Prof. Dr. G. Bringmann

    Stereoselective Total Synthesis of Axially Chiral Products

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    1. Key Words:

    Total synthesis of axially chiral natural products by oxidative aryl coupling reactions and by employing the 'lactone concept' (see also 'The Lactone Concept'); atropo-divergent synthesis of naphthylisoquinoline alkaloids (e.g., korupensamines A and B) (see also 'The Naphthylisoquinoline Alkaloids'); stereoselective total synthesis of phenylanthraquinones (see also 'Anthraquinones and Knipholones'); atroposelective synthesis of the sesquiterpenes mastigophorenes A and B and the bicoumarin (+)-isokotanin by dynamic and by non-dynamic kinetic resolution strategies via six- and seven-membered biaryl lactones; atroposelective construction of the AB biaryl fragment of the glycopeptide antibiotic vancomycin; total synthesis of naphthylisoquinoline alkaloids by atroposelective biaryl coupling with chiral catalysts; convergent total synthesis of N,C-coupled naphthylisoquinoline alkaloids (e.g., ancisheynine); total synthesis of the N,C-bonded axially chiral biscarbazole murrastifoline-F by oxidative coupling.

    Figure 1: Axially chiral biaryl natural products from plants, liverworts, and microorganisms as targets for asymmetric synthesis.

    2. Graphical Abstract:

    Subtopic A:

    The ‘Lactone Concept’ – a New Methodology for the Atroposelective Synthesis of Axially Chiral Natural Products

    Figure 2: Application of the 'lactone method' for the atroposelective synthesis of the antimalarial naphthylisoquinoline alkaloid dioncopeltine A.
    Figure 3: No 'free' C1 unit next to the axis – but a 'cryptic' one: atropo-divergent synthesis of the korupensamines A and B by the lactone method, as the molecular portions of the antiviral dimeric naphthylisoquinoline alkaloid michellamine B.
    Figure 4: Atropo-enantioselective total synthesis of the axially chiral phenylanthraquinone (+)-knipholone and related antiplasmodial natural products by application of the lactone concept.
    Figure 5: Controlling centrochirality and axial chirality via lactones: synthesis of the sesquiterpene herbertenediol and its 'dimers', the mastigophorenes A and B involving six- and seven-membered biaryl lactones.
    Figure 6: Two atroposelective pathways to the bicoumarin (+)-isokotanin A using the 'lactone concept': by dynamic or – optionally – by nondynamic kinetic resolution.
    Figure 7: Atroposelective construction of the AB biaryl fragment of the glycopeptide antibiotic vancomycin using the 'lactone concept' (with B.H. Lipshutz, Santa Barbara, USA).

    Subtopic B:

    Atroposelective Intermolecular Biaryl Coupling with Chiral Catalysts

    Figure 8: Total synthesis of the antileishmanial naphthylisoquinoline alkaloid ancistrotanzanine B and its atropo-diastereomer, ancistroealaine A, by construction of the rotationally hindered biaryl axis by Suzuki coupling in the presence of chiral catalysts, and their separation by chromatography on a chiral phase (actually treated like enantiomers due to the fact that these two atropo-diastereomers behaved chromatographically identically).

    Subtopic C:

    Convergent Total Synthesis of N,C-Coupled Naphthylisoquinoline Alkaloids

    Figure 9: Total synthesis of the chiral and configurationally stable ancisheynine by condensing a monocyclic diketone with an N-Boc-protected aminonaphthalene – Resolution of its two atropoenantiomers by HPLC on a chiral phase with LC-CD coupling, and assignment of their axial configurations by quantum chemical CD calculations.

    Subtopic D:

    Oxidative Aryl Coupling Reactions – A Biomimetic Approach to Axially Chiral Biaryl Natural Products

    Figure 10: Oxidative non-phenolic coupling as the decisive step in the total synthesis of murrastifoline-F, an unsymmetrically N,C-bonded axially chiral biscarbazole, its atropisomer resolution, and configurational assignment by CD spectroscopy in combination with quantum chemical CD calculations – the natural enantiomeric ratio of murrastifoline-F in the root extract of Murraya koenigii was determined using LC-CD coupling.

    3. Brief Description:

    The importance of axially chiral biaryls has steadily grown during the past decades [1]. One reason is that nature offers a large number of representatives of this class of compounds exhibiting, in many respects, interesting pharmacological activities. Likewise intriguing is the broad structural variety of naturally occurring biaryls (see Figure 1), among them e.g., dimeric sesquiterpenes like mastigophorene B or bicoumarins like (+)-isokotanin A, but also mixed, constitutionally unsymmetric biaryls such as the phenylanthraquinone knipholone or naphthylisoquinoline alkaloids like dioncopeltine A, ancistroealaine A, or korupensamine B. Of particular importance among these natural products are the biscarbazole murrastifoline-F and the naphthylisoquinoline ancisheynine, which represent very rare natural N,C-bonded biaryls.

    In view of the increasing importance of atropisomerism, it is astonishing that synthetically useful methods for the atroposelective construction of axially chiral biaryls are still rare. For the regio- and stereoselective formation of axially chiral biaryl systems, even sterically highly hindered, we have developed a fundamentally new approach, the 'lactone method'. It differs from most other coupling reactions by solving the two formal partial tasks of atropisomer-selective synthesis separately: the C-C bond formation and the asymmetric induction (see also 'The Lactone Concept'). The method has almost no restrictions concerning the substitution pattern, works even for substrates with high steric hindrance at the ortho-position(s) of the axis, and allows the optional, atropo-divergent preparation of either of the two atropisomers from the same biaryl lactone precursor, and it permits a recycling of the undesired minor product in the sense of a chiral economy. A broad series of successful applications in natural product syntheses underlines the high value of this pathway to axially chiral compounds [2-6].

    A rewarding synthetic target molecule is the antimalarial naphthylisoquinoline alkaloid dioncopeltine A from the Westafrican tropical liana Triphyophyllum peltatum (Dioncophyllaceae). Its stereoselective total synthesis [2,3] is shown in Figure 2. The bromoester 1 was 7,1'-coupled and O-deisopropylated to provide lactone 2 in 92% yield. For the stereochemical key step, the now atropo-diastereoselective ring opening, the chiral oxazaborolidine-borane system gave the best asymmetric induction, leading to the rotationally stable biaryl (M)-3 in good optical yields (> 90% de, matched case). Its conversion into natural dioncopeltine A was completed by N-debenzylation. The small amount of the undesired diastereomer (P)-3, obtained during the dynamic kinetic resolution of the lactone 2, can be reused by re-cyclization to 2 (here with oxidation).

    The korupensamines A and B, two antimalarial naphthylisoquinoline alkaloids and also halves of the quaterarylic anti-HIV active michellamine B (see Figure 3), constituted a special challenge for the lactone methodology [4-7]. These two atropo-diastereomeric metabolites of the Cameroonian vine Ancistrocladus korupensis have, at first sight, no evident C1-unit next to the biaryl axis for the prefixation of the two aromatic portions in the form of an ester bridge. Therefore, all initial synthetic approaches – including the first total synthesis by our group [8] – were based on intermolecular coupling steps, giving mostly moderate chemical yields and low asymmetric inductions (always in favor of P), with no possibility to direct the stereochemical outcome atropo-diastereodivergently. A closer look at the structures of the korupensamines, however, does reveal the presence of the required C1-unit, but only 'cryptic', i.e., hidden as part of the second naphthalene ring. Our atropo-divergent synthesis of korupensamine A and B was therefore performed via the respective atropisomers of 5 (see Figure 3). These phenyltetrahydroisoquinolines are, indeed, equipped with a C1-unit in the proximity of the axis for the subsequent construction of the second naphthalene ring and as a 'bridgehead' for their synthesis from a joint lactone precursor 4. By use of the appropriate oxazaborolidine enantiomers, the two possible atropisomeric products, (P)-5 or, optionally, (M)-5, were obtained with high asymmetric inductions (dr 94:6 or 4:96) from 4. The first atropo-divergent korupensamine synthesis was completed by Stobbe reaction and subsequent ring closure to give korupensamine A from (P)-5 and korupensamine B from (M)-5, respectively [7]. Dimerization (or mixed coupling) of these two components by phenolic oxidation to give the corresponding michellamines, e.g., michellamine B, has been achieved even without any O- or N-protective groups [9].

    An interesting biaryl natural product without centrochirality and without nitrogen, is knipholone [10] (see Figure 4), an antimalarial phenylanthraquinone from the torch lily Kniphofia foliosa and other African plants, endemic to East Africa. Being composed of an anthraquinone (viz. chrysophanol) and a phenyl (viz. xanthophylline) moiety, it represents one of the rare 'true' examples of a constitutionally unsymmetric natural biaryl. One of the characteristics of our synthesis [4,5,11,12] (and of the lactone method in general) is its convergent character, allowing independent preparation of the two molecular portions 6 and 7. Attachment of the carboxylic acid 6 and the phenolic part 7 was achieved by conversion to the bromoester 8. Good to excellent yields were obtained for the decisive steps, the biaryl bond formation and the enantioselective lactone cleavage, despite strong steric hindrance. The atroposelective ring opening of the configurationally unstable lactone 9 with (R)-oxazaborolidine-activated borane afforded the biaryl 10 in an excelllent er of 98:2 and in 72% chemical yield. Compound 10 was further converted into knipholone and other likewise naturally occurring antimalarial phenylanthraquinones such as knipholone anthrone, which is the 10-dihydrodeoxy analog of knipholone [11,12].

    The preparation of the nerve-growth stimulating dimeric sesquiterpenes mastigophorenes A and B (see Figure 5) represents an instructive example to compare the advantages and disadvantages of two different approaches of the lactone concept, one including a dynamic kinetic resolution of the configurationally unstable six-membered lactone 12 [4,5,13], while the second one uses related, but configurationally stable seven-membered lactones 13 [4,14]. These owe their stereochemical stability to an additional CH2-unit in the bridge, thus necessitating to perform the ring cleavage reaction according to the principle of a 'normal', i.e., non-dynamic kinetic resolution.

    Key substrate is the configurationally stable 'aromaticaliphatic' lactone 11. It has proven to be an ideal substrate for a virtually perfect (krel > 300!) non-dynamic kinetic resolution of (rac)-11, by the oxazaborolidine borane system. The remaining unreacted enantiomer, (R,R)-11, as obtained in excellent chemical and optical yields, was then converted to the natural monomer herbertenediol as the starting material for the preparation of both, the six- and the seven-membered biaryl lactones 12 and 13 by standard transformation reactions [13,14].

    The configurational instability of six-membered lactone 12 permitted its ring cleavage to proceed atropo-diastereo-divergently, according to the principle of a dynamic kinetic (here diastereomeric) resolution. By use of the appropriate oxazaborolidine enantiomers, the two atropisomeric mastigophorenes A and B were obtained with high asymmetric inductions (dr 97:3 or 92:8) from the six-membered biaryl lactone 12 [5,13].

    Application of the seven-membered lactone methodology has been used for a short synthesis of mastigophorene B by non-dynamic kinetic resolution of (M/P)-13 using (R)-oxazaborolidine-activated borane leading to stereochemically partially enriched (M)-13 with a diastereomeric ratio of 81:19. Reduction of (M)-13 with lithium aluminum hydride, followed by a few further (standard) steps gave stereochemically pure mastigophorene B [4,14]. Although the atropisomer-differentiating selectivity in the resolution step was only moderate, this pathway applying a non-dynamic kinetic resolution of a configurationally stable lactone-bridged biaryl represents the as yet shortest und most convergent synthesis of mastigophorene B. In comparison to our lactone method via configurationally unstable biaryl lactones, the approach via seven-membered biaryl lactones is especially well-suited for constitutionally symmetric biaryls, since it avoids the need of first building up two different aryl compounds (a bromo acid and a phenolic portion) for the construction of a six-membered lactone, thus significantly reducing the number of required reaction steps. The biaryl bond of seven-membered lactones such as (M/P)-13 is generally formed in an Ullmann-type coupling of identical aryl halides, thus permitting an easy construction of symmetric biaryls like the mastigophorenes from only one 'monomeric' unit [4,14]. This makes also understandable that the lactone methodology via six-membered lactones is particularly useful for the synthesis of constitutionally unsymmetric target molecules.

    Based on the same concept, the biaryl portions of (+)-isokotanin A was prepared both via six- and seven-membered biaryl lactones (see Figure 6). Given the constitutionally symmetric structure of isokotanin, an approach via seven-membered biaryl lactones like 18 appeared to be more efficient, because the preparation of the lactone 18 required just one aromatic substrate for the Ullmann coupling, viz. bromo ester 17 (R = Me), but it also circumvented the regioselectivity problem arising in the Pd-mediated coupling of diaryl ester 14, being the precursor of the configurationally unstable six-membered lactone 15. The atropisomer-selective ring cleavage of 15 with potassium (1R)-mentholate as an O-nucleophile resulted in a dr of 74:26 in favor of (M)-16 [4-6]. The non-dynamic kinetic resolution of 18 with the oxazaborolidine-borane system proceeded with high relative rate constants (krel = 43). After 56% conversion, 46% of the ring opened diol (M)-19 were obtained with an enantiomeric ratio of 87.5:12.5 in favor of the M-product (further enriched to 97.5:2.5 by a single crystallization step). The remaining unreacted enantiomer of 18 can be reused, by brief thermal racemization (t1/2 = 6 min, 100°C) and renewed ring cleavage. Diol (M)-19 was taken as the starting material for the completion of the synthesis of (+)-isokotanin [3-6,15].

    Again by using the 'lactone concept', a novel, highly stereoselective approach to the AB fragment of vancomycin, a glycopeptide antibiotics clinically used against bacterial infections, has been realized (see Figure 7). Starting from the substituted benzoic acid 20 (representing ring fragment A) and the phenolic building block 21, i.e., (R)-p-hydroxyphenylglycine (the proposed ring B portion), the biaryl lactone 23 was obtained by intramolecular coupling of 22 in high yields. Ring opening of 23 using 'S-BINAL-H' as the chiral H-nucleophile afforded the configurationally instable AB fragment (P)-24, which was, however, found to isomerize slowly at room temperature, resulting in a ca. 1:1 mixture of the two atropo-diastereomers, (P)- and (M)-24. Their configurational instability was circumvented by inclusion of two chlorine atoms in the B ring to give (M)-26. The stereochemical key step of this approach proceeded in the sense of a dynamic kinetic resolution of an atropodiastereomeric mixture of a configurationally labile lactone-bridged intermediate 25. Oxazaborolidine- mediated reduction finally gave the stereochemically stable biaryl AB fragment (M)-26 with high atroposelectivity (dr 94:6) [16].

    The total synthesis of the antileishmanial naphthylisoquinoline alkaloid ancistrotanzanine B (from the East African liana Ancistrocladus tanzaniensis) and its atropodiastereomer, ancistroealaine A (from the Central African liana Ancistrocladus ealaensis), was accomplished via a short and efficient synthetic pathway (see Figure 8). The key step was the construction of the stereogenic biaryl axis by Suzuki coupling of the naphthylboronic acid 27 and the dihydroisoquinoline iodide 28. Particularly remarkable is the fact that the Suzuki coupling still worked in the presence of a free imino function, and when using chiral palladium catalysts like the ferrocene 29 or the C2-symmetric diphosphine (P)-30 (BINAP). It even gave quite good asymmetric inductions, leading to atropoisomeric ratios of up to 75:25, in favor of ancistrotanzanine B as it became evident from LC-CD analysis, although it was not yet possible to likewise produce the other atropisomer, ancistroealaine A, preferentially, by using the other reagent enantiomers [17,18].

    The first total synthesis of an N,C-coupled naphthylisoquinoline alkaloid, ancisheynine (see Figure 9) from the Indian liana Ancistrocladus heyneanus (Ancistrocladaceae), was performed by condensing a monocyclic diketone (like 31) or the respective benzopyrylium salt with an aminonaphthalene (like 32) [19]. The introduction of the amino function at C-8 of the naphthalene core was achieved by Buchwald-Hartwig amination with tert-butyl carbamate as an ammonia equivalent. The best results were obtained by using Pd2(dba)3 and DAV-Phos as the catalytic system. The electronic property of the counterion has a substantial impact on the stability of ancisheynine, with the electron-poor trifluoroacetate as the best counterion. The presence of a rotationally hindered axis in ancisheynine was demonstrated by resolution of its two atropo-enantiomers by HPLC on a chiral phase with LC-CD coupling. The assignment of their axial configurations succeeded by quantum chemical CD calculations.

    In contrast to its publication as a 'flat' structure, the Murraya alkaloid murrastifoline-F is a stereochemically interesting unsymmetric, N,C-bonded heterobiarylic biscarbazole (see Figure 10). Starting from the likewise naturally occurring, but synthetically prepared 'monomer' murrayafoline-A, lead tetraacetate-mediated oxidative non-phenolic biaryl coupling gave murrastifoline-F as the main regioisomer [9,20]. The existence of this biaryl as a pair of stable atropo-enantiomers was demonstrated by chromatography on chiral phase with LC-CD coupling. Preparatively, the racemate resolution succeeded by O-demethylation, derivatization with Mosher's reagent, and chromatographic separation of the resulting diastereomers. The absolute configurations of the atropisomers were assigned by CD spectroscopy in combination with quantum chemical CD calculations at the stage of the alkaloid murrastifoline-F, and by ROESY experiments of the diastereomeric Mosher derivatives. In the root extract of the Asian curry leaf plant Murraya koenigii (Rutaceae), murrastifoline-F was found to exist as a 56:44 mixture in favor of the M-enantiomer, by LC-CD coupling [20].

    4. Selected Publications

    [1] G. Bringmann, C. Günther, M. Ochse, O. Schupp, S. Tasler; Biaryls in Nature: A Multi-Facetted Class of Stereochemically, Biosynthetically, and Pharmacologically Intriguing Secondary Metabolites. In: Progress in the Chemistry of Organic Natural Products (W. Herz, H. Falk, G.W. Kirby, R.E. Moore, eds.), Vol. 82, Springer-Verlag, Wien, New York, 2001.
    [2] 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.
    [3] 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.
    [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, 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.
    [8] G. Bringmann, R. Götz, P.A. Keller, R. Walter, P. Henschel, M. Schäffer, M. Stäblein, T.R. Kelly, M.R. Boyd; First total synthesis of korupensamines A and B. Heterocycles 1994, 39, 503-508.
    [9] G. Bringmann, S. Tasler; Oxidative aryl coupling reactions: a biomimetic approach to configurationally unstable or axially chiral biaryl natural products and related bioactive compounds. Tetrahedron 2001, 57, 331-343.
    [10] G. Bringmann, K. Maksimenka, J. Mutanyatta-Comar, M. Knauer, and T. Bruhn; The absolute axial configurations of knipholone and knipholone anthrone by TDDFT and DFT/MRCI CD calculations: a revision. Tetrahedron 2007, 63, 9810-9824.
    [11] 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.
    [12] G. Bringmann, D. Menche, J. Kraus, J. Mühlbacher, K. Peters, E.-M. Peters, R. Brun, M. Bezabih, B.M. Abegaz; Atropo-enantioselective total synthesis of knipholone and related antiplasmodial phenylanthraquinones. J. Org. Chem. 2002, 67, 5595-5610.
    [13] 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.
    [14] G. Bringmann, J. Hinrichs, T. Pabst, P. Henschel, K. Peters, E.-M. Peters; From dynamic to non-dynamic kinetic resolution of lactone-bridged biaryls: synthesis of mastigophorene B. Synthesis 2001, 155-167.
    [15] 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.
    [16] 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.
    [17] G. Bringmann, A. Hamm, M. Schraut; Atroposelective biaryl coupling with chiral catalysts: total synthesis of the antileishmanial naphthylisoquinoline alkaloids ancistrotanzanine B and ancistroealaine A. Org. Lett. 2003, 5, 2805-2808.
    [18] 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.
    [19] G. Bringmann, T. Gulder, M. Reichert, F. Meyer; Ancisheynine, the first N,C-coupled naphthylisoquinoline alkaloid: total synthesis and stereochemical analysis. Org. Lett. 2006, 8, 1037-1040.
    [20] G. Bringmann, S. Tasler, H. Endress, J. Kraus, K. Messer, M. Wohlfarth, W. Lobin; Murrastifoline-F: First total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid. J. Am. Chem. Soc. 2001, 123, 2703-2711.

    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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