Ferrocenes diastereoselective lithiation

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. ... 

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... 

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. 

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]. 

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). 

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 ". ... 

Some headway has been made using sulphoxides to direct the lithiation of arenechromium tricarbonyls in the manner of Kagan s work with ferrocenes . Diastereoselectiv-ities in the lithiation-quench of 392 are excellent, though yields are poor with most electrophiles. Diastereoselectivity reverses on double lithiation, because the last-formed anionic site in 394 is the most reactive (Scheme 163). 

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],... 

As chiral ligands for transition metal complex-catalyzed asymmetric reactions, a variety of novel chiral ferrocenylchalcogen compounds, which possess a planar chirality due to the 1,2-unsymmetrically disubstituted ferrocene structure, have been prepared from chiral ferrocenes (Scheme 1). Thus, chiral diferrocenyl dichalcogenides bearing an optically active dimethylaminoethyl or p-tolyl-sulfoxide moiety 1-10 were prepared by lithiation of the corresponding chiral ferrocenes, highly diastereoselectively, in moderate to high chemical yields. 

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>. 

Planar chiral compounds usually (and for the purpose of this review, always) contain unsymmetrically substituted aromatic systems. Chirality arises because the otherwise enantiotopic faces of the aromatic ring are differentiated by the coordination to a metal atom - commonly iron (in the ferrocenes) or chromium (in the arenechromium tricarbonyl complexes). Withdrawal of electrons by the metal centre means that arene-metal complexes and metallocenes are more readily lithiated than their parent aromatic systems, and the stereochemical features associated with the planar chirality allow lithiation to be diastereoselective (if the starting material is chiral) or enantioselective (if only the product is chiral). 

Most of the chiral ferrocenylphosphines are prepared by diastereoselective ort/zo-lithiation of ferrocene and subsequent reaction with a chlorophosphine (Scheme 2.46). Chen and co-workers " extended this reaction to dichlor-ophosphines to have a more flexible approach (Scheme 2.48). 

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