We report a novel, asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of Aspidosperma alkaloids. This method was utilized in the ...concise total syntheses of classical targets (−)-aspidospermidine, (−)-tabersonine, and (−)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch–Rubiralta spirocyclization to prepare the C-ring.
The development and application of the arene-fused domino Michael/Mannich route to the tetrahydrocarbazole (ABE) core of Aspidosperma alkaloids is described. The scope of this novel transformation ...was studied in terms of the nucleophilic component (i.e., N-sulfinyl metallodienamine) and the electrophilic component (i.e., Michael acceptor). The successful application of this methodology toward the concise total syntheses of classical indole alkaloids (−)-aspidospermidine, (−)-tabersonine, and (−)-vincadifformine in 10–11 steps, respectively, is also discussed.
Herein, we report the first asymmetric total synthesis of aspidospermatan indole alkaloid (+)-epi-condyfoline (1) in 15 steps from commercially available 2-methylindole-3-carboxaldehyde. Key steps ...include (1) our domino Michael/Mannich annulation method of N-sulfinyl metallodienamines to set three contiguous stereocenters, (2) LiHMDS-mediated cyclization of an ω-tosyloxy N-sulfinamide to prepare the signature indole-fused 2-azabicyclo3.3.1nonane framework, and (3) DMTSF-promoted spirocyclization of a dithioacetal intermediate to access the final pyrrolidine ring. Functional group manipulations delivered the targeted alkaloid (+)-epi-condyfoline (1) in 13 steps and 1.25% overall yield from N-sulfinylimine (+)-8.
Concise asymmetric total syntheses of Strychnos alkaloids (−)-leuconicine A (14 steps, 9% overall yield) and B (13 steps, 10% overall yield) have been accomplished. Key steps include (1) our ...sequential one-pot spiro-cyclization/intramolecular aza-Baylis-Hillman method to prepare the ABCE framework; (2) a novel domino acylation/Knoevenagel cyclization to prepare the F-ring; and (3) a Heck cyclization to access the D-ring.
Efficiency is a key organizing principle in modern natural product synthesis. Practical criteria include time, cost, and effort expended to synthesize the target, which tracks with step-count and ...scale. The execution of a natural product synthesis, that is, the sum and identity of each reaction employed therein, falls along a continuum of chemical (abiotic) synthesis on one extreme, followed by the hybrid chemoenzymatic approach, and ultimately biological (biosynthesis) on the other, acknowledging the first synthesis belongs to Nature. Starting materials also span a continuum of structural complexity approaching the target with constituent elements on one extreme, followed by petroleum-derived and “chiral pool” building blocks, and complex natural products (i.e., semisynthesis) on the other. Herein, we detail our approach toward realizing the first synthesis of (−)-melodinine K, a complex bis-indole alkaloid. The total syntheses of monomers (−)-tabersonine and (−)-16-methoxytabersonine employing our domino Michael/Mannich annulation is described. Isolation of (−)-tabersonine from Voacanga africana and strategic biotransformation with tabersonine 16-hydroxylase for site-specific C–H oxidation enabled a scalable route. The Polonovski–Potier reaction was employed in biomimetic fragment coupling. Subsequent manipulations delivered the target. We conclude with a discussion of efficiency in natural products synthesis and how chemical and biological technologies define the synthetic frontier.
In this work, a study of resonance effects in the Raman spectra of twisted bilayer graphene (tBLG) is presented. The analysis takes into account the effect of the mismatch angle straighttheta between ...the two layers, and also of the excitation laser energy on the frequency, linewidth, and intensity of the main Raman features, namely the rotationally induced R band, the G band, and the second-order G' (or 2D) band. The resonance effects are explained based on the straighttheta dependence of the tBLG electronic structure, as calculated by ab initio methodologies. The twist angle straighttheta also defines the observation of a "D-like" band which obeys the double-resonance process, but relies on the superlattice along with long-range defects in order to fulfill momentum conservation. The study was possible due to the development of a route to produce and identify rotationally stacked bilayer graphene by means of atomic force microscopy (AFM).
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Albocycline (ALB) is a unique macrolactone natural product with potent, narrow-spectrum activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate ...(VISA), and vancomycin-resistant S. aureus (VRSA) strains (MIC = 0.5–1.0 μg/mL). Described herein is the synthesis and evaluation of a novel series analogs derived from albocycline by functionalization at three specific sites: the C2-C3 enone, the tertiary carbinol at C4, and the allylic C16 methyl group. Exploration of the structure-activity relationships (SAR) by means of minimum inhibitory concentration assays (MICs) revealed that C4 ester analog 6 was twice as potent as ALB, which represents a class of lead compound that can be further studied to address multi-drug resistant pathogens.
Motivation
The understanding of physiological adaptations, of evolutionary radiations and of ecological responses to global change urges for global, comprehensive databases of the functional traits ...of extant organisms. The ability to maintain an adequate water balance is a critical functional property influencing the resilience of animal species to climate variation. In terrestrial or semi‐terrestrial organisms, total water loss includes a significant contribution from evaporative water loss (EWL). The analysis of geographic and phylogenetic variation in EWL rates must however account for differences in methods and potential confounding factors, which influence standard measures of whole‐organism water loss. We compiled the global and standardized SquamEWL database of total, respiratory and cutaneous EWL for 325 species and subspecies of squamate reptiles (793 samples and 2,536 estimates) from across the globe. An extensive set of companion data and annotations associated with the EWL measurements of potential value for future investigation, including metabolic rate data, is provided. We present preliminary descriptive statistics for the compiled data, discuss gaps and biases, and identify promising avenues to update, expand and explore this database.
Main types of variables contained
Standard water loss rates, geographic data, metabolic rates.
Spatial location
Global.
Time period
Data were obtained from extant species and were collected between 1945 and 2020.
Major taxa
Reptilia, Squamata including lizards, snakes and amphisbaenians.
Level of measurements
Individual samples of animals from the same species, locality, age class and sex category.
Software format
csv.
Concise total syntheses of Strychnos alkaloids strychnine (1) and akuammicine (2) have been realized in 13 and 6 operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) a ...novel, sequential one-pot spirocyclization/intramolecular aza-Baylis−Hillman reaction; and (3) a Heck cyclization. The synthesis of 1 proceeds via the Wieland−Gumlich aldehyde (26).
The marked rise in bacterial drug resistance has created an urgent need for novel antibacterials belonging to new drug classes and ideally possessing new mechanisms of action. The superior biological ...activity of solithromycin against streptococci and other bacteria causative of community-acquired pneumonia pathogens, compared to telithromycin and other macrolides encouraged us to extensively explore this class of antibiotics. We, thus, present the design and synthesis of a novel series of solithromycin analogs. Three main strategies were pursued in structure-activity relationship studies covering the N-11 side chain and the desosamine motif, which are both chief elements for establishing strong interactions with the bacterial ribosome as the molecular target. Minimal inhibitory concentration assays were determined to assess the in vitro potency of the various analogs in relation to solithromycin. Two analogs exhibited improved activity compared to solithromycin against resistant strains, which can be assessed in further pre-clinical studies.
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•Rational approaches to design new-generation analogs of solithromycin.•Developing structure-activity relationships via novel synthetic tactics.•Four analogs were equipotent with solithromycin against one or more resistant strains.•Two analogs showed enhanced activity against resistant strains.
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