Chelation-Controlled Additions to α-Silyloxy Aldehydes: An Autocatalytic Approach

Raffier, Ludovic; Stanton, Gretchen R.; Walsh, Patrick J.

doi:10.1021/ol4030259

Cited by 9 publications

(4 citation statements)

References 46 publications

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“…The desired transformation required formation of metal vinyl species 25 generated from vinyl iodide 2 to add to β-azido ketone 3 in a diastereoselective fashion by chelation to the α-alkoxy group ( 27 to 28 ) to finally access alcohol 26 . 10 Extensive screening and reaction optimization 29 revealed that the addition proceeded in high yield and remarkable diastereoselectivity when dimethylzinc 30 was used to generate vinyl zincate complex 25 as the precursor for the chelation-controlled addition. The success of the zincate addition highly depends on the quality of the organometallic reagent employed, and the reaction temperature must be kept rigorously under −50 °C in order to avoid decomposition of ketone 3 .…”

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confidence: 99%

A Highly Convergent Total Synthesis of Leustroducsin B

et al. 2015

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Leustroducsin B exhibits a large variety of biological activities and unique structural features. An efficient and highly convergent total synthesis of Leustroducsin B was achieved in 17 longest linear and 39 total steps by disconnecting the molecule into three fragments having similar levels of complexity. These pieces were connected via a highly efficient chelate-controlled addition of a vinyl zincate to an α-hydroxy ketone and a silicon-mediated cross-coupling. The stereochemistry of the central and western fragments was set catalytically in high yields and excellent de by a zinc-ProPhenol-catalyzed aldol reaction and a palladium-catalyzed asymmetric allylic alkylation.

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confidence: 99%

A Highly Convergent Total Synthesis of Leustroducsin B

et al. 2015

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“…The high diastereoselectivities in Scheme 7 suggest that this approach should be appropriate to a host of related aldehydes. Further studies led to development of an autocatalytic version of this reaction, 42 which is covered elsewhere.…”

Section: Highly Diastereoselectivementioning

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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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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“… 2 , 6 We recently demonstrated, however, that a remarkable class of Lewis acids, RZnX (X = halide or OSO 2 R), promotes the addition of a wide range of alkyl and vinyl organozinc reagents to α- and β-silyloxy aldehydes and ketones via chelation control with very high diastereomeric ratios (Scheme 1 B). 7 …”

Section: Introductionmentioning

confidence: 99%

“…It is well known that α- and β-silyloxy aldehydes and ketones react with nucleophiles via the Felkin–Anh pathway with few exceptions (Scheme A). , We recently demonstrated, however, that a remarkable class of Lewis acids, RZnX (X = halide or OSO 2 R), promotes the addition of a wide range of alkyl and vinyl organozinc reagents to α- and β-silyloxy aldehydes and ketones via chelation control with very high diastereomeric ratios (Scheme B) …”

Section: Introductionmentioning

confidence: 99%

Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

et al. 2014

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Alkenes have been discovered to be chelating groups to Zn(II), enforcing highly stereoselective additions of organozincs to β,γ-unsaturated ketones. 1H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation-controlled carbonyl additions from heteroatom Lewis bases to simple C–C double bonds, broadening the 60 year old paradigm.

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Chelation-Controlled Additions to α-Silyloxy Aldehydes: An Autocatalytic Approach

Cited by 9 publications

References 46 publications

A Highly Convergent Total Synthesis of Leustroducsin B

A Highly Convergent Total Synthesis of Leustroducsin B

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

Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

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