Aldol reactions with acetones

The a-alkoxy iron-acyl complex 5 may be deprotonated to generate the lithium enolate 6, which undergoes a highly diastereoselective aldol reaction with acetone to generate the adduct 7 as the major product. Deprotonation of acetone by 6 is believed to be a competing reaction 30% of the starting complex 5 is found in the product mixture48 40. 

Hoppe has extended this work to d3 reagents 159 (homoenolates - see chapter 13 for achiral versions) by the addition of a double bond.29 Lithiation occurs at C-l by removal of one of the enantiotopic protons at C-3. Aldol reaction with acetone occurs at C-3 of the complex 160 as expected for a homoenolate (chapter 13) giving a single enantiomer of the homoaldol product 161. All these reactions use an excess of sparteine. 

With 41 in hand, a two-step nitro reduction and protection, followed by partial reduction of the lactam and resulting cyclization furnished aminal 42. Further treatment with cyanogen azide generated Wcyanoamidine 43. Hydrolysis and amide protection followed by alkylation with allyl iodide yielded olefin 44 as a single diastereomer. Conversion of 44 to aldehyde 45 was the followed reaction of the mesylate with azide, a cross-aldol reaction with acetone, lactam reprotection with Boc, and trimethylphosphine-mediated reductive rearrangement to provide spiro-y-lactam 46. Methyllithium addition to lactam 46 and similar chemistry as reported by Qin et al. gave communesin F (17) (Scheme 6). 

Two independent syntheses of the naturally occurring sulphoxide carpetimycinA (C-19393 H2) have been published 134, 135). A major problem in this series is to obtain the m-stereochemistry of P-lactam protons, while introducing the hydroxyisopropyl substituent at C(6). Most methods of introducing such side-chains lead to the more thermodynamically favoured traws-compounds. Sulphenylation of the oxazine (114) to (168) was followed by the normal aldol reaction with acetone to give (169). 

Scheme 21.30 Dipeptide catalyzed ball-milled aldol reaction with acetone. ...

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

An analogous reaction has been carried out using malononitrile and different products derived by a Cross-Aldol reaction of acetone (Scheme 32). The cyclic furanimide 91 was then reacted under microwave irradiation in the presence of NaOEt with a second molecule of malononitrile to give the furanone 92 [66]. The NLO chromophore 93 was prepared using this procedure. 

Antibodies produced by this procedure were screened for their ability to react with the hapten to form the vinylogous amide 6, which has a convenient UV chromophore near 318nm, clear of the main protein absorption. Two antibodies selected in this way catalysed the expected aldol reaction of acetone with aldehyde 7 by way of the enamine 8 (Scheme 3) the remainder did not. These two effective aldolase mimics have been studied in some detail, and a crystal structure is available for (a Fab fragment of) one of them.126,281... 

Simple addition to carbonyl compounds occnrs nnder mild acidic conditions. Examples given illns-trate reaction with acetone, an aldol-like reaction, and conjngate addition to methyl vinyl ketone, a Michael-like reaction. The first-formed alcohol products in aldol-like reactions usually dehydrate to give a 3-alkylidene-3//-indolium cation. 

The first reaction involves a ketone reaction with an aldehyde under basic conditions, so enolate anion chemistry is likely. This is a mixed aldol reaction the acetone has acidic a-hydrogens to form an enolate anion, and the aldehyde is the more reactive electrophile. The reaction is then driven by the ability of the intermediate alcohol to dehydrate to a conjugated ketone. 

Munson and Haw (151) reported the first in situ NMR study of acetaldehyde in a zeolite. Figure 27 shows 13C spectra of this species reacting on HZSM-5 in the presence of water to form crotonaldehyde with high selectivity (an example of aldol condensation). We later reported a very detailed study of the aldol reactions of acetone and cyclopentanone on various zeolites (Scheme 4) (147). Dimerization of acetone followed by dehydration gives mesityl oxide (31), and the I3C isotropic shifts of this conjugated ketone are strongly dependent on state of protonation. Farcasiu and Ghen-ciu (152,153) have reported extensive measurements of the 13C shifts of 31... 

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

Diketone 4 was used for immunization, and two out of twenty monoclonal antibodies produced showed the characteristic enaminone absorb-tion at 315 nm after incubation with the diketone. Only these two antibodies, 38C2 and 33F12, were aldol catalysts (Wagner et al 1995). For example, 38C2 catalyzes the aldol reaction between acetone and aldehyde 5 to give aldol 6 with cat = 6.7 X 10 3 min-1 and = 17 (Scheme 4). 

Although typical equilibrium constants for formation of a tertiary aldol prohibit direct forward aldol synthesis (0.002 M 1 for the aldol reaction of acetone with acetophenone) (Guthrie and Wang, 1992), the retro-aldol reaction is greatly favored (a 1 mM solution of the resulting tertiary aldol is converted almost completely to acetone and acetophenone at equilibrium) (List et al., 1999). 

An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid L-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When L-proline was mixed with acetone... 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

The aldol reaction catalyzed by Ab33F12 is outlined in Scheme 5.65. Regardless of the stereochemistry at C(2) of the aldehyde substrate shown (Scheme 5.65), its antibody catalyzed reaction with acetone resulted in a diastereoselective addition of acetone to the S/ -facc of the aldehyde. The products were formed with similar yields, and thus kinetic resolution was observed. However, the degree of facial stereochemical control of the reaction is surprising, since no stereochemical information was built into the hapten. For the... 

Houk has further explored conformational factors that may play a role in determining selectivity. The proline ring can be puckered in two orientations, up 57 or down 58. Consideration of the four TSs with the up orientation and the four with the down orientation for the aldol reaction of acetone with p-nitrobenzaldehyde is necessary. The up TSs predict an ee that is too low, while the down TSs predict an... 

Sunoj also predicted the enantioselectivity offered by a series of bicyclic proline analogs in the aldol reaction of acetone with p-nitrobenzaldehyde. The two best performing catalysts are 59 and 60 both are predicted to give an ee greater than 90 percent, which exceeds the selectivity afforded by proline itself. The TS geometries all display the Houk-List characteristics. 

Tor a study of the rate and equilibrium constants in the reaction between acetone and benzaldehyde, see Guthrie, J.P. Cossar, J. Taylor, K.F. Can. J. Chem. 1984, 62, 1958. For a microwave induced reaction using aqueous NaOH, see Kad, G.L. Kaur, K.P. Singh, V. Singh, J. Synth. Commun. 1999, 29, 2583. " For some other aldol reactions with preformed enol derivatives, see Mukaiyama, T. Isr. J. Chem. 1984, 24, 162 Caine, D., in Augustine, R.L., Carbon-Carbon Bond Formation, Vol. 1, Marcel Dekker, NY, 1979, pp. 264-276. 

When 2-azidoaldehydes are used as substrates in the RAMA-catalyzed aldol reaction with dihydroxy acetone phosphate (DHAP), the azidoketones thus obtained can be reduced into the corresponding primary amines. Subsequent equilibration to imine intermediates, followed by reduction, generates the corresponding pyrrolidines (Scheme 13.16) [22,33]. 1,4-Dideoxy-1,4-imino-D-arabinitol 11 was prepared from azidoacetaldehyde. Both 2R,5R) and 2S,5R)-bis(hydroxymethyl)-(3R,4R)-dihydroxypyrrolidine (12 and 13) were derived from racemic 2-azido-3-hydroxypropanol. The aldol product resulting from kinetic control was converted into the (2R,2R) derivative 12, whereas the product resulting from thermodynamic control gave the... 

The immobilized catalyst (SiO2-[bmim]BF4-L-prohne, 70) displayed higher enantioselectivity (64% ee) with acceptable activity (51% yield) than the homogeneous conditions (60% ee, 62% yield) in the aldol reaction of acetone and benzaldehyde [71b]. Additionally, this system was even more efficient than the PEG-prohne-... 

In the same way, the fluorous proline-derivative 7 (see Scheme 5.4) was applied as a catalyst (30mol%) in the intermolecular aldol reaction between acetone and p-nitrobenzaldehyde in BTF as a solvent. The chemical yield (72%) and enantioselectivity (73% ee) were fuUy comparable to those obtained with proline in dimethyl sulfoxide (DMSO), but attempts to recover and reuse the fluorous catalyst failed [35]. 

Commercially available Amberlite IR-120 (H -form) was used as an acid catalyst this resin is a divinylbenzene-crosslinked partially sulfonated gel-type polystyrene. As a base catalyst, PEG-PS resin-supported proline was employed. The reaction was performed in water-acetone-tetrahydrofuran (1 1 1 v/v/v) at room temperature in the presence of 20 mol. % of resin-supported proline and Amberlite. After 20 h, the reaction mixture contained the starting 4-nitro-benzaldehyde dimethyl acetal, 4-nitrobenzaldehyde and the corresponding aldol product with acetone in a ratio of 4 9 87. This means that both the... 

The aldehyde was then used in an aldol reaction with the anion from 3-isopropylbut-2-enolide. [The lactone was prepared in the following way bromination of 3-methyl-2-butanone under kinetic conditions (-15 °C) afforded the 1-bromo derivative. The bromine was displaced by acetate on refluxing a solution in acetone with anhydrous KOAc. Reaction of the resulting keto-acetate with the anion from triethylphosphonoacetate afforded the desired butenolide in 55% yield.] The anion was generated in tetrahydrofuran from the butenolide and lithium diisopropylamide and was cooled to -78 °C before addition of the aldehyde. The temperature was maintained below -70 °C for 5h and the reaction was quenched with ammonium chloride at this temperature. Under these conditions (kinetic) the 22R23R intermediate (3) was obtained in 65% yield (26). 

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