Catalytic Asymmetric Intramolecular α-Alkylation of Aldehydes

Vignola, Nicola; List, Benjamin

doi:10.1021/ja0392566

Cited by 263 publications

(182 citation statements)

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“…2 of Scheme 1) (9), and to several other reactions including prolinecatalyzed asymmetric Mannich (10), Michael (11), ␣-amination (12), and intramolecular enolexo aldolization reactions (10 3 11) (13) (Eq. 3 of Scheme 1) (14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates. D iscovered in the early 1970s, the Hajos-Parrish-EderSauer-Wiechert reaction (1, 2), a proline-catalyzed intramolecular aldol reaction, represents not only the first asymmetric aldol reaction invented by chemists but also the first highly enantioselective organocatalytic transformation [1(4) 3 2(5) 3 3(6)] (Eq. 1 of Scheme 1) (3-6). Inspired by Nature's phenomenal enzymes, which catalyze direct asymmetric aldolizations of unmodified carbonyl compounds (7, 8), we have recently extended the Hajos-Parrish-Eder-Sauer-Wiechert reaction to the first intermolecular variant (7 ϩ 8 3 9) (Eq. 2 of Scheme 1) (9), and to several other reactions including prolinecatalyzed asymmetric Mannich (10), Michael (11), ␣-amination (12), and intramolecular enolexo aldolization reactions (10 3 11) (13) (Eq. 3 of Scheme 1) (14-18).Similar to the aldolase enzymes, proline catalyzes direct asymmetric aldol reactions between two different carbonyl compounds to provide aldol products in excellent yields and enantioselectivities. Early on it has been speculated that in addition to operating on related substrates, both class I aldolases and proline may also share a similar enamine mechanism (19,20). However, there has been some debate over several mechanistic aspects of the reaction, and a number of alternative models have been proposed. For example, Hajos (1) suggested a mechanism that involves the ''activation'' of one of the enantiotopic acceptor carbonyl groups as a carbinol amine (A of Scheme 1). At least the stereochemistry of this model was questioned by Jung (19) soon after its initial proposal. An enamine mechanism was suggested by various groups already in the 1970s and 1980s (19-21). Nonlinearity studies by Agami and colleagues (21) have led to the proposal of a side-chain enamine mechanism that involves two proline molecules in the C-C-bondforming transition state, one engaged in enamine formation and the other as a proton transfer mediator (B of Scheme 1). Swaminathan et al. (22) favor a heterogeneous aldolization mechanism on the surface of crystalline proline (C of Scheme 1), despite the fact that many proline-catalyzed aldolizations are completely homogenous. Agami's widely accepted twoproline mechanism was recently challenged when we proposed a homogenous one-proline enamine mechanism for the intermolecular variant in which the various proton transfers are mediated by proline's carboxylic acid functionality (9). On the basis of density functional theory calculations, subsequently proposed a very similar mechanism for the in...

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confidence: 99%

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

Proc. Natl. Acad. Sci. U.S.A.

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324

144

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“…[7] In contrast, α-methyl-L-proline (28), a very efficient organocatalyst for the intramolecular α-alkylation of aldehydes, [38] was not effective in the 1,4-addition after long reaction periods ( presented as a valid alternative to proline and proline derivatives in different asymmetric organocatalytic processes due to its high solubility in organic solvents. [39] However, the catalytic activity of 30 in the conjugate addition of 3-pentanone to nitrostyrene in MeOH resulted very low affording 27aa in a 58% conversion and 38%…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts

et al. 2007

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Different L-prolinamides 21, prepared from L-proline and chiral β-amino alcohols are active bifunctional catalysts for the direct nitro-Michael addition of ketones to β-nitrostyrenes. In particular, catalyst 21e prepared from L-proline and (1S,2R)-cis-1-amino-2-indanol exhibits the highest catalytic performance working in polar aprotic solvents such as NMP especially in the presence of 20 mol% of acid additives such as 4-nitrobenzoic acid or under microwave heating. High syn-diastereoselectivities (up to 94% de) and good enantioselectivities (up to 80% ee) are obtained at r.t. Moreover, [a] Transition state structures for the rate-limiting C-C bond-forming step are calculated.Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for Re-face attack to form syn-(4S,5R) products is lower than that for the Si-face attack leading to syn-(4R,5S) products.

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“…To this aim, benzylic and propargylic alcohols 3d and e were synthesized from readily available N-Tos-(2,2-dimethoxyethylamine) 5. [17] Here, initial alkylation with 4-fluorobenzyl bromide followed by hydrolysis under acid conditions led the desired aldehyde 6 in 77% overall yield (Scheme 2). Finally, the corresponding secondary benzylic and propargylic alcohols 3d and e were obtained in good yields (73-92%) through the condensation of 6 with PhMgCl or PhC CLi, respectively.…”

Section: H T U N G T R E N N U N G (Otf) 2 a C H T U N G T R E N N U mentioning

confidence: 99%

Iron(III)‐Catalyzed Intramolecular Friedel–Crafts Alkylation of Electron‐Deficient Arenes with π‐Activated Alcohols

2009

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"Deficient" but "efficient", the first example of a catalytic Friedel-Crafts alkylation of arenes, carrying electron-withdrawing groups, with alcohols is reported. The optimized ironA C H T U N G T R E N N U N G (III) chloride (97%) catalyzed allylation, benzylation and propargylation procedures open an access to a range of tetrahydronaphthalenes, tetrahydroisoquinolines and tetrahydrobenzo [d]azepines featuring tertiary benzylic stereocenters in excellent yields (up to 92%) and short reaction times.

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Catalytic Asymmetric Intramolecular α-Alkylation of Aldehydes

Cited by 263 publications

References 16 publications

New mechanistic studies on the proline-catalyzed aldol reaction

New mechanistic studies on the proline-catalyzed aldol reaction

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts

Iron(III)‐Catalyzed Intramolecular Friedel–Crafts Alkylation of Electron‐Deficient Arenes with π‐Activated Alcohols

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