Stereoselectivity directed lithiation

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

The principle of asymmetric lithiation involves both the fact that formation of diastereomeric intermediates should involve different energies of activation, and the idea that, in directed lithiations, a lithium atom is coordinated with nitrogen or some other heteroatom (see above). When the coordinating nitrogen atom resides in a chiral environment, one of the two possible diastereomeric lithio intermediates is energetically favored for steric or other reasons. Thus one of the two possible intermediates should be formed preferentially, with the resulting condensation products reflecting the stereoselectivity of the lithiation. 

Ortiz [47] recently described the ortho-directed lithiation of R,R-diphenylami-nophosphazenes 64 followed by electrophilic quenching as an efficient process for the preparation of / -chiral ort/io-functionahzed P-chirogenic amidophosphinates 65 in good yields and diastereoselectivities. The usefulness of the method was shown with the preparation under mild reaction conditions of a variety of functionalized P-chiral compounds 66 in high yield and excellent stereoselectivity, including phosphinic esters, amides, thioamides, phosphine oxides, and (2-aminophenyl)phosphine boranes (Scheme 21). 

This procedure illustrates a general method for the preparation of alkenes from the pal 1 adium(Q)-cata1yzed reaction of vinyl halides with organo-lithium compounds, which can be prepared by various methods, including direct regioselective lithiation of hydrocarbons. The method is simple and has been used to prepare a variety of alkenes stereoselectively. Similar stoichiometric organocopper reactions sometimes proceed in a nonstereoselective... 

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. 

Sulphoxide removal using sulphoxide-lithium exchange is also effective. It was employed in tandem with a sulphoxide-directed stereoselective ortholithiation of the ferrocene 105 in the synthesis of the phosphine ligand 106 (Scheme 45). Ferrocene lithiation is discussed further in Section III. 

Ferrocene is best deprotonated by f-BuLi/f-BuOK in THF at 0 since BuLi alone will not lithiate ferrocene in the absence of TMEDA and leads to multiple lithiation in the presence of TMEDA. In the example in Scheme 134, a sulphur electrophile and a Kagan-Sharpless epoxidation lead to the enantiomerically pure sulphinyl ferrocene 278. The sulphinyl group directs stereoselective ortholithiation (see Section I.B.2), allowing the formation of products such as 279. Nucleophilic attack at sulphur is avoided by using triisopropylphenyllithium for this lithiation. 

The directing effect of the amide group can then be used a second time in the lateral lithiation of 503 to give an organolithium 507 which adds to the imine 508 in a stereoselective manner, probably under thermodynamic control (imine additions of laterally lithiated amides appear to be reversible). Warming the reaction mixture to room temperature leads to a mixture of 509 and some of the (ultimately required) cyclized product... 

Sulphoxides direct lateral lithiation in a reaction which is also highly stereoselective. In common with other electrophiles, ClC02Et produces as a single diastereoisomer of 544... 

Sulfoxides direct lateral lithiation in a reaction which is also highly stereoselective.409 In common with other electrophiles, ClC02Et produces as a single diastereoisomer of 455 from 454, and Raney nickel can be used to remove the sulfinyl group from the product, making this a very versatile method for asymmetric functionalisation of a benzyl group. 

Treatment of the laterally lithiated amide generated from lactam 273 with LDA with /ra r-2-phenylsulfonyl-3-phenyloxaziridine 33 afforded hydroxyl product 274 in 85% yield as a single isomer <1999JOC8627>. Use of (+)-(camphorsulfonyl)oxaziridine 202 gave similar results. The /ra t-stereoselectivity is consistent with the earlier finding that the hydroxylation stereochemistry is controlled by nonbonded steric interactions in the transition state such that the oxygen of the oxaziridine is delivered from the sterically least hindered direction. Treatment of 275 with LDA followed by (+)-(camphorsulfonyl)oxaziridine 202 afforded hydroxyl product 276 in 47% yield and 60% ee <1997T8881>. 

A regioselective method affording directly 3-phenyl-5-substituted isoxazoles 341, without isolation of isoxazoline intermediates, exploited reactions of NH2OH and a-benzotriazolyl-a,/3-unsaturated ketones 340, stereoselectively generated from benzotriazolylacetophenone and aldehydes in the presence of piperidine (Scheme 83) <2001JOC6787>. Treatment of /3-lithiated benzotriazolylvinyl ethyl ether with acid chlorides followed by cyclocondensation with hydroxylamine hydrochloride gave 4-benzotriazolyl-substituted isoxazoles <2005S245>. 

The conjugated addition of the lithiated bis-lactim ether derived from cyclo-[Gly-D-Val] (263) to a-substituted vinylphosphonates (264) or electrophilic substitution on the lithiated bis-lactim ether derived from cyc/o-[L-AP4-D-Val] (265) take place regio- and stereoselectively. These reactions allow direct access... 

In the case of 2-decyl-l-lithio-l-(methylseleno)cyclopropane and methyl iodide, the alkylation leads to a 1 1 mixture of the stereoisomers35 (Scheme 16), but it is not known which of the alkylation or the lithiation steps is not stereoselective as both stereoisomers of this cyclopropyllithium are formed. Trimethylsilyl chloride reacts efficiently with a-lithiocyclobutyl selenides35 and a-lithiocyclopropyl selenides 77 and produces the corresponding a-silyl selenides (Scheme 23). Trimethyl-silyl-(methylseleno)cyclopropame was found77 to be a powerful precursor of a-silylcyclopropyl lithium which cannot be directly alkylated 78,94), as already mentioned. 

The syntheses of six different ribonucleoside phosphoramidites with fluorobenzenes or fluorobenzimidazoles as nucleobase analogues and of one inosine analogue have been described. Lithiation of the required bromoarene with BuLi was followed by its addition to 2,3,5-tri-O-benzyl-D-ribono-1,4-lac-tone to yield an intermediate lactol which was directly dehydroxylated with triethylsilane and BFj-OEti to afford stereoselectively the respective precursors to (57a-f).""... 

Reductive lithiations of substituted tetrahydropyrans are often highly stereoselective reactions as a direct consequence of the anomeric radical intermediates involved. The mechanism involves one-electron reduction of a thiophenyl ether (or an equivalent reactive functional group) to generate an axial anomeric radical that is reduced by a second electron to form an axial a-alkoxylithium species, which can then be alkylated or protonated. Thus the high selectivities observed in reductive lithiations are a direct reflection of the axial preference for a-oxygenated radicals. 

Even a remote Boc-NH unit exerts a directing effect on the lithiation at a benzylic r< sition. Cyclic phosphonamidates form stabilized carbanions that react with elec-Tophiles stereoselectively. A bulky (e.g., f-Pr) group on the nitrogen atom impedes ne approach of the reagents from its side. ... 

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