Diastereoselective lithiation oxazolines

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. 

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. 

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). 

Lithiation of the conformationally constrained ferrocenyloxazoline 308 (Scheme 142) provided useful information about the mechanism by which lithiation of 305 achieves diastereoselectivity . The product 310 must have arisen from an organolithium 309 in which the oxazoline nitrogen coordinates to the hthium (Scheme 142). It is likely that... 

A ferrocenyloxazoline with only one adjacent position available for deprotonation will lithiate at that position irrespective of stereochemistry. This means that the same oxazoline can be used to form ferrocenes with either sense of planar chirality. The synthesis of the diastereoisomeric ligands 311 and 313 illustrates the strategy (Scheme 143), which is now commonly used with other substrates to control planar chirality by lithiation (see below). Ferrocene 311 is available by lithiation of 305 directly, but diastereoselective silylation followed by a second lithiation (best carried out in situ in a single pot) gives the diastereoisomeric phosphine 313 after deprotection by protodesilylation ". ... 

In removing the oxazoline auxiliary from the products, Richards and coworkers have demonstrated the use of the diastereoselective ferrocenyloxazoline lithiation in the synthesis of conformationally constrained amino acid derivatives (Scheme 146) °. Amination of 305 was achieved by nitration, reducing to the amino group after removal of the oxazoline under standard conditions. Using the trick of silylating the more reactive diastereotopic site, it was possible to make either enantiomer of 321 from the same oxazoline starting material. 

The synthesis of ferrocene 9 relied on chemistry introduced by Sammakia, Uemura, and Richards [18]. They had shown that 2-ferrocenyl oxazoline 10 derived from t-leucine could be selectively deprotonated and trapped with electrophiles to afford ortho-functionalized planar-chiral products 11 with excellent diastereoselectivities (Scheme 2.1.2.3). Following this strategy, 9 became accessible in a highly straightforward manner by trapping the lithiated intermediate derived from 10 with benzophenone [10, 11],... 

Lateral lithiation of (d )-4-isopropyl-2-(o-tolyl)oxazoline and reaction with aldehydes provides the addition products 1148 with moderate to good diastereoselectivity. The addition of TMEDA is vital for any diastereoselectivity to be observed. The major (,S,A)-products lactonize faster under acidic conditions providing dihydroisocoumarins 1149 in up to ee 97% (Scheme 286, Table 53) <2005T3289>. Similarly, the addition of laterally metallated o-toluates to chiral aldehydes provides a key dihydroisocoumarin during a total synthesis of AI-77-B <1999J(P1)1083>. 

The Darzens reaction of the oxazoline 360 with a series of aldimines has been shown to form aziridine 362 in good yields and with high diastereoselectivity <2005X3251>. Deprotonation of the aziridine to form the aziridinyl anion and subsequent reaction with an electrophile provide the highly substituted aziridines 363 in moderate yields. The diphenylphosphinyl group on the nitrogen provides optimal yields in the lithiation reaction (Scheme 94). 

Various ferrocene-based organosilanols 165 have been synthesized in two steps fi om chiral 2-ferrocenyl oxazolines 163. Diastereoselective ortho-lithiation with sec-BuLi followed by electrophilic attack with chlorosilanes gave diastereomerically enriched 164, which were oxidized in air with [IrCl(C8Hi2)]2 as catalyst to give, after purification, stereochemically homogeneous samples of 165. Their application in asymmetric phenyl transfer reactions to substituted benzaldehydes afforded products with high ee (up to 91%) <050L1407>. 

Methylation by MeOTf can also be carried out asymmetrically. Treatment of a-lithio benzyl 2-quinolyl sulfide with MeOTf in the presence of a bis(oxazoline) as an external chiral ligand yielded chiral 1-phenylethanethio quinolyl sulfide (eq 17). Lithiation adjacent to nitrogen of chiral 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution with MeOTf offered general routes to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. ... 

It was demonstrated that the diastereoselectivity of ort/io-lithiation depends on a fine balance between ligand and alkyUithium choice [31]. The optimization of the reaction conditions with starting oxazoline derivative 76 (prepared analogously to compound 73) led to the conclusion that the direction of asymmetric ortho-lithiation, imposed by a chiral oxazoline moiety, can be completely reversed by the choice of a suitable achiral ligand (Scheme 3.18). Thus, the best result was obtained by the combination of lV,A, A, A -tetramethylethylenediamine (TMEDA) and sec-BuLi in pentane, that led to diastereomer 77 in 96 % yield and dr = 9 1... 

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