C−H Activation as a Strategic Reaction:  Enantioselective Synthesis of 4-Substituted Indoles

Davies, Huw M. L.; Manning, James R.

doi:10.1021/ja057768+

Cited by 68 publications

(34 citation statements)

References 26 publications

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“…A spectacular example of such an event is termed the 'combined C-H activation/Cope rearrangement' [51][52][53][54][55][56] . One of the earliest examples of this reaction is shown between the vinyldiazoacetate 15 and 1,3-cyclohexadiene in Fig.…”

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

“…In contrast, the C-H functionalization strategy results in a very efficient method for generating 4-substituted indoles with high enantioselectivity (Fig. 8) 56 . These types of compounds and related structures have not been extensively studied as potential therapeutic agents, presumably because they were not readily accessible.…”

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

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Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

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2,174

812

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Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.I n 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in phase I or II of clinical development 1 . The majority of these were smallmolecule (relative molecular mass ,1,000) organic compounds 2 . As knowledge about the specific interactions of drugs in vivo increases, often so does the structural complexity of new drug targets. A major obstacle to the development of such drugs is the difficulty associated with synthesizing large quantities in an economical fashion, because complex multi-step syntheses are usually required. In the general media, it is often overlooked that the accessibility of the components required for these new treatments will often govern their eventual success or failure. Likewise, a design element of any pharmaceutical agent is the expectation that the target compounds can be made economically. Therefore, new strategies for synthesis can become enabling technologies, making available new targets and materials that would have been previously out of range. For example, new methodologies such as metal-catalysed crosscoupling 3 and olefin metathesis 4-6 have rapidly become central transformations in the synthesis of new pharmaceutical agents. Selective C-H functionalization is a class of reactions that could lead to a paradigm shift in organic synthesis, relying on selective modification of ubiquitous C-H bonds of organic compounds instead of the standard approach of conducting transformations on pre-existing functional groups. The reactive sites in each type of transformation are very different, as illustrated in Fig. 1.The many opportunities associated with C-H functionalization has made this field an active area of research. Organometallic chemists have focused much attention on developing 'C-H activation' strategies, whereby a highly reactive metal complex inserts into a C-H bond, activating the system for subsequent transformations 7-9 . One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex 10 . A partial solution to this problem has been to use neighbouring functionality to direct less reactive metal complexes to the site for functionalization. Numerous reviews have been written about this method for C-H functionalization [11][12][13][14][15][16][17] . Here, however, we highlight another approach, in which a divalent c...

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Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

Self Cite

2,174

812

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“…Recent examples of indole functionalization include asymmetric C-3 Friedel-Craft reactions, 1,2,3 allylations, 4,5 radical couplings, 6 arylations, 7,8,9 Michael-additions, 10 C-H activation, 11 and N-arylations. 12 Indoles containing a fused 5-membered ring at the C-2 and C-3 positions are well represented in nature, and include the penitrems 13 and kopsane 14 alkaloids.…”

Section: Introductionmentioning

confidence: 99%

C-2/C-3 Annulation and C-2 Alkylation of Indoles with 2-Alkoxycyclopropanoate Esters

et al. 2007

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Abstract:The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported. Both high efficiency and complete stereochemical control was observed in some cases with this annulation process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.

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“…While complexes with α,α,α,α-and α,α,α,β-conformations, which have non-equivalent catalyst faces, are likely to induce low or no enantioinduction as their more accessible and kinetically active face is achiral. This previous proposal from Davies et al originates from their discovery of Rh2(S-DOSP)4 catalyst (Scheme 2) [36], which offered extraordinary enantioselectivity in a wide range of chemical transformations (up to 99% ee) [7,13,36,40,42,44,47,48,[55][56][57][58][59][60][61][62][63][64][65][66][67][68]. This exceptional enantioselectivity of Rh2(S-DOSP)4 was proposed to originate from a favored α,β,α,β-arrangement of ligands adapted during catalysis.…”

Section: Ligand Blocking Groups Arrangementsmentioning

confidence: 99%

On the Structure of Chiral Dirhodium(II) Carboxylate Catalysts: Stereoselectivity Relevance and Insights

Adly

2017

Catalysts

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Abstract:Modern experiments have offered alternative interpretations on the symmetry of chiral dirhodium(II) carboxylate complexes and its relationship to their level of enantioselectivity. So, this contribution is to provide an insight on how the knowledge around the structure of these catalysts has evolved with a particular emphasis on the impact of this knowledge on enantioselectivity prediction and catalyst design.

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C−H Activation as a Strategic Reaction: Enantioselective Synthesis of 4-Substituted Indoles

Cited by 68 publications

References 26 publications

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

C-2/C-3 Annulation and C-2 Alkylation of Indoles with 2-Alkoxycyclopropanoate Esters

On the Structure of Chiral Dirhodium(II) Carboxylate Catalysts: Stereoselectivity Relevance and Insights

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