Cyclobutanones annulation

Trost developed a general method of synthesis of vinylcyclqnopanes (and their sulfur and oxygen analogs) through the application of ylide addition to carbmyl compounds. Three major methods involve the cyclopentene annulation, cyclobutanone synthesis, and ring expansion with concomitant alkylation (Scheme 51). °... 

Annulated cyclobutanones (83-86) were obtained in high yields upon reaction of ketenes with a number of heterocycles containing a vinyl ether moiety (Table II).29,30,83-85 The reported cycloadducts 83 and 84 were all formed in a stereospecific manner, in agreement with the polarization of the two -electron systems.30,83 The reactions were fast except when the reacting endocyclic carbon-carbon double bond was not substituted with an oxygen atom, such as the formation of 87 from 2,5-dihydrofuran (Table II). Furthermore, the various ketenes showed... 

Cyclobutanone annulation onto a carbonyl group translates into y-butyrolactone annulation because of the facility of the Baeyer-Villiger reaction (Eq. 68 a)8). Indeed, the reaction proceeds sufficiently rapidly that even basic hydrogen peroxide effects the oxidation whereas, with less reactive carbonyl partners, peracids must be used. 

Whereas lactone annulation invokes a relief of strain of the four membered ring by migration of the ring bond to an electron deficient oxygen, a similar migration to an election deficient carbon creates a cyclopentanone synthesis (Eq. 73). The release of approximately 84 kJ/mole (20 kcal/mole) provides a strong driving force. Thus, the 1,1-cyclobutanone annulation of ketones translates into a 1,1-cyclopentanone annulation. 

For example, an oxaspirohexane <52, readily available by condensing cyclobutanone 61 with dimethylsulfonium methylide, rapidly rearranges (isomerizes) to the cyclopentanone 63 upon exposure to a catalytic amount of lithium bromide55). The high diastereoselectivity of the initial cyclobutanone formation translates into a high diastereoselectivity for cyclopentanone annulation as this example of Eq. 74 demonstrates. 

Placing the electron deficient migration terminus within the original carbonyl partner converts the 1,1-cyclobutanone annulation into a 1,2- or lateral cyclo-pentenone annulation as summarized in Eq. 77. In the ring enlargement of 65 to 66,... 

In a projected synthesis of verrucarol in which the tetrahydropyranone 175 is envisioned to play a role, the lactone 176 can serve as a viable intermediate (Scheme 6)7S>. Using cyclobutanone annulation methodology, 177 becomes the required intermediate. The geminal substitution of 177 can also be recognized to derive from a spiroannulation approach as previously analyzed. 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

Only a few examples exist where diazocyclopropane has been used for annulations via oxa-spiropentanes. 1,3-Bisdiazopropane reacted with cyclohexanone, probably by previous formation of diazocyclopropane, to give spiro[2.6]nonan-4-one (2, 27%) and spiro[3.5]nonan-l-one (1, 10%).82 83 The latter was formed from the corresponding oxaspiropentane.83 Diazocyclopropane, as generated from /V-cyclopropyl-iV-nitrosourea or /V-cyclopropyl-iV-nitrosocarba-mate, behaves similarly. It reacts with cyclobutanone to give spiro[2.4]heptan-4-one (4, 80%) and spiro[3.3]heptan-l-one (3, 7%).84... 

A [2+2] cycloaddition that involves a ketene has been used to make a dioxepane annulated to a cyclobutanone... 

Two reactions formerly used widely in the formation of carbo-cycles have now been successfully extended to the synthesis of heterocyclic systems. Thus the intramolecular cycloaddition of the olefinic alkoxyketenes (36) leads to cyclobutanone annulated heterocycles (37), where better yields are obtained by using the... 

Ashida S, Murakami M (2008) Nickel-catalyzed 4+2+2 -type annulation reaction of cyclobutanones with diynes and enynes. Bull Chem Soc Jpn 81(7) 885-893. doi 10.1246/ bcsj.81.885... 

Cyclobutanone 58 reacted with alkyne in the presence of nickel(O) catalysts to produce cyclohexenone 59 via a [4-1-2]-type annulation (Scheme 3.32) [41]. Oxidative cyclization of the carbonyl group of cyclobutanone and the alkyne with nickel(O) was followed by p-carbon elimination from the resulting oxanickelacy-clopentene and subsequent reductive elimination. 

The reaction of cyclobutanone 58 with the diyne 62 resulted in [4+2+2] annulation to produce the bicyclic eight-membered ring ketone 63 (Scheme 3.36) [46]. The substrate scope was good, wherein different combinations of cyclobutanone... 

Scheme 3.36 Ni(0)-catalyzed [4H-2-I-2] annulation of cyclobutanone 58 with diyne 62.

The cyclopentene-annulated sugar derivative 27, prepared in several steps by ring expansion of cyclobutanone 28 (itself ultimately derived from the addition of dichloroketene to a glycal) has been shown to be a useful precursor directed towards the sythesis of the ABC ring system of forskolin. ... 

The nickel-catalyzed intermolecular reaction [4+2+2]-annulation of diynes with cyclobutanone as C4 fragment includes the ring expansion... 

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