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Asymmetric Organocatalysis Stefan Jaroch,*[A] Hilmar Weinmann,*[A] and Kirsten Zeitler*[B]

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Asymmetric Organocatalysis Stefan Jaroch,*[A] Hilmar Weinmann,*[A] and Kirsten Zeitler*[B] DOI: 10.1002/cmdc.200700109 Asymmetric Organocatalysis Stefan Jaroch,*[a] Hilmar Weinmann,*[a] and Kirsten Zeitler*[b] Chemical synthesis is one of the key technologies underlying thesis and invaluable to pharmaceutical industry. Recent develop- modern drug discovery and development. For the design and ac- ments in the field of asymmetric catalysis point to a third class cessibility of novel structures and the rapid preparation of new of catalysts besides the established enzymes and metal com- test compounds and development candidates with often highly plexes, the so-called organocatalysts. In an effort to increase the complex chemical architecture, it is essential to use state-of-the- awareness within the community of medicinal and process chem- art chemical synthesis technologies. As the number of chiral ists as well as to learn more about recent developments in this drugs is increasing, asymmetric synthesis and efficient chiral sep- rapidly evolving field, the Schering Foundation organized a sym- aration technologies are steadily gaining importance. Regarding posium on “Organocatalysis”, which took place in Berlin on April asymmetric catalysis, enzymatic transformations, and reactions 18–20, 2007. This minireview summarizes some of the important employing metal, catalysts are important tools for organic syn- results presented at the symposium. Introduction Chemical synthesis is one of the key technologies underlying modern drug discovery and development. For the design and accessibility of novel structures and the rapid preparation of new test compounds and development candidates with often highly complex chemical architecture, it is essential to use state-of-the-art chemical synthesis technologies. As the Scheme 1. Asymmetric Robinson annulation catalyzed by l-proline leading [1] [2] number of chiral drugs is increasing, asymmetric synthesis to the steroid CD fragment. a) 1) 3 mol% l-Pro, DMF, 208C, 2) TosOH, ben- and efficient chiral separation technologies[3] are steadily gain- zene, quant., 93% ee. ing importance. With respect to the first, (diastereoselective) asymmetric syntheses[4] the application of chiral auxiliaries or chiral pool strategies has become well implemented into the Schering Foundation organized a symposium on “Organocatal- arsenal of industrial processes. Regarding asymmetric catalysis, ysis”, which took place in Berlin on April 18–20, 2007. enzymatic transformations[5] and reactions employing metal catalysts are important tools for organic synthesis and invalua- ble to the pharmaceutical industry.[6,7] Recent developments in the field of asymmetric catalysis point to a third class of cata- Developments and Applications lysts, besides the established enzymes and metal complexes, Amine Catalysis the so-called organocatalysts. These low-molecular weight or- ganic molecules can even contain a metal possibly playing a The Hajos-Parrish-Eder-Sauer-Wiechert reaction[11] involves an structure defining, but not a catalytic, role. Essentially, organo- enamine catalysis increasing the HOMO of the nucleophile and catalysts can be considered as small molecule enzymes.[8] additionally, due to the bifunctional character of proline, the As for metal and enzyme-mediated asymmetric catalysis,[9] LUMO of the electrophilic reaction partner is lowered through the utility and efficiency of organocatalysts has been impres- sively illustrated with the de novo synthesis of carbohy- [a] Dr. S. Jaroch, Dr. H. Weinmann [10] Medicinal Chemistry drates. Despite that and the considerable efforts to explore Bayer Schering Pharma and extend the scope of asymmetric organocatalytic reactions 13342 Berlin (Germany) throughout the last years, their use in medicinal and process Fax: (+ 49)30-46892146 (S. J.) chemistry is still rather low. This is even more surprising as the Fax: (+ 49)30-46818170 (H. W.) E-mail: [email protected] field was pioneered by the medicinal chemistry laboratories of [email protected] Schering AG and Hoffmann La Roche in the late 1960s and [b] Dr. K. Zeitler early 1970s by using proline as asymmetric catalyst for a Rob- Institute of Organic Chemistry inson annulation (see Scheme 1).[11] University of Regensburg In an effort to increase the awareness within the community Universitätsstrasse 31 93053 Regensburg (Germany) of medicinal and process chemists as well as to learn more Fax: (+ 49)941-9434121 about recent developments in this rapidly evolving field, the E-mail: [email protected] ChemMedChem 2007, 2, 1261 – 1264 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1261 MED S. Jaroch, H. Weinmann, K. Zeitler a hydrogen bond interaction with the proline carboxylic acid ated planar-chiral pyridine (formation of chiral ion pairs) as [12] moiety. Starting from the extension of proline-mediated en- postulated for the asymmetric addition of NH3 to ketenes (see amine catalysis to intermolecular processes and its generaliza- Scheme 3).[22] Such chiral ion pairs might also play a role for a tion to different electrophiles as a means to access a-function- novel route to enantiopure tertiary a-chlorinated esters.[23] alized aldehydes, Benjamin List presented a straightforward Besides amines another privileged class of Lewis basic orga- classification of organocatalysts. Whereas secondary amines nocatalysts are nucleophilic carbenes,[24] which have been (Lewis base catalysts) can provide alternate modes of activa- proven to be extremely versatile for different transformations, tion through iminium ion formation, he stressed the increasing albeit strongly dependent on the electronic and steric nature importance of Brønsted acid catalysis. With respect to the cru- of the catalyst. Apart from the well-known Stetter reaction,[25] cial formation of close-contact chiral ion pairs within the pro- Frank Glorius applied N-heterocyclic carbenes (NHCs) for a con- posed mechanisms, Brønsted acid catalysis can be seen as a jugate umpolung[26] of a,b-unsaturated aldehydes into homo- specialized case of a more general strategy, named asymmetric enolates, which are then reacted with aldehydes or ketones to counterion-directed catalysis (ACDC),[13] which is related to the g-butyrolactones or b-lactones depending on the reaction con- already established chiral phase-transfer catalysis. ditions;[27] the reaction can be monitored via important inter- Dieter Enders elegantly employed the different modes of en- mediates with MS techniques.[28] Whereas for a-substituted amine and iminium activation in domino reactions leading to enals, a dimethylbenzimidazolium-derived carbene proved to highly functionalized cyclohexenes (see Scheme 2).[14] Starting be an ideal catalyst, the sterically demanding N,N’-bismesityl- imidazoliumACHTUNGRE (IMes) carbene is otherwise the reagent of choice. A nitrogen-free nucleophilic catalyst is Varinder Aggarwal’s chiral [2.2.1] bicyclic sulfide, synthesized from camphorsulfonyl chloride, which is a powerful catalyst in the catalytic asymmet- ric synthesis of epoxides[29] and aziridines,[30] and Morita-Baylis– Hillman reactions of enones with acyliminium species.[31] The asymmetric epoxidation of olefins of various geometry using chiral ketones derived from d-fructose as catalysts is constantly Scheme 2. Domino reaction using enamine and iminium activation for the [32] construction of highly functionalized cyclohexenes. a) toluene, 08C, (58%, enhanced by Yian Shi (see Figure 1). His reliable, stereopre- >99% ee). from dihydroxyacetoneACHTUNGRE acetonide the amine organocatalyst functions like an artificial aldolase eventually leading to carbo- hydrates,[15] sphingolipids,[16] and carbasugars.[17] Nucleophilic Catalysis Figure 1. Aggarwal’s sulfide catalyst for Corey-Chaykovsky-type epoxidation and Morita-Baylis–Hillman reaction and Shi’s ketone organocatalysts for ACHTUNGRE One of the most acclaimed and applied nucleophilic organoca- stereoselective oxidation of cis-disubstituted and terminal olefins. talyst is dimethylaminopyridine (DMAP).[18] Greg Fu[19] has intro- duced planar-chiral versions of DMAP and pyrrolidinopyridine (PPY)[20] and has reported their versatility for various applica- dictable method is often complementary to metal-catalyzed tions, such as Staudinger reactions. Careful selection of the epoxidations and has attracted wide spread application in dif- imine protecting groups, that is, tosyl versus triflyl, allows for ferent total syntheses. As the reaction can be conducted with directing the stereochemistry at the b-lactam from cis- to the simple hydrogen peroxide as oxidant, large amounts of inor- unusual trans-stereochemistry with the more electrophilic tri- ganic byproducts are avoided, which makes the process ame- [33] flylimine.[21] Interestingly, Fu presented a further switch in ste- nable for larger scale. reoselectivity for reactions involving ketenes by changing the Mathias Christmann showed examples for organocatalytic reaction mechanism from standard Lewis base conditions (ad- key steps in the total synthesis of the natural product and telo- [34] dition to ketene) to a Brønsted acid catalytic cycle with proton- merase inhibitor UCS 1025A. In addition to an intramolecular Diels–Alder reaction for the formation of the decaline frame- work using MacMillan’s imidazolidinone catalyst,[35] an unprece- dented alkaloid-mediated lactone formation was applied to build upthe tricyclic partof the target molecule. During this investigation an useful enantioenrichment of scalemic mixtures of the key intermediate in solution could be observed,
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