Cuprate nucleophiles

The results for conjugate additions to pseudodipeptides 83 and 86 may be interpreted along similar lines. Thus, addition of the fairly slim lithium dimethyl-cuprate nucleophile proceeded non-selectively (84, Scheme 6.17) [34, 35]. Con-... 

The reverse regiochemistry in additions to 43 was accomplished with cuprate nucleophiles. Thus 506, the regioisomer of 496, could be obtained in good yield as shown (examples include R = Me, Bu, Ph E = H, allyl, acyl). 

With a P-ketoester such as 159 there are very good chances to easily secure the desired double bond configuration, and the cuprate nucleophile offers additionally a very broad choice of possible substituents in 162 and 163. 

The preference of cuprate nucleophiles to add to the more sterically accessible olefin of 26 led into examining the possible functionalization of the endocyclic olefin [4a] After regioselective hydrogenation of the exocyclic olefin in the presence of Wilkinson s catalyst, cuprate addition to phosphate 31 preferentially occurred at... 

A key step in the reaction mechanism appears to be nucleophilic attack on the alkyl halide by the negatively charged copper atom but the details of the mechanism are not well understood Indeed there is probably more than one mechanism by which cuprates react with organic halogen compounds Vinyl halides and aryl halides are known to be very unreactive toward nucleophilic attack yet react with lithium dialkylcuprates... 

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. 

The conversion of a thiolactone to a cyclic ether can also be used as a key step in the synthesis of functionalized, stereochemically complex oxacycles (see 64—>66, Scheme 13). Nucleophilic addition of the indicated higher order cuprate reagent to the C-S double bond in thiolactone 64 furnishes a tetrahedral thiolate ion which undergoes smooth conversion to didehydrooxepane 65 upon treatment with 1,4-diiodobutane and the non-nucleophilic base 1,2,2,6,6-pentamethylpiperidine (pempidine).27 Regio- and diastereoselective hydroboration of 65 then gives alcohol 66 in 89 % yield after oxidative workup. Versatile vinylstannanes can also be accessed from thiolactones.28 For example, treatment of bis(thiolactone) 67 with... 

Bromo-2-(t-butylsulfonyl)propene (79) reacts with nucleophiles such as lithium benzenethiolate, lithium enolates and Grignard reagents to give a, /(-unsaturated sulfones, which undergo nucleophilic addition of lithium cuprates (equation 68)58. 

Scheme 4.10 gives some examples of application of alkyne carboalumination in synthesis. The reaction in Entry 1 was carried out as part of a synthesis of the immunosuppressant drug FK-506. The vinyl alane was subsequently transmetallated to a cuprate reagent (see Chapter 8). In Entry 2, the vinyl alane was used as a nucleophile for opening an epoxide ring and extending the carbon chain by two atoms. In Entries 3 to 5, the vinyl alane adducts were converted to vinyl iodides. In Entry 6, the vinyl alane was converted to an ate reagent prior to reaction with formaldehyde. 

The 2 1 species are known as cuprates and are the most common synthetic reagents. Disubstituted Cu(I) species have the 3c 10 electronic configuration and would be expected to have linear geometry. The Cu is a center of high electron density and nucleophilicity, and in solution, lithium dimethylcuprate exists as a dimer [LiCu(CH3)2]2.3 The compound is often represented as four methyl groups attached to a tetrahedral cluster of lithium and copper atoms. However, in the presence of Lil, the compound seems to be a monomer of composition (CH3)2CuLi.4... 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

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