Threo aldol reaction

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. ... 

By this concept, a reversible enzymatic aldol reaction generates a mixture of l-threo/erythro aldol diastereomers (133) from which the i-threo isomer is preferentially decomposed by an irreversible decarboxylation to furnish aromatic aminoalcohol (R)-(134) vhth 78% ee in high yield. 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

Treating boron reagent 45a with an oxazoline compound gives the azaeno-late 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threo-product (anti-53) with good selectivities (Scheme 3-18).38... 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

Acetals of benzaldehydes may undergo EGA-catalyzed aldol reactions also with alkyl enol ethers, (22) (R = alkyl), as nucleophiles [31] but in contrast to the reaction with enol silyl ethers the threo isomer is favored in this case. 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

The reaction has been further extended into a tandem conjugate addition/ enolate trapping sequence, whereby the in situ generated zinc enolate was trapped with benzaldehyde. This resulted in an approximately 3 7 mixture of trans-erythro trans-threo aldol adducts, isolated in 88% yield. Subsequent oxidation of these products gave a single isomer of the corresponding diketone with 95% ee. 

Simple, clear-cut examples of aldol reactions exhibiting such solvent effects are scarce. Heathcock et al. [526] have reported that the erythro threo equilibration of lithium aldolates via retro-aldol reaction) is much faster in pentane than in tetrahy-drofuran or diethyl ether. 

The Mukaiyama aldol reaction of l-(trimethylsiloxy)-l-cyclohexene and benzalde-hyde has also been effected with the bidentate 188, giving the aldol products (erythro/ threo 1 3) in 87 % yield, though its monodentate counterpart 190 showed no evidence of reaction under similar conditions (Sch. 145). 

The diastereoselectivity in the montmorillonite-catalyzed aldol reaction of 14a and 15b was considerably dependent on the nature of the reaction solvent. A threo isomer was preferentially formed in toluene (Table XV, Entries 1, 2), whereas an erythro isomer was dominant in DME (Table XV, Entries 5, 6). 

I n 1993, the first cinchona-catalyzed enantioselective Mukaiyama-type aldol reaction of benzaldehyde with the silyl enol ether 2 of 2-methyl-l -tetralone derivatives was achieved by Shioiri and coworkers by using N-benzylcinchomnium fluoride (1, 12 mol%) [2]. However, the observed ee values and diastereoselectivities were low to moderate (66-72% for erythro-3 and 13-30% ee for threo-3) (Scheme 8.1). The observed chiral inductioncan be explained by the dual activation mode ofthe catalyst, that is, the fluoride anion acts as a nucleophilic activator of the silyl enol ethers and the chiral ammonium cation activates the carbonyl group of benzaldehyde. Further investigations on the Mukaiyama-type aldol reaction with the same catalyst were tried later by the same [ 3 ] and another research group [4], but in all cases the enantioselectivities were too low for synthetic applications. 

The frans-oxazolines with high enantiomeric excess can readily be converted to optically active fhreo-P-hydroxy-a-amino acids without epimerization by acid hydrolysis. Moreover, the aldol reaction was applied to the total synthesis of Cyclosporin s unusual amino acid MeBmt [ 16], and to the asymmetric synthesis of D-threo- and D-eryfhro-sphingosine, important membrane components [ 17]. The [substrate]/[catalyst] ratio can be raised to 10,000/1 without significant loss of the stereoselectivity in the reaction of 3 with 3,4-methylenedioxybenzalde-hyde (91% ee, translcis=9 l9), indicating that the gold-catalyzed aldol reaction may provide a practical process to produce optically active fhreo-P-hydroxy-a-amino acids [6]. 

Boron enolates (other names are vinyloxyboranes, enol borinates, or boron enol ethers) are often employed in the aldol reaction because they show higher stereoselectivity than alkali and magnesium enolates. Extensive developmental work in this area has been carried out by Evans, Masamune and Mukaiyama, and their respective coworkers. - - The correspondence between enolate geometry and aldol stereochemistry is exceptional (Z)-enolates give syn/erythro aldol products, whereas ( )-enolates give anti/threo aldol products, albeit with slightly lower selectivity. 

Tin(IV) enolates are generated by the reaction of lithium enolates with trialkyltin chlorides. The best stereoselectivity in the aldol reaction with tin(IV) enolates has been achieved by employing tri-phenyltin chloride. Syn/erythro aldol products were predominantly produced irrespective of the geometry of the starting enolates (Scheme 39). However, the aldol condensation via the enolate derived from norbomanone gave the anti/threo product predominantly (Scheme 40). ... 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

The concentrations of erythro and threo aldols as a function of time are presented in Figure 1 (a) for a relatively nonpolar solvent (90 10 THF-MeOH) and in Figure 1(b) for a polar solvent (pure MeOH). In the nonpolar solvent the threo aldol is formed more rapidly than the erythro isomer. However, as a result of the reversibility of the system, its concentration peaks and then diminishes to eventually reach an equilibrium value. In pure MeOH, on the other hand, the erythro. threo equilibrium composition is maintained throughout the reaction. Thus, the reaction is under thermodynamic control in the polar solvent and under kinetic control in the less polar one. 

Diene (14) reacted with a series of aldehydes under BFs-OEtz catalysis in CH2CI2 to give predominantly trans products (Table lO). " Aldol-type products, such as p-hydroxy enones, are isolated (along with dihydropyrones) from the reaction mixtures. Using TFA as a catalyst, the p-hydroxy enones are, as previously described, converted into dihydropyrones. The stereoselectivity of these reactions is consistent with a Mukaiyama-aldol reaction rather than a Diels-Aider cycloaddition. The stereochemistry of the P-hydroxy enones is also consistent with the observation that the (Z)-alkoxysilane reacts with the aldehyde in an extended transition state to give anti (threo) aldol products (Scheme 16). In the cases using ZnCh or lanthanide ions as catalysts aldol products have not been detected. 

The diastereoselectivity of the reaction was independent of the catalyst but was affected by the nature of the solvent. The threo isomer was preferentially formed in toluene, while the erythro isomer was formed in 1,2-dimethoxy-ethane. The proton-exchanged montmorillonite (H+-mont) showed similar activity and diasteroselectivity to Al3+-mont. This fact suggests that the exchangeable Al3+ cations in the montmorillonite do not function as Lewis acid sites and it is the Bronsted acid sites that are essential for catalysis of the aldol reaction. 

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