Rapid-injection nuclear magnetic resonance investigation of the reactivity of .alpha.- and .beta.-alkoxy ketones with dimethylmagnesium: kinetic evidence for chelation

Frye, Stephen V.; Eliel, Ernest L.; Cloux, R.

doi:10.1021/ja00240a047

Cited by 64 publications

(42 citation statements)

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“…The significant increase in the rate of reaction in the presence of EtZnX can be compared with prior investigations by Eliel and Frye 19-21. Using dimethylmagnesium in THF at –70 °C, the methylation of silyl protected 3-hydroxy-2-butanone was performed.…”

Section: Resultsmentioning

confidence: 76%

“…In contrast, sterically encumbering silyl protecting groups disfavor chelation, instead promoting a non-chelation pathway leading to Felkin addition products with moderate to excellent diastereoselectivity 5,7,18. Exceptions to this paradigm are scarce19-25 and are detailed in later sections. The importance of these principles has resulted in their coverage in many organic textbooks 26-29…”

Section: Introductionmentioning

confidence: 99%

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Overriding Felkin Control: A General Method for Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Aldehydes

2010

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According to the Felkin-Anh and Cram-chelation models, nucleophilic additions to α-silyloxy aldehydes procees through a non-chelation pathway due to the steric and electronic properties of the silyl group, giving rise to Felkin addition products. Herein we describe a general method to promote chelation-control in additions to α-silyloxy aldehydes. Dialkylzincs, functionalized dialkylzincs, and (E)-disubstituted, (E)-trisubstituted, and (Z)-disubstituted vinylzinc reagents add to silyl-protected α-hydroxy aldehydes with high selectivity for chelation-controlled products (dr of 10:1 to >20:1) in the presence of alkylzinc halides or triflates, RZnX. With the high functional group tolerance of organozinc reagents, the mild Lewis acidity of RZnX, and the excellent diastereoselectivities favoring the chelation-controlled products, this method will be useful in the synthesis of natural products. A mechanism involving chelation is supported by 1) NMR studies of a model substrate, 2) a dramatic increase in reaction rate in the presence of an alkylzinc halide, and 3) higher diastereoselectivity with larger alkyl substituents on the α-carbon of the aldehyde. This method provides access to chelation-controlled addition products with high diastereoselectivity previously unavailable using achiral organometallic reagents.

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Section: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Overriding Felkin Control: A General Method for Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Aldehydes

2010

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“…22–24 These researchers studied the reaction of MgMe 2 in THF with silyl-protected 3-hydroxy-2-butanone at −70 °C (Table 4). Smaller silyl groups, such as TMS, resulted in very high diastereoselectivities favoring the chelation-controlled product (entry 1, dr = 99:1).…”

Section: Resultsmentioning

confidence: 99%

“…5,7,21 There are very few exceptions to this paradigm. 22–28 Thus, when the desired protecting group for the global protecting group strategy does not provide the requisite stereochemistry in the diastereoselective addition, chemists have relied on the use of enantioenriched stoichiometric auxiliaries, optically active stoichiometric additives, 5,29–37 or chiral catalysts 38–42 to override substrate control.…”

Section: Introductionmentioning

confidence: 99%

Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Ketones

2011

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The polar Felkin-Anh, Cornforth, and Cram-chelation models predict that the addition of organometallic reagents to silyl–protected α–hydroxy ketones proceeds via a non-chelation pathway to give anti-diol addition products. This prediction has held true for the vast majority of additions reported in the literature and few methods for chelation-controlled additions of organometallic reagents to silyl–protected α–hydroxy ketones have been introduced. Herein, we present a general and highly diastereoselective method for the addition of dialkylzincs and (E)-di-, (E)-tri- and (Z)-disubstituted vinylzinc reagents to α-silyloxy ketones using alkyl zinc halide Lewis acids, RZnX, to give chelation-controlled products (dr ≥18:1). The compatibility of organozinc reagents with other functional groups makes this method potentially very useful in complex molecule synthesis.

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“…Thus, subjection of 3 b , with a TIPS‐protected alkoxy group at C7, to KHMDS in THF at −78 °C for 1 hour gave rise to 2 b as the major isomer ( cis / trans =1:71) in excellent yield (95 %; entry 10 in Scheme ). The TIPS‐protected alkoxy group is known to be a poor coordinating group for steric and electronic reasons,,,,,,,, and the observed stereoselectivity could be rationalized by invoking a nonchelated transition‐state geometry ( B2 ) which minimizes steric repulsions present, between the bulky TIPS‐protected alkoxy group and the amide enolate moiety, in the alternative nonchelated transition‐state ( B1 ). Diminished diastereoselectivity was obtained when smaller silyl groups were used.…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Substrate‐Controlled Asymmetric Syntheses of both 2,5‐cis‐ and 2,5‐trans‐Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation

et al. 2016

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The concise,h ighly stereoselective,s ubstrate-controlled asymmetric total syntheses of both 2,5-cis-and 2,5trans-tetrahydrofuranoid nematocidal oxylipids from the Australian brown algae Notheia anomala have been accomplished in as tereodivergent fashion. The highly stereoselective intramolecular amide enolate alkylation strategy provides access to both stereoisomers of the 3-hydroxy-2,5-disubstituted tetrahydrofuran core of these marine natural products through chelate and nonchelate control, whichi sd riven by the C3-hydroxy protecting group.This approach offers an optional and highly stereoelective access to any of the eight possible stereoisomers of the 2,5-disubstituted-3-oxygenated tetrahydrofuran skeleton, an important structural feature which is present in many biologically active natural products.

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Rapid-injection nuclear magnetic resonance investigation of the reactivity of .alpha.- and .beta.-alkoxy ketones with dimethylmagnesium: kinetic evidence for chelation

Cited by 64 publications

References 0 publications

Overriding Felkin Control: A General Method for Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Aldehydes

Overriding Felkin Control: A General Method for Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Aldehydes

Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Ketones

Stereoselective Substrate‐Controlled Asymmetric Syntheses of both 2,5‐cis‐ and 2,5‐trans‐Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation

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