Ring-Opening Reactions of Phosphoramidate Heterocycles.

We present protocols for the conversion of phosphoramidate heterocycles into 1,3-chloroamines and 1,3-aminoalcohols. For the formation of chloroamines, our optimized protocol involves heating the phosphoramidate starting material with 4 equivalents of HCl in a dioxane/toluene solvent mixture. The substituents on the phosphoramidate starting material have a profound influence on product formation. Phosphoramidates with a variety of aza-heterocyclic substituents engage, but those containing a 5-chloro-8-quinolinol arm are most competent for 1,3-chloroamine formation. Furthermore, only the phosphoramidate cis diastereomers allow for 1,3-chloroamine formation. X-ray crystallography studies coupled with DFT analysis provide a basis for the stark difference in reactivity between the cis and trans diastereomers. Amino-alcohol products form by heating phosphoramidate heterocycles with aqueous HF in toluene. Here, there is no diastereomeric preference or a requirement for an aza-heterocyclic arm. Based on a substrate survey, both reactions tolerate a broad range of substitution patterns and functional groups. This work establishes that phosphoramidates are competent synthons for interesting amine products and further increases the prominence of tethered aza-Wacker technology.

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications.

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

Unusual Rearrangement-Remercuration Reactions of Allylic Silanols.

We present the first examples of rearrangement reactions of allylic silanol substrates into linear ketone and 5-membered cyclic silanediol organomercurial products. Both reactions are mediated by Hg(OTf)2 but differ in the use of base, solvent, and temperature. The substrate scope of both transformations was explored, and the product organomercurials were shown to be valuable synthons. Mechanistic studies suggest that both products are the result of a series of transformations, cascading in one pot. DFT analysis provides a basis for understanding the rearrangement of a 6-endo intermediate into the 5-exo cyclic silanediol product.

A Formal Rearrangement of Allylic Silanols.

We show that 1M aqueous HCl/THF or NaBH4/DMF allows for demercurative ring-opening of cyclic organomercurial synthons into secondary silanol products bearing terminal alkenes. We had previously demonstrated that primary allylic silanols are readily transformed into cyclic organomercurials using Hg(OTf)2/NaHCO3 in THF. Overall, this amounts to a facile two-step protocol for the rearrangement of primary allylic silanol substrates. Computational investigations suggest that this rearrangement is under thermodynamic control and that the di-tert-butylsilanol protecting group is essential for product selectivity.

Tethered Silanoxyiodination of Alkenes.

We present the first examples of tethered silanoxyiodination reactions of allylic alcohols. The products are useful silanediol organoiodide synthons and are formed with high regioselectivity and diastereocontrol. The reaction is scalable greater than 10-fold without loss of yield or selectivity. Furthermore, the products are starting materials for further transformations, including deiodination, C-N bond installation, epoxide synthesis, and desilylation. DFT calculations provide a basis for understanding the exquisite 6-endo selectivity of this silanoxyiodination reaction and show that the observed products are both kinetically and thermodynamically preferred.

Catalytic Regio- and Enantioselective Haloazidation of Allylic Alcohols.

Herein we report a highly regio- and stereoselective haloazidation of allylic alcohols. This enantioselective reaction uses readily available materials and can be performed on a variety of alkyl-substituted alkenes and can incorporate either bromine or chlorine as the electrophilic halogen component. Both halide and azido groups of the resulting products can be transformed into valuable building blocks with complete stereospecificity. The first example of an enantioselective 1,4-haloazidation of a conjugated diene is reported as well as its application to a concise synthesis of an aza-sugar.

Enantiospecific Solvolytic Functionalization of Bromochlorides.

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (-)-anverene.

The scope of a recently reported method for the catalytic enantioselective bromochlorination of allylic alcohols is expanded to include a specific homoallylic alcohol. Critical factors for optimization of this reaction are highlighted. The utility of the product bromochloride is demonstrated by the first total synthesis of an antibacterial polyhalogenated monoterpene, (-)-anverene.

Catalytic chemo-, regio-, and enantioselective bromochlorination of allylic alcohols.

Herein we describe a highly chemo-, regio-, and enantioselective bromochlorination reaction of allylic alcohols, employing readily available halogen sources and a simple Schiff base as the chiral catalyst. The application of this interhalogenation reaction to a variety of substrates, the rapid enantioselective synthesis of a bromochlorinated natural product, and preliminary extension of this chemistry to dibromination and dichlorination are reported.

Self-association of water-soluble peptoids comprising (S)-N-1-(naphthylethyl)glycine residues.

Peptoids (N-substituted glycine oligomers) are widely used peptidomimetics, and an enhanced understanding of their structures is needed to expand their utility, particularly in aqueous applications. We report the synthesis and structural study of four water-soluble peptoids that include strongly helix-promoting (S)-N-1-(naphthylethyl)glycine residues. Peptoid structure changes with both peptoid length and solvent composition. Multiple data support the self-association of the longest peptoid studied here, 1, via hydrophobic interactions in aqueous solutions.

A fluorescent peptoid pH-sensor.

Peptoids, N-substituted glycine oligomers, can adopt stable three-dimensional structures and have found diverse application as peptide surrogates and as nanomaterials. In this report, we have expanded peptoid function to include pH sensing by coupling pH-induced peptoid conformational changes with fluorescence intensity changes. We report two new peptoids (2 and 3) that comprise carboxylic-acid functionalized side chains and undergo conformational rearrangement in response to pH. Peptoids 2 and 3 are also labeled at one side-chain with an environmentally sensitive fluorophore, 4-N,N-dimethylamino-1,8-naphthalimide (4DMN). The fluorescence intensity of 2 varies 24-fold over the pH range studied. These spectroscopic properties make 2 a sensitive, biocompatible pH sensor.

Use of the environmentally sensitive fluorophore 4-N,N-dimethylamino-1,8-naphthalimide to study peptoid helix structures.

Peptoids, oligomers of N-substituted glycine, have been valuable targets for study and diverse application as peptidomimetics and as nanomaterials. Their conformational heterogeneity has made the study of peptoid structures using high-resolution analyses challenging, limiting our understanding of the physiochemical features that mediate peptoid folding. Here, we introduce a new method for the study of peptoid structure that relies on the environmentally sensitive fluorescence properties of 4-N,N-dimethylamino-1,8-naphthalimide (4-DMN). We have prepared a 4-DMN-functionalized primary amine that is compatible with the traditional submonomer peptoid synthesis methods and incorporated it sequence-specifically into 11 of 13 new peptoids. When included as a peptoid side chain modification, the fluorescence emission intensity of 4-DMN correlates with predictions of the fluorophore's local polarity within a putative structure. 4-DMN fluorescence is maximized when the fluorophore is placed in the middle of the hydrophobic face of an amphiphilic helical peptoid. When the fluorophore is placed near the peptoid terminus or on a polar face of an amphiphilic sequence, 4-DMN fluorescence is diminished. Disruption of the peptoid secondary structure or amphiphilicity also modulates 4-DMN fluorescence. The peptoids' helical secondary structures are moderately disrupted by inclusion of a 4-DMN-modified side chain as evaluated by changes in the peptoids' CD spectral features. This new method for peptoid structure evaluation should be a valuable complement to existing peptoid structural analysis tools.