Prof. Dr. G. Bringmann

    The Directed Construction of Biaryl Axes by the ‘Lactone Concept’: Novel Bioactive Compounds and Chemical Tools

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    1. Key Words:

    Regio- and stereoselective construction of sterically even highly encumbered chiral biaryl systems by the directed ring cleavage (atroposelective ‘twisting’) of configurationally labile lactone-bridged biaryls with O-, N-, or H-nucleophiles; mechanistic exploration of the reaction principle – experimentally and by methods of computational chemistry: studies on the principles of stereocontrol and elucidation of the stereochemical course of the ring cleavage reactions; preparative application of the methods within the total synthesis of pharmacologically active biaryl natural products (see also ‘Naphthylisoquinoline Alkaloids’, 'Anthraquinones and Knipholones', and 'Natural Product Synthesis'), and within the synthesis of novel biaryl ligands and reagents.

    2. Graphical Abstract:

    Subtopic A: The 'Lactone Concept' – a New Methodology for the Directed Synthesis of Axially Chiral Biaryls

    Figure 1: The lactone methodology: cleavage of configurationally not yet defined lactones 2, to give, atroposelectively (= with directed 'twisting'), axially chiral biaryls (here, e.g., M-3).

    Subtopic B: Atroposelective Ring-Opening Reactions – Principal Options of Activating the Lactones

    Figure 2: Three principal approaches elaborated for (metal assisted) atroposelective ring opening reactions. – Approach I: Cleavage of the ester bridge by metal-activated chiral O-, N-, or H-nucleophiles. – Approach II: Activation of the carbonyl group with a Lewis acid and subsequent attack of a non-charged chiral nucleophile or, alternatively, activation with a chiral Lewis acid allowing the attack of a simple achiral nucleophile. – Approach III: Activation and stereo-differentiation of the aromatic system by 6-bonded transition metal fragments, with the additional element of planar chirality permitting an internal asymmetric induction and thus the use of achiral nucleophiles.



    Figure 3: Atroposelective ring opening of the lactones 2b and 2c with chiral N-, O-, or H-nucleophiles.
    Figure 4: Synthesis and atropo-diastereomeric equilibrium ratios of the ruthenium-complexed thionolactones 17, which had been obtained from the corresponding thionolactones 15, activated and chirally modified by the coordinatively unsaturated complex fragment {CpRu[(S,S)-CHIRAPHOS)]}+. Twofold hydride addition to 17 and stepwise decomplexation of the Ru-thiolates 18 gave rise to the enantiomerically enriched thioether 21.
    Figure 5: Highly atropo-diastereoselective ring opening of the 6-activated Cp*-ruthenium-complexed lactone exo-22b (racemic) with NaOMe as a small and simple O-nucleophile giving rise to the biaryl ester exo-23b, exclusively. All the experimental observations matched with the results of DF calculations, using the Fukui function.

    Subtopic C: Non-Dynamic Kinetic Resolution by Ring Cleavage Reactions of Configurationally Stable Lactones

    Figure 6: Non-dynamic kinetic resolution of configurationally stable biaryl lactones by reduction with oxazaborolidine-activated borane: (A) Atropo-enantioselective reduction of the 7-membered lactone P-24 with high relative rate constants, leading to the enantiomerically pure C2-symmetric diol M-25 (top). (B) Cleavage of the highly distorted, tert-butyl substituted, 6-membered lactone P-2f with virtually complete atropo-enantioselectivitiy (krel > 200!) to afford the enantiopure M-configured alcohol M-12f (or, optionally, the P-enantiomer by using the R-oxazaborolidine). Quantum chemical calculations (AM1) and experimental verification on the mechanism of this kinetic resolution revealed the first hydride transfer to be the selectivity-determining step of the reaction.

    Subtopic D: The 'Lactone Concept': An Efficient Pathway to Axially Chiral Natural Products and Useful Reagents

    Figure 7: A selection of axially chiral biaryl natural products that have been prepared by applying the lactone method – the biaryls marked in black have been synthesized by our group [9-13], the orange-red colored compounds have been prepared by Suzuki et al. [14], Molander et al. [15], and Abe, Harayama et al. [16,17].
    Figure 8: (A) Synthesis of novel non-C2 symmetric N,O-ligands for the asymmetric addition of diethylzinc to aldehydes (Scheme A, top), and synthesis of MOP ligands for the enantioselective hydrosilylation of styrenes (Scheme A, bottom). – (B) The use of axially chiral tripodal ligands for stereoselective alkylations of aldehydes. – (C) First synthesis of a twofold lactone-bridged teraryl.

    3. Brief Description:

    Compounds with chiral biaryl axes are gaining increasing importance as pharmacologically active compounds and as useful tools in asymmetric synthesis. The atroposelective total synthesis of biaryl target molecules is a most useful device for the elucidation of the full absolute stereostructure of axially chiral biaryls and it provides reliable access to bioactive natural compounds or simplified analogs (e.g., for biotests) and to biarylic ligands and catalysts [1-6].
    Yet, compared with the numerous sophisticated techniques for the asymmetric synthesis of stereogenic centers, truly practicable methods for the regio- and stereoselective construction of chiral axes are still rare. We have developed a conceptionally novel and preparatively efficient concept for the directed synthesis of even highly hindered axially chiral biaryls [1-6]. Key step is the atroposelective cleavage of lactone-bridged biaryl precursors (see Figure 1) by various metal-activated chiral nucleophiles (see Figure 2). The required lactones are easily available by intramolecular coupling of appropriately substituted bromo esters, they can be cleaved atropo-enantio- or atropo-diastereo-divergently to the one or the other stereoisomeric form, e.g., to the M-configured biaryl, or, optionally, to the P-configured product. Mechanistically, this reaction constitutes a dynamic kinetic resolution at the level of the rapidly interconverting lactone enantiomers: Only one of them is ring cleaved, to give the axially chiral, now configurationally stable biaryl product, whereas the other, non-reactive lactone enantiomer will, by the rapid atropo-enantiomeric interconversion, provide more of the reactive species and thus permit a high-yield conversion of virtually all of the racemic starting material into one particular atropisomeric biaryl [1-6].
    Reagents that can effect such highly atropisomer-selective ring cleavage reactions, are chiral O-, N-, or H-nucleophiles (Approach I in Figure 2):
    Potassium S-1-phenylethylamide (S-5) and sodium R-menthoxide (R-7) were the N- and O-nucleophiles of choice for the atropo-diastereoselective ring opening of 2a and 2b, leading to the respective biaryl amides 4 and esters 6 in good yields (70-97%) and diastereoselectivity (74-90% de). Almost complete control of the configuration at the biaryl axis was attained in the atropo-diastereoselective cleavage of 2c with the sterically more demanding sodium R-8-phenylmenthoxide (R-8), delivering exclusively the ester M,R-9c in 95% yield (see Figure 3, top) [1,2,3,6]. Using amino acid esters of type 10 as inexpensive and efficient N-nucleophiles, the atropo-diastereoselective ring cleavage afforded configurationally stable axially chiral biaryl amides 11 in good chemical yields and excellent diastereomeric ratios of up to > 99.5:0.5 (see Figure 3, right) [7].
    An atropo-enantioselective reduction of 2 was successfully accomplished either with aluminates like P-BINAL-H (P-12), or, even better, with oxazaborolidine-activated borane like S-13. The biaryl diols P-14b and M-14c were obtained in high yields (> 90%) and with up to 97% ee (see Figure 3, bottom) [2,3,6]. The size of the ortho-substituent next to the axis (and the structure of the lactone 2 in general) usually has no influence on the direction of chirality transfer, making the ring-opening reactions not only efficient concerning the chemical yields and optical purities, but also reliable with respect to the expected configuration. By the use of the corresponding enantiomeric O-, N-, or H-nucleophiles, also the other respective atropisomeric products are accessible in mostly excellent optical and chemical yields. Moreover, any undesired atropisomeric by-products are not lost, but can easily be recycled - literally by re-cyclization back to the configurationally unstable biaryl lactone.
    An alternative approach that does not have to rely on an activation of the nucleophile is the activation of the lactones 2 themselves, by coordination of a Lewis-acidic transition metal, which in addition can serve as the chiral auxiliary for the ring opening step (Approach II in Figure 2). As an example (see Figure 4), the thionolactones 15, which were easily prepared from the 'normal' (oxo)lactones 2, were transformed in high yields (>95% for all representatives 2a-f) into the chiral (cationic) ruthenium S,S-CHIRAPHOS complexes 17, using the thiophene ruthenium complex 16. Reductive ring cleavage of 17 with lithium aluminum hydride gave the configurationally stable thiolate complexes 18 in good yields and in some cases quite good diastereoselectivities. As presented for 18a-c, methylation and decomplexation led to the enantiomerically enriched free thioethers 21a-c. The chiral iodo ruthenium complex 20 thus recovered can be converted back into the original complex 16 in one step, without loss of stereochemical purity [2,3,6].
    A third option is the activation and stereodifferentiation of the aromatic system by hapto6-bonded transition metal fragments (see Figure 5), with the additional element of planar chirality permitting an internal asymmetric induction and thus the use of cheap, since achiral nucleophiles (Approach III in Figure 2). A typical example of hapto6-activation and stereochemical modification of the lactone system is the synthesis and ring cleavage reaction of the Cp*-ruthenium complexed lactone 22b with the sterically demanding metal fragment located on the distal naphthalene, i.e., on the sterically better accessible, yet less electron-rich ring as compared with the phenolic part (which, in turn, had been the site of coordination in the case of the less bulky Cr(CO)3 fragment; for a chromium-complexed lactone: see Figure 2). The equilibrium of the two atropisomers in the RuCp* complex 22b is entirely pushed towards the sterically less constrained atropo-diastereomer exo-22b. In agreement with this array and with an axial attack of the nucleophile anti to the RuCp* fragment, ring cleavage of exo-22b (racemic) even with NaOMe as a small and simple O-nucleophile thus gave the biaryl ester exo-23b, exclusively. All the experimental observations perfectly matched with the results of DF calculations using the Fukui function.
    As an extension of the lactone methodology, configurationally stable biaryl lactones such as the highly distorted, tert-butyl substituted, 6-membered lactone P-2f (see Figure 6, bottom) or its 7-membered analog P-24 (see Figure 6, top) are likewise excellent substrates for atroposelective cleavage reactions, now through a ‘normal’, i.e., non-dynamic kinetic resolution, giving very high relative rate constants and leading to an enantiomerically pure C2-symmetric diol like M-25 for the 7-membered lactone or to an enantiomerically pure alcohol like M-12f with krel > 200 (!) for the tert-butyl lactone, values usually found for enzymatic reactions. Semiempirical quantum chemical calculations (AM1) on the mechanism of this kinetic resolution revealed that the first hydride transfer is the selectivity-determining step of the reaction, which was fully confirmed experimentally. The respective residual lactone enantiomers display extremely high enantiomeric purities, they can be reduced to the corresponding diol or alcohol just by lithium aluminum hydride - or they can be racemized thermally and can then again be submitted to the kinetic deracemization - likewise a very efficient technique of stereoselective biaryl synthesis [8].
    The potential and practicability of the lactone method has been demonstrated by its application in the atroposelective synthesis of more than 30 natural products (see also 'Natural Product Synthesis'), some examples of which are presented in Figure 7. Among a broad series of axially chiral biaryls are most different structures, such as the naphthylisoquinoline alkaloid korupensamine B [9] (see also ‘The Naphthylisoquinoline Alkaloids’), the bicoumarin (+)-isokotanin A [2,4,5,10], the dimeric sesquiterpene mastigophorene A [4,5,11], the phenylanthraquinone knipholone [4,5,12] (see also ‘Anthraquinones and Knipholones’), and a precursor for the AB system of vancomycin [13]. The lactone approach has meanwhile also been used by other groups, i.a., by Suzuki et al. [14] for the regio- and stereoselective total synthesis of the benanomicin-pradimicin antibiotics. Key step of the synthesis of the aglycon was the diastereoselective ring-opening of a biaryl lactone by using (R)-valinol as a chiral N-nucleophile. In constructing (+)-isoschizandrin as a single atropisomer, Molander et al. [15] utilized a kinetic resolution of a seven-membered lactone using a chiral CBS-oxazaborolidine. A similar methodology with the enantioselective ring opening reaction of a six-membered lactone as the key step (performed with a combination of chiral CBS-oxazaborolidine and BH3•THF), was applied by Abe, Harayama et al. for a formal total synthesis of (-)-steganone [16], and for the enantioselective synthesis of trimethyl octa-O-methylvaloneate, an important part of the structure of the ellagitannins [17].
    Furthermore, the lactone methodology has also been an efficient device for the design, preparation, and fine-tuning of a wide spectrum of useful auxiliaries, varying in electronic, steric demands, and symmetry. A most rewarding advantage of the lactone methodology is that it gives rise to constitutionally symmetric and unsymmetric biaryls, and thus also to most promising novel 'non C2-symmetric' reagents and ligands for asymmetric synthesis, which are usually accessible in just a few synthetic steps, and with any desired axial configuration from the atropisomerically pure lactone ring cleavage products (see Figure 8) [2,4,6,18-20]. As an example, the novel bidentate ligand M-26 (see Figure 8A, top), equipped with an N- and O-functionality, efficiently catalyzes diethylzinc additions to various aldehydes in high enantiomeric ratios, i.a., the ethylation of benzaldehyde to S-1-phenylpropanol (er 99:1). Another novel C1-symmetric biaryl is the monodentate phosphine (MOP) ligand M-27 (see Figure 8A, bottom). It catalyzes the enantioselective hydrosilylation of styrenes to benzylic alcohols in satisfying enantiomeric ratios, with the R-configured product prevailing in all cases. We have also developed an economical and simple access to a novel type of enantiomerically pure, C3-symmetric tripodal ligands (see Figure 8B) possessing three axially chiral biaryl subunits. The triol M,M,M-28 with its central mesitylene-derived core turned out to be a suitable catalyst for the enantioselective addition of dialkylzinc to various aromatic aldehydes with asymmetric inductions of up to 98% ee [19]. In view of the mostly very high asymmetric inductions in the lactone cleavage reactions, we extended our method to the construction of twofold lactone-bridged teraryls like 29 (see Figure 8C), which may be suitable precursors for the formation of C2-symmetric teraryls, as novel reagents or as materials for liquid crystals. Since the meso-configured bislactone M,P-29 was found to be far more stable and hence dominant over the two enantiomeric chiral isomers, P,P-29 and M,M-29, it still remains a rewarding task to design, synthesize, and atropo-selectively cleave constitutionally more appropriate bislactones.


    4. Selected Publications:

    [1] G. Bringmann, T. Gulder, T.A.M. Gulder; Asymmetric synthesis of biaryls by the 'lactone method'. In: Asymmetric Synthesis – The Essentials (M. Christmann, S. Bräse, eds.), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007, pp. 246-250.
    [2] G. Bringmann, A.J. Price Mortimer, P.A. Keller, M.J. Gresser, J. Garner, M. Breuning; Atroposelective synthesis of axially chiral biaryl compounds. Angew. Chem. 2005, 117, 5518-5563; Angew. Chem. Int. Ed. 2005, 44, 5384-5427.
    [3] G. Bringmann, M. Breuning, R.-M. Pfeifer, W.A. Schenk, K. Kamikawa, M. Uemura; The lactone concept – a novel approach to the metal-assisted atroposelective construction of axially chiral biaryl systems. J. Organomet. Chem. 2002, 661, 31-47.
    [4] G. Bringmann, S. Tasler, R.-M. Pfeifer, M. Breuning; The directed synthesis of axially chiral ligands, reagents, catalysts, and natural products through the 'lactone methodology'. J. Organomet. Chem. 2002, 661, 49-65.
    [5] G. Bringmann, D. Menche; Stereoselective total synthesis of axially chiral natural products via biaryl lactones. Acc. Chem. Res. 2001, 34, 615-624.
    [6] G. Bringmann, M. Breuning, S. Tasler;
    The Lactone Concept: An Efficient Pathway to Axially Chiral Natural Products and Useful Reagents;
    Synthesis 1999, 525-558.
    [7] G. Bringmann, H. Scharl, K. Maksimenka, K. Radacki, H. Braunschweig, P. Wich, C. Schmuck; Atropodiastereoselective cleavage of configurationally unstable biaryl lactones with amino acid esters. Eur. J. Org. Chem. 2006, 4349-4361.
    [8] G. Bringmann, J. Hinrichs, J. Kraus, A. Wuzik, T. Schulz; Non-dynamic kinetic resolution of configurationally stable biaryl lactones by reduction with oxazaborolidine-activated borane: AM1 studies and experimental verification. J. Org. Chem. 2000, 65, 2508-2516.
    [9] G. Bringmann, M. Ochse, R. Götz; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J. Org. Chem. 2000, 65, 2069-2077.
    [10] G. Bringmann, J. Hinrichs, P. Henschel, J. Kraus, K. Peters, E.-M. Peters; Atropo-enantioselective synthesis of the natural bicoumarin (+)-isokotanin A via a configurationally stable biaryl lactone. Eur. J. Org. Chem. 2002, 1096-1106.
    [11] G. Bringmann, T. Pabst, P. Henschel, J. Kraus, K. Peters, E.-M. Peters, D.S. Rycroft, J.D. Connolly; Nondynamic and dynamic kinetic resolution of lactones with stereogenic centers and axes: stereoselective total synthesis of herbertenediol and mastigophorenes A and B. J. Am. Chem. Soc. 2000, 122, 9127-9133.
    [12] G. Bringmann, D. Menche; First, atropo-enantioselective total synthesis of the axially chiral phenylanthraquinone natural products knipholone and 6'-O-methylknipholone. Angew. Chem. 2001, 113, 1733-1736; Angew. Chem. Int. Ed. 2001, 40, 1687-1690.
    [13] G. Bringmann, D. Menche, J. Mühlbacher, M. Reichert, N. Saito, S.S. Pfeiffer, B.H. Lipshutz; On the verge of axial chirality: atroposelective synthesis of the AB-biaryl fragment of vancomycin. Org. Lett. 2002, 4, 2833-2836.
    [14] M. Tamiya, K. Ohmori, M. Kitamura, H. Kato, T. Arai, M. Oorui, K. Suzuki; General synthesis route to benanomicin-pradimicin antibiotics. Chem. Eur. J. 2007, 13, 9791-9823.
    [15] G.A. Molander, K.M. George, L.G. Monovich; Total synthesis of (+)-isoschizandrin utilizing a samarium(II) iodide-promoted 8-endo ketylolefin cyclization. J. Org. Chem. 2003, 68, 9533-9540.
    [16] S. Takeda, H. Abe, Y. Takeuchi, T. Harayama; Intramolecular biaryl coupling reaction of benzyl benzoate and phenyl benzoate derivatives, and its application to the formal synthesis of ()-steganone. Tetrahedron 2007, 63, 396-408.
    [17] H. Abe, Y. Sahara, Y. Matsuzaki, Y. Takeuchi, T. Harayama; Enantioselective synthesis of valoneic acid derivative. Tetrahedron Lett. 2008, 49, 605-609.
    [18] G. Bringmann, J. Hinrichs, K. Peters, E.-M. Peters; Synthesis of a chiral aryl-ferrocenyl ligand, by intramolecular coupling to a biaryl-related lactone. J. Org. Chem. 2001, 66, 629-632.
    [19] G. Bringmann, R.-M. Pfeifer, C. Rummey, K. Hartner, M. Breuning; Synthesis of enantiopure axially chiral C3-symmetric tripodal ligands and their application as catalysts in the asymmetric addition of dialkylzinc to aldehydes. J. Org. Chem. 2003, 68, 6859-6863.
    [20] G. Bringmann, R.-M. Pfeifer, P. Schreiber, K. Hartner, M. Schraut, M. Breuning; The 'lactone method': enantioselective preparation of novel P,N-biaryl ligands and their use in the synthesis of the biarylic alkaloids, ancistrotanzanine B and ancistroealaine A. Tetrahedron 2004, 60, 4349-4360.

    5. Cooperations and Research Grants

    a) Within a special research project entitled "A New Class of Active Agents against Infectious Diseases" incorporated into the Collaborative Research Centre „Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases“ (Sonderforschungsbereich 630), sponsored by the Deutsche Forschungsgemeinschaft (DFG).

    b) Work on the partial and total synthesis of isoplagiochin-type natural products in collaboration with PD Dr. Andreas Speicher (Universität des Saarlandes, Fachrichtung 8.1. Chemie – Organische Chemie), sponsored by the Deutsche Forschungsgemeinschaft ("Enantioselective Synthesis of Bisbibenzyl Natural Products of the Isoplagiochin-Type with Combined Axially and Helical Chirality", Individual Grant Br 699/12);

    c) Within a special research project entitled "Atroposelective Synthesis of Axially Chiral Bi- and Quateraryl Agents: Korupensamines and Michellamines", sponsored by the Deutsche Forschungsgemeinschaft (Individual Grant Br 699/5) (completed);

    d) Within a special research project entitled "Metal-Induced Synthesis and Utilization of Axially Chiral Biaryls" incorporated into the collaborative research centre „Selective Reactions of Metal-Activated Molecules“ (Sonderforschungsbereich 347), sponsored by the Deutsche Forschungsgemeinschaft (DFG) (completed).



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