Cyclobutanones 2+2 cycloaddition synthesis

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

An attractive synthesis of cyclobutanones involves the titanium(IV) chloride catalyzed cycloaddition of mixed ketene acetals 46 with divinylsulfone (49) used as an ethene equivalent, The primary 2-vinylsulfonylcyclobutanones 50 formed can be desulfonylated to the corresponding cyclobutanones 51 in the presence of an aluminum amalgam.20... 

Spirocyclic 2-alkylidenecyclobutanones can be prepared from vinylidenecycloalkane additions with dimethylketene (see Tabic 1). Alternatively, cycloaddition of cycloalkylidenemethanone to allenes permits synthesis of spirocyclic cyclobutanones. This latter route is more attractive because of the greater availability of simple allcnes as compared with the alkylidenecycloalka-nes. The in situ generation of cyclohexylidenemethanone in the presence of excess tetramethyl-allcnc produced the spirocyclic ketone 9 in reasonable yield.5... 

An ab initio study of the 2 + 2-cycloadditions of allene to isocyanic acid and ketene to vinylimine found the reactions to be concerted and mostly asynchronous.28,29 The diastereoselective 2 + 2-cycloaddition of dichloroketene with a chiral enol ether (26) produced the cyclobutanone (27), which leads to a key intermediate (28) in (g) the total synthesis of the natural alkaloid (-)-Swainsonine (29) (Scheme 8).30 The... 

Irradiation of carbene complexes in CO atmosphere generates the ketene 305 and its [2+2] cycloaddition to alkene gives the cyclobutanone 306 [93], Total synthesis of (+)-cerulenin (310) has been carried out by the formation of cyclobutanone 309 by cycloaddition of 307 to the double bond of 308 as the key reaction without attacking the triple bond. Then cyclobutanone 309 was converted to (+)-cerulenin (310) via regioselective Bayer-Villiger reaction of 309, and side-chain elongation using n-methallylnickel bromide, epoxidation and hydrolysis [94],... 

Both the Baeyer-Villiger and the Beckmann rearrangement are used on the cyclobutanones formed in these cycloadditions. Dechlorination of adduct 12 with zinc and rearrangement with a peroxy-acid gives a lactone 25 widely used in prostaglandin synthesis.5 Note that the more substituted carbon migrates and does so with retention of configuration. 

P Volume 1,1991,283 pp. 109.50/ 69.50 ISBN 1-55938-180-9 CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Brian Halton. Strain in Organic Chemistry A Perspective, Brian Halton. Gem-Dihalocyclopropanes in Chemical Synthesis, Martin G. Banwell and Monica E. Re-um. 1-Halo- and 1, 2-Dihalocyclopropenes Useful Synthetic Intermediates, Mark S. Baird. Cyciization and Cycloaddition Reactions of Cyclopropenes, Albert Padwa and Glen E. Fryx-ell. New Synthetic Pathways From Cyclobutanones, Edward Lee-Ruff. Cyclic Alkynes, Enynes and Dienynes A Synthetic Challenge, Herbert Meier. Index. 

Another common strategy for construction of fused cyclooctanones is to first build a fused cyclobutanone by [2 + 2] cycloaddition of a vinylketene to a cycloalkene. Equation (58) illustrates this approach with Paquette s synthesis of the tricyclic skeleton of the ophiobolins. Cyclobutanone (108) is assembled by addition of a vinylketene to cyclopentadiene. Cyclopentenyllithium then adds to the less-hindered face of (108), and the lithium alkoxide undergoes a spontaneous anionic oxy-Cope rearrangement to afford the central cyclooctane ring. 

Cycloadditions of ketenes with alkenes and alkynes constitute the most popular method for the synthesis of cyclobutanones and cyclobutenones. Unfoitunately, however, this process is truly general only for highly nucleophilic ketenophiles such as conjugated dienes and enol ethers. In general, unactivated alkenes and alkynes fail to react in good yield with either alkyl- or aryl-substituted ketenes, or with ketene itself To circumvent this limitation, dichloroketene is usually employed as a ketene equivalent, since this electrophilic ketene reacts well with many types of unactivated multiple bonds, and the resultant cycloadducts undergo facile dechlorination under mild conditions. ... 

In general, cyclobutanones are synthesized by either ketene cycloadditions or by ring expansions of cyclopropyl precursors. For the synthesis of simple a-substituted monocyclic cyclobutanones, the latter method is usually employed, and a variety of approaches have been used to prepare the required eyclopropyl intermediates. 

Cyclobutane.—Further reports of grandisol (90) synthesis include Magnus s full paper (Vol. 6, p. 22) and an almost identical Japanese report of an earlier synthesis (Vol. 3, p. 25) based upon a dihydropyranone-ethylene cycloaddition.A third synthesis utilizes cyclopropanation of 4-methoxy-3,6,6-trimethylcyclohexa-2,4-dienone to yield (91) followed by rearrangement of the a-oxycyclopropylcarbinyl cation of (91) to (92). After reduction of the cyclobutanone, second-order Beckmann cleavage of the cyclopentanone oxime gave (93) from which grandisol (90) was readily obtained. 

A general synthesis of fused methylenecyclopropanes employs the carbenoid ring contraction of bicyclic cyclobutanone tosylhydrazones, available from [2-1-2] cycloaddition of dichloro-ketene to alkenes. ... 

It was actually in the course of a synthesis of Mori that the true absolute configuration of ( + )-lineatin (296) was definitely confirmed. This started with a [2 + 2] cycloaddition between isoprene and dichloroketene, giving a mixture of two isomeric dichlorocyclobutanones 333 and 334 (3.3 1). After reduction with zinc and acetic acid, the major cyclobutanone 335 was separated. Aldol condensation of the anion of 335 with acetone enabled the isopropyl side chain to be introduced. The later stages of the synthesis of ( )-lineatin are shown in Scheme 27, and the overall yield was 3.8%. In the course of diis synthesis, however, the alcohol 336 was resolved using the chiral hydroxy lactone 252, available fix>m commercial (lR,3/f)-c s-chrysanthemic acid. The ether 337 was shown by X-ray crystallography to have the absolute configuration demonstrated. Since it was related to natural (+)-lineatin, the absolute configuration of the latter was established. ... 

Subsequently, the absolute configuration of the natural lineatin was determined as (lR,4S,5R,7R)-77 by our second synthesis, as shown in Figure 4.16.35 The first step was the cycloaddition of dichloroketene to isoprene to construct a cyclobutane ring. The symmetrical cyclobutanone A was then converted to ( )-bicyclic lactone B. Enantiomer separation (optical resolution) of ( )-B was executed as follows. Reaction of ( )-B with the resolving agent C (derived from chrysanthemic acid) yielded a diastereomeric mixture... 

Another convenient synthesis of cyclobutanones employs cycloadditions of keten-immonium ions. These have previously been generated by the rather expensive method of dechlorination of an a-chloro-enamine with silver fluoroborate, but a new procedure which uses zinc chloride instead is reported to give high yields (Scheme 26). Even ethylene was found to react with the complex (319) at room temperature and atmospheric pressure. ... 

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... 

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