Enantioselective Indole Friedel−Crafts Alkylations Catalyzed by Bis(oxazolinyl)pyridine−Scandium(III) Triflate Complexes

Evans, David A.; Scheidt, Karl A.; Fandrick, Keith R.; Lam, Hon Wai; Wu, Jimmy

doi:10.1021/ja036985c

Cited by 229 publications

(76 citation statements)

References 10 publications

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“…Indoles are present in a number of pharmaceutical agents 57 and there has been much interest in the enantioselective synthesis of 1-aryl-1-indolylalkyl derivatives. Normally the indole is functionalized at the 2-or 3-position because these are the most reactive sites using conventional chemistry [58][59][60] . In contrast, the C-H functionalization strategy results in a very efficient method for generating 4-substituted indoles with high enantioselectivity (Fig.…”

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,145

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%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,145

812

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“…When running the reaction in mixed organic-aqueous media (THF/H 2 O) the cyclized product 107 was isolated in high yield (83-90 %) and remarkable enantioselectivity (87 %, Scheme 33, b). The use of a pybox ligand combined with Sc(OTf) 3 [87] has been described by Evans and co-workers in the synthesis of 1-functionalized tetrahydrocarbazoles 110 by an intramolecular Michael addition. [88] Here, the importance of 2-acyl imidazole as an easily removable two-site-binding auxiliary was underlined in order to guarantee a high level of enantioselectivity.…”

Section: Catalytic Enantioselective Strategiesmentioning

confidence: 99%

Innovative Catalytic Protocols for the Ring‐Closing Friedel–Crafts‐Type Alkylation and Alkenylation of Arenes

et al. 2006

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Over the past years an astonishing number of highly chemoand regioselective intramolecular Friedel-Crafts (IMFC)-type alkylations of aromatic compounds have been described in the literature that allow remarkable synthetic shortcuts for the preparation of challenging aromatic compounds. In particular, both transition metal and conventional and unusual Lewis acids (LAs) have been described to promote ring-clos- Index

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“…There have been reports in the literature of two crystal structures of Sc-pybox complexes; [Sc(Ph-pybox)(OTf) 3 (H 2 O)] and [Sc(Inda-pybox)(OTf) 3 -(H 2 O)]. [15,16] In both cases, Sc has a CN of seven: the three nitrogen atoms of the pybox, one triflate ion, and one water molecule define the equatorial plane of the complex, while the two remaining triflate anions occupy the two residual apical positions. In the case of La, the reported crystal structure of [La(trans-4',5'-diPh-pybox)(OTf) 3 (H 2 O) 4 ] shows that La has a CN of nine, because besides the three nitrogen atoms of the chiral ligand, two axial triflates and four water molecules are bound to La.…”

Section: (S)mentioning

confidence: 99%

A New Pyridine‐2,6‐bis(oxazoline) for Efficient and Flexible Lanthanide‐Based Catalysts of Enantioselective Reactions with 3‐Alkenoyl‐2‐oxazolidinones

Desimoni

Faita

Guala

et al. 2005

Chemistry A European J

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A new pyridine-2,6-bis(oxazoline) (4) has been easily synthesised from the reaction of (1S,2S)-2-amino-1-phenylpropane-1,3-diol (1) and dimethyl pyridine-2,6-dicarboximidate (2), followed by TIPS (TIPS=triisopropylsilyl) protection of the 4'-CH2OH group. The catalysts derived from 4 and eight lanthanide(III) triflates have been tested over three reactions involving 3-acryloyl- and 3-crotonoyloxazolidinones (5 a,b): the Diels-Alder (DA) reaction with cyclopentadiene, the 1,3-dipolar cycloaddition with diphenyl nitrone and the Mukaiyama-Michael reaction with 2-trimethylsilyloxyfuran. Several reactions exhibit very good enantioselectivity (ee>90 %), and the opposite enantiomers can be easily obtained simply by changing the cation. This specific feature of the ligand can be appreciated in the DA reaction of 5 a, since the catalyst [Sc(III)4] gives the adduct (2'S)-9 a with 99 % ee, whereas the catalyst [Y(III)4] gives the opposite enantiomer with 95 % ee. A rationale of the enantioselectivity is proposed on the basis of the NMR spectra of La-based complexes involving 4 and 5 as ligands.

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Enantioselective Indole Friedel−Crafts Alkylations Catalyzed by Bis(oxazolinyl)pyridine−Scandium(III) Triflate Complexes

Cited by 229 publications

References 10 publications

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Innovative Catalytic Protocols for the Ring‐Closing Friedel–Crafts‐Type Alkylation and Alkenylation of Arenes

A New Pyridine‐2,6‐bis(oxazoline) for Efficient and Flexible Lanthanide‐Based Catalysts of Enantioselective Reactions with 3‐Alkenoyl‐2‐oxazolidinones

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