Environmentally Sensible Organocatalytic Fmoc/t-Bu Solid-Phase Peptide Synthesis.

Despite numerous reports on catalytic amide bond formation (ABF), these methods have thus far had a minimal impact on the universal fluorenylmethoxycarbonyl (Fmoc)/t-Bu solid-phase peptide synthesis (SPPS) methodology. We now report a proof-of-principle Fmoc/t-Bu SPPS in which both couplings and Fmoc deprotections were catalyzed by readily available reagents in an inexpensive green solvent. Couplings were carried out with >99% stereoselectivity, employing 1.1 equiv of Fmoc amino acids (AAs), using diisopropylcarbodiimide (DIC) as a coupling agent and 1-hydroxy-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt) (TON ∼ 30) as a catalyst, while Fmoc deprotections were carried out using 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (TON ∼ 7), facilitating synthesis of a model pentapeptide in 95% HPLC purity while also enabling minimization of solvent washing.

Circular Aqueous Fmoc/t-Bu Solid-Phase Peptide Synthesis.

Circular economy and aqueous synthesis are attractive concepts for sustainable chemistry. Here it is reported that the two can be combined in the universal method for peptide chemistry, fluorenylmethoxycarbonyl(Fmoc)/t-Bu solid-phase peptide synthesis (SPPS). It was demonstrated that Fmoc/t-Bu SPPS could be performed under aqueous conditions using standard Fmoc amino acids (AAs) employing TentaGel S as resin and 4 : 1 mixture of water with inexpensive green solvent PolarClean. This resin/solvent combination played a crucial dual role by virtue of improving resin swelling and solubility of starting materials. In a model coupling, TCFH and 2,4,6-collidine afforded a full conversion at only 1.3 equiv. AA, and these conditions were used in SPPS of Leu enkephaline amide affording the model peptide in 85 % yield and 86 % purity. A method to recycle the waste by filtration through a mixed ion exchange resin was developed, allowing reusing the waste without affecting quality of the peptide. The method herein obviates the use of unconventional or processed AAs in aqueous SPPS while using lower amounts of starting materials. By recycling/reusing SPPS waste the hazardous dipolar aprotic solvents used in SPPS were not only replaced with an aqueous medium, solvent use was also significantly reduced. This opens up a new direction in aqueous peptide chemistry in which efficient use of inexpensive starting materials and waste minimization is coupled with the universal Fmoc/t-Bu SPPS.

1,4-Benzenedimethanethiol (1,4-BDMT) as a scavenger for greener peptide resin cleavages.

Aiming at elevating the environmental profile of the solid-phase peptide synthesis (SPPS) methodology by improving the quality of crude peptides that SPPS provides we assessed a series of benzylthiols (BTs) as scavengers for global deprotection/TFA cleavage of exenatide peptide resin accessed by Fmoc SPPS. In these studies we identified 1,4-BDMT as a scavenger that affords the peptide in higher quality than the standard aliphatic thiol reagents, not least in terms of the content of critical peptide impurities in the crude material. Further, 1,4-BDMT exhibited favorable UV detectability as well as stability and solubility in TFA. Finally, based on the MS assessment of the crude exenatide products herein we propose that thiol scavengers in the cleavage of Trp containing peptide resins do not minimize the content of Trp oxidants by means of inhibiting Trp oxidation but rather by forming a peptide-thiol adduct via a mechanism involving an attack of a thiol on an oxindolylalanine (Oia) impurity present in the crude material.

Discovery of selective nonpeptidergic neuropeptide FF2 receptor agonists.

We report the discovery and initial characterization of a novel class of selective NPFF2 agonists. HTS screening using R-SAT, a whole cell based functional assay, identified a class of aryliminoguanidines as NPFF1 and NPFF2 ligands. Subsequent optimization led to molecules exhibiting selective NPFF2 agonistic activity. Systemic administration showed that selective NPFF2 agonists (1 and 3) are active in various pain models in vivo, whereas administration of a nonselective NPFF1 and NPFF2 agonist (9) increases sensitivity to noxious and non-noxious stimuli.

Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.

Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.

A one-pot access to 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes.

[reaction: see text] A one-pot, t-BuLi-induced synthesis of 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes is reported. Aryl- and hetaryl nitriles, cyanamides, and trimethylacetonitrile gave phenanthridine products. The method was extended to provide bisphenanthridine 10 by a one-pot bis-cyclization, using 1,3-dicyanobenzene and PhF in 1:5 ratio. Reaction of 1-fluoronaphthalene and 4-chlorofluorobenzene with benzonitrile afforded the regioisomerically pure products 11 and 12, respectively.

Femtosecond excitation energy transport in triarylamine dendrimers.

The search for a model that can be used to describe the optical excitation migration in dendrimers has attracted great attention. In most cases in a dendrimer the conjugation is disrupted at the branching point; however, the excitation is delocalized. The strength of interactions among neighboring chromophores plays a key role in determining the energy migration mechanism. Conversely, having many identical chromophores held tightly together in an ordered macromolecular architecture will allow for many dipoles to be accessible for optical excitation. Therefore, the relative orientation of dipoles will be important in determining the mechanism of energy migration. Here we report the synthesis and photo-physical investigation of triarylamine-based dendrimers. Two important synthetic steps were utilized in the synthesis. First, we employed diphenylmethyl protective groups on the amines to assist in deprotective hydrogenolysis of the larger structures. Second, highly active catalysts for formation of both di- and triarylamines that are based on a 1:1 ratio of P(t-Bu)3 and Pd(dba)2 improved reaction yields of the C-N bond formation and decreased reaction times The energy migration processes in the dendrimers were investigated utilizing ultrafast time-resolved fluorescence anisotropy measurements. The fluorescence anisotropy of all three dendrimers decayed to a residual value within approximately 100 fs. This fluorescence anisotropy decay showed a general trend in decreasing with increasing dendrimer generation. The residual anisotropy value also showed a gradual decrease with an increase in the dendrimer generation. This fast energy depolarization is discussed through a coherent excitonic mechanism among dipoles oriented in different directions. We believe that the formation of coherent domains leads to fast energy migration extending over a large part of the dendrimer.

A general nickel-catalyzed hydroamination of 1,3-dienes by alkylamines: catalyst selection, scope, and mechanism.

A simple colorimetric assay of various transition-metal catalysts showed that the combination of DPPF, Ni(COD)(2), and acid is a highly active catalyst system for the hydroamination of dienes by alkylamines to form allylic amines. The scope of the reaction is broad; various primary and secondary alkylamines react with 1,3-dienes in the presence of these catalysts. Detailed mechanistic studies revealed the individual steps involved in the catalytic process. These studies uncovered unexpected thermodynamics for the addition of amines to pi-allyl nickel complexes: instead of the thermodynamics favoring the reaction of a nickel allyl with an amine to form an allylic amine, the thermodynamics favored reaction of a nickel(0) complex with allylic amine in the presence of acid to form a Ni(II) allyl. The realization of these thermodynamics led us to the discovery that nickel and some palladium complexes in the presence or absence of acid catalyze the exchange of the amino groups of allylic amines with free amines. This exchange process was used to reveal the relative thermodynamic stabilities of various allylic amines. In addition, this exchange reaction leads to racemization of allylic amines. Therefore, the relative rate for C-N bond formation and cleavage influences the enantioselectivity of diene hydroaminations.

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.