2- cycloalkanones synthesis

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

Cycloalkanones. The synthesis of cycloalkenes by intramolecular coupling of a diketone with a Ti(0) reagent (8, 483) has been extended to a cycloalkanone synthesis. Thus reaction of a keto ester with TiCli/LiAlHj in the presence of triethylamine results in cycloalkanones in moderate to high yield. ... 

This cycloalkanone synthesis furnishes a short synthesis of isocaryophyllenc (1), the (Z)-isomer of natural caryophyllene. In this example, the double bond isomerizes during the keto cyclization. ... 

McMurry, J. E., Miller, D. D. Titanium-induced cyclization of keto esters a new method of cycloalkanone synthesis. J. Am. Chem. Soc. 

One-pot stereocontrolled cycloalkanone synthesis using dithiane oxides... 

A full paper i has been published on a general cycloalkanone synthesis involving intramolecular electrophilic alkylation of 2-chloro-l-olefins. 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

The preparation of several medium- and large-sized 2-carbo-methoxycycloalkanones has been accomplished by treatment of the cycloalkanone with sodium triphenylmethyl, followed by carbonation with dry ice, and esterification with diazomethane. 1 The yields are good but the procedure is laborious. The synthesis of 2-carbomethoxycycIooctanone via the Dieckmann cyclization of dimethyl azelate with sodium hydride yields 48% of this product when the procedure is carried out over a 9-day period.3... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

The radicals derived by hydrogen abstraction from 1,3-dithianes and 1,3-oxathianes undergo intramolecular addition to ot,P-unsaturated esters and hence facilitate the synthesis of cycloalkanones <96T9713>. 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

Enantlomerically pure B-suhstituted carbonyl compounds serve as useful intermediates in the synthesis of many chiral organic compounds. The enantloselective synthesis of acyclic 0-substituted carboxylic acids has been reported by Meyers, Mukaiyama, and Koga. However, no effective, general method for the enantio-controlled preparation of P-substituted cycloalkanones was available prior to the investigations by the submitters. For example, poor enantloselectivity was observed in conjugate additions of organometallic... 

The synthesis of some 2,2-spiroannelated chroman-4-ones from o-hydroxyacetophenone and a cycloalkanone in the presence of a secondary amine has been described (78S886). The reaction has also been used to prepare a range of chromanones bearing non-identical or... 

Again, the extension of this route to the synthesis of pyrylium salts with fused alicyclic moieties has been reported involving the use of cycloalkanones as the ketonic component (67T1565). 

The synthesis of cycloalkenyllithiums from cycloalkanones is particularly attractive [315]. The required cycloalkenyl sulfides were obtained in good yields according to [316]. 

An unexpected rearrangement was observed during studies directed towards the synthesis of bicyclic keto silanes by the thermal rearrangement of cycloalkanones bearing an co-silylacetylenic chain P to the carbonyl group. Thus, the bicyclic enol silyl ether 2 was formed in 60-65% yield when the ketone 1 was heated neat at 300°C for 2 hours. 

Scheme 12.2. Tandem conjugate addition/electrophilic trapping for the three-component synthesis of 1,2-disubstituted cycloalkanones.

The classical Biginelli synthesis of heterocycles from /3-diketones, urea, and aldehydes has been extended by the replacement of the dione with a cycloalkanone.343 The... 

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