Enolate achiral

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... 

Each act of proton abstraction from the a carbon converts a chiral molecule to an achiral enol or enolate ion. The 5/) -hybridized carbon that is the chirality center in the starting ketone becomes 5/) -hybridized in the enol or enolate. Careful kinetic studies have established that the rate of loss of optical activity of 5cc-butyl phenyl ketone is equal to its rate of hydrogen-deuterium exchange, its rate of bromination, and its rate of iodina-tion. In each case, the rate-detennining step is conversion of the starting ketone to the enol or enolate anion. 

The achiral enolate 1 reacts with symmetrical ketones to provide aldol-type products1. 

Volume F. 21 D. 1.3.4.3. Addition of Achiral Enolates to Chiral Carbonyl Compounds... 

Addition of Achiral Enolates to Chiral Carbonyl Compounds... 

I.3.4.3.1. Cram-Felkin-Anh Selective Additions of Achiral Enolates to Chiral Aldehydes... 

Examples of both chelation-controlled and nonchelation-controlled additions of achiral enolates to enantiomerically pure aldehydes are listed in Tabic 1. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

Addition of Achiral Enolates to Achiral Carbonyl Compounds in the Presence of Chiral Additives and Catalysts... 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

I.5.3.2.I. synjanti Diastereoselection Achiral Enolates and Related Anions... 

Substrate control This refers to the addition of an achiral enolate (or allyl metal reagent) to a chiral aldehyde (generally bearing a chiral center at the a-position). In this case, diastereoselectivity is determined by transition state preference according to Cram-Felkin-Ahn considerations.2... 

Most of the asymmetric aldol reactions discussed thus far deal with the nucleophilic addition of a chiral or achiral enolate onto a chiral or achiral aldehyde,... 

In general, a good level of predictability is now associated with the sense of asymmetric induction in aldol condensations of achiral enolates and chiral a-substituted aldehydes. At present, the perturba-... 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Diastereomer analysis on the unpurified aldol adduct 52b revealed that the total syn anti diastereoselection was 400 1 whereas enantioselective induction in the syn products was 660 1. On the other hand, Evans in some complementary studies also found that in the condensation of the chiral aldehyde 53 with an achiral enolate 56a only a slight preference was noted for the anti-Cram aldol diastereomer 58a (58a 57a = 64 36). In the analogous condensation of the chiral enolate 56b. however, the yn-stereoselection was approximately the same (57b 58b > 400 1) as that noted for enolate 49 but with the opposite sense of asymmetric induction (Scheme 9.17). Therefore, it can be concluded that enolate chirality transfer in these systems strongly dominates the condensation process with chiral aldehydes. 

Following Heathcock s reasoning, suppose that an achiral enolate (601 reacts with chiral aldehydes (59) to give the two possible syn aldols 6 and 61b in a 10 1... 

Now, if we allow one enantiomer of the chiral aldehyde 59 to react with the two enantiomers of the chiral enolate M, in one case the two chiral reagents will both promote the same absolute configuration at the two new chiral centres (65a ). However, no such effect will be observed in the other possible combination (c/. 65) (Scheme 9.21). In the first case, the effective "Cram s rule selectivity" shown by the aldehyde will be greater than in its reactions with achiral enolates. For the selectivities chosen the "Cram anti-Cram ratio" should be in our example of the order of 100 1 (see below 9.3.4., Masamune s "double asymmetric induction"). 

The significance of the results of these two reactions is threefold 1) both ratios are far greater than the 3 2 ratio obtained with the achiral enolate ii) the chirality of R in 74b is directly correlated with the stereochemistry at the 3,4-positions of the... 

The formation of diastereomers is also possible when two new chiral centers are produced from achiral starting materials. A pertinent example is found in aldol-type reactions between enolates and carbonyl compounds. The achiral enolate and the achiral aldehyde or ketone gives a product with two new... 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

Enantiofacial discrimination of achiral enolates by chiral electrophiles is also possible. Duhamel and co-workers reported that the reaction of the... 

All of the methods in categories 2 to 5 have been designed and developed on the basis of the achiral enolate structure. The methods in category 1 involve chiral enolates where the enolate subunit (achiral on its own) covalently links to a chiral element. In contrast to these methodologies, the next section describes a novel asymmetric induction based on dynamic chirality of the enolate structure. 

A possible rationale for the asymmetric a-methylation of 40 involves the participation of mixed aggregate E in which the undeprotonated starting material functions as a chiral ligand of the potassium cation of the achiral enolate. To test the feasibility of E, a crossover experiment between 40 and 44 was conducted (Scheme 3.12). A 1 1 mixture of racemic 40 and (5)-44 (>99% ee) was treated with KHMDS (1.1 equiv of the total amount of 40 and 44) followed by methyl iodide according to the protocol in Table 3.5, to give racemic 41 (79% yield) and (5)-45 (74% ee, 79% yield). This means that transfer of chirality between substrates did not occur. Thus mixed aggregate E is not responsible for the present asymmetric induction. 

In the early twentieth century Leuchs reported a surprising example of the a-chlorination of chiral ketone 73, which gave optically active 74 in the absence of additional chiral sources.36 From a mechanistic point of view, however, there remains some ambiguity. Possible mechanisms for the formation of optically active 74 include (1) asymmetric chlorination via an enol intermediate (i.e., memory of chirality), (2) direct electrophilic chlorination of the C-H bond at the stereogenic carbon center, (3) complex formation of an achiral enol intermediate with optically active 73, (4) resolution of dl-74 by co-crystallization with optically active 73, and (5) simultaneous resolution of dl-74. 

While many chemists are familiar with the problems posed by abnormally large barriers to rotation about single bonds when it comes to interpreting NMR spectra, few have sought to make use of these barriers as tools for stereoselective synthesis. A renewal of interest in this prospect followed Fuji s remarkable observation, published in 1991, of stereospecific alkylation of ketone 1. The stereochemistry of the starting material was retained in the product 2 despite the intermediacy of an apparently achiral enolate (Scheme 1) [1]. 

---