Copper enolates synthesis

Scheme 10.6 Total synthesis of (-)-sugiresinol dimethyl ether using copper enolates.

Diketones (8, 126 127). Complete details of the synthesis of 1,4-diketones by oxidative coupling of ketone enolales and trimethylsilyl enol ethers with Cu(OTf)2 are available.1 Use of isobutyronitrile is essential for the coupling it is not only a suitable solvent, but the nitrile group apparently facilitates reduction of the intermediate copper enolate to CuOTf.2 When acetonitrile is used by-products containing a nitrile group are formed. 1,4-Diketones are formed only in traces when DMF, DMSO, or HMPT is used. 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

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 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]. 

The copper complex of these bis(oxazoline) compounds can also be used for hetero Diels-Alder reactions of acyl phosphonates with enol ethers.43 5 A favorable acyl phosphonate-catalyst association is achieved via complexation between the vicinal C=0 and P=0 functional groups. The acyl phosphonates are activated, leading to facile cycloaddition with electron-rich alkenes such as enol ethers. The product cyclic enol phosphonates can be used as building blocks in the asymmetric synthesis of complicated molecules. Scheme 5-36 shows the results of such reactions. 

A different approach towards titanium-mediated allene synthesis was used by Hayashi et al. [55], who recently reported rhodium-catalyzed enantioselective 1,6-addition reactions of aryltitanate reagents to 3-alkynyl-2-cycloalkenones 180 (Scheme 2.57). In the presence of chlorotrimethylsilane and (R)-segphos as chiral ligand, alle-nic silyl enol ethers 181 were obtained with good to excellent enantioselectivities and these can be converted further into allenic enol esters or triflates. In contrast to the corresponding copper-mediated 1,6-addition reactions (Section 2.2.2), these transformations probably proceed via alkenylrhodium species (formed by insertion of the C-C triple bond into a rhodium-aryl bond) and subsequent isomerization towards the thermodynamically more stable oxa-jt-allylrhodium intermediates [55],... 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

Certain acyclic diazoketones react with electron-rich alkenes (such as enol ethers) to form dihydrofurans. The catalyst of choice is Rh2(OAc)4 for these and related transformations, although copper catalysts have been used as well. A variety of ot-diazoketones and ot-diazoaldehydes can be used, including PhCOCHN2, NjCHCOCOOEt, MeCOC(N2)COMe, and MeCOC(N2)COOR (345,346). Wenkert (347) and Alonso (348) studied the scope of this dihydrofuran synthesis [Scheme 8.75 e.g., 304 305 R = H (349), COOEt (350)]. 

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