Aldol-reduction reactions

Scheme 2 Transition metal-catalyzed reductive aldol reaction...

This reaction sequence of conjugate reduction followed by aldol reaction is known as the reductive aldol reaction. In certain instances, reductive elimination from the M-TM-enolate species may occur to furnish M-enolate, which itself may participate in the aldol reaction (Scheme 3). This detour may be described as the background path or stepwise path in one-pot. Indeed, it has been reported that certain cationic Rh complexes such as [Rh(COD)(DPPB)] (COD = 1,5-cyclooctadiene, DPPB = diphenylphosphinobutane) catalyze the aldol reactions of silyl enol ethers and carbonyl compounds by serving as Lewis acids [5-8]. 

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Motherwell and Whitehead et al. reported a similar intramolecular reductive aldol reaction of aldehyde-enoate derivatives. The cyclization of 6-oxo-ester 23 was catalyzed by RhCl(PPh3)3 (1 mol%) with Et3SiH (210 mol%) as terminal reductant (Scheme 9) [17,18]. The cyclization proceeded at 50 °C for 18 h to give the aldol product 24 in 81% yield with ds-selectivity (cis trans =... 

Scheme 9 Rh-catalyzed intramolecular reductive aldol reaction of 6-oxo-hex-2-enoates...

Scheme 10 Rh-catalyzed reductive aldol reaction with aldehydes as reductants...

In 2000, Morken et al. reported the first examples of catalytic asymmetric reductive aldol reactions [21]. Using Rh(BINAP) (5mol%) as catalyst and Et2MeSiH as reductant, the syn-selective (1.7 1) coupling of benzalde-hyde and methyl acrylate produced the diastereomers 35-syn and 35-anti in 91% ee and 88% ee, respectively. Using phenyl acrylate as the nucleophilic partner, a favorable yield of 72% was obtained for the aldol product 36 (Scheme 12). Several aldehydes were examined, which exhibit higher levels of syn-selectivity. Expanding the scope of substrates and acrylates under... 

The intramolecular reductive aldol reaction of keto-enones was successfully conducted under conditions similar to those described above, employing a cationic Rh complex and PI13P (Scheme 20) [34]. The keto-enone 63 was cyclized in the presence of added K2CO3 to give the ketone-aldol 64 in 72% yield with exclusive ds-selectivity. Dione-enone derivatives, for example 68 and 70, were efficiently cyclized to furnish bicyclic aldol products 69 and 71, respectively, wherein three stereogenic centers of the bicyclic product form stereoselectivity through the intermediacy of a Rh-enolate. 

Scheme 25 Anti-Felkin-Anh selectivity in the reductive aldol reaction of a-alkoxy and a-aminoaldehydes...

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... 

Scheme 28 Intramolecular reductive aldol reaction promoted by stoichiometric Stryker s...

Riant et al. in 2006 reported an enantioselective reductive aldol reaction of acetophenone and methyl acrylate mediated by PhSiH3 (140 mol %) and catalyzed by a complex generated in situ from [CuF(Ph3P)3]2MeOH (1-3 mol %) and a chiral bisphosphine (1-3 mol %) [57]. According to Mori s... 

It is well known that acrylates undergo transition metal catalyzed reductive aldol reaction, the silanes R3SiH first reacting in a 1,4 manner and the enolsilanes then participating in the actual aldol addition.57,58 A catalytic diastereoselective version was discovered by arrayed catalyst evaluation in which 192 independent catalytic systems were screened on 96-well microtiter plates.59 Conventional GC was used as the assay. A Rh-DuPhos catalyst turned out to be highly diastereoselective, but enantioselectivity was poor.59... 

Although a cobalt-catalyzed intermolecular reductive aldol reaction (generation of cobalt enolates by hydrometal-lation of acrylic acid derivatives and subsequent reactions with carbonyl compounds) was first described in 1989, low diastereoselectivity has been problematic.3 6 However, the intramolecular version of this process was found to show high diastereoselectivity (Equation (37)).377,377a 378 A Co(i)-Co(m) catalytic cycle is suggested on the basis of deuterium-labeling studies and the chemistry of Co(ll) complexes (Scheme 81). Cobalt(m) hydride 182, which is... 

A number of rhodium-catalyzed reductive aldol reactions using silanes have been reported since the first report... 

Krische and co-workers have revealed efficient reductive generation of rhodium enolates under hydrogenation conditions.403 40311-403 Both inter- and intramolecular reductive aldol reactions proceed smoothly and stereoselec-tively, although intermolecular reactions generally show low diastereoselectivity (Equations (52) and (53)). 

The first iridium-catalyzed reductive aldol reaction was reported in 2001.422 Methyl acrylate reacts with certain aldehydes and diethylmethylsilane with high enantio- and diastereoselectivies (Equation (69)). 

For cobalt-catalyzed reductive aldol reaction, see Isayama, S. Mukaiyama, T. Chem. Lett. 1989, 2005-2008. 

For palladium-catalyzed reductive aldol reaction, see Kiyooka, S. Shimizu, A. Torii, S. Tetrahedron Lett. 1998, 39, 5237-5238. 

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

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

A domino reduction-aldol reaction of ketones with methyl acrylate produces tertiary alcohols bearing an ester group (51) in high ee and de.151 Using a diphosphine- modified copper fluoride complex in the presence of phenylsilane, the method avoids having to preactivate the nucleophile prior to the C—C bond-forming step. 

Three types of one-pot catalytic enantioselective reductive aldol reactions of ketones have been described,158 giving fair to excellent ees with a BINAP auxiliary. (g)... 

Reductive aldol reaction of an allenic ester (52) to a ketone such as acetophenone can give y- (53-y) or a-product (53-cy).159 Using as catalysts a copper salt and a range of chiral phosphines, together with phosphine additives such as the triphenyl or tricy- clohexyl compounds, a highly selective set of outcomes can be achieved, e.g. (53-y) almost exclusively cis- with 99% ee, or - without additive - significant amounts of (53-a) can be formed (as a syn-anti mixture). A diastereoselective implementation of the latter has also been developed. 

Five- and six-membered /3-hydroxylactones have been synthesized diastereo- and (g) enantio-selectively from a,/l-unsaturated esters bearing a ketone tethered as the ester R group, in an intramolecular reductive aldol reaction catalysed by chiral bisphosphine complexes of copper .133... 

The Et3SiH-promoted diastereoselective reductive aldol reaction proceeds by using InBr3 as a catalyst. This three-component reaction affords only silyl aldolates as products without any side-reaction. The //-selectivity obtained here is higher than that of any other reductive aldol reactions (Scheme 111).382 A catalytic amount of In(OAc)3 also promotes... 

SCHEME 124. Reductive aldol reaction on electrodeficient furans588. BMEA = bis(methoxyethyl)... 

Birch reductions of acylpyrroles have been studied in some detail <07MI1888 07OL421>. A Birch reductive aldol reaction of 72 in the presence of acetaldehyde gave 3-pyrroline 73, a useful intermediate for the production of pyrrolidinone-based building block 74 <07OL421>. 

Conjugate reduction. The reagent generated from PhMejSiH, CuCl has practical application in the reduction of enones and enoic esters. Triphenylphosphine-coordinated CuF and [(PhjPlCuHlg can be used instead of CuCl. A more complex reducing system is made up of PhSiHj, Li, Nilj, and PhjP, and the reduction is assisted by ultrasound. Reductive aldol reaction of acrylic acid derivatives with arylaldehydes occurs when they are treated with (Ph3P) Pd, and HSiClj, and aldehydes. ... 

In the reductive aldol reaction r-butyl acrylate is formally transformed into an enolate of the propanoate ester. Such a reaction requires Phi in addition to Ni(cod)2 and... 

Reductive aldol reaction of l-alken-3-ones and cinnamic esters depends on generating Rh enolates and the presence of chiral ligands turns such a process enantioselective. Effective ligands of very different structural types have been identified, and they include TADDOL phosphine 71 and BOX ligand 72. ... 

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