Cyclohexanone asymmetric synthesis

Before the emergence in the mid-1980s of the asymmetric deprotonation of cA-dimethyl cyclohexanone using enantiomerically pure lithium amide bases, few reports pertaining to the chemistry of these chiral reagents appeared. Although it is not the focus of this chapter, the optically active metal amide bases are still considered to be useful tools in organic synthesis. Readers are advised to consult the appropriate literature on the application of enantiomerically pure lithium amides in asymmetric synthesis.6... 

A very effective method for removal of the chiral auxiliary from cyclohexenones 34 involves treatment with I2 in THF-H2O to give the iodolactones 35 (Scheme 9). These highly functionalized chiral cyclohexanones have figured prominently in the asymmetric synthesis of natural products e.g. Scheme 15. Furthermore, selective cleavage of the cyclohexanone ring in 35... 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

Asymmetric synthesis of ketones (7, 17). Meyers and Williams have extended the asymmetric alkylation of cyclohexanones via the imines formed from 1 to acyclic ketones. Initially optical yields were only 3-44%, but they can be increased to 20-98% by heating the lithioenamines to reflux (THF) prior to alkylation at -78°. Evidently the lithioenamines formed at —20° are mixtures of (E)- and (Z)-isomers. The optical yields are lowered as the size of substituents on the ketone increases. Example ... 

It was most convenient to isolate the products after acidic conversion to cyclohexenones. Structures of the products were assigned by chemical correlation and circular dichroism and the enantiomeric purities were based on optical rotations. The selectivities obtained, although impressive for the era, are moderate at best, despite significant attempts to optimize the substrates and reaction conditions. Use of substituted cyclohexanones (29) and other aldehydes (30) lead to optically active products but the extent of enantiomeric induction in these products was not determined. This technology was used for the partial asymmetric synthesis of (+ )-mesembrine (12.1) (29) and (+ )-podocarpic acid (12.2) (31). 

K. Hiroi and S.I. Yamada have reported for the first time, in 1973, the asymmetric synthesis of a halo ketones by the diastereoselective bromination of a-enamines of L-proline esters (ref. 1). Thus cyclohexanone was converted, via its enamine, to the (R)-2-bromo cyclohexanone (Fig. 1). 

A new, general method is developed for preparation of various 3-substituted carbonyl compounds of high enantiomeric purity. Application of this method is made to asymmetric synthesis of either enantiomer of 3-methylalkanoic acids, of enantiomerically pure 3-methylcyclopentanone, 3-methyl-cyclohexanone, 3-naphthylcyclopentanone and 3-vinylcyclopentanone 18. 9,11-Seco steroid 3 6... 

Asymmetric alkylation of cyclohexanone. Hashimoto and Koga have reported an asymmetric synthesis of a-alkylated cyclohexanones by conversion of cyclohexanone to the chiral imine 1 by reaction with the /-butyl ester of /-leucine. The imine is treated with LDA in THF at - 78°, and after 30 minutes the alkylating agent is added to the lithioenamine (a). a-Alkylated cyclohexanones (2) are obtained in chemical yields of 60-75% and in optical yields of 84-98 (four examples). 

Scheme 7.65 68a-Catalyzed cascade Michael/Michael reaction for the asymmetric synthesis of polysubstituted cyclohexanones.

The DAAA has successfully been applied as a key step in the total synthesis of a number of natural products due to its ability to generate quaternary carbon centres enantioselectively. For example (-H)-dichroanone (81), [42] oxybutynin, [43] (-)-cyanthiwigin F (84) [44] and other examples (Scheme 4.22) [45, 46]. As alluded to above the DAAA has also been extended to the asymmetric synthesis of a-fluorinated cyclohexanones, an important class of compounds for medicinal chemistry [47]. 

Despite the number of reports of the asymmetric synthesis of tertiary a-aryl cyclohexanones, there have only been three reports which describe the asymmetric synthesis of tertiary a-aryl cyclopentanones. The first of these was reported by Shi via asymmetric epoxidation of benzylidene cyclobutanes and epoxide rearrangement in a subsequent step [76]. Backvall used a dynamic kinetic resolution of aUyhc alcohols-aUylic substitution-oxidative cleavage sequence to access 2-phenylcyclopentanone [77]. The first direct catalytic asymmetric synthesis of tertiary a-aryl ketones was recently described by Kingsbury using a series of Sc-catalysed diazoalkane-carbonyl homologations with bis/tris oxazohne ligands [78]. 

Following the previous successful application of the asymmetric decarboxylative protonation reaction in the catalytic asymmetric synthesis of isoflavanones we hoped to expand the scope of this work to the catalytic asymmetric synthesis of tertiary a-aryl cyclohexanones and, in particular, cyclopentanones given the dearth of reported methods for their direct asymmetric synthesis to date (see Sect. 4.6). 

In conclusion, we have described the catalytic asymmetric synthesis of a series of tertiary a-aryl cyclopentanones and cyclohexanones. This offers a new route to access these important structural motifs with moderate to good levels of enantioselectivity. This is only the second report of the direct catalytic asymmetric synthesis of tertiary a-aryl cyclopentanones. A major advantage of this methodology is the ability to insert a number of different aryl groups prior to the enantiodetermining... 

The acceptor properties of nitro-alkenes are well known and have been utilised for the asymmetric synthesis of a-alkylated cyclohexanones via Michael addition of chiral enamines to (3-nitro-styrenes, the conjugate addition of... 

Mea-Jacheet D, Horeau A. Asymmetric synthesis of methol 2-cyclohexanone optical purity of the product obtained. Bull. Soc. Chem. Fr. 1968 4571 575. 

SCHEME 22.42. First total, asymmetric synthesis of the cyclohexanone subunit of baconipyrones A and B. 

Turks M, Murcia MC, Scopelliti R, Vogel P. First asymmetric synthesis of the cyclohexanone subunit of baconipyrones A and B. Revision of its structure. Org. Lett. 2004 6 (18) 3031-3034. 

Pioneering studies in the area of chiral phosphorus reagents for asymmetric synthesis were reported by Bestmann (Equation 12) [68]. Treatment of phosphorus ylide 109 with 4-substituted cyclohexanones thus led to the formation of enantioenriched benzylidenecyclohexanes, such as 111 in... 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

More recently, Tardella and co-workers disclosed the use of this reagent in the synthesis of Af-(ethoxycarbonyl)-a-amino ketones from enamines and nitrene 18 [12b]. Their attempts to obtain asymmetric induction started with the use of proline-derived optically active enamines of cyclohexanone. Slow addition of sulfonyl-oxycarbamate 6e (1 equiv.) to a stirred solution of the enamine 19 and triethylamine (1 equiv.) in dichloromethane at room temperature, followed by work-up with petroleum ether and silica gel chromatographic purification afforded the aminated product 20 in low yield and good enantiomeric excess [12c] (Scheme 8). 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

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