Aldol reactions steric effects

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

In the reverse reaction, the addition anion reforms the carbonyi group by expeiiing the enoiate anion as ieaving group. This reverse aldol reaction is sufficientiy important in its own right, and we shaii meet exampies. Note that, as we saw with simpie aidehyde and ketone addition reactions, aidehydes are better eiectrophiies than ketones (see Section 7.1.1). This arises from the extra alkyl group in ketones, which provides a further inductive effect and extra steric hindrance. Accordingly, the aldol reaction is more favourable with aldehydes than with ketones. With ketones, it is absolutely essential to disturb the equilibrium in some way. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

B Uoster 7 has pointed out the parallelism of the aldol and Darkens reactions -with respect to electronic effects. It is conceivable that steric effects can also play an important role in the reactivity of the carbonyl component, but there is insufficient evidence in the literature at present to warrant any definitive conclusion on this subject.183 ... 

Diastereoselective aldol reaction. Alkyl trityl ketones (2) are readily prepared by reaction of 1 with an aldehyde followed by Cr03 oxidation (50-70% overall yield). Because of steric effects these ketones undergo highly diastereoselective aldol condensation to give syn-adducts (95-99% syn). After protection of the hydroxyl group, the adduct is cleaved by lithium triethylborohydride.1... 

A stereoselective Mukaiyama-type aldol reaction of bis(trimethylsilyl)ketene acetals produces silyl aldols with syn stereoselectivity, predominantly due to steric effects.23... 

In the Weiss reaction (Scheme 4), an 7-dicarbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c w-bicyclo [3.3.0] oct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if deshed. While die reaction involves aldol and Michael sequences, die intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence diat diey are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

Hydrogen bonding and steric effects have been investigated in a theoretical study of the origin of the diastereoselectivity in the remote 1,5-stereoinduction of boron aldol (g) reactions of /3-alkoxy methyl ketones 125 high levels of 1,5-anti-stereocontrol have been achieved in such reactions of tf-methyl-a-alkoxy methyl ketones, giving both Felkin and anti-Felkin products.126 (g)... 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

As with most camphor-based chiral auxiliaries, the size and steric congestion at the C-8 position of the camphor moiety can determine its efficiency. Through the formation of a connection between C-8 and C-2, a novel camphor-based oxazinone auxiliary 29, which can be prepared from camphor in 3 steps,52 becomes highly effective in directing stereoselective aldol reactions (Scheme 5.11).53... 

To determine the aetivated faee of a carbonyl group in an acetylenic aldehyde-CAB 2 complex, an aldol reaction of acetylenic aldehydes with the trimethylsilyl enol ether derived from acetophenone was performed in the presence of 20 mol % 2 under conditions similar to those in the Diels-Alder reaction (Eq. 32). Good enantioselec-tivity was, with the predominant enantiomer corresponding to attack on the re face, as expected. Although it is essential to stress that the results of an aldol reaction cannot be directly used to explain the transition state in cycloaddition, the effective steric shielding of the si face of the coordinated aldehyde is consistent with cycloaddition via the proposed transition-state model 16. 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Eor comparison, ATPH can be used for this kind of differentiation more efficiently in the hetero-Diels-Alder reaction [58]. With ATPH, silyl enol ether Si-1 exhibited adequate potential for the aldolization unlike the observed poor reactivity with KSA alone using the above Eu-catalyst (Scheme 2-26 Table 2-4). Even the /i-sub-stituents of the aldehydes can be differentiated (entries 4 and 5, Table 2-4). The het-ero-atom-containing aldehyde was effectively discriminated, showing non-chelation ability of ATPH (entry 6, Table 2-4). When aldehydes are encapsulated in the ATPH cavity, the hitherto small steric effects turned out in these cases to be dominant. The importance of the effect of the cavity was illustrated further by a comparative experiment with bulky MAD (5 6=3.7 1). 

Activation of the (f )-binolato-Ti(OiPr)2 (2) by highly acidic and sterically demanding alcohols as achiral rather than chiral activators is also effective to provide higher levels of enantioselectivity than those attained by the parent enantio-pure binolato-Ti(OiPr) catalyst (2) in the Mukaiyama aldol reaction of silyl enol ethers (Eq. (7.22)) [55]. 

Under kinetic control the aldol reaction is very stereospecifie (Fig. 8.5). The lithium enolate is generated in an aprotic solvent, and then the carbonyl compound is added. The reaction proceeds via the metal-chelated minor path 6e. The minimization of steric effects in the chair transition state and the stereochemistry of the enolate (Section 9.3) determine the stereochemistry of the product. 

Other efforts have been focused on a conceptually new, directed aldol condensation [54]. Mixed aldol condensations between two different carbonyl compounds with several possible sites for enolization are extremely difficult and there is a variety of undesired pathways involving proton transfer and over-alkylation. The aldol reaction of an a,/ -unsaturated carbonyl compound with an aldehyde was investigated in the presence of ATPH. The reaction first involves fhe demand for control of reactivity and selectivity of the a, -unsaturated carbonyl compound, which upon deprotonation leads to the corresponding extended dienolate of ATPH. A second carbonyl compound aldehyde which serves as an electrophile is activated electronically (but sterically deactivated) by complexation with ATPH. This activation would enable rapid in-situ capture of fhe extended dienolate. ATPH was the reagent of choice, because it could effectively make a strong coordination bond upon encapsulating a number of a, -unsaturated carbonyl compounds. 

Bosnich et al. have found fhat 0.5 mol% Cp2Ti(OTf)2 or Cp2Zr(OTf)2 effects an efficient aldol reaction of aldehydes and ketones in CH3NO2 at 25 °C [64]. It has been proposed fhat Cp2Ti(OTf)2 acts only as a precursor of fhe actual catalyst TMSOTf. In contrast, fhe Cp2Zr(OTf)2-catalyzed reaction of sterically unhindered or aromatic aldehydes would proceed via a Zr-catalyzed rafher fhan a Si-catalyzed mechanism (Scheme 10.14) [65]. 

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