Cyclohexanone derivatives, selectivity

As the WT CHMO was known to react (S) selectively with simple four-substituted cyclohexanone derivatives [84—87], it was logical to test mutant 1-K2-F5 as a catalyst in the BV reaction of other ketones. For example, when 4-methoxycyclohexanone (38) was subjected to the BV reaction catalyzed by mutant 1-K2-F5, almost complete enantioselectivity was observed in favor of the (S)-lactone (39) (98.5% ee), in contrast to the WT, which is considerably less selective (78% ee) (see Scheme 2.11) [89]. 

Laube and Hollenstein [21, 61] studied the single crystal structures of cyclohexanone derivatives complexed with a Lewis acid and found pyramidalization of the carbonyl carbon (4, Fig. 4), in agreement with the observed selectivity [61]. 

The role of the metal catalyst in the hydrogenation reaction and its stereoselectivity has been widely studied (9). Group Vtll metals are generally used, but different behaviours are observed. In the hydrogenation of disubstituted phenols palladium mainly gives cyclohexanone derivatives, rhodium and platinum are very selective for the c/5 isomer, whereas nickel is more selecive for the tra/ 5 isomer (9). 

The range of suitable aldehydes was investigated using the organocatalyst (S,S)-52 and the cyclohexanone-derived trichlorosilyl enolate 51 as prototypical ( )-enolate (Scheme 6.27) [84], Irrespective of the aldehyde used high yields of 90 to 98% were obtained. The diastereoselectivity was excellent for aromatic and unsaturated aldehydes, with anti/syn ratios between 61 1 and >99 1. Enantioselectivity for the anti enantiomer was high, between 88 and 97% ee. Selected examples are given in Scheme 6.27. The acetylenic aldehyde led to somewhat lower diastereo- and enantioselectivity (anti/syn ratio 5.3 1 anti-adduct 82% ee). 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

The cycloaddition reactions of chiral 2-amino-l, 3-dienes with Fischer-type carbene complexes have been examined by Barluenga et al. Reactions with tungsten vinyl carbene complexes A and with boron-nitrogen-chelated chromium complexes B lead very selectively to cyclohexanone derivatives. However, when employing chromium vinyl carbene complexes in acetonitrile at room temperature in these reactions, cycloheptadienes were obtained selectively by cyclopropanation and subsequent Cope rearrangement. 

The combination of NaBH3CN/ZnCl2 in ether also reduces aldehydes and ketones to alcohols. With 5% H2O present, cyclohexanones are selectively reduced in the presence of aliphatic derivatives. With NaBHsCN/Z/iic Iodide, however, aryl aldehydes and ketones are converted to aryl alkanes. ... 

The antitumour alkaloids of the pancratistatin and narciclasine classes have been the subject of several synthetic efforts this year. The L-mannonolactone derivative 51 is the starting material for a synthesis of narciclasine analogue 55 and two related compounds. The key transformations are elaboration of the carbohydrate adduct 53, derived by base-catalysed coupling of 51 with the anion derived from benzamide 52 to the cyclohexanone derivative 54. This involves selective removal of the C5,C6 isopropylidene group, oxidative cleavage of the C5,C6 bond and an intramolecular aldol reaction involving the C5-derived aldehyde and the benzylic ketone enolate (Scheme 10). ... 

In the acylation of enamines derived from 3-substituted cyclohexanones, 6-acylated products were favored over 2-acylated products (398), thus revealing another selective enamine reaction sequence. The use of oxalyl bromide for the acylation of enamines has also been described (399). 

Recendy, Darzens reaction was investigated for its synthetic applicability to the condensation of substituted cyclohexanes and optically active a-chloroesters (derived from (-)-phenylmenthol). In this report, it was found that reaction between chloroester 44 and cyclohexanone 43 provided an 84% yield with 78 22 selectivity for the axial glycidic ester 45 over equatorial glycidic ester 46 both having the R configuration at the epoxide stereocenter. 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

The diastereoselective addition to imines proceeds well with aromatic enolsi-lanes (249). Propiophenone- and tetralone-derived enolsilanes provide good levels of diastereoselectivity (>95 5) and excellent enantioselectivity (>98% ee) with selective formation of the anti diastereomer. Nonaromatic enolsilanes are somewhat less selective although cyclohexanone enolsilane still provides useful levels of diastereoselectivity and enantioselectivity (92 8 anti/syn and 88% ee at -78°C). A one-pot procedure using glyoxylate, sulfonamide, and enolsilane as coupling partners was developed subsequently, leading to the product in comparable yields and selectivities (250, 251). 

This process (also known as the Ferrier II Reaction ) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry. ... 

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