Aldol reactions features

The synthesis of polypropionate by the (3-ketoimide-aldol reaction features the subsequent stereoselective reduction of the (3-ketone. As shown in the total synthesis of 6-deoxyerythronolide B 59 (Scheme 8.8), aldol adduct... 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

Montmorillonite K10 was also used for aldol the reaction in water.280 Hydrates of aldehydes such as glyoxylic acid can be used directly. Thermal treatment of K10 increased the catalytic activity. The catalytic activity is attributed to the structural features of K10 and its inherent Bronsted acidity. The aldol reactions of more reactive ketene silyl acetals with reactive aldehydes proceed smoothly in water to afford the corresponding aldol products in good yields (Eq. 8.104).281... 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

One of the key features of such stereocontrolled aldol reactions is the predictability of the absolute stereochemistry of the enantiomers (or diastereo-mers) that will be formed as the major products. The preferred intermediate for an archetypal aldol reaction, proceeding by way of a metal enolate, can be tracked using the Zimmerman Traxler transition state and the results from the different variations of the aldol reaction can be interpreted from similar reasoning, and hence predictions made for analogous reactions1129]. 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

One interesting feature here is that both acetyl-CoA and oxaloacetic acid have the potential to form enolate anions, and that oxaloacetic acid is actually more acidic than acetyl-CoA, in that there are two carbonyl groups flanking the methylene. That citrate synthase achieves the aldol reaction as shown reflects that the enzyme active site must have a basic residue appropriately positioned to abstract a proton from acetyl-CoA rather than oxaloacetic acid, thus allowing acetyl-CoA to act as the nucleophile. 

Note that harsher conditions may lead to further changes, e.g. epimerization at C-3 in fmctose, plus isomerization, or even reverse aldol reactions (see Section 10.3). In general, basic conditions must be employed with care if isomerizations are to be avoided. To preserve stereochemistry, it is usual to ensure that free carbonyl groups are converted to acetals or ketals (glycosides, see Section 12.4) before basic reagents are used. Isomerization of sugars via enediol intermediates features prominently in the glycolytic pathway of intermediary metabolism (see Box 10.1). 

The present procedure is based on the original report by the author and co-workers, and utilizes the characteristic features of the boron-mediated aldol reaction of carboxylic... 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

Aldol reactions provide a valuable synthetic method for forming carbon-carbon bonds. They can be adapted to extend the length of a carbon chain, to form cyclic compounds, and to provide intermediates that can be transformed into more useful materials. An important feature of these intermediates is that functional groups useful for later reactions are located close to or on the carbons of the newly formed C-C bond. There is an almost bewildering number of variations on the aldol reaction and we shall not mention all of them. The main thing to recognize in all of these reactions is that the acceptor molecule always is a carbonyl compound, best an aldehyde, sometimes a ketone, even an ester (see Section 18-8E). The donor molecule is some type of carbanion usually, but not always, an enolate anion. However, any substance that has a... 

Figure 8C.8. Kinetic feature of two-directional aldol reaction.

The basic principles of the mechanism of this Lewis-base-catalyzed aldol reaction have already been described in Section 6.2.1.1. With regard to the course of the enantio- and diastereoselective formation of aldol adducts with two stereogenic centers, it is proposed that synthesis of anti-products proceeds via a chair-like transition structure. A distinctive feature of the cationic transition state complex is a hexacoordinated silicon atom bearing two chiral phosphoramide molecules as ligands (Scheme 6.30). 

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

Stereocontrol of aldol reactions of 4-phenylsulfanyltetrahydrothiopyran-4-carbaldehyde 283 forms an essential feature of syntheses of l-oxa-8-thiaspiro[4.5]decanes (Scheme 38) <1996TL4581>. 

In addition to broad-scope substrate specificity, 38C2 exhibits high enantioselectivity for the aldol reaction. Although this high degree of enantioselectivity has been observed for antibody-catalyzed ester hydrolysis reactions, it is certainly not a feature common to all such catalysts (Janda et al., 1989 Lo et al., 1997 Pollack et al., 1989 Tanaka et al., 1996 Wade and Scanlan, 1996). Furthermore, the rules for the enantioselectivity for 38C2-catalyzed aldol reactions are both simple and general (Hoffmann et al., 1998). For most ketone donors, attack occurs on the si side of the acceptor. However, when a ketone with an a-hydroxy substituent (such as hydroxyacetone) acts as donor, attack occurs on the reside (Scheme 5). 

The main class of electrophiles which reacts on the sulfur atom of enethiolates are alkyl halides. This was applied by Vallee and Tchertchian [121] in a one pot synthesis of hydroxy-ketenedithioacetals which elegantly uses the preceding features. Deprotonation of alkyl dithioacetates by LDA at -78 °C provided enethiolates which were treated by aldehydes. Comparable to the case of enolates, the aldol reaction takes place on the carbon atom. When water is added to the reaction mixture, 3-hydroxyalkanedithioates are obtained. However, if the quench is replaced by an alkyl halide addition, hydroxyketenedithioacetals are obtained. Formation of these compounds... 

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