Cyclopentenones addition

Unique chemistry is associated with the cyclopentenone all five carbon atoms can be functionalized, and the endo-methyl groups of the acetonide assure clean stereoselective addition of the alkenylcopper reagent from the convex side. The use of the acetonide group to control enolate regioselectivity and to mask alcohols should be generally applicable. 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

The reaction of allyl halides with terminal alkynes by use of PdClifFhCNji as a catalyst affords the l-halo-l,4-pentadienes 297. 7r-AlIylpalladium is not an intermediate in this reaction. The reaction proceeds by chloropalladation of the triple bond by PdCh, followed by the insertion of the double bond of the allyl halide to generate 296. The last step is the regeneration by elimination of PdCh, which recycles[148]. The cis addition of allyl chloride to alkynes is supported by formation of the cyclopentenone 299 from the addition product 298 by Ni(CO)4-catalyzed carbonylation[149]. 

Formal Diels-Alder additions of dienesters (111,332-335) and dien-ketones (336) to enammes have provided synthetic paths which may be applied to some natural products syntheses. However, a reaction of tetra-cyclone (330) gave only the cyclopentenone, rather than a Diels-Alder adduct. 

In addition to the synthesis of heterocycles, the Corey-Chaykovsky reaction bestows an entry to carbocycles as well. The reaction of (trialkylsilyl)vinylketene 89 with substituted ylide 90 led exclusively to rrans-4,5-dimethyl cyclopentenone 91. The substituted ylide 90 here serves as a nucleophilic carbenoid reagent in the formal [4 +1] annulation reaction. 

Sdieine 6.2. Diactereocelective addition of a functionalized cuprate to cyclopentenone 14 in the cynthecic of proctaglandin E (PCE ) (TBS = t-butyldimethylcilyl,... 

A variant of the Nazarov reaction is the cyclization of allyl vinyl ketones 8. These will first react by double bond isomerization to give divinyl ketones, and then cyclize to yield a cyclopentenone 9 bearing an additional methyl substituent ... 

The Michael addition of nitro ilkanes to enones followed by reaction with TiCT provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cii -jasmone is readily obtained," as shown in Eq. 6.18. 

There are numerous examples of cuprate additions to 4-alkoxy-2-cyclopentenones, which proceed with excellent tram diastereoselection16. 

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

The addition of the anions of racemic 1-(diphenyl)- and l-(diethoxyphosphinyl)-2-butenes to 2-cyclopentenone or 2-cyclohexenone gives y-l,4-add ucls. () A1 ly 1 systems give exclusively. vy/t-adducts while (Z)-allyl systems give exclusively //-adducts. 2-Cycloheptenone gives diastereomeric mixtures of 1,4-adducts and 1,2-addition products1. 

Lithiated (E)- and (Z)-l-(diphenylphosphinyl)-2-methyl-2-butenes undergo 1,4-addition to 2-cyclopentenone to mainly (E)-syn- and ( )-a /-adducts respectively2. 

The anion of (Zs)-4-(diphenylphosphinyl)-6-methyl-2-heptene undergoes addition to 2-cyclopentenone and 2-methyl-2-cyclopentenone to give predominately yn-adducts3. 

Addition of the anion of l-(diphenylphosphinyl)-2-octene to 4-/er/-butoxy-2-cyclopentenone occurs exclusively opposite to the rwr-butoxy moiety to give a mixture of. syn- and twr/ -adducls. As discussed above, the geometry of the alkcnc in the allylic moiety determines the relative configuration of the newly created stereogenic centers1. 

Addition of 2-butenyl sulfone anions to 2-cyclopentenone and 2-cyclohexenone at low temperatures ( — 85 °C) gives mixtures of y-1, 4- and a-1,2-addition products. When these reactions are warmed to 1 2CC, then y-l,4-addition products predominate7,8. The lithium salts of the a-1,2-adducts rearrange to 1,4-adducts at 0°C. 

In contrast to 2-cyclopentenone, 4-to7-butoxy-3-cyclopentenone gives mixtures of a-1,2- and y-1,4-adducts at — 70°C. Warmer reaction temperatures (0°C) give mainly the syn-y- 1,4-ad-duct, although in poor yield (43%). Addition of HMPA gives mixtures of a- and y-1,4-adducts plus 1,2-adducts. 2(5//)-Furanone gives mixtures of a- and y-1,4-addition products at — 70 C7. 

The addition of the anion of the racemic 2-methyl-2-propenyl sulfoxides, rac-2-methyl-3-(phenyl-sulfinylpl-propene and /w-3-(rerr-butylsulfinyl)-2-methyl-l-propene to 2-cyclopentenone gives mixtures of (E)- and (Z )-y-l, 4-addition products which are a mixture of diastereomers at sulfur2. The (T )-products usually predominate, with the relative proportions of the (Z)-product increasing as the reaction temperature is increased. No asymmetric induction originating from the stereocenter at sulfur was observed when the sulfoxide substituent was phenyl however, there was a marginal improvement in the case of the (Zi)-product when the sulfoxide substituent was ferf-butyl. 

The addition of the anion of the 1,3-dimethyl-2-butenyl sulfoxides to 2-cyclopentenone was examined2. The anion of rar-2-methyl-4-(phenylsulfinyl)-2-pentene gave a 50 50 mixture of ( )- and (Z)-y-1,4-adducts which differed in the relative configuration of the new stereocenter regarding the stereocenter at sulfur. That is, for either the (Z)- or the ( )-product there is complete asymmetric induction from the stereocenter at sulfur, but in the opposite direction. When the rm-butyl analog, ruc-4-(/wt-butylsulfinyl)-2-methyl-2-pcntcne, was reacted, it gave exclusively the ( )-adduct, likewise as a single diastereomer. 

In a study concerned with the synthesis of prostaglandins, it was reported that the anion of 3-phenylsulfinyl-l-octene underwent addition to 2-cyclopentenone to give a y-1,4-adduct (57%), which appeared to be a single diastereomer by 13C NMR16... 

The 1,4-addition of the anion of a racemic /1-oxo sulfoxide to racemic 2-cyclopentenone was reported to give a single diastereomeric adduct resulting from addition opposite to the y-ace-toxy group20, t he relative configuration of the exocyclic stereocenter was not determined. 

The addition of the anions of racemic cyclic allylic sulfoxides to various substituted 2-cyclopentenones gives y-l,4-adducts as single diastereomeric products22. The modest yields were due to competing proton-transfer reactions between the anion and enone. The stereochemical sense of these reactions is identical to that for the 1,4-addition reaction of (Z)-l-(/erf-butylsulfinyl)-2-methyl-2-butene to 2-cyclopentenone described earlier. 

To a cold (—78 C) solution of 0.8 g (3.9 mmol) of 3-(phenylsulfinyl)-l-cyclohcxcnc in 20 mL of THF is added a cold ( — 78 lC) solution of 4.37 mmol of LDA in 20 mL of THF via a cannula. The resulting yellow solution is stirred at —78 C for 30 min, and then 0.7 mL (4.0 mmol) of HMPA is added, followed after 5 min by the addition of 0.320 g (3.9 mmol) of 2-cyclopentenone, and the solution is stilted at —78 C for 15 min. A solution of 0.26 mL of acetic acid in 2 mL of diethyl ether is added and the solution warmed to 25 C, diluted with aq NH4C1, and extracted with three portions ol diethyl ether. The combined extracts are washed with aq NaCl, dried over MgSC)a, concentrated, and column chromatographed to give the title compound yield 0.562 g (50%). Starting sulfoxides and enones were also recovered. 

From studies on the addition of racemic allylic sulfoxide anions of 3-substituted l-(phenyl-sulfinyl)-2-propenes to racemic 4-tcrr-butoxy-2-cyclopentenone, it was found that (El-allylic sulfoxides give. vyw-products, and (Z)-allylic sulfoxides give anti-productsx. 

The asymmetric 1,4-addition of the dienolate of the optically active camphor derived 3-methyl-3-butenoate to 2-cyclopentenone gives a mixture of four diastereomers. The major adduct was applied in the synthesis of (—)-khusimone188. 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

The few exceptions to this general rule arise when the a-carbon carries a substituent that can stabilize carbonium-ion development well, such as oxygen or sulphur. For example, 1-trimethylsilyl trimethylsilyl enol ethers give products (72) derived from electrophilic attack at the /J-carbon, and the vinylsilane (1) reacts with a/3-unsaturated acid chlorides in a Nazarov cyclization (13) to give cyclopentenones such as (2) the isomeric vinylsilane (3), in which the directing effects are additive, gives the cyclopentenone (4) ... 

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

When enantiomerically pure allyl p-tolyl sulfoxide is deprotonated and then treated with electrophilic 2-cyclopentenone, a conjugate addition occurs forming a new carbon-carbon bond with very high control of absolute stereochemistry (equation 25)65. See also Reference 48. Similarly, using more substituted enantiomerically pure allylic sulfoxides leads to virtually complete diastereocontrol, as exemplified by equations 26 and 27 the double bond geometry in the initial allylic sulfoxide governs the stereochemistry at the newly allylic carbon atom (compare equations 26 vs. 27)66. Haynes and associates67 rationalize this stereochemical result in terms of frontier molecular orbital considerations... 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Enantiomerically pure 3-tolyl-2-sulfinyl-2-cyclopentenone 37 undergoes smooth, mild and diastereoselective conjugate hydride addition with lithium tri(sec-butyl)borohydride to afford ultimately 3-tolylcyclopentanone 38 in 93% enantiomeric purity (equation 35)78. The absolute stereochemistry of product 38 is consistent with a chelated intermediate directing hydride addition from that diastereoface containing the sulfoxide lone pair. 

An intramolecular version of enolate Michael addition to enantiomerically pure vinylic sulfoxides is represented by reaction of a cyclopentenone sulfoxide with dichloroketene (Scheme 5)90 this type of additive Pummerer rearrangement has been developed by Marino and coworkers91 into a highly effective way of constructing variously substituted lactones in very high enantiomeric purity (equation 43). 

---