Ketones five-membered carbocycles

An interesting strategy for the diastereoselective synthesis of five-membered carbocycles was achieved by the reaction of alkenylcarbene complexes and lithium enolates derived from simple methyl ketones [79]. The use of more or less coordinating solvents (THF or Et20) or the presence of cosolvents such as PMDTA allows the selective synthesis of one or the other diastereoisomer of the final cyclopentene derivative (Scheme 32). 

The work reported by Eaton and coworkers can be summarized as reactions where an allene system in conjugation with a further unsaturated functionality reacts with carbon monoxide in the presence of an iron-carbonyl complex such as Fe(CO)5 under photochemical and thermal conditions when Fe2(CO)9 is used. When diallenes are used (X=R2C=C, Scheme 9.24), five-membered carbocyclic products are obtained [51, 52], whereas when allenyl ketones (X = O) are applied, five-membered lactones are generated [53, 54]. The use of allenylimines (X = NR) leads to five-membered lactams under these conditions [55]. 

The synthetic value of the photoinduced electron-transfer reactions of ketones has been expanded (Scheme 8.62) by generating a five-membered carbocyclic framework, as shown in the preparation of compound 226. 

Compound I must be activated by the strongly acidic medium. One possible protonation site is the basic pyrrolidinium nitrogen atom (structure X), which would favor the formation of carbenium ion XI (see Scheme 16.3). This intermediate would gain additional stabilization from the polar solvent. Conditions for an SnI substitution would prevail to yield XII, whose fragmentation would resemble, formally speaking, the retro cycloaddition process used in the synthesis of I (i.e., VIII - I). The resulting ketone (XIII) would contain the elements required for the construction of a five-membered carbocycle with the desired incorporation of the functional carbon of one of the nitrile groups, as... 

Carbonyl-activated or imino-activated cyclopropanes can undergo Ni-catalyzed dimerization, or [3+2] cycloaddition with a,p-unsaturated ketones, generally at a much slower rate, to give five-membered carbocycles. This topic was tactfully investigated by Ogoshi [115-117] and Montgomery [118, 119] (Scheme 14). 

The Nazarov reaction is a conrotatory [4rt]electrocychzation. Overall, the transformation involves conversion of a divinyl ketone 1 into a cyclopentenone 5 (Scheme 3.1). The reaction is triggered by complexation of the ketone with a Lewis acid (LA) or protonation, leading to the formation of the pentadienyl cation 2. This intermediate undergoes cyclization to yield the oxyallyl cation 3, which, after deprotonation, affords the cychc dienol 4, which tautomerizes to the final cyclopentenone 5. Owing to the frequent occurrence of five-membered carbocycles in natural products, the usefulness of the Nazarov reaction in total synthesis becomes evident. 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Krische and coworkers employed a rhodiumconjugate addition in combination with an intramolecular enolate trapping by a ketone (Scheme 8.15). Starting from simple keto enones 53, they obtained five- and six-membered carbocycles 54 with high levels of relative and absolute stereochemical control and created three new stereogenic centers in the domino process accordingly [26b]. 

Practicable syntheses of four-, five, and six-membered carbocyclic rings have been achieved by reaction of a,to-di-Grignard reagents with silver(i) salts. Conversion of l,3-bis(chloromethyl)cyclopentane into norbornane was effected in 82% yield, but was the only bridged-ring synthesis reported. Stereospecific cyclic ketone formation using iron(O) compounds has been reviewed. ... 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare a number of five-, six-, and seven-membered rings from electron-deficient olefins. Treatment of acyclic enol ether 18 with 7 mol % of 3 in refluxing benzene provided the corresponding cyclic enol ether 19 in 94% yield. Deprotection of the silyl ether 19 (not shown) resulted in the corresponding cyclic ketone, a valuable synthetic intermediate in natural products synthesis and a number of industrial processes. The authors reported additional examples of the synthesis of five-membered ring carbocycles as part of this study. 

The iron carbonyl-promoted cyclocoupling reaction of polybromo-ketones and unsaturated substrates provides a powerful tool for the synthesis of five- and seven-membered carbocycles. The intramolecular version of this reaction has now been reported for the synthesis of polycyclic terpenes. Reaction of the dibromo-ketone (54), obtained from geraniol, with [Fe2(CO)9] in benzene under pressure gives, in 70% yield, a Cio fraction, the major component (54%) of which is camphor. The other major component (20%) is dihydrocarvone (56). Other cyclic terpenes can be synthesized by similar reactions. 

Similarly to cyclopropanes, four-membered carbocyclic compounds undergo oxidative addition to low-valent transition metals to form five-membered metallacycles. Rhodium(I) inserts into C-C bonds next to the carbonyl group of ketones to form a rhodacycloalkanone species [49]. The C-C bond of cyclobutanone was cleaved, even at room temperature, by oxidative addition to a rhodium(I) complex having a PBP pincer ligand [50]. In the case of cyclobutanone 70, catalytic decarbonylation was possible and afforded the alkene 71 and cyclopropane 72 (Scheme 3.40). 

The Dieckmann condensation is an intramolecular variant of the Claisen condensation where a diester is converted to a 3-ketoester. Typically, an alkoxide is used as the base to form the enolate which attacks the remaining ester to form the carbocycle. Five- and six-membered rings are formed readily with this method. Reviews (a) Davis, B. R. Garrett, P. J. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 1. Eds. Pergamon Press Oxford, 1991 Vol. 2, Chapter 3.6 Acylation of Esters, Ketones, and Nitriles, pp. 806-829. (b) Schaefer, J. P Bloomfield, J. J. Org. React. 1967,15, 1-203. 

In view of the wide distribution of the cyclohexanehexols (called inositols or cyclitols) and the importance of one in particular (myo-inositol) to certain bacteria, plants, and perhaps even to warm-blooded animals, the naturally occurring and synthetic compounds of this carbocyclic class have received considerable study. Naturally occurring members include four inositols, monomethyl ethers, a dimethyl ether, monodeoxy derivatives, one dideoxy derivative, a methyl homolog, and deoxy carboxylic acids. Five inositols and many other synthetic members, including ketones (cycloses or inososes), are known. 

---