Chiral cyclohexanones, synthesis

F E R R I E R Chiral cyclohexanone synthesis Transtormatlon o< unsaturated glycosides into cyclohexanone derivatives by heating in aqueous acetone with mercury (II) salts... 

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 copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

Chiral cyclohexanones obtained by the Ferrier carbocyclization reaction are useful precursors for the synthesis of cyclitols and aminocyclitols, some of which are found in clinically important aminoglycoside antibiotics. Additionally, highly substituted cyclohexenones, prepared by the Ferrier carbocyclization followed by (3-elimination, can undergo various further transformations, also making these compounds potential chiral building blocks for the preparation of structurally complex compounds having cyclohexane unit(s). This section provides an overview of the reported synthetic strategies toward various types of natural products based on utilization of the Ferrier carbocyclization reaction. 

Fig. 12 Synthesis of chiral cyclohexanone bearing a terminal alkyne and chiral cycloheptanone by copper-NHC-catalysed ECA of Grignard reagents to cyclic enynones by Alexalds [84]...

Organic chemists often use enantiomerically homogeneous starting materials for the synthesis of complex molecules (see Chiral Drugs, p. 296). A novel preparation of the S enantiomer of compound B has been described using a bacterial cyclohexanone monooxygenase enzyme system. 

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... 

Another chiral synthesis of the azepine nucleus of Balanol (397) was developed by Wu and Jacobsen, once again converting a cyclohexanone oxime tosylates 399 to a seven-membered lactam (equation 162). The use of a mixture of oxime isomers did not cause... 

Chiral sulfinimines 236 are very useful intermediates for the preparation of enantiomer-ically pure primary amines 237 (equation 158) . This reaction has been applied to the synthesis of a-amino acids . For sulfinimines obtained from simple ketones, lithium reagents are preferable for the addition , while for cyclic ketones organomagnesium compounds gave the best results. Addition of alkyl and aryl Grignard compounds to sulfinimines, derived from 3- and 4-substituted cyclohexanones, proceeds with excellent diastereoselectivity, depending on the stereochemistry of the ring substituents rather than the sulfinyl group . 

This a-aminooxylation has subsequently been successfully extended to the use of ketones as donors [12]. For example, use of cyclohexanone as donor led to (R)-12a in 79% yield and with an excellent enantioselectivity of >99% ee (Scheme 7.12) [12a]. Very recently, the Cordova group reported further examples of this proline-catalyzed a-aminooxylation [13]. In addition, this method has been successfully applied in the synthesis of corresponding chiral 1,2-diols after subsequent derivatiza-tion [13]. Furthermore, computational studies of transition states were carried out [13b],... 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

A preparatively useful synthesis of (R)-lipoic acid involves Baeyer-Villiger monooxygenase-catalyzed biotransformation of 2-(2-acetoxyethyl)cyclohexanone 351 to the key precursor, that is, chiral lactone 352 (Scheme 68) < 1997BMCL253, 1995CC1563>. The enzyme-catalyzed lactone 352 was then converted by a standard reaction procedure into the desired acid on enantioselective esterification of racemic lipoic acid, using C. rugosa lipase. 

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