[2+2+2] Cycloadditions of Alkynylynamides – A Total Synthesis of Perlolyrine and the First Total Synthesis of “Isoperlolyrine”

The total syntheses of the carboline alkaloids perlolyrine and "isoperlolyrine" are reported. Key-steps of the syntheses are Negishi coupling reactions on alkynylynamides and their metal-catalyzed [2+2+2] cycloadditions with nitriles to form the β- and γ-carboline cores. The choice of the catalyst strongly affects the β/γ ratio. Spectroscopic features of the γ-isomer are distinctly different from those of the naturally occurring isoperlolyrine.

[1]  J. Louie,et al.  [2+2+2] Cycloaddition Reactions Catalyzed by Transition Metal Complexes , 2006 .

[2]  L. Du,et al.  Flazinamide, a novel beta-carboline compound with anti-HIV actions. , 2007, Biochemical and biophysical research communications.

[3]  P. Reider,et al.  Syntheses of Indoles via a Palladium-Catalyzed Annulation between Iodoanilines and Ketones. , 1997, The Journal of organic chemistry.

[4]  T. Ohira,et al.  Effects of β- and γ-carboline derivatives on DNA topoisomerase activities , 1996 .

[5]  Tian-Shung Wu,et al.  Alkaloids and other constituents from Tribulus terrestris , 1999 .

[6]  K. Shin‐ya,et al.  Structure of mescengricin, a novel neuronal cell protecting substance produced by Streptomyces griseoflavus , 1997 .

[7]  B. Heller,et al.  The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions. , 2007, Chemical Society reviews.

[8]  D. Kingston,et al.  Synthesis and biological evaluation of analogues of cryptolepine, an alkaloid isolated from the Suriname rainforest. , 1999, Journal of natural products.

[9]  P. Sedmera,et al.  Alkaloids of Gloriosa superba L. , 1984 .

[10]  D. Boger,et al.  Formal total synthesis of streptonigrin , 1983 .

[11]  H. Bönnemann.  Organocobaltverbindungen in der Pyridinsynthese – ein Beispiel für Struktur‐Wirkungs‐Beziehungen in der Homogenkatalyse , 1985 .

[12]  A. Moretto,et al.  Synthesis of Pyridine-Containing Macrocycles by Cobalt-Mediated Trimerization of Triply-Bonded Species , 2001 .

[13]  Björn C. G. Söderberg,et al.  A novel palladium-catalyzed synthesis of β-carbolines: application in total synthesis of naturally occurring alkaloids , 2003 .

[14]  D. Hildebrand,et al.  β‐Carbolin‐Alkaloide, II Tributyl(1‐ethoxyvinyl)stannan als C2‐Baustein für die Synthese von β‐Carbolin‐Alkaloiden , 1993 .

[15]  Yoshihiko Yamamoto,et al.  Synthesis of 2-Haloalkylpyridines via Cp*RuCl-Catalyzed Cycloaddition of 1,6-Diynes with α-Halonitriles. Unusual Halide Effect in Catalytic Cyclocotrimerization , 2005 .

[16]  A. Brossi,et al.  β‐Carbolines from Japanese Sake and Soy Sauce: Synthesis and Biological Activity of Flazin and Yellow Substance YS (Perlolyrine) , 1988, Archiv der Pharmazie.

[17]  W. Schunack,et al.  beta-Carbolines as benzodiazepine receptor ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of beta-carboline-3-carboxylic acid. , 1983, Journal of Medicinal Chemistry.

[18]  L. Castedo,et al.  Synthesis of Annelated Substituted Bipyridines and Terpyridines by Cobalt(I)-Catalyzed [2 + 2 + 2] Cycloaddition† , 1997 .

[19]  A. Moretto,et al.  Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions. , 2005, Journal of the American Chemical Society.

[20]  P. Skolnick,et al.  Synthesis of 6-substituted beta-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists. , 1987, Journal of medicinal chemistry.

[21]  K. Itoh,et al.  Significant chemo- and regioselectivies in the Ru(II)-catalyzed [2+2+2] cycloaddition of 1,6-diynes with dicyanides. , 2001, Journal of the American Chemical Society.

[22]  B. Love.  SYNTHESIS OF β-CARBOLINES. A REVIEW , 1996 .

[23]  J. Panek,et al.  Palladium (O) mediated β-carboline synthesis: Preparation of the CDE ring system of lavendamycin , 1984 .

[24]  R. Larock,et al.  Synthesis of Annulated γ-Carbolines by Palladium-Catalyzed Intramolecular Iminoannulation , 2002 .

[25]  S. Kotha,et al.  Transition Metal Catalyzed (2+2+2) Cycloaddition and Application in Organic Synthesis , 2005 .

[26]  Tun Liu,et al.  Perlolyrine: A β-Carboline Alkaloid from Codonopsis pilosula , 1988 .

[27]  Ken Tanaka,et al.  Cationic Rhodium(I)/Modified-BINAP Catalyzed [2+2+2] Cycloaddition of Alkynes with Nitriles , 2006 .

[28]  Jesús A. Varela,et al.  Construction of pyridine rings by metal-mediated [2 + 2 + 2] cycloaddition. , 2003, Chemical reviews.

[29]  L. Castedo,et al.  One-Step Synthesis of Symmetrical 3,3‘-Substituted 2,2‘-Bipyridine Ligands by Cobalt(I)-Catalyzed [2 + 2 + 2] Cycloadditions , 1998 .

[30]  S. Okamoto,et al.  On-Demand Generation of an Efficient Catalyst for Pyridine Formation from Unactivated Nitriles and α,ω-Diynes Using CoCl2-6H2O, dppe, and Zn , 2007 .

[31]  S. Apers,et al.  Inhibitors of Xanthine Oxidase and Scavengers of Superoxide Anions from Cryptolepis sanguinolenta (Lindl.) Schlechter (Periplocaceae) , 2000 .

[32]  F. Marsais,et al.  Convergent synthesis of streptonigrin and Lavendamycin analogues , 1993 .

[33]  O. Walker,et al.  NMR screening applied to the fragment-based generation of inhibitors of creatine kinase exploiting a new interaction proximate to the ATP binding site. , 2007, Journal of medicinal chemistry.

[34]  Yoshihiko Yamamoto,et al.  Ruthenium-catalyzed cycloaddition of 1,6-diynes and nitriles under mild conditions: role of the coordinating group of nitriles. , 2006, Chemistry.

[35]  T. Sakamoto,et al.  Novel synthetic strategy of carbolines via palladium-catalyzed amination and arylation reaction , 1999 .

[36]  M. Lautens,et al.  Transition Metal-Mediated Cycloaddition Reactions. , 1996, Chemical reviews.

[37]  J. Kavitha,et al.  Jusbetonin, the first indolo[3,2-b]quinoline alkaloid glycoside, from Justicia betonica. , 2004, Journal of natural products.

[38]  Waya Sengpracha,et al.  A Revised Structure for the Alkaloid, Tribulusterine, from Tribulus terrestris L. , 2004 .

[39]  V. Gandon,et al.  Synthesis of tricyclic fused 3-aminopyridines through intramolecular Co(I)-catalyzed [2+2+2] cycloaddition between ynamides, nitriles, and alkynes. , 2009, Chemistry.

[40]  G. Oehme,et al.  Photoassisted cocyclization of acetylene and nitriles catalyzed by cobalt complexes at ambient temperature and normal pressure , 1989 .

[41]  T. Parella,et al.  Microwave‐Enhanced Rhodium‐Catalyzed [2+2+2] Cycloaddition Reactions To Afford Highly Functionalized Pyridines and Bipyridines , 2010 .

[42]  A. A. Semenov,et al.  Pyrido[2,3-b]indoles (α-carbolines) (review) , 1984 .

[43]  R. Larock,et al.  Synthesis of β- and γ-carbolines by the palladium/copper-catalyzed coupling and copper-catalyzed or thermal cyclization of terminal acetylenes , 2002 .

[44]  K. Vollhardt,et al.  Cobalt‐katalysierte einstufige Synthese von anellierten Pyridinen , 1977 .

[45]  M. Guyot,et al.  Grossularine-1 and grossularine-2, cytotoxic α-carbolines from the tunicate: Dendrodoa grossularia , 1989 .

[46]  K. Vollhardt.  Cobalt-vermittelte [2+2+2]-Cycloadditionen: eine ausgereifte Synthesestrategie , 1984 .

[47]  L. Castedo,et al.  Synthesis of carbazoles by dehydro Diels–Alder reactions of ynamides , 2008 .

[48]  Nicola Della Ca’,et al.  New Protocols for the Synthesis of Condensed Heterocyclic Rings Through Palladium-Catalyzed Aryl Coupling Reactions , 2010 .

[49]  De novo synthesis of substituted pyridines , 2004 .

[50]  S. Paul,et al.  Biomimetic approach to potential benzodiazepine receptor agonists and antagonists. , 1984, Journal of medicinal chemistry.

[51]  Aldo Previero,et al.  Des structures simples aux potentialités pharmacologiques élevées : les β-carbolines. origines, synthèses, propriétés biologiques , 1985 .

[52]  S. Saito,et al.  Recent advances in the transition-metal-catalyzed regioselective approaches to polysubstituted benzene derivatives. , 2000, Chemical reviews.

[53]  F. Bracher,et al.  β‐Carbolin‐Alkaloide, I. Synthese von 1‐Aryl‐ und 1‐Alkenyl‐β‐carbolinen durch Palladium‐katalysierte Kupplungsreaktionen , 1992 .

[54]  R. Ramsay,et al.  Inhibition of Monoamine Oxidase A by β-Carboline Derivatives , 1997 .

[55]  K. Vollhardt,et al.  Catalytic co-cyclisation of α,ω-cyanoalkynes with alkynes: a versatile chemo- and regio-selective synthesis of 2,3-substituted 5,6,7,8-tetrahydroquinolines and other cycloalka[1,2-b]pyridines , 1982 .

[56]  N. Schore.  Transition metal-mediated cycloaddition reactions of alkynes in organic synthesis , 1988 .

[57]  D. Schollmeyer,et al.  First total synthesis of antiostatin A1, a potent carbazole-based naturally occurring antioxidant. , 2009, Chemical communications.

[58]  Yoshihiko Yamamoto,et al.  Cp*RuCl-Catalyzed [2 + 2 + 2] Cycloadditions of α,ω-Diynes with Electron-Deficient Carbon−Heteroatom Multiple Bonds Leading to Heterocycles , 2005 .

[59]  Yoshihiko Yamamoto,et al.  Ruthenium(II)-catalyzed [2 + 2 + 2] cycloaddition of 1,6-diynes with electron-deficient nitriles , 2001 .

[60]  F. Marsais,et al.  A new approach to the synthesis of lavendamycin analogues. , 1993 .

[61]  C. Meester.  Genotoxic potential of beta-carbolines: a review. , 1995 .

[62]  C. W. Andrews,et al.  The isolation and structure determination of cryptomisrine, a novel indolo[3,2‐b]quinoline dimeric alkaloid from cryptolepis sanguinolenta , 1996 .

[63]  I. Nakamura,et al.  Transition-metal-catalyzed reactions in heterocyclic synthesis. , 2004, Chemical reviews.

[64]  J. Jeffreys.  The alkaloids of perennial rye-grass (Lolium perenne L.). Part IV. Isolation of a new base, perlolyrine; the crystal structure of its hydrobromide dihydrate, and the synthesis of the base , 1970 .

[65]  Anlong Xu,et al.  β-Carboline Alkaloids: Biochemical and Pharmacological Functions , 2007 .