One-pot multi-step synthesis

Broadwater, S.J., Roth, S.L., Price, K.E., Kobaslija, M., McQuade, D.T. (2005) One-Pot Multi-Step Synthesis A Challenge Spawning Innovation. Organic and Biomolecular Chemistry, 3, 2899-2906. 

Microwave-induced imine formation, subsequent reduction with NaBH(OAc)3 and cyclisation of the resulting amino acid with isothiocyanates was used in an efficient one-pot multi-step synthesis of thiohydantoins (Scheme 4.26). The reductive animation was conducted as a two-step procedure to avoid direct reduction of the aldehyde at high temperatures48. 

Seki T, Grunwaldt J-D, Baiker A (2007) Continuous catalytic one-pot multi-step synthesis of 2-ethylhexanal from crotonaldehyde. Chem Commun 34 3562-3564... 

Fig. 8.1 One-pot multi-step synthesis. (From SJ. Broadwater, S.L Roth, K.E. Price, M. Kobaslija, D.T. McQuade, One-pot multi-step synthesis a challenge spawning innovation, Org. Biomol. Chem. 3 (2005) 2899-2906. Copyright 2005 Royal Society of Chemistry).

One-Pot Multi-Step Enzymatic Synthesis of 2 -Deoxyribonucleoside from Glucose, Acetaldehyde and a Nucleobase... 

Previously we pointed out that the oxidation of alkenes in water allows one-pot multi-step reactions to be carried out involving tandem epoxidation and ring-opening reactions. Further examples are the synthesis of optically active trifluorolactic acid by aqueous nitric acid ring-opening oxidation of (-)-l,2-epoxy-3,3,3-trifluoropropane [19] in the presence of a catalytic amount of copper metal ... 

An impressive one-pot six-step enzymatic synthesis of riboflavine from glucose on the laboratory scale has been reported with an overall yield of 35-50%. Six different enzymes are involved in the various synthesis steps, while two other enzymes take care for the in situ cofactor regenerations [12]. This example again shows that many more multi-enzyme cascade conversions will be developed in the near future, as a much greater variety of enzymes in sufficient amounts for organic synthetic purposes will become available through rapid developments in genomics and proteomics. 

So far only we have scratched the surface of what might be possible with polymer-bound reagents in multi-step organic synthesis. We believe it is possible to use these reagents in many elaborate one-pot multi-reagent combinations, even with the aim of discovering new chemical reactions. 

Li M, Zuo Z, Wen L et al (2008) Microwave-assisted combinatorial synthesis of hexa-substituted 1,4-dihydropyridines scaffolds using one-pot two-step multi-component reaction followed by a S-alkylation. J Comb Chem 10 436-441... 

On the other hand, the example of the pentakis(tri luoromethyl)cyclopentadie-nide anion demonstrates impressively that this type of reaction can also be employed highly selectively to supplant a previous complex multi-step synthesis [39] by a one-pot procedure [40] (Scheme 2.115). 

Stereoselective multi-steps synthesis of fluorinated 2,3-dihydroquinolin (lH)-ones proceeding as a one-pot transformation has been described [50]. The Ts-protected 0-(2-anilino)- 0-ketoesters 75 are capable of reacting with a variety of aldehydes under mild conditions to form fluorinated quinolines 76 in good yields (up to 98 %) and high diastereo selectivities (dr up to 99 1) (Scheme 30). The compounds 76 are considered as versatile synthetic intermediates, and, indeed, they can be transformed into functionalized heterocyclic derivatives. For example, decarboxylation of compounds 76 results in the formation of 3-fluoroquinolines 77, while reduction with NaBH4 affords a-fluoro-)3-hydroxy esters 78. 

This multi-step one-pot synthetic concept has been applied to the synthesis of a variety of /i-amino acids of type 51 in the presence of methanol as ring-opening nucleophile it was found to be an efficient method leading to the products 51 with high diastereoselectivity (d.r. ratio 10 1 to 14 1) and enantioselectivity (94-96% ee)... 

Selected examples are shown in Scheme 5.31. For example, the product 51b was obtained in 63% yield with a high d.r. ratio of 14 1 and high enantioselectivity of 95% ee. This multi-step one-pot synthesis has also been applied to the synthesis of, e.g., tripeptides and an L-tkreo-/Miydroxyasparagine derivative [58]. 

Abstract Recent developments in the microwave-assisted synthesis of heterocycles are surveyed with the focus on diversity-oriented multi-component and multi-step one-pot procedures. Both solution- and solid-phase as well as polymer-supported methodologies for the preparation of libraries of heterocycles are reviewed. Advantages of microwave dielectric heating are highlighted by comparison with conventional thermal conditions. 

Peptides are not the only potential drug candidates. In most cases, other kinds of small organic molecules are preferred, because of their reduced susceptibility to enzymatic degradation. The split-mix method is fully applicable in the synthesis of organic libraries. Both sequential type and cyclic libraries can easily be prepared if the reaction conditions for solid phase are well developed. It has to be emphasized, however, that the advantages of the split-mix method can be fully exploited only in the case of multi-step synthetic procedures. For realization of the one-pot procedures suggested by Ugi [10], for example, the parallel procedures are better-suited. 

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