Ketones, Esters, Lactones and Lactams

It was found that simple benzene derivatives of 6, (S,S)-(-)-l,4-bis[3-(o-chloro-phenyl)-3-hydroxy-3-phenyl-l-propynyl]benzene (46a) and (S,S)-(-)-l,3-bis[3-(o-chlorophenyl)-3-hydroxy-3-phenyl-l-propynyl]benzene (46b) are useful for the direct enanhomeric separation of 44a [20]. When a soluhon of 46a and two molar equivalents of rac-44a in EtOH was kept at room temperature for 12 h, a 1 1 1 complex of 46a, (-)-44a and EtOH was obtained as colorless prisms, which upon heating in vacuo gave (-)-44a of 100% ee in 55% yield. Interestingly, when the complexation was carried out in toluene, a 1 2 complex of 46a and (-r)-44a was formed. 

From the complex, (+)-44a of 100% ee was obtained by distillation. By the same complexation of rac-47 with 46a, (+)-47 of 100% ee was obtained in 47% yield. Bi-cycHc ketones 48 and 49, which are also important materials for prostaglandin synthesis, were separated into their enantiomers by complexation with 46b to give enantiomerically pure (-)-48 and (-i-)-49 in 26 and 29% yields, respectively [21]. 

For enantiomeric separation of lactones (50-53) and ketones (54-55), 8 is a useful host By complexation with 8, enantiomerically pure (-i-)-50 (10%), (-i-)-51 (10%), (-i-)-52 (13%), (-i-)-53 (32%), (-)-54 (20%) and (-i-)-55b (24%) were obtained in the yields indicated [21]. Interestingly, however, trans-isomers of 53 and 54 did not form complexes with 8. This shows that the shape of the molecule may be important for the formation of the inclusion complex. For enantiomeric separation of 55-58, the chiral host la is very effective, and enantiomerically pure (-)-55a (41%), (-)-55b (62%), (-)-55c (43%), (-i-)-56 (80%), (-)-57 (58%) and (-)-58 (70%) were obtained by complexation in the high yields indicated [3]. The mechanisms of these precise chiral recognitions between la and bicyclic ketones have been clarified by X-ray study of two inclusion complexes of la with (-)-55b and with (-)-58 [22]. 

Enantiomeric separations of bicyclic acid anhydride 69, lactones 70 and 71 and carboximides 72 and 73 by complexation with la-c in organic solvents were also successful (Table 3.3-3) [26]. These complexations can probably be carried out in a water suspension medium and hence be described as green processes. rac-Panto-lactone (74) was separated to produce (S)-(-)-74 of 99% ee in 30% yield by complexation with Ic [27]. Enantiomerically impure monoterpenes were purified by inclusion complexation with a chiral host compound. For example, (lS,5S)-(-)-verbe-none (75a) of 78% ee gave 99% ee enantiomer by complexation with la. By similar treatment of 75b of 91% ee with la as above, (lR,5R)-(-i-)-75b of 98% ee was obtained [28]. 

Enantiomeric separations of glycidic esters (76), which are important synthons for various biologically active substances, were accomplished efficiently by complexation with the chiral hosts la-c. For example, when a solution of lb and an equimolar amount of rac-ethyl 2,2-diethylglycidate (76g) in ether-hexane was kept 

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Table 4 Dehydrogenation of Ketone, Ester, Lactone and Lactam Enolates ...

Selenenylations of ketones, esters, lactones and lactams are usually effected by the reaction of the corresponding lithium enolates with PhSeCl, PhSeBr and PhSeSePh (with the exception of ketones) at low temperature. Aldehydes have not been selenenylated in this manner. Table 4 illustrates some typical products that have been made in this way. Selenenylation has been especially useful in natural piquet synthesis for the formation of a-methylenelactones from the parent a-methyl compounds (Scheme 15 and Table 4), and has significant advantages over the more traditional methods for ef-... 

Treatment of a-silyl esters with a base readily affords the corresponding enolates, which can be utilized for Peterson reactions (Scheme 2.70) [189-196]. LDA is the most widely used base for the deprotonation of a-silyl esters. The carbonyl compounds used in the above reactions are aldehydes, saturated and unsaturated ketones, amides, lactones, and lactams. The products, a,j8-unsaturated esters, are obtained as mixtures of the E- and Z-isomers in most cases. When another trimeth-ylsilyl group is present on the anionic carbon atom, the reactions of the carban-ion derived from the a,a-bis(trimethylsilyl) esters with ketones are unsuccessful, probably because of steric reasons, and result only in enolization [197]. 

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

A variety of Michael donors such as ketones, esters, thioesters, amides, lactones and lactams may be used and in all of these cases the problems of stereoselectivity apply. 

Ketones,nitriles,and carboxylic esters can be alkylated in the a position in a reaction similar to 10-104, ° but a stronger base must be employed, since only one activating group is present. Both lactones and lactams are similarly alkylated. 

The following data are closely related to the results of a Russian team, who synthesized lactone- and lactam-bridged photochromes and studied their transformations. 2,5-Dimethyl-3-thienylacetic acid with a-chloro ketone in base gives ester 206, which undergoes cyclization when heated with K2CO3 in DMF under an inert atmosphere to give lactone 207 in 70-75% yields (Scheme 61). The reaction can be performed in situ without isolation of the ester (06ZOR1827)... 

BC13 convert 0=0 groups of ketones, lactones, and lactams to G=S groups119 and H2S-Me3SiCl-i-Pr2NLi converts carboxylic esters to thiono esters.120 Carboxylic acids RCOOH can be converted directly to dithiocarboxylic esters RCSSR, 120a in moderate yield, with P4S, and a primary alcohol R OH.121 Thioketones can also be prepared by treatment of ketones with P4SI0,122 and from oximes or various types of hydrazone (overall conversion C=N------> C=S).123... 

Lactones and Lactams Unstrained lactones (cyclic esters) and lactams (cyclic amides) absorb at typical frequencies for esters and amides. Ring strain raises the carbonyl absorption frequency, however. Recall that cyclic ketones with five-membered or smaller rings show a similar increase in carbonyl stretching frequency (Section 18-5A). Figure 21-5 shows the effect of ring strain on the C=0 stretching frequencies of lactones and lactams. 

Hydrolysis Oxidation Photolysis Esters, lactones, amides, lactams, oximes, imides, and malonic ureas Amines, sulfides, disulfides, sulfoxides, phenol anions, thiols, nitriles, and catechols Aromatic hydrocarbons, aromatic heterocyclics, aldehydes, and ketones... 

Desulfurization of sulfides (or thiols) by TBTH-AIBN tolerates nitriles, esters, ketones, ethers, lactones, 3-lactams and isolated alkenes. In contrast, halides are reduced and the stereochemistry of the starting sulfides is not conserved. Yields of these desulfurizations vary considerably, and 3 eliminations may occur with vicinally substituted compounds. Some examples of TBTH desulfurizations are given in Scheme 17. 

In this section are discussed aldol reactions of achiral aldehydes with chiral enolates. In previous sections, many such examples have already been given for enolates derived from rigid cyclic ketones, lactones and lactams. The emphasis here is on reactions of the enolates of conformationally flexible, achiral ketones, esters and amides. 

Asymmetric hydroxylation of etiolates. Davis and Chen1 have reviewed this reaction using in particular (R,R)- and (S,S)-2-phenylsulfonyl)-3-phcnyloxaziridene (1) and (camphorylsulfonyl)oxaziridine (2). Of these reagents, 1 and ( + )- and (—)-2, derived from (lR)-lO-camphorsulfonic acid, provide highest enantioselectivity and in addition are easy to prepare. They are effective for hydroxylatation of ketones, esters, /2-keto esters, amides, lactones, and lactams. 

Suitable solvents, or diluents, in the hydroformylation reaction are aliphatic, cycloaliphatic and aromatic hydrocarbons, aliphatic, cyclic and aromatic ethers, aliphatic alcohols, nitriles, anhydrides, ketones, esters, lactones, lactams, orthoesters and water. 

Hayashi and Miyaura pioneered the enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to a variety of Michael acceptors a,P-unsaturated ketones, esters, lactones, amides, and lactams [215]. Generally, water is used as a cosolvent and plays a key role in the catalytic cycle, illustrated in Scheme 5.111 (cycle A) for the conjugate addition of phenylboronic acid to cyclohexenone that, when catalyzed by the Rh(I)-(S)-BINAP complex, leads to 3-phenylcyclohexanone in 97% ee and 93% chemical yield [205a]. The key intermediates of the catalytic cycle, the hydroxorhodium complex 433, the phenylrhodium complex 434, and -bound rhodium enolate 435 were characterized by NMR spectroscopy. The reaction of the hydrorhodium complex 433 with phenylboronic acid leads to a transmetallation to give the phenylrhodium complex 434. Then, the insertion of the carbon-carbon double bond of cyclohexenone into the phenylrhodium bond leads to the formation of the... 

Limited progress has been achieved in the enantioselective hydrogenation of a,/ -unsaturated carboxylic acid esters, amides, lactones, and ketones (Scheme 26.10). The Ru-BINAP system is efficient for the hydrogenation of 2-methy-lene-y-butyrolactone, and 2-methylene-cyclopentanone [98]. With a dicationic (S)-di-t-Bu-MeOBIPHEP-Ru complex under a high hydrogen pressure, 3-ethoxy pyr-rolidinone could be hydrogenated in isopropanol to give (R)-4-ethoxy-y-lactam in 98% ee [39]. 

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