Reversibility chiral enolates

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

We can now consider the reaction between the chiral aldehyde (-)-TO with the chiral enolate (5)-74b (Scheme 9.25). This aldol condensation affords two diastereomers 81 and 82 in a ratio of >100 1. A change in the chirality of the enolate reverses the result. Thus, the reaction of (-)-TO with t/ )-74b leads to the formation of 81 and 2 in a ratio of 1 30, favouring therefore with respect to 81. 

Mukaiyama variant of the Michael reaction and Michael additions of 1,3-diketones to 2-oxo-3-butenoate esters. However, these examples have always involved activation of bidentate electrophiles by Cu(II) followed by the addition of a weak nucleophile to the resultant complex. The attempts to employ bis(oxazoline)copper(II) complexes to catalyze a classical Michael reaction with p-ketoesters and monodentate enones are precedented however, racemic products were obtained in such cases. Interestingly, the Michael reaction developed in our studies is most likely to proceed via reversed activation (Scheme 11). Thus, we proposed that Cu(II) complex H chelates the enol form of p-ketoester 12a, and the resultant chiral enol complex 22 undergoes addition to electrophile (5) to provide 23. It should be noted that the precise mechanism of this reaction and particularly the step for the addition of 22 to 5 to provide 23 are yet to be investigated. 

These correlation studies indicate a dominating influence of the chiral enolate 15 versus the chirality of the aldehyde. In the case of (S)-phenyl-propionaldehyde 28 the chirality of enolate 15 overrides the directing effect of the aldehyde chirality, still producing a 2.5 1 ratio in favor of the 6(R),7(S),8(R)-stereochemical triad. The use of the (R)-phenylpropionalde-hyde 31 forms exclusively the 6(R),7(S),8(R)-stereo chemical triad in a 40 1 ratio. In this case the matched pair is the (S)/(R)-combination of chirality. The (R)-enantiomer of the enolate reverses the stereochemical outcome. 

Among the peculiar features of 2-bromoamides there are the following i) possibility of substitution at the tertiary C-Br (RCO2H, RR NH, or a saccharide, as the nucleophiles) ii) chiral stability and stereochemical control at the secondary C-Br atom (RR NH, ROH or a saccharide as the nucleophiles) iii) the presence of bromine allows cyclic voltammetry and electroreduction at controlled potential both of starting compounds and relevant intermediates iv) the Ca polarity can be reversed upon electroreduction, and the resulting Ca enolate forms a C-C bond (CO2 as the electrophile). 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

By contrast, lithium enolates derived from tertiary amides do react with oxiranes The diastereoselectivity in the reaction of simple amide enolates with terminal oxiranes has been addressed and found to be low (Scheme 45). The chiral bicyclic amide enolate 99 reacts with a good diastereoselectivity with ethylene oxide . The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case ) interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103. By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the hthium enolate 104 with the chiral oxiranes 105 and 106 °. It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselec-tivities can be achieved. 

Protected amino acids with either a free amino or carboxyl function can usually be prepared by proven methods or are even commercially available. Therefore stages (i) - (iii) may be considered as simple routine nowadays, although great care must be taken that the protected starting materials are pure enantiomers. The reactions that cause most trouble are in stages (iv), (v) and (vii). In these stages an activated carboxyl group is involved and the chiral centre adjacent to it is at peril from racemization. A typical reaction which causes epimerization is azlactone formation. With acids or bases these cyclization products may reversibly enolize and racemize. Direct racemization of amino acids has also been observed. 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

Fujisawa et al. [89] have reported the stereodivergent synthesis of spiro-[S-1 act a ms 64, 65 (Scheme 17) by reaction of lithium or titanium ester enolates 62 with single chiral imines 63 by taking advantage of different coordination states of the enolate metals. Almost complete reversal of the diastereofacial-discrimination with respect to the C-4 of the (3-lactam skeleton has been attained in this reaction coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary. 

The corresponding Wittig reagent, CHj PPhj, reacts smoothly with both aldehydes and ketones to give methylenated products In high yield but with one subtle limitation. The problem cannot be detected with aldehydes because they react rapidly even at temperatures as low as -78°C, but ketones react more slowly, and an adjacent enolizable chiral center can be epimerized as a result of competitive reversible enolization. This limitation of the Wittig... 

It should be noted that in the absence of the organocatalyst the E enolate affords mainly the syn adduct (syn/anti ratio 49 1, 92% yield, reaction temperature 0 °C [82, 84]) whereas in the presence of (S,S)-52 by dramatic reversal in diastereoselectivity the anti-aldol product anti-53 is preferentially formed (anti/syn ratio 50 1 anti 93% ee) [84], Other types of chiral phosphoramide, e.g. based on optically active 1,2-cyclohexyldiamine, had less satisfactory catalytic properties. 

Asymmetric aldol reactions5 (11, 379-380). The lithium enolate of the N-propionyloxazolidinone (1) derived from L-valine reacts with aldehydes with low syn vs. anti-selectivity, but with fair diastereofacial selectivity attributable to chelation. Transmetallation of the lithium enolate with ClTi(0-i-Pr)3 (excess) provides a titanium enolate, which reacts with aldehydes to form mainly the syn-aldol resulting from chelation, the diastereomer of the aldol obtained from reactions of the boron enolate (11, 379-380). The reversal of stereocontrol is a result of chelation in the titanium reaction, which is not possible with boron enolates. This difference is of practical value, since it can result in products of different configuration from the same chiral auxiliary. 

Schiff base 52 in one-pot under mild phase-transfer conditions. For example, the initial treatment of a toluene solution of 52 and (S,S)-32e (1 mol%) with allyl bromide (1 equiv.) and CsOHH20 at —10 °C, and the subsequent reaction with benzyl bromide (1.2 equiv.) at 0 °C, resulted in formation of the double alkylation product 53 in 80% yield with 98% ee after hydrolysis. Notably, in the double alkylation of 52 by the addition of the halides in reverse order, the absolute configuration of the product 53 was confirmed to be opposite, indicating intervention of the chiral ammonium enolate 54 at the second alkylation stage (Scheme 4.17) [50]. 

The situation is complex. In another study we examined the cyclization of compound 54 catalyzed by cyclodextrin bis-imidazoles [140]. This dialdehyde can perform the intramolecular aldol reaction using the enol of either aldehyde to add to the other aldehyde, forming either 55 or 56. In solution with simple buffer catalysis both compounds are formed almost randomly, but with the A,B isomer 46 of the bis-imidazole cyclodextrin there was a 97 % preference for product 56. This is consistent with the previous findings that the catalyst promotes enolization near the bound phenyl ring, but in this case the cyclization is most selective with the A,B isomer 46, not the A,D that we saw previously. Again the enolization is reversible, and the selectivity reflects the addition of an enol to an aldehyde group. The predominant product is a mixture of two stereoisomers, 56A and 56B. Both were formed, and were racemic despite the chirality of the cyclodextrin ring. 

Boryl enolates prepared from A-propionylsultam reacted with aliphatic, aromatic and a,/Tunsaturated aldehydes to provide diastereomerically pure. qw-aldols (Equation (174), whereas the presence of TiCl4 caused complete reversal of the diastereoface selectivity giving anti-aldols (Equation (175)).676-678 Camphor-derived chiral boryl enolates 423 were highly reactive and highly anti-selective enolate synthon system in aldol addition reactions promoted by TiCl4 or SnCl4 co-catalyst (Equation (176)).679... 

Enantiopure bis-P-amino acids can be prepared from chiral bis-sulfinimines.37 Bis-sulfinimine (Ss,Ss)-160 and the sodium enolate of methyl acetate react to give 161 as a diastereomeric mixture. The major isomer (5s,/ ,Ss,/ )-161 can be isolated by preparative reverse-phase HPLC in 46% yield. Hydrolysis of (Ss,/ ,Ss,/ )-161 gave bis-P-amino ester (/ ,/ )-162 in >97% ee and 86% yield.37... 

The second reaction creates a lithium enolate and alkylates it. It is again stereospecific at the unchanged chiral centre but stereoselective at the newly created quaternary centre. Finally, acetal hydrolysis preserves the new quaternary centre unchanged (stereospecific) by a mechanism that is the reverse of the first step... 

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