A Chiral Primary Amine Thiourea Catalyst for the Highly Enantioselective Direct Conjugate Addition of α,α‐Disubstituted Aldehydes to Nitroalkenes

Lalonde, Mathieu P.; Chen, Yonggang; Jacobsen, Eric N.

doi:10.1002/ange.200602221

Cited by 126 publications

(32 citation statements)

References 94 publications

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“…[9] Jacobsen and co-workers further explored a primary amine-thiourea catalyst 4 to catalyze the addition of a,a-disubstituted aldehydes to nitroolefins using only a two-fold excess of aldehyde. [10] Wennemers et al designed tripeptides 5, which was among the most efficient asymmetric catalysts for conjugate addition reaction to date.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Asymmetric Michael Reaction of Aldehydes to Nitroalkenes with Diphenylperhydroindolinol Silyl Ethers as Organocatalysts

Luo

Weng

et al. 2009

Adv Synth Catal

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New dihydroindole and perhydroindole derivatives were synthesized in good yields and evaluated as chiral catalysts in the asymmetric Michael reaction of aldehydes to nitroalkenes. (2S,3aS,7aS)-Diphenylperhydroindolinol silyl ether 10 facilitated the reaction of a wide range of aldehyde and nitroalkene substrates, providing Michael adducts in nearly optically pure form (99% ee), good yields and high diastereoselectivities (syn/anti up to 99:1). These results show for the first time that perhydroindole derivatives can also be highly efficient organocatalysts for the asymmetric Michael reaction, exhibiting comparable or even better enantioselectivities than proline derivatives.

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Section: Introductionmentioning

confidence: 99%

Highly Efficient Asymmetric Michael Reaction of Aldehydes to Nitroalkenes with Diphenylperhydroindolinol Silyl Ethers as Organocatalysts

Luo

Weng

et al. 2009

Adv Synth Catal

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“…Indeed, whereas there are several examples of primary amine catalyzed Michael reaction of aldehydes and nitroolefins, most of them used a,a-disubstituted aldehydes as donors. [12] To explore the potential application of these principles to the anti-Michael reaction we chose (tert-butyldimethylsilyloxy)acetaldehyde (1) as a donor, and examined the Michael reaction using b-nitrostyrene (2) as a model acceptor (Table 1). Hydroxyacetaldehyde protected with tert-butyldimethylsilyl (TBS) was chosen based on our successful use of TBS-protected dihydroxyacetone in anti-Mannich and synaldol reactions.…”

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confidence: 99%

anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

2009

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In the last decade, remarkable progress has been made toward direct catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and environmentally friendly conditions. [1] In enamine catalysis, significant effort has focused on understanding the origin of diastereo-and enantioselectivity in organocatalysis. These studies have facilitated the design of syn-selective aldol and anti-selective Mannich reactions not originally addressed by organocatalytic methods. [2][3][4][5] The organocatalytic Michael reaction is often regarded as one of the most efficient and broadly applicable carbon-carbon bond-forming reactions known because a wide variety of acceptors can be employed and high stereoselectivity has been realized. [6] Although a large number of reports on the organocatalytic Michael reaction of aldehydes have been published, to the best of our knowledge, all of these reactions are syn selective.[7] Several studies, however, have reported success in the anti-selective organocatalytic Michael reaction of ketones.[8] Herein, we report the first highly anti-selective asymmetric Michael reactions of aldehydes and nitroolefins using a strategy designed to control the configuration of the reacting enamine.The predominant stereochemical outcome of the enamine-based Michael reaction was first explained in the classic studies of Seebach and co-workers.[9] Seebach deduced that high syn selectivity can be explained by an acyclic synclinal transition-state model (Scheme 1 a).[9a] In this transition state, the thermodynamically stable E enamine reacts with E nitroolefins in a synclinal arrangement, in which the actual donor and acceptor atoms are situated close to each other (see NO 2 and NR'R'' in Scheme 1 a).We have explored two routes for control of the overall diastereoselectivity of organocatalytic enamine reactions: 1) controlling the face selectivity of the reactive enamine to affect anti-Mannich reactions [2] and 2) controlling the E/Z configuration of the reactive enamine to affect anti-Mannich and syn-aldol reactions (Scheme 1 b). [3] For the anti-Michael reactions described herein, we have taken the latter approach.The classic organocatalytic Michael reaction of aldehydes and ketones utilizes pyrrolidine-based catalysts which react via E-enamine intermediates with nitroolefins and other Michael acceptors in synclinal transition states to provide predominately syn-configured Michael products. The Z-enamine intermediate formed using secondary amine catalysts are significantly less favored. Movement from a secondary amine catalyst to a primary amine catalyst provides steric latitude which enables Z-enamine formation with ketones. A caveat, however, is that Z-enamine formation from aldehydes is likely to be more difficult than that from ketones since the E-configured enamine derived from an aldehyde minimizes steric conflicts between the catalyst and Scheme 1. a) Synclinal transition-state model, b) anti-Mannich and synaldol...

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“…N-Alkyl ethyl ketones afforded Michael adducts with complete regioselectivity, high enantiomeric excesses (up to 99 % ee), and diastereoselectivity favoring the anti isomers (up to 20:1 dr). Jacobsen and co-workers [51] have also shown that a similar chiral primary amine/thiourea catalyst is highly effec- Scheme 28. tive in the addition of α,α-disubstituted aldehydes to nitro alkenes, generating synthetically versatile nitro aldehyde adducts. Simultaneous activation of both nucleophile and electrophile allows this challenging transformation to take place under mild reaction conditions and with broad substrate scope (Scheme 28).…”

Section: Direct Michael Additions Of Unmodified Aldehydes and Ketonesmentioning

confidence: 99%

Recent Advances in Asymmetric Organocatalytic 1,4‐Conjugate Additions

2007

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A Chiral Primary Amine Thiourea Catalyst for the Highly Enantioselective Direct Conjugate Addition of α,α‐Disubstituted Aldehydes to Nitroalkenes

Cited by 126 publications

References 94 publications

Highly Efficient Asymmetric Michael Reaction of Aldehydes to Nitroalkenes with Diphenylperhydroindolinol Silyl Ethers as Organocatalysts

Highly Efficient Asymmetric Michael Reaction of Aldehydes to Nitroalkenes with Diphenylperhydroindolinol Silyl Ethers as Organocatalysts

anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

Recent Advances in Asymmetric Organocatalytic 1,4‐Conjugate Additions

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