Stereoselective Multicomponent Reactions

Glycosyl imines from aliphatic aldehydes are sensitive to anomerization. However, the anomerization can be avoided by conducting the reactions at lower temperatures (-78 °C). Recrystallization of the crude products (methanol/water for aliphatic, heptane for aromatic compounds) gave the diastereomerically pure D-amino acid amides (Table 4.3). 

L-Amino acids amides 31 can be synthesized easily according to this procedure in high yields and high diastereoselectivity using the pivaloylated D-arabinosylamine 10 as the auxiliary [19]. 

Ibble 4.4 Diastereoselective Ugi synthesis of L-amino acid amides with D-arabinosylamine 10 

D-Arabinosylamine 10 is more reactive and shows even higher asymmetric induction than D-galactosylamine 2 in this case [19b]. A variation of this method was reported by Ugi et al., who used 2-acetamidoglucosyl imine derivatives for the synthesis of (/ )-amino acid derivatives [46]. 

R-NC R-CHO R-COOH r-nh2 Solvent/time Yield (%) (Diaste- Product reomeric ratio (R S)  

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Byk G, Kabha E (2006) A solid-supported stereoselective multicomponent reaction One-pot generation of three asymmetric carbons. Synlett 747-748... 

This brief review places emphasis on (1) the use of stereoselective multicomponent reactions to access diverse and complex pure analogues in a powerful combinatorial way and (2) to review recent synthetic pathways and concepts devoted to exploring chemical space (both defined or expanded). 

Jean Rodriguez was born in Gieza, Spain, on 25 June 1958, and in 1959 his family emigrated to France. After studying chemistry at the University Paul Cezanne in Marseille, France, he completed his PhD as a CNRS student with Prof. B. Waegell and Prof. P. Brun in 1987. He completed his Habilitation in 1992, also at Marseille, where he is currently Professor and Director of the UMR-CNRS-6178-SYMBIO. His research interests include the development of domino and multicomponent reactions, and their applications in stereoselective synthesis. In 1998, he was awarded the Acros prize in Organic Chemistry from the French Chemical Society. 

Pyrane derivatives were obtained through a stereoselective isocyanide-based multicomponent reaction. The reaction between an isocyanide, a dialkyl acetylene-... 

Combinations of enamine-iminium ion activations together with other organo-catalytic activations in asymmetric organocatalytic domino and multicomponent reactions have been developed to achieve the enantioselective consecutive formation of two or more bonds in a stereoselective fashion. 

Multicomponent reactions (MCRs) can be defined as three or more reactants that join together in a single synthetic step to form new products containing portions of all the components. These time and cost-effective reactions are powerful tools that are applicable to combinatorial and parallel syntheses in particular (16-20). However, MCRs for library synthesis are often selected to produce only high quantities of new compounds rather than high quality products (i.e., more diverse and chiral products in pure form). Thus, recent efforts have been made to offset this trend by building chirality into collections of new componnds with the help of efficient stereoselective MCRs (21). 

The multicomponent reaction of o-dialdehydes with two molecules of cyclic 1,3-dicarbonyls in acetic acid involves a stereoselective [4 + 1]/[3+ 2 + 1] biscydizations to give indeno-fused xanthenes (Scheme 82) (13TL6341). 

O. Martinez, G. A. Arroyo, F. J. Perez, M. Suarez, R. Miranda, Int. J. Mol. Sci. 2011, 12, 2641-2649. Infrared assisted production of 3,4-dihydro-2(lfl) Pytidones in solvent-free conditions. (b) M. I. Flores-Conde, L. Reyes, R. Herrera, H. Rios, M. A. Vazqnez, R. Miranda, J. Tamariz, F. Delgado, Ira. J. Mol. Sci. 2012,13, 2590-2617. Highly regio- and stereoselective Diels-Alder cycloadditions via two-step and multicomponent reactions promoted by infrared irradiation under solvent-free conditions. 

F. Cruz-Acosta, P. de Armas, F. Garcia-Tellado, Chem.-Eur. J. 2013, 19, 16550-16554. Water-compatible hydrogen-bond activation a scalable and organocatalytic model for the stereoselective multicomponent aza-Henry reaction. 

C. S. Junker, M. E. Welker, Tetrahedron 2012, 68, 5341-5345. Ruthenium carbenes as catalysts in stereoselective ene-yne metathesis/Diels-Alder and ene-yne metathesis/ Diels-Alder/cross coupling multicomponent reactions. 

X. Wang, S.-Y. Wang, S.-J. Ji, Org. Lett. 2013,15,1954-1957. Isocyanide-hased multicomponent reactions catalyst-free stereoselective construction of polycyclic spiroindolines. 

A. Znabet, E. Ruijter, F. J. J. de Kanter, V. Khler, M. Helliwell, N. J. Turner, R. V. A. Orru, Angew. Chem. Int. Ed. 2010, 49, 5289-5292. Highly stereoselective synthesis of substituted prolyl peptides using a combination of biocatalytic desymme-trization and multicomponent reactions. 

See, for instances (a) S. Santra, R R. Andreana, Org. Lett. 2007, 9, 5035-5038. A one-pot, microwave-influenced synthesis of diverse small molecules by multicomponent reaction cascades, (b) M. Presset, Y. Coquerel, J. Rodriguez, Org. Lett. 2009, 11, 5706-5709. Microwave-assisted domino and multi-component reactions with cyclic acyUcetenes expeditious syntheses of oxazinones and oxazindiones. (c) W.-J. Hao, B. Jiang, S.-J. Tu, X.-D. Cao, S.-S. Wu, S. Yan, X.-H. Zhang, Z.-G. Han, F. Shi, Org. Biomol. Chem. 2009, 7,1410-1414. A new mild base-catalyzed Mannich reaction of hetero-arylamines in water highly efficient stereoselective synthesis of 3-aminoketones under microwave heating, (d) P. Nun, J. Martinez, F. Lamaty, Synthesis 2010, 2063-2068. Microwave-assisted neat procedure for the Petasis reaction. 

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

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