Enones vinylation

The corresponding methylenecyclopentanes are readily formed from a wide variety of activated alkenes, such as unsaturated esters, lactones, and nitriles, enones, vinyl sulfones, and nitro-aUcenes.4 The breadth of utility of this reaction is exemplified below by its use as key steps in syntheses of albene (eq 3), brefeldin A (eq 4), hirsutene (eq 5), the core spirocarbocyclic rings of the ginkgolides (eq 6), cephalotaxine (eq 7), and kem-panes (eq 8). The use of doubly activated alkenes, as in eq 8, is of particular advantage in the annulation of 2-cycloalkenones. ... 

Conjugate addition of vinyllithium or a vinyl Grignard reagent to enones and subsequent oxidation afford the 1.4-diketone 16[25]. 4-Oxopentanals are synthesized from allylic alcohols by [3,3]sigmatropic rearrangement of their vinyl ethers and subsequent oxidation of the terminal double bond. Dihydrojasmone (18) was synthesized from allyl 2-octenyl ether (17) based on Claisen rearrangement and oxidation[25] (page 26). 

The carbopalladation of allylamine with malonate affords the chelating complex 510, which undergoes insertion of methyl vinyl ketone to form the amino enone 511[463]. The allylic sulfide 512 has the same chelating effect to give the five-membered complex 513 by carbopalladation[463.464]. 

A further improvement in the cuprate-based methodology for producing PGs utilizes a one-pot procedure (203). The CO-chain precursor (67) was first functionalized with zirconocene chloride hydride ia THF. The vinyl zirconium iatermediate was transmetalated direcdy by treatment with two equivalents of / -butyUithium or methyUithium at —30 to —70° C. Sequential addition of copper cyanide and methyUithium eUcited the /V situ generation of the higher order cyanocuprate which was then reacted with the protected enone to give the PG. 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

TL2403). Thus, or /io-cyclopalladation of acetanilide 138 gave organo-palladium reagent 139. The or /io-vinylation of 139 afforded enone 140, which was then cyclized to quinoline 141 under acidic conditions. Notice this reaction requires stoichiometric amounts of Pd(OAc)2. 

Organoboron reagents ate pariictdarly well suited for 1,4-additions of aryl and vinyl groups to enones. Hayasbi et al. developed a highly enantioselective RliQ)/ BlNAP-catalyzed 1,4-addilion of pbenylbotonic add lo cyclic and acyclic enones [24] fSclieme 7.5) and 1-alkenylpbospbonales [25]. 

The stage is now set for the crucial polycyclization event. Tertiary carbinol 8, derived from the action of methyllithium on enone 9, is a rather unstable substance, and it was submitted to the polycyclization reaction without purification. When intermediate 8 is treated with trifluoroacetic acid (TFA) and the vinyl cation trapping agent ethylene carbonate in 1,2-dichloroethane at 0°C, the desired... 

The key step in a short and efficient synthesis of pleraplysillin-1 (127) is the palladium-catalyzed cross-coupling of vinylstannane 125 with vinyl triflate 126 (see Scheme 33). This synthesis is noteworthy in two respects. First, vinyl triflate 126 is generated regio-specifically from the kinetic enolate arising from a conjugate reduction of enone 124 the conjugate reduction of an enone is, in fact, a... 

A retrosynthetic analysis of fragment 152 can be completed through cleavage of the C16-C17 bond in enone 155, the projected precursor of epoxide 152. This retrosynthetic maneuver furnishes intermediates 156 and 157 as potential building blocks. In the forward sense, acylation of a vinyl metal species derived from 156 with Weinreb amide 157 could accomplish the construction of enone 155. Iodide 153, on the other hand, can be traced retrosynthetically to the commercially available, optically active building block methyl (S)-(+)-3-hydroxy-2-methyIpropionate (154). 

Cory and Renneboog53 have devised an efficient bicycloannulation for the synthesis of tricyclo[3.2.1.02,7]octane-6-one (66) as shown in equation 63. The method involves three steps (1) the enolate undergoes an initial conjugate addition to phenyl vinyl sulfone, (2) the resulting sulfone-stabilized carbanion undergoes an intramolecular Michael addition to the enone, and (3) the resulting enolate displaces phenylsulfinyl moiety from the tricyclooctanone. The amount of HMPA (3 mol equivalents) is critical for effective cyclization of the enolate. 

Radical Diels-Alder reactions have been used mainly to synthesize polycyclic molecules. These reactions, like those that involve cations and anions as components, proceed quickly but generally do not give high yields. Thus, the tricyclic enone 14 is the result of an intramolecular Diels-Alder reaction of quenched vinyl radical intermediate 13 obtained by treating the iododienynone 12 with n-tributyltin hydride/2,2 -azobisisobutyronitrile (AIBN) [28] (Equation 1.11). 

The basic pattern of the Claisen rearrangement is the conversion of a vinyl allyl ether to a y,8-enone. The reaction is also observed for allyl phenyl ethers, in which case the products are o-allylphenols. 

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

Scheme 24) [38]. Chemoselective enolization of the less substituted enone moiety under hydrogenation conditions accompanied by subsequent aldol reaction provided the corresponding hydroxyl-enones, such as 87-89, which could be converted to various building blocks for polypropionate synthesis. p-Me2N styryl vinyl enone also was employed successfully as an enolate precursor, as demonstrated by the formation of hydroxy enone 90. 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

The Nazarov cyclization of vinyl aryl ketones involves a disruption of the aromaticity, and therefore, the activation barrier is significantly higher than that of the divinyl ketones. Not surprisingly, the Lewis acid-catalyzed protocols [30] resulted only in decomposition to the enone derived from 46,47, and CO. Pleasingly, however, photolysis [31] readily delivered the desired annulation product 48 in 60 % yield. The photo-Nazarov cyclization reaction of aryl vinyl ketones was first reported by Smith and Agosta. Subsequent mechanistic studies by Leitich and Schaffner revealed the reaction mechanism to be a thermal electrocyclization induced by photolytic enone isomerization. The mildness of these reaction conditions and the selective activation of the enone functional group were key to the success of this reaction. 

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