Chiral cuprates

Hie first example of a diital catbanionic residual ligand has recently been reported [238]. Chiral mixed cuprates generated from alkyilitliium reagents... 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

The reaction of propargylic chiral acetals with a catalytic copper reagent (RMgX/5% CuX) provides the expected alkoxy allenes in quantitative yield (Table 3)61. The diastereomeric excess is highly dependent on the size of the ring of the acetal and on the type of substituents it contains. The best diastereomeric excess is 85% with the acetal derived from cyclooctanediol. The use of lithium dimethylcuprate results in 1,2-addition lo the triple bond and the resulting lithium alkenyl cuprate bearing a cyclic acetal does not eliminate even at reflux temperature ( + 35°C). 

The conjugate addition of lithium cuprates to cinnamates 1 bearing a chiral oxazolidine or imidazolidine ring at the ortho position produced 2 in good to excellent yield upon hydrolysis14. 

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

The addition to 2-cyclohexcnone or (fj-d-phenyl-S-penten -one gave products with d.r. 99 1. Since the configuration of 5 was not determined, a detailed interpretation of the stereoselectivity is not possible. The 1,4 addition of the chiral cuprate reagent, lithium [2-(l-dimethylamino-ethyl)phenyl](2-thienyl)cuprate, to ( )-2,2-dimethyT5-phenyl-4-penten-3-one produced predominantly one diastereomer with d.r. 99 1, while the 1,4-addition of [2-(l-dimethylaminoethyl)-phenyl]lithium to the same enone gave predominantly the opposite diastereomer (d.r. 3 97). 

Another chiral cuprate that shows high diastereoselectivity on addition to cycloalkcnones is the dihydropyrazine derivative 12. The adducts 13 were obtained in good chemical yield with diastereoselectivities exceeding 90% A Lower diastereoselectivities resulted on addition of 12 to /(-substituted cycloalkenones or to acyclic ( )-enones. 

In these reactions one equivalent of chiral azaenolate remains unused. This can be overcome when a mixed azaenol cuprate 9 is employed with an acetylide as nontransferable ligand or when a mixed azaenol dimethylzincate 10 is used. Higher diastereoselectivities are achieved with zincates than with copper azaenolates and with (li ,2S )-2-methoxy-1,2-diphenylethanamine as auxiliary231. 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

Conjugate addition reactions involving organocopper intermediates can be made enantioselective by using chiral ligands.86 Several mixed cuprate reagents containing... 

Nicolas, E., Russell, K. C., and Hruby, V. J. (1993). Asymmetric 1,4-addition of organo-cuprates to chiral a, b-unsaturated N-Acyl-4-phenyl-2-oxazolidinones A new approach to the synthesis of chiral b-branched carboxylic acids. J. Org. Chem. 58, 766—770. 

Chiral allenylstannanes can be prepared by Sjv2 displacement of propargylic halides sulfinates or sulfonates with tin cuprates (Table 14)78. The nonracemic propargylic mesylate (74) afforded a nonracemic allene, [a]D —570, whose configuration was assigned by application of Brewster s rules (equation 38)78. Displacements on the steroidal mesylates 75 and 76 afforded the allenic products with complete inversion of configuration (Scheme 32)78. 

In solution, organocopper compounds may exist as an equilibrium of several species, and a loss of enantioselectivity may be inevitable if this equilibrium process produces some achiral but more reactive cuprate species. The way to overcome this problem is to develop a highly reactive chiral reagent to suppress the undesired, nonchiral species-mediated reactions. 

DesilylbrominationThis reaction was first used by Fleming et al. (8, 196 11, 75) in connection with protection of enones, but it is also useful for synthesis of chiral 5-alkylcyclohexenones. Thus reaction of (R)-(-)-l with lithium dialkyl-cuprates gives the trans-adduct 2 as the only product. Of several bromination reagents, only CuBr2 in DMF is useful for conversion of 2 to optically active 3. 

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

Due to its reliability, the SN2 substitution is often used in applications which require the highly enantioselective formation of the allene for example, Brummond et al. [19g] prepared the yneallene 19 (a starting material for intramolecular allenic Pauson-Khand cycloadditions) through the anti-selective SN2 substitution of the chiral propargylic mesylate 18 with a suitable magnesium cuprate (Scheme 2.6). 

Initial attempts to perform the 1,5-substitution enantioselectively with chiral enyne acetates proceeded disappointingly. For example, treatment of the enantio-merically pure substrate 51 with the cyano-Gilman cuprate tBu2CuLi LiCN at -90 °C provided vinylallene 52 as a 1 3 mixture of E and Z isomers with 20 and 74% ee, respectively (Scheme 2.19) [28], As previously described for the corresponding Sn2 substitution of propargylic electrophiles, this unsatisfactory stereoselection may be attributed to a racemization of the allene by the cuprate or other organome-... 

Scheme 2.29 Diastereoselective 1,6-cuprate addition to chiral 5-alkynylidene-l, 3-dioxan-4-one 82.

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