Lithiation diastereoselective

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. 

Diastereoselective lithiation of chiral arenechromium tricarbonyl complexes... 

Bidentate ferrocene ligands containing a chiral oxazoline substituent possess both planar chiral and center chiral elements and have attracted much interest as asymmetric catalysts.However, until recently, preparation of such compounds had been limited to resolution. In 1995, four groups simultaneously communicated their results on the asymmetric synthesis of these structures using an oxazoline-directed diastereoselective lithiation (Scheme 8.141). " When a chiral oxazolinylferrocene 439 was metalated with butyllithium and the resulting aryllithium species trapped with an electrophile, diastereomer 442 was favored over 443. The structure of the major diastereomer 442 was confirmed, either by conversion to a compound of known stereochemistry or by X-ray crystallography of the product itself or of the corresponding palladium complex. ... 

Bolm and co-workers expanded the diastereoselective lithiation to include the ri -cyclopentadienylrhenium(l) tricarbonyl oxazoline complex 451 (Scheme 8.148). The selectivity was determined to be 9 1 favoring diastereomer 452. The strucmre of 452 was determined by crystallography. Interestingly, lithiation of 451 with jec-butyllithium resulted in the formation of nucleophilic addition products. 

Ortho-lithiation of an O-protected m-fluorophenol, followed by treatment with phosphorus tribromide and aqueous acid deprotection, has given the phosphino-phenol 18. In the presence of potassium t-butoxide in an aprotic solvent, this is converted into the non-planar system 19, which exhibits pyroelectric properties. An organolithium route to the alkynylphosphine 20 has been developed. The same paper also reports a new route to the lithiated alkynylphosphine 21 and a study of its reactivity towards electrophiles. Diastereoselective lithiation of... 

The ligand, 1 -[4-(5)-terf-butyl-2-oxazolin-2-yl]-2-(.S )-(diphenylphosphino)fcrro-cene (1), is prepared in three steps from readily available ferrocenecarboxylic acid chloride (5).[4] The steps involved are firstly amide bond formation secondly cyclisation to the oxazoline and finally diastereoselective lithiation/phosphinylation to afford (1) (Figure 5.4). 

Since amines of type 3 (or the corresponding alcohols as synthetic equivalents) still remain the most versatile starting materials for diastereoselective lithiation processes, and because the amino group can easily be substituted in a process occuring with retention of configuration [3a], methods have been developed for their enantioselective preparation. Recent work includes the aminoal-cohol-catalyzed addition of dialkylzinc reagents to ferrocene-carbaldehyde [7], and the... 

Fig. 3 Chiral acetal auxiliaries employed for diastereoselective lithiation...

Quirion has reported the first application of chiral carboxylic acids as activating agents and chiral inducers for a-lithiation of tetrahydroisoquinolines [67]. The diastereoselective lithiation and alkylation of acid-derived amides 78 provided 79 in 41-57% yields with moderate drs of up to 92 8 (Scheme 22). The chiral auxiliary can be removed under refluxing basic conditions (KOH/MeOH) in 60-70% yields. 

The recent use of M-indole-substituted gulonic amides by Quirion and coworkers demonstrates diastereoselective lithiation and alkylation of 86 to afford a... 

SAMP hydrazones derived from acylferrocenes will direct the diastereoselective lithiation of the ferrocene ring (Scheme 14). For example, treating benzoylfer-rocene 50 with (S)-N-amino-O-methylproUnol 51 generates 52 after siHca-cata-lysed equilibration to the more stable -hydrazone [42]. Lithiation of 52 gives or-ganolithium 53 selectively after electrophihc quench, products 54 were obtained in 80-95% yield and with <2% of a minor diastereoisomer. Removal of the auxiliary is achieved by oxidative or reductive means. 

An acyclic methoxyamine, 0-methylephedrine 55, fulfils a similar role in the diastereoselective lithiation of 56. Substitution with 55 gives 56 from 44, and lithiation of 56 typically gives products 57 with >90 10 diastereoselectivity (Scheme 15) [46]. Auxiliary removal is possible by quaternisation and substitution with dimethylamine (giving 58) or other nucleophiles, producing potential ligands with planar chirality only. Usefully, the products formed by this method are enantiomeric with those formed by most other auxiliary methods when the more readily available enantiomers of the starting materials are used. 

The diastereoselective lithiation of 74 shows that ferrocenes bearing electron-withdrawing directors of lithiation are sufficiently acidic to allow deprotonation with lithium amide bases. By replacing LDA with a chiral lithium amide, enantioselectivity can be achieved in some cases. The phosphine oxide 82, for example, is silylated in 54% ee by treatment with N-Hthiobis(a-methylbenzyl)amine 83 in the presence of Me3SiCl (Scheme 20) [58]. 

In 1991, Green showed that slow addition of n-BuLi to a solution of the tartrate-derived acetal 109 leads to diastereoselective lithiation and hence allows formation of the complexes 111 (Scheme 27) [77,78]. Similar acetals 112 and 113 (R= H) performed much less successfully. Formation of the organolithium 110 required an excess of alkyllithium base, and its stereoselectivity appeared to be under thermodynamic control arising from equilibration of various lithiated species [78]. Unfortunately, removal of the auxiliary from 111 and its analogues proved problematic. 

Note added in proof. The diastereoselective lithiation of N,N-dimethylferrocenylethylamine) 9 (Scheme 2) and sparteinemediated enantioselective lithiation of (diisopropylamido)fer-rocene 84 (Scheme 21) using MeLi were modeled through an assumed reversible adduct for-... 

Product 27 of entry 31 also deserves some comment since it was found that the oxazaphospholidine oxide group turns out to be an excellent ortho directing group for the diastereoselective lithiation of ferrocene (Scheme 3.15). 

The acetal 3 has been used to access the alcohol 1 in a straightforward way (Scheme 5.2). The first step is a diastereoselective lithiation of compound 3, which is directed in only one position on the substimted Cp ring by the acetal moiety. Electrophilic quenching of the lithiated intermediate by Ph2PCl yields a diaste-reoisomerically pure phosphine-acetal which can be efficiently hydrolyzed under acidic conditions to yield the aldehyde (5 )-4 [42,43]. The desired alcohol could be obtained after reduction by NaBH4 and protection of the phosphine by Sg. 

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