Reductive aldol, enantioselective

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. 

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... 

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]. 

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)... 

New 4-substituted phenyl(bisoxazoline) ligands (PHEBOX ligands) have been com-plexed with rhodium and examined as enantioselective catalysts of the reductive aldol of acrylates and aldehydes.160 The results have been compared with the corresponding pyridine-centred (PYBOX) ligand complexes. 

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. ... 

Scheme 8.22 Intermolecular enantioselective hydrogenative reductive aldol reaction by...

Scheme 9.13 Copper-catalyzed enantioselective domino reductive aldol reaction.

Scheme 11.26 First catalytic, enantioselective intermolecular reductive aldol reaction [43, 44].

Scheme 11.29 First enantioselective, reductive aldol couplings of vinyl ketones with aldehydes [48].

Riant developed a versatile methodology for the diastereo- and enantioselective domino reductive aldol cycHzation reaction of functionabzed a.fJ-unsaturated esters 147 into the corresponding bicyhc domino products 148 in high yields and enantios-electivities. The reaction was catalyzed by a Cu(I) complex of chiral bisphosphine 146 in the presence of phenylsilane as reductant The product 148 with three contiguous stereocenters was formed with high diastereoselectivities. The stereoselectivity of the process increased with the steric hindrance of the ester moiety, since the best results were obtained with the tert-butyl esters (Scheme 11.31) [50]. 

Fukuzawa [51] designed click-ferrophos 149 and tested for the Cu(I)-catalyzed, enantioselective reductive aldol reaction of ketones with an acryHc ester in the... 

Lipshutz and co-workers have developed an enantioselective version of the silane-mediated intramolecular reductive aldol cyclization catalyzed by Cu complexes (Scheme 112) (182). The reaction of enones 251 with Cu-Josiphos complexes L3 or L4 in the presence of diethoxymethylsilane (DBMS) gave a single diastereomers of the products 252 in high enantiomeric excess (up to 98% ee). 

Lipshutz BH, Amorelli B, Unger JB (2008) CuH-catalyzed enantioselective intramolecular reductive aldol reactions generating three new contiguous asymmetric stereocenters. J Am Chem Soc 130 14378-14379. doi 10.1021/ja8045475... 

The enantioselective intermolecular reductive aldol reaction with enone instead of ester is also an important C-C bond formation reaction. The coupling reaction of cyclopent-2-enone and benzaldehyde with hydrosilane in the presence of 1 mol% of the phebox-Rh complex 5-Ph smoothly proceeded to give the corresponding anti-p-hydroxyketone 29 with the high ee value (Scheme 20) [25], On the basis of the absolute configuration of 29, the transition state of the reaction might involve the Re face attack of the Rh enolate to the Re face of the aldehyde captured on the rhodium atom leading to form 2S, l R-diastereomeric product. 

Furthermore, the reductive aldol reaction can be used for the construction of ot,p,y-stereotriads. When the racemic phebox-Rh acetate complex 32 was subjected to the coupling reactions of (5)-2-phenylpropanal with acrylate, the Felkin-Anh product 31a with (2R,3/ ,45)-configuration was predominantly formed (Scheme 22) [27]. The anri -Felkin-Anh product 31b (enantiomer) was a minor diastereomer. The use of the chiral (S,S)-phebox-Rh complex 5- Pr for the coupling reaction with (S)-2-phenylpropanal resulted in the formation of the Felkin-Anh product with high ee and de. On the other hand, the use of (R)-2-phenylpropanal afforded the anti-Felkin-Anh product 31b as a major diastereomer with moderate enantioselectivity. Thus, a combination of (S)-2-phenylpropanal with the (S,S)-phebox-Rh complex 5- Pr is a matched pair. 

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