Cuprates higher order

Cuprates are very useful but there are a few problems associated with them. In an attempt to circumvent these problems, Lipshutz developed the so-called higher order mixed cuprates (R2Cu(CN)Li2), prepared by reaction of 2 equivalents of organolithium reagent with cuprous cyanide (CuCN). 35 Mixed cuprates react 

Chapter 8. Nucleophilic Species That Form Carhon-Carhon Bonds 

Dieter et al. developed an a-aminoalkylcuprate, that allows nitrogen to be incorporated into a substrate. When cyanocuprate 484 reacted with cyclohexenone, for example, in the presence of chlorotrimethylsilane, a 98% yield of the conjugate addition product 485 was ohtained.  

The disconnections for the higher order cuprate are identical to those observed with Gilman reagents. 

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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... 

Addition of 15-crown-5 to the higher-order cuprate led to a reagent that is totally unrcac-tive towards 2-phenylpropanal even at room temperature18. If, however, boron trifluoride-diethyl ether complex was added as additional ingredient, the reactivity was restored and, furthermore, the Cram selectivity increased to 90 10 (Table 4). Analogous results could be obtained by placing the crown-ether effect within the cuprate itself, as in reagent 10. 

Rate enhancement and an improved stereoselectivity was also found for higher-order cuprates when chlorotrimethylsilane was addedl9. H- and 29Si-NMR studies revealed that higher-order... 

Another way is to dissolve an alkylcopper compound in an alkyllithium solution. Higher order cuprates can also be prepared, as well as non-ate copper reagents. Metallocenes (see p. 53) are usually made by this method ... 

The reaction has also been used to prepare 1,3-dilithiopropanes" and 1,1-dilithio-methylenecyclohexane" from the corresponding mercury compounds. In general, the equilibrium lies in the direction in which the more electropositive metal is bonded to that alkyl or aryl group that is the more stable carbanion (p. 228). The reaction proceeds with retention of configuration an Sgi mechanism is likely. Higher order cuprates (see Ref. 1277 in Chapter 10) have been produced by this reaction starting with a vinylic tin compound ... 

Scheme 36). Interestingly, the higher order cuprate 206 underwent conjugate addition with only moderate selectivity. This is likely due to the intervention of an electron transfer pathway. Competing electron transfer reactions involving a-alkoxymetal reagents of this type have also been reported by Cohen [81]. 

R2Cu(CN)Li2 reaction with vie-epoxy mesylatesA higher-order cuprate reacts selectively with the epoxide group of the epoxy mesylate 1 to provide 2 with inversion at C3. Ring closure of 2 furnishes the epoxide 3, which reacts with a second equivalent of the higher-order cuprate to furnish meso-4, with inversion at both C, and C3. This two-step reaction provides a route to acyclic alcohols with useful stereocontrol at both adjacent centers. 

The use of stannylcuprate reagents is well established.112,113 The reactions occur under mild conditions. They are reversible, and the reactivity and regio- and stereo-selectivity are sensitive to the structure and reaction conditions, as illustrated by the reaction of allene with the lower-order cuprate Bu3SnCuCNLi and, more readily, with the higher order cuprate (Bu3Sn)2CuCNLi (Equation (29)).114... 

So far, only cuprates with a 1 1 copper/lithium ratio have been considered. Treatment of phenyllithium with various substoichiometric quantities of copper bromide in DMS as solvent afforded so-called higher order cuprates, of which two were characterizable by X-ray crystallography. These have the overall stoichiometries Cu2Li3Ph5(DMS)4 and Cu4Li5Ph9(DMS)4 [114, 115). The structure of the former compound in the solid state is shown in Fig. 1.26. 

When the non-coordinating mesitoate system 156 was treated with lithium di-methylcuprate, formation of the anti-S 2 substitution product 157 was observed. Notably, the exclusive formation of the y-substitution product is the result of severe steric hindrance at the a-position, originating from the adjacent isopropyl group [78]. Conversely, the corresponding carbamate 158 was reported, on treatment with a higher order cuprate, to form the syn-SN2 product 159 exclusively [74]. The lithi-ated carbamate is assumed to coordinate the cuprate reagent (see 160), which forces the syn attack and gives trans-menthene (159). 

A 1,2-metalate rearrangement of a higher order cuprate, known as a Kodenski rearrangement [64], was used as a key step in the synthesis of the marine antiinflammatory sesterterpenoid manoalide 95 (Scheme 9.20) [65]. Treatment of the alkenyl lithium 89 (prepared from the alkenylstannane 88 with s-BuLi in a diethyl ether-pentane mixture) with the homocuprate 91 (produced from iodoalkane 90) gave the iodoalkene 94 in 72% overall yield from 88. The reaction proceeds as fol-... 

Another interesting example for an unusual transformation of bicyclopropylidene (1) is the reaction of the higher-order cuprate 279 [154] derived from 1 with the electrophilic glycine cation equivalent 276 [155] which produces the... 

Scheme 63. Reaction of the higher-order cuprate 279 derived from 1 with O Donnell s acetoxy-glycine derivative 276 occurring with opening of a three-membered ring [156]...

Give the products to be expected from each of the following reactions involving mixed or higher-order cuprate reagents. 

Hexyne, reaction with diisobutyl aluminum hydride, 66, 63 Higher order cuprates, 66, 57... 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Higher order cuprates (see Ref. 1277 in Chapter 10) have been produced by this reaction starting with a vinylic tin compound 414... 

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