Stereoselective synthesis of complex polycyclic aziridines: use of the Brønsted acid-catalyzed aza-Darzens reaction to prepare an orthogonally protected mitomycin C intermediate with maximal convergency.

A concise synthesis of a highly functionalized intermediate lacking only C10 of the mitomycin backbone is described. The key to this development is the Brønsted acid-catalyzed aza-Darzens reaction used to forge the cis-aziridine. Additionally an oxidative ketalization fortuitously occurs during the quinone-enamine coupling step, leading to an orthogonally protected hydroquinone.

[1]  J. N. Johnston,et al.  To protonate or alkylate? Stereoselective Brønsted acid catalysis of C-C bond formation using diazoalkanes. , 2010, Angewandte Chemie.

[2]  Jean-Christophe Andrez.  Mitomycins syntheses: a recent update , 2009, Beilstein journal of organic chemistry.

[3]  Don L. Warner,et al.  Internal azomethine ylide cycloaddition methodology for access to the substitution pattern of aziridinomitosene A. , 2007, The Journal of organic chemistry.

[4]  J. Srinivasan,et al.  Synthesis of an advanced intermediate en route to the mitomycin natural products. , 2006, Organic letters.

[5]  R. S. Coleman,et al.  Mitomycin synthetic studies: stereocontrolled and convergent synthesis of a fully elaborated aziridinomitosane. , 2004, The Journal of organic chemistry.

[6]  J. Harwood,et al.  Effect of methoxyl group position on the regioselectivity of ammonia substitution reactions involving 3,3'-dichloro-2,2'-binaphthoquinones. , 2004, The Journal of organic chemistry.

[7]  J. N. Johnston,et al.  The Brønsted acid-catalyzed direct aza-Darzens synthesis of N-alkyl cis-aziridines. , 2004, Journal of the American Chemical Society.

[8]  T. Ling,et al.  Unified synthesis of quinone sesquiterpenes based on a radical decarboxylation and quinone addition reaction. , 2002, Journal of the American Chemical Society.

[9]  T. Ling,et al.  Synthesis of (-)-ilimaquinone via a radical decarboxylation and quinone addition reaction. , 2002, Organic letters.

[10]  J. N. Johnston,et al.  Use of the vicinal element effect for regiochemical control of quinone substitutions and its implication for convergent mitomycin construction. , 2001, Organic letters.

[11]  J. Antilla,et al.  Catalytic Asymmetric Aziridination with Arylborate Catalysts Derived from VAPOL and VANOL Ligands This work was supported by the National Institutes of Health and was performed at the University of Chicago. VAPOL=2,2'-diphenyl- , 2000, Angewandte Chemie.

[12]  H. Beall,et al.  Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development. , 2000, Frontiers in bioscience : a journal and virtual library.

[13]  J. Antilla,et al.  CATALYTIC ASYMMETRIC AZIRIDINATION WITH A CHIRAL VAPOL-BORON LEWIS ACID , 1999 .

[14]  F. Ziegler,et al.  A synthesis of (+)-9a-desmethoxymitomycin A via aziridinyl radical cyclization , 1998 .

[15]  M. Tomasz,et al.  Mitomycin C-DNA adducts generated by DT-diaphorase. Revised mechanism of the enzymatic reductive activation of mitomycin C. , 1997, Biochemistry.

[16]  Z. Wang,et al.  A total synthesis of (±)-Mitomycin K. Oxidation of the mitosene C9-9a double bond by (hexamethylphosphoramido)oxodiperoxomolybdenum (VI) (MoO5 · HMPA) , 1996 .

[17]  T. Ashizawa,et al.  Synthesis and antitumor activity of novel mitomycin derivatives containing functional groups at the C-6-methyl position. , 1994, Journal of medicinal chemistry.

[18]  S. Danishefsky,et al.  Intramolecular cycloaddition reactions of dienyl nitroso compounds: application to the synthesis of mitomycin K , 1993 .

[19]  G. Schulte,et al.  The Total Synthesis of (±)‐Mitomycin K , 1992 .

[20]  P. Furth,et al.  Silicon-directed decarbonylation of trimethylsilyl .beta.,.gamma.-enals by photolysis , 1989 .

[21]  T. Fukuyama,et al.  Practical total synthesis of (.+-.)-mitomycin C , 1989 .

[22]  W. Remers,et al.  Structure-activity comparison of mitomycin C and mitomycin A analogues (review). , 1989, Anticancer research.

[23]  T. Fukuyama,et al.  Total synthesis of (.+-.)-mitomycins via isomitomycin A , 1987 .

[24]  K. Nakanishi,et al.  Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. , 1987, Science.

[25]  H. Kohn,et al.  Mechanistic Studies on the Mode of Reaction of Mitomycin C under Catalytic and Electrochemical Reductive Conditions , 1987 .

[26]  J. Barluenga,et al.  Stereoselective Synthesis of 2,4-Diamino-2-alkenes (γ-Aminoenamines Formally Derived from 1-Alkenyl Methyl Ketones) via Catalytic Aminomercuriation of 3-Alken-1-ynes , 1986 .

[27]  A. Sartorelli,et al.  The role of mitomycin antibiotics in the chemotherapy of solid tumors. , 1986, Biochemical pharmacology.

[28]  H. Rapoport,et al.  Routes to mitomycins. Chirospecific synthesis of aziridinomitosenes , 1985 .

[29]  U. Hornemann,et al.  Stereochemical relationship between mitomycins A, B, and C , 1985 .

[30]  J. Barluenga,et al.  Catalytic Aminomercuriation of Propargyl Ethers and Thioethers: Synthesis of β-Oxy- and β-Thioenamines and Related Compounds , 1984 .

[31]  N. Hirayama,et al.  Revised absolute configuration of mitomycin C. X-ray analysis of 1-N-(p-bromobenzoyl)mitomycin C , 1983 .

[32]  H. Rapoport,et al.  Routes to mitomycins. New syntheses of the 2,3,5,8-tetrahydro-5,8-dioxo-1H-pyrrolo[1,2-a]indole ring system. An efficient synthesis of 7-methoxymitosene , 1983 .

[33]  H. Rapoport,et al.  Amine addition to unsymmetrical benzoquinones , 1981 .

[34]  R. Rodes,et al.  Catalytic and non-catalytic addition of aromatic amines to terminal acetylenes in the presence of mercury(II) chloride and acetate , 1980 .

[35]  A. Cocuzza,et al.  Synthetiic studies toward mitomycins. III. Total syntheses of mitomycins A and C , 1977 .

[36]  I. Matsubara,et al.  The molecular structure of 7-demethoxy-7-p-bromoanilino mitomycin B. , 1976, The Journal of antibiotics.

[37]  A. Tulinsky,et al.  The crystal and molecular structure of n-brosylmitomycin A. , 1967, Journal of the American Chemical Society.

[38]  N. Bohonos,et al.  Isolation and Characterization Mitiromycin and other Antibiotics , 1962 .

[39]  J. Webb,et al.  The Structures of Mitomycins A, B and C and Porfiromycin--Part I , 1962 .