Intramolecular Enolate Alkylation Research Articles

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization.

Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.

Recyclization reactions of 8,10-dibromocamphor with Grignard and organolithium compounds

Grignard reagents and organolithium compounds react with 8,10-dibromocamphor to afford substituted 1-methyl-2-methylenebicyclo[3.2.0]heptanes. Recyclization proceeds via intramolecular enolate alkylation and Grob fragmentation of the reaction intermediates. All compounds have been characterized by 1H, 13C and 19F NMR spectroscopy and their chemical composition proved by HRMS analyses. The relative spatial arrangement of substituents in the molecule of (1-methyl-2-methylenebicyclo[3.2.0]heptan-6-yl)diphenylmethanol was studied by NOESY experiments.

Synthesis of platencin core structures via twist-brendane

The formation of a twist-brendane via intramolecular enolate alkylation is described. Conversion of bicyclo[2.2.1]heptane scaffold present in this twist-brendane through a Grob-type fragmentation to unravel a functionalized bicyclo[2.2.2] system which contains all the necessary carbon atoms of the lipophilic core structure of nor -platencin, a platencin analogue is presented. Synthesis of core structure of platencin was also accomplished by extending this strategy to a starting material possessing a surrogate for the exocyclic methylene group.

ChemInform Abstract: Intramolecular Enolate Alkylation: From Steroids Through Cladiellins to Isolaurallene

AbstractReview: 60 refs.

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

ChemInform Abstract: A Synthesis of (.+-.)-Stemodinone: An Application of Organoiron Chemistry to the Construction of Sterically Congested Quaternary Carbon Centers.

A synthesis of racemic stemodinone is described, using tricarbonyl(1−5-η-4-methoxy-1,3-dimethylcyclohexadienyl)iron(I) hexafluorophosphate (9) as an electrophile that is the A-ring precursor. Reaction of 9 with the tin enolate from 4,4-(ethylenedioxy)cyclohexanecarbaldehyde proceeded with excellent regioselectivity and high yield to generate an intermediate representing the A and C rings of the target molecule. The B ring was constructed by introducing a two-carbon electrophilic group onto the A ring, followed by ring closure using an intramolecular enolate alkylation. Installation of the D ring and manipulation to give the final product followed transformations precedented with this series of compounds.

Chemoenzymatic and enantioselective assembly of the (1α,3aβ,6α,7aβ)-octahydro-1,6-methano-1 H-indene framework associated with 2-isocyanoallopupukeanane: validation of a new synthetic strategy and the identification of enantiomeric switching regimes

The octahydro-1,6-methano-1 H-indene framework associated with the marine sesquiterpenoid 2-isocyanoallopupukeanane ( 1) has been prepared in enantiomerically pure form from the cis-1,2-dihydrocatechol 8 using Diels–Alder cycloaddition, oxa-di-π-methane rearrangement and intramolecular enolate alkylation steps as the key bond-forming events. Three distinct strategies for employing such sequences in the selective synthesis of either enantiomeric form of the target framework have been identified.

Utilization of a Michael Addition: Dipolar Cycloaddition Cascade for the Synthesis of (±)-Cylindricine C

A new approach to the marine alkaloid (+/-)-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting cycloadduct was converted into (+/-)-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation, and conjugate addition to introduce the n-hexyl side chain.

A Synthetic Alternative to the Type‐II Intramolecular [4 + 3] Cycloaddition Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A synthetic alternative to the type-II intramolecular 4 + 3 cycloaddition reaction.

Oxyallyl cations generated in situ from dihaloketones have been found to undergo the Favorskii rearrangement in preference to an intramolecular Type-II 4 + 3 cycloaddition reaction in trifluoroethanol and hexafluoropropan-2-ol solvents, generating acrylate esters with high cis selectivity. A synthetic alternative to the intramolecular Type-II 4 + 3 cycloaddition has been developed on the basis of intramolecular enolate alkylation to close a 7-membered ring with an exocyclic double bond.

Practical asymmetric synthesis of a selective endothelin A receptor (ETA) antagonist.

[structure: see text]. A practical, chromotography-free asymmetric synthesis was developed for the large scale preparation of an endothelin receptor antagonist 2. This synthesis includes a new efficient process for the preparation of 6-bromo-2,3-dihydrobenzofuran, a stereoselective conjugate addition of an aryllithium followed by stereospecific addition of the Grignard reagent of the top aryl bromide, and an aminophosphate-mediated sterospecific intramolecular enolate alkylation, which led to the formation of the five-membered ring bearing three contiguous asymmetric centers.

A Synthesis of (±)-Stemodinone: An Application of Organoiron Chemistry to the Construction of Sterically Congested Quaternary Carbon Centers

A synthesis of racemic stemodinone is described, using tricarbonyl(1−5-η-4-methoxy-1,3-dimethylcyclohexadienyl)iron(I) hexafluorophosphate (9) as an electrophile that is the A-ring precursor. Reaction of 9 with the tin enolate from 4,4-(ethylenedioxy)cyclohexanecarbaldehyde proceeded with excellent regioselectivity and high yield to generate an intermediate representing the A and C rings of the target molecule. The B ring was constructed by introducing a two-carbon electrophilic group onto the A ring, followed by ring closure using an intramolecular enolate alkylation. Installation of the D ring and manipulation to give the final product followed transformations precedented with this series of compounds.

Studies on the synthesis of aphidicolin. The Diels–Alder route to spirocyclic intermediates

The isopropylidene cyclohexylidenemalonates (6; R1= R2= H; R1, R2= OCH2CH2O; and R1, R2= SCH2CH2S) undergo cycloaddition with butadiene, 2-trimethylsilyloxybuta-1,3-diene, and 3-trimethylsilyloxypenta-2,4-diene to give the corresponding spirocyclic adducts (7; R1= R2= H), (11; R1, R2= OCH2CH2O; R1, R2= SCH2CH2S), and (23; R1, R2= OCH2CH2O; R1, R2= SCH2CH2S). The trimethylsilylenol ether (11; R1, R2= SCH2CH2S) was converted via compounds (12), (14), (15), (16), and (17) to the toluene-p-sulphonate (18) which undergoes base-catalysed intramolecular enolate alkylation to give the bicyclo[3.2.1 ]octanones (19) and (20) which serve as models for aphidicolin (1) and stemodine (2) synthesis. The adduct (23; R1, R2= SCH2CH2S) was converted via the trione (25) into the ester (27) whose enol ether derivative (28) is a promising precursor to the key aphidicolin intermediate (4).