Prior to Clemson | The Kim Group

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

GSO — Mon, 20 Apr 2020 00:14:14 +0000

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

GSO — Mon, 20 Apr 2020 01:57:12 +0000

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

GSO — Mon, 20 Apr 2020 02:11:29 +0000

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

GSO — Mon, 20 Apr 2020 02:44:51 +0000

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.

Stereodynamic Quinone–Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion

GSO — Mon, 20 Apr 2020 02:50:30 +0000

5. Stereodynamic Quinone–Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion

Since the discovery of molecular chirality, nonsuperimposable mirror-image organic molecules have been found to be essential across biological and chemical processes and increasingly in materials science. Generally, carbon centers containing four different substituents are configurationally stable, unless bonds to the stereogenic carbon atom are broken and re-formed. Herein, we describe sp3-stereogenic carbon-bearing molecules that dynamically isomerize, interconverting between enantiomers without cleavage of a constituent bond, nor through remote functional group migration. The stereodynamic molecules were designed to contain a pair of redox-active substituents, quinone and hydroquinone groups, which allow the enantiomerization to occur via redox-interconversion. In the presence of an enantiopure host, these molecules undergo a deracemization process that allows observation of enantiomerically enriched compounds. This work reveals a fundamentally distinct enantiomerization pathway available to chiral compounds, coupling redox-interconversion to chirality.

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Kim, B.; Storch, G.; Banerjee, G.; Mercado, B. Q.; Castillo-Lora, J.; Brudvig, G. W.; Mayer, J. M.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 15239–15244.

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

GSO — Mon, 20 Apr 2020 03:06:35 +0000

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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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.

Inhibition of Steroid Sulfatase with 4-Substituted Estrone and Estradiol Derivatives

GSO — Mon, 20 Apr 2020 03:20:05 +0000

3. Inhibition of Steroid Sulfatase with 4-Substituted Estrone and Estradiol Derivatives

Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast cancer. We previously demonstrated that 4-formyl estrone is a time- and concentration-dependent inhibitor of STS. We have prepared a series of 4-formylated estrogens and examined them as irreversible STS inhibitors. Introducing a formyl, bromo or nitro group at the 2-position of 4-formylestrone resulted in loss of concentration and time-dependent inhibition and a considerable decrease in binding affinity. An estradiol derivative bearing a formyl group at the 4-position and a benzyl group at the 17β-position yielded a potent concentration and time-dependent STS inhibitor with a K(I) of 85 nM and a k(inact) of 0.021 min(-1) (k(inact)/K(I) of 2.3 × 10(5)M(-1)min(-1)). Studies with estrone or estradiol substituted at the 4-position with groups other than a formyl group revealed that good reversible inhibitors can be obtained by introducing small electron withdrawing groups at this position. An estradiol derivative with fluorine at the 4-position and a benzyl group at the 17β-position yielded a potent, reversible inhibitor of STS with an IC(50) of 40 nM. The introduction of relatively small electron withdrawing groups at the 4-position of estrogens and their derivatives may prove to be a general approach to enhancing the potency of estrogen-derived STS inhibitors.

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Phan, C.-M.; Liu, Y.; Kim, B.; Mostafa, Y.; Taylor, S. D. Bioorg. Med. Chem. 2011, 19, 5999–6005.

Phthalides by Rhodium-Catalyzed Ketone Hydroacylation

GSO — Mon, 20 Apr 2020 03:13:10 +0000

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

Synthesis of 4-Formyl Estrone Using a Positional Protecting Group and Its Conversion to Other C-4-Substituted Estrogens

GSO — Mon, 20 Apr 2020 03:23:31 +0000

1. Synthesis of 4-Formyl Estrone Using a Positional Protecting Group and Its Conversion to Other C-4-Substituted Estrogens

4-Formyl estrone was synthesized in overall good yield in three steps starting from estrone. This was achieved by conducting an electrophilic aromatic substitution reaction using formaldehyde, triethylamine, and MgCl2 on 2-tert-butyl estrone, which was readily prepared in 96% yield from estrone using tert-butyl alcohol and BF3OEt2. The tert-butyl group acted as a positional protecting group to prevent reaction at the 2-position. The tert-butyl group was readily removed in good yield using AlCl3 in dichloromethane/CH3NO2. To our knowledge, this represents the first use of a positional protecting group for the synthesis of a C-4-modified estrogen. 4-Formyl estrone was used as a common precursor to obtain a variety of other C-4 modified estrogens in very high yields such as 4-methylestrone and 4-hydroxymethylestrone as well as the novel estrogen 4-carboxyestrone. The syntheses of 4-formyl, -methyl-, and -hydroxymethyl estrone represent dramatic improvements over previously reported syntheses of these compounds.

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Liu, Y.; Kim, B.; Taylor, S. D. J. Org. Chem. 2007, 72, 8824–8830.

Prior to Clemson | The Kim Group

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.

Hydrogenation Catalyst Generates Cyclic Peptide Stereocenters in Sequence

8. Hydrogenation Catalyst Generates Cyclic Peptide Stereocenters in Sequence

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

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

Stereodynamic Quinone–Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion

5. Stereodynamic Quinone–Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion

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

Inhibition of Steroid Sulfatase with 4-Substituted Estrone and Estradiol Derivatives

3. Inhibition of Steroid Sulfatase with 4-Substituted Estrone and Estradiol Derivatives

Phthalides by Rhodium-Catalyzed Ketone Hydroacylation

2. Phthalides by Rhodium-Catalyzed Ketone Hydroacylation

Synthesis of 4-Formyl Estrone Using a Positional Protecting Group and Its Conversion to Other C-4-Substituted Estrogens

1. Synthesis of 4-Formyl Estrone Using a Positional Protecting Group and Its Conversion to Other C-4-Substituted Estrogens

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.