Conjugate addition of lithium dimethylcuprate

The conjugate addition of lithium dimethylcuprate to spiroketone 5 gave predominantly (S j-6 [(S)/(R) 92 8] in which methyl group attacked from the side syn to the oxygen atom, whereas the addition of lithium dimethylcuprate-chlorotrimethylsilane afforded exclusively the anti-adduct (S)-621,... 

The conjugate addition of lithium dimethylcuprate to chalcone in the presence of (2S)-1-(2,2-dimethyl-l-oxopropyl)-2-diphenylphosphinomethylpyrrolidine gave the corresponding S-adduct with 84% ec in 79% yield79. 

The first naturally occurring tricyclo[6.3.0.0 ]undecane to be synthesized was isocomene (757), a colorless oily sesquiterpene hydrocarbon isolated from several plant sources. In 1979, Paquette and Han reported an efficient, stereospecific approach starting with a preformed bicyclic enone, to which the third five-membered ring was appended with proper attention to stereochemistry and position of unsaturation (Scheme LXXX) The pivotal steps are seen to be the stannic chloride-induced cyclization of aldehyde 732 and the conjugate addition of lithium dimethylcuprate to 733 which sets the stereochemistry of the last methyl group. 

Cuprate conjugate additions. One step in a recent synthesis of (-t-)-modhephene (3). a natural sesquiterpene with a (3.3.3)propellane skeleton, involved conjugate addition of lithium dimethylcuprate to 1. The desired reaction proved difficult... 

Stereocontrolled conjugate addition of lithium dimethylcuprate to the electron deficient 2,3-double bond of allenes 851 leads to 5,6-dihydropyranM-oncs 852 in moderate yield (Equation 343) <2000J(P1)3188>. Similarly, the Ag(l)-catalyzed intramolecular cyclization of the allenic acid 853 is accelerated upon addition of diisopropylethyl-amine to afford the 3,6-dihydropyran-2-one 854, an intermediate during the total synthesis of (—)-malyngolide (Equation 344) <2000JA10470>. 

Chelation control has also been implicated in conjugate addition reactions. For example, during a synthesis of the macrolide antibiotic 6-ep/-erythromycin, Mul-zer and co-workers86 found that the stereochemistry at the anomeric centre (l position) of the tetrahydropyranyl protecting group had a profound effect on the stereochemistry of conjugate addition of lithium dimethylcuprate to the ynone 49.1 [Scheme 1.49]. 

Marshall and Ruden (196) have reported a conjugate addition of lithium dimethylcuprate to a cyclopropyl enone. The major products are the 1,4-adduct and one from a previously unreported 1,6-addition to the cyclopropyl ring [Eq. (96)]. 1,6-Conjugate additions are known for dienoates (206) and 2,2-di(carboxyethyl)vinylcyclopropane 94, cf. 59). 

The hydroxypentanoic acid segment was obtained via metalation and carbonylation of l-silyloxy-3-butyne (141). Conjugate addition of lithium dimethylcuprate followed by reduction provided a 45% yield of allylic alcohol 142. Coupling with alcohol 140 was effected via conversion of 142 to the... 

Enantioselective conjugate addition The bidentate ligand 1, prepared from L-proline, can effect enantioselective conjugate addition of lithium dimethylcuprate to chalcone at —20° in 84% ee. When the acyl group of 1 is replaced by methyl, the adduct... 

Compound 6 was treated with n-butyllithium (1 equiv), and the resulting acetylide was added to 5 in tetrahydrofuran to give the adduct (15). Conjugate addition of lithium dimethylcuprate followed by treatment with pyridinium p-toluenesulfonate (PPTS) gave segment A (4) [5b, c]. 

Wallace and Saengchantara have reported that the conjugate addition of lithium dimethylcuprate to racemic 3-(p-tolylsulfinyl)chromanone (111) proceeds with at least 90% diastereoseleetivity to yield (112) as the major product (Scheme 5.39) [102]. 

Conjugate addition of lithium dimethylcuprate to the optically pure a-(methoxycarbonyl)alkenyl sulphoxide (8), followed by reduction and saponification, gives (R )-(+)-3-methylnonanoic acid (9) (Scheme 8). The utility of this scheme clearly depends on the accessibility of the required optically active sulphoxides. 

Stoichiometric rather than catalytic amounts of cuprates are also mandatory in numerous other instances if one wishes to achieve clean transformations and to obtain high yields of products. This holds for example for the conjugate addition of lithium dimethylcuprate or dibutylcuprate onto 2-(l-methylethenyl)oxirane ("isoprene oxide"), giving rise to mainly the ( ) isomers of 3-methyl-2-penten-l-ol (39a) or ( )-3-methyl-2-octen-l-ol (39b), respectively (Scheme 1-31). " Efficient coupling with 1-alkenyl bromides " or tosylates requires again stoichiometric amounts of cuprates or even an excess thereof. 

There have been many applications of conjugate additions in synthesis. Some representative reactions are shown in Scheme 8.2. Entries 1 and 2 are examples of addition of lithium dimethylcuprate to cyclic enones. The stereoselectivity exhibited in Entry 2 is the result of both steric and stereoelectronic effects that favor the approach syn to the methyl substituent. In particular, the axial hydrogen at C(6) hinders the a approach. 

Additions to cyclopentenones.5 Conjugate addition of cuprates to 4-substi-tuted cyclopentenones can show moderate to high trarw-diastereoselection, which can be attributed to a steric effect. Surprisingly, addition of lithium dimethylcuprate to (R)-5-methoxy-2-cyclopentenone also shows high frans-diastereoselectivity (equation I). The stereoselectivity is decreased somewhat by addition of ClSi(CH3)3. 

In 1987, Marshall and Crooks reported the addition of lithium dimethylcuprate to the conjugated cycloalkynone 276 to yield, after equilibration, a single -enone 277, which was converted via acidic hydrolysis, oxidation, and reduction to... 

Better stereosdectivities have been noted for conjugate addition reactions to the steroidal enone 95 (Scheme 6.20, Tab. 6.2). Irrespective of the enone geometry, addition of lithium dimethylcuprate provided the anti addition product 96 in hi yid-d and with good diastereoselectivity (Tab. 6.2, entries 1 and 2). Interestin y, addition of chlorotrimethylsilane to the reaction mixture had a dramatic effect. The E isomer of enone 95 still gave the anti addition product 96 with perfect stereoselectivity (entry 3). "With the 2 isomer of the enone, however, the syn addition product 97 was formed in good yield and with hi diastereoselect vity (entry 4)... 

Regiosp>ecific synthesis of enol silyl ethers can also be achieved from enones either by reductive silylation or by 1,4-addition of the conjugated system. Thus, Li/NH reduction of the decalone (27) and silylation give the enol silyl ether (28). Similarly, addition of lithium dimethylcuprate to cyclohexenone followed by silylation gives the enol silyl ether (29). Trimethylsilyl cyanide (30) normally adds 1,2 to conjugated ketones (e.g. carvone, 31). However, in the presence of trialkylaluminum, 1,4-addition bdces place to give the enol silyl ether (32 Scheme 9). The same overall transformation can be accomplished by diethylaluminum cyanide and trimethylchlorosilane. ... 

Conjugate Addition Reactions.—The use of polymer-bound dialkylcuprates gives comparable or higher than normal yields in the conjugate addition to enones the major advantage lies in the ease of work-up. The mechanism of conjugate addition of cuprates and the mechanism and stereochemistry of the addition of lithium dimethylcuprate to jS-cyclopropyl-substituted enones have been reported. 

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