Scott J. Miller

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Name: Miller, Scott J.

Organization: Yale University , USA

Department: Department of Chemistry

Title: (PhD)

TOPICS

Organic Chemistry

Asymmetric Synthesis Hydrogenation allene Peptide Synthesis

Chemicals
References

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

Co-reporter:Byoungmoo Kim, Golo Storch, Gourab Banerjee, Brandon Q. Mercado, Janelle Castillo-Lora, Gary W. Brudvig, James M. Mayer, and Scott J. Miller

Journal of the American Chemical Society October 25, 2017 Volume 139(Issue 42) pp:15239-15239

Publication Date(Web):September 20, 2017

DOI:10.1021/jacs.7b09176

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.

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst

Co-reporter:Anna E. Hurtley, Elizabeth A. Stone, Anthony J. Metrano, and Scott J. Miller

The Journal of Organic Chemistry November 3, 2017 Volume 82(Issue 21) pp:11326-11326

Publication Date(Web):October 11, 2017

DOI:10.1021/acs.joc.7b02339

Diarylmethylamido bis(phenols) have been subjected to peptide-catalyzed, enantioselective bromination reactions. Desymmetrization of compounds in this class has been achieved such that enantioenriched products may be isolated with up to 97:3 er. Mechanistically, the observed enantioselectivity was shown to be primarily a function of differential functionalization of enantiotopic arenes, although additional studies unveiled a contribution from secondary kinetic resolution of the product (to afford the symmetrical dibromide) under the reaction conditions. Variants of the tetrapeptide catalyst were also evaluated and revealed a striking observation—enantiodivergent catalysis is observed upon changing the achiral amino acid residue in the catalyst (at the i+2 position) from an aminocyclopropane carboxamide residue (97:3 er) to an aminoisobutyramide residue (33:67 er) under a common set of conditions. An expanded set of catalysts was also evaluated, enabling structure/selectivity correlations to be considered in a mechanistic light.

Site- and Stereoselective Chemical Editing of Thiostrepton by Rh-Catalyzed Conjugate Arylation: New Analogues and Collateral Enantioselective Synthesis of Amino Acids

Co-reporter:Hanna M. Key and Scott J. Miller

Journal of the American Chemical Society November 1, 2017 Volume 139(Issue 43) pp:15460-15460

Publication Date(Web):October 4, 2017

DOI:10.1021/jacs.7b08775

The synthesis of complex, biologically active molecules by catalyst-controlled, selective functionalization of complex molecules is an emerging capability. We describe the application of Rh-catalyzed conjugate arylation to the modification of thiostrepton, a complex molecule with potent antibacterial properties for which few analogues are known. By this approach, we achieve the site- and stereoselective functionalization of one subterminal dehydroalanine residue (Dha16) present in thiostrepton. The broad scope of this method enabled the preparation and isolation of 24 new analogues of thiostrepton, the biological testing of which revealed that the antimicrobial activity of thiostrepton tolerates the alteration of Dha16 to a range of amino acids. Further analysis of this Rh-catalyzed process revealed that use of sodium or potassium salts was crucial for achieving high stereoselectivity. The catalyst system was studied further by application to the synthesis of amino esters and amides from dehydroalanine monomers, a process which was found to occur with up to 93:7 er under conditions milder than those previously reported for analogous reactions. Furthermore, the addition of the same sodium and potassium salts as applied in the case of thiostrepton leads to a nearly full reversal of the enantioselectivity of the reaction. As such, this study of site-selective catalysis in a complex molecular setting also delivered synergistic insights in the arena of enantioselective catalysis. In addition, these studies greatly expand the number of known thiostrepton analogues obtained by any method and reveal a high level of functional group tolerance for metal-catalyzed, site-selective modifications of highly complex natural products.

Peptide-Catalyzed Kinetic Resolution of Formamides and Thioformamides as an Entry to Nonracemic Amines

Co-reporter:Brandon S. Fowler, Peter J. Mikochik and Scott J. Miller

Journal of the American Chemical Society March 10, 2010 Volume 132(Issue 9) pp:2870-2871

Publication Date(Web):February 16, 2010

DOI:10.1021/ja9107897

We report a fundamentally unique approach to the catalytic kinetic resolution of amine derivatives based on formamide and thioformamide substrates. Readily accessible histidine-containing peptides mediate the kinetic resolutions with as little as 5 mol % catalyst. Selectivity factors (krel) as high as 43.7 were observed under simple reaction conditions utilizing Boc2O as the reagent at room temperature. Mechanistic experiments were conducted that established a higher level of reactivity for thioformamide substrates than for their formamide analogues. The products of these asymmetric reactions were shown to be readily converted to desirable building blocks such as N-Boc-amines and the parent chiral formamide compounds.

Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences

Co-reporter:Anthony J. Metrano, Nadia C. Abascal, Brandon Q. Mercado, Eric K. Paulson, Anna E. Hurtley, and Scott J. Miller

Journal of the American Chemical Society 2017 Volume 139(Issue 1) pp:

Publication Date(Web):December 28, 2016

DOI:10.1021/jacs.6b11348

X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H–1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.

A bottom up approach towards artificial oxygenases by combining iron coordination complexes and peptides

Co-reporter:Olaf Cussó;Michael W. Giuliano;Xavi Ribas;Miquel Costas

Chemical Science (2010-Present) 2017 vol. 8(Issue 5) pp:3660-3667

Publication Date(Web):2017/05/03

DOI:10.1039/C7SC00099E

Supramolecular systems resulting from the combination of peptides and a chiral iron coordination complex catalyze asymmetric epoxidation with aqueous hydrogen peroxide, providing good to excellent yields and high enantioselectivities in short reaction times. The peptide is shown to play a dual role; the terminal carboxylic acid assists the iron center in the efficient H2O2 activation step, while its β-turn structure is crucial to induce high enantioselectivity in the oxygen delivering step. The high level of stereoselection (84–92% ee) obtained by these supramolecular catalysts in the epoxidation of 1,1′-alkyl ortho-substituted styrenes, a notoriously challenging class of substrates for asymmetric catalysis, is not attainable with any other epoxidation methodology described so far. The current work, combining an iron center ligated to N and O based ligands, and a peptide scaffold that shapes the second coordination sphere, may be seen as a bottom up approach towards the design of artificial oxygenases.

Aqueous Glycosylation of Unprotected Sucrose Employing Glycosyl Fluorides in the Presence of Calcium Ion and Trimethylamine

Co-reporter:Guillaume Pelletier; Aaron Zwicker; C. Liana Allen; Alanna Schepartz

Journal of the American Chemical Society 2016 Volume 138(Issue 9) pp:3175-3182

Publication Date(Web):February 9, 2016

DOI:10.1021/jacs.5b13384

We report a synthetic glycosylation reaction between sucrosyl acceptors and glycosyl fluoride donors to yield the derived trisaccharides. This reaction proceeds at room temperature in an aqueous solvent mixture. Calcium salts and a tertiary amine base promote the reaction with high site-selectivity for either the 3′-position or 1′-position of the fructofuranoside unit. Because nonenzymatic aqueous oligosaccharide syntheses are underdeveloped, mechanistic studies were carried out in order to identify the origin of the selectivity, which we hypothesized was related to the structure of the hydroxyl group array in sucrose. The solution conformation of various monodeoxysucrose analogs revealed the co-operative nature of the hydroxyl groups in mediating both this aqueous glycosyl bond-forming reaction and the site-selectivity at the same time.

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

Co-reporter:Byoungmoo Kim; Alex J. Chinn; Daniel R. Fandrick; Chris H. Senanayake; Robert A. Singer

Journal of the American Chemical Society 2016 Volume 138(Issue 25) pp:7939-7945

Publication Date(Web):June 2, 2016

DOI:10.1021/jacs.6b03444

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.

Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination

Co-reporter:A. J. Metrano, N. C. Abascal, B. Q. Mercado, E. K. Paulson and S. J. Miller

Chemical Communications 2016 vol. 52(Issue 26) pp:4816-4819

Publication Date(Web):02 Mar 2016

DOI:10.1039/C6CC01428C

We describe herein a crystallographic and NMR study of the secondary structural attributes of a β-turn-containing tetra-peptide, Boc-Dmaa-D-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-D-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I′ β-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well.

Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer–Villiger Oxidation

Co-reporter:Nadia C. Abascal and Scott J. Miller

Organic Letters 2016 Volume 18(Issue 18) pp:4646-4649

Publication Date(Web):September 2, 2016

DOI:10.1021/acs.orglett.6b02282

The structural analysis of a peptide-based catalyst for the Baeyer–Villiger oxidation (BVO) is reported. This unique structure is then analyzed in the context of its previously documented facility to control selectivity (both enantioselectivity and migratory aptitude) in catalytic reactions. The effects of additives on the solution conformation of the peptide are found to be dramatic, revealing substrate-specific interactions and a possible “induced fit” model. The experimental observation of dynamic behavior supports the notion that flexibility in stereoselective catalysts can be an advantageous feature.

Synthesis and evaluation of phenylalanine-derived trifluoromethyl ketones for peptide-based oxidation catalysis

Co-reporter:Aaron L. Featherston, Scott J. Miller

Bioorganic & Medicinal Chemistry 2016 Volume 24(Issue 20) pp:4871-4874

Publication Date(Web):15 October 2016

DOI:10.1016/j.bmc.2016.07.012

We report the synthesis of phenylalanine-derived trifluoromethyl ketones for the in situ generation of dioxiranes for the purpose of oxidation catalysis. The key features of this synthesis include the use of a masked ketone strategy and a Negishi cross-coupling to access the parent amino acid. The derivatives can be readily incorporated into a peptide for use in oxidation chemistry and exhibit good stability and reactivity.Figure optionsDownload full-size imageDownload as PowerPoint slide

A stepwise dechlorination/cross-coupling strategy to diversify the vancomycin ‘in-chloride’

Co-reporter:Tyler J. Wadzinski, Katherine D. Gea, Scott J. Miller

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 3) pp:1025-1028

Publication Date(Web):1 February 2016

DOI:10.1016/j.bmcl.2015.12.027

In an effort to rapidly access vancomycin analogues bearing diverse functionality at the 6c-Cl (the ‘in-chloride’) position, a two-step dechlorination/cross-coupling protocol was developed. Conditions for efficient cross-coupling of the relatively unreactive 6c-Cl group were found that ensure high conversion with minimal product decomposition. A set of 2c-dechloro-6c-functionalized vancomycin derivatives was prepared, and antibiotic activities of the compounds were evaluated against a panel of vancomycin-resistant and vancomycin-susceptible strains. Results from biological testing further underscore the steric sensitivity of vancomycin’s binding pocket.

Aspartyl Oxidation Catalysts That Dial In Functional Group Selectivity, along with Regio- and Stereoselectivity

Co-reporter:Joshua S. Alford, Nadia C. Abascal, Christopher R. Shugrue, Sean M. Colvin, David K. Romney, and Scott J. Miller

ACS Central Science 2016 Volume 2(Issue 10) pp:733

Publication Date(Web):September 13, 2016

DOI:10.1021/acscentsci.6b00237

A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions. The analogous portability of a small-molecule catalyst for truly orthogonal chemical reactivity is rare. Herein, we report aspartic acid containing peptides that can be directed to different sectors of a substrate for which the danger of cross-reactivity looms large. A transiently formed aspartyl peracid catalyst can participate either as an electrophilic oxidant to catalyze alkene epoxidation or as a nucleophilic oxidant to mediate the Baeyer–Villiger oxidation (BVO) of ketones. We show in this study that an appended peptide sequence can dictate the mode of reactivity for this conserved catalytic functional group within a substrate that has the potential to undergo both alkene epoxidation and BVO; in both cases the additional aspects of chemical selectivity (regio- and stereoselectivity) are high. This sequence-dependent tuning of a common catalytic moiety for functional group selective reactions constitutes a biomimetic strategy that may impact late-stage diversification of complex polyfunctional molecules.

Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

Co-reporter:Matthew E. Diener; Anthony J. Metrano; Shuhei Kusano

Journal of the American Chemical Society 2015 Volume 137(Issue 38) pp:12369-12377

Publication Date(Web):September 6, 2015

DOI:10.1021/jacs.5b07726

We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide–substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki–Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald–Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.

Regioselective Derivatizations of a Tribrominated Atropisomeric Benzamide Scaffold

Co-reporter:Kimberly T. Barrett and Scott J. Miller

Organic Letters 2015 Volume 17(Issue 3) pp:580-583

Publication Date(Web):January 12, 2015

DOI:10.1021/ol503593y

The enantioselective synthesis of atropisomeric, tribrominated benzamides and subsequent regioselective transformations to afford derivatized, axially chiral molecules is reported. The enantioenriched tribromides were carried through sequential Pd-catalyzed cross-coupling and lithium–halogen exchange with high regioselectivity and enantioretention. A variety of complexity-generation functional group installations were performed to create a library of homochiral benzamides. The potential utility of these molecules is demonstrated by using a phosphino benzamide derivative as an asymmetric ligand in a Pd-catalyzed allylic alkylation.

Structure Diversification of Vancomycin through Peptide-Catalyzed, Site-Selective Lipidation: A Catalysis-Based Approach To Combat Glycopeptide-Resistant Pathogens

Co-reporter:Sabesan Yoganathan

Journal of Medicinal Chemistry 2015 Volume 58(Issue 5) pp:2367-2377

Publication Date(Web):February 11, 2015

DOI:10.1021/jm501872s

The emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, we disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. We have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliphatic hydroxyls on vancomycin, generating three new derivatives 9a, 9b, and 9c. Incorporation of lipid chains into the vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for 9a, 9b, and 9c against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. We have also performed a structure–activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.

A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts for Asymmetric BaeyerVilliger Oxidation

Co-reporter:Michael W. Giuliano;Chung-Yon Lin;David K. Romney;Eric V. Anslyn

Advanced Synthesis & Catalysis 2015 Volume 357( Issue 10) pp:2301-2309

Publication Date(Web):

DOI:10.1002/adsc.201500230

Phosphothreonine as a Catalytic Residue in Peptide-Mediated Asymmetric Transfer Hydrogenations of 8-Aminoquinolines

Co-reporter:Christopher R. Shugrue ; Scott J. Miller

Angewandte Chemie International Edition 2015 Volume 54( Issue 38) pp:11173-11176

Publication Date(Web):

DOI:10.1002/anie.201505898

Abstract

Phosphothreonine (pThr) was found to constitute a new class of chiral phosphoric acid (CPA) catalyst upon insertion into peptides. To demonstrate the potential of these phosphopeptides as asymmetric catalysts, enantioselective transfer hydrogenations of a previously underexplored substrate class for CPA-catalyzed reductions were carried out. pThr-containing peptides lead to the observation of enantioselectivities of up to 94:6 e.r. with 2-substituted quinolines containing C8-amino functionality. NMR studies indicate that hydrogen-bonding interactions promote strong complexation between substrates and a rigid β-turn catalyst.

Phosphothreonine as a Catalytic Residue in Peptide-Mediated Asymmetric Transfer Hydrogenations of 8-Aminoquinolines

Co-reporter:Christopher R. Shugrue ; Scott J. Miller

Angewandte Chemie 2015 Volume 127( Issue 38) pp:11325-11328

Publication Date(Web):

DOI:10.1002/ange.201505898

Abstract

Multivalency as a Key Factor for High Activity of Selective Supported Organocatalysts for the BaylisHillman Reaction

Co-reporter:Dr. Kerem Goren;Jeny Karabline-Kuks;Yael Shiloni;Einav Barak-Kulbak; Scott J. Miller; Moshe Portnoy

Chemistry - A European Journal 2015 Volume 21( Issue 3) pp:1191-1197

Publication Date(Web):

DOI:10.1002/chem.201404560

Abstract

The polystyrene-supported N-alkylimidazole-based dendritic catalysts for the Baylis–Hillman reaction exhibit one of the strongest beneficial effects of multivalent architecture ever reported for an organocatalyst. The yields in the model reaction of methyl vinyl ketone with p-nitrobenzaldehyde are more than tripled when a non-dendritic catalyst is replaced by a second- or third-generation analogue. Moreover, the reaction of the less active substrates will not occur with the non-dendritic catalyst and will proceed to a significant extent only with the analogous catalysts of higher generations. A substantial additional enhancement of the reaction yield could be achieved by increasing the content of water in the reaction solvent. The plausible cause of the dendritic effect is the assistance of the second, nearby imidazole moiety in the presumably rate-determining proton transfer in the intermediate adduct, after the first imidazole unit induced the formation of the new carbon–carbon bond.

Diastereo- and Enantioselective Addition of Anilide-Functionalized Allenoates to N-Acylimines Catalyzed by a Pyridylalanine-Based Peptide

Co-reporter:Curren T. Mbofana

Journal of the American Chemical Society 2014 Volume 136(Issue 8) pp:3285-3292

Publication Date(Web):February 14, 2014

DOI:10.1021/ja412996f

A selective peptide-catalyzed addition of allenic esters to N-acylimines is reported. Tetrasubstituted allenes were achieved with up to 42:1 diastereomeric ratio and 94:6 enantiomeric ratio (up to 99:1 er after recrystallization of the major diastereomer). An exploration of the role of individual amino acids within the peptide was undertaken. The scope of the reaction was explored and revealed heightened reactivity with thioester-containing allenes. A mechanistic framework that may account for the observed reactivity is also described.

Experimental Lineage and Functional Analysis of a Remotely Directed Peptide Epoxidation Catalyst

Co-reporter:Phillip A. Lichtor

Journal of the American Chemical Society 2014 Volume 136(Issue 14) pp:5301-5308

Publication Date(Web):April 1, 2014

DOI:10.1021/ja410567a

We describe mechanistic investigations of a catalyst (1) that leads to selective epoxidation of farnesol at the 6,7-position, remote from the hydroxyl directing group. The experimental lineage of peptide 1 and a number of resin-bound peptide analogues were examined to reveal the importance of four N-terminal residues. We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity. Both 1D and 2D 1H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH. The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.

Catalyst Control over Regio- and Enantioselectivity in Baeyer–Villiger Oxidations of Functionalized Ketones

Co-reporter:David K. Romney ; Sean M. Colvin

Journal of the American Chemical Society 2014 Volume 136(Issue 40) pp:14019-14022

Publication Date(Web):September 24, 2014

DOI:10.1021/ja508757g

We report a peptide-based catalyst that can strongly influence the regio- and enantioselectivity of the Baeyer–Villiger (BV) oxidation of cyclic ketones bearing amide, urea, or sulfonamide functional groups. Both types of selectivity are thought to arise from a catalyst–substrate hydrogen-bonding interaction. Furthermore, in selected cases, the reactions exhibit the hallmarks of parallel kinetic resolution. The capacity to use catalysis to select between BV products during an asymmetric process may have broad utility for both the synthesis and diversification of complex molecules, including natural products.

Phosphine-Catalyzed Annulation Reactions of 2-Butynoate and α-Keto Esters: Synthesis of Cyclopentene Derivatives

Co-reporter:Curren T. Mbofana and Scott J. Miller

ACS Catalysis 2014 Volume 4(Issue 10) pp:3671

Publication Date(Web):September 5, 2014

DOI:10.1021/cs501117h

We have developed phosphine-catalyzed annulation reactions for the synthesis of highly substituted cyclopentene derivatives from 2-alkynoate and α-keto esters. These transformations involve carbon–carbon bond cleavage of α-keto esters. Preliminary mechanistic studies suggest that, in addition to facilitating carbon–carbon bond formation, the phosphine catalyst plays a role in promoting methanolysis.Keywords: alkynoates; annulation reactions; C−C bond cleavage; fused rings; organocatalysis; phosphines; α-keto esters

Function-oriented investigations of a peptide-based catalyst that mediates enantioselective allylic alcohol epoxidation.

Co-reporter:Nadia C. Abascal, Phillip A. Lichtor, Michael W. Giuliano and Scott J. Miller

Chemical Science 2014 vol. 5(Issue 11) pp:4504-4511

Publication Date(Web):2014/08/11

DOI:10.1039/C4SC01440E

We detail an investigation of a peptide-based catalyst (6) that is effective for the site- (>100:1:1) and enantioselective epoxidation (86% ee) of farnesol. Studies of the substrate scope exhibited by the catalyst are included, along with an exploration of optimized reaction conditions. Mechanistic studies are reported, including relative rate determinations for the catalyst and propionic acid, a historical perspective, truncation studies, and modeling using NMR data. Our compiled data advances our understanding of the inner workings of a catalyst that was identified through combinatorial means.

Peptide-Catalyzed Conversion of Racemic Oxazol-5(4H)-ones into Enantiomerically Enriched α-Amino Acid Derivatives

Co-reporter:Anthony J. Metrano and Scott J. Miller

The Journal of Organic Chemistry 2014 Volume 79(Issue 4) pp:1542-1554

Publication Date(Web):February 12, 2014

DOI:10.1021/jo402828f

We report the development and optimization of a tetrapeptide that catalyzes the methanolytic dynamic kinetic resolution of oxazol-5(4H)-ones (azlactones) with high levels of enantioinduction. Oxazolones possessing benzylic-type substituents were found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis.

X-ray Crystal Structure of Teicoplanin A2-2 Bound to a Catalytic Peptide Sequence via the Carrier Protein Strategy

Co-reporter:Sunkyu Han, Binh V. Le, Holly S. Hajare, Richard H. G. Baxter, and Scott J. Miller

The Journal of Organic Chemistry 2014 Volume 79(Issue 18) pp:8550-8556

Publication Date(Web):August 22, 2014

DOI:10.1021/jo501625f

We report the X-ray crystal structure of a site-selective peptide catalyst moiety and teicoplanin A2-2 complex. The expressed protein ligation technique was used to couple T4 lysozyme (T4L) and a synthetic peptide catalyst responsible for the selective phosphorylation of the N-acetylglucosamine sugar in a teicoplanin A2-2 derivative. The T4L-Pmh-dPro-Aib-dAla-dAla construct was crystallized in the presence of teicoplanin A2-2. The resulting 2.3 Å resolution protein–peptide–teicoplanin complex crystal structure revealed that the nucleophilic nitrogen of N-methylimidazole in the Pmh residue is in closer proximity (7.6 Å) to the N-acetylglucosamine than the two other sugar rings present in teicoplanin (9.3 and 20.3 Å, respectively). This molecular arrangement is consistent with the observed selectivity afforded by the peptide-based catalyst when it is applied to a site-selective phosphorylation reaction involving a teicoplanin A2-2 derivative.

Asymmetric Catalysis at a Distance: Catalytic, Site-Selective Phosphorylation of Teicoplanin

Co-reporter:Sunkyu Han

Journal of the American Chemical Society 2013 Volume 135(Issue 33) pp:12414-12421

Publication Date(Web):August 7, 2013

DOI:10.1021/ja406067v

We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A2-2. Two of the catalysts are based on a design that capitalizes on a catalyst–substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a dXaa–dXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 Å, based on the X-ray crystal structure of teicoplanin A2-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself.

Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination

Co-reporter:Kimberly T. Barrett

Journal of the American Chemical Society 2013 Volume 135(Issue 8) pp:2963-2966

Publication Date(Web):February 14, 2013

DOI:10.1021/ja400082x

We report the enantioselective synthesis of atropisomeric benzamides employing catalytic electrophilic aromatic substitution reactions involving bromination. The catalyst is a simple tetrapeptide bearing a tertiary amine that may function as a Brønsted base. A series of tri- and dibrominations were accomplished for a range of compounds bearing differential substitution patterns. Tertiary benzamides represent appropriate substrates for the reaction since they exhibit sufficiently high barriers to racemization after ortho functionalization. Mechanism-driven experiments provided some insight into the basis for selectivity. Examination of the observed products at low conversion suggested that the initial catalytic bromination may be regioselective and stereochemistry-determining. A complex between the catalyst and substrate was observed by NMR spectroscopy, revealing a specific association. Finally, the products of these reactions may be subjected to regioselective metal–halogen exchange and trapping with I2, setting the stage for utility.

A Fully Synthetic and Biochemically Validated Phosphatidyl Inositol-3-Phosphate Hapten via Asymmetric Synthesis and Native Chemical Ligation

Co-reporter:Brent D. Chandler ; Anne L. Burkhardt ; Klaudia Foley ; Courtney Cullis ; Denise Driscoll ; Natalie Roy D’Amore

Journal of the American Chemical Society 2013 Volume 136(Issue 1) pp:412-418

Publication Date(Web):December 17, 2013

DOI:10.1021/ja410750a

We report the synthesis and biochemical validation of a phosphatidyl inositol-3 phosphate (PI3P) immunogen. The inositol stereochemistry was secured through peptide-catalyzed asymmetric phosphorylation catalysis, and the subsequent incorporation of a cysteine residue was achieved by native chemical ligation (NCL). Conjugation of the PI3P hapten to maleimide-activated keyhole limpet hemocyanin (KLH) provided a PI3P immunogen, which was successfully used to generate selective PI3P antibodies. The incorporation of a sulfhydryl nucleophile into a phosphoinositide hapten demonstrates a general strategy to reliably access phosphoinositide immunogens.

N-Methylimidazole-catalyzed Synthesis of Carbamates from Hydroxamic Acids via the Lossen Rearrangement

Co-reporter:Sabesan Yoganathan and Scott J. Miller

Organic Letters 2013 Volume 15(Issue 3) pp:602-605

Publication Date(Web):January 17, 2013

DOI:10.1021/ol303424b

An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.

A β-Boronopeptide Bundle of Known Structure As a Vehicle for Polyol Recognition

Co-reporter:Michael S. Melicher, John Chu, Allison S. Walker, Scott J. Miller, Richard H. G. Baxter, and Alanna Schepartz

Organic Letters 2013 Volume 15(Issue 19) pp:5048-5051

Publication Date(Web):September 13, 2013

DOI:10.1021/ol402381n

Despite significant progress in the design of receptors and sensors for simple polyols and monosaccharides, few synthetic receptors discriminate among multiple saccharide units simultaneously, especially under physiological conditions. Described here is the three-dimensional structure of a supramolecular complex—a β-peptide bundle—designed for the potential to interact simultaneously with as many as eight discrete monosaccharide units. The preliminary evaluation of this construct as a vehicle for polyol binding is also presented.

Chiral Copper(II) Complex-Catalyzed Reactions of Partially Protected Carbohydrates

Co-reporter:C. Liana Allen and Scott J. Miller

Organic Letters 2013 Volume 15(Issue 24) pp:6178-6181

Publication Date(Web):November 26, 2013

DOI:10.1021/ol4033072

Catalyst-controlled regioselective functionalization of partially protected saccharide molecules is a highly important yet under-developed area of carbohydrate chemistry. Such reactions allow for the reduction of protecting group manipulation steps required in syntheses involving sugars. Herein, an approach to these processes using enantiopure copper–bis(oxazoline) catalysts to control couplings of electrophiles to various partially protected sugars is reported. In a number of cases, divergent regioselectivity was observed as a function of the enantiomer of catalyst that is used.

An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin

Co-reporter:Sabesan Yoganathan, Ning Yin, Yong He, Michael F. Mesleh, Yu Gui Gu and Scott J. Miller

Organic & Biomolecular Chemistry 2013 vol. 11(Issue 28) pp:4680-4685

Publication Date(Web):29 May 2013

DOI:10.1039/C3OB40924D

Herein we report a direct and efficient method for the synthesis of four new carboxylate-isostere analogs of daptomycin. The side chain carboxylic acid moieties of the aspartic acids (Asp-3, Asp-7 and Asp-9) and β-methyl glutamic acid (MeGlu-12) were all converted into the corresponding carboxylate isosteres using direct synthetic procedures. The present study also describes an esterification protocol to overcome the possible backbone cyclization of the activated side chain carboxylic acid group of either Asp or Glu onto the backbone amide.

Combined Lewis acid and Brønsted acid-mediated reactivity of glycosyl trichloroacetimidate donors

Co-reporter:Nathan D. Gould, C. Liana Allen, Brandon C. Nam, Alanna Schepartz, Scott J. Miller

Carbohydrate Research 2013 Volume 382() pp:36-42

Publication Date(Web):15 December 2013

DOI:10.1016/j.carres.2013.09.011

•Carboxylic acids were proposed as biomimetic catalysts for glycosylation reactions.•‘Weaker’ acids reacted with the glycosyl donor to form the glycosyl ester.•Rate difference among five of these esterification reactions was ∼104.•Mg2+ ions were found to inhibit esterification and allow glycosylation.Biomimetic conditions for a synthetic glycosylation reaction, inspired by the highly conserved functionality of carbohydrate active enzymes, were explored. At the outset, we sought to generate proof of principle for this approach to developing catalytic systems for glycosylation. However, control reactions and subsequent kinetic studies showed that a stoichiometric, irreversible reaction of the catalyst and glycosyl donor was occurring, with a remarkable rate variance depending upon the structure of the carboxylic acid. It was subsequently found that a combination of Brønsted acid (carboxylic acid) and Lewis acid (MgBr2) was unique in catalyzing the desired glycosylation reaction. Thus, it was concluded that the two acids act synergistically to catalyze the desired transformation. The role of the catalytic components was tested with a number of control reactions and based on these studies a mechanism is proposed herein.

Site-Selective Bromination of Vancomycin

Co-reporter:Tejas P. Pathak

Journal of the American Chemical Society 2012 Volume 134(Issue 14) pp:6120-6123

Publication Date(Web):March 30, 2012

DOI:10.1021/ja301566t

We report the site-selective bromination of vancomycin to produce, with substantial efficiency, previously unknown monobromovancomycins, a dibromovancomycin, and a tribromovancomycin. We document the inherent reactivity of native vancomycin toward N-bromophthalimide. We then demonstrate significant rate acceleration and perturbation of the inherent product distribution in the presence of a rationally designed peptide-based promoter. Alternative site selectivity is observed as a function of solvent and replacement of the peptide with guanidine.

Catalytic Site-Selective Thiocarbonylations and Deoxygenations of Vancomycin Reveal Hydroxyl-Dependent Conformational Effects

Co-reporter:Brandon S. Fowler ; Kai M. Laemmerhold

Journal of the American Chemical Society 2012 Volume 134(Issue 23) pp:9755-9761

Publication Date(Web):May 23, 2012

DOI:10.1021/ja302692j

We have examined peptide-based catalysts for the site-selective thiocarbonylation of a protected form of vancomycin. Several catalysts were identified that either enhanced or altered the inherent selectivity profile exhibited by the substrate. Two catalysts, one identified through screening and another through rational design, were demonstrated to be effective on 0.50-g scale. Deoxygenations led ultimately to two new deoxy-vancomycin derivatives, and surprising conformational consequences of deoxygenation were revealed for one of the new compounds. These effects were mirrored in the biological activities of the new analogues and support a structural role for certain hydroxyls in the native structure.

A Peptide-Embedded Trifluoromethyl Ketone Catalyst for Enantioselective Epoxidation

Co-reporter:David K. Romney and Scott J. Miller

Organic Letters 2012 Volume 14(Issue 4) pp:1138-1141

Publication Date(Web):February 8, 2012

DOI:10.1021/ol3000712

The development of peptide-based oxidation catalysts that use a transiently generated dioxirane as the chemically active species is reported. The active catalyst is a chiral trifluoromethyl ketone (Tfk) with a pendant carboxylic acid that can be readily incorporated into a peptide. These peptides were capable of epoxidizing alkenes in high yield (up to 89%) and enantiomeric ratios (er) ranging from 69.0:31.0 to 91.0:9.0, depending on the alkene substitution pattern.

An Approach to the Site-Selective Deoxygenation of Hydroxy Groups Based on Catalytic Phosphoramidite Transfer

Co-reporter:Peter A. Jordan ;Dr. Scott J. Miller

Angewandte Chemie International Edition 2012 Volume 51( Issue 12) pp:2907-2911

Publication Date(Web):

DOI:10.1002/anie.201109033

An Approach to the Site-Selective Deoxygenation of Hydroxy Groups Based on Catalytic Phosphoramidite Transfer

Co-reporter:Peter A. Jordan ;Dr. Scott J. Miller

Angewandte Chemie 2012 Volume 124( Issue 12) pp:2961-2965

Publication Date(Web):

DOI:10.1002/ange.201109033

Chemoselective and Enantioselective Oxidation of Indoles Employing Aspartyl Peptide Catalysts

Co-reporter:Filip Kolundzic ; Mohammad N. Noshi ; Meiliana Tjandra ; Mohammad Movassaghi

Journal of the American Chemical Society 2011 Volume 133(Issue 23) pp:9104-9111

Publication Date(Web):May 3, 2011

DOI:10.1021/ja202706g

Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.

Divergent Reactivity in Amine- and Phosphine-Catalyzed C–C Bond-Forming Reactions of Allenoates with 2,2,2-Trifluoroacetophenones

Co-reporter:Lindsey B. Saunders and Scott J. Miller

ACS Catalysis 2011 Volume 1(Issue 10) pp:1347

Publication Date(Web):August 30, 2011

DOI:10.1021/cs200406d

A divergent reactivity pattern of allenoates with 2,2,2-trifluoroacetophenones under Lewis base catalysis is reported. Whereas phosphine catalysis leads to a [3 + 2]-cycloaddition to form dihydrofurans, an alternative pathway was discovered in which 1,4-diazabicyclo-[2.2.2]-octane catalyzes a formal [2 + 2]-cycloaddition to form oxetanes. This unusual mode of reactivity leads to structurally complex products in moderate to excellent yields (32–86%) and adds to the repertoire of Lewis base-catalyzed allenoate transformations.Keywords: allenoate; cycloaddition; dihydrofuran; Lewis base catalysis; oxetane;

Quasi-biomimetic ring contraction promoted by a cysteine-based nucleophile: Total synthesis of Sch-642305, some analogs and their putative anti-HIV activities

Co-reporter:Alpay Dermenci, Philipp S. Selig, Robert A. Domaoal, Krasimir A. Spasov, Karen S. Anderson and Scott J. Miller

Chemical Science 2011 vol. 2(Issue 8) pp:1568-1572

Publication Date(Web):20 Jun 2011

DOI:10.1039/C1SC00221J

Cysteine plays a number of important functional and structural roles in nature, often in the realm of catalysis. Herein, we present an example of a cysteine-promoted Rauhut-Currier reaction for a potentially biomimetic synthesis of Sch-642305 and related analogs. In this key step of the synthesis we discuss interesting new discoveries and the importance of substrate-catalyst recognition, as well as cysteine's structural features. Also, we investigate the activity of Sch-642305 and four analogs in HIV-infected T-cells.

One-Bead-One-Catalyst Approach to Aspartic Acid-Based Oxidation Catalyst Discovery

Co-reporter:Phillip A. Lichtor and Scott J. Miller

ACS Combinatorial Science 2011 Volume 13(Issue 3) pp:321

Publication Date(Web):March 22, 2011

DOI:10.1021/co200010v

We report an approach to the high-throughput screening of asymmetric oxidation catalysts. The strategy is based on application of the one-bead-one-compound library approach, wherein each of our catalyst candidates is based on a peptide scaffold. For this purpose, we rely on a recently developed catalytic cycle that employs an acid-peracid shuttle. To implement our approach, we developed a compatible linker and demonstrated that the library format is amenable to screening and sequencing of catalysts employing partial Edman degradation and MALDI mass spectrometry analysis. The system was applied to the discovery (and rediscovery) of catalysts for the enantioselective oxidation of a cyclohexene derivative. The system is now poised for application to unprecedented substrate classes for asymmetric oxidation reactions.Keywords: asymmetric catalysis; asymmetric epoxidation; peptides

ortho-Acidic aromatic thiols as efficient catalysts of intramolecular Morita–Baylis–Hillman and Rauhut–Currier reactions

Co-reporter:Philipp S. Selig, Scott J. Miller

Tetrahedron Letters 2011 Volume 52(Issue 17) pp:2148-2151

Publication Date(Web):27 April 2011

DOI:10.1016/j.tetlet.2010.11.077

ortho-Mercaptobenzoic acid and ortho-mercaptophenols were discovered as efficient thiol catalysts of both the intramolecular Morita–Baylis–Hillman (MBH) and Rauhut–Currier (RC) reaction. High reaction rates were achieved under mildly basic, aqueous conditions. The unprecedented catalytic activity of these protic nucleophiles could originate from a Brønsted acid induced destabilization of intermediate thioethers and thus represent a unique mechanism of multifunctional Lewis base catalysis.

Chemoenzymatic Synthesis of Each Enantiomer of Orthogonally Protected 4,4-Difluoroglutamic Acid: A Candidate Monomer for Chiral Brønsted Acid Peptide-Based Catalysts

Co-reporter:Yang Li and Scott J. Miller

The Journal of Organic Chemistry 2011 Volume 76(Issue 23) pp:9785-9791

Publication Date(Web):October 31, 2011

DOI:10.1021/jo2018679

We have accomplished an asymmetric synthesis of each enantiomer of 4,4-difluoroglutamic acid. This α-amino acid has been of interest in medicinal chemistry circles. Key features of the synthesis include highly scalable procedures, a Reformatsky-based coupling reaction, and straightforward functional group manipulations to make the parent amino acid. Enantioenrichment derives from an enzymatic resolution of the synthetic material. Conversion of the optically enriched compounds to orthogonally protected forms allows for the selective formation of peptide bonds. 4,4-Difluoroglutamic acid, in a suitably protected form, is also shown to exhibit enhanced catalytic activity in both an oxidation reaction and a reduction reaction, in comparison to the analogous glutamic acid derivative.

Synthesis of Atropisomerically Defined, Highly Substituted Biaryl Scaffolds through Catalytic Enantioselective Bromination and Regioselective Cross-Coupling

Co-reporter:Jeffrey L. Gustafson;Dr. Daniel Lim;Kimberly T. Barrett ;Dr. Scott J. Miller

Angewandte Chemie International Edition 2011 Volume 50( Issue 22) pp:5125-5129

Publication Date(Web):

DOI:10.1002/anie.201101147

Synthesis of Atropisomerically Defined, Highly Substituted Biaryl Scaffolds through Catalytic Enantioselective Bromination and Regioselective Cross-Coupling

Co-reporter:Jeffrey L. Gustafson;Dr. Daniel Lim;Kimberly T. Barrett ;Dr. Scott J. Miller

Angewandte Chemie 2011 Volume 123( Issue 22) pp:5231-5235

Publication Date(Web):

DOI:10.1002/ange.201101147

n → π* Interaction and n)(π Pauli Repulsion Are Antagonistic for Protein Stability

Co-reporter:Charles E. Jakobsche ; Amit Choudhary ; Scott J. Miller ;Ronald T. Raines

Journal of the American Chemical Society 2010 Volume 132(Issue 19) pp:6651-6653

Publication Date(Web):April 26, 2010

DOI:10.1021/ja100931y

In many common protein secondary structures, such as α-, 310, and polyproline II helices, an n → π* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Bürgi−Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi−1) of a peptide bond over the antibonding orbital (π*) of Ci═Oi of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of Oi−1 and the bonding orbital (π) of Ci═Oi. We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n → π* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n → π* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n → π* interaction and emphasizes the quantum-mechanical nature of the interaction between adjacent amide carbonyl groups in proteins.

Linear Free-Energy Relationship Analysis of a Catalytic Desymmetrization Reaction of a Diarylmethane-bis(phenol)

Co-reporter:Jeffrey L. Gustafson, Matthew S. Sigman and Scott J. Miller

Organic Letters 2010 Volume 12(Issue 12) pp:2794-2797

Publication Date(Web):May 20, 2010

DOI:10.1021/ol100927m

Linear free-energy relationships have been found for enantioselectivity and various steric parameters in an enantioselective desymmetrization of symmetrical bis(phenol) substrates. The potential origin of this observation and the role of different steric parameters are discussed.

Pyridylalanine (Pal)-Peptide Catalyzed Enantioselective Allenoate Additions to N-Acyl Imines Proceed via an Atypical “aza-Morita−Baylis−Hillman” Mechanism

Co-reporter:Lindsey B. Saunders, Bryan J. Cowen, and Scott J. Miller

Organic Letters 2010 Volume 12(Issue 21) pp:4800-4803

Publication Date(Web):September 28, 2010

DOI:10.1021/ol101947s

Mechanistic experiments, including kinetics and hydrogen/deuterium kinetic isotope effects, reveal an “atypical” rate-determining step in a pyridylalanine-peptide catalyzed enantioselective coupling of allenoates and N-acyl imines. Typically, acrylates participate in both the aldehyde-based “Morita−Baylis−Hillman (MBH)” reaction and the imine-based variant (the “aza-MBH”) through similar mechanisms, with proton transfer/catalyst regeneration often rate-determining. In contrast, the title reaction exhibits kinetics wherein proton transfer is kinetically silent.

Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: Enantioselective synthesis of d-myo-inositol-6-phosphate

Co-reporter:Peter A. Jordan;Katherine J. Kayser-Bricker

PNAS 2010 Volume 107 (Issue 48 ) pp:20620-20624

Publication Date(Web):2010-11-30

DOI:10.1073/pnas.1001111107

Despite the ubiquitous use of phosphoramidite chemistry in the synthesis of biophosphates, catalytic asymmetric phosphoramidite transfer remains largely unexplored for phosphate ester synthesis. We have discovered that a tetrazole-functionalized peptide, in the presence of 10-Å molecular sieves, functions as an enantioselective catalyst for phosphite transfer. This chemistry in turn has been used as the key step in a streamlined synthesis of myo-inositol-6-phosphate. Mechanistic insights implicate phosphate as a directing group for a highly selective kinetic resolution of a protected inositol monophosphate. This work represents a distinct and efficient method for the selective catalytic phosphorylation of natural products.

Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric Bromination

Co-reporter:Scott J. Miller;Daniel Lim;Jeffrey L. Gustafson

Science 2010 Volume 328(Issue 5983) pp:1251-1255

Publication Date(Web):04 Jun 2010

DOI:10.1126/science.1188403

Enantioselective catalysis and complexity generation from allenoates

Co-reporter:Bryan J. Cowen and Scott J. Miller

Chemical Society Reviews 2009 vol. 38(Issue 11) pp:3102-3116

Publication Date(Web):24 Jul 2009

DOI:10.1039/B816700C

Lewis base catalysis of reactions with allenoates using phosphine and amine nucleophiles has emerged as a key platform for the generation of molecular complexity. Investigations in this area have established a range of suitable coupling partners for allenoates, including electron-deficient olefins, imines, and aldehydes. This tutorial review will describe these methodologies, with a special emphasis on recent work regarding asymmetric reactions using chiral Lewis base catalysts.

Regio- and Stereoselective Synthesis of Fluoroalkenes by Directed Au(I) Catalysis

Co-reporter:Benjamin C. Gorske, Curren T. Mbofana and Scott J. Miller

Organic Letters 2009 Volume 11(Issue 19) pp:4318-4321

Publication Date(Web):August 27, 2009

DOI:10.1021/ol9016782

Au-catalyzed hydrofluorination reactions of a range of functionalized alkynes are reported. In the presence of an appropriate directing group, localized with particular spacing from the pendant alkyne, regioselective and predictable conversion of the alkyne to the Z-vinyl fluoride may be achieved. In selected cases, yields and selectivities are excellent. Additional experiments with two directing groups installed have established some initial principles with respect to a hierarchy of directing groups and their capacity for influencing hydrofluorination regioselectivity.

An Approach to the Site-Selective Diversification of Apoptolidin A with Peptide-Based Catalysts

Co-reporter:Chad A. Lewis, Kate E. Longcore, Scott J. Miller and Paul A. Wender

Journal of Natural Products 2009 Volume 72(Issue 10) pp:1864-1869

Publication Date(Web):September 21, 2009

DOI:10.1021/np9004932

We report the application of peptide-based catalysts to the site-selective modification of apoptolidin A (1), an agent that displays remarkable selectivity for inducing apoptosis in E1A-transformed cell lines. Key to the approach was the development of an assay suitable for the screening of dozens of catalysts in parallel reactions that could be conducted using only microgram quantities of the starting material. Employing this assay, catalysts (e.g., 11 and ent-11) were identified that afforded unique product distributions, distinct from the product mixtures produced when a simple catalyst (N,N-dimethyl-4-aminopyridine (10)) was employed. Preparative reactions were then carried out with the preferred catalysts so that unique, homogeneous apoptolidin analogues could be isolated and characterized. From these studies, three new apoptolidin analogues were obtained (12−14), each differing from the other in either the location of acyl group substituents or the number of acetate groups appended to the natural product scaffold. Biological evaluation of the new apoptolidin analogues was then conducted using growth inhibition assays based on the H292 human lung carcinoma cell line. The new analogues exhibited activities comparable to apoptolidin A.

Disparate Behavior of Carbonyl and Thiocarbonyl Compounds: Acyl Chlorides vs Thiocarbonyl Chlorides and Isocyanates vs Isothiocyanates

Co-reporter:Kenneth B. Wiberg, Yi-gui Wang, Scott J. Miller and Angela L. A. Puchlopek, William F. Bailey and Justin D. Fair

The Journal of Organic Chemistry 2009 Volume 74(Issue 10) pp:3659-3664

Publication Date(Web):April 16, 2009

DOI:10.1021/jo9004316

The reaction of benzoyl chloride with methanol catalyzed by pyridine is 9 times more rapid than is the same reaction with thiobenzoyl chloride. The difference in reactivity, as well as the dealkylation reactions that occur when the reaction of thiobenzoyl chloride is catalyzed by bases such as Et3N, can be understood in terms of the charge distributions in the intermediate acylammonium ions. The reaction of PhNCO with ethanol occurs at a much higher rate (4.8 × 104) than that of PhNCS, corresponding to a difference in activation free energies for the additions of 6 kcal/mol. Transition states for each of these reactions were located, and each involves two alcohol molecules in a hydrogen bonded six-membered ring arrangement. Information concerning differences in reactivity was derived from analysis of Hirshfeld atomic charge distributions and calculated hydrogenolysis reaction energies.

The Rauhut–Currier reaction: a history and its synthetic application

Co-reporter:Carrie E. Aroyan, Alpay Dermenci, Scott J. Miller

Tetrahedron 2009 65(21) pp: 4069-4084

Publication Date(Web):

DOI:10.1016/j.tet.2009.02.066

Asymmetric Syntheses of l,l- and l,d-Di-myo-inositol-1,1-phosphate and their Behavior as Stabilizers of Enzyme Activity at Extreme Temperatures

Co-reporter:ChristinaM. Longo;Yang Wei;MaryF. Roberts ;ScottJ. Miller

Angewandte Chemie International Edition 2009 Volume 48( Issue 23) pp:

Publication Date(Web):

DOI:10.1002/anie.200900480

Asymmetric Syntheses of l,l- and l,d-Di-myo-inositol-1,1-phosphate and their Behavior as Stabilizers of Enzyme Activity at Extreme Temperatures

Co-reporter:ChristinaM. Longo;Yang Wei;MaryF. Roberts ;ScottJ. Miller

Angewandte Chemie 2009 Volume 121( Issue 23) pp:

Publication Date(Web):

DOI:10.1002/ange.200900480

A Case of Remote Asymmetric Induction in the Peptide-Catalyzed Desymmetrization of a Bis(phenol)

Co-reporter:Chad A. Lewis ; Jeffrey L. Gustafson ; Anna Chiu ; Jaume Balsells ; David Pollard ; Jerry Murry ; Robert A. Reamer ; Karl B. Hansen

Journal of the American Chemical Society 2008 Volume 130(Issue 48) pp:16358-16365

Publication Date(Web):November 12, 2008

DOI:10.1021/ja807120z

We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 Å. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure−selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst−substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst−substrate binding event.

Catalytic site-selective synthesis and evaluation of a series of erythromycin analogs

Co-reporter:Chad A. Lewis, Janie Merkel, Scott J. Miller

Bioorganic & Medicinal Chemistry Letters 2008 Volume 18(Issue 22) pp:6007-6011

Publication Date(Web):15 November 2008

DOI:10.1016/j.bmcl.2008.09.019

The generation of a series of analogs of erythromycin A (EryA, 2) is described. In this study, we compared two peptide-based catalysts—one originally identified from a catalyst screen (5) and its enantiomer (ent-5)—for the selective functionalization of EryA. The semi-synthetic analogs were subjected to MIC evaluation with two bacterial strains and compared to unfunctionalized EryA.

Functional Analysis of an Aspartate-Based Epoxidation Catalyst with Amide-to-Alkene Peptidomimetic Catalyst Analogues

Co-reporter:CharlesE. Jakobsche;Gorka Peris ;ScottJ. Miller

Angewandte Chemie International Edition 2008 Volume 47( Issue 35) pp:6707-6711

Publication Date(Web):

DOI:10.1002/anie.200802223

Functional Analysis of an Aspartate-Based Epoxidation Catalyst with Amide-to-Alkene Peptidomimetic Catalyst Analogues

Co-reporter:CharlesE. Jakobsche;Gorka Peris ;ScottJ. Miller

Angewandte Chemie 2008 Volume 120( Issue 35) pp:6809-6813

Publication Date(Web):

DOI:10.1002/ange.200802223

Site-Selective Derivatization and Remodeling of Erythromycin A by Using Simple Peptide-Based Chiral Catalysts

Co-reporter:Chad A. Lewis

Angewandte Chemie 2006 Volume 118(Issue 34) pp:

Publication Date(Web):21 JUL 2006

DOI:10.1002/ange.200601490

Umkehrung: Einfache peptidische nucleophile Katalysatoren können die „natürliche“ Reaktivitätsabstufung von Hydroxygruppen im Polyol-Naturstoff Erythromycin A verändern (siehe Bild). Solche katalysatorabhängigen Modifizierungen könnten für die Erzeugung von Naturstoffanaloga von Nutzen sein.

Site-Selective Derivatization and Remodeling of Erythromycin A by Using Simple Peptide-Based Chiral Catalysts

Co-reporter:Chad A. Lewis

Angewandte Chemie International Edition 2006 Volume 45(Issue 34) pp:

Publication Date(Web):21 JUL 2006

DOI:10.1002/anie.200601490

Reversal: Simple peptide-based nucleophilic catalysts can perturb the inherent reactivity hierarchy of the polyol natural product erythromycin A (see picture). Such catalyst-dependent modifications that reorganize natural product architecture may be of utility for generation of natural product analogs.

d-3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway

Co-reporter:Cheryl S. Gradziel, Peter A. Jordan, Delilah Jewel, Fay J. Dufort, Scott J. Miller, Thomas C. Chiles, Mary F. Roberts

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (November 2016) Volume 1861(Issue 11) pp:

Publication Date(Web):1 November 2016

DOI:10.1016/j.bbalip.2016.09.001

•NMR shows cytotoxic and non-toxic PIAs bind to the same Akt1 PH domain site.•MCF-7 cells exhibit reduced levels of constitutively active Akt.•d-3-deoxy-diC8PI induces apoptosis in MCF-7 cells.•d-3-deoxy-diC8PI downregulates the D-type cyclin-retinoblastoma protein pathway.•The effect of this PIA is independent of its interaction with Akt.Phosphatidylinositol analogs (PIAs) were originally designed to bind competitively to the Akt PH domain and prevent membrane translocation and activation. d-3-Deoxy-dioctanoylphosphatidylinositol (d-3-deoxy-diC8PI), but not compounds with altered inositol stereochemistry (e.g., l-3-deoxy-diC8PI and l-3,5-dideoxy-diC8PI), is cytotoxic. However, high resolution NMR field cycling relaxometry shows that both cytotoxic and non-toxic PIAs bind to the Akt1 PH domain at the site occupied by the cytotoxic alkylphospholipid perifosine. This suggests that another mechanism for cytotoxicity must account for the difference in efficacy of the synthetic short-chain PIAs. In MCF-7 breast cancer cells, with little constitutively active Akt, d-3-deoxy-diC8PI (but not l-compounds) decreases viability concomitant with increased cleavage of PARP and caspase 9, indicative of apoptosis. d-3-Deoxy-diC8PI also induces a decrease in endogenous levels of cyclins D1 and D3 and blocks downstream retinoblastoma protein phosphorylation. siRNA-mediated depletion of cyclin D1, but not cyclin D3, reduces MCF-7 cell proliferation. Thus, growth arrest and cytotoxicity induced by the soluble d-3-deoxy-diC8PI occur by a mechanism that involves downregulation of the D-type cyclin-pRb pathway independent of its interaction with Akt. This ability to downregulate D-type cyclins contributes, at least in part, to the anti-proliferative activity of d-3-deoxy-diC8PI and may be a common feature of other cytotoxic phospholipids.Download high-res image (92KB)Download full-size image

Peptide-Catalyzed Kinetic Resolution of Formamides and Thioformamides as an Entry to Nonracemic Amines

Co-reporter:Brandon S. Fowler ; Peter J. Mikochik

Journal of the American Chemical Society () pp:

Publication Date(Web):February 16, 2010

DOI:10.1021/ja9107897

Chemical Tailoring of Teicoplanin with Site-Selective Reactions

Co-reporter:Tejas P. Pathak

Journal of the American Chemical Society () pp:

Publication Date(Web):May 21, 2013

DOI:10.1021/ja4038998

Semisynthesis of natural product derivatives combines the power of fermentation with orthogonal chemical reactions. Yet, chemical modification of complex structures represents an unmet challenge, as poor selectivity often undermines efficiency. The complex antibiotic teicoplanin eradicates bacterial infections. However, as resistance emerges, the demand for improved analogues grows. We have discovered chemical reactions that achieve site-selective alteration of teicoplanin. Utilizing peptide-based additives that alter reaction selectivities, certain bromo-teicoplanins are accessible. These new compounds are also scaffolds for selective cross-coupling reactions, enabling further molecular diversification. These studies enable two-step access to glycopeptide analogues not available through either biosynthesis or rapid total chemical synthesis alone. The new compounds exhibit a spectrum of activities, revealing that selective chemical alteration of teicoplanin may lead to analogues with attenuated or enhanced antibacterial properties, in particular against vancomycin- and teicoplanin-resistant strains.

An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin

Co-reporter:Sabesan Yoganathan, Ning Yin, Yong He, Michael F. Mesleh, Yu Gui Gu and Scott J. Miller

Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 28) pp:NaN4685-4685

Publication Date(Web):2013/05/29

DOI:10.1039/C3OB40924D

Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination

Co-reporter:A. J. Metrano, N. C. Abascal, B. Q. Mercado, E. K. Paulson and S. J. Miller

Chemical Communications 2016 - vol. 52(Issue 26) pp:NaN4819-4819

Publication Date(Web):2016/03/02

DOI:10.1039/C6CC01428C

Function-oriented investigations of a peptide-based catalyst that mediates enantioselective allylic alcohol epoxidation.

Co-reporter:Nadia C. Abascal, Phillip A. Lichtor, Michael W. Giuliano and Scott J. Miller

Chemical Science (2010-Present) 2014 - vol. 5(Issue 11) pp:NaN4511-4511

Publication Date(Web):2014/08/11

DOI:10.1039/C4SC01440E

Quasi-biomimetic ring contraction promoted by a cysteine-based nucleophile: Total synthesis of Sch-642305, some analogs and their putative anti-HIV activities

Co-reporter:Alpay Dermenci, Philipp S. Selig, Robert A. Domaoal, Krasimir A. Spasov, Karen S. Anderson and Scott J. Miller

Chemical Science (2010-Present) 2011 - vol. 2(Issue 8) pp:NaN1572-1572

Publication Date(Web):2011/06/20

DOI:10.1039/C1SC00221J

Enantioselective catalysis and complexity generation from allenoates

Co-reporter:Bryan J. Cowen and Scott J. Miller

Chemical Society Reviews 2009 - vol. 38(Issue 11) pp:NaN3116-3116

Publication Date(Web):2009/07/24

DOI:10.1039/B816700C

A bottom up approach towards artificial oxygenases by combining iron coordination complexes and peptides

Co-reporter:Olaf Cussó, Michael W. Giuliano, Xavi Ribas, Scott J. Miller and Miquel Costas

Chemical Science (2010-Present) 2017 - vol. 8(Issue 5) pp:NaN3667-3667

Publication Date(Web):2017/03/03

DOI:10.1039/C7SC00099E

CAS:1391438-73-5

Propanedioic acid, (cyclohexylphenylmethyl)-, diethyl ester

CAS:203565-36-0

Propanedioic acid, (cyclohexylphenylmethyl)-, diethyl ester

CAS:146285-80-5

(3-(Aminomethyl)phenyl)boronic acid

Propanoic acid, 3-iodo-2-methyl-, methyl ester, (R)-

CAS:110556-30-4

Propanoic acid, 3-iodo-2-methyl-, methyl ester, (R)-

CAS:102039-75-8

3-deoxysucrose

CAS:100869-80-5

4-[1-(4-aminophenyl)ethenyl]aniline

a-D-Glucopyranoside, b-D-fructofuranosyl 6-deoxy-

CAS:92596-12-8

a-D-Glucopyranoside, b-D-fructofuranosyl 6-deoxy-

1-aminocyclopentanecarboxylic acid hydrochloride

CAS:92398-48-6

1-aminocyclopentanecarboxylic acid hydrochloride

Acetamide, N-[3-(1-methylethenyl)phenyl]-

CAS:89664-23-3

Acetamide, N-[3-(1-methylethenyl)phenyl]-

(2S,3R,4S,5R,6R)-2-[(2R,3S,4R,5R,6R)-6-[(2S,3S,4S,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol

CAS:87419-56-5

(2S,3R,4S,5R,6R)-2-[(2R,3S,4R,5R,6R)-6-[(2S,3S,4S,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol