Tandem Aldol−Tishchenko Reactions of Lithium Enolates:  A Highly Stereoselective Method for Diol and Triol Synthesis

Bodnar, Paul M.; Shaw, Jared T.; Woerpel, K. A.

doi:10.1021/jo971012e

Cited by 78 publications

(14 citation statements)

References 21 publications

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“…Analogously, reductive amination of the ketone in scaffold 53 with benzyl amine provided β‐aminolactam 55 in 76 % yield and 94:6 d.r., favoring the anti diastereomer, assigned based on extensive 2D NMR studies . Finally, a one‐pot aldol–Tishchenko reaction generated anti ‐1,3‐diol 56 in good yield as a single diastereomer with four contiguous stereocenters . Relative stereochemistry was assigned via conversion to the corresponding acetonide and 1D and 2D NMR studies (see Supporting Information).…”

Section: Resultsmentioning

confidence: 96%

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Guney

Wenderski

Boudreau

et al. 2018

Chemistry A European J

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Medium-ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization-ring-expanding rearomatization (ODRE) reaction that generates benzannulated medium-ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.

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Section: Resultsmentioning

confidence: 96%

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Guney

Wenderski

Boudreau

et al. 2018

Chemistry A European J

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“…The diastereoselective synthesis of acyclic 1,3-diols is an important target in organic chemistry, since these units are present either in a syn or an anti relationship in the structures of a large variety of natural products. [65] In the case of 1,3-induction for the stereoselective reduction of β-hydroxy ketones it is possible to obtain anti-diols by a Tishchenko reduction [66] or by using reducing agents that are able to bind the hydroxyl function and then to intramolecularly transfer the hydride to the carbonyl group. [67] To obtain syn-diols it is necessary to add a coordinating agent that is able to build up a sufficiently rigid cyclic complex prior to intramolecular addition of the hydride ion from an external source.…”

Section: Diastereoselectivity In the Reduction Of α-Alkyl-β-hydroxy Kmentioning

confidence: 99%

Diastereoselective Lewis Acid Mediated Reductions of α‐Alkyl‐β‐Functionalized Carbonyl Compounds

et al. 2005

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A high stereochemical induction has often been observed in the reduction of ketones with stereogenic centres close to the carbonyl function. The level of stereoselectivity is particularly high when “hard” donor groups such as nitrogen or oxygen atoms are present in the molecule. These results have been commonly explained in terms of a chelate‐controlled process. However, this interpretation has recently been challenged, and in many cases an open‐chain mechanism can better account for the observed results. Thus, Lewis‐acid‐mediated chelation and nonchelation control is one of the most fundamental and practical concepts in transferring a nucleophile moiety to carbonyl compounds. In order to clarify the role of a hard Lewis acid in controlling the stereochemical outcome of a given reaction, the Lewis acid mediated reduction of a series of α‐alkyl‐β‐functionalized carbonyl compounds with metallic hydrides in various solvents was recently investigated. In particular, the results derived from the reductions in the presence of dry CeCl3 were compared to those obtained under the same experimental conditions but in the presence of TiCl4, whose ability to form chelation complexes is well established. These investigations show a stereochemical outcome that is fully consistent with a chelation‐controlled pathway in the case of titanium, and an open‐chain‐controlled pathway in the case of CeCl3. The strongly chelating TiCl4 led to the syn isomer in high diastereomeric excess in noncoordinating solvents at –78 °C with borane–Lewis base complex reducing agents, while nonchelating CeCl3 produced a high excess of the anti isomer in coordinating solvents at the same temperature with metal borohydrides as reducing agent. Therefore, our method based on the choice of CeCl3 or TiCl4 as a Lewis acid under the reported conditions represents a significant contribution to the development of new stereoselective reductions of α‐alkyl‐β‐functionalized ketones. These procedures are one of the best known ways to obtain an alcoholic moiety. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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“…The aldol Tishchenko methodology, initially restricted to homocoupling of three identical aldehydes,14a,b was later developed by application of lithium ketone enolates14c,d furnishing cross aldol‐Tishchenko products with an exceptional level of stereoselectivity. Furthermore, the same reaction was performed by using silyl,14e,f zinc,14g and samarium enolates 14h…”

Section: Introductionmentioning

confidence: 99%

Chiral Ytterbium Complex‐Catalyzed Direct Asymmetric Aldol‐Tishchenko Reaction: Synthesis of anti‐1,3‐Diols

Młynarski

Rakiel

Stodulski

et al. 2006

Chemistry A European J

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The asymmetric aldol-Tishchenko reaction of aromatic aldehydes with aliphatic and aromatic ketones has been developed as an efficient strategy for the synthesis of anti-1,3-diols in good yield with high diastereocontrol and good levels of enantioselectivity. This domino-type reaction is catalyzed by a chiral ytterbium complex that promotes both the aldol reaction through enolization of the carbonyl compound and the Evans-Tishchenko reduction of the aldol intermediate. The stereochemistry of the resulting diols is also investigated and finally proved by using CD techniques.

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Tandem Aldol−Tishchenko Reactions of Lithium Enolates: A Highly Stereoselective Method for Diol and Triol Synthesis

Cited by 78 publications

References 21 publications

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Diastereoselective Lewis Acid Mediated Reductions of α‐Alkyl‐β‐Functionalized Carbonyl Compounds

Chiral Ytterbium Complex‐Catalyzed Direct Asymmetric Aldol‐Tishchenko Reaction: Synthesis of anti‐1,3‐Diols

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