Jennifer Stockdill - Academia.edu (original) (raw)

Papers by Jennifer Stockdill

Journal of Organic Chemistry, Dec 19, 2018

We establish herein conditions for the cyclization of unprotected N-acyl urea-linked peptides to ... more We establish herein conditions for the cyclization of unprotected N-acyl urea-linked peptides to form macrocyclic peptides mediated by N-terminal cysteine. We report a detailed investigation of the parameters of the reaction, including variation of the reaction conditions, the C-terminal residue, and the macrocycle size. C-terminal epimerization was not observed. The synthesis of macrocyclic targets ranging from tetrapeptides to the disulfide-linked 14-mer, sunflower trypsin inhibitor 1 are demonstrated. For most substrates, hydrolysis and head-to-tail dimer formation are avoided.

Journal of Organic Chemistry, Jan 25, 2018

Sequence diversification at the C terminus is traditionally limited by significant epimerization ... more Sequence diversification at the C terminus is traditionally limited by significant epimerization of the C-terminal residue during its activation toward nucleophilic attack, thus mandating repetition of the peptide synthesis for each targeted variation. Here, we accomplish divergent C-terminal elongation of a single peptide substrate with concomitant resin cleavage via displacement of an Nacyl urea moiety. Sterically hindered amino acids such as Ile and Pro are well-tolerated in this approach, which proceeds reasonable conversion and no detectable epimerization of the starting peptide's C-terminal amino acid.

ACS central science, Apr 12, 2023

Organic Letters, Nov 22, 2016

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of ... more The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine.

APS March Meeting Abstracts, Mar 1, 2003

Magnetic nanoparticles (MNPs) have potential applications in drug delivery and as anti-cancer age... more Magnetic nanoparticles (MNPs) have potential applications in drug delivery and as anti-cancer agents through hyperthermia, which is induced by hysteric magnetic heating. In order to determine the potential value of the MNPs in these applications, their interactions with cell membranes and phospholipid vesicles must be understood. As the primary structure of the cell membrane is a phospholipid bilayer, a phospholipid

Tetrahedron Letters, Oct 1, 2018

Journal of Great Lakes Research, Feb 1, 2023

Organic Letters, Sep 28, 2018

5-exo, 5-exo Cyclizations of conformationally unbiased propargylic aminyl radicals proceed with e... more 5-exo, 5-exo Cyclizations of conformationally unbiased propargylic aminyl radicals proceed with excellent yield, chemoselectiv ity, and diastereoselectivity under tin-free reductive cyclization conditions, regardless of the electronic environments and intermediate radical stabilization resulting from various olefin substituents. These conditions avoid the need for slow addition of initiator and reductant. By contrast, analogous 6-exo, 5-exo cyclizations require substituents capable of intermediate radical stabilization to avoid premature reduction products. These experimental results are corroborated by computations that further establish the reactivity of these aminyl radicals upon exposure to tin-free cyclization conditions.

Organic and Biomolecular Chemistry, 2017

The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptid... more The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or Sallylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

Chemical Science, 2023

Phosphines and phosphites are critical tools for non-metal desulfurative methodologies due to the... more Phosphines and phosphites are critical tools for non-metal desulfurative methodologies due to the strength of the P]S bond. An overarching premise in these methods has been that stoichiometric (or excess) P(III) reagent is required for reactivity. Despite decades of research, a desulfurative process that is catalytic in phosphine/phosphite has not been reported. Here, we report the successful merging of two thermal radical processes: the desulfurization of unactivated and activated alkyl thiols and the reduction of P(V) = S to P(III) by reaction with a silyl radical species. We employ catalytic trimethyl phosphite, catalytic azobis(cyclohexyl)nitrile, and two equivalents of tris(trimethylsilyl)silane as the stoichiometric reductant and sulfur atom scavenger. This method is tolerant of common organic functional groups and affords products in good to excellent yields.

Tetrahedron Letters, 2019

α4/7-Conotoxin LvIA is an isoform-selective inhibitor of the α3β2 nicotinic acetylcholine recepto... more α4/7-Conotoxin LvIA is an isoform-selective inhibitor of the α3β2 nicotinic acetylcholine receptor. An efficient strategy for the synthesis of this toxin is critical to advancing its utility as a probe for receptor function and as a potential pharmaceutical lead target. On-resin methods for peptide synthesis offer potential synthetic advantages; however, strategies for on-resin formation of multiple disulfides have historically been low-yielding. Here, we harness the reactivity of the Allocam protecting group and employ 3-amino acid spacer strategy to synthesize α4/7-conotoxin LvIA via three different on-resin strategies, each of which results in an isolated yield higher than prior fully on-resin approaches.

Chemical Science, 2018

C-Terminal cysteine peptide acids are difficult to access without epimerization of the cysteine a... more C-Terminal cysteine peptide acids are difficult to access without epimerization of the cysteine astereocenter. Diversification of the C-terminus after solid-phase peptide synthesis poses an even greater challenge because of the proclivity of the cysteine a-stereocenter to undergo deprotonation upon activation of the C-terminal carboxylic acid. We present herein two general strategies to access Cterminal cysteine peptide derivatives without detectable epimerization, diketopiperazine formation, or piperidinylalanine side products. C-Terminal cysteine peptides, including prenylated and farnesylated peptides, 1 disulde linked peptide toxins, 2 and insulinotropic peptides, 3,4 comprise an important but synthetically challenging class of biologically active peptides. Many of these peptides are modied at the C-terminus. C-terminal modications such as esters and amides can be critical to maintaining a peptide's active conformation, 5 in vivo activity, and pharmacokinetics; 6 therefore, the ability to vary the peptide structure in this location is crucial to drug development efforts. 7 Although several methods have been reported for C-terminal functionalization aer solid-phase peptide synthesis (SPPS) is complete, 8 these approaches either result in epimerization when applied to C-terminal Cys peptides 9 or the applicability of the method to Cterminal Cys peptides is not addressed. 10,11 While activation of the C-terminal carboxylic acid can induce epimerization via oxazolone formation in most amino acids, 12 cysteine is also prone to epimerization via direct deprotonation during its attachment to the resin 13 and upon prolonged or repeated exposure to base (i.e., during peptide elongation via Fmoc SPPS). 14 Therefore, even the preparation of simple carboxylic acids or carboxamides of C-terminal cysteine peptides can be fraught with contamination by epimerized products, 1f,g,13a,15 reducing the overall yield and complicating the purication of the target peptides. A method for the epimerization-free synthesis and subsequent C-terminal modication of C-terminal Cys peptides would be highly impactful. In this work, we report the rst mild and convenient method for the epimerization-free diversication of peptides bearing a Cterminal cysteine. 16 Carboxylic acids, primary and secondary amides, and esters are accessed without epimerization or formation of diketopiperazine and piperidinyl-alanine side products. 17 We apply this strategy to the total synthesis of the nicotinic acetylcholine receptor (nAChR) antagonist a-conotoxin ImI. 18 Additionally, we include an alternate strategy employing Ndeprotected cysteine derivatives as nucleophiles, and we demonstrate its utility via the synthesis of the insect pheromone a-factor. 1 In the context of our ongoing efforts toward the synthesis of disulde-linked aand m-conotoxins, 19,20 we were concerned about possible epimerization of the C-terminal cysteine during the SPPS. We recently reported a strategy for C-terminal functionalization of non-cysteine peptides involving activation of the methyl-diaminobenzoyl (MeDbz) linker (1 / 2) 21 followed by nucleophilic cleavage of the N-acyl urea (MeNbz) group 22 to yield various protected (3) or unprotected (4) peptides (Scheme 1). 23 If this approach were to prove mild enough to enable Scheme 1 Our strategy for C-terminal functionalization of non-Cys terminated peptides.

Chemical Science, 2019

Facile trifl ic acid-catalyzed α-1,2-cis-thio glycosylations: scope and application to the synthe... more Facile trifl ic acid-catalyzed α-1,2-cis-thio glycosylations: scope and application to the synthesis of S-linked oligosaccharides, glycolipids, sublancin glycopeptides, and TN/TF antigens Catalytic trifl ic acid cleanly knits together glycan donors with thiol acceptors to form glycosyl linkages to peptides, sugars and lipids with excellent α-selectivity. This back cover art was generated from images downloaded from the Protein Data Bank's NGL viewer.

Journal of the American Chemical Society, Jan 17, 2012

The scope of isonitrile-mediated amide bond-forming reactions is further explored in this secondg... more The scope of isonitrile-mediated amide bond-forming reactions is further explored in this secondgeneration synthetic approach to cyclosporine (cyclosporin A). Both type I and type II amidations are utilized in this effort, allowing access to epimeric cyclosporins A and H from a single precursor by variation of the coupling reagents. This work lends deeper insight into the relative acylating ability of the formimidate carboxylate mixed anhydride (FCMA) intermediate, while shedding light on the far-reaching impact of remote stereochemical changes on the effective preorganization of seco-cyclosporins.

Organic Letters, May 16, 2018

Analytical Methods, 2015

General Information. Unless otherwise specified, all commercially available reagents were purchas... more General Information. Unless otherwise specified, all commercially available reagents were purchased from Sigma-Aldrich and used without further purification. Anhydrous Et 2 O, PhMe, nhexane, MeCN, DMF, DMSO, CH 2 Cl 2 were purchased from Fisher, THF was purchased from EMD, and PhH was purchased from Sigma-Aldrich. These were passed through a commercial solvent purification system (2 columns of alumina) and used without further drying. Triethylamine, diisopropylamine, pyridine, and Hünig's base were distilled over CaH 2 immediately prior to use. Unless otherwise noted, all reactions were performed in flame-dried glassware under 1 atm of prepurified anhydrous N 2 or argon gas. 1 H NMR spectra and 13 C NMR spectra were recorded on a Varian Mercury-400 MHz or a Varian VNMRS-500MHz spectrometer with a multinuclear broadband probe at ambient temperature unless otherwise stated. Chemical shifts are reported in parts per million relative to residual solvent peaks (as established by Stoltz, et. al. in Organometallics 2010, 29, 2176). All 13 C spectra are recorded with complete proton decoupling. High-resolution mass spectral analyses were performed by the Lumigen Instrument Center, Wayne State University. All purifications were performed on SiliaFlash® P60 40-63µm (230-400 mesh) 60Å Irregular Silica Gels (cat. # R12030B) or on a Biotage Isolera IV flash purification system using SNAP cartridges (cat. # FSKO-1107-XXXX). Thin layer chromatography was performed using glass-backed SiliaPlate™ TLC Plates (cat. # TLG-R10011B-323) cut to the desired size then visualized with shortwave UV lamps and KMnO 4 , CAM, PMA, or Anisaldehyde stains prepared according to standard recipes. All yields refer to chromatographically and spectroscopically pure products. IR data was obtained on a Varian/Digilab Excalibur 3100 High Resolution FT-IR, and optical rotation data was collected on a Perkin-Elmer 341 automated Polarimeter at the concentration noted. Azidomethylferrocene was synthesized according to literature procedures. 1 Experimental Procedures and Spectroscopic Data.

Journal of the American Chemical Society, Mar 3, 2010

Recent developments in the use of isonitriles to furnish secondary and tertiary amide bond format... more Recent developments in the use of isonitriles to furnish secondary and tertiary amide bond formations are applied to a novel total synthesis of the important cyclic polypeptide cyclosporine A. Specifically, the disclosed synthetic route demonstrates the utility of microwave-mediated carboxylic acid isonitrile couplings, thioacid isonitrile couplings at ambient temperature, and isonitrile-mediated couplings of carboxylic acids and thioacids with amines to form challenging amide bonds. Recently, we described a series of findings using isonitriles in the formation of amide bonds. 1,2,3,4 These early works suggested that isonitrile-mediated bond constructions might be applicable to the synthesis of tertiary amides. There is currently a great deal of interest in such systems, particularly with respect to improving the pharmaco-availability of biologically active polypeptides. 5 We thought that our findings in this area were sufficiently promising that it would be appropriate to explore various ways for generating tertiary amides in the context of a total synthesis of a challenging target system. Given these considerations, it was only natural to turn to cyclosporine A as a worthy goal. Cyclosporine A (1), a reversible inhibitor of cytokines in T helper cells, 6 was isolated from the fungus Tolypocladium inflatum gams. 7 Its structure was confirmed by chemical degradation, NMR, and X-ray crystallographic studies, 8 and its total synthesis was reported by Wenger in 1984. 9 The immunosuppressive properties of cyclosporine A, which enable otherwise non-sustainable transplantations, are very well established. 10 In addition, cyclosporine A has been applied to the treatment of Beçhet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Chron's disease, and nephrotic syndrome. 10 Indeed, its bioavailability with respect to proteolysis is highly dependent on the pattern of N-methylation present in 7 of the 11 amino

Tetrahedron, Apr 1, 2018

The β-subunit of human thyroid stimulating hormone (hTSH) has been synthesized as a single glycof... more The β-subunit of human thyroid stimulating hormone (hTSH) has been synthesized as a single glycoform bearing a chitobiose disaccharide at the native glycosylation site. Key to the successful completion of this synthesis was the introduction of an arginine-tagged acetamidomethyl group, which served to greatly facilitate handling of a glycopeptide fragment with poor aqueous solubility. This general solution to the challenge of working with intractable peptides is expected to find wide use in protein synthesis.

Tetrahedron Letters, Sep 1, 2009

The coupling reaction between hindered thioacids and isonitriles is developed and described. The ... more The coupling reaction between hindered thioacids and isonitriles is developed and described. The mechanism for the formation of the thiopyruvamide products is explored, and the method is applied to a selection of substrates. Recently, our laboratory described a novel microwave-mediated coupling reaction between carboxylic acids and isonitriles leading to the formation of N-formyl amides. 1 These N-formyl amides are readily converted to biologically important linkages such as amides, Nhydroxymethyl amides and N-methyl amides. 2 Further experimental 3 and computational 4 investigations showed that E and/or Z formimidate carboxylate mixed anhydrides (FCMAs), formed from the merger of 1 and 2, underwent [1,3]-O→N acyl migration to generate 3 via microwave thermolysis at 150 °C (Scheme 1). We have also reported on the coupling of carboxylic thioacids with isonitriles to provide N-thioformyl amides at ambient temperature. 5 In this communication, we disclose some unexpected results in the context of attempts to extend the above findings to highly hindered substrates. We first explored the feasibility of coupling t-butyl carboxylic acid 4 and t-butyl isonitrile 5 (Scheme 2A). Unfortunately, microwave irradiation of 4 with 5 in 1,2-dichloroethane (DCE) at 160 °C for 30 minutes did not afford N-formyl imide 8. Adjustments of reaction conditions such as temperature, reaction time, and molar ratios of reactants were not fruitful. The decreased reactivity observed in attempts to merge these hindered reactants may be ascribed to several causes. First, the formation of FCMA intermediate 6 might not occur with neopentylic coupling partners. Second, the bulky nature of the tert-butyl groups could undermine the critical [1, 3]-O→N migration en route to 8. The former of these possibilities was tested by introducing a nucleophile that could intercept the putative FCMA intermediate (6). Indeed, when the coupling reaction was repeated in the presence of p-methoxy benzylamine (9), amide 10 as well as formamide 11 were observed (Scheme 2B). The formation of these products suggested to us that FCMA intermediate 6 does form under these conditions, but that the rearrangement to provide the expected N-formyl imide 8 does not proceed.

Angewandte Chemie, Feb 24, 2012