Chiral stereoselective lithiation

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Ligands whose chirality is the result of atropisomerism, and not of an asymmetric center on phosphorus or carbon (Table 5), are highly enantioselective when complexed to Ru °. Heterobimetallic complexes form with metal-containing chiral ligands. Stereoselective lithiation of (S)- or (R)-a-ferrocenylethyldimethylamine (an easily resolved derivative of ferrocene) allows introduction of one or two phosphino groups, to need ferrocenylphosphinite (Table 6). ... 

The foregoing examples do not represent useful chiral formyl anion equivalents in a direct sense since the stereoselectivity of the initial addition to aldehydes is poor, although as has been explained, the situation is salvaged by oxidation and re-reduction. On the other hand, by lithiation at the 2 position of the achiral oxazo-lidine 53 in the presence of (-)-sparteine followed by addition of benzaldehyde, useful levels of d.e. and e.e. are achieved directly (98TA3125). For example, by adding MgBr2 before the benzaldehyde, the major product obtained is 54 in 80% d.e. and 86% e.e. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

Haynes, R.K., Lam, W.W.-L., and Yeung, L.-L., Stereoselective preparation of functionalized tertiary P-chiral phosphine oxides by nucleophilic addition of lithiated tert-butylphenylphosphine oxide to carbonyl compounds, Tetrahedron Lett., 37, 4729, 1996. 

The reaction of lithiated 2-alkyl-2-oxazolines with nitrones enables stereoselective and enantioselective syntheses of 5-isoxazolidinones, which are used as precursors of 3-amino acids. Highly enantiomerically enriched 5-izoxazolido-nones and 3-amino acids of inverse configuration can be generated by simply changing the chirality of the initial 2- . sopropyl-2-oxazoline (600). 

Some success has been achieved by a method which bridges the gap between the use of a chiral base and the use of an auxiliary to functionalize ferrocenes stereoselectively. Double protection of the dialdehyde 340 by addition of the chiral amine 341, and lithiation with t-BuLi, gives a mixture of Uthiated species which lead to 342 and 343, in proportions dependent on the amount of f-BuLi employed (Scheme 151). Though the yields of each are not high, both products 342 and 343 are obtained in very high enantiomeric excess . ... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Recently, compounds of this type were also prepared by the stereoselective alkylation of a lithiated (LDA) chiral camphor-based phosphonoglycine imine with high selectivity (82— >99% ee). When using ( + )-ketopinic acid, S -configurated a-amino-a-alkyl diethylphospho-nates w crc obtained95. 

How ever, deprotonation/alkylation of enantiomerically pure 1-iminomethyl-substituted 1,2,3,4-tetrahydro-1-methylisoquinoline bearing an achiral auxiliary similar to the chiral auxiliary of c led to racemic product only21. Therefore, the lithiated intermediate 8 turned out to be configurationally unstable and stereoselectivity in the alkylation of 4 relies on the higher thermodynamic stability of 5 versus its benzyelic epimer (Model B). 

While chiral 2-amino-4.5-dihydrooxazoles are not very successful as auxiliaries/precursors for the stereoselective alkylation of lithiated aliphatic amines28, they can be used effectively to obtain asymmetric induction in the alkylation of the a-position in benzylic amines. 

Substituted 3,6-dialkoxy-2,5-dihydropyrazines are regioselectively metalated by strong alkyl-lithium bases, such as butyllithium, (l-methylpropyl)lithium, fcrf-butyllithium, or lithium diiso-propylamide, at the less substituted carbon atom (C5). Metalation proceeds at low temperatures (in general, below — 70 C) in THF as solvent. Electrophiles suitable for alkylation of the lithiated derivatives include alkyl iodides, bromides and chlorides, as well as alkyl methanesulfonates, 4-methylbenzenesulfonates and trifluoromethanesulfonates. The electrophile adds trans to the substituent at C2 in a highly stereoselective fashion, with typical diastereomeric excesses of greater than 90% (syn addition has been reported in only one case where a-methylphenyl alanine was used as chiral auxiliary and an alkyl trifluoromethanesulfonate as electrophile18). 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

As stated above, intermolecular coupling reactions between carbon atoms are of limited use. In the classical Wurtz reaction two identical primary alkyl iodide molecules are reduced by sodium. n-Hectane (C100H202), for example, has been made by this method in 60% yield (G. Stallberg, 1956). The unsymmetrical coupling of two alkyl halides can be achieved via dialkylcuprates. The first halide, which may have a branched carbon chain, is lithiated and allowed to react with copper(I) salts. The resulting dialkylcuprate can then be coupled with alkyl or aryl iodides or bromides. Although the reaction probably involves radicals it is quite stereoselective and leads to inversion of chiral halides. For example, lithium diphenyl-cuprate reacts with (R)-2-bromobutane with 90% stereoselectivity to form (S)-2-phenylbutane (G.M. Whitesides, 1969). 

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

Chiral ligand-mediated lithiation-substitution sequences to promote stereoselectivity in pro-chiral compounds have been exploited widely over the past decade25. An asymmetric deprotonation carried out by the organolithium can be the enantio-determining step, or an asymmetric substitution as a postdeprotonation step. (—)-Sparteine, a readily available alkaloid, has been extensively used in this type of stereoselective transformation, giving high yields of enantiomeric excess. 

Af-(Phenylsulfanylmethyl)oxazolidinones derived from camphor 494 can be lithiated with n-BuLi at —78°C to give the chiral formyllithium equivalent 478683 (Scheme 128). This intermediate added to aldehydes in good yields, but lower stereoselectivity than compound 477, to afford crystalline adducts, which allowed the isolation of the major diastereomer 495. Hydrolysis of these adducts gave a-hydroxy aldehydes, which can be oxidized with PCC to the corresponding a-hydroxy acids. 

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