Ketoaldehyde aldol reaction

The samarium-catalyzed reduction was utilized in the asymmetric synthesis of the marine macrolide bryostatin 2 (42) to furnish an intermediate (46)12 (Scheme 4.21). The ketone 43 underwent an aldol reaction with the ketoaldehyde 44 via the isopinylboryl enolate to give the aldol adduct 45 in good yield and 93 7 diastereoselectivity. Subsequent samarium-catalyzed Evans-Tishchenko reduction of the (3-hydroxy ketone 45 provided the p-nilrobenzoale 46 with excellent stereoselectivity. Silylation and saponification readily converted compound 46 into the alcohol 47 in 88% yield over two steps. 

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]. 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

The synthesis involved the formation of an enamine 46 from the aldehyde 45 and alkylation with chloroacetone to give the ketoaldehyde 43. Then events took a twist. Aldol reaction under equilibrating conditions (KOH, THF, H20) gave 41 rather than 42. 

In many reactions there is an equilibrium between reactants and products so that only the more stable of the two alkenes is produced. In the Claisen ester condensation of cyclohexanone 8 with ethyl formate, the true product under the conditions of the reaction is the stable enolate 9 and this is reversibly protonated on workup to give the more stable H-bonded enol of the ketoaldehyde Z-10. In the aldol reaction between the same ketone and benzaldehyde, the initial product 7 gives the enolate 6 and dehydration is reversible only the more sterically favourable E isomer of 5 is formed. Note that it is irrelevant that the aldol 7 is a mixture of diastereoisomers all stereochemistry is lost in the formation of the enolate 6. In later parts of this chapter a more specific relationship between 3D and 2D stereochemistry will be established. 

The aldol reaction of 6 proceeded analogously to that of the model ketoaldehyde 12, although in lower yield. Treatment of crude 6 with Kr-BuO in t-BuOH followed by a cleavage-step of the Boc group provided 41% of a unseparated mixture of the desired aldol adduct 25 and the bad regioisomer 27, compound 26 being isolated in 16% yield. The use of NaOMe in MeOII in this process did not improve the yield of the desired compound 25. 

Ketoaldehyde (55) undergoes a hydroxide-catalysed intramolecular aldol reaction. Initial deprotonation gives an enolate. This step has been shown to be effectively irreversible by determination of the rate constant ratio for the two possible fates of the... 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

Other removal procedures include reaction of the bicyclic lactam 4 with hydride (R6 = H) or an alkyl metal (R6 = alkyl). After hydrolysis of the bicyclic azahemiketal 5, ketoaldehydes or diketones 6 result. These can then be used in intramolecular aldol-type reactions to furnish enantiomerically pure cyclopentenones 7 (n = 1). The same reaction sequence can be used to prepare cyclohexenones (see Table 9)3-6 7l 1 ... 

Oxygen-bridged dioxocin 213 reacted with methanolic NaOH to give the enone 214 in 90% yield. The reaction went through the intermediacy of the ketoaldehyde 215 by cleavage of the 0-0 bond (Scheme 43). The base catalyzed not only the deformylation but also the aldolization and dehydration. When the base was added to the corresponding nonacetylated derivative obtained from the crude ozonolysis mixture, the yield was 42% <1995JA9927>. 

Chiral 2-substituted benzaldehyde chromium tricarbonyl complexes have been reacted with chloroacetophenone in the presence of KO-fert-Bu [544], After decomplexation, the E-epoxyketone is obtained with a high selectivity (Figure 6.88). This Darzens reaction with ClCF COO-tert-Bu is poorly stereoselective. Condensation of the same aldehydes with methyl aaylate or acrylonitrile in the presence of DABCO, followed by decomplexation, also leads highly selectively to P-hydroxyesters or -nitriles 6.105 (Y = COOMe or CN) [547] (Figure 6.88). An anti aldol product is also obtained with a high selectivity from a chromium complex and the titanium enolate of PhCF OCF COS-tert-Bu at -78°C [1281, 1282], Chiral aminals of a-ketoaldehydes react with lithium or sodium enolates of ethyl acetate. After treatment with acid, compounds 6.106 are obtained with a high enantiomeric excess (Figure 6.88). 

Fukuyama also presented an alternative route to the advanced intermediate 114 as shown in Scheme 18 with an early introduction of the protected amino functionality. Reaction of y-butyrolactone with the Grignard reagent derived from 1,4-dibromobutane (120) afforded diol 121. Mesylation of the primary hydroxyl functionality with concomitant elimination of the tertiary one was followed by reaction with methylamine and protection of the resulting secondary amine to give alkene 122. Ozonolysis of the double bond in 122 and subsequent intramolecular aldol condensation of the resulting ketoaldehyde afforded cycohexenone 123. Rubottom oxidation and acetylation gave 124, which served as substrate in the lipase-... 

Other proposals [698] need allyl acetyl acetone 331 (or its ketal 332 of one carbonyl group). Addition of chlorocarbene to the free carbonyl gives the epoxide 333, which, under the strongly basic conditions of this reaction, rearranges to a highly functional ketoaldehyde 334, ready for aldol condensation to allethrolone (Reaction scheme 232) at a different position to that in the La Forge synthesis. 

A more smeUy reaction in scheme 234 consists of the a-allylation of an arylmercapto acetone 338 and anionic addition of this activated tertiary carbon to a-nitropropene yielding 339. Alkahne treatment triggers the Nef reaction to give a ketoaldehyde 340, similar to Reaction scheme 232 [702, 703,704]. Strong basic conditions cause internal aldol condensation and ehmination of thiophenol. 

In an intramolecular case, it was shown that, in an aqueous medium, the nature of the acidic or basic catalyst had a dramatic effect on the outcome of the aldolisation (Denmark and Lee, 1992). Acid-induced aldol condensation of ketoaldehyde 1 provided the syn hydroxyketone 2, while the anti isomer 3 arose from base-catalyzed reactions ... 

The aqueous medium influences not only the reaction rate but also the stereoselection of the aldol addition. One significant example [13] is the intramolecular cyclization of ketoaldehyde depicted in Scheme 7.2. In organic solvents there is a preference for syn or anti adduct depending on the presence of coordinating cations (K, Na, Li, MgBr ) or a complexing agent such as... 

Real-time ultrafast 2D NMR observations of an acetal hydrolysis at natural abundance have enabled observation of the reactive hemiacetal intermediate. Mutual kinetic enantioselection (MKE) and enantioselective kinetic resolution (KR) have been explored for aldol coupling reactions of ketal- and dithioketal-protected -ketoaldehydes expected to have high Felkin diastereoface selectivity with a chiral ketone enolate. ... 

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