Intramolecular aldol reaction mechanism

The selectivity observed in the intramolecular aldol reaction of 2,5-hexanedione is due to the fact that all steps in the mechanism are reversible, so an... 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

The following reaction involves an intramolecular Michael reaction followed by an intramolecular aldol reaction. Write both steps., and show their mechanisms. 

The second stage is the formation of a new enolate on the other side of the ketone from the first. Note that the original enolate, the intermediate in the conjugate addition, can cyclize to give only an unstable four-membered ring so this cyclization would be reversible, The next intermediate, the aldol product, is often isolated from Robinson annelations, the Robinson annelation mechanism—stage 2 the intramolecular aldol reaction... 

Agami C, Puchot C (1986) Kinetic analysis of dual catalysis by proline in an asymmetric intramolecular aldol reaction. J Mol Catal 38 341-343 Agami C, Puchot C, Sevestre H (1986) Is the mechanism of the proline-cata-lyzed enantioselective aldol reaction related to biochemical processes Tetrahedron Lett 27 1501-1504... 

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

Clemente FR, Houk KN (2004) Computational evidence for the enamine mechanism of intramolecular aldol reactions catalyzed by praline. Angew Chem Int Ed Engl 43 5766-5768... 

Apart form the aforementioned highly enantioselective hetero-Diels-Alder reactions, that proceed with very low catalyst loadings, the catalytically accessible enolates have also been used for related intramolecular Michael reactions (Philips et al. 2007) and for the desym-metrization of 1,3-diketones yielding cyclopentenes via an intramolecular aldol reaction (Wadamoto et al. 2007). The formation of cyclopentenes, however, presents a special case, so—depending on the stereochemical nature of the enone substrates (s-cis or s-trans) and the stereochemistry of the final products—two different mechanisms are discussed in the literature. Whereas /ran.v-cycl open (cries are proposed to be available upon conjugate addition of a homoenolate to chalcones,... 

Prior to the determination of the aldolase mechanism and the development of catalytic antibodies for the aldol reaction, Hajos and Parrish and independently Wiechert et al. discovered that (5)-proline catalyzes the intramolecular aldol reaction of cyclic triketones (Scheme 6.7). This is not only a catalytic effect the reaction proceeds with high yields and large enantiomeric excess. 

Mechanism of Proline-Catalyzed Intramolecular Aldol Reactions... 

The mechanism of intramolecular aldol reactions is similar to that of inter-molecular reactions. The only difference is that both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule. One complication, however, is that intramolecular aldol reactions might lead to a mixture of products, depending on which eiiolate ion is formed. For example, 2,5-hexanedione might yield either the five-membered-ring product 3-methyl-2-cyclopentenone or the three-membered-ring product (2-methyl-cyclopropenyl)ethanone (Figure 23.4). In practice, though, only the cycio-pentenone is formed. 

The mechanism of the Robinson annulation consists of two parts a Michael addition to the a,p-unsaturated carbonyl compound to form a 1,5-dicarbonyl compound, followed by an intramolecular aldol reaction to form the six-membered ring. The mechanism is written out in two parts (Mechanisms 24.7 and 24.8) for Reaction [2] between methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. 

In theory, the intramolecular aldol reaction of 6-oxoheptanal could yield the three compounds shown. It turns out, though, that 1 -acetylcyclopentene is by far the major product. Why are the other two compounds formed in only minor amounts Draw a stepwise mechanism to show how all three products are formed. 

On the basis of Kiyooka s working hypothesis for the aldol reaction mechanism, the reduction proceeds via by an intramolecular hydride transfer this is accelerated by matching between the chirality of the promoter and that of the newly formed aldol (Eq. 50). An alternative mechanism without chelation is also possible, and involves hydride delivery to the preferred O-silyl oxocarbenium ion conformer (Eq. 51). 

For once, you could have worked out the structure fi-om the mechanism, though this is generally a good idea. Only the ketone can enolize and it must react with the aldehyde intramolecular aldol reaction followed by dehydration. 

The selectivity observed in the intramolecular aldol reaction of 2,5-h anedione is due to the fact that all steps in the mechanism are rever and an equilibrium is reached. Thus, the relatively strain-free cyclopentenoi product is considerably more stable than the highly strained cycloprop alternative. For similar reasons, intramolecular aldol reactions of 1,5 ketones lead only to cyclohexenone products rather than to cydobutenea. ... 

The mechanism of these intramolecular aldol reactions is similan that of inlermolecular reactions. The only difference is that both the nu philic carbonyl anion donor and the electrophilic carbonyl acceptor are in the same molecule. 

The Robinson annulation has three distinct steps the Michael addition of the enol or enolate across the double bond of the a,(3-unsaturated ketone to produce a 1,5-diketone (Michael adduct), followed by an intramolecular aldol reaction, which affords a cyclic (3-hydroxy ketone (keto alcohol), and finally a base-catalyzed dehydration which gives rise to the substituted cyclohexenone. An alternative mechanism via disrotatory electrocyclic ring closure is possible. ... 

On the basis of the structures of the three isolated important intermediates 119-121, we proposed a reaction mechanism for the production of lactone 114 (Scheme 41). In this mechanism, catalytic amounts of water or TfOH would play an important role. Oxonium 120 may be obtained by an intramolecular aldol reaction of the intermediate 122. Compound 122 may be derived from olefin 119 by acidic hydration, subsequent fragmentation, and isomerization. Oxonium 120 may undergo intramolecular cyclization to give acetal 123 then fragmentation... 

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