2.6- Dimethylcyclohexanone, synthesis

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

Schaeffer and Jain (19) have also reported the synthesis of optically active dehydrocycloheximide (24) by using optically active piperidine enamine derived from (+)-/ra 5-2,4-dimethylcyclohexanone. 

A convenient synthesis of 3,3-dimethylcyclohexanone, a compound obtained otherwise with difficulty, involves hydrogenolysis of 5,5-dimethyl-l,3-cydohexanedione (55). The reduction is believed to go through 3,3-dimelhyl-cyclohexenone (24). Hydrogenation virtually ceases after absorption of 2 mol of hydrogen. 

Dimethylcyclohexanone and 2-benzyl-2-methylcyclohex-anone have been prepared similarly in yields of 60% and 55%, respectively.2 The procedure has been extended to the synthesis of 9-methyl-, 9-w-butyl-, and 9-benzyl-l-decalone from the dianion of 2-formyl-l-decalone in yields of 55%, 48%, and 58%, respectively.2... 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

Intramolecular C—H insertion. The key step in a recent synthesis of pen-talenolactone E methyl ester (3) is the reaction of the a-diazo-p-keto ester (1), prepared in several steps from 4,4-dimethylcyclohexanone, with Rh2(OAc)4. A single product (2) is obtained in high yield even though insertion involves bond formation with a nonfunctionalized carbon atom.4... 

Enzymatic Baeyer-Villiger oxidations have been studied for a long time some very useful applications in natural product synthesis date back more than two decades. For example, prochiral (3A, 5,S )-4-hydroxy-3,5-dimethylcyclohexanone was successfully oxidized using a CHMO from Acinetobacter sp. NCIMB 9871. In this case the seven-membered ring formed rearranges spontaneously into the thermodynamically more stable y-lactone. The rearranged lactone has been used in the synthesis of natural products such as tirandamycin or calyculin A (Fig. 25) [157-159],... 

S)-3-Hydroxy-2,2-dimethylcyclohexanone as a Building Block. Reduction of 2,2-dimethylcyclohexane-l,3-dione (24) with baker s yeast gives (S)-3-hydroxy-2,2-dimethylcyclohexanone (25) of 98-99% e.e. 21). This hydroxy ketone 25 was proved to be a versatile chiral building block in terpene synthesis (3). 

An approach to the polycyclic diterpenes, including veatchine, was initiated by Meyer. 2,2-Dimethylcyclohexanone was converted to the cyano-enone (110). This was elaborated into the cyano-phenol (111) which has potential for the synthesis of the alkaloids. 

The first total synthesis of 80 has been reported. Pyridoxatin was prepared in seven steps from cis-2,4-dimethylcyclohexanone [222],... 

The preparation of optically active (-)-cis- and (-)- r ms-2,4-dimethylcyclohexanones by enantioselective double-bond reduction with B. sulfurescens and the application of these products to the synthesis of cycloheximides has recently been reported93. The same reaction was explored later using Geotrichum candidum for the reduction of 3-carboxy-2-cyclohexenone ester leading to a single optically pure (15,35 )-hydroxy ester. The product of this bioconversion was used in a synthesis of chiral glutamic acid analogs99. 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from acid derivatives by alkylation (see p. 45fT.), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethylcyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial cis-trans mixture, e.g. by distillation or chromatography. 

Janot and co-workers used the cyclization to achieve the total synthesis of ellipticine and some important derivatives. The synthesis of the ellipticine derivatives began with phenyl hydrazine 26 and 2,5-dimethylcyclohexanone 27 that were heated with hydrochloric acid in ethanol to achieve both the tetrahydrocarbazole 28 and a minor component of indole 29, which differ only in the regioselectivity of the cyclization. The tetrahydrocarbazole was isolated and then oxidized by treatment with... 

The actual synthesis of 8.15 and 8.16 was accomplished as shown in Equation 8.11. We expect 2,3-dimethylcyclohexanone to give an enolate or enol preferentially at carbon 2 to form 8.16. Equation 8.11 shows this step under acidic conditions and the continuation to 8.15 [16]. 

Safety aspects and experimental scale apart, there are no fundamental differences in the reaction of aliphatic C—H acidic compounds with labeled or unlabeled methyl iodide. For example (Figure 5.56), the alkylation of deprotonated 2,6-dimethylcyclohexanone (202), key step in the synthesis of [ CJvitamin A , of the A,A-dimethyUiydrazone of dihydrotestosterone of mevinolin (20 and tricarbethoxymethane (208) , furnishing... 

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