Enantioselective Total Synthesis of (+)-Alterbrassicicene C.

Herein, the first total synthesis of (+)-alterbrassicicene C (2) is described. Key features of the synthesis include an oxiranium mediated ether ring expansion, an oxa-Michael/retro-oxa-Michael cascade, and installation of a vinyl methoxy ether moiety via Stille coupling.

Total Syntheses of (+)-Ineleganolide and (-)-Sinulochmodin C.

Described herein are the first total syntheses of the nor-furanocembranoid natural products (+)-ineleganolide (1) and (-)-sinulochmodin C (2). The synthetic strategy is predicated on a transannular Michael reaction that provides both natural products from a common macrocyclic intermediate and leverages a diastereoselective radical cyclization to furnish a key bicyclic lactone. The latter is further advanced to a macrocyclic precursor via a Nozaki-Hiyama-Kishi cyclization and a one-pot furan oxidation/oxa-Michael cascade. Unexpected stereochemical nuances that guided the evolution and eventual completion of the total synthesis are discussed.

A Ring Expansion Approach To N-oxy-2,5-diketopiperazines.

A ring expansion of tetramic acids (pyrrolidine-2,4-diones) to N-oxy-2,5-diketopiperazines (DKPs) is described. This method allows for the facile and late-stage construction of the hydroxamic acid moiety and can thereby serve as a general method for accessing N-oxy-2,5-DKP natural products.

Total Syntheses of (±)-Dracocephalone A and (±)-Dracocequinones A and B.

Described herein are the first total syntheses of (±)-dracocephalone A (1) and (±)-dracocequinones A (4) and B (5). The synthesis was initially envisioned as proceeding through an intramolecular isobenzofuran Diels-Alder reaction, a strategy that eventually evolved into a Lewis acid-promoted spirocyclization. This highly diastereoselective transformation set the stage for trans-decalin formation and a late-stage Suárez oxidation that produced a [3.2.1] oxabicycle suited for conversion to 1. Brønsted acid-mediated aromatization, followed by a series of carefully choreographed oxidations, allowed for rearrangement to a [2.2.2] oxabicycle poised for conversion to 4 and 5.

Supercharging Prions via Amyloid-Selective Lysine Acetylation.

Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace: a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.

Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.

Total Synthesis of (±)-Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen-Oxygen Bonds.

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.

Total Synthesis of Herquline B and C.

The total syntheses of (-)-herquline B (2) and a heretofore-unrecognized congener, (+)-herquline C (3), are described. The syntheses require 14 and 13 steps, respectively, and feature a key oxazoline reduction that sets the stage for piperazine construction.

Total Synthesis of Caesalpinnone A and Caesalpinflavan B: Evolution of a Concise Strategy.

The total syntheses of caesalpinnone A (1) and its putative biosynthetic precursor caesalpinflavan B (3) are described. Herein, we describe the evolution of a synthetic strategy toward 1 and 3, which entails a convergent Barluenga coupling that quickly delivers a heavily functionalized benzopyran containing the core carbon framework and exploration of two distinct synthetic routes for forging the flavanoid C-ring by reducing a sterically encumbered embedded alkene: one via a stepwise approach and a second, more direct and atom-economical, enabled by a Shenvi-HAT hydrogenation. The latter strategy allowed access to caesalpinflavan B in 6 steps after Pd-mediated deallylation. A late-stage dearomative phenolic oxidation and deallylation/oxa-Michael cascade was implemented to access caesalpinnone A (1) in 7 steps. We also describe an enantioselective total synthesis and stereochemical revision of (-)-caesalpinflavan B, as well as a formal enantioselective synthesis of (-)-caesalpinnone A, by implementing an enantioselective Pd-catalyzed conjugate addition developed by Stoltz.

Synthetic studies towards the penicisulfuranols: Synthesis of an advanced spirocyclic diketopiperazine intermediate.

The 2,5-diketopiperazine (DKP) moiety is a core feature of many natural products and medicinally relevant scaffolds. As part of our efforts directed towards a total synthesis of penicisulfuranol B, we have developed and report herein: (1) the preparation of an N-hydroxy diketopiperazine intermediate accessible via a molybdenum-mediated oxidation of a parent diketopiperazine, and (2) further synthetic studies leading to a novel spirocyclic dihydrobenzofuran-containing diketopiperazine.

Total Synthesis of (+)- and (±)-Hosieine†A.

Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold-catalyzed Rautenstrauch reaction.

Total Synthesis of (±)-Phomoidride†D.

Described herein is a synthetic strategy for the total synthesis of (±)-phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels-Alder cycloaddition. A subsequent SmI2 -mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion.

Total Synthesis of (±)-Aspergilline A.

The total synthesis of (±)-aspergilline A (1) is described. Key features of the synthesis include pyrrolinone formation via reaction of an intermediate propargyl amine with a methyl malonyl chloride derived ammonium enolate and a formal [3+2] cycloaddition between an imidate and cyclopropenone.

Total Syntheses of (+)- and (-)-Tetrapetalones A and C.

Described herein are syntheses of the naturally occurring polyketides (-)-tetrapetalones A and C and their respective enantiomers. The employed strategy involves initial assembly of a masked N-aryl tetramic acid which is advanced via a highly selective conjugate addition/intramolecular Friedel-Crafts acylation sequence to deliver a key azepine intermediate. Application of recently developed C-H activation chemistry and subsequent Heck cyclization delivers the aglycone framework in an overall 12 steps. Resolution of the aglycone via stereospecific glycosylation with an enantiopure glycosyl donor followed by separation of the derived diastereomers enables further advancement to either (+)- or (-)-tetrapetalones A and C.

Collaborative Total Synthesis: Routes to (±)-Hippolachnin A Enabled by Quadricyclane Cycloaddition and Late-Stage C-H Oxidation.

Described herein are synthetic efforts toward the synthesis of hippolachnin A. Two independently devised routes from the Brown and Wood groups allowed for the synthesis of hippolachnin A from the unusual starting material, quadricyclane, by harnessing the power of late-stage C-H oxidation. Collaborative union of the best features of the two routes allowed for preparation of the molecule with improved efficiency.

Synthetic Applications and Methodological Developments of Donor-Acceptor Cyclopropanes and Related Compounds.

Donor-acceptor cyclopropanes are convenient precursors to reactive and versatile 1,3-dipoles, and have found application in the synthesis of a variety of carbo- and heterocyclic scaffolds. This perspective review details our laboratory's use of donor-acceptor cyclopropanes as intermediates toward the total synthesis of various natural products. We also discuss our work in the development of novel cycloadditions and rearrangements of donor-acceptor cyclopropanes and aziridines, as well as an example of an aryne insertion proceeding via fragmentation of a transient donor-acceptor cyclobutane.

Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate.

This manuscript describes the enantioselective preparation of a spirooxindole that is suited for advancedment to either Citrinadin A or B.

Universal pictures: A lithophane codex helps teenagers with blindness visualize nanoscopic systems.

People with blindness have limited access to the high-resolution graphical data and imagery of science. Here, a lithophane codex is reported. Its pages display tactile and optical readouts for universal visualization of data by persons with or without eyesight. Prototype codices illustrated microscopy of butterfly chitin-from N-acetylglucosamine monomer to fibril, scale, and whole insect-and were given to high schoolers from the Texas School for the Blind and Visually Impaired. Lithophane graphics of Fischer-Spier esterification reactions and electron micrographs of biological cells were also 3D-printed, along with x-ray structures of proteins (as millimeter-scale 3D models). Students with blindness could visualize (describe, recall, distinguish) these systems-for the first time-at the same resolution as sighted peers (average accuracy = 88%). Tactile visualization occurred alongside laboratory training, synthesis, and mentoring by chemists with blindness, resulting in increased student interest and sense of belonging in science.