Synthesis of Pentacyclic Framework of Herquline A.

The highly strained bowl-shaped pentacyclic structure of herquline A has rendered it one of the most difficult problems in organic synthesis yet to be solved. The challenges associated with the synthesis of herquline A have been well documented in four Ph.D. dissertations and in multiple reports regarding syntheses of its structurally simpler congeners. Herein, we report the construction of the pentacyclic core of herquline A that contains both N10-C2 and C3-C3' bonds. The key for success was the development of the tandem aza-Michael addition/enolate capture protocol that set the stage for subsequent palladium catalyzed C3(sp2)-C3'(sp2) coupling reaction. Ensuing oxidative dearomatization of the left aryl ring allowed the formation of the pentacyclic diketone core of herquline A.

[1]  D. Weix,et al.  LiCl-Accelerated Multimetallic Cross-Coupling of Aryl Chlorides with Aryl Triflates , 2019, Journal of the American Chemical Society.

[2]  C. Schindler,et al.  Total Syntheses of Herqulines B and C. , 2019, Journal of the American Chemical Society.

[3]  Phil S Baran,et al.  Concise Total Synthesis of Herqulines B and C. , 2018, Journal of the American Chemical Society.

[4]  J. L. Wood,et al.  Total Synthesis of Herquline B and C. , 2019, Journal of the American Chemical Society.

[5]  C. Schindler,et al.  Scalable Synthesis of Mycocyclosin. , 2018, Organic Letters.

[6]  D. Weix,et al.  Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling To Form Highly Substituted 1,3-Dienes. , 2018, Journal of the American Chemical Society.

[7]  P. Carr,et al.  A Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Route to the Carbazole Natural Products 3-Methyl-9H-carbazole, Glycoborine, Glycozoline, Clauszoline K, Mukonine, and Karapinchamine A. , 2017, The Journal of organic chemistry.

[8]  S. Ōmura,et al.  Herquline A, produced by Penicillium herquei FKI-7215, exhibits anti-influenza virus properties , 2017, Bioscience, biotechnology, and biochemistry.

[9]  K. Houk,et al.  Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A. , 2016, Journal of the American Chemical Society.

[10]  J. Cochrane,et al.  Total synthesis of mycocyclosin. , 2012, Organic letters.

[11]  Daniel A. Everson,et al.  Replacing Conventional Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides , 2012, Journal of the American Chemical Society.

[12]  R. Sarpong,et al.  Reconciling icetexane biosynthetic connections with their chemical synthesis: total synthesis of (+/-)-5,6-dihydro-6alpha-hydroxysalviasperanol, (+/-)-brussonol, and (+/-)-abrotanone. , 2007, Organic letters.

[13]  S. Buchwald,et al.  Palladium-Catalyzed α-Arylation of Ketones , 1997 .

[14]  S. Ōmura,et al.  Herquline B, a new platelet aggregation inhibitor produced by Penicillium herquei Fg-372. , 1996, The Journal of antibiotics.

[15]  S. Ōmura,et al.  X-Ray crystal structure of herquline, a new biologically active piperazine from Penicillium herquei Fg-372 , 1980 .

[16]  S. Ōmura,et al.  Herquline, a new alkaloid produced by Penicillium herquei. Fermentation, isolation and properties. , 1979, Journal of antibiotics (Tokyo. 1968).