3- Pentanone aldol reaction

Problem 23.2 Using curved arrows to indicate the electron flow in each step, show how the base-catalyzed reverse aldol reaction of 4-hydroxy-4-methyi-2-pentanone takes place to yield 2 equivalents of acetone. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

A jy -diastereoselective aldol reaction based on titanium enolates from (A)-l-benzyloxy-2-methyl-3-pentanone was developed by Solsona et al. (Equation (12)).64 The titanium enolate of this chiral ketone afforded the corresponding syn-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes. 

Furthermore, this reaction was applied to the aldol reaction of 3-pentanone. When the chiral oxazolidine was prepared from 3-pentanone and the aldol reaction was carried out by the same procedure, the a, 6-anti 6-hydroxy ketones were produced predominantly over the syn-isomer 8i with excellent optical purities.(5) (See Table 2.)... 

The aldol reaction of 3-pentanone with acetaldehyde provides an example52 of control by an external chiral ligand 9. The relative configuration at the newly created stereogenic centers (syn vs. anti) of the adduct 10 was determined by NMR, while the absolute configuration was assigned by a chemical correlation (see p 452)101 -I02. 

Aldol reactions.1 The chiral oxazolidine (1), formed from 3-pentanone and (-)-norephedrine, after conversion to the tin azaenolate reacts with aldehydes to give predominantly anti-aldols (2) in >90% ee. Reduction of the carbonyl group of the anti-aldol 2 provides (3S,4R)-4-methyl-3-heptanol (3) in 95% ee. 

In a more recent approach (Scheme 11), Schin-zer solved the problem of the C4-C5 retro-aldol reaction with Braun s (S)-HYTRA (51) [44] by replacing the keto group in /(-ketoaldehyde 49 with a C=C double bond cf. 52, derived in four steps from ethyl-2-bromo-Ao-butyrate and 3-pentanone in 13% overall yield). The thus formed intermediate 53 is later deprotected and cleaved oxidatively to give the desired C5 ketone 7 in 52 % yield and 96 % ee from aldehyde 52 [22]. 

Figure 15 Hapten 49, a hybrid of transition state analog and reactive immunization, elicited antibody 93F3 that catalyzes the aldol reaction of ketone 51 with 3-pentanone.

Paterson et have prepared the enolate of 3-pentanone, an achiral ketone, with (-( )- or (-)-IpcaBOTf and have found that its aldol reactions with various aldehydes proceed with high syn.anti ratios (>9 1) and respectable enantioselectivities (5 1-20 1) (Scheme 44). High degrees of asymmetric induction are noted with unhindered aldehydes, llie combination of the chiral ethyl ketone (104) and (-t-)-Ipc2BOTf constitutes a matched pair, which enhances the diastereofacial selectivity of the resulting enolate (compared to that obtained with an achiral boron reagent), and provides via aldol reactions high... 

Because the steps in an aldol addition mechanism are readily reversible, a tetro-aldol reaction can occur that converts a jS-hydroxy aldehyde or ketone back to the precursors of an aldol addition. For example, when 4-hydroxy-4-methyl-2-pentanone is heated with hydroxide in water, the final equilibrium mixture consists primarily of acetone, the retro-aldol product. 

The carbon-carbon bond cleavage step in a retro-aldol reaction involves, under basic conditions, a leaving group that is an enolate, or under acidic conditions, an enol. Write a mechanism for the retro-aldol reaction of 4-hydroxy-4-methyl-2-pentanone under basic conditions (shown above). 

As mentioned before [14c], the use of 3-pentanone as nucleophiles in the direct aldol reaction with aldehydes failed. As an alternative, tetrahydro-4/f-thiopyran-4-one (14) can be used to give mainly the expected products anti-15 (Scheme 4.5), giving after reductive desulphurization using Raney nickel (W-2), the corresponding 5-hydroxy-4-methylpentanone [27]. 

Draw the product of the crossed aldol reaction between benzaldehyde and 3-pentanone and the product formed by its base-catalyzed dehydration. 

First, recognize that the two carbonyl-containing compounds to be joined in the aldol reaction are 3-pentanone and acetaldehyde. Treat the symmetrical ketone with LDA to form its lithium enolate. Treatment of this enolate anion with acetaldehyde followed by aqueous workup gives the desired aldol product. 

As already noted, the aldol reaction is reversible (Schemes 9.41 and 9.42, et seq) but it is possible to adjust the conditions (low temperature, rapid workup) so that the kinetic enolate anion (frequently (Z)-) leads to a kinetic product. Alternatively, higher temperatures and longer reaction times lead to the thermodynamic product. As shown in Scheme 9.47, when the enolate anion of 2,2-dimethyl-3-pentanone is... 

Ketones can undergo the aldol reaction too, and the mechanism is similar to that for the aldol condensation of aldehydes. We will use acetone as an example (Fig. 19.72). In base, the enolate is formed first, and adds to the electrophilic carbonyl compoimd. Protonation by water yields a molecule once known as diacetone alcohol, 4-hydroxy-4-methyl-2-pentanone. 

In the real world of practical organic synthesis, one rarely needs to do a simple aldol condensation between two identical aldehydes or two identical ketones. Far more common is the necessity to do a crossed aldol between two different aldehydes, two different ketones, or an aldehyde and a ketone. As noted earlier, there are difficulties in doing crossed aldol reactions. Suppose, for example, that we want to condense 2-pentanone with benzaldehyde. Benzaldehyde has no a hydrogen, so no enolate can be formed from it. Some version of the Claisen-Schmidt reaction (p. 984) seems feasible. But 2-pentanone can form two enolates, and the first problem to solve is the specific formation of one or the other enolate (Fig. 19.127). 

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