Intermolecular aldol condensation

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

Syntheses in this category consist of intermolecular thioalkylation of 5-oxo+,5-dihydro-pyrazole-l-carbothioic acid phenyl amides 253 followed by intramolecular aldol condensation to give substituted pyrazolothiazole-type compounds 254 (Equation 111) < 1998PS119>. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Compared to the intramolecular reactions that benefit, at least for a small part, from a favorable thermodynamic component due to the formation of a cyclic product, intermolecular additions of enolates to alkenes are rather challenging and constitute the so-called olefinic version of the aldol condensation 281. 

Borrelidin 1 has attracted attention because it inhibits angiogenesis, and so potentially blocks tumor growth, with an IC of 0.8 nM. Retrosynthetic analysis of 1 led the investigators to the prospective intermediates 2 and 3. To assemble these two fragments, they interatively deployed the elegant enantio- and diastereoselective intermolecular reductive ester aldol condensation that they had recently developed. This transformation is exemplified by the homologation of 4 to 6 catalyzed by the enantiomerically-pure Ir complex 5. 

Intermolecular Michael reactions continue to be developed. Karl Anker Jorgensen of Aarhus University, Denmark, has found (Angew. Chem. Ini. Ed. 2004,43, 1272) that the organocatalyst 3 mediates the addition of 2 to 1 with high enantiomeric excess. What is more, under the reaction conditions the intial Michael addition is followed by an aldol condensation, to give 4 as essentially a single diastereomer. 

The reaction is carried out in vapour phase (250°C) using a flow system (see methods section). This procedure turned out to be essential in order to mantain the hydrogen transfer as the main reaction pathway. A batch experiment carried out in an autoclave actually showed a wide range of condensation products besides some saturated ketone [6]. Reactions of ketones over oxide catalysts can lead to a variety of products due inter alia to aldol condensation, intramolecular dehydration and intermolecular disproportionation [16]. However, the presence of a good hydrogen donor such as a secondary alcohol and vapour phase conditions favour the transfer hydrogenation as the major reaction [16,17]. In our reaction conditions, products attributable to crotonic condensations and subsequent 1,4 Michael addition [18] were observed by g.l.c.-m.s. (Table 1). 

Rate and equilibrium constants have been measured for representative intramolecular aldol condensations of dicarbonyls.60a For the four substrates studied (32 n = 2, R = Me n = 3, R = H/Me/Ph), results have been obtained for both the aldol addition to give ketol (33), and the elimination to the enone (34). A rate-equilibrium mismatch for the overall process is examined in the context of Baldwin s rales. The data are also compared with Richard and co-workers study of 2-(2-oxopropyl)benzaldehyde (35), for which the enone condensation product tautomerizes to the dienol60b (i.e. /(-naphthol). In all cases, Marcus theory can be applied to these intramolecular aldol reactions, and it predicts essentially the same intrinsic barrier as for their intermolecular counterparts. 

Detailed analysis of the rate and equilibrium constants determined for both phases of intramolecular aldol condensation reactions (13 —>15, 16—>18, and 19—>21) in terns of Marcus theory, has established that the intrinsic barriers for die intramolecular reactions are the same as those determined previously for the intermolecular counterparts.31 Consequently, rate constants for intramolecular aldol reactions are predictable from the energetics of the reactions and the effective molarity can be calculated. An associated discussion of Baldwin s rales suggests that they are a consequence of the need to achieve a conformation from which reaction can take place... 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

This procedure illustrates a general method for preparing a wide range of spirocyclohexenones and hence spirocyclohexadienones. A number of intramolecular and intermolecular reactions are known to give spirodi-enones however, these methods have limited synthetic application.2 This procedure is superior3 to that developed by Bordwell and Wellman,4 for side reactions such as aldol condensation of the aldehyde and polymerization of methyl vinyl ketone are avoided. These spirodienones are useful intermediates in the synthesis of paracyclophanes.5 6... 

Since simple aliphatic aldehydes readily undergo aldol condensation under basic conditions, their intermolecular a-arylation is not successful. However, the intramolecular reaction is possible (Eq. 20) [59]. It is interesting that an unusual cyclization product via cleavage of the aldehyde C-H bond is observed in addition to the normal a-arylation product. Other examples of this kind of arylation are described in Sect. 3.3. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

I, 5-dicarbonyl compounds and their interesting and varied chemistry, e.g., the formation of cyclohexenones from aldol condensation of the products. As an extension of the de Mayo reaction (the photocycloaddition of enolated /i-diketones to double bonds) enol esters, enol ethers, vinylogous esters and amides, and dioxinone have been employed as the enone components. Some intermolecular examples have already been discussed in Section 1.6.1.4.2.1.6. (cf. Table 4, entries 2 and 3) and some intramolecular systems are collected in Table 5, entries 10,... 

Warwel et al. [27] synthesized 1,8-nonadiene in 75 % yield via ethenolysis of cy-cloheptene over a Rc207/Al203 catalyst (at 60 °C and an ethene pressure of 80 bar). The diene was subsequently subjected to intermolecular metathesis (release of ethene), again over a rhenium oxide catalyst (at 35 °C and 15 torr vacuum), giving 80% yield of 1,8,15-hexadecatriene. The latter was converted, via oxidation, intramolecular aldol condensation, and hydrogenation, to muscone (3-methylcyclo-pentadecanone), an important perfume ingredient. 

The tin(IV) enolate can be quenched with a variety of electrophiles to form new carbon-carbon bonds, including carbonyl addition (aldol-type) reactions, alkylations and conjugate additions of tin(IV) enolates. Tin(IV) enolates react readily with aldehydes in both intra- and intermolecular aldol-type reactions [5J]. The best conditions for the intermolecular aldol condensation reaction were to initially generate the tin enolate by reacting the desired enone with tributyltin hydride and then... 

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