Enones acylation

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

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). 

Friedel-Crafts disconnection (38a) Is unambiguous because of the synunetry of (39). Further disconnection requires FGA. A carbonyl group next to the aromatic ring gives a 1,4-dicarbonyl compound (40) and allows disconnection of an acyl anion equivalent to give an enone (41). This can be made by Mannich reaction from (42). 

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

Enones and enoates undergo 1,2-reduction [115, 191]. Lipshutz et al. reported the effective protection of carbonyl functions by the triisopropylsilyl acyl silane group (TIPS), which allowed the selective conversion of alkenes or alkynes to the corresponding zirconocene complexes [24]. The aldehyde could subsequently be regenerated by desilylation with TBAF [186]. 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

Nitronate anions react with (jl-allyl)cobalt complexes prepared from acylation of 1,3-dienes by acetylcobalt tetracarbonyl to produce nitro enones (Eq. 5.50).74... 

A Nazarov-type cyclization was exploited to prepare annelated pyrroles <06OL163>. Acylation of iV-tosylpyrrole 65 with carboxylic acid 66 promoted by trifluoroacetic anhydride gave intermediate 2-ketopyrrole 67 which underwent a Nazarov-type cyclization to give cyclopenta[fc> pyrrolc 68. Another route to cyclopenta[fc]pyrroles involved a novel cyclization involving pyrrole-substituted enones and isocyanides <06OL3975>. 

Condensation of aromatic acyl compounds with N,N-dimethylformamide diethyl acetal in a pressure tube under the action of microwave irradiation affords easy access to l-aryl-3-dimethylaminoprop-2-enones in almost quantitative yield after 6 min. These intermediates can then be reacted with hydrazine hydrate under conventional reflux in ethanol to form the corresponding 3-substituted pyrazoles [95] (Scheme 8.69). 

As mentioned earlier (cf. chapter 2.1.1), p,y-enones undergo an 1,3 acyl shift from the Si-state. In sensitized reactions they rearrange to cyclopropyl ketones in the so termed oxadi-pi-methane rearrangement, as illustrated for... 

An alternative route to nonracemic a-alkoxy stannanes entails the reduction of acyl stannanes with chiral hydrides61 62. Accordingly, conjugated stannyl enones yield (S)-a-alkoxy allylic stannanes by reduction with (J )-(+)-BINAL-H. As expected, (S)-(—)-BINAL-H gives rise to the enantiomeric (7 )-a-alkoxy allylic stannanes (equation 29)61. Upon treatment with Lewis acids, these stannanes undergo a stereospecific anti 1,3-isomerization to the (Z)-y-alkoxy allylic stannanes61. 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

Cyclization of N-acyl meroquinenes with neat polyphosphoric acid (PPA, thick reaction mixture) required 5 days at ambient temperature and resulted in a 2.4 1 mixture of trans cis-enones, respectively (55% yield, eq 1).5 The diastereomeric mixture could easily be separated by column chromatography to provide pure samples of either substance. It was also shown that the pure trans- and cis-enones equilibrated... 

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