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Chapter 5. Oxidative Inter-/Intermolecular Alkene Diamination of Hydroxy

Styrenes with Electron-Rich Amines via Hypervalent Iodine

5.1. Background

1,2-Diamines are ubiquitous among natural products, pharmaceutical agents, chiral ligands and bases, and other organic reagents. The biological activity associated with many of these systems and their synthetic utility has ensured that the development of new methods for the preparation of vicinal diamines is of high importance.62 To date, many synthetic strategies for the preparation of 1,2-diamine scaffolds have been established, facilitating access to naturally occurring vicinal diamines and those within pharmaceuticals.

In the natural world, vicinal diamines are commonly found in the form of non- proteinogenic α,β-diamino carboxylic acids.62 _{The simplest members of this group include 2,3-}

diaminopropionic acid (105) and 2,3-diaminobutanoic acid (106), which can be found as

61 _{Danneman, M. W.; Hong, K.; Johnston, J. N. Org. Lett. 2015, 17, 2558-2561.} 62 _{De Jong, S.; Nosal, D. G.; Wardrop, D. J. Tetrahedron 2012, 68, 4067-4105.}

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components of non-ribosomal peptide antibiotics such as bleomycin (107) (Figure 21).63 L- Capreomycidine (108), a key structural subunit of the tuberculostatic agent capreomycin 1B (109), has also been identified as a component of non-ribosomal peptides.64 Additionally, certain α,β- diamino acids are of considerable interest due to their biological role as excitatory amino acids (EAA). L-Quisqualic acid (110), isolated from the traditional Chinese medicine Shih-chun-tze, is a highly potent agonist of EAA receptors in both mammals and insects.62 (−)-Dysibetaine (111), isolated from the marine sponge Dysidea herbacea, is also a neuroexcitotoxin, which may bind to the glutamate receptors present in the central nervous system of mice.65 Other α,β-diamino acids include streptothricin F (112), an antibiotic,66 and nucleotide sugar UDP-2,3-diacetamido-2,3- dideoxy-D-mannuronic acid (UDP-2,3-DDMA) (113), a key building block in the biosynthesis of the lipopolysaccharide of Pseudomonas aeruginosa, an opportunistic pathogen.67

Numerous alkaloid natural products are known to possess 1,2-diamine scaffolds that are associated with significant biological activity. Loline (114), a pyrrolizidine alkaloid, is known for its insecticidal activity,68 while the pentacyclic citrinadin A (115) exhibits cytotoxicity against murine leukemia L1210 and human epidermoid carcinoma KB cell lines (Figure 22).69 The vicinal diamine moiety is also present in tetrahydroisoquinoline-derived alkaloids, such as lemonomycin (116), an antitumor antibiotic.70 Pactamycin (117), a terrestrial alkaloid isolated from a fermentation broth of Streptomyces pactum, exhibits activity against Gram-positive and Gram- negative bacteria.71 In addition to terrestrial sources, marine organisms have proven to be a rich source of biologically active 1,2-diamines as well. These marine alkaloids include the antineoplastic agent agelastatin A (118),72 anti-tuberculosis agent manadomanzamine A (119),73

63 _{Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem. Rev. 2005, 105, 739-758.} 64 _{DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003, 125, 8561-8565.}

65 _{Sakai, R.; Oiwa, C.; Takaishi, K.; Kamiya, H.; Tagawa, M. Tetrahedron Lett. 1999, 40, 6941-6944.} 66 _{Jackson, M. D.; Gould, S. J.; Zabriskie, M. T. J. Org. Chem. 2002, 67, 2934-2941.}

67 _{(a) Wenzel, C. Q.; Daniels, C.; Keates, R. A. B.; Brewer, D.; Lam, J. S. Mol. Microbiol. 2005, 57, 1288-1303; (b)}

Larkin, A.; Imperiali, B. Biochemistry 2009, 48, 5446-5455.

68 _{Schardl, C. L.; Grossman, R. B.; Nagabhyru, P.’ Faulkner, J. R.; Mallik, U. P. Phytochemistry 2007, 68, 980-996.} 69 _{(a) Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.; Mikami, Y.; Kobayashi, J. Org. Lett. 2004, 6, 3087-}

3089; (b) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem. 2005, 70, 9430-9435.

70 _{Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 15000-15001.}

71 _{Hanessian, S.; Vakiti, R. R.; Dorich, S.; Banerjee, S.; Lecomte, F.; DelValle, J. R.; Zhang, J.; Deschenes-Simard,}

B. Angew. Chem. Int. Ed. 2011, 50, 3497-3500.

72 _{Hama, N.; Matsuda, T.; Sato, T.; Chida, N. Org. Lett. 2009, 11, 2687-2690.}

73 _{Allin, S. M.; Duffy, L. J.; Towler, J. M. R.; Page, P. C. B. Elsegood, M. R. J.; Saha, B. Tetrahedron 2009, 65,}

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and eudistomin C (120), a member of the eudistomin family that displays activity against both RNA and DNA viruses.74

Vicinal diamines are also found in a wide array of pharmaceutical agents. For example, fluoroquinoline antibacterial agent moxifloxacin (121)75 _{and anticancer agent 122}76 _{both possess}

a 1,2-diamine functionality within conformationally restricted bicyclononane ring systems (Figure 23). Target compound Sch 425078 (123), an anti-emetic agent and NK1-antagonist, contains a 1,2-

diamine framework in the form of a cyclic urea.77 α-Galactosylceramide analog HS161 (124) is a potent stimulator of invariant natural killer T cells,78 while sphingoid analog SG14 (125) is a specific inhibitor of human sphingosine kinase, an emerging target for cancer therapeutics.79 Furthermore, stilbene diamine derivative 126 has been shown to be a potent inhibitor of hepatitis C virus RNA replication,80 whereas cis-imidazoline Nutlin-3 (35) exhibits anticancer activity via

74 _{Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038-15039.}

75 _{De Souza, M. V. N.; Vasconcelos, T. R. A.; De Almeida, M. V.; Cardoso, S. H. Curr. Med. Chem. 2006, 13, 455-}

463.

76 _{Geiger, C.; Zelenka, C.; Weigl, M.; Frohlich, R.; Wibbeling, B.; Lehmkuhl, K.; Schepmann, D.; Grunert, R.;}

Bednarski, P. J.; Wunsch, B. J. Med. Chem. 2007, 50, 6144-6161.

77 _{Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang, C.; Tiberi, R.; McPhail, A. T.;}

Piwinski, J. J.; Shih, N. Y. Org. Lett. 2003, 5, 4249-4251.

78 _{Harrak, Y.; Barra, C. M.; Delgado, A.; Castano, A. R.; Llebaria, A. J. Am. Chem. Soc. 2011, 133, 12079-12084.} 79 _{Kim, J. W.; Kim, Y. W.; Inagaki, Y.; Hwang, Y. A.; Mitsutake, S.; Ryu, Y. W.; Lee, W. K.; Ha, H. J.; Park, C. S.;}

Igarashi, Y. Bioorg. Med. Chem. 2005, 13, 3475-3485.

80 _{Gastaminza, P.; Pitram, S. M.; Dreux, M.; Krasnova, L. B.; Whitten-Bauer, C.; Dong, J.; Chung, J.; Fokin, V. V.;}

Sharpless, K. B.; Chisari, F. V. J. Virol. 2011, 85, 5513-5523.

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MDM2-p53 protein-protein inhibition.81,82 Other small molecule therapeutics bearing vicinal diamines include ethambutol analog SQ109 (127), which shows potent activity against multi-drug resistant tuberculosis,83 as well as viral neuraminidase inhibitors oseltamivir (128)84 and zanamivir (129),85 which are used for the treatment of influenza A and B.

5.2. Known Methods of Alkene Diamination

As previously mentioned, there are many known strategies for the preparation of 1,2- diamine scaffolds. The most direct and efficient means of accessing these systems is through the diamination of alkenes. Alkene diamination is an area that has been explored extensively, and as a result, can be achieved via a variety of methods.

81 _{Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs,}

C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004, 303, 844-848.

82 _{Davis, T. A.; Johnston, J. N. Chem. Sci. 2011, 2, 1076-1079.}

83 _{Protopopova, M.; Hanrahan, C.; Nikonenko, B.; Samala, R.; Chen, P.; Gearhart, J.; Einck, L.; Nacy, C. A. J.}

Antimicrob. Chemother. 2005, 56, 968-974.

84 _{Magano, J. Tetrahedron 2011, 67, 7875-7899.} 85 _{Magano, J. Chem. Rev. 2009, 109, 4398-4438.}

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One method of diamination involves the treatment of alkenes with binary nitrogen oxides. Jacobsen demonstrated the efficiency of these nitrogen oxides by using dinitrogen tetroxide (N2O4)

to ultimately arrive at C2-symmetric trans-1,2-diamine 130 (Scheme 66).86 Here, the reaction of N2O4 with dimethylcyclohexene 131 under chilled conditions affords dinitro species 132 as the

trans-diastereomer. Subsequent palladium-mediated hydrogenation of 132 yielded desired diamine 130, which was resolved by way of its mandelate salt.

Wilkinson and colleagues have successfully conducted the nitronitrosylation of alkenes under medium pressure (Scheme 67).87 This reaction was readily achieved by the disproportionation of nitric oxide (NO) to nitrous oxide (N2O) and nitrogen dioxide (NO2).

Mechanistically, it is envisioned that this transformation proceeds through a radical pathway in

which NO2 adds to alkene 133, generating a β-nitro radical (134). This radical can then trap NO at

100 psi to arrive at nitronitrosylation product 135. To complement these findings, dinitrogen trioxide (N2O3) can be effectively employed for nitronitrosylation of alkenes as well (Scheme 67).

86 _{Zhang, W.; Jacobsen, E. N. Tetrahedron Lett. 1991, 32, 1711-1714.}

87 _{Chiu, K. W.; Savage, P. D.; Wilkinson, G.; Williams, D. J. Polyhedron 1985, 4, 1941-1945.}