Publications

54 publications

54. Herstellung von polyzyklischen Diterpenen

R. Janke, M. Fuchs, M. Christmann, T. Brück, B. Loll

Biospektrum 2017, 23, 709-711

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Diterpenes constitute a versatile class of natural biomolecules predominantly derived from plants, fungi and prokaryotes. Properties of these natural products include anti-tumour, anti-inflammatory, antibiotic, and insecticidal activities, which makes these compounds high value commercial targets for the chemical and pharmaceutical industry. Since chemical synthesis of terpenes can be difficult, production can be alternatively performed in engineered microorganisms on natural occurring routes.

53. Bioinspired Synthesis of Pentacyclic Onocerane Triterpenoids

F. Bartels, Y. J. Hong, D. Ueda, M. Weber, T. Sato, D. J. Tantillo, M. Christmann

Chem. Sci. 2017, 8, accepted

Full TextSupporting Information

The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies.

52. Asymmetric Synthesis of Carbocyclic Propellanes

L. M. Schneider, V. M. Schmiedel, T. Pecchioli, D. Lentz, C. Merten, M. Christmann

Org. Lett. 2017, 19, 2310-2313

Full TextSupporting Information

A modular synthesis of functionalized carbocyclic propellanes was developed. Formation of the first of two quaternary bridgehead centers has been achieved by desymmetrization of prostereogenic ketones by either Hajos-Parrish-Eder-Sauer-Wiechert-type processes or Werner’s catalytic asymmetric Wittig reaction. The obtained bicyclic enones were subjected to conjugate additions upon which the remaining ring was formed by olefin metathesis. All bridges are amenable to further derivatization, which renders those compounds useful as central units in fragment-based drug discovery or as ligand scaffolds.

51. Picomolar, selective and subtype specific small-molecule inhibition of TRPC1/4/5 channels

H. N. Rubaiy, M. J. Ludlow, M. Henrot, H. J. Gaunt, K. Miteva, S. Y. Cheung, Y. Tanahashi, N. Hamzah, K. E. Musialowski, N. M. Blythe, H. L. Appleby, M. A. Bailey, L. McKeown, R. Taylor, R. Foster, H. Waldmann, P. Nussbaumer, M. Christmann, R. S. Bon

J. Biol. Chem. 2017, 292, 8158-8173

Full TextSupporting Information

The concentration of free cytosolic Ca2+ and the voltage across the plasma membrane are major determinants of cell function. Ca2+-permeable non-selective cationic channels are known to regulate these parameters but understanding of these channels remains inadequate. Here we focus on Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) which assemble as homomers or heteromerize with TRPC1 to form Ca2+-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested including in epilepsy, innate fear, pain and cardiac remodeling but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools which are high-quality, reliable, easy to use and readily accessible for all investigators. Here, through chemical synthesis and studies of native and over-expressed channels by Ca2+ and patch-clamp assays, we describe compound 31 (C31), a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pM, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8 and store-operated Ca2+ entry mediated by Orai1. These findings suggest identification of an important experimental tool compound which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.

50. A straightforward approach to N-substituted-2H-indazol-2-amines through reductive cyclization

J. Schoene, H. Bel Abed, M. Christmann, M. Nazaré

Tetrahedron Lett. 2017, 58, 1633-1635

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A versatile two-step, one-pot reaction to access N-substituted-2H-indazol-2-amine derivatives has been elaborated. A diverse set of analogues was obtained by a sequential hydrazone formation and reductive cyclization in moderate to good yields from readily available starting materials. The strategy tolerates a broad range of substitutions pattern and functional groups allowing further derivatizations.

49. Synthesis of (+)-Greek Tobacco Lactone via a Diastereoablative Epoxidation and a Selenium-Catalyzed Oxidative Cyclization

S. Leisering, I. Riaño, C. Depken, L. J. Gross, M. Weber, D. Lentz, R. Zimmer, C. B. W. Stark, A. Breder, M. Christmann

Org. Lett. 2017, 19, 1478-1481

Full TextSupporting Information

An asymmetric synthesis of the C11-homoterpenoid (+)-Greek tobacco lactone is developed starting from readily available (R)-linalool. The synthesis is comprised of four operations and features a diastereoablative epoxidation and an oxidative tetrahydropyran formation using vanadium-, palladium-, and selenium-catalyzed cyclizations.

48. Organophosphorus-mediated N–N bond formation: facile access to 3-amino-2H-indazoles

H. B. Abed, J. Schoene, M. Christmann, M. Nazaré

Org. Biomol. Chem. 2016, 14, 8520-8528

FulltextSupporting Information

A convenient and efficient strategy has been devised to access 3-amino-2H-indazole derivatives in two steps from readily available starting materials. The conversion of 2-nitrobenzonitriles to substituted benzamidines followed by an organophosphorus-mediated reductive cyclization and a subsequent N–N bond formation afforded 3-amino-2H-indazoles in good to excellent yields.

47. One-Pot Synthesis of 5-Hydroxy-4H-1,3-thiazin-4-ones: Structure Revision, Synthesis, and NMR Shift Dependence of Thiasporine A

T. Seitz, P. Fu, F.-L. Haut, L. Adam, M. Habicht, D. Lentz, J. B. MacMillan, M. Christmann

Org. Lett. 2016, 18, 3070-3073

Full TextSupporting Information

An annulation of arylthioamides with 3-bromopyruvic acid chloride to 5-hydroxy-4H-1,3-thiazin-4-ones has been developed. The initial condensation affords two regioisomeric thiazolinone intermediates in a temperature-dependent manner. The synthesis of the 2-aminophenylthiazinone derivative led to the revision of the previously proposed structure of thiasporine A. Synthesis of the revised structure and NMR analysis revealed that thiasporine A had been isolated as a carboxylate.

46. Mechanistic Characterisation of two Sesquiterpene Cyclases from the Plant Pathogenic Fungus Fusarium fujikuroi

I. Burkhardt, T. Siemon, M. Henrot, S. Rösler, L. Studt , B. Tudzynski, M. Christmann, J. S. Dickschat

Angew. Chem. Int. Ed. 2016, 55, 8748-8751

Full TextSupporting Information

Two sesquiterpene cyclases from Fusarium fujikuroi were expressed in Escherichia coli and purified. The first enzyme was inactive because of a critical mutation, but activity was restored by sequence correction through site-directed mutagenesis. The mutated enzyme and two naturally functional homologues from other fusaria converted farnesyl diphosphate into guaia-6,10(14)-diene. The second enzyme produced eremophilene. The absolute configuration of guaia-6,10(14)-diene was elucidated by enantioselective synthesis, while that of eremophilene was evident from the sign of its optical rotation and is opposite to that in plants but the same as in Sorangium cellulosum. The mechanisms of both terpene cyclases were studied with various 13C- and 2H-labelled FPP isotopomers.

45. Multivalent Polyglycerol Supported Imidazolidin-4-one Organocatalysts for Enantioselective Friedel–Crafts Alkylations

T. Pecchioli, M. K. Muthyala, R. Haag, M. Christmann

Beilstein J. Org. Chem. 2015, 11, 730-738

Full TextSupporting Information

The first immobilization of a MacMillan’s first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a–c was tested in the asymmetric Friedel–Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.

44. Enantiogroup-differentiating biocatalytic reductions of prochiral Cs-symmetrical dicarbonyl compounds to meso compounds

M. Skoupi, C. Vaxelaire, C. Strohmann, M. Christmann, C. M. Niemeyer

Chem. Eur. J. 2015, 20, 8701-8705

Full TextSupporting Information

The stereoselective reduction of symmetrical prochiral dicarbonyl compounds bearing enantiotopic carbonyl groups yields several stereogenic centers in one step. In a proof-of-concept study, a new approach is described for the enzymatic desymmetrization of 5-nitrononane-2,8-dione via sequential biocatalytic reduction steps utilizing ketoreductases to yield all possible diastereomers of 5-nitrononane-2,8-diol.

43. (-)-Englerin A: A Potent and Selective Activator of TRPC4 and TRPC5 Calcium Channels

Y. Akbulut, H. J. Gaunt, K. Muraki, M. J. Ludlow, M. S. Amer, A. Bruns, N. S. Vasudev, L. Radtke, M. Willot, S. Hahn, T. Seitz, S. Ziegler, M. Christmann, D. J. Beech, H. Waldmann

Angew. Chem. Int. Ed. 2015, 54, 3787-3791, (featured in: Chemical & Engineering News, 93 (9), March 2, 2015)

Full TextSupporting Information

Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (−)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (−)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.

42. Oxidation of Allylic and Benzylic Alcohols to Aldehydes and Carboxylic Acids

D. Könning, T. Olbrisch, F. D. Sypaseuth, C. C. Tzschucke, M. Christmann

Chem. Commun. 2014, 50, 5014-5016

Full TextSupporting Information

An oxidation of allylic and benzylic alcohols to the corresponding carboxylic acids is effected by merging a Cu-catalyzed oxidation using O2 as terminal oxidant with a subsequent chlorite oxidation (Lindgren oxidation). The protocol was optimized to obtain pure products without chromatography or crystallization. Interception at the aldehyde stage allowed for a Z/E-isomerization, thus rendering the oxidation stereoconvergent with respect to the configuration of the starting material.

41. A Formal, One-Pot β-Chlorination of Primary Alcohols and Its Utilization in the Transformation of Terpene Feedstock and the Synthesis of a C2-Symmetrical Terminal Bis-Epoxide

J. Swatschek, L. Grothues, J. O. Bauer, C. Strohmann, M. Christmann

J. Org. Chem. 2014, 79, 976-983

Full TextSupporting Information

A one-pot transformation of alkan-1-ols into 2-chloroalkan-1-ols is described. As a practical application, terpene-derived primary alcohols were converted into semiochemicals such as olfactory lactones (aerangis lactone, whisky lactone, and cognac lactone) and pheromones (cruentol and ferrugineol). Using heptane-1,7-diol as a bifunctional substrate, the corresponding bis-epoxide was synthesized by bidirectional synthesis in good yield and high enantioselectivity.

40. Catalytic and Stereoselective ortho-Lithiation of a Ferrocene Derivative

P. Steffen, C. Unkelbach, M. Christmann, W. Hiller, C. Strohmann

Angew. Chem. Int. Ed. 2013, 52, 9836-9840

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N,N-Dimethylferrocenylmethylamine can be lithiated stereoselectively by iPrLi in pentane/Et2O using catalytic amounts of the chiral auxiliary (R,R)-TMCDA. In homogenous reactions, high e.r. values were obtained upon crystallization of the lithiated species. The catalytic activity of TMCDA is made possible by its release from the stereomerically pure lithioferrocene as it dimerizes to a homochiral dimeric etherate.

39. Enantioselective Rauhut-Currier-Type Cyclizations via Dienamine Activation: Scope and Mechanism

E. Marqués-López, R. P. Herrera, T. Marks, W. C. Jacobs, M. Christmann

Synthesis 2013, 1016-1028 (Feature Article).

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This Feature Article describes our mechanistic studies in organocatalytic Rauhut–Currier-type reactions and some applications in target-oriented synthesis. The developed approach involves the cyclization of two tethered Michael acceptors via dienamine intermediates and leads to highly functionalized cycloalkenes. The utility of these intermediates is further demonstrated by the synthesis of biologically important targets, such as optically active iridoid derivatives.

38. One-Pot Oxidation/Isomerization of Z-Allylic Alcohols with Oxygen as Stoichiometric Oxidant

D. Könning, W. Hiller, M. Christmann

Org. Lett. 2012, 14, 5258-5261

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A method for generating (E)-α,β-unsaturated aldehydes from Z-allylic alcohols or E/Z-mixtures is described. The one-pot procedure involves a Cu-catalyzed oxidation followed by an organocatalytic Z/E-isomerization with N,N-dimethylaminopyridine (DMAP).

37. Synthesis of β-Lactones via Catalytic Asymmetric Heterodimerization of Ketenes

E. Marqués-López, M. Christmann

Angew. Chem. Int. Ed. 2012, 51, 8696-8698

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Simple, but effective: The asymmetric heterodimerization of two different ketenes (see scheme) has been developed 65 years after the first seminal studies on ketene dimerization. The key to sufficiently suppressing the competing homodimerization of the monosubstituted ketene donor (shown in blue) is its slow addition to the disubstituted acceptor (shown in red).

36. Enantioselective Tandem Reactions at Elevated Temperatures: One-Pot Hydroformylation/SN1 Alkylation

J. Stiller, A. J. Vorholt, K. A. Ostrowski, A. Behr, M. Christmann

Chem. Eur. J. 2012, 18, 9496-9499; (highlighted in Synfacts 2012, 8, 1094)

Full TextSupporting Information

Canned heat: The optimization of a tandem sequence of a metal-catalyzed and a subsequent organocatalytic reaction is described (see figure). The tandem sequence was initially optimized toward a high yield by variations of substrate ratio, rhodium precursor, and ligands. The tandem reaction is also extendable to more complex alkenes and to substrates with additional functional groups.

35. Access to Skipped Polyene Macrolides by Ring Closing Metathesis: Total Synthesis of the RNA Polymerase Inhibitor Ripostatin B

P. Winter, W. Hiller, M. Christmann

Angew. Chem. Int. Ed. 2012, 51, 3396-3400

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Rip-Roaring! A convergent total synthesis of antibiotic ripostatin B was developed. A key step in the synthesis is a metathesis reaction allowing for a ring closure to the labile doubly skipped triene macrolide.

34. Transforming Terpene-Derived Aldehydes into 1,2-Epoxides via Asymmetric α-Chlorination: Subsequent Epoxide Opening with Carbon Nucleophiles

P. Winter, J. Swatschek, M. Willot, L. Radtke, T. Olbrisch, A. Schäfer, M. Christmann

Chem. Commun. 2011, 47, 12200-12202

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Merging Jørgensen's and MacMillan's organocatalytic aldehyde chlorinations enables the synthesis of chiral vinylcyclopropanes and (−)-cis-aerangis lactone via terpene-derived 1,2-epoxides.

33. Chlorinated isomers of nonylphenol differ in estrogenic and androgenic

P. G. Cormio, M. Christmann, A. Rastall, S. Grund, H. Hollert, I. Schuphan, B. Schmidt

J. Environ. Sci. Health. Part A 2011, 46, 329-336

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Technical mixtures of nonylphenol (NP) contain over 20 p-substituted isomers. Mono- and di-chlorinated derivatives are generated during the chlorination process in water treatment. Four NP isomers (i.e. 4n-, p353-, p33-, p363-NP) and their mono- (MCl) and di-chlorinated (DCl) derivatives were tested for their estrogenic and androgenic potency using yeast estrogenic and androgenic assay. The p353-NP and 4n-MClNP isomers showed the highest and the lowest estrogenic potency, respectively. The p363-MClNP exhibits estrogenic potency comparable to the parent isomer, whereas all p-DClNP compounds displayed a decrease in the estrogenic potency. In the anti-androgenic screen, all substances exhibited a positive response; the mono- and di-chlorinated derivatives exhibit lower potency than the parent isomers. The isomer p363-NP and its corresponding mono- and di-chlorinated derivatives were almost inactive. Furthermore, all compounds were tested for anti-estrogenic and androgenic assays, but none of them showed a positive response. These results indicate that for assessing the xeno-hormone potency of chlorinated derivatives of NP, the use of pure compounds is essential because the mixtures are not representative. In fact the concentrations of NP isomers differ in technical mixtures according to the producers; after chlorination different technical mixtures can generate dissimilar ratios of chlorinated derivatives. Finally, the chlorinated derivatives of NP didn’t show an increase in xeno-hormone potency compared to the parent isomers, and for this reason the many oxidized by-products generated during chlorination process mask the xeno-hormone potency of the pure chlorinated isomers of NP.

32. Total Synthesis and Biological Evaluation of (–)-Englerin A and B: Synthesis of Analogues with Improved Activity Profile

L. Radtke, M. Willot, H. Sun, S. Ziegler, S. Sauerland, C. Strohmann, R. Fröhlich, P. Habenberger, H. Waldmann, M. Christmann

Angew. Chem. Int. Ed. 2011, 50, 3998-4002

Full TextSupporting Information

The large-scale synthesis of englerin A and subsequent structure-activity relationship studies have led to the discovery of highly potent analogues.

31. One-Pot Reactions Accelerate the Synthesis of Active Pharmaceutical Ingredients

C. Vaxelaire, P. Winter, M. Christmann

Angew. Chem. Int. Ed. 2011, 50, 3605-3607

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All in one: A one-pot synthesis of the dipeptidylpeptidase IV selective inhibitor ABT-341 (see structure) by using an “uninterrupted sequence of reactions” has been developed. This strategy broadens the spectrum of one-pot reactions and is poised to speed up the synthesis of medicinally relevant drug compounds.

30. Transforming Terpene Feedstock into Polyketide Architecture

P. Winter, C. Vaxelaire, C. Heinz, M. Christmann

Chem. Commun. 2011, 47, 394-396

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The Cu-catalyzed synthesis of skipped 1,4-dienes from allylic acetates and vinyl-Grignard reagents is key to bidirectional modifications of acyclic terpene acetates. As a result, trisubstituted double bond containing subunits can be readily transferred into complex polyketides from inexpensive bulk terpenes.

29. Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Strategy and Component Assembly

B. Wang, T. M. Hansen, T. Wang, D. Wu, L. Weyer, L. Ying, M. M. Engler, M. Sanville, C. Leitheiser, M. Christmann, Y. Lu, J. Chen, N. Zunker, R. D. Cink, F. Ahmed, C.-S. Lee, C. J. Forsyth

J. Am. Chem. Soc. 2011, 133, 1484-1505

Full TextSupporting Information

The phorboxazole natural products are among the most potent inhibitors of cancer cell division, but they are essentially unavailable from natural sources at present. Laboratory syntheses based upon tri-component fragment coupling strategies have been developed that provide phorboxazole A and analogues in a reliable manner and with unprecedented efficiency. This has been orchestrated to occur via the sequential or simultaneous formation of both of the natural product’s oxazole moieties from two serine-derived amides, involving oxidation−cyclodehydrations. The optimized preparation of three pre-assembled components, representing carbons 3−17, 18−30, and 31−46, has been developed. This article details the design and syntheses of these three essential building blocks. The convergent coupling approach is designed to facilitate the incorporation of structural changes within each component to generate unnatural analogues, targeting those with enhanced therapeutic potential and efficacy.

28. Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Convergent Total Synthesis

B. Wang, T. M. Hansen, L. Weyer, D. Wu, T. Wang, M. Christmann, Y. Lu, L. Ying, M. M. Engler, R. D. Cink, C.-S. Lee, F. Ahmed, C. J. Forsyth

J. Am. Chem. Soc. 2011, 133, 1506-1516

Full TextSupporting Information

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3−C17 and C18−C30 building blocks via formation of the C16−C18 oxazole, followed by macrolide ring closure involving an intramolecular Still−Genarri olefination at C2−C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product’s (2Z)-acrylate with remarkable geometrical selectivity. The C31−C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product’s oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation−cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3−C17 and C18−C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

27. Enantioselective α- and γ-Alkylation of α,β-Unsaturated Aldehydes using Dienamine Activation

J. Stiller, E. Marqués-López, R. P. Herrera, R. Fröhlich, C. Strohmann, M. Christmann

Org. Lett. 2011, 13, 71-73

Full TextSupporting Information

The enantioselective alkylation of α,β-unsaturated aldehydes with stabilized carbocations as electrophiles via the activation as dienamine intermediates is described. This unique application of dienamine catalysis allows for the first enantioselective γ-alkylation of linear α,β-unsubstituted enals.

26. Otto Wallach: Founder of Terpene Chemistry and Nobel Laureate 1910

M. Christmann

Angew. Chem. Int. Ed. 2010, 49, 9580-9586

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A blast from the past: Through his contributions on derivatization and structural elucidation Otto Wallach revolutionized terpene chemistry. His research in this area, begun in 1884, earned him the Nobel Prize in Chemistry a hundred years ago.

25. Total synthesis: Towards artificial terpene cyclases

M. Willot, M. Christmann

Nature Chem. 2010, 2, 519-520

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The plant-derived sesquiterpene englerin A is a potent inhibitor of several renal cancer cell lines. Two recent total syntheses have utilized cationic gold(I)-complexes to coax readily available open-chain precursors into englerin's challenging oxotricyclic core with enzyme-like precision.

24. Asymmetric organocatalysis in total synthesis – a trial by fire

E. Marqués-López, R. P. Herrera, M. Christmann

Nat. Prod. Rep. 2010, 27, 1138-1167

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This review covers the most recent applications of organocatalysis in the synthesis of natural products and non-natural biologically active molecules. Our aim is to showcase how organocatalytic reactions have overcome some of their teething problems and how they frequently offer very practical solutions to long-standing synthetic challenges. 161 references are cited.

23. Silyl-modified Analogues of 2-Tritylpyrrolidine: Synthesis and Applications in Asymmetric Organocatalysis

J. O. Bauer, J. Stiller, E. Marqués-López, K. Strohfeldt, M. Christmann, C. Strohmann

Chem. Eur. J. 2010, 16, 12553-12558

Full TextSupporting Information

Silicon-based organocatalysts: In an effort to study the effects of substituting carbon by silicon within the catalyst backbone, we developed an efficient synthesis of (S)-2-triphenylsilylpyrrolidine [(S)-2]. The evaluation of (S)-2 against its carbon analogue (S)-1 in two organocatalytic reactions is complemented by computational studies.

22. Total Synthesis and Absolute Configuration of the Guaiane Sesquiterpene Englerin A

M. Willot, L. Radtke, D. Könning, R. Fröhlich, V. H. Gessner, C. Strohmann, M. Christmann

Angew. Chem. Int. Ed. 2009, 48, 9105-9108; (highlighted in Synfacts 2010, 262; featured in: Chemical & Engineering News, 87(46), November 16, 2009.)

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Catnip craze: Nepetalactone, the psychoactive ingredient of catmint, was selected as starting material for the first enantioselective synthesis of englerin A. This cytotoxic guaiane sesquiterpene is a highly selective inhibitor (1–87 nM) of several renal cancer cell lines. The absolute configuration of this natural product was determined by total synthesis.

21. Crossed Intramolecular Rauhut-Currier-Type Reactions via Dienamine Activation

E. Marqués-López, R. P. Herrera, T. Marks, W. C. Jacobs, D. Könning, R. M. de Figueiredo, M. Christmann

Org. Lett. 2009, 11, 4116-4119; (highlighted in Synfacts 2009, 1276)

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The intramolecular Rauhut−Currier reaction creates a carbon−carbon bond between two tethered Michael acceptors. Previous asymmetric versions have relied on 1,4-additions of chiral nucleophilic catalysts. Herein, we investigate a novel strategy that involves the formation of electron rich dienamines as key intermediates. Our methodology provides an efficient entry to the iridoid framework.

20. Selective Oxidation of Aliphatic C-H Bonds in the Synthesis of Complex Molecules

M. Christmann

Angew. Chem. Int. Ed. 2008, 47, 2740-2742

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Tamed cat: Iron-catalyzed selective C[BOND]H oxidation reactions present new possibilities in the synthesis and modification of natural products. As a model reaction of a possible C[BOND]H oxidation as part of a total synthesis, the natural product (+)-artemisinin was converted into (+)-10β-hydroxyartemisinin in 34 % yield (see scheme). The combination of nontoxic metal catalyst with H2O2 is an environmentally friendly process.

19. Amine-Catalyzed Cylizations of Tethered Unsaturated Carbonyl Compounds

R. M. de Figueiredo, R. Fröhlich, M. Christmann

Angew. Chem. Int. Ed. 2008, 47, 1450-1453; (HOT PAPER, highlighted in Synfacts 2008, 421)

Full TextSupporting Information

Various linked unsaturated dicarbonyl compounds were cyclized by dienamine catalysis. Depending on the substrates, alternative pathways were observed, leading to mono- and bicyclic products in high enantiomeric excess.

18. Synthesis of 4-Maleimidobutyric Acid and Related Maleimides

R. M. de Figueiredo, P. Oczipka, M. Christmann

Synthesis 2008, 1316-1318

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Maleimidoalkanoic acids and their activated derivatives, such as their N-hydroxysuccinimide esters, are important, though expensive, linkers for the conjugation of biomolecules. During our synthesis of UCS1025A, we have developed a chromatography-free preparation of 4-maleimidobutyric acid on a one-mole scale.

17. Synthesis of Amaminol B

W. C. Jacobs, M. Christmann

Synlett 2008, 247-251

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The synthesis of the cytotoxic marine natural product amaminol B is described. Key steps include an organocatalytic intramolecular Diels-Alder reaction, an HWE olefination and a dia­stereoselective ketone reduction.

16. Organocatalytic Synthesis of Drugs and Bioactive Natural Products

R. M. de Figueiredo, M. Christmann

Eur. J. Org. Chem. 2007, 2575-2600

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Catalytic reactions are a key element in the design of sustainable chemical processes. As witnessed in the field of transition metal-catalysed processes, only those reactions that are reliable over a broad substrate range and tolerant toward a multitude of functional groups have found their way into the repertoire of preparative chemists. Natural product synthesis provides a good benchmark for the maturity of a new synthetic method and in this microreview we discuss the scope and limitations of organocatalytic reactions in the synthesis of biologically important molecules. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

15. Efficient Synthesis and Resolution of Pyrrolizidines

R. M. de Figueiredo, R. Fröhlich, M. Christmann

Angew. Chem. Int. Ed. 2007, 46, 2883-2886; (HOT PAPER, highlighted in Synfacts 2007, 795)

Full TextSupporting Information

In only two steps the commercially available maleimide 1 is converted into the key pyrrolizidine carboxylic acid unit (2) of the telomerase inhibitor UCS1025A. A kinetic resolution through an enantioselective oxa-Michael lactonization and trituration of the resulting scalemic mixture allow for a virtually quantitative separation of a racemate into the enantiomers.

14. Synthesis of a Malimide Analogue of the Telomerase Inhibitor UCS1025A Using a Dianionic Aldol Strategy

R. M. de Figueiredo, M. Voith, R. Fröhlich, M. Christmann

Synlett 2007, 391-394

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The synthesis of a simplified analogue of UCS1025A via an aldol coupling is described.

13. Bidirectional, Organocatalytic Synthesis of Lepidopteran Sex Pheromones

R. M. de Figueiredo, R. Berner, J. Julis, T. Liu, D. Türp, M. Christmann

J. Org. Chem. 2007, 72, 640-642; (Featured in the media, e.g. http://www.g-o.de/wissen-aktuell-6700-2007-06-21.html)

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Shuffling of two simple building blocks and a regioselective transfer hydrogenation allow for the rapid synthesis of a small collection of lepidopteran sex pheromones, e.g., 8E,10Z-tetradeca-8,10-dienal 5c, from the horse chestnut leafminer (Cameraria ohridella).

12. N,N'-Carbonyldiimidazole-Mediated Cyclization of Amino Alcohols to Substituted Azetidines and Other N-Heterocycles

R. M. de Figueiredo, R. Fröhlich, M. Christmann

J. Org. Chem. 2006, 71, 4147-4154; (highlighted in Synfacts 2006, 879)

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Amino alcohols are important synthons for N-heterocycles. We have developed an efficient method to activate hydroxyl groups, which avoids the use of toxic reagents and tolerates a wide variety of functional groups. Our strategy has been applied to the synthesis of functionalized p-methoxyphenyl-protected azetidines, pyrrolidines, and piperidines. The required amino alcohols were synthesized according to an optimized proline-catalyzed Mannich protocol. An azetidine analogue of ezetimibe was synthesized to demonstrate the potential for the synthesis of drug-like molecules.

11. New Developments in the Asymmetric Stetter Reaction

M. Christmann

Angew. Chem. Int. Ed. 2005, 44, 2632-2634

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Highly active carbene catalysts have revitalized the interest in the asymmetric Stetter reaction as a method for the construction of 1,4-dicarbonyl compounds. With the latest generation of a catalyst developed by Rovis and co-workers (1, for example), products with quaternary stereocenters such as 2 can be generated in 85 % yield and 99 % ee.

10. Asymmetric Total Synthesis of Complex Marine Natural Products

J. Hassfeld, T. Stellfeld, M. Kalesse, M. Christmann

Adv. Biochem. Engin. Biotechnol. 2005, 97, 133-203

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The synthesis of natural products is one of the most important research topics in organic chemistry [1, 2]. Apart from the more classical fields such as isolation and structure elucidation, a special focus is placed on efficient and selective synthesis of biologically important naturally occurring compounds. On the other hand, the synthesis of complex natural products, which is judged by the highest synthetic standards, can no longer be the sole reason for the initiation of research programs. The variety of different techniques and new methods in organic chemistry allows for synthesizing even the most complex natural products. In this context, the evaluation of biological mechanisms and targets connects synthetic organic chemistry with cell biology. Only the combination of both allows for broadly addressing biological questions such as cell cycle regulation or transport through membranes. In this context, we will focus on marine natural products that offer an extension to the structural diversity of known terrestrial natural products. Furthermore, we will emphasize elegant techniques that allow for the rapid assembly of complex structures in addition to their application in simplifying and deconvoluting structure-activity relationships as a starting point for more detailed biological investigations. All natural products covered herein have unique biological activities and synthetically challenging frameworks. At the beginning of each chapter, we will introduce the reader to their chemical and biological properties and provide a short overview on the status quo. Additionally, the focus on particular transformations allows readers who are not accustomed to synthetic problems to appreciate the covered achievements and to put the retrosynthetic analyses into perspective with the biological properties. The selection of marine natural products covered herein provides examples where synthesis had to overcome shortages of supply from natural sources (leucascandrolide). Modified natural products are the essential tools for target identification (bryostatin), and simplified structures provide a practical access to structures relevant for pharmacology (bryostatin, ciguatoxin).

9. A Mannich-Cyclization Approach for the Asymmetric Synthesis of Saturated N-Heterocycles

A. Münch, B. Wendt, M. Christmann

Synlett 2004, 2751-2755

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A concise asymmetric synthesis of disubstituted N-heterocycles is reported. Our approach utilizes an optimized Mannich reaction of functionalized aldehydes, followed by a novel dehydrative cyclization mediated by the Staab reagent (1,1′-carbonyldiimidazole, CDI). The method was applied to the synthesis of azetidines, piperidines and pyrrolidines.

8. The Chemistry and Biology of the Leptomycin Family

M. Kalesse, M. Christmann

Synthesis 2002, 981-1003

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Natural products play a dominant role in providing ligands that interfere with biopolymers such as receptors or enzymes. In many cases the exact mode of action or the targets are not known and synthesis of analogs provides a more detailed insight into the mode of action and helps to identify the protein target. We discuss the synthetic endeavors that led to the synthesis of members of the leptomycin family and will provide a picture of the mode of action.

7. Rapid Access to Polyketide Scaffolds via Vinylogous Mukaiyama Aldol Reactions

J. Hassfeld, M. Christmann, M. Kalesse

Org. Lett. 2001, 3, 3561-3564

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The use of the Z-configured vinylogous silyl ketene acetals in Mukaiyama aldol reactions is described. Isopropyl alcohol as scavanger and the use of tris(pentafluorophenyl)borane as the Lewis acid are required for obtaining the γ-alkylated syn-product selectively. In cases of α-chiral aldehydes, Felkin−Anh selectivity was observed.

6. The Chemistry and Biology of Ratjadone

M. Kalesse, M. Christmann, U. Bhatt, M. Quitschalle, E. Claus, A. Saeed, A. Burzlaff, C. Kasper, L. O. Haustedt, E. Hofer, T. Scheper, W. Beil

ChemBioChem 2001, 2, 709-714

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The total synthesis of ratjadone enables a thorough investigation of its mode of action and of structure–activity relationships. In this highly convergent approach, three subunits are joined together by a Wittig olefination and a selective Heck reaction as the pivotal steps. Diastereomeric ratjadones were synthesized by using enantiomeric subunits. They display a range of biological activities that can be correlated to their overall conformational preferences. The overlay of two diastereomers shows that the configuration at C10 induces a helix-like conformation.

5. The First Total Synthesis of (+)-Ratjadone

U. Bhatt, M. Christmann, M. Quitschalle, E. Claus, M. Kalesse

J. Org. Chem. 2001, 66, 1885-1893

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The first total synthesis of ratjadone was achieved using a highly convergent approach joining three subunits together with a Wittig olefination and a selective Heck reaction as the pivotal steps. Besides establishing a robust and reliable route for the synthesis of this orphan ligand, the configuration of unknown stereocenters could also be determined. This synthesis not only provides an additional access to a biologically important compound but also enables the synthesis of structural analogues for biological target identification.

4. Vinylogous Mukaiyama Aldol Reactions with Triarylboranes

M. Christmann, M. Kalesse

Tetrahedron Lett. 2001, 42, 1269-1271

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The first vinylogous Mukaiyama aldol reactions with tris(pentafluorophenyl)borane and triphenylborane are described. Both Lewis acids diastereoselectively generate the C19–C21 all-syn stereo triad of ratjadone, and in the case of tris(pentafluorophenyl)borane the reaction proceeds with substoichiometric amounts.

3. Synthesis of Unsaturated Lactone Moieties by Asymmetric Hetero-Diels-Alder Reactions with Binaphthol Titanium Complexes

M. Quitschalle, M. Christmann, U. Bhatt, M. Kalesse

Tetrahedron Lett. 2001, 42, 1263-1265

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Natural products like ratjadone and callystatin A contain an α,β-unsaturated lactone moiety which adds to the biological activity of these compounds. Here we report a rapid and practical access to lactone precursor 3 by an asymmetric hetero Diels–Alder reaction as the key step and its subsequent transformation into a suitable building block 4.

2. Total Synthesis of (+)-Ratjadone

M. Christmann, U. Bhatt, M. Quitschalle, E. Claus, M. Kalesse

Angew. Chem. 2000, 112, 4535-4538; Angew. Chem. Int. Ed. 2000, 39, 4364-4366

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The coupling of three fragments by a Wittig olefination and a subsequent selective Heck reaction are the pivotal steps in the the first total synthesis of ratjadone (see picture), a cytotoxic as well as antibiotically effective polyketide. This synthesis enabled the elucidation of the absolute configuration of the natural product. In this way it should also be possible to synthesize structural analogues with which the various cellular processes mediated by ratjadone can be studied.

1. Synthesis of the C14-C24-Fragment of Ratjadone

M. Christmann, M. Kalesse

Tetrahedron Lett. 1999, 40, 7201-7204

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Ratjadone is an antifungal and highly cytotoxic polyketide from Sorangium cellulosum. The tetrahydropyran ring is supposed to result from an intramolecular opening of a C16–C17 epoxide. Herein we report the biomimetic synthesis of the C15–C24 segment of ratjadone.