DOI: 10.1002/chem.201403880

Communication

& Natural Products

Total Synthesis of Isoquinocyclinone Mike Dischmann, Timo Frassetto, M. Andr Breuning, and Ulrich Koert*[a] cinose B.[4] Synthetic solutions for this rare sugar have already been reported, while no synthesis of the quinocyclines or the aglycones exists so far.[5] Here, a total synthesis of isoquinocyclinone is communicated. The heptacyclic structure of isoquinocylinone consists of an anthraquinoide tetracycle (rings A–D) and a bicyclic amidine (rings F,G) that connects C7 and C9O by an N,O-spiro center C2’ in ring E (Scheme 1). The bicyclic F,G-heterocycle, a 2,4,5,6-

Abstract: The total synthesis of the heptacyclic natural product isoquinocyclinone has been achieved. A Hauser annulation was used to assemble the anthraquinone core structure. The unique 2,4,5,6-tetrahydropyrrolo[2,3-b]pyrrole substructure was prepared by alkyne addition to a lactone intermediate and subsequent Ni0-mediated cyanide addition, the conversion of an O,O- into an N,O-acetal, and final intramolecular N-alkylation.

Isoquinocyclinone is the common aglycone of isoquinocycline A and B. Both natural products belong to the quinocyclines, a class of anthracycline natural products consisting of quinocycline A and B as well as isoquinocycline A and B (Figure 1). These antimicrobial and cytotoxic compounds were isolated first from Streptomyces aureofaciens[1] and later from micromonospora sp. (TP-A0468)[2] and Streptomyces violaceus niger.[3] The structure of isoquinocycline A was established by X-ray crystal structure analysis.[1e] The sugar part of quinocycline A and isoquinocycline A is the branched octose dihydrotrioxacarScheme 1. Retrosynthetic analysis for isoquinocyclinone.

tetrahydropyrrolo[2,3-b]pyrrole, is unique among natural products. A retrosynthetic consideration that takes account model studies for the construction of the pyrrolopyrrole[6, 7] leads from isoquinocyclinone to a lactone 1 as a key intermediate. This anthraquinoide tetracycle of 1 could be assembled by annulation of the cyanoisobenzofuranone 2 and the cyclohexenone 3. The starting point for the synthesis of enone 3 is the iodide 4[8] (Scheme 2), which was transformed via its organolithium

Figure 1. Structures of quinocyclines.

[a] Dipl.-Chem. M. Dischmann, Dr. T. Frassetto, Dr. M. A. Breuning, Prof. Dr. U. Koert Fachbereich Chemie Philipps-Universitt Marburg Hans-Meerwein-Straße, 35043 Marburg (Deutschland) Fax: (+ 49) 6421-2825677 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403880. Chem. Eur. J. 2014, 20, 11300 – 11302

Scheme 2. Synthesis of enone 3: a) tBuLi, THF, 78 8C, methacroleine; b) Ac2O, py; c) cat. PdCl2, PPh3, Na2CO3, dioxane, 110 8C; d) Me2AlCl, CH2Cl2, 78!35 8C, 80 h; e) 17 % HCl, THF/H2O, RT; f) TBSCl, imidazole, DMF, RT.

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Communication compound into acetate 5. A Pd-mediated elimination resulted in the E-selective formation of diene 6.[9] The subsequent Diels–Alder reaction with enone 7 led to the racemic cyclohexene 8. An acid-catalyzed aldol condensation produced the desired cyclohexenone 3. An enantioselective variant (82 % ee) of this cycloaddition/aldol condensation sequence is described in the Supporting Information. Hauser annulation[10] of cyano-1(3H)-isobenzofuranone 2[11] with enone 3 gave after oxidative aromatization anthraquinone 9 (Scheme 3). Methyl ether formation and subsequent

Scheme 4. a) TBSO(CH2)2CCH, LiHMDS, THF, 78 8C, 45 min; then 15, THF, 78 8C to RT, 6 h; b) K2[Ni(CN)4], KCN, Zn, H2O, RT, 4 h; then 0 8C, MeOH, 16 THF/MeOH, 0 8C, 30 min; c) TsCl, Et3N; d) HCl; e) TsCl, Et3N; f) TMSCl, NH3, CHCl3 ; g) CAN, MeCN, H2O; h) 2,6-lutidine, 120 8C; i) TBAF, THF, 90 min, RT; j) 3 HF  NEt3, CH2Cl2, RT, 18 h; k) BCl3 (1 m in CH2Cl2), CH2Cl2, 10 8C then 1 h RT. CAN = cerium ammonium nitrate; LiHMDS = lithium hexamethyl disilazide; TBAF = tetrabutylammonium fluoride.

Scheme 3. a) LDA, THF, 78 8C, then 3, 78 8C!RT, 8 h; b) DMF, O2, 95 8C, 16 h; c) Me2SO4, K2CO3, acetone reflux. 4 h; d) HCl; e) Dess–Martin reagent; f) KH2PO4, NaClO2, amylene, tBuOH, RT, 1 h; g) KI/I2, NaHCO3 ; h) K2CO3, MeOH/THF 0 8C; i) 3 m H2SO4, acetone/H2O; j) Na2S2O4, KOH, Me2SO4, phasetransfer catalysis, CH2Cl2/H2O; k) TBSCl, imidazole.

TBS deprotection led to the primary alcohol 10 that was oxidized to the carboxylic acid 11. An iodolactonization afforded lactone 12 and subsequently the epoxy methyl ester 13. The latter was converted into the hydroxyl lactone 14. The direct epoxidation of 11 gave a mixture of diastereomers and caused purification problems. Initial experiments revealed an interference of the anthaquinone structure with the introduction of the pyrrolopyrrol part. Therefore, this substructure was protected as anthrahydroquinone dimethyl ether. After TBS protection of the benzylic alcohol the TBS-lactone 15 was obtained. Elaboration of the bicyclic amidine (rings F,G) is summarized in Scheme 4. Acylation of lactone 15 with 4-tert-butyldimethylsilyloxy-butyne gave hydroxyketone 16, which was isolated as a 1:1 mixture of the hemiacetal and the hydroxyl ketone. Hydrocyanation of the alkynone 16 with in situ generated [Ni0(CN)4]4 gave the cyclic imidate 17. The structure of 17 was Chem. Eur. J. 2014, 20, 11300 – 11302

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confirmed by comparison with NMR spectroscopic data of a related structure, in which an X-ray structure had been obtained.[7] The following conversion into the ditosylate 18 required a three-step sequence with a separate introduction of the sulfonamide first and the sulfonate second. Attempts for a simultaneous introduction of both tosyl groups led to side reactions (lactam formation). Treatment of compound 18 with ammonia and TMSCl resulted in a conversion of the O,O-acetal into an epimeric mixture of the N,O-acetals 19 and 20. Compound 19 corresponds to the configuration of isoquinocycline A/B, whereas compound 20 shows the configuration of quinocycline A/B. Both epimers could be separated by chromatography. While focussing on the final ring-closure of the pyrrolopyrrol substructure it was found advantageous to regenerate the anthraquinone first. CAN-oxidation of anthrahydroquinone dimethyl ether 19 resulted in the corresponding anthraquinone. After lutidine-mediated[7] ring G closure via intramolecular amidine alkylation, the complete isoquinocyclinone structure 21 was obtained. The optimal order for final deprotection of the three different protective groups was TBAF-initiated TBS-cleavage first, HF-mediated sulfonamide removal second, and last methyl-ether deprotection by BCl3. Racemic isoquinocylinone obtained after deprotection matched the reported analytical and spectroscopic data for the natural product.[2, 12] The

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Communication epimeric N,O-acetal 20 could not be cyclised towards quinocyclinone by using lutidine. Instead, it could be epimerized with trifluoroacetic acid (TFA) to the isoquinocyclinone precursor 19. In conclusion, an efficient synthesis of the heptacyclic isoquinocyclinone structure was achieved. Noteworthy is the construction of the pyrrolopyrrol substructure in the presence of the anthracyclinone moiety. The 2,4,5,6-tetrahydropyrrolo[2,3b]pyrrole substructure was prepared by acylation of a lactone intermediate, subsequent conversion of an O,O- into an N,Oacetal and ring G-closure by intramolecular N-alkylation. The synthesis opens the route for the study of the mode of action of this structurally unique natural product, which may result from intercalation of the anthracyclinone part between DNA base pairs and covalent fixation of the N,O-acetal to DNA amino groups.

[2]

[3] [4]

[5]

[6] [7]

Acknowledgements Financial support by the DFG (KO 1349/8-2) is gratefully acknowledged. Keywords: acetals · Hauser annulation · isoquinocyclinone · natural products · total synthesis [1] a) W. D. Celmer, K. Murai, K. V. Rao, F. W. Tanner, W. S. Marsh, Antiobiotics Annual 1957 – 1958; Medical Enceclopedia Inc.: New York, 1958, pp. 484 – 492; b) T. J. McBride, A. R. English, Antiobiotics Annual 1957 – 1958; Medical Enceclopedia Inc.: New York, 1955; pp. 493 – 501; c) J. H. Martin, A. J. Shay, L. M. Pruess, J. N. Porter, J. H. Mowat, N. Bohonos, Antiobiotics Annual 1954 – 1955; Medical Enceclopedia Inc.: New York, 1955; pp. 1020 – 1024; d) D. B. Cosulich, J. H. Mowat, R. W. Broschard,

Chem. Eur. J. 2014, 20, 11300 – 11302

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[8] [9] [10] [11] [12]

J. B. Patrick, W. E. Meyer, Tetrahedron Lett. 1963, 7, 453 – 458; Erratum, Tetrahedron Lett. 1964, 13, 750; e) A. Tulinsky, J. Am. Chem. Soc. 1964, 86, 5368 – 5369. a) T. Furumai, Y. Igarashi, H. Higuchi, N. Saito, T. Oki, J. Antibiot. 2002, 55, 128 – 133; Corrections, J. Antibiotics 2003, 56, C1; b) Y. Igarashi, H. Higuchi, T. Oki, T. Furumai, J. Antibiot. 2002, 55, 134 – 140; Corrections J. Antibiotics 2003, 56, C1. M. Y. El-Naggar, J. Microbiol. 2007, 45, 262 – 267. a) J. S. Webb, R. W. Broschard, D. B. Cosulich, J. H. Mowat, J. Am. Chem. Soc. 1962, 84, 3183 – 3184; b) U. Matern, H. Grisebach, W. Karl, H. Achenbach, Eur. J. Biochem. 1972, 29, 1 – 4; c) U. Matern, H. Grisebach, Eur. J. Biochem. 1972, 29, 5 – 11. a) C. M. Kçnig, K. Harms, U. Koert, Org. Lett. 2007, 9, 4777 – 4779; b) H. Paulsen, V. Sinnwell, Chem. Ber. 1978, 111, 869 – 878; c) H. Paulsen, V. Sinnwell, Chem. Ber. 1978, 111, 879 – 889; d) T. Suami, K. Nakamura, T. Hara, Chem. Lett. 1982, 1245 – 1248; e) T. Suami, K. Nakamura, T. Hara, Bull. Chem. Soc. Jpn. 1983, 56, 1431 – 1434; f) T. Magauer, A. G. Myers, Org. Lett. 2011, 13, 5584 – 5587. M. A. Breuning, K. Harms, U. Koert, Org. Lett. 2011, 13, 1402 – 1405. a) J. Cordes, K. Harms, U. Koert, Org. Lett. 2010, 12, 3808 – 3811; b) M. Kitamura, K. Kubo, S. Yoshinaga, H. Matsuzaki, K. Ezaki, T. Matsuura, D. Matsuura, N. Fukuzumi, K. Araki, M. Narasaki, Tetrahedron Lett. 2014, 55, 1653 – 1656. Y. S. Lee, L. D. Valle, G. L. Larson, Synth. Commun. 1987, 17, 385 – 391. P. Hewawasam, Y. S. Rho, F. M. Hauser, J. Org. Chem. 1989, 54, 5110 – 5114. a) F. M. Hauser, R. P. Rhee, J. Org. Chem. 1978, 43, 178 – 180; b) D. Mal, P. Pahari, Chem. Rev. 2007, 107, 1892 – 1918. J. N. Freskos, G. W. Morrow, J. S. Swenton, J. Org. Chem. 1985, 50, 805 – 810. We thank Prof. Igarashi for kindly supply of copies of the NMR spectra of isoquinocycline A and isoquinocyclinone. The NMR spectra of the pyrrolo–pyrrol substructure, in particular, C3’, C4’, and C5’ exhibited signal broadening that indicates a dynamic process associated with amidine tautomers.

Received: June 9, 2014 Published online on July 22, 2014

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Total synthesis of isoquinocyclinone.

The total synthesis of the heptacyclic natural product isoquinocyclinone has been achieved. A Hauser annulation was used to assemble the anthraquinone...
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