Reductive aldolization

Substrate Catalyst Ligand Additive (mol%) Yield Aldol (Syn-Anti) Yield 1,4-Reduction 

For the cycloreduction of keto-enones, competitive 1,4-reduction in response to the reduced electrophilicity of the carbonyl partner is observed. Diones are more susceptible to addition by viture of inductive effects and the relief of di- 

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Representative procedure for conjugate reduction-aldol 3-CC 2- Hydroxy-[l-[tolue sulfonyl)- H-indol-3-yl]-methyl -4,4-dimethylcyclohexanone [35]... 

Vinyl Ketone-C=X (X=0, NR) Coupling (Reductive Aldol and Mannich Additions)... 

Scheme 6 Complementary regioselectivities in direct aldol couplings of 2-butanone and corresponding hydrogen-mediated reductive aldol couplings of MVK...

Asymmetric catalysis Reductive aldol Reductive Mannich... 

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...

Chiu et al. developed a catalytic reductive aldol cyclization of alkyne-diones such as 115 and 117 using [Ph3PCuH]6 (10mol%) as catalyst and polymethylhydrosiloxane PMHS (200 mol %) as terminal reductant. The... 

Scheme 29 Reductive aldol cydization of alkyne-diones catalyzed by Stryker s reagent...

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... 

In 1985, Matsuda et al. reported that Rh-H species promote a reaction sequence involving conjugate reduction, aldol type C - C bond formation, and... 

Nishiyama H, Shiomi T (2007) Reductive Aldol, Michael, and Mannich Reactions. 279 105-137... 

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 intermediate enolate or enol ether from the initial reduction of an enone may be alkylated in situ (Eq. 281).455 / -Substituted cyclopentenones may be asymmetrically reduced and alkylated459 (see section on asymmetric reductions of enones). Enolates may also be trapped with an aldehyde in a reductive aldol condensation of an enone with an aldehyde,455 permitting a regioselective aldol condensation to be carried out as shown in Eq. 282.455 This class of reductive aldol condensation reactions can also occur in a cyclic manner (Eq. 283).460... 

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