Racemic 2-substituted ketones

I.3.3.3.3.2.2. Simple Diastereoselection Reactions of Racemic -Substituted Allylboron Reagents with Achiral Aldehydes and Ketones... 

Cells of Acinetobacter sp. NCIB 9871 grown with cyclohexanol carried out enantiomeri-cally specific degradation of a racemic substituted norbomanone to a single ketone having >95% enantiomeric excess (Levitt et al. 1990). 

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... 

Racemic substituted aminoindanol 9 was synthesized in a 5-step sequence by nitration of 1-indanone, followed by ketone reduction and dehydration to give 6-nitro-l-indene and subsequent epoxidation of the olefin and final regioselective animation (Scheme 8.5). Optically pure (IR,2R)-and (1 S,2S)-6-nitro-1 -amino-2-indanol 9 were eventually obtained by resolution with mandelic... 

Michael reaction with an o , S-unsaturated ketone followed by an intramolecular aldol reaction has proven to be a valuable method for the synthesis of 2-cyclohexenones. An especially important example of a Michael-aldol sequence is the Robinson annulation, in which treatment of a cyclic ketone, 8-ketoester, or S-diketone with an a,)8-unsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring. When the following racemic 8-ketoester, for example, is treated with methyl vinyl ketone in the presence of sodium ethoxide in ethanol, the Michael adduct forms and then, in the presence of sodium ethoxide, undergoes a base-catalyzed intramolecular aldol reaction followed by dehydration to give a racemic substituted cyclohexenone. 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

In the hydrogenation of cyclic / -keto esters (ketones substituted with an al-koxycarbonyl moiety), Ru(II)-binap reduced a racemic substrate in DCM with high anti-diastereoselectivity to give a 99 1 mixture of the trans-hydroxy ester (92% ee) and the ds-hydroxy ester (92% ee), quantitatively [Eq. (18)] [119, 120]. 

An example of the method described is the synthesis of saphenic acid (47) that has recently been reported by Nielsen et al. [81]. Starting from properly substituted aromatic precursors 92 and 93, the naturally occurring 1,6-disub-stituted phenazine was synthesized in racemic form. Here, the first major step involves an intermolecular nucleophilic aromatic substitution that, due to the substitution pattern, has proved to be relatively unproblematic and after hydrolysis of the acetal yields the o-nitrodiphenylamine 94. Much more difficult is the ring formation leading to the final phenazine, which can best be achieved through a high excess of NaBH4, accompanied by reduction of the methyl ketone. But at 32%, the yield is still rather poor. 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

For the construction of the methyl-substituted alkene, the Wittig alkenation method described in Section 10.5.2.1.2.1 has been used, starting from the Boc-Phe-methyl ketone. 125 The more nucleophilic diethyl [3-(trimethylsilyl)prop-2-ynyl]phosphonate gave the best yield (57%) of a mixture of Z- and is-enynes (81 19). A major limitation, however, was extensive racemization, resulting in an ee of only 48% of the final dipeptide isostere. The methods described below are therefore preferable. 

Several reactions of carbonyl compounds that have one or more a hydrogens proceed through the enol form. Reaction of ketones with chlorine, bromine, and iodine result in substitution of halogen for a hydrogen rates are typically first-order in ketone and independent of halogen concentration and even of which halogen is used. Racemization of ketones with asymmetric centers adjacent to the... 

Racemic N-methylimines derived from 4-substituted 1-tetralones were ki-netically resolved by asymmetric hydrosilylation with phenylsilane (1 equivalent) as a reducing agent using the titanocene catalyst (R)-ll (substrate Ti= 100 1) at 13 °C, followed by a workup procedure to afford the corresponding chiral ketones and chiral cis amines with very high enantio- and diastere-oselectivity (Scheme 12) [28], The extent of the enantiomeric differentiation, kfast/kslow was calculated to be up to 114. The ris-selectivity of this reaction was... 

One of the most valuable and widely used applications of C=N bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from a-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277. 

In analogy with iron-catalyzed Barbier-type reactions with Sml2 (cf. Scheme 8.5), intramolecular nucleophilic acyl substitutions (SNt) can be used to prepare cyclic ketones from esters [50]. An illustrative example is shown in Scheme 8.13 [51], Again, tris(l,3-diphenyl-l,3-propanedionato)iron(III) [Fe(dbm)3] is used as the catalyst. Compound 40 is obtained as one racemic diastereoisomer. 

---