Enone-aldehyde coupling

Enone-aldehyde coupling. A recent synthesis of the ring system 2 of mevino-lin (3), a fungal metabolite used for treatment of hypercholesterolemia, depends on... 

Shibasaki has shown that ALB is also effective for the three-component coupling of enones, aldehydes, and malonates [23]. The above-mentioned mechanistic consideration suggested that the reaction of a lithium enolate derived from a malonate derivative with an enone would lead to the formation of an intermediary aluminum enolate. Thus, further studies were carried out to obtain direct evidence for the formation of an aluminum enolate. The larger electronegativity of aluminum (1.5) as compared with that of lithium, sodium, or lanthanoid suggests that the protonation of the aluminum enolate should be slower than that of the corresponding lithium, sodium, and/or lanthanoid enolates. Then, is it possible to trap such an Al-enolate by an... 

SCHEME 3.34 Synthesis of 1,3-diketones by Ni-catalyzed redox coupling of enones, aldehydes, and aUcynes. 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

For use of conjugated enones as nucleophilic partners in catalytic intermolecular reductive couplings to aldehydes, see ... 

Coupling of vinyl iodides with aldehydes (12, 137). Further study1 of this 1,2-addition of alkenylchromium compounds to aldehydes to form allylic alcohols indicates that the reaction is applicable to a-alkoxy and a,(i-bisalkoxy aldehydes by use of a solvent other than DMF, which can promote elimination to an enal. A wide number of other functional groups can also be accommodated. Both vinyl iodides and p-iodo enones can be used as precursors to the alkenylchromium reagent. The reaction is only modestly diastereoselective, but the stereochemistry of a disubstituted vinyl iodide is retained. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

More recently, using the cyclometallated iridium C,(7-benzoate derived from allyl acetate, 4-methoxy-3-nitrobenzoic acid and BIPHEP, catalytic carbonyl crotylation employing 1,3-butadiene from the aldehyde, or alcohol oxidation was achieved under transfer hydrogenation conditions [274]. Carbonyl addition occurs with roughly equal facility from the alcohol or aldehyde oxidation level. However, products are obtained as diastereomeric mixtures. Stereoselective variants of these processes are under development. It should be noted that under the conditions of ruthenium-catalyzed transfer hydrogenation, conjugated dienes, including butadiene, couple to alcohols or aldehydes to provide either products of carbonyl crotylation or p,y-enones (Scheme 16) [275, 276]. 

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 triene 1 was prepared from the enone 4, available in enantiomerically-pure form over several steps from pulegone. Triply-convergent coupling with the cuprate 5 and the aldehyde 6 led to the furan... 

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