Enantiomeric ketone

Cyclobutanones were found to be much more reactive under these conditions, presumably due to relief of ring strain (131). Racemic cyclobutanone (192) is oxidized under the conditions described above to provide lactones 193 and 194 in a ratio of 55 45, Eq. 111. The expected lactone product 193 is formed in 67% ee while the abnormal product 194 is formed in 92% ee. The major enantiomers of the two products are complementary, resulting from enantiomeric ketones. 

The deprotonation of meso oxiranes 144 and 145 by the system alkyllithium/diamine leads to the enantiomeric ketones (S)- and (R)-146 (Scheme 63). Due to the general propensity of these systems to achieve deprotonation at the R carbon of the oxirane ring, it was then concluded that this rearrangement follows exclusively a 1,2-H shift. 

In a different NMR approach, deuterium-labeled p eM o-enantiomeric ketones are reduced to diastereomeric alcohols (theoretically by a hydrogenase), and the product ratio is measured by NMR spectroscopy 100). The method has yet to be tested in enzyme-catalyzed reactions. 

Eaton and Leipzig chose to resolve racemic trishomocubanone by reaction with /-ephedrine and separation of the diastereomers by fractional crystallization. Subsequent acid hydrolysis delivered the enantiomeric ketones Successive removal of a diagonal CHj bridge from —)-451 furnishes (—)-ditwist-brendane (Cj symmetry) 454) and (—)-twist-brendane C symmetry) 455). Also,... 

If 2-camphanyloxyacrylonitrile (15 R = C8H 02C00) is taken for cycloaddition, diastereoisomeric cycloadducts can be separated, and the basic system, 7-oxabicyclo-[2.2.1]hept-5-en-2-one 17, can be obtained in optically pure form [36]. Another way of obtaining enantiomeric ketones is based on crystallization of a brucine complex obtained from the corresponding cyanohydrines (see Sec. III). Ketone 17 can be converted [e.g., by cis-hydroxylation (—>18), protection of the diol system, and Baeyer-Villiger oxidation] to lactone 19, the opening of which leads to furanuronic acid 20. A new development in this field is based in cycloaddition between furan and 2-chloro- or 2-bromoacrolein in the presence of 5 mol% chiral oxazaborolidine 21 as catalyst [37],... 

Enantiomerically pure Diels-Alder adducts of Ceo were prepared by Tsuji and co-workers by use of a chiral auxiliary in the diene component and separation of the diastereoisomeric intermediates.385 The starting material for the diene component was a cyclic cyclopentenone acetal (224, Scheme 1.21) derived from L-threitol, reacting via its cyclopentadiene-containing enol ether isomer.385,386 The diastereoisomeric products 225 and 226, formed without significant diastereoselectivity, were isolated as the acetals, separated and subsequently hydrolyzed to afford the enantiomeric ketones (+)-227 and (—)-227. NOE measurements allowed the determination of the absolute configuration of the diastereoisomeric intermediates 225 and 226 and, therefore, also of the enantiomeric ketones (+)-(R,R)-227 and (—)-(S,S)-227 (Scheme 1.21).385... 

Apparently, the reaction proceeds in an enantiodivergent manner, i.e., the re-gioisomeric lactones 8a and 8b emanate from opposite enantiomeric ketones and show different ee values. Transformations of this kind are rare, and the most significant examples of these have been summarized by Kagan [27]. 

A new method for the resolution of ketones depends upon the formation of an iminium salt containing an optically active anion.2 A ketone of one type, exemplified by (1), is converted into the pyrrolidine enamine (2), which is then treated with d-10-camphorsulfonic acid (3) to give the salt (4), which was resolved by systematic crystallization. Each enantiomeric salt was then crystallized and hydrolyzed to a pure enantiomeric ketone (1). 

This was accomplished by anaerobic reduction with Sporotrichum exile in which the 4a(S),8a(R)-enantiomer 51 is reduced six times more rapidly than the other enantiomer. This process in combination with chromic acid oxidation of the derived alcohol gave approximately 70% optically pure enantiomers. Resolution was completed by recrystallization from benzene in which the racemic form is significantly more soluble. The absolute configurations and optical purity of these enantiomeric ketones were confirmed by obtaining the 4a(S),8a(R)-enantiomer 51 from naturally occurring cinchonine (45) via meroquinene... 

Deprotonation of meso-cycloheptene oxide diastereoisomers 100 and 102, possessing a pseudoasymmetric C-5 carbon, led to the enantiomeric ketones... 

A key intermediate of diltiazem was efficiently synthesised by an asymmetric reduction of a 1,5-benzothiazepine derivative with NaBH4 and chiral a-amino acids such as (5)-tert-leucine." This asymmetric reduction proceeded via DKR and made it possible to control the two adjacent asymmetric carbons through a keto-enol tautomerism (Scheme 1.36). The role of AcOH was to promote the racemisation between the two enantiomeric ketones. 

Figure 7.4. Schematic representation of the orientations of the enantiomers of bicy-clo[3.2.1]-2-octanone in their preferred flat positions within the diamond lattice section of HLADH. Delivery of H to the carbonyl group from the e-re direction ensures the formation of an exo-alcohol. In (a) orientation of (H-)-isomer as shown does not place any substituents at undesirable positions. Reduction to the observed (—)-product is thus facile. The corresponding orientation of the enantiomeric ( —)-ketone is shown in (b). Here, C-7 is required to locate close to the unsatisfactory position I and reduction in this mode is not favored. Formation of (-h)-product is thus a relatively slow process (282). Reproduced with permission. Copyright 1978 by the American Chemical...

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

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. 

The milder metal hydnde reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodexnins reduce ketones to opucally active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc bromide-MMA. A -tetra-methylethylenediamme (TMEDA) reduces a,a-difluoro-[i-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The three isomers are formed on reduction with aluminum isopropoxide... 

Asymmetric induction by sulfoxide is a very attractive feature. Enantiomerically pure cyclic a-sulfonimidoyl carbanions have been prepared (98S919) through base-catalyzed cyclization of the corresponding tosyloxyalkylsulfoximine 87 to 88 followed by deprotonation with BuLi. The alkylation with Mel or BuBr affords the diastereomerically pure sulfoximine 89, showing that the attack of the electrophile at the anionic C-atom occurs, preferentially, from the side of the sulfoximine O-atom independently from the substituent at Ca-carbon. The reaction of cuprates 90 with cyclic a,p-unsaturated ketones 91 was studied but very low asymmetric induction was observed in 92. 

Because ketones are generally less reactive than aldehydes, cycloaddition reaction of ketones should be expected to be more difficult to achieve. This is well reflected in the few reported catalytic enantioselective cycloaddition reactions of ketones compared with the many successful examples on the enantioselective reaction of aldehydes. Before our investigations of catalytic enantioselective cycloaddition reactions of activated ketones [43] there was probably only one example reported of such a reaction by Jankowski et al. using the menthoxyaluminum catalyst 34 and the chiral lanthanide catalyst 16, where the highest enantiomeric excess of the cycloaddition product 33 was 15% for the reaction of ketomalonate 32 with 1-methoxy-l,3-butadiene 5e catalyzed by 34, as outlined in Scheme 4.26 [16]. 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Several chiral selectors have been used in the separation of enantiomers by distillation [198]. Among them, the bisalcohol 8 (Fig. 1-6) has permitted obtainment of the ketone (+)-9 with an enantiomeric excess of 95 %. This example shows the feasibility of the process even though, in this particular case, the price of the chiral selector might prohibit scale-up of the separation. 

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.

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