The Α-Alkylation OF ENOLATES FROM THE LITHIUM-AMMONIA REDUCTION OF Α,β-Unsaturated KETONES

Stork, Gilbert; Rosen, Perry; Goldman, Norman L.

doi:10.1021/ja01474a051

Cited by 82 publications

(27 citation statements)

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“…[34] Since pure lophanol (4b) proved to be inaccessible by alkylation of 5α-cholestan-3-one (1), we devised an alternative approach. Following a procedure developed by Stork, [35][36][37] reduction of 4-cholesten-3-one (8) with lithium Scheme 2. in liquid ammonia and subsequent alkylation using iodomethane afforded lophanone (4α-methyl-5α-cholestan-3-one) (2) (Scheme 3). [38,39] Stereoselective reduction of lophanone (2) with lithium aluminum hydride provided as major product lophanol (4b), [38] previously isolated from different natural sources.…”

Section: Synthesis Of Cholesterol Derivativesmentioning

confidence: 99%

“…In order to achieve specific functionalizations at C-6 and C-7 of cholesterol we started from commercial 6-keto-5α-cholestan-3β-ol (35). Protection of 35 as trimethylsilyl ether 36, regioselective formation of the lithium enolate, and subsequent treatment with chlorotrimethylsilane afforded the silyl enol ether 37 (Scheme 9).…”

Section: Synthesis Of Cholesterol Derivativesmentioning

confidence: 99%

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Regio‐ and Stereospecific Synthesis of Cholesterol Derivatives and Their Hormonal Activity in Caenorhabditis elegans

Schmidt¹,

Doert²,

Goutal³

et al. 2006

Eur J Org Chem

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Cholesterol is essential for the survival of the nematode Caenorhabditis elegans. Recent studies have demonstrated that cholesterol derivatives regulate two processes in the life cycle of worms: controlling molting and inducing a specialized non‐feeding larval stage. However, the chemical structure of the cholesterol‐derived signalling molecules for these or any other functions has not yet been identified. Herein, we describe the regio‐ and stereospecific synthesis of a number of cholesterol derivatives. The lithium–ammonia reduction of 4‐cholesten‐3‐one was utilized to develop a general method for the introduction of diverse functional groups at C‐4α of 5α‐cholestan‐3β‐ol. Stereoselective functionalization at C‐7 was achieved starting from 7‐ketocholesterol derivatives. 6‐Keto‐5α‐cholestan‐3β‐ol was utilized for specific functionalizations at C‐6 and C‐7. The structure–activity relationships of the different cholesterol derivatives have been investigated by feeding worms of different genetic background with these compounds. Our study is the first step in assigning the relationships of hormonal activity in C. elegans on the substitution at different positions of cholesterol. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Synthesis Of Cholesterol Derivativesmentioning

confidence: 99%

Section: Synthesis Of Cholesterol Derivativesmentioning

confidence: 99%

Regio‐ and Stereospecific Synthesis of Cholesterol Derivatives and Their Hormonal Activity in Caenorhabditis elegans

Schmidt¹,

Doert²,

Goutal³

et al. 2006

Eur J Org Chem

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“…Consequently, a number of effective methodologies have been developed over the years. In a series of elegant studies, Stork and co-workers have shown that lithium-ammonia reduction of enones leads to stoichiometric generation of enolates 2. Since then, reductive aldol reactions in which conjugate reduction followed by aldol reaction of the resulting enolates led to the development of a wide variety of methodologies for the synthesis of β-hydroxy carbonyl derivatives 3.…”

mentioning

confidence: 99%

L-Selectride-Mediated Highly Diastereoselective Asymmetric Reductive Aldol Reaction: Access to an Important Subunit for Bioactive Molecules

et al. 2008

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L-Selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active α-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting α,α-dimethyl-β-hydroxy ketones are inherent to a variety of biologically active natural products.Asymmetric aldol reactions leading to the stereocontrolled generation of β-hydroxy carbonyl derivatives are among the most important reactions in organic synthesis. 1 Consequently, a number of effective methodologies have been developed over the years. In a series of elegant studies, Stork and co-workers have shown that lithium-ammonia reduction of enones leads to stoichiometric generation of enolates. 2 Since then, reductive aldol reactions in which conjugate reduction followed by aldol reaction of the resulting enolates led to the development of a wide variety of methodologies for the synthesis of β-hydroxy carbonyl derivatives. 3 In recent years, impressive progress has been made in both catalytic 4 and enantioselective 5 reductive aldol processes. In the context of our enantioselective synthesis of (+)-peloruside A, we recently carried out a L-selectride mediated reductive aldol coupling of enone 1 and aldehyde 2 to provide aldol product 3 and its diastereomer as a 4:1 mixture in 92% yield at −78 °C for 1 h. 6,7 The major aldolate 3 was subsequently converted to peloruside A. The overall process is quite practical and offers significant improvement over the direct aldol reaction of related ketone enolate and aldehyde reported recently. 8 Of particular importance, these α,α-dimethyl β-hydroxy carbonyl derivatives are structural features of numerous bioactive natural products like epothilones, 9 mycalamide A 10 and peloruside A. 6 Encouraged by the reasonable diastereoselectivity of the L-selectride mediated reductive aldol process, we have now examined the stereochemical outcome with a variety of chiral and achiral enones and aldehydes bearing an α-β-alkoxy stereocenter. Herein, we report the results of our investigations. Excellent levels of diastereoselectivity are attainable when the enolate from L-selectride reduction is reacted with aldehydes containing an α-chiral center.Our preliminary investigations focused on reactions with model 5 and optically active isopropylidene glyceraldehyde 4. As shown in Scheme 1, enone 5 was prepared in a two stepakghosh@purdue.edu . Supporting Information Available: Experimental procedures and 1 H-and 13 C-NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 September 22. (1) reaction of isopropenyl magnesium bromide in diethyl ether followed by Dess-Martin oxidation 11 of the resulting diastereomeric alcohols to enone 5 in 63% yield in 2-steps. Enone 5 was treated with 1·1 equiv of L-selectride at −78 °C for 10 min to form the corresponding lithium enolate. To the resulting enolate, 2 equiv of isopropylidene-Dglyceraldehyde...

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“…In light of the well-known regiospecific two-step protocol involving (i) conjugate reduction or addition of α,β-unsaturated enones to regiospecifically generate enolates and (ii) regiospecific α-substitution [268], the senior author envisioned a novel strictly regiocontrolled and potentially general alternative for α-substitution of carbonyl compounds as outlined in Scheme 3.82.…”

Section: Pd-catalyzed α-Substitution Of Enolates and Related Derivativesmentioning

confidence: 99%

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

Kamada

Kim

et al. 2013

Metal‐Catalyzed Cross‐Coupling Reactions and More

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The Pd-or Ni-catalyzed cross-coupling reactions of organometals containing Zn, Al, Zr, and B as well as related reactions of those containing Mg and several other metals collectively have emerged as arguably the most widely applicable organic skeleton construction method discovered and developed over the past several decades, allowing synthetic chemists to prepare practically all types of organic compounds. In this chapter, some of the seminal and critically important discoveries and early developments in the 1970s as well as their current scope are briefly discussed. Some of the notable discoveries and developments include (i) identification of superior properties of Pd as a critical element for crosscoupling relative to Ni, (ii) the broad scope of Pd-or Ni-catalyzed cross-coupling with respect to metal countercations including Zn, Al, Zr, B, and Mg, (iii) the hydrometallation-Pd-catalyzed cross-coupling sequential processes for selective syntheses of alkenes, dienes, oligoenes, and oligoenynes, (iv) double metal catalysis involving Pd or Ni and added metal compounds containing Zn, In, Li, and others, and (v) realization of high turnover numbers (TONs) (≥10 3 -10 9 ) through the use of chelating phosphines, such as bis-[2-(diphenylphosphino)phenyl] ether (DPEphos) and 1,1 -Bis(diphenylphosphino)ferrocene (dppf).The Zr-catalyzed alkyne carboalumination and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction) have provided efficient and selective routes to (E)-trisubstituted alkenylalanes and 2-substituted chiral alkylalanes, respectively. These reactions provide two additional examples of prototypical transition metal-catalyzed organometallic reactions. Significantly, they can be readily combined with the Pd-or Ni-catalyzed cross-coupling for the synthesis of trisubstituted alkenes embracing a wide variety of natural products, such as terpenoids, carotenoids, and others, as well as various chiral organics including deoxypolypropionates and saturated terpenoids. The Zr-catalyzed alkyne carboalumination has been applied to the synthesis of a large number (>100) of natural products, while the ZACA reaction has been transformed from a mere scientific novelty to a full-fledged asymmetric synthetic method that is catalytic in both transition metal (Zr) and chiral auxiliaries through a series of breakthroughs.

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The Α-Alkylation OF ENOLATES FROM THE LITHIUM-AMMONIA REDUCTION OF Α,β-Unsaturated KETONES

Cited by 82 publications

References 0 publications

Regio‐ and Stereospecific Synthesis of Cholesterol Derivatives and Their Hormonal Activity in Caenorhabditis elegans

Regio‐ and Stereospecific Synthesis of Cholesterol Derivatives and Their Hormonal Activity in Caenorhabditis elegans

L-Selectride-Mediated Highly Diastereoselective Asymmetric Reductive Aldol Reaction: Access to an Important Subunit for Bioactive Molecules

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

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