Recent developments in isocyanide based multicomponent reactions in applied chemistry

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.

Multicomponent Reactions with Isocyanides.

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.1,2 Among all asymmetric catalytic methods, asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines, have become one of the most efficient methods for constructing chiral compounds.3 The development of homogeneous asymmetric hydrogenation was initiated by Knowles4a and Horner4b in the late 1960s, after the discovery of Wilkinson’s homogeneous hydrogenation catalyst [RhCl(PPh3)3]. By replacing triphenylphosphine of the Wilkinson’s catalystwithresolvedchiralmonophosphines,6Knowles and Horner reported the earliest examples of enantioselective hydrogenation, albeit with poor enantioselectivity. Further exploration by Knowles with an improved monophosphine CAMP provided 88% ee in hydrogenation of dehydroamino acids.7 Later, two breakthroughs were made in asymmetric hydrogenation by Kagan and Knowles, respectively. Kagan reported the first bisphosphine ligand, DIOP, for Rhcatalyzed asymmetric hydrogenation.8 The successful application of DIOP resulted in several significant directions for ligand design in asymmetric hydrogenation. Chelating bisphosphorus ligands could lead to superior enantioselectivity compared to monodentate phosphines. Additionally, P-chiral phosphorus ligands were not necessary for achieving high enantioselectivity, and ligands with backbone chirality could also provide excellent ee’s in asymmetric hydrogenation. Furthermore, C2 symmetry was an important structural feature for developing new efficient chiral ligands. Kagan’s seminal work immediately led to the rapid development of chiral bisphosphorus ligands. Knowles made his significant discovery of a C2-symmetric chelating bisphosphine ligand, DIPAMP.9 Due to its high catalytic efficiency in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids, DIPAMP was quickly employed in the industrial production of L-DOPA.10 The success of practical synthesis of L-DOPA via asymmetric hydrogenation constituted a milestone work and for this work Knowles was awarded the Nobel Prize in 2001.3k This work has enlightened chemists to realize * Corresponding author. 3029 Chem. Rev. 2003, 103, 3029−3069

New Chiral Phosphorus Ligands for Enantioselective Hydrogenation

Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis.






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Figure 1


Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.

Chemistry and Biology Of Multicomponent Reactions

A New Planar Chiral Bisphosphine Ligand for Asymmetric Catalysis: Highly Enantioselective Hydrogenations under Mild Conditions

Semisynthetic Artemisinin, the Chemical Path to Industrial Production

An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired α-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.

Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation†

Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524

Kai Rossen

Papers

A New Planar Chiral Bisphosphine Ligand for Asymmetric Catalysis: Highly Enantioselective Hydrogenations under Mild Conditions

Semisynthetic Artemisinin, the Chemical Path to Industrial Production

Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation†

Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524

Kinetic Resolution of rac-4,12-Dibromo[2.2]paracyclophane in a Palladium [2.2]PHANEPHOS Catalyzed Amination