Ketones optical resolution

Newman, P. Optical Resolution Procedures for Chemical Compounds, (1978) Vol. 1, Amines and Related Compounds, (1981) Vol. 2, Acid, (1984) Vol. 3, Alcohols, Phenols, Thiols, Aldehydes and Ketones, Optical Resolution Information Center, New York. 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

K. Naemura, K. Kittaka, M. Murata, H. Ida, K. Hirose, Y. Tobe, Lipase-Catalyzed Enantioselective Alcoholysis of Enol Acetates Optical Resolution of Ketones and Aldehydes Using Lipases in Organic Solvents , Enantiomer 1996, 1, 219-222. 

In certain cases, especially for neutral substrates, the formation of covalent p,n-pairs, instead of salts, may be necessary to achieve optical resolution by crystallization. Suitable derivatives are esters of camphanic acid (1) or chrysanthemic acid (2) with racemic alcohols, or esters of menthol (3) and 1-phenylethanol (5) with racemic acids, or hydrazones of menthylhydrazine (4) with racemic aldehydes and ketones. 

The use of sulfoximines in the syntheses of optically active compounds has been reported [429]. A remarkable ketone methylcnation with optical resolution was realized. A highly selective diastereofacial addition of an enantiopure sulfoximine to a racemic ketone, chromatographic separation of the two diastereoisomers and reductive cleavage yielded both enantiomers of p-panasinsene [430], isolated from the root of ginseng, a herb used in Chinese folk medicine. 

Ketone mcthylenation can be coupled with concomitant optical resolution effected by chromatography by use of the related reagent 5. The adduct with a prochiral ketone has three asymmetric centers.2... 

Ketone methylenation with optical resolution. The key step in a synthesis of p-pnnnsinscnc (5), an important component of Ginseng, involves methylenation of the... 

Racemization of the Mannich ba.se may be caused by intrinsic instability " of the optically active final product, or it may occur during the synthesis or the optical resolution. The former case is fiequently observed in the preparation of cyclic derivatives of natural products and concerns Mannich reactions of different types, including the tandem aza-Cope-Mannich rearrangement, which affords more or less extensively ra-cemized products starting from optically active materials. -" -" - This finding is explained on the basis of the equilibrium involved in the 3,3-reanangement leading to ketones 201 (Fig. 72), key intermediates for the synthesis of alkaloids. 

The combination of the chromatographic separation of enan-tiopure p-hydroxysulfoximine diastereomers and reductive elimination results in a method of ketone methylenation with optical resolution. The technique is illustrated in the synthesis of the ginseng sesquiterpene (—)-p-panasinsene and its enantiomer (eq 5). The addition of the enantiopure lithiosulfoximine to prochiral enones or the diastereoface selective addition to racemic enones results in the formation of two diastereomeric adducts. The hydroxy group in these adducts can be used to direct the Simmons-Smith cyclopropanation (eq 6 and eq 7). Catalytic osmylation of such adducts is directed by the anti effect of the hydroxy augmented by chelation by the methylimino group (eq 7). ... 

To continue the synthesis (Figure 2.52), (-)-ketone E was treated with methylene triphenylphosphorane to give F. Deprotection followed by oxidation of F afforded the naturally occurring (+)-mispyric acid (59), whose absolute configuration was determined as 25,45. Similarly, the other diastereomer G obtained by optical resolution afforded unnatural (2R,4R)-(—)-59. ... 

Asymmetric transformation of fluorine-containing ketones or esters into the corresponding optically active alcohols or acids by enzymes along with the discussion on the effect of fluorinated alkyl groups during the enzymatic optical resolution or diastereoselective reactions is described. 

It might be mentioned in passing that a recent study (80) on microbial reduction of ( )-60 with Rhodotorula rubra offered a convenient method for its optical resolution in that the microbe preferentially reduced the (- )-( )-enantiomer and left (+)-(R)-ketone intact with 58% optical purity. 

Chiloschyphone (1) is a sesquiterpene ketone isolated from Chiloscyphus polyanthos and its absolute configuration has not been determined (3). The structure of this compound was first reported in 1972 (4), but later a total synthesis of this compound revealed that this original structure was wrong (5). Quite recently the correct structure was proposed by Connolly and his co-workers to be that depicted as in 1 (3). The synthesis of this correct structure has not been achieved yet. We plan to introduce cw-dimethyl groups by 1,4-addition, followed by an intramolecular aldol cyclization to yield a hydrindane skeleton (Scheme 1). The optical resolution must be possible at the stage of compound 4. 

The photochemical procedure, referred to in the previous section, by the Quinkert group (ref.129) has been adapted to afford an asymmetric total synthesis (ref. 145) for which the chiral ring D component (A) has been derived by three distinct methodologies, two of which involved conventional optical resolution and the third used asymmetric induction. In the route shown, the tricyclic ketone (X)was obtained from the racemate by resolution with (+)-1-phenylethylamine. 

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