Allylic copper enolate

Interestingly, treatment of the allylic carbonate 23, which had proven problematic in the previous study, under analogous reaction conditions with the copper enolate derived from 24 furnished the a,/9-disubstituted ketone. Subsequent ring-closing metathesis furnished the 1,2-cyclohexenes 25a/25b in 75% overall yield favoring the trans-dia-stereomer 25a (2° 1°=30 1, ds=10 l) [14]. Overall, this reaction provides an alternative approach to an exo-selective Diels-Alder cycloaddition, and indicates that a-substituted enolates are even more tolerant nucleophiles than the unsubstituted derivatives. 

Evans and Leahy reported on a method for the rhodium-catalyzed allylic alkylation using copper enolates, generated by transmetalation of the corresponding lithium enolates (equation 19). These enolates are softer and less basic nucleophiles than lithium enolates and therefore problems typically associated with enolate nncleophiles in metal-allyl chemistry can be avoided. A copper(I) enolate, derived from acetophenone derivative 63, was used as nucleophile in a regio- and stereoselective rhodinm-catalyzed alkylation of the in situ activated allylic alcohol 62. Thereby, the synthesized ketone 64, a key intermediate in the total synthesis of (—)-sugiresinol dimethyl ether (65), was produced as the only detectable regioisomer with complete conservation of enantiomeric excess. 

The ultimate in the three-component coupling approach to prostaglandins has now been achieved by Noyori (48). As illustrated in Fig. 15, the cuprate derived from iodide [82] was added to enone [80] in the usual fashion. Then, after addition of hexamethylphosphoramide, triphenyltin chloride was used to effect enolate interchange. As opposed to lithium (or copper) enolates, the tin enolate is cleanly alkylated with allylic iodide [81]. The protected PGE2 [83] was obtained in 78% yield. Two-step deprotection to PGEj was straightforward. 

Copper dienolates of a,/3-unsaturated acids, prepared by Copper(I) Iodide transmetalation, can be selectively y-alkylated with allylic halides the use of nonallylic electrophiles leads mainly to a-alkylation (eq 20). Copper enolates of a,fi-unsaturated esters and amides show similar behavior. 

The challenge of three-component synthesis of prostaglandines has been met by Ryoji Noyori et /. with extraordinary success. The assembly of the "lower" ((d) and the "upper" (a) side chain is accomplished in a "one-pot" protocol. The (D-side chain is attached by addition of (5)-/raiw-3-terr-butyldimethylsiIyIoxy-l-octenyllithium complexed with one equivalent of dimethylzinc or, alternatively, with copper iodide and tributylphosphine. To install the a-chain, the zinc enolate formed in the preceding step is directly condensed with the functionalized cts-allylic or propargylic part, whereas the copper enolate has to be added in the presence of triphenyltin chloride and hexamethylphosphoric acid triamide (HMPA). ... 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Tab. 10.3 The scope of the regioselective rhodium-catalyzed allylic alkylation with copper(l) enolates.

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

The addition of Grignard reagents or organolithiums (alkenyl, alkyl, alkynyl, allyl or aryl) to nitroenamines (281)213 was reported by Severin to afford P-substituted-a-nitroalkenes.214 b Similarly, ketone enolates (sodium or potassium), ester enolates (lithium) and lactone enolates (lithium) react to afford acr-nitroethylidene salts (294) which, on hydrolysis with either silica gel or dilute acid, afford 7-keto-a,(3-unsaturated esters or ketones (295)2l4c-d or acylidene lactones (296).214 Alternatively, the salts (294, X s CH2) can be converted to -y-ketoketones (297) with ascorbic acid and copper catalyst. 

The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homo-chiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3). 

Copper-catalyzed reactions of [(tosylimino)iodo]benzene with unsaturated compounds sometimes lead to tosylamidation. Examples include conversions of silyl enol ethers to a-tosylamido ketones [173], and tosylamidation of allylic silanes with loss of the silyl group [190] (Scheme 69). 

But this strategy is doomed too as the allylic bromide will almost certainly react at its less hindered end on the vinyl group. However, we might choose the alternative branchpoint disconnection 38a and consider conjugate addition of some vinyl-metal (copper ) derivative to the enone 41 that could be made by some aldol process from the ketone 42 and an enol(ate) of acetone 43. 

The prostaglandin approach above (Eq. 29) also shows that the reaction with the carbenoid is compatible with further functions and even a second olefinic unit. However, this second double bond is left unattacked only because of its deactivation by the allylic siloxy group. Competition experiments have demonstrated that simple olefins like styrene or cyclohexene react with methyl diazoacetate under copper-catalysis in rates comparable to those of silyl enol ethers57). 

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