Aldol selectivity

In this system, the chiral phase transfer catalyst (PTC) is able to recognize one aldolate selectively. There is an equilibrium between syn- and anti-aldolates via retro-aldol addition, and the formation of a stable, chelated lithium salt blocks the non-catalyzed subsequent reaction from yielding the epoxide product ... 

With crotonate esters, it was observed that the presence of the -methyl group spoiled the electrophilic reactivity an awfi-Michael selectivity prevailed over the. vyw-aldol selectivity (Scheme 34). The presence of three contiguous stereogenic centers in adduct 98 affords a mixture of four diastereomers (98A-98D), of which 98A and 98D were obtained as major isomers89. 

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

Hydrogenation experiments confirmed that the commercial catalysts studied, i.e. silica-supported NiCr was able to hydrogenate the aldol selectively to triol. The comparison of methanolic and water solvents revealed that the absence of methanol increased the total hydrogenation velocity, especially when the starting mixture contained high quantities of formaldehyde. The experimental data produced with NiCr were reasonably well described by the kinetics model, which account for competitive adsorption of reagents, surface reactions and the inhibitory effect of formaldehyde. 

In order to circumvent this general lack of aldol selectivity with chiral aldehydes, one typically needs to employ a chiral enolate... 

It is, therefore, possible to prepare syn and anti aldols selectively when the appropriate protecting group is chosen for the alkoxy part of the molecule. This method has been applied to the synthesis of several monosaccharides including branched, deoxy, and amino sugars [69]. One example is shown below (Scheme 3.5) [69c]. 

Ketone donors have only rarely been used in amine-catalyzed aldolizations. Selected examples that have been published over the last 70 years are shown in Scheme 4.7 [57-68]. 

Gong group designed chiral primary amine-amide type catalyst for the aldoliza-tion of hydroxyacetone [24] with excellent iyn-aldol selectivity (up to >20 1 dr.) and stereoselectivity (up to 98% ee) (Scheme 5.12). Recently, Zhao and Da have further explored this type of primary amine catalysts [25]. Feng developed bispidine-derived chiral primary amine catalyst 45 for the aldolization of activated ketone acceptors with excellent enantioselectivity (Scheme 5.12) [26]. 

In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult... 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

Lithium Iodide. Lithium iodide [10377-51 -2/, Lil, is the most difficult lithium halide to prepare and has few appHcations. Aqueous solutions of the salt can be prepared by carehil neutralization of hydroiodic acid with lithium carbonate or lithium hydroxide. Concentration of the aqueous solution leads successively to the trihydrate [7790-22-9] dihydrate [17023-25-5] and monohydrate [17023-24 ] which melt congmendy at 75, 79, and 130°C, respectively. The anhydrous salt can be obtained by carehil removal of water under vacuum, but because of the strong tendency to oxidize and eliminate iodine which occurs on heating the salt ia air, it is often prepared from reactions of lithium metal or lithium hydride with iodine ia organic solvents. The salt is extremely soluble ia water (62.6 wt % at 25°C) (59) and the solutions have extremely low vapor pressures (60). Lithium iodide is used as an electrolyte ia selected lithium battery appHcations, where it is formed in situ from reaction of lithium metal with iodine. It can also be a component of low melting molten salts and as a catalyst ia aldol condensations. 

Aldol reaction of campholenic aldehyde with propionic aldehyde yields the intermediate conjugated aldehyde, which can be selectively reduced to the saturated alcohol with a sandalwood odor. If the double bond in the cyclopentene ring is also reduced, the resulting product does not have a sandalwood odor (161). Reaction of campholenic aldehyde with -butyraldehyde followed by reduction of the aldehyde group gives the aHyUc alcohol known commercially by one manufacturer as Bacdanol [28219-61 -6] (82). 

Neo acids are prepared from selected olefins using carbon monoxide and acid catalyst (4) (see Carboxylic Acids, trialkylacetic acids). 2-EthyIhexanoic acid is manufactured by an aldol condensation of butyraldehyde followed by an oxidation of the resulting aldehyde (5). Isopalmitic acid [4669-02-7] is probably made by an aldol reaction of octanal. 

Titanium tetrakis(diethylamide) selectively adds to aldehydes in the presence of ketones and to the least hindered ketone in compounds containing more than one ketone. The protection is in situ, which thus avoids the usual protection-deprotec-tion sequence. Selective aldol and Grignard additions are readily performed employing this protection methodology. ... 

Kelkar and McCarthy (1995) proposed another method to use the feedforward experiments to develop a kinetic model in a CSTR. An initial experimental design is augmented in a stepwise manner with additional experiments until a satisfactory model is developed. For augmenting data, experiments are selected in a way to increase the determinant of the correlation matrix. The method is demonstrated on kinetic model development for the aldol condensation of acetone over a mixed oxide catalyst. 

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

The key step to this first reported case of the highly diastereoselective addition of a fluorinated enolate in an aldol process is the selective formation of the enolate a,a-Difluonnated enolates prepared by a metallation process employing either a zinc-copper couple [S] or reduced titanium species [9] undergo aldol condensation smoothly (equation 9) (Table 5)... 

Stannous triflate is an efficient catalyst for aldol-type condensations [ 23, 124, 125 Under conditions of kinetic control, it provides excellent diastereo-selectivity in various cross-aldol reactions (equation 61)... 

Given the relatively rare appearance of oxetanes in natural products, the more powerful functionality of the Patemo-Biichi reaction is the ability to set the relative stereochemistry of multiple centers by cracking or otherwise derivitizing the oxetane ring. Schreiber noted that Patemo—Btlchi reactions of furans with aldehydes followed by acidic hydrolysis generated product 37, tantamount to a threo selective Aldol reaction. This process is referred to as photochemical Aldolization . Schreiber uses this selectivity to establish the absolute stereochemistry of the fused tetrahydrofuran core 44 of the natural product asteltoxin. ... 

The aldol condensation of phenylthiobutenone 304 with aldehydes in CH2CI2 via dienodibutylborinates 305 leads to the adduct 306 in 61% yield (diastereo-selectivity >97%) (90TL2213). 

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