A Concise, Enantioselective Approach for the Synthesis of Yohimbine Alkaloids.

We report a concise, enantioselective synthesis of the yohimbine alkaloids (-)-rauwolscine and (-)-alloyohimbane. The key transformation involves a highly enantio- and diastereoselective NHC-catalyzed dimerization and an amidation/N-acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations. This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future biomedical investigations.

Formation of Aza-ortho-quinone Methides Under Room Temperature Conditions: Cs2CO3 Effect.

Since the first report of a facile, room temperature process to access aza-ortho-quinone methides (aoQMs) by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014. We report a theoretical and experimental study of the key to success behind these successful examples to enable broader exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (ΔG > 30 kcal/mol), precluding their formation under mild conditions. The use of Cs2CO3 as base is critical. It provides a thermodynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The exothermic formation of salt byproducts provides a driving force (average ΔG = -30.8 kcal/mol) compensating for the majority of the inherent unfavorable thermodynamics of aoQM formation.

A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products.

The Armillaria and Lactarius genera of fungi produce the antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. We report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The key features of these syntheses are 1) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, 2) the utility of a key 1,2-cyclobutanediol intermediate to serve as a precursor to each natural product class, and 3) a direct chemical conversion of a protoilludane to a marasmane through serendipitous ring contraction, which provides experimental support for their proposed biosynthetic relationships.

Azaindole synthesis through dual activation catalysis with N-heterocyclic carbenes.

A convergent, transition-metal-free synthesis of 2-aryl-azaindoles has been developed. The interception of a reactive aza-ortho-azaquinone methide intermediate by an acyl anion equivalent generated through carbene catalysis provides high yields, a wide substrate scope, and the synthesis of previously inaccessible azaindoles.

Stereoselective synthesis of (+)-loline alkaloid skeleton.

The loline alkaloids present a compact polycyclic pyrrolizidine skeleton and contain a strained five-membered ethereal bridge, structural features that have proven challenging for synthetic chemists to incorporate since the discovery of this natural product family more than 100 years ago. These alkaloids are produced by mutualistic fungal symbionts (endophytes) living on certain species of pasture grasses and protect the host plant from insect herbivory. The asymmetric total synthesis of loline alkaloids is reported and extends our first-generation (racemic) synthesis of this alkaloid family. Key to the synthesis is a diastereoselective tethered aminohydroxylation of a homoallylic carbamate function and a Petasis Borono-Mannich addition.

A Cooperative N-Heterocyclic Carbene/Palladium Catalysis System.

N-heterocyclic carbenes (NHC) have been extensively studied as organocatalysts and ligands for transition metals, but the successful integration of NHCs and late transition metals in cooperative catalysis remains an underexplored area. We have developed a cooperative palladium-catalyzed allylation of NHC-activated aldehydes to access a variety of 3-allyl dihydrocoumarin derivatives. Kinetic experiments support a cooperative pathway for this transformation.

N-heterocyclic-carbene-catalyzed synthesis of 2-aryl indoles.

A convergent and efficient transition-metal-free catalytic synthesis of 2-aryl-indoles has been developed. The interception of a highly reactive and transient aza-ortho-quinone methide by an acyl anion equivalent generated through N-hetereocyclic carbene catalysis is central to this successful strategy. High yields and a wide scope as well as the streamlined synthesis of a kinase inhibitor are reported.

Synthesis of (±)-acetylnorloline via stereoselective tethered aminohydroxylation.

Loline alkaloids exhibit a strained ether-bridged pyrrolizidine skeleton and possess insecticidal and insect antifeedant properties. The synthesis of acetylnorloline, a prototypical member of the alkaloid family, is described. Central to the route is a stereoselective tethered aminohydroxylation (TA) of a homoallylic carbamate. Allylic (A1,3) strain is exploited to enforce diastereofacial selectivity during the aminohydroxylation.

Incarcerated rectal prolapse--rupture and ileal evisceration after failed reduction: report of a case.

We report a case of incarcerated rectal prolapse that could not be reduced after using the previously described application of ordinary table sugar. Gentle pressure caused the prolapsed rectum to perforate, and the small bowel herniated through the tear. This is only the second case reported in the literature of an ileal herniation through a perforated rectum after an attempted reduction of an incarcerated prolapse. It is the only reported case occurring after sugar application and the 42nd case of ileal herniation through the rectum from all causes.

Indicators of woman abuse based on a chart review at a family practice center.

OBJECTIVE: To identify demographic and health indicators of domestic violence. DESIGN: Anonymous questionnaire survey of patients regarding violence and a chart review regarding symptoms and diagnoses. SETTING: Community-based family practice residency training center in a midwestern city. PARTICIPANTS: Women 18 years of age or older visiting the center over a 2-month period in 1990. Of 476 eligible participants, 394 (82.7%) consented to complete the survey. MEASURES: A detailed, standardized measure of violence was used. Physical and psychological problems were given codes from the International Classification of Diseases, Ninth Revision (ICD-9). RESULTS: Younger women and those separated or divorced from their partners were more likely to have been victims. Never-married women also had substantially high rates of victimization. Depression was the strongest indicator of victimization, even when controlling for demographic factors. Back pain, ulcers, headaches, and anxiety were not strong indicators of abuse. A classification analysis showed that a combination of all variables could predict lifetime injury only about half the time and violence in the past year only about 20% of the time. CONCLUSIONS: Since neither demographic nor health factors could accurately predict who had been victimized, all women need to be asked about abuse. Physicians should also keep in mind that divorced and unmarried women are often affected by abuse, either immediately or by its long-term aftereffects.

Prevalence of domestic violence in community practice and rate of physician inquiry.

BACKGROUND: National surveys show that each year in the United States approximately 2 million women are battered by their husbands. Only a small percentage of these women are identified by physicians. The objective of this research was to determine the incidence and prevalence of spouse abuse among women seeking health care in a family practice clinic (or setting). METHODS: During a two-month period, all adult women seeking health care from a family practice clinic in a medium-sized Midwestern community were asked to complete an anonymous questionnaire about whether they had ever been physically assaulted by their partners. RESULTS: Of 476 consecutive women seen in practice, 394 (82.7%) agreed to participate. Of these, 22.7% had been physically assaulted by their partners within the last year. The lifetime rate of physical abuse was 38.8%. Only six women in the sample had ever been asked about abuse by their physician in a recent visit [corrected]. CONCLUSIONS: Although spouse abuse is common, physicians rarely ask about it. Physicians should be trained to detect and assess abuse among female patients.

Thyroid hormone stimulation of phosphatidylcholine synthesis in cultured fetal rabbit lung.

To investigate the mechanism of thyroid hormone action on pulmonary surfactant synthesis, we characterized the effect of triiodothyronine on phosphatidylcholine synthesis in cultured fetal rabbit lung. Since glucocorticoids stimulate surfactant synthesis and reduce the incidence of Respiratory Distress Syndrome in premature infants, we also examined the interaction of triiodothyronine and dexamethasone. The rate of choline incorporation into phosphatidylcholine was determined in organ cultures of rabbit lung maintained in serum-free Waymouth's medium. In 23-d lung cultured for 72 h, the increase in choline incorporation with triiodothyronine alone, dexamethasone alone, and triiodothyronine plus dexamethasone was 50, 62, and 161%, respectively. Both triiodothyronine and dexamethasone also increased incorporation rates with glucose, glycerol, and acetate as precursors, and stimulation with triiodothyronine plus dexamethasone was at least additive. Dexamethasone, but not triiodothyronine, affected distribution of radioactivity from [3H] acetate among phospholipids. Stimulation was first detected 8-12 h after addition of triiodothyronine, and then increased in a linear fashion. With triiodothyronine plus dexamethasone, stimulation was maximal at 48-72 h, and was supra-additive at all times. Exposure of cultured lung to dexamethasone enhanced the subsequent response to triiodothyronine, but not vice versa. When triiodothyronine was removed from cultures, there was no further stimulation and the triiodothyronine effect was partially reversed within 24 h. Half-maximal stimulation of choline incorporation occurred at a triiodothyronine concentration (0.10 nM) very similar to the dissociation constant for triiodothyronine binding to nuclear receptor (0.11 nM). The relative potencies of thyroid hormone analogs for nuclear binding and stimulation of phosphatidylcholine synthesis were also similar: triiodothyroacetic acid greater than triiodothyronine-proprionic acid greater than L-triiodothyronine approximately D-triiodothyronine much greater than thyroxine much greater than 3,5-diethyl-3'-isopropyl-DL-thyronine approximately 3,5-dimethyl-3'-isopropyl-L-thyronine approximately reverse triiodothyronine. The effect of triiodothyronine was blocked by the presence of either actinomycin D or cycloheximide, inhibitors of ribonucleic acid and protein synthesis, respectively. We conclude that triiodothyronine stimulates phosphatidylcholine synthesis by a process involving nuclear receptors and de novo ribonucleic acid and protein synthesis. These findings support the concept that endogenous triiodothyronine has a physiologic role in lung maturation and suggest that a combined antenatal therapy with thyroid hormone and glucocorticoid may be useful for prevention of Respiratory Distress Syndrome in the premature infant.

Resistivity of axoplasm. II. Internal resistivity of giant axons of squid and Myxicola.

The specific resistivity of the axoplasm of giant axons of squid and Myxicola was measured utilizing a single metal microelectrode subjected to alternating current in a circuit in which the voltage output varies with the conductivity of the thin layer of fluid at the exposed electrode tip. The average specific resistivity of stellar axons of Loligo pealei was 31 omegacm (1.55 times seawater [X SW]) while for Loligo opalescens it was 32 omegacm (1.30 X SW). Smaller giant axons had a higher average resistivity. Myxicola giant axons had a resistivity of 68 omegacm (2.7 X SW) in normal seawater, and 53 omegacm (2.1 X SW) in a hypertonic high-Mg++ seawater. The temperature dependence of squid axon resistivity does not differ from that of an equally conductive dilution of seawater.

Low internal conductivity of Aplysia neuron somata.

The internal conductivity of Aplysia neuron somata was measured by passing constant current pulses across a calibrated four-electrode array. The intracellular medium is less than one-tenth as conductive as seawater. The low conductivity probably results from structured cell water since ions are present in quantity and do not appear to be bound.