Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

Raffier, Ludovic; Gutiérrez, Osvaldo; Stanton, Gretchen R.; Kozlowski, Marisa C.; Walsh, Patrick J.

doi:10.1021/om5007006

Cited by 4 publications

(3 citation statements)

References 72 publications

(45 reference statements)

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“…The remarkable selectivity with Et 2 Zn/EtZnCl provides support for our hypothesis that the reaction takes place via chelation control. Further evidence was gained through computational work performed in collaboration with Prof. Marisa Kozlowski and Osvaldo Gutierrez and correlated with solution 1 H NMR binding studies …”

Section: Additions To βγ-Unsaturated Ketonesmentioning

confidence: 76%

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Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Fan

Walsh

2017

Acc. Chem. Res.

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The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and -trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation-control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral α- and β-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation-controlled additions. α-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to α-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C═C bonds can play the role of chelatin...

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Section: Additions To βγ-Unsaturated Ketonesmentioning

confidence: 76%

“…Further evidence was gained through computational work performed in collaboration with Prof. Marisa Kozlowski and Osvaldo Gutierrez and correlated with solution 1 H NMR binding studies. 55…”

Section: Additions To βγ-Unsaturated Ketonesmentioning

confidence: 99%

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Fan

Walsh

2017

Acc. Chem. Res.

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“…This is an emerging and exciting area of organometallic chemistry, one we hope to see more prominently featured in future issues of Organometallics . Other contributions include one from Bernd Straub et al on selective routes to heterobimetallic NHC complexes, Patrick Walsh, Marisa Kozlowski, and co-workers on alkenes as chelating groups in zinc-mediated additions to ketones, and Christina Rotsides and Keith Woerpel’s mechanistic study of insertion reactions with silacyclopropanes . Suzanne Blum and co-workers uncover an interesting and “non-innocent” role for sodium chloride in a kinetic study of Lewis acid catalyzed oxyboration, and a collaborative paper from Rory Waterman, Dave Morris, Jaqueline Kiplinger, et al describes the rich chemistry available with heavy elements and reports silane dehydrogenation chemistry with uranium hydrides.…”

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confidence: 99%

Introduction to the Virtual Issue Honoring Robert Bergman’s 2017 Wolf Prize in Chemistry

Chirik

2017

Organometallics

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Reactions of Aldehydes and Ketones and their Derivatives

Murray

2017

Organic Reaction Mechanisms · 2014

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Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

Cited by 4 publications

References 72 publications

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Introduction to the Virtual Issue Honoring Robert Bergman’s 2017 Wolf Prize in Chemistry

Reactions of Aldehydes and Ketones and their Derivatives

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