Proline-Catalyzed One-Step Asymmetric Synthesis of 5-Hydroxy-(2<i>E</i>)-hexenal from Acetaldehyde

Córdova, Armando; Notz, Wolfgang; Barbas, Carlos F.

doi:10.1021/jo015881m

Cited by 267 publications

(105 citation statements)

References 28 publications

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“…When the reactions were performed under completely air-and moisture-free conditions (except of course for the purposely added water), and when both the substrate and proline catalyst had been carefully dried azeotropically, and when dried solvent (DMSO) was used, high 18 O incorporation was indeed observed. Triketone 4 in the presence of proline (25 mol %) and 16 O-or 18 O-enriched water (3 vol %) gave after 4 days' reaction time Ϸ40% of the aldol addition product 5, Ϸ50% of the aldol condensation product 6, and Ϸ10% of dieneamine 16 as detected by GC (Scheme 4). If run in the presence of 16 O water, the corresponding M ϩ• at 196 (5), 178 (6), and 231 (16-CO 2 ) can be identified.…”

Section: Resultsmentioning

confidence: 99%

“…Triketone 4 in the presence of proline (25 mol %) and 16 O-or 18 O-enriched water (3 vol %) gave after 4 days' reaction time Ϸ40% of the aldol addition product 5, Ϸ50% of the aldol condensation product 6, and Ϸ10% of dieneamine 16 as detected by GC (Scheme 4). If run in the presence of 16 O water, the corresponding M ϩ• at 196 (5), 178 (6), and 231 (16-CO 2 ) can be identified. However, in the presence of 18 O-enriched water, both the M ϩ• of the aldol addition and aldol condensation products appear at two mass units higher at 198 (5) and 18 0 (6), respectively, clearly demonstrating efficient (Ͼ 90%) 18 O incorporation.…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

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

323

144

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

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

323

144

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show abstract

“…5 and 6). In particular, the intermolecular aldol condensation of ketones and aldehydes under stereospecific catalysis by proline and its derivatives has been studied in detail (7)(8)(9)(10)(11)(12). These studies have offered insights into the possible mimicking of bioenzymatic processes by simple organic molecules (13,14) and comprise an ample, well reviewed literature (15).…”

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confidence: 99%

The peptide-catalyzed stereospecific synthesis of tetroses: A possible model for prebiotic molecular evolution

Weber

Pizzarello

2006

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

113

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Using a water-based prebiotic model of sugar synthesis involving glycolaldehyde self-condensation, we demonstrate that homochiral L-dipeptide catalysts lead to the stereospecific syntheses of tetroses. The asymmetric effect is largest for erythrose, which may reach a D-enantiomeric excess of >80% with L-Val-L-Val catalyst. Based on results obtained with various peptides, we propose a possible catalytic-reaction intermediate, consisting of an imidazolidinone ring formed between the two nitrogen atoms of the peptide catalyst and the C1 of one glycolaldehyde molecule. The study was motivated by the premise that exogenous material, such as the nonracemic amino acids found in meteorites, could have participated in the terrestrial evolution of molecular asymmetry by stereospecific catalysis. Because peptides might have formed readily on the early Earth, it is possible that their catalytic contribution was relevant in the prebiotic processes that preceded the onset of life.prebiotic chemistry ͉ chirality ͉ catalysis A lthough the chemical environments that led to life's origin on the Earth are unknown, our knowledge of current and extinct life processes allows us to postulate some possible working assumptions. For example, we may describe life as an autocatalytic chemical process where simple molecules, such as amino acids and nucleotides, assemble into larger proteins and nucleic acids that, in turn, control their metabolism and synthesis (1). In these terms, we may also identify key requirements that make such processes possible. One such prerequisite is the exclusive one-handedness of the chiral constituents of proteins and nucleotides (L-amino acids and D-sugars) that is essential to extant biopolymers' structure and function and whose origin is unknown.Several general theories have been brought forward in regard to the origin of this terrestrial homochirality (2). Some propose that life first arose from a racemic environment and later evolved to chiral homogeneity; this ''biotic'' premise circumvents the ease with which prebiotic amino acids and sugars would have lost any incremental gain in asymmetry to racemization. Abiotic theories, on the other hand, propose that some asymmetry preceded the onset of life, overcame racemization, and contributed to homochirality. The finding in meteorites of amino acids resistant to racemization and displaying enantiomeric excesses (ee) that, if less extensive, have the same sign (L-) as in terrestrial amino acids (3, 4) supports, albeit does not prove, the latter hypothesis.Apart from either hypothesis, because abiotic syntheses of chiral molecules would produce only racemic mixtures if unaided by catalysts and meteorites' composition shows that any preexisting ee available for the formation of biomolecules would not have been large (4), it is reasonable to assume that the development of chiral homogeneity was an evolutionary process that involved catalysis. This inference, in turn, leads to the question of whether the unique nonracemic amino acids of meteorites might have play...

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“…Organocatalysis have some favorable properties, such as mild reaction conditions, being environmentally friendly, and the allowing for the facile recovery of catalysts [6]. Organic small molecules, especially proline and its structural analogues, as catalysts in the aldol condensation reactions [7][8][9][10][11][12][13][14][15][16][17][18][19] and Knoevenagel condensations [20][21][22] have been reported. As a rule, the major products of most aldol condensations are β-hydroxy ketones; also, the organic solvents employed in these reactions, such as DMSO and DMF, are not environmentally friendly.…”

Section: Introductionmentioning

confidence: 99%

Solvent-Free Selective Condensations Based on the Formation of the Olefinic (C=C) Bond Catalyzed by Organocatalyst

Song

Jin

et al. 2016

Catalysts

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Pyrrolidine and its derivatives were used to catalyze aldol and Knoevenagel condensations for the formation of the olefinic (C=C) bond under solvent-free conditions. The 3-pyrrolidinamine showed high activity and afforded excellent yields of α,β-unsaturated compounds. The aldol condensation of aromatic/heterocyclic aldehydes with ketones affords enones in high conversion (99.5%) and selectivity (92.7%). Good to excellent yields of α,β-unsaturated compounds were obtained in the Knoevenagel condensation of aldehydes with methylene-activated substrates.

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Proline-Catalyzed One-Step Asymmetric Synthesis of 5-Hydroxy-(2E)-hexenal from Acetaldehyde

Cited by 267 publications

References 28 publications

New mechanistic studies on the proline-catalyzed aldol reaction

New mechanistic studies on the proline-catalyzed aldol reaction

The peptide-catalyzed stereospecific synthesis of tetroses: A possible model for prebiotic molecular evolution

Solvent-Free Selective Condensations Based on the Formation of the Olefinic (C=C) Bond Catalyzed by Organocatalyst

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