Copper‐Catalyzed Asymmetric Conjugate Addition

Alexakis, Alexandre; Krause, Norbert; Woodward, Simon

doi:10.1002/9783527664573.ch2

Cited by 61 publications

(54 citation statements)

References 183 publications

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“…9,10 More importantly, copper shows excellent reactivity: Cu 0 , Cu I , Cu II , and Cu III oxidation states can be easily accessed, enabling radical pathways or two-electron bond formations. In addition to its redox properties, copper has the additional possibility of acting as a Lewis acid either through σ coordination to basic oxygen functionality or through π coordination with numerous functional groups.…”

Section: Introductionmentioning

confidence: 99%

Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air

et al. 2018

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A mild and operationally simple copper-catalyzed vinylogous aerobic oxidation of β,γ- and α,β-unsaturated esters is described. This method features good yields, broad substrate scope, excellent chemo- and regioselectivity, and good functional group tolerance. This method is additionally capable of oxidizing β,γ- and α,β-unsaturated aldehydes, ketones, amides, nitriles, and sulfones. Furthermore, the present catalytic system is suitable for bisvinylogous and trisvinylogous oxidation. Tetramethylguanidine (TMG) was found to be crucial in its role as a base, but we also speculate that it serves as a ligand to copper(II) triflate to produce the active copper(II) catalyst. Mechanistic experiments conducted suggest a plausible reaction pathway via an allylcopper(II) species. Finally, the breadth of scope and power of this methodology are demonstrated through its application to complex natural product substrates.

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Section: Introductionmentioning

confidence: 99%

Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air

et al. 2018

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“…Linear E - and Z -trisubstituted alkenes occur widely in nature and are used regularly in preparative chemistry 1,2 (for example, in catalytic enantioselective hydrogenations 3 , allylic substitutions 4 , or conjugate additions 5 ). Several approaches have been developed for generating acyclic trisubstituted alkenes, but these have key shortcomings.…”

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confidence: 99%

Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

Nguyen

Koh

Mann

et al. 2017

Nature

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Catalytic cross-metathesis is a central transformation in chemistry, and yet, corresponding methods for stereoselectively generating acyclic trisubstituted alkenes in either isomeric form do not exist. The key problems are lack of chemoselectivity, namely, the preponderance of side reactions involving only the less hindered starting alkene, ensuing nonproductive processes of homo-metathesis byproducts, and formation of short-lived methylidene complexes. In contrast, in catalytic cross-coupling, another widely used process, substrates are more distinct and homocoupling is less of a problem. Here, we show that through cross-metathesis reactions involving E- or a Z-trisubstituted alkenes, easily prepared from commercially available starting materials by cross-coupling processes, many otherwise desirable and difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to >98% E or 95% Z). Utility is highlighted through concise stereoselective syntheses of biologically active compounds such as indiacen B (anti-fungal) and coibacin D (anti-inflammatory).

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“… Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates 1 . However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown 2 .…”

mentioning

confidence: 99%

“…In contrast, with an amine base and water, the corresponding β-substituted aldehydes were formed exclusively: 15a - c and 16 , containing a quaternary carbon stereogenic center, were obtained in 49–58% yield. These transformations offer an attractive entry for synthesis of β-substituted enantiomerically enriched aldehydes that cannot be prepared easily by alternative protocols; as already mentioned, there are no catalytic enantioselective 1,4-propargyl additions 1 . Synthesis of this type of enantiomerically enriched aldehydes by conjugate addition of an aryl- or alkyl-metal reagent (e.g., PhMgCl or Me 2 Zn) to an unsaturated ester followed by oxidation state adjustment would be problematic due to sensitivity of the methylene unit in the α,β,δ,ω- dienoate (or the corresponding enyne).…”

mentioning

confidence: 99%

Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

Meng

Torker

et al. 2016

Nature

124

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Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates1. However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown2. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable, as the resulting products would be subjected to further modifications; such reactions, especially when dienoates contain two equally substituted olefins, are scarce3 and are confined to reactions promoted by a phosphine–copper (with alkyl Grignard4,5, dialkylzinc or trialkylaluminum compounds6,7), a diene–iridium (with arylboroxines)8,9, and a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)10. 1,6-conjugate additions are otherwise limited to substrates where there is full substitution at C411. It is not clear why certain catalysts favor bond formation at C6, and – while there are a small number of catalytic enantioselective conjugate allyl additions12,13,14,15 – related 1,6-additions and processes involving a propargyl unit are non-existent. In this manuscript, we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenylboron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 percent yield, >98 percent diastereo- (for allyl additions) and 99:1 enantiomeric ratio. Mechanistic details, including the origins of high site- (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, have been elucidated by means of density functional theory (DFT) calculations.

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Copper‐Catalyzed Asymmetric Conjugate Addition

Cited by 61 publications

References 183 publications

Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air

Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air

Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

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