Enantioselectivity tandem aldol reaction

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

Scheme 7.14. Enantioselective tandem conjugate addition-aldol reactions.

Very recently, a catalytic enantioselective route to prostaglandin i methyl ester was developed based on a tandem 1,4-addition-aldol reaction [84]. 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

Scheme 9.10. Catalytic enantioselective tandem Michael-aldol reaction.

Scheme 9.11. Catalytic enantioselective tandem conjugate addition-aldol reaction of dialkylzincs.

Wang and coworkers found that the quinine-derived thiourea catalyst 81b (1 mol%) was also highly reactive and enantioselective for the tandem thio-Michael-aldol reaction of various 2-mercaptobenzaldehydes (103) with a,P-unsaturated oxazolidi-nones (104), furnishing benzothiopyranes (105) with three stereogenic centers in... 

Krische disclosed an intramolecular tandem 1,4-addition/aldol process in the presence of water (Scheme 8.40) [118]. Here, the rate of the aldol cyclization was faster than the competing hydrolysis of the rhodium enolate, so that 150 was isolated in 88% yield and 88% enantioselectivity. The configuration observed for the aldol reaction could be accounted for by the Zimmerman-Traxler-type transition state of the (Zj-enolate. 

SCHEME 11.44. Enantioselective tandem O-nitroso aldol/Michael reaction. 

This methodology has also been applied by Backvall s group to the DKR of S-hydroxyesters. The reaction was carried out in tandem with an aldol reaction and the jS-hydroxyester formed, after neutralisation, underwent DKR using a combination of Novozym 435 and Shvo s ruthenium catalyst, as shown in Scheme 4.2. Excellent enantioselectivities of up to 99% ee were obtained, albeit associated with moderate to good yields for the expected acetates. 

Hydroformylation of olefins has been established as an important industrial tool for the production of aldehydes. In recent years, novel asymmetric tandem reactions have included a rhodium-catalysed enantioselective hydroformylation. In this context, in 2007 Abillard and Breit ° and Chercheja and Eilbracht independently reported a novel domino hydroformylation-aldol reaction catalysed by an achiral rhodium catalyst and L-proline catalyst (Scheme 7.49). Possibly owing to the fact that proline is hard but the rhodium catalyst is soft, the proline can be compatible with the rhodium catalyst to allow this domino reaction to be achieved. By fine adjustment of the hydroformylation rate to that of the L-proline-catalysed aldol addition, the undesired homodimerisation of the aldehyde could be avoided. As a result, by in situ hydroformylation reaction, the donor aldehyde of a... 

Xu, Y.-J., Liu, Q.-Z., Dong, L. (2007). Copper-catalyzed enantioselective tandem conjugate addition/A-nitroso aldol reaction. Synletf 273-277. 

Lee, S. L, Jang, J. H., Hwang, G.-S., Ryu, D. H. (2013). Asymmetric synthesis of a-aUcylidene-fS-hydroxy-Y-butyrolactones via enantioselective tandem Michael-aldol reaction. Journal of Organic Chemistry, 78, 770-775. 

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