Copper aldolate

The Tol-BINAP complexes of CuFa, CuF, and CuOt-Bu also work as efficient chiral catalysts of the aldol reactions of aromatic and a, -unsaturated aldehydes wifh dienolate 64 (Scheme 10.62) [164]. IR spectroscopy has revealed fhat the stoichiometric reaction of 64 wifh Cu(Ot-Bu)(S)-Tol-BINAP forms a Cu(I) enolate, and fhat subsequent reaction wifh an aldehyde gives a copper aldolate. The copper enolate is also obtained by stepwise treatment of 64 with Bu4NPh3SiF2 and Cu(C1O4)(S)-To1-BINAP. These results, with the known reduction of Cu(II) to Cu(I) by SEE, indicate that fhe Cu-catalyzed aldol reactions proceed fhrough a transmetalation mechanism involving a chiral Cu(I) enolate. 

Propionylcyclopentadienyliron carbonyl complexes 1.151 (R = MeCH2) form enolates whose aldol condensations are highly selective. Depending on the associated metal, either anti (aluminum) or syn (copper) aldols are predominantly formed at -100°C. The absolute configuration of these aldols depends upon that of the starting complex [408, 522] (Figure 6.87). 

A plausible catalytic cycle for the direct asymmetric aldol reaction is shown in Fig. 7. Key to the success of the reaction is chemoselective enolate formation of ynones 8 in the presence of enolizable aldehydes, which is mediated by soft-soft interaction 10 between the ynone moiety and the copper catalyst. This interaction selectively acidifies the a-protons of ynones. The aldol addition of chiral Cu (I) enolate 12 to an aldehyde affords copper aldolate 13. The soft-soft interaction between the Cu(I) atom and the n electrons of the alkyne moiety in 13 would help suppress the imdesired retro-aldol reaction due to the existence of additional coordination. Nevertheless, facile protonation of imstable 13 and formation of aldol product 14 is crucial, rationahzing the inquiry of (sub)stoichiometric amounts of trifluoroethanol. Protonation of 13 regenerates the copper alkoxide catalyst. 

The proposed catalytic cycle of Evans enantioselective Cu(II)-catalyzed aldol addition is shown in Scheme 5.68. First, benzyloxyacetaldehyde 219a forms a chelate complex 226 with the metal, thus activating the carbonyl compound to become sufficiently reactive. The nucleophilic addition of silyl 0,S-ketene acetal 220 to this complex leads to the copper aldolate 227. Silylation yields the intermediate 228, whose decomplexation results in the formation of the silyl-protected aldol adduct and liberates the PYBOX catalyst 217. Crossover experiments revealed that the silyl transfer is a clear intermolecular process. 

The authors assumed that the catalytically active species might be a copper(I) complex originating from reduction by the silyl dienolate 214. As a consequence, the aldol reaction was performed with the chiral copper(I) complex [Cu(OfBu)-(S)-270], and identical results in terms of the stereochemical outcome were obtained. In addition, the reaction was followed by react IR. The study led to evidence of a copper(I) enolate as the active nucleophile, and the catalytic cycle also shown in Scheme 5.77 was proposed. The reaction of the copper(I) complex Cu(OiBu)-(S)-270 with silyl dienolate 214 represents the entry into the catalytic cycle. Under release of trimethylsilyl triflate, the copper enolate 272 forms, whose existence is indicated by in situ IR spectroscopy. Its exact structure remains unclear, but the description as O-bound tautomer is plausible. Upon reaction with the aldehyde, the copper aldolate 273 is generated, which is then silylated by means of the silyl dienol ether 214 to give the (isolable) silylated alcohol 274 from which the aldol product 271 is liberated during the acidic workup [132b]. 

Kinetic studies revealed that whereas the addition of the copper enolate to the carbonyl compound is a rapid reaction, the trapping of the copper aldolate is the rate-determining step. In order to enhance its rate, the additives (EtO)jSiF and PhBFgK are used that are assumed to facilitate the sUyl transfer to the copper aldolate [134]. 

The key step to this first reported case of the highly diastereoselective addition of a fluorinated enolate in an aldol process is the selective formation of the enolate a,a-Difluonnated enolates prepared by a metallation process employing either a zinc-copper couple [S] or reduced titanium species [9] undergo aldol condensation smoothly (equation 9) (Table 5)... 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

The diastereoselectivity of the copper enolate 2b may be rationalized by suggesting that the chair-like cyclic transition state J is preferred which leads to the major diastereomer 4. The usual antiperiplanar enolate geometry and equatorial disposition of the aldehyde substituent are incorporated into this model. Possible transition states consistent with the stereochemistries of the observed minor aldol products are also illustrated. 

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

Johnson J. S., Evans D. A. Chiral Bis(Oxazoline) Copper(II) Complexes Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions Acc. Chem. Res. 2000 33 325-335... 

The synthesis in Scheme 13.5 also makes use of an aromatic starting material and follows a retrosynthetic plan similar to that in Scheme 13.3. The starting material was 4-methoxybenzaldehyde. This synthesis was somewhat more convergent in that the entire side chain except for C(14) was introduced as a single unit by a mixed aldol condensation in step A. The C(14) methyl was introduced by a copper-catalyzed conjugate addition in Step B. 

Chiral //A(oxazolinc) ligands disubstituted at the carbon atom linking the two oxazolines by Frechet-type polyether dendrimers coordinated with copper(II) triflate were found to provide good yields and moderate enantioselectivities for Mukaiyama aldol reactions in water that are comparable with those resulting from the corresponding smaller catalysts.291 AgPF6-BINAP is very active in this reaction and the addition of a small amount of water enhanced the reactivity.292... 

Copper hydride species, notably Stryker s reagent [Ph3PCuH]6, are capable of promoting the conjugate reduction of a,( >-unsalurated carbonyl compounds [42], Taking advantage of this trustworthy method, Chiu et al. demonstrated in 1998 an intramolecular reductive aldol reaction in the synthesis of novel terpenoid pseudolaric acids isolated from Chinese folk medicine (Scheme 28) [43]. Two equivalents of [Ph3PCuH]6 enabled cycli-zation of keto-enone 104 to provide the bicyclic diastereomers 105 (66%) and 106 (16%). The reaction also was applied to the transformation of 107... 

The selectivity of the aldol addition can be rationalized in terms of a Zimmer -man-Traxler transition-state model with TS-2-50 having the lowest energy and leading to dr-values of >95 5 for 2-51 and 2-52 [18]. The chiral copper complex, responsible for the enantioselective 1,4-addition of the dialkyl zinc derivative in the first anionic transformation, seems to have no influence on the aldol addition. To facilitate the ee-determination of the domino Michael/aldol products and to show that 2-51 and 2-52 are l -epimers, the mixture of the two compounds was oxidized to the corresponding diketones 2-53. 

Many examples of asymmetric reactions catalyzed by copper complexes with chiral ligand systems have been reported. In particular, various copper-bis(oxazoline) catalysts (e.g., complexes (H) to (L), Scheme 48) are effective for carbon-carbon bond-forming reactions such as aldol,204 Mukaiyama-Michael, Diels-Alder,206 hetero Diels-Alder,207,208 dipolar cycloaddition,209,210... 

Asymmetric reactions using chiral copper Lewis acids are also performed in aqueous media. It has been reported that an asymmetric Diels-Alder reaction proceeds smoothly in water using Cu(OTf)2 and abrine as a chiral ligand (Scheme 49).214 The Cu -bis(oxazoline) system is effective in asymmetric aldol reactions in an aqueous solvent such as water/ethanol and even in pure water.215... 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

Shibasaki et al. also developed catalytic reactions of copper, some of which can be applied to catalytic asymmetric reactions. Catalytic aldol reactions of silicon enolates to ketones proceed using catalytic amounts of CuF (2.5 mol%) and a stoichiometric amount of (EtO)3SiF (120 mol%) (Scheme 104).500 Enantioselective alkenylation catalyzed by a complex derived from CuF and a chiral diphosphine ligand 237 is shown in Scheme 105.501 Catalytic cyanomethyla-tion by using TMSCH2CN was also reported, as shown in Scheme 106.502... 

For copper-catalyzed reductive aldol reaction, see Ooi, T. Doda, K. Sakai, D. Maruoka, K. Tetrahedron Lett. 1999, 40, 2133-2136. 

The catalytic asymmetric aldol reaction has been applied to the LASC system, which uses copper bis(-dodecyl sulfate) (4b) instead of CufOTf. 1261 An example is shown in Eq. 6. In this case, a Bronsted add, such as lauric add, is necessary to obtain a good yield and enantioseledivity. This example is the first one involving Lewis acid-catalyzed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivity are still not yet optimized, it should be noted that this appredable enantioselectivity has been attained at ambient temperature in water. 

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