The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

No description available.

A set of five new C3-symmetric phosphites were synthesized and tested in palladium-catalyzed asymmetric Suzuki coupling. The observed reactivity and selectivity were dependent upon several factors. One of the phosphites was able to achieve some of the highest levels of enantioselectivity in asymmetric Suzuki couplings with specific substrates. Different hypotheses have been made for understanding the ligand effects and reaction selectivities, and those hypotheses were tested via various methods including DOSY NMR experiments, X-ray crystallography, and correlation of catalyst selectivity with Tolman cone angles. Although only modest enantioselectivities were observed in most reactions, the ability to synthesis these phosphites in only three steps on gram scales and to readily tune their properties by simple modification of the binaphthyl 2´-substituents makes them promising candidates for determining structure-selectivity relationships in asymmetric transition metal catalysis, in which phosphites have been previously shown to be successful. A series of novel chiral oxazoline-based carbodicarbene ligands was targeted for synthesis. Unfortunately, the chosen synthetic route could not be completed due to unwanted reactivity of the oxazoline ring. However, a new and efficient route for Pd-catalyzed direct amination of aryl halides with oxazoline amine was developed and optimized during these studies. Chiral binaphthyl based Pd(II) ADC complexes with different substituent groups have been synthesized and tested in asymmetric Suzuki coupling reactions. Although only low enantioselectivities were observed in Suzuki coupling, this represents a new class of chiral metal-ADC catalysts that could be tested in further catalytic.

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The thesis entitled “Regioselective Functionalization of Indoles using Directing Group Strategy: An Efficient Transition Metal Catalysis” is divided into two sections. Section A, which is presented in three chapters, describes the regioselective alkenylation of indoles using directing group strategy. Whereas, Section B, which is divided in to two chapters, narrates the synthesis of 4-amino indoles using directing group strategy and site selective addition of maleimide to indole at C2-position. Section A Chapter 1. C2-Alkenylation of indoles The indole ring system is one of the most abundant heterocycles present in nature. The synthesis and functionalization of indoles is one of the major areas of focus for synthetic organic chemists.1 Alkenylation of indole at C2-position is a challenging task due to the electrophilic nature of the reaction. For this reason, the functionalization of indole at C2-position is less addressed. In this chapter, a highly regioselective alkenylation of indole at the C2-position has been described by using the Ru(II) catalyst and employing a directing group (DG) strategy.2 This directing group strategy offers rare selectivity for the alkenylation of N-benzoylindole at the C2-position in the presence of the more reactive C3-position. A variety of N-benzoylindole derivatives are shown to undergo alkenylation at C2-positon. Deprotection of the benzoyl group has also been demonstrated, and the resulting products serve as a useful synthon for synthesizing a variety of natural products. A few representative examples are highlighted in Scheme 1.3 1 (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Karamyan, K. A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. 2 (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. (c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 3 Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. Scheme 1: C2- Alkenylation of indoles Chapter 2 describes a highly regioselective alkenylation of indoles at the C4-position by employing aldehyde functional group as a directing group, and Ru as a catalyst, under a mild reaction conditions. This approach leads to a short synthetic route for C4-alkenylated indoles, which serve as precursors for ergot alkaloids and related heterocyclic compounds.4 Further The potential of the present strategy has been demonstrated by performing (i) scale up reaction, (ii) selective reduction of olefin double bond and (iii) synthesizing substituted 1,3,4,5-tetrahydrobenzo[cd] in two steps with an overall yield of 68%. 1,3,4,5-Tetrahydrobenzo[cd] is one of the key intermediates for synthesizing ergot alkaloids. A few examples are highlighted in Scheme 2.5 4 (a) Horwell, D. C. Tetrahedron 1980, 36, 3123. (b) Kozikowski, A. P.; Ishida, H. J. Am. Chem. Soc. 1980, 102, 4265. (c) Oppolzer, W.; Grayson, J. I.; Wegmann, H.; Urrea, M. Tetrahedron 1983, 39, 3695. (d) Hatanaka, N.; Ozaki, O.; Matsumoto, M. Tetrahedron Lett. 1986, 27, 3169. (e) Horwell, D. C.; Verge, J. P. Phytochemistry 1979, 18, 519. 5 anke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. Scheme 2: C4- Alkenylation of indoles Chapter 3 of Section A, presents a novel mode of selective alkenylation of indoles using Ru and Rh catalyst. In these alkenylation reactions, selectivity between C2- and C4-positions of indole framework has been achieved by altering the property of directing group. Methyl ketone, as directing group, furnishes exclusively C2-alkenylated product, whereas trifluoromethyl ketone as a directing group changes the selectivity to C4, indicating that electronic nature of the directing group controls the choice between a 5-membered and 6-membered metallacycle. Developing such divergent and selective C-H functionalizations, between C2- and C4-positions, on the indole framework can lead to easy and short synthetic routes for natural, unnatural and biologically-active compounds.6 Further screening of other carbonyl derived directing groups revealed that strong and weak directing groups exhibit opposite selectivity. Experimental 6 (a) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832. (b) Nathel, N. F. F.; Shah, T. K.; Bronner, S. M.; Garg, N. K. Chem. Sci., 2014, 5, 2184. (c) A Beilstein/Crossfire search shows that more than 600 C4- substituted indole-containing natural products exist and nearly 10,000 bioactive C4-substituted indoles have been reported. controls, deuteration experiments and preliminary DFT calculations lend support to the proposed mechanism. A few representative examples are highlighted in Scheme 3.7 Scheme 3: C4- vs C2-Alkenylation of ndoles Deuterium Labeling studies were carried out to shed light on the site of metallacycle formation and hence the origin of selectivity. Both COCF3 and COCH3 substrates were independently subjected to both standard conditions A and B, along with either D2O or AcOD as deuterium sources (Scheme 4). 7 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Manuscript submitted. Scheme 4: Deuterium labeling studies The Section B is divided into 2 chapters. Chapter 1 presents a method for synthesizing of 3-(indol-2-yl) succinimide derivatives by using a directing group strategy. Selective functionalization at C2-position of indole in the presence of highly reactive C3-position has been achieved. A conjugate addition, instead of Heck-type reaction, has been achieved by careful selection of the alkene partner (maleimides and maleate esters). This selectivity has been achieved by avoiding β-hydride elimination. Succinimide derivatives are structural motifs that are found in many natural products and drug molecules. Moreover, succinimides can be easily reduced into 5-membered pyrrolidine rings, γ-lactams and lactims, which are part of structural scaffolds of useful natural products.8 Further the application of the protocol has been showcased by performing reduction to obtain pyrrolidine and 1,4 diols. A few representative examples are highlighted in Scheme5.9 8 (a)Crider, A. M.; Kolczynski, T. M.; Yates, K. M. J. Med. Chem. 1980, 23, 324. (b) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (c) Uddin, J.; Ueda, K.; Siwu, E. R. O.; Kita, M.; Uemura, D. Bioorg. Med. Chem. 2006, 14, 6954. (d) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437. (e) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179. 9 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4662. Scheme 5: Addition of Maleimide to Indole at C2-position Chapter 2 describes a highly regioselective amidation of unprotected indoles at the C4-position by employing aldehyde functional group as a directing group. This reaction has been performed using Ir(III) catalyst, under mild reaction conditions. Thus, an efficient, simple, short synthetic route for C4-amido indoles has been achieved. C4-Amido indoles are privileged molecules, which serve as precursors for indolactum V,10 teleocidin and related heterocyclic compounds.11 To the best our knowledge, this is the first report of using aldehyde as a directing group for amidation reactions. The potential of the present strategy has been demonstrated by performing scaling up reaction, and deprotection of tosyl group to obtain corresponding amines. A few representative examples are highlighted in Scheme 6.12 10 Garg, N. K. et al., J. Am. Chem. Soc. 2011, 133, 3832 11 Kehler, J. J. Med. Chem. 2014, 57, 5823 12 Lanke, V.; Prabhu, K. R. (Manuscript submitted). Scheme 6: C4- amidation of indoles 7

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No description available.