Dynamic Kinetic Resolution via Asymmetric Conjugate Reduction:  Enantio- and Diastereoselective Synthesis of 2,4-Dialkyl Cyclopentanones

Jurkauskas, Valdas; Buchwald, Stephen L.

doi:10.1021/ja025603k

Cited by 105 publications

(56 citation statements)

References 11 publications

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“…In addition to being effective for the reduction of ␤-heteroatom-containing ␣,␤-unsaturated esters, these new conditions were also successful in the reduction of simple ␣,␤-unsaturated ketones and esters (Table 1, entries 13 and 14), affording yields and enantioselectivities comparable to those obtained by using previous systems (19)(20)(21)(22)(23)(24).…”

Section: Resultsmentioning

confidence: 71%

“…This entailed the use of Cu(I) chloride, (S)-p-tol-BINAP, sodium tert-butoxide (1 eq relative to CuCl), and PMHS, a mild and inexpensive hydride source, in toluene (19)(20)(21)(22)(23)(24). Although our initial results were promising, further optimization was required.…”

Section: Resultsmentioning

confidence: 99%

“…The asymmetric synthesis of these compounds has been realized through a variety of methods (1, 4, 5), most notably asymmetric Mannich reactions (6-8), diastereoselective or enantioselective conjugate additions (9-13), and the reduction of ␤-amido ␣,␤-unsaturated esters or nitriles (6,(14)(15)(16)(17)(18). Although the reduction of ␣,␤-unsaturated esters has proven to be a particularly powerful tool for this transformation, the various methods used are generally limited to substrates that contain a primary amido group in the ␤ position.We recently described a versatile system for the asymmetric conjugate reduction of a wide variety of ␣,␤-unsaturated carbonyl compounds (19)(20)(21)(22)(23)(24)(25)(26)(27). Appropriately substituted acyclic ␣,␤-unsaturated esters, cyclopentenones, lactones, and lactams could all be reduced in high yield and with excellent levels of enantioselectivity.…”

mentioning

confidence: 99%

“…We recently described a versatile system for the asymmetric conjugate reduction of a wide variety of ␣,␤-unsaturated carbonyl compounds (19)(20)(21)(22)(23)(24)(25)(26)(27). Appropriately substituted acyclic ␣,␤-unsaturated esters, cyclopentenones, lactones, and lactams could all be reduced in high yield and with excellent levels of enantioselectivity.…”

mentioning

confidence: 99%

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Copper-catalyzed asymmetric conjugate reduction as a route to novel β-azaheterocyclic acid derivatives

Rainka

Aye

Buchwald

2004

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

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104

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A chiral copper-hydride catalyst for the asymmetric conjugate reduction of ␣,␤-unsaturated carbonyl compounds has been used for the reduction of substrates containing ␤-nitrogen substituents. A new set of reaction conditions has allowed for a variety of ␤-azaheterocyclic acid derivatives to be synthesized in excellent yields and with high degrees of enantioselectivity. In addition, the effect that the nature of the nitrogen substituent has on the rate of the conjugate reduction reaction has been explored. Many ␤-amino acids and their derivatives are of interest as structural components and because of their biological activity (1-3). The asymmetric synthesis of these compounds has been realized through a variety of methods (1, 4, 5), most notably asymmetric Mannich reactions (6-8), diastereoselective or enantioselective conjugate additions (9-13), and the reduction of ␤-amido ␣,␤-unsaturated esters or nitriles (6,(14)(15)(16)(17)(18). Although the reduction of ␣,␤-unsaturated esters has proven to be a particularly powerful tool for this transformation, the various methods used are generally limited to substrates that contain a primary amido group in the ␤ position.We recently described a versatile system for the asymmetric conjugate reduction of a wide variety of ␣,␤-unsaturated carbonyl compounds (19)(20)(21)(22)(23)(24)(25)(26)(27). Appropriately substituted acyclic ␣,␤-unsaturated esters, cyclopentenones, lactones, and lactams could all be reduced in high yield and with excellent levels of enantioselectivity. However, to our knowledge there have been no successful conjugate reductions of substrates containing ␤-heteroatoms. One possible explanation for this is that deactivation of the enoate can occur by the interaction of a lone pair of electrons on the heteroatom with the conjugated system of the enoate. We therefore reasoned that suitable substrates for this reaction that contained ␤-heteroatoms would possess functional groups in which this interaction is minimized. We report here a method for the asymmetric conjugate reduction of ␣,␤-unsaturated carbonyl compounds substituted with a nitrogen in the ␤ position. This method allows for the preparation of a variety of azaheterocycles and derivatives not available by other methods of asymmetric reduction. MethodsPreparation of Substrates. Various ␤-iodo enoates were effectively coupled with azaheterocycles by using a modified protocol derived from our recently reported copper-catalyzed vinylation of amides and carbamates (Scheme 1) (28-31). For small quantities of material, an oven-dried Schlenk flask equipped with a Teflon-coated magnetic stir bar was allowed to cool to room temperature under nitrogen and then was charged with Cu(I) iodide (0.10 mmol), potassium phosphate (1.5 mmol), and (if a solid) the nitrogen nucleophile (1.5 mmol). The flask was then capped with a rubber septum, evacuated, and backfilled with nitrogen; this process was repeated one time. Toluene (0.50 ml) was added, followed by the diamine (0.20 mmol), the nitrogen nucleophile (if a liqui...

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Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Copper-catalyzed asymmetric conjugate reduction as a route to novel β-azaheterocyclic acid derivatives

Rainka

Aye

Buchwald

2004

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

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104

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“…[21b] In another example of DKR involving enolization to interconvert ketone enantiomers, Jurkauskas and Buchwald were able to hydrogenate 3,5-disubstituted racemic cyclopent-2-enones rac-18 to highly enriched (89-95 % ee) cyclopentanones 19 by using poly(methylhydrosiloxane) (PMHS) and a chiral catalyst consisting of p-tol-binap/CuCl in the presence of sodium tert-butoxide (Scheme 5). [22] The reaction proceeds with yields of 90 % or more, and with > 90 % selectivity for the syn-disubstituted products (Table 5). If the tert-butanol additive is omitted, interconversion via the enolate is no longer fast enough to allow DKR, and the reaction proceeds as a simple KR process with s = 25-52.…”

Section: Dkr By Enolizationmentioning

confidence: 99%

Efficiency in Nonenzymatic Kinetic Resolution

2005

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The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.

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