Enolate Alkylation Research Articles

Total synthesis of (-)-calyciphylline N.

The total synthesis of the architecturally complex Daphniphyllum alkaloid (-)-calyciphylline N has been achieved. Highlights of the synthesis include a Et2AlCl-promoted, highly stereoselective, susbtrate-controlled intramolecular Diels-Alder reaction, a transannular enolate alkylation, an effective Stille carbonylation/Nazarov cyclization sequence, and a high-risk diastereoselective hydrogenation of a fully substituted conjugated diene ester.

Asymmetric Total Synthesis of (+)‐Bermudenynol, a C15Laurencia Metabolite with a Vinyl Chloride Containing Oxocene Skeleton, through Intramolecular Amide Enolate Alkylation

A substrate-controlled asymmetric total synthesis of (+)-bermudenynol, a compact and synthetically challenging C15 Laurencia metabolite that contains several halogen atoms, is reported. The oxocene core, which contains a vinyl chloride, was constructed by an efficient and highly stereoselective intramolecular amide enolate alkylation (IAEA). This result showcases the broad utility of the IAEA methodology as a useful alternative for cases in which the ring-closing metathesis is inefficient.

Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

This account of the author’s contributions over his career attempts to sketch out a research arc that stretches all the way from very simple beginnings, taking inspiration from the steroidal <i>trans</i>-hydrindane problem, to the development of a general strategy for the stereoselective construction of cycloalkanecarboxylates via a folding and allylic strain controlled intramolecular ester enolate alkylation, with applications thereof to the total syntheses of natural products of modest complexity. Examination of the corresponding S_N2′ version of this methodology led to a serendipitous discovery that ultimately produced the olefin geometry dependent intramolecular amide enolate alkylation. Applications and extensions of this methodology have enabled completely substrate-controlled asymmetric total syntheses of diverse medium-ring oxacyclic marine natural products, and a fortuitous discovery along the way involving an organoselenium-based method led to an intriguing biomimetic synthesis of <i>Laurencia</i> metabolites. Observations are made regarding aspects of a research career in retrospect. 1 Introduction 2 Intramolecular S_N2 Enolate Alkylation 3 Intramolecular S_N2′ Enolate Alkylation 4 Synthesis of α,α′-<i>cis</i>-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products 5 Synthesis of α,α′-<i>trans</i>-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products 6 General Synthetic Plan for Dioxabicyclic Bromoallene ­Marine Natural Products Having either a 2,10-Dioxabi­cyclo[7.3.0]dodecene or 2,9-Dioxabicyclo[6.3.0]undecene Skeleton 7 Conclusion

Synthesis of an Inhibitor of Human Arginases I and II

Key words arginase inhibitor - quaternary amino acid - chiral auxiliary - enolate alkylation - boronic acids

Metalated nitriles: S(N)i and S(N)i' installation of contiguous quaternary-tertiary and quaternary-quaternary centers.

Metalated nitriles are exceptional nucleophiles for sterically demanding alkylations,[1] installing hindered centers even in cases where comparable enolate alkylations are unsuccessful.[2] The nucleophilicity derives from two unusual features of metalated nitriles; an extremely small steric demand[3] and a powerful inductive stabilization that localizes a high electron density on carbon.[4] Metal cations and solvent[5] modulate the structure of these nucleophilic chameleons that can be predictably varied between N-metalated nitriles 1, C-metalated nitriles 2, and nitrile-stabilized carbanions 3 (Figure 1).[1] Collectively, structures 1–3 span geometries ranging from planar to tetrahedral. Selective access to three different metalated nitrile nucleophiles allows complementary stereo- and regioselective alkylations.[6]

ChemInform Abstract: Rhodium‐Catalyzed Allylic Substitution with an Acyl Anion Equivalent: Stereospecific Construction of Acyclic Quaternary Carbon Stereogenic Centers.

AbstractThis allylic substitution of tertiary allylic carbonates proceeds with high regioselectivity yielding products with quarternary stereocenters while circumventing the problems of conventional enolate alkylation reactions.

ChemInform Abstract: Palladium‐Catalyzed Reactions of Enol Ethers: Access to Enals, Furans, and Dihydrofurans.

AbstractThe present oxidation reaction of alkyl enol ethers to enals employs low loadings of the palladium catalyst.

Synthesis of Novel 2'-Spirocyclopropanoid 4'-Deoxythreosyl Phosphonic Acid Nucleoside Analogues

E-mail: hongjh@chosun.ac.krReceived December 5, 2012, Accepted December 20, 2012Efficient synthetic route to novel 2'-spirocyclopropanoid 4'-deoxythreosyl phosphonic acid nucleosides wasdescribed from 1,4-dihydroxy-2-butene. Cyclopropane moiety was prepared via ester enolate alkylation using(2-chloroethyl)dimethylsulfonium iodide. Synthesized nucleoside analogues 16, 19, 23 and 26 were tested foranti-HIV activity as well as cytotoxicity. However, none of them showed any anti-HIV activity or cytotoxicityup to 100 µM.Key Words : Antiviral agent, Spironucleoside, Deoxythreosyl nucleoside, Phosphonic acid nucleosideIntroductionPhosphorus-modified nucleoside analogues, bearing aphosphonate group in the sugar moiety, have shown potentantiviral activity.

ChemInform Abstract: Enantioselective Synthesis of Tertiary α‐Hydroxyketones from Unfunctionalized Ketones: Palladium‐Catalyzed Asymmetric Allylic Alkylation of Enolates.

AbstractHighly functionalized tertiary α‐hydroxyketones are obtained in high yield with excellent enantioselectivity.

Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]undecene skeleton from commercially available glycidol as a common starting material. The former include (-)-isolaurallene (1), the enantiomeric form of natural (+)-neolaurallene (2), and (+)-itomanallene A (3c), and the latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α'-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.

Palladium-Catalyzed Reactions of Enol Ethers: Access to Enals, Furans, and Dihydrofurans

The palladium-catalyzed oxidation of alkyl enol ethers to enals, which employs low loadings of a palladium catalyst, is described. The mild oxidation conditions tolerate a diverse array of functional groups, while allowing the formation of di-, tri-, and tetrasubtituted olefins. The application of this methodology to intramolecular reactions of alkyl enol ethers containing pendant alcohols provides furan and 2,5-dihydrofuran products.

Rhodium-Catalyzed Allylic Substitution with an Acyl Anion Equivalent: Stereospecific Construction of Acyclic Quaternary Carbon Stereogenic Centers

A highly regio- and stereospecific rhodium-catalyzed allylic alkylation of tertiary allylic alcohol derivatives with a cyanohydrin pronucleophile is described. This direct and operationally simple protocol provides a fundamentally novel approach toward the synthesis of α-quaternary substituted ketones and circumvents many of the inherent problems associated with conventional enolate alkylation reactions. The stereospecific variant of this reaction provides the enantiomerically enriched α-quaternary substituted allylic aryl ketone, which is a particularly challenging intermediate for more conventional enolate-based strategies.

Azaphosphatrane Cations: Weak Acids, Robust Phase‐transfer Catalysts

AbstractThe use of azaphosphatrane derivatives, which are the acidic counterparts of the well‐known proazaphosphatrane superbases (also named Verkade’s superbases), are found to function as phase‐transfer catalysts. In four representative protocols of phase‐transfer catalytic reactions—two alkylations of enolates, one generation of carbene, and one oxidation of an electrophilic alkene—azaphosphatranes act as catalysts in biphasic heterogeneous media.

A Theoretical Study on the Alkylation of the Ambident Enolate from a Methyl Glycinate Schiff Base

The alkylation of the ambident enolates of a methyl glycinate Schiff base with ethyl chloride was studied at B3LYP and MP2 levels with basis set. The free (E)-enolates and (Z)-enolate are similar in energy and geometry. The transition states for the alkylation of the free (E)/(Z)-enolate with ethyl chloride have similar energy barriers of ~13 kcal/mol. However, with a lithium ion, the (E)-enolate behaves as an ambident enolate and makes a cyclic lithium-complex in bidentate pattern which is more stable by 11-23 kcal/mol than the (Z)-enolate-lithium complexes. And the TS for the alkylation of (E)-enolate-lithium complex coordinated with one methyl ether is lower in energy than those from (Z)-enolate-lithium complexes by 4.3-7.3 kcal/mol. Further solvation model (SCRF-CPCM) and reaction coordinate (IRC) were studied. This theoretical study suggests that the alkylation of ambident enolates proceeds with stable cyclic bidentate complexes in the presence of metal ion and solvent.

Enantioselective Synthesis of Tertiary α‐Hydroxyketones from Unfunctionalized Ketones: Palladium‐Catalyzed Asymmetric Allylic Alkylation of Enolates

Bestnoten: Über die Titelreaktion sind tertiäre α-Hydroxyketone zugänglich. Die als Ausgangsmaterialien für diesen Schritt verwendeten geschützten 1,2-Endiolcarbonate wurden aus gut verfügbaren Enolcarbonaten hergestellt. Hoch funktionalisierte tertiäre α-Hydroxyketone können in hohen Ausbeuten und mit ausgezeichneten Enantioselektivitäten erhalten werden (siehe Schema). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Enantioselective Synthesis of Tertiary α‐Hydroxyketones from Unfunctionalized Ketones: Palladium‐Catalyzed Asymmetric Allylic Alkylation of Enolates

Aiming high: The title reaction for the synthesis of tertiary α-hydroxyketones is reported. Protected 1,2-enediol carbonates, the starting materials, were accessed from simple and readily available enol carbonates. Highly functionalized tertiary α-hydroxyketones can be obtained in high yield with excellent enantioselectivity using this method (see scheme).

ChemInform Abstract: Re‐Evaluating the Nucleophilicity of Zinc Enolates in Alkylation Reactions.

AbstractThe allylic and benzylic alkylation of zinc enolates, generated by asymmetric copper‐catalyzed conjugate addition of dialkylzinc (II) towards cyclic enones (I), with various electrophiles is described.

Asymmetric Total Synthesis of ent-Tetrahydrolipstatin from an Epoxy Alkenol

A highly efficient asymmetric total synthesis of ent-­tetrahydrolipstatin (THL) was accomplished from the known epoxy alkenol. The β-lactone portion of THL was synthesized by the epoxide opening with cyanide and stereoselective enolate alkylation method. The side chain was introduced by cross metathesis of the alkene part with 1-decene. Coupling with a protected leucine completed the synthesis of ent-tetrahydrolipstatin.

ChemInform Abstract: 2‐Trifluoromethyl‐2‐methyl‐4‐phenyloxazolidine: A New Chiral Auxiliary for Highly Diastereoselective Enolate Alkylation.

AbstractThe alkylation of the enolate of amide (I) bearing a new auxiliary proceeds in good yields and excellent diastereoselectivity (&lt;98% d.e.).

Complementary α-alkylation approaches for a sterically hindered spiro[pyrazolopyranpiperidine]ketone

Complementary α-alkylation methods are used to derivatize a sterically hindered spiro[pyrazolopyranpiperidine]ketone. More specifically, enolate alkylations in the presence of DMPU and aldol condensations are employed to deliver these compounds.