Nucleophile organometallics

Nonaqueous Bases Nonaqueous Nucleophiles Organometallic Catalytic Reduction Acidic Reduction Basic or Neutral Reduction Hydride Reduction Lewis Acids Soft Acids Radical Addition Oxidizing Agents... 

The optically active iodide 153 (Scheme 43) can be conveniently prepared from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate (154) (see Scheme 41). At this stage of the synthesis, our plan called for the conversion of 153 to a nucleophilic organometallic species, with the hope that the latter would combine with epoxide 152. As matters transpired, we found that the mixed higher order cuprate reagent derived from 153 reacts in the desired and expected way with epoxide 152, affording alcohol 180 in 88% yield this regioselective union creates the C12-C13 bond of rapamycin. 

Direct attachment of a functional group to the carbon atoms of the cyclopropane ring is fairly difficult. gem-Dibromocyclopropanes are readily available through the addition of dibromocarbene to olefinic compounds. Their synthetic versatility is reviewed in a previous volume of this series [77]. Substitution of the bromide with the aid of nucleophilic organometallics to form a new carbon-carbon bond has been investigated [78]. 

Asymmetric synthesis of amino acids.1 These lactones can serve as an optically active form of glycine for synthesis of either D- or L-amino acids. Thus (+ )-1 (or (—)-l) on radical bromination is converted into a single monobromide (2), which can be coupled with nucleophilic organometallic reagents, by either an SN1... 

Metallic tin, Sn(0), is even more effectively employed. For example, in the presence of Sn(0), allyl bromide and a-halocarbonyl compounds afford nucleophilic organometallic species, which add to aldehydes in good yields to give homoallylic alcohols (12) and g-hydroxycarbonyl compounds (13,14) respectively. a-Diketones could be reduced by activated Sn(0), to give tin(II) enediolates which in turn undergo aldol reaction to form a,g-dihydroxyketones (15,16). This reaction was successfully applied to a stereoselective synthesis of methyl D-glucosaminate (17). 

Three-component reactions between organic electrophile (halide, ester, etc.), carbon monooxide, and organic nucleophile (organometallic compound) (Equation (1)) catalyzed by transition metal complexes afford a powerful method for the synthesis of various ketones. The pioneering works in this area appeared in the early 1980s. 

The disconnection strategies summarised on p. 586 reveal that the nucleophilic organometallic reagents derived from alkyl halides (e.g. R MgX, RLi) require... 

Arenes and heteroarenes which are particularly easy to metalate are tricarbo-nyl( 76-arene)chromium complexes [380, 381], ferrocenes [13, 382, 383], thiophenes [157, 158, 181, 370, 384], furans [370, 385], and most azoles [386-389]. Meta-lated oxazoles, indoles, or furans can, however, be unstable and undergo ring-opening reactions [179, 181, 388]. Pyridines and other six-membered, nitrogen-containing heterocycles can also be lithiated [59, 370, 390-398] or magnesiated [399], but because nucleophilic organometallic compounds readily add to electron-deficient heteroarenes, dimerization can occur, and alkylations of such metalated heteroarenes often require careful optimization of the reaction conditions [368, 400, 401] (Schemes 5.42 and 5.69). 

Some nucleophiles (organometallics RM and hydride equivalents, featuring very weak conjugate acids) show a different stereochemical outcome, the attack of the nucleophile taking place at the palladium atom to form a neutral rj3 complex. Reductive elimination—or, in other words, intramolecular delivery of the nucleophile to the allylic framework—occurs with retention of configuration. In short, the reactions with these types of nucleophiles occur with overall inversion (inversion + retention) of configuration. 

Fig. 6.47. Top three reactions chemoselective acylations of weakly nucleophilic organometallic compounds with carboxylic acid chlorides.

As an example, consider the following proposed synthesis. The necessary Grignard reagent could not be made because the aldehyde carbonyl group would react with its own nucleophilic organometallic group. 

Like other strong nucleophiles, organometallic reagents—RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols. 

Usually, less nucleophilic organometallic reagents such as tin (26 or 27 ), zirconium (28 ) and cadmium have been used for selective transmetallation (equations 36 , 37 , 38 and 39 ). CgHjSiFs has been used to prepare (CgH5)2SbF from SbFs (equation 40) . 

Less nucleophilic organometallic reagents, such as derivatives of tin , zirconium lead and cadmium , have usually been used for selective transmetallation (equations 65 , 66 , 67 and 68 ). Enamines have also been used (equation 69) . 

Thus far we have discussed numerous examples whereby selective ketone formation has been achieved through organometallic acylation. The problem was approached by choosing a less nucleophilic organometallic which can be acylated but does not interact wiA the desired product. Thus far, few reagents with this type of selectivity have been found (organocuprates). Most often, the strategy was to either preserve the tetrahedral intermediate formed upon nucleophilic addition or to activate the substrate... 

Benzamides (N-Bz) are formed by the reaction of amines with benzoyl chloride in pyridine or trimethylamine. The group is stable to pH 1-14, nucleophiles, organometallics (except organolithium reagents), catalytic hydrogenation, and oxidation. It is cleaved by strong acids (6N HCl, HBr) or diisobutylaluminum hydride. ... 

This remarkable reaetion is relevant first because the process did not require an expensive and toxic metal catalyst and second because an aromatic hydrocarbon ArH (mesitylene in the reported example) was directly used as the nucleophile, in contrast to what happens with thermal reactions, where a nucleophilic organometallic derivative Ar M is used, as in the Stille (M = SnR3), Kumada (M = MgX) and Suzuki [M = 11(011)2] reactions. 

---