A Stereodynamic Redox-Interconversion Network of Vicinal Tertiary and Quaternary Carbon Stereocenters in Hydroquinone-Quinone Hybrid Dihydrobenzofurans

9.  A Stereodynamic Redox-Interconversion Network of Vicinal Tertiary and Quaternary Carbon Stereocenters in Hydroquinone-Quinone Hybrid Dihydrobenzofurans

Storch, G.; Kim, B.; Mercado, B. Q.; Miller, S. J. Angrew. Chem. Int. Ed. 2018, 57, 15107-15111.

Reversible redox processes involving hydroquinones and quinones are ubiquitous in biological reaction networks, materials science, and catalysis. While extensively studied in intermolecular settings, less is known about intramolecular scenarios. Herein, we report hydroquinone-quinone hybrid molecules that form two-stereocenter dihydrobenzofurans via intramolecular cyclization under thermodynamic control. A π-methylhistidine peptide-catalyzed kinetic resolution allowed us to study the stereodynamic behavior of enantio- and diastereo-enriched dihydrofurans. In the course of this study, it was revealed that a reversible intramolecular redox-interconversion network connects all four possible stereoisomers via inversion of a quaternary carbon stereocenter without achiral intermediates. As a result, these findings on hydroquinone-quinone hybrid molecules provide insights into potential natural origin and synthetic access of the common dihydrobenzofuran motif.

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Hydrogenation Catalyst Generates Cyclic Peptide Stereocenters in Sequence

8. Hydrogenation Catalyst Generates Cyclic Peptide Stereocenters in Sequence

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.
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Le, D. N.; Hansen, E.; Khan, H. K.; Kim, B.; Wiest, O.; Dong, V. M. Nat. Chem. 2018, 10, 968–973.

Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C-N Bond-Forming Cross-Coupling and Catalyst-Controlled Atroposelective Cyclodehydration

7. Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C-N Bond-Forming Cross-Coupling and Catalyst-Controlled Atroposelective Cyclodehydration

Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon centers and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl copper complexes catalyze an unprecedented remote desymmetrization involving enantioselective C-N bond-forming cross-coupling. Then, chiral phosphoric acid catalysts set an axis of chirality through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral copper complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.
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Kwon, Y.; Chinn, A. J.; Kim, B.; Miller, S. J. Angew. Chem. Int. Ed. 2018, 57, 6251–6255.

Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

6. Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

We report a series of enantioselective C-O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence of an intervening tBu group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective reactions are possible when there are phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse complex molecular settings.
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Chinn, A. J.; Kim, B.; Kwon. Y.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 18107–18114.

Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullmann Cross-Coupling

4. Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullmann Cross-Coupling

We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic C-terminal carboxylate of the peptides with the distal arene of the substrate.
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ja 2016 034444 0016

Kim, B.; Chinn, A. J.; Fandrick, D. R.; Senanayake, C. H.; Singer, R. A.; Miller, S. J. J. Am. Chem. Soc. 2016, 138, 7939–7945.

Phthalides by Rhodium-Catalyzed Ketone Hydroacylation

2. Phthalides by Rhodium-Catalyzed Ketone Hydroacylation

Phthalides are biologically relevant five-membered lactones found in herbs, fruits, and vegetables. Herein we communicate the first atom-economical approach to phthalides by using enantioselective ketone hydroacylation. In the presence of Rh[(Duanphos)]X (X = NO3, OTf, OMs), various 2-ketobenzaldehydes undergo intramolecular hydroacylation to produce phthalide products in good yields and 92−98% ee’s. Our study highlights the key role counterions play in controlling both reactivity and enantioselectivity. A concise asymmetric total synthesis of the celery extract (S)-(−)-3-n-butylphthalide is also presented.
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ja 2009 07711a 0004

Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Soc. Chem. 2009, 131, 15608–15609.