Ketone racemization

Early reports of the persistance of optical activity in nitro-substituted carbanions have since been shown to be erroneous.365 366 The treatment of optically active 2-nitrooctane with sodium ethoxide or hydroxide produces an optically inactive salt.366 Optically active 4-nitropentanoic acid racemizes and enolizes at the same rate in the presence of a base.368 Optically active phenyl sec-butyl ketone racemizes and undergoes deuterium exchange at the same rate in the presence of DQ<-)a 7 Of course this could conceivably be due to the tendency of the... 

At this point, we investigated the reduction of the ketone to the phenethyl alcohol followed by Mitsunobu displacement as well as direct reductive amination. We were able to efficiently reduce the ketone racemically using NaBH4 in MeOH to alcohol 32. However, the subsequent Mitsunobu reaction proved problematic and no desired product was observed (Scheme 5.12). 

Chae, W.K., Chae, M.Y., Park, M.K., Lee, C.H., and You, E.H., Singlet- triplet reactivity of 1-methyl-2-cyclohexenyl aryl ketones racemization vs 1,3-acylshift in the excited states. Bull. Korean Chem. Soc., 11, 241, 1990. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

If the a carbon atom of an aldehyde or a ketone is a chnality center its stereo chemical integrity is lost on enolization Enolization of optically active sec butyl phenyl ketone leads to its racemization by way of the achiral enol form... 

Appllca.tlons. MCA is used for the resolution of many classes of chiral dmgs. Polar compounds such as amines, amides, imides, esters, and ketones can be resolved (34). A phenyl or a cycloalkyl group near the chiral center seems to improve chiral selectivity. Nonpolar racemates have also been resolved, but charged or dissociating compounds are not retained on MCA. Mobile phases used with MCA columns include ethanol and methanol. 

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

Also due to the high barrier of inversion, optically active oxaziridines are stable and were prepared repeatedly. To avoid additional centres of asymmetry in the molecule, symmetrical ketones were used as starting materials and converted to oxaziridines by optically active peroxyacids via their ketimines (69CC1086, 69JCS(C)2648). In optically active oxaziridines, made from benzophenone, cyclohexanone and adamantanone, the order of magnitude of the inversion barriers was determined by racemization experiments and was found to be identical with former results of NMR study. Inversion barriers of 128-132 kJ moF were found in the A-isopropyl compounds of the ketones mentioned inversion barriers of the A-t-butyl compounds lie markedly lower (104-110 kJ moF ). Thus, the A-t-butyloxaziridine derived from adamantanone loses half of its chirality within 2.3 days at 20 C (73JCS(P2)1575). 

Compound A can be resolved to given an enantiomerically pure substance, [a]p = —124°. Oxidation gives the pure ketone B, which is optically active, [aJo — —439°. Heating the alcohol A gives partial conversion (an equilibrium is established) to an isomer with [a]p = +22°. Oxidation of this isomer gives the enantiomer of the ketone B. Heating either enantiomer of the. ketone leads to the racemic mixture. Explain the stereochemical relationships between these compounds. 

General acid and base Halogenation exchange racemization of ketones RCOCHj+X. =RCOCH.X + XH... 

Ethynylation of the totally synthetic racemic 18-methyl-17-ketone (63) with acetylene and potassium t-butoxide in t-butanol-toluene or with alkali metal acetylide in liquid ammonia gives a low yield of rac-18-methyl-17a-ethynyl-3-methoxyestra-l,3,5(10)-trien-17/ -ol (64). 

The carbonyl carbon of an unsymmetrical ketone is a prochiral center reaction with a Grignard reagent 2 (R 7 R, R") can take place on either face of the carbonyl group with equal chance. The products 8a and 8b are consequently formed in equal amounts as racemic mixture, as long as no asymmetric induction becomes effective ... 

By treatment of a racemic mixture of an aldehyde or ketone that contains a chiral center—e.g. 2-phenylpropanal 9—with an achiral Grignard reagent, four stereoisomeric products can be obtained the diastereomers 10 and 11 and the respective enantiomer of each. 

The fragmentation/cyclization ratio is determined by the relative orientation of the respective molecular orbitals, and thus by the conformation of diradical species 2. The quantum yield with respect to formation of the above products is generally low the photochemically initiated 1,5-hydrogen shift from the y-carbon to the carbonyl oxygen is a reversible process, and may as well proceed back to the starting material. This has been shown to be the case with optically active ketones 7, containing a chiral y-carbon center an optically active ketone 7 racemizes upon irradiation to a mixture of 7 and 9 ... 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

It is convenient to here mention the hydrocarbon verbenene, C,gH,4, on account of its relationship with pinene. It results from the action of acetic anhydride on verbenol, thei alcohol corresponding with the ketone, verbenone. So produced it is laevo-rotatory. The dextro-rotatory and racemic varieties are also known. The sesquiterpenes have the following characters when regenerated from their respective dibromides —... 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

With this single example we have in tact described two uses of enzymes in alicyclic chemistry, the reduction of ketone groups and the resolution of racemic mixtures. 

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