Cannabicitran: Its unexpected racemic nature and potential origins.

Cannabicitran is a cannabinoid found in levels up to ~10% in commercial "purified" cannabidiol (CBD) extracts. The structure of this natural product was first reported more than 50 years ago. However, few studies have investigated cannabicitran or its origin despite the rapidly increasing interest in the use of cannabinoids for the treatment of a wide range of physiological conditions. Following on a recent detailed NMR and computational characterization of cannabicitran, our group initiated ECD and TDDFT studies aimed at unequivocally determining the absolute configuration of cannabicitran present in Cannabis sativa extracts. To our surprise, we discovered the natural product was racemic, raising questions around its presumed enzymatic origin. Herein, we report the isolation and absolute configuration of (-)-cannabicitran and (+)-cannabicitran. Several possible scenarios for production of the racemate in the plant and/or during extract processing are discussed.

Calculated and experimental 1 H and 13 C NMR assignments for cannabicitran.

Cannabicitran is an important cannabinoid natural product produced by Cannabis sativa and is often found at surprisingly high levels (up to ~10%) in "purified" commercial cannabidiol (CBD) extract preparations. Despite the prevalence of this molecule in CBD oil and other cannabinoid-related products, and the rapidly expanding interest in cannabinoids for treatment of a wide range of physiological conditions, only unassigned 1 H NMR data and partial unambiguous 13 C assignments have been published. Herein, we report the complete 1 H and 13 C NMR assignments of cannabicitran and comparatively evaluate the performance of several density functional theory (DFT) methods with varying levels of theory for the calculation of NMR chemical shifts.

Palladium-Catalyzed, Enantioselective Desymmetrization of N-Acylaziridines with Indoles.

Ring opening reactions of meso-aziridines generate chiral amine derivatives where the control of stereochemistry is possible through enantioselective catalysis. We report the use of a diphosphine-palladium(II) catalyst for the highly enantioselective desymmetrization of N-acylaziridines with indoles. The ß-tryptamine products are isolated in moderate to high yield across a range of indole and aziridine substitution patterns. The synthetic utility of ß-tryptamine products is demonstrated by conversion to the brominated pyrroloindoline derivative.

Structural revision of a Wnt/ß-catenin modulator and confirmation of cannabielsoin constitution and configuration.

In this report, we revise the structure for a previously reported synthetic product proposed to be the 1R,2S-cannabidiol epoxide and reassign it as cannabielsoin using anisotropic NMR and synthetic chemistry methods. These results provide a direct link to the first known biological target and function of cannabielsoin.

Palladium-Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ-Lactams with Aryl Chlorides and Bromides.

Herein, we report the first Pd-catalyzed enantioselective arylation of α-substituted γ-lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron-rich dialkylphosphine ligand we have been able to construct α-quaternary centers in good yields (up to 91 % yield) and high enantioselectivities (up to 97 % ee).

Quinine-Promoted, Enantioselective Boron-Tethered Diels-Alder Reaction by Anomeric Control of Transition-State Conformation.

Diels-Alder reactions of tethered vinyl-metal species offer the opportunity to fashion highly functionalized diol intermediates for synthesis. We have developed the first enantioselective boron-tethered Diels-Alder reaction using quinine as a chiral promoter. Quinine recovery, enantioselectivity enhancement, and manipulation of the cyclohexene core are also investigated. DFT modeling calculations confirm the role of quinine as a bidentate ligand enhancing reaction rates. The enantioselectivity of the cycloaddition is proposed to originate from a boron-centered anomeric effect.

Enantiospecific Synthesis of ß-Substituted Tryptamines.

Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis where isomer formation can be controlled. 3,5-Dinitrobenzoyl (DNB)-protected aziridines undergo regioselective, enantiospecific ring opening to produce ß-substituted tryptamines for a series of indoles. Attack at the more substituted aziridine carbon occurs in an SN2-like fashion to generate DNB-tryptamine products as synthetic precursors.

Palladium-Catalyzed, Enantioselective Heine Reaction.

Aziridines are important synthetic intermediates for the generation of nitrogen-containing molecules. N-Acylaziridines undergo rearrangement by ring expansion to produce oxazolines, a process known as the Heine reaction. The first catalytic, enantioselective Heine reaction is reported for meso-N-acylaziridines where a palladium(II)-diphosphine complex is employed. The highly enantioenriched oxazoline products are valuable organic synthons and potential ligands for transition-metal catalysis.

Synthesis of ß-substituted tryptamines by regioselective ring opening of aziridines.

Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis if site selectivity can be controlled. 4-Nitrobenzyl carbamate (PNZ)-protected aziridines undergo regioselective ring opening to produce ß-substituted tryptamines for a series of indoles. The PNZ-protected tryptamines can be further manipulated by PNZ removal under mild conditions.

Photodegradation of the antihistamine cetirizine in natural waters.

The photodegradation rate of the anti-histamine cetirizine (Zyrtec®) was investigated in various water matrices. The average observed first-order photodegradation rate coefficient (kobs ), obtained by linear regression of the logarithmic-transformed cetirizine concentrations versus irradiation time in simulated sunlight, was 0.024 h(-1) (n = 6; standard deviation ± 0.004) in deionized water corresponding to a half-life of approximately 30 h. There was no statistical difference in the kobs of cetirizine photodegradation in coastal seawater compared with deionized water or deionized water amended with dissolved chromophoric organic matter. The quantum yield of cetirizine photodegradation decreased dramatically with increasing wavelength and decreasing energy of incoming radiation, with the average value ranging from 5.28 × 10(-4) to 6.40 × 10(-3) in the ultraviolet wavelength range (280-366 nm). The activation energy of cetirizine photodegradation was 10.3 kJ mol(-1) with an observed increase in cetirizine photodegradation as temperature increased. This is a significant environmental factor influencing half-life and an important consideration, given that cetirizine has been detected in wastewater and receiving waters from different locations globally.

Scalable synthesis of N-acylaziridines from N-tosylaziridines.

N-Acylaziridines are important starting materials for the synthesis of chiral amine derivatives. The traditional methods for producing these activated aziridines have significant drawbacks. The gram scale synthesis of N-acylaziridines by deprotection of N-tosylaziridines and reprotection with N-hydroxysuccinimide derivatives is described. Mono- and disubstituted aziridines perform well, with complete retention of stereochemical purity. The consistently moderate yields are linked to the N-tosylaziridine deprotection step, while acylation with N-hydroxysuccinimide derivatives is highly efficient.

Enantioselective synthesis and stereoselective ring opening of N-acylaziridines.

Kinetic resolution of N-acylaziridines by nucleophilic ring opening was achieved with (R)-BINOL as the chiral modifier under boron-catalyzed conditions (see scheme; Ar=3,5-dinitrophenyl). The consumed enantiomer of aziridine can be further converted to an enantioenriched 1,2-chloroamide with recovery of (R)-BINOL.

Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.

Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN.

Phosphine-catalyzed Heine reaction.

Aziridines are important synthetic intermediates which readily undergo ring-opening reactions. It is demonstrated that electron-rich phosphines are efficient catalysts for the regioselective rearrangement of N-acylaziridines to oxazolines. The reactions occur in excellent yield under neutral conditions. Evidence is provided for an addition/elimination mechanism by generation of a phosphonium intermediate. Similar intermediates may be useful for the development of alternate aziridine ring-opening processes and stereoselective synthesis with enantiopure phosphines.

Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines.

The reaction of alkene-tethered alpha-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. alpha-Methoxy-alpha,beta-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. alpha-Ketoesters, alpha-ketoamides, and alpha-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.

Rh-catalyzed enantioselective diboration of simple alkenes: reaction development and substrate scope.

[Reaction: see text]. The rhodium-catalyzed reaction between bis(catecholato)diboron and simple alkenes results in the syn addition of the diboron across the alkene. The resulting 1,2-bis(boronate) is subsequently oxidized to provide the 1,2-diol. In the presence of enantiomerically enriched Quinap ligand, high enantioselection in the diboration can be achieved. The reaction is highly selective for trans- and trisubstituted alkenes and can be selective for some monosubstituted alkenes as well. The development of this reaction is described as is the substrate scope and experiments that are informative about the reaction mechanism and competing pathways.

Catalytic enantioselective hydrogenation of vinyl bis(boronates).

Catalytic enantioselective hydrogenation of prochiral vinylmetallic reagents can provide an attractive alternative to hydrometalation and bismetalation of alkenes. In this contribution, the first highly enantioselective hydrogenation of vinyl boronic esters is described. The chiral reduction products are versatile intermediates for chemical synthesis.

Catalytic asymmetric carbohydroxylation of alkenes by a tandem diboration/Suzuki cross-coupling/oxidation reaction.

[reaction: see text] Chiral nonsymmetric 1,2-diboron adducts are generated by catalytic enantioselective diboration. Oxidation of these adducts provides 1,2-diols in good yield. Alternatively, 1,2-diboron compounds may be reacted, in situ, with aryl halides wherein the less hindered C-B bond participates in cross-coupling. The remaining C-B bond is then oxidized in the reaction workup thereby allowing for net asymmetric carbohydroxylation of alkenes in a tandem one-pot diboration/Suzuki coupling/oxidation sequence.

Rhodium-catalyzed enantioselective diboration of simple alkenes.

Enantioselective catalytic reactions that operate directly on inexpensive unactivated alkenes are extraordinarily useful for the preparation of chiral organic building blocks and new materials. While a number of such processes have been developed, our ability to meet the intensifying demand for inexpensive stereochemically complex materials will require a significant expansion of practical catalytic asymmetric reaction methodology. In this regard, the rhodium-catalyzed enantioselective diboration reaction has been developed in order to address a number of extant problems in catalytic alkene transformation simultaneously. This process provides an enantiomerically enriched reactive dimetalated intermediate which can be converted to a variety of difunctional reaction products.

Platinum-catalyzed tandem diboration/asymmetric allylboration: access to nonracemic functionalized 1,3-diols.

[reaction: see text] A single-pot tandem catalytic diene diboration/carbonyl allylation reaction is described that uses a commercially available chiral diboron reagent. The chirality of the intermediate diboration adduct is transferred to the product in the carbonyl allylation reaction, thereby providing access to enantioenriched chiral products. Notably, the reaction allows for construction of a quaternary stereocenter and furnishes a synthetically versatile C-B bond in the reaction product.