Enone carvone

Allylmagnesium, allylindium, and allylbismuth generally showed a preference for axial addition to cyclohexanones. Allylmagnesium was the most stereoselective. Reactions with an a-methylated enone (carvone) were the most selective, except that allylbismuth was unreactive with this substrate [25c]. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

In Yamada s retrosynthetic analysis (Scheme 11), elisabethin C (26) is traced back to lactone 64 which would be converted into 26 by deoxygenation and chain elongations. Key intermediate 64 could be obtained by a stereoselective Dieckmann cyclization. The required ester lactone precursor 65 would be accessible from 66 by a series of oxidation reactions. Further disconnection would lead to commercially available (+)-carvone (67). Stereoselective successive alkylation of 67 and reduction of the enone should deliver 66 [30]. 

The linear sequence starts from (-l-)-carvone (67) (Scheme 12). Establishing the quaternary center at Cl was achieved via a successive enolate alkyla-tion/hydroxyalkylation to furnish hydroxyketone 68. Reduction of the enone... 

An alternative, in situ source of (Ph3P)CuH can be fashioned from CuCl/PPhs/ TBAF and PhMe2SiH (1.2 equivalents) in DMA, initially made at 0° with the reaction then being run at room temperature [25]. Unhindered acyclic enones require 20 mol% of CuCl, PPhs, and TBAF for best results (Eq. 5.15). Cyclic examples are more demanding, with substituted cyclohexenones such as carvone undergoing reduction when excess reagents are present (1.6 equivalents). Acetylcyclohexene was unreactive to the catalytic conditions above. 

The optically active 1,4-cyclohexenediol monoacetate 525, prepared by hydrolysis of the /we.so-diacetate with lipase, was converted into the optically pure cyclohex enone 526 by an elimination reaction in the presence of ammonium formate. Optically active carvone (527) was prepared from 526[343]. 

Reduction of 0,/3-enones. NaBH4 forms a nearly homogeneous solution in pyridine at 25°. This solution reduces /-carvone (1) at 25° (12 hours) mainly to the dihydrocarveols 2. A minor product is 3. Jones oxidation of the mixture gives dihydrocarvone (4).1 This method was first reported by Kupfer.2... 

The photocyclization of carvone, 36, to carvonecamphor, 37, is a good example of intramolecular cycloaddition of an enone to an isolated double bond422 ... 

High stereoselectivity was found in the first example of intramolecular [2 + 2] photocycloaddition discovered by Ciamician and Silber111 in the irradiation of camphor 233 to carvon camphor 234. Generally, if the tethered alkenyl side chain is connected to the enone via an asymmetric center, the configuration of this center plays an important role on the diastereofacial selectivity. For example, high stereoselectivity was found in the irradiation of the diketone 235 or its corresponding enol acetates112, when substituents on the alkenyl side chain affect the selectivity of the enolization of 235 but not the diastereofacial selectivity (Scheme 50). 

These reactions may show considerable selectivity. Corey and Chaykovsky19 give an example with the terpene carvone 80. The ylid 78 is made with NaH and reacts only with the enone and not with the unconjugated alkene. The product is one diastereoisomer 81 as the ylid has added to the opposite side of the ring to the only substituent. It also has retained the stereochemistry of the cis alkene but that is inevitable as 3/6 ring fusion must be cis. 

The first such reaction published in 1908 by Ciamician and Silber was the light induced carvone —> carvonecamphor isomerization, corresponding to type b [1]. Between 1930 and 1960 some examples of photodimerizations (type c) of steroidal cyclohexenones and 3-alkylcyclohexenones were reported [2-5]. In 1964, Eaton and Cole accomplished the synthesis of cubane, wherein the key step is again a type b) photocycloisomerization [6]. The first examples of type a) reactions were the cyclopent-2-enone + cyclopentene photocycloaddition (Eaton, 1962) and then the photoaddition of cyclohex-2-enone to a variety of alkenes (Corey, 1964) [7,8]. Very soon thereafter the first reviews on photocycloaddition of a,(3-unsaturated ketones to alkenes appeared [9,10]. Finally, one early example of a type d) isomerization was communicated in 1981 [11]. This chapter will focus mainly on intermolecular enone + alkene cycloadditions, i.e., type a), reactions and also comprise some recent developments in the intramolecular, i.e., type b) cycloisomerizations. 

The reaction of racemic 147 with (R)-carvone, initially at -78 °C followed by warming to room temperature for 1 h, gave the vinylcyclopropane 151 in 72% yield and moderate diastereoselectivity (d.r. = 75 25). The stereochemistry of the major diastereoisomer shown in structure 151 from H NMR studies was that expected based on the stereochemical outcome of the reaction of racemic 147 with the achiral cyclic enones 146 and is consistent with our previously proposed chelated transition state90 for cyclic enones (compare with the transition state B). 

Regeneratable polymeric organotin dihydride beads have been used to reduce halides selectively (e.g. 3-bromocamphor to camphor).52 /3-Unsubstituted cyclohex-enones undergo exclusive and almost quantitative 1,4-reduction by potassium tri-s-butylborohydride to the corresponding saturated ketone [e.g. (16)] 53 reductive alkylation of carvone proceeds similarly to (17 R = Me, X = H).53 In contrast,... 

Mariano and co-workers also reported a similar C-Si bond cleavage of the cation radical of dimethyl(trimethylsilylmethyl)amine 13 in the photochemical reaction. Photoirradiation of a mixture of 13 and carvone 14 gives the addition product 15 of the diethylaminomethyl radical to the enone (Scheme 21). ... 

Enones. Two groups have reported the oxidation of silyl enol ethers to o,/3-unsaturated ketones using DDQ. This method is most suitable for cyclohexanone derivatives. Fleming and Paterson report that yields are generally improved by addition of collidine (1.5 equiv.), which presumably removes the by-product DDQHj. This last communication also reports improvements in the preparation of either the kinetic or thermodynamic silyl enol ethers by House s method (3, 310-311). By a combination of the two reactions, carvone (6) can be prepared from 2-methylcyclohexanone (1) in an overall yield of 28% (equation I). 

Carbonyl-selective asymmetric hydrogenation of 2-cyclohexenone - a simple cyclic conjugated enone - is stdl difficult, but some substituted 2-cydohexenones such as 2,4,4-trimethyl-2-cyclohexenone, (R)-carvone, a chiral dienone, and (R)-pule-gone, an s-cis chiral enone have been used successfully [66, 68, 81b, 107]. 

Of special interest are the relative rates of reduction of various cyclic enones, such as carvone, acetylcyclohexene and pulegone (Scheme 60). While the enone system in carvone is frozen in its transoid... 

Sodium dithionite under nitrogen at 80 °C in a water/benzene mixture and in the presence of a phase transfer catalyst reduces dienoic carboxylic acids and esters in a 1,6-mode. Enones such as isopho-rone, pulegone and carvone are similarly reduced to the saturated ketones. Citral and dimethyl maleate are also reduced in a 1,4-manner in moderate yield. ... 

The double bonds of enones easily undergo Michael additions and this may be used for their temporary masking. Thus dimethylamine or, better, propanethioP may be added to the conjugated system. From the adducts thus formed, the alkene may finally be recovered via pyrolysis of the derived meth-iodide. In a recent development the silylcuprate derived fiom dimethylphenylsilyllithium and copper iodide is added to the -position of enones. The silyl ketones (107) produced in this way can conveniently be used for further syntheses. The double bond may be reobtained by bromination followed by desilylbromination (Scheme 101). The sequence was, for instance, successful in syntheses of carvone (108) and dehydrojasmone. 

Thermal and mercury(ii)-catalysed [3,3]sigmatropic rearangement of allylic trichloroacetimidates and allylic pseudo-ureas" e.g. geraniol, linalool) are useful for the 1,3-transposition of hydroxy- and amino-groups the former is synthetically preferred. The [2,3]sigmatropic rearrangement of allylic sulphoxides has been used to effect an alkylative 1,3-carbonyl transposition of enones (e.g. carvone). ... 

For more conformationally-constrained chiral substrates, however, diastereoselectivity can be expected to be good to excellent. Lithium enolates derived from sterically unencumbered cyclohexanones undergo preferential axial acylation as illustrated by the reductive acylation of (R)-(-)-carvone 4 to afford a 3 1 mixture of esters 5 and 6. whereas equatorial acylation is favored in compounds that possess an alkyl substituent in a 1,3-syn-axial relationship to the reacting center, as in the conversion of tricyclic enone 7 to ester 8 (epimeric with the product from the more traditional sequence of acylation followed by alkylation). (In substrates of this kind it is assumed that the transition state structure is based on a twist-boat conformation which permits the reagent to approach along an axial-like trajectory on the less encumbered, lower face of the substrate.) ... 

A single electron transfer is again involved in formation of the ketone (14) together with the well-known intramolecular adduct (15) when carvone is irradiated in the presence of triethylamine (Givens et al.). In related work, Bischof and Mattay showed that the presence of triethylamine deflected the normal course of intramolecular photoaddition within the enones (16) to produce the spiro compounds (17) preferentially. Regio- and stereospecific adducts from cyclopentenones and the bicyclo[2.2.1]heptene (18) have been used by Salomon et al. as a route to spatane diterpenes. Photoadditions of alkenes to enones can give oxetans and/or cyclobutanes. Cruciani et al. have reported that the use of acetonitrile as solvent favours the formation of cyclobutanes. The oxetanes may be formed via a contact ion pair whereas the cyclobutanes may arise from an exciplex. 

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