Cyclobutanone derivatives, synthesis

Formula 366) gives a bicyclic enol ether (Formula 367) which is hydrolyzed to Formula 368 (161,162). The sequence of Formulas 366-368 represents a potentially general synthesis of bicyclic cyclobutanone derivatives. A clever synthesis of m-3-cyclobutene-l,2-dicarboxylic acid anhydride (Formula 369) has been accomplished by irradiation of muconic anhydride (Formula 370) in ether (163). 

They react with alkenes to give cyclobutanone derivatives, and their intramolecular cycloadditions are well known. Ketenes have been used in the synthesis of y-lactams, drug intermediates and other area as chemical intermediates. 

This procedure was used for the asymmetric total synthesis of the steroid (+)-equilenin (7-7) [3]. Cyclopropylidene derivates 7-4 could be converted into the cyclobutanones 7-5 in good yields by applying an asymmetric epoxidation using the chiral (salen)Mnm complex 7-6 (Scheme 7.2) [4]. It is of interest that the demethoxy-lated substrate 7-4b led to 7-5b with a very high enantiomeric excess of 93%, whereas 7-4a gave 7-5a with only 78% ee. 

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. 

This modification of the Curtius reaction has been used extensively in many laboratories and has been found to be generally applicable. Some examples from the literature include the stereoselective synthesis of a wide variety of cyclopropylamine derivatives from the corresponding acids,11-13 the stereoselective preparation of some substituted norbornylamines from easily isomerized acids,14 the preparation of some 1-aminocyelobutancearboxylic acids from the corresponding acid esters,18 the preparation of a substituted cyclobutanone from... 

The synthesis of chiral cyclobutanone 3 involving asymmetric induction in the a-alkylation of the chiral cyclic transition metal acyl enolate derived from 1 has been reported. The resulting aldol product 2 can be demetalated to the cyclobutanone with 100% ee.24... 

The present procedure represents another synthesis of cyclobutanone through the unique acetylenic bond participation in solvolysis. Cyclobutane derivatives prepared in this way include 2-methyl-, 2-ethyl-, 2-isopropyl-, and 2-trifluoromethylcyclobutanone from the corresponding acetylenic compounds.1 ... 

J. W. Pan, I. Hanna, and J. Y. Lallemand, Optically active cyclobutanones from glycals. 2. Synthesis of chiral cyclobutane derivatives by tetrahydropyran ring-opening, Tetrahedron Lett. 32 7543 (1991). 

The cyclobutanone ring in the ether 7, derived by ring expansion of an oxaspiropentane, intramolecularly alkylates the activated aromatic system on treatment with PTSA, leading to 2W-cyclobuta[c]chroman-4-ols 8 (X = OH). Subsequent fission of the four-membered ring yields 3,4-disubstituted 2//-chromenes <02SL796>. A variation of this approach allows the synthesis of the 4P-phenylsulfanyl derivative of 8 (X = SPh), oxidation of which affords the cyclopropa[c]chroman entity <02OL2565>. 

Ylide (1) adds selectively to the least hindered side of a spirocyclic cyclobutanone to afiord epoxide (10) as the sole product in 65% yield (Scheme 3). Where only steric factors are likely to be important, complementary stereochemical results are often possible by methylene addition to a carbonyl group or alternatively, by carrying out an epoxidation reaction on the derived alkene. In each case, the reagent approaches a double bond from the same stereochemical face. This point is nicely illustrated by the synthesis of epoxide (11). 

Iwata s synthesis of subergorgic acid (30), a silphiperfolane derivative isolated from a gorgonian coral, involved the reductive fragmentation of the cyclobutanone (28) to the alcohol (29) via an intermediate aldehyde (Scheme 13). 

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