Aldol-cyclisation reaction

On the other hand, another cooperative catalysis approach was developed by Oh and Kim with a highly diastereo- and enantioselective domino aldol-cyclisation reaction occurring between aldehydes and methyl a-isocyanoacetate. The process employed a combination of a chiral cobalt complex derived from brucine amino diol and an achiral thiourea. The reaction was applicable to a range of aliphatic, aromatic and heteroaromatic aldehydes, providing the corresponding chiral oxazolines in good yields and diastereoselectivities of up to >90% de combined with good to excellent enantioselectivities of up to 98% ee, as shown in Scheme 7.12. 

In 2010, Shibata and co-workers developed an enantioselective enamine-trifluoropyruvate domino aldol-cyclisation reaction to yield chiral pyrroli-dones. Several commercially available derivatives of cinchona alkaloids were screened in combination with Ti(Oi-Pr)4. Hydroquinine diether ((DHQD)2AQN) was found to be the best ligand and afforded the products in high yields and enantioselectivities of up to 92% ee, as shown in Scheme 7.19. Using this system, five cyclic enamines with different protecting groups were screened with remarkable results. The enantiomers of the products were also accessible by applying the pseudoenantiomeric cinchona alkaloid. 

Scheme 7.19 Domino aldol-cyclisation reaction catalysed by chiral cinchona catatysis and titanium catalysis.

Until 1968, not a single nonenzymic catalytic asymmetric synthesis had been achieved with an enantiomeric excess above 50%. Now, the intramolecular aldol cyclisation, catalyzed by chiral amino acids has proven to be a very useful synthetic tool. This reaction was extensively covered by two reviews 23,68). Two more papers 72 published recently, should also be cited. 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

Scheme 4.9 Domino aldol-type/cyclisation reaction of aldehydes with isothiocyanatooxindoles.

Finally, aldol reactions can, with suitable dicarbonyl compounds, e.g. (99), be intramolecular, i.e. cyclisations ... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

Combining aldol and Michael reactions in one sequence is very powerful, particularly if one of the reactions is a cyclisation. The Robinson annelation9 makes new rings in compounds like 73 that were needed to synthesise steroids. Disconnection of the enone reveals triketone 74 having 1,3- and 1,5-dicarbonyl relationships. The 1,3-disconnection would not remove any carbon atoms but the 1,5-disconnection at the branchpoint gives a symmetrical 3-diketone that should be good at conjugate addition. 

Chalcones such as 80 are very easily made by an aldol reaction between acetophenone and benzaldehyde conjugate addition of the enolate of 81 and cyclisation occur all in the same reaction.15 The ester 82 is formed as a mixture of diastereomers in high yield hydrolysis and decarboxylation give 78. 

In the synthesis we should not wish to make 21 as it would cyclise and, in any case, we d rather reduce nitrile, nitro and alkene all in the same step by catalytic hydrogenation. The very simple method used for the conjugate addition is possible only because of the slow aldol reaction of the hindered aldehyde 24. The aldol 25, also called a Henry reaction, needs a separate dehydration step but the three functional groups in 26 are reduced in one step in good yield.7... 

The sequence of cyclohexene cleavage and aldol reaction on the dicarbonyl product gives ring-contracted cyclopentenes. This proved particularly valuable when Iwata6 wanted to make subergorgic acid 41 that has three five-membered rings awkwardly joined around a quaternary carbon atom. So crowded are these compounds that they are difficult to draw clearly. Ozono-lysis of the synthetic cyclohexene 38 gave the unstable dialdehyde 39 that cyclised by an aldol condensation to 40 and hence could be oxidised to 41. 

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