc-4,4-dimethyl-l,3-oxazolidine with s-BuLi-(—)-sparteine affords a lithium derivative that adds unselectively to aldehydes. However, the transmetalation from lithium to magnesium, and addition of the resulting Grignard to benzaldehyde occurs with 90% diastereoselectivity and 93% enantioselectivity. The authors speculate that deprotonation and lithiation occur stereoselectively to give the R organolithium compound, and subsequent transmetalation and addition to benzaldehyde proceed with retention (Scheme 40). 

Gaul and Seebach showed that lithiated methylthiomethyl-substituted chiral oxazolidi-nones react with aldehydes, ketones, imines and chalcones (Scheme 41). In this case, the oxazolidinone is derived from diphenylvalinol. The products, with two new asymmetric centers, are formed in good yield and excellent diastereoselectivity.A detailed mechanistic study of this and related systems, using computational methods, IR and NMR... 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

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