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A Comprehensive History of Arynes in Natural Product …

Syngas has 50% of the energy density of natural gas. It cannot be burnt directly, but is used as a fuel source. The other use is as an intermediate to produce other chemicals. The production of syngas for use as a raw material in fuel production is accomplished by the gasification of coal or municipal waste. In these reactions, carbon combines with water or oxygen to give rise to carbon dioxide, carbon monoxide, and hydrogen. Syngas is used as an intermediate in the industrial synthesis of ammonia and fertilizer. During this process, methane (from natural gas) combines with water to generate carbon monoxide and hydrogen.

Nitrogen-containing functionalities append notable physical and bioactivity properties to organic molecules. Among them, amides are considered a privileged scaffold in medicinal chemistry, natural products, and materials science. Despite the ability to use amides as directing groups for C—H functionalizations proceeding via organometallic intermediates, there is no general means for effecting non-directed, remote aliphatic C—H hydroxylation of simple amide-containing molecules. The intermediate electron-richness of simple amide-containing molecules renders them not electron-deficient enough to enable remote oxidations without protection and not sufficiently electron-rich to be amenable to the N-protection strategies previously developed in our group (i.e. irreversible binding with acids, see publication 41). Using information gleaned from a systematic study of the main features that makes remote oxidations of amides in peptide settings possible, we developed an imidate salt protecting strategy that employs methyl trifluoromethanesulfonate (MeOTf) as a reversible alkylating agent to convert the amide to cationic imidate salt. The imidate salt strategy enables, for the first time, remote, non-directed, site-selective C(sp3)—H oxidation with Fe(PDP) and Fe(CF3PDP) catalysis in the presence of a broad scope of tertiary amides, anilide, 2-pyridone, and carbamate functionalities. This novel imidate strategy facilitates late-stage oxidations on a broader scope of medicinally important molecules and may find use in other C—H oxidations and metal-mediated reactions that do not tolerate amide functionality.


the one matching the NMR data of the natural product ..

Putting aside the downstream applications of natural-product synthesis in the interrogation ..

A novel strategy for the synthesis of 6-deoxyerythronolide B is reported that uses a late-stage C-H oxidative macrocyclization reaction to forge the key macrocyclic core found in the erythromycins. Starting from a linear alkenoic acid intermediate lacking oxygen at C13, a Pd(II) catalyzed C-H oxidation reaction generated the 14-memebred macrocycle with the natural configuration at C13 in >40:1 diastereoselectivity. Controlling the functionalization mechanism allowed for the alternative C13 diastereomer to be synthesized for the first time. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the "oxygen load" over lengthy linear sequences. Moreover, this work provides a new way to think about constructing macrolide natural products.

In this article, a Bronsted base activation mode for oxidative, Pd(II)/sulfoxide-catalyzed, intermolecular C-H allylic amination is described. A catalytic amount of -diisopropylethylamine was found to efficiently promote the linear allylic amination reaction with high levels of stereo-, regio-, and chemoselectivity. This departure from Lewis acid activation allows unprecedented functional group tolerance for a C-H amination method. For example, powerful synthetic building blocks and natural product derivatives containing reactive Lewis basic functionality such as epoxides, aldehydes, esters, nitriles, phenols, and even alcohols can be aminated without the use of protecting groups. Useful transformations of -tosylcarbamate products as well as evidence to support this novel activation mode are discussed.

Natural Product Synthesis | Bastien Nay Research Group

and (2012) A Comprehensive History of Arynes in Natural Product TotalSynthesis. Chemical Reviews, 112 (6). pp. 3550-3577. ISSN 0009-2665.

history of natural products as ..

Why Natural Products?

Natural products remain the best sources of drugs and drug leads

Natural products remain the best sources of drugs and drug leads, and this remains true today despite the fact that many pharmaceutical companies have deemphasized natural products research in favor of HTP screening of combinatorial libraries during the past 2 decades. From 1940s to date, 131 (74.8%) out of 175 small molecule anticancer drugs are natural product-based/inspired, with 85 (48.6%) being either natural products or derived therefrom. From 1981 to date, 79 (80%) out of 99 small molecule anticancer drugs are natural product-based/inspired, with 53 (53%) being either natural products or derived therefrom. Among the 20 approved small molecule New Chemical Entities (NCEs) in 2010, a half of them are natural products.

Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries. About 40% of the chemical scaffolds found in natural products are absent in today’s medicinal chemistry repertoire. Based on various chemical properties, combinatorial compounds occupy a much smaller area in molecular space than natural products. Although combinatorial compounds occupy a well-defined area, natural products and drugs occupy all of this space as well as additional volumes. Most importantly, natural products are evolutionarily optimized as drug-like molecules. This is evident upon realization that natural products and drugs occupy approximately the same molecular space.

Natural products represent the richest source of novel molecular scaffolds and chemistry. No one can predict, in advance, the details of how a small molecule will interact with the myriad of targets that we now know drive fundamental biological processes. The history of natural product discovery is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and therapy. For instance, Taxol's impact on tubulin polymerization, and correlation to antitumor action or rapamycin's binding to mTOR and the ramifications of mTOR inhibitors could never be predicted . The discovery of new natural products promises significant advances not only in chemistry, but also, biochemistry and medicine.

Natural products are significantly underrepresented in current small molecule libraries

In spite of the great success of natural products in the history of drug discovery, natural products are significantly underrepresented in current small molecule libraries. Challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures posing enormous difficulty for structural modifications, and (iv) complex structures precluding practical synthesis. These difficulties lead to the pharmaceutical industry to embrace new technologies in the past two decades, particularly combinatorial chemistry, at the detriment to interest in natural product discovery.

Microbial natural products as preferred sources of new drugs and drug leads

Microbial natural products have several intrinsic properties favoring their consideration in drug discovery and development. Microbial natural products can be produced by large-scale fermentation. Microorganisms can be engineered to overproduce the desired natural products hence to solving the supply bottleneck. Microbial natural product analogues can be produced by metabolic pathway engineering, thereby providing a focused library for structure-activity-relationship studies. The vast, untapped, ecological biodiversity of microbes holds great promise for the discovery of novel natural products, thereby improving the odds of finding novel drug leads.

The exponential growth in cloning and characterization of natural product biosynthetic machinery from microbes in the last two decades has unveiled unprecedented molecular insights into natural product biosynthesis, including the observation that genes for natural product biosynthesis are clustered in the microbial genome and that variations of a few common biosynthetic machineries can account for vast structural diversity observed for natural products. These findings have fundamentally changed the landscape of natural product research by enabling the revision of known natural product structures, the prediction of yet-to-be isolated novel compounds on the basis of gene sequences, and the systematic generation of “unnatural” natural products by manipulating genes governing their biosynthesis (also known as combinatorial biosynthesis).

Whole genome sequencing has revealed far more biosynthetic gene clusters than actual metabolites currently known for a given organism, suggesting that the biosynthetic potential for natural products in microorganisms is greatly under-explored by traditional natural product discovery methods. Among the whose genomes have been sequenced, every one of them has the potential to produce up to 30 natural products on average, and this optimism has already translated into the discovery of new natural products by fermentation optimization from strains that otherwise were not previously known as natural product producers.

Only 1% of the microbial community has been estimated to be cultivated in the lab, implying that the vast biodiversity of microbial natural products remains underappreciated. Emerging new cultivating techniques, culture-independent methods by expressing gene clusters in model heterologous hosts, and diligent effort and innovative approaches in novel microbial strain collection, identification, and classification have started to permit access to these previously inaccessible natural product resources.

The future of microbial natural product drug discovery and development remains bright. (i) Advances in DNA sequencing will greatly facilitate genome sequencing and genomics-based natural products discovery. (ii) Advances in DNA synthesis and synthetic biology will greatly facilitate natural product pathway reconstruction, engineering, and expression in model or industrial hosts for natural product production. (iii) Advances in HTS will further enable rapid screening of natural product libraries for an ever broader range of biological application. (iv) Advances in isolation technologies, analytic methods, automatic robotics, and database management will greatly facilitate natural products library construction. (v) Environmental concerns will further favor bio-based natural products drug discovery and development processes, i.e., fermentation, metabolic pathway engineering, and renewable resources.

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The Organic Synthesis Archive; Natural product syntheses ..

Natural Product Synthesis, Mechanism, ..

iii ACKNOWLEDGEMENTS iv This is by far the most important part of my thesis. Synthetic chemists often define their achievements in terms of the number of natural products they have made or the number of novel reactions they have developed. Yet, I realize that my greatest achievements have been the professional and personal relationships I have developed that have gotten me to this stage in life. So it is with tremendous gratitude that I write these acknowledgements to show my appreciation to some of the people who have helped me throughout the years. Caltech is an amazing place to conduct research, and its commitment to excellence is showcased by the individuals who kindly agreed to serve on my thesis committee: Professors David MacMillan, Robert Grubbs, and Jonas Peters. Dave MacMillan is a motivated and fearless scientist who is never afraid of thinking big. I cannot begin to describe how much I have learned from Dave through all of our discussions. He has had a tremendous influence on how I think of chemistry, and I hope

scaffolds that are important in natural product synthesis and ..

Lee even cited a study that found women with sufficient levels of progesterone were 90% less likely to develop cancer of any kind.

Experiments have shown progesterone to help control hot flashes, PMS, depression, relieve anxiety,improve memory, protect brain cells, and even prevent epileptic seizures. It promotes respiration, and has been used to improve emphysema. In thecirculatory system, it prevents bulging veins by increasing the tone of bloodvessels, and improves the efficiency of the heart.

It reverses many of the signs of aging in the skin, andpromotes strong bone growth. It can relieve many types of arthritis, too,and helps a variety of immunological problems.

The best way to intake natural progesterone isdissolved in vitamin E because it can enter the blood stream almost as soon asit contacts any membrane, such as lips, tongue, gums, or palate. And whenswallowed, it continues to be absorbed by the digestive process.

If progesterone is dissolved in vitamin E, it isabsorbed very efficiently, and quickly dispersed to all tissues. If awoman has ovaries, progesterone helps them to produce both progesterone andestrogen as needed, and also helps to restore normal functioning of the thyroidgland and other glands as well. If ovaries have been removed, progesteronemay be taken consistently to replace the lost supply, since a progesteronedeficiency has often been associated with increased susceptibility to cancer andprogesterone has been used to treat some types of cancer.

It is important to emphasize that progesteroneis not just the hormone of pregnancy. To use it only to nourish the uteruswould be similar to telling a man he doesn't need testosterone if he doesn'tplan to father children, except that progesterone is far greater and more basicsignificance than testosterone.

While men do naturally produce progesterone, andcan sometimes benefit from using it, it is not a male hormone. Somepeople get that impression, because some physicians recommend combining estrogenwith either testosterone or progesterone to protect against some of estrogen'sharmful side effects, but progesterone is the body's natural complement toestrogen. Used alone, progesterone often makes it unnecessary to useestrogen for hot flashes or insomnia, or other symptoms of menopause.

Beware of progesterone creams using ingredientsthat become toxic when ingested. Some products are labeled as "progestogens" or "progestins"which do not produce thedesired results and contain toxic synthetic substances.

While use of vitamin E is the best vehicle forprogesterone intake, beware of tocopherol acetate (synthetic vitamin E) since itis only about half as efficiently absorbed as the simple tocopherol (naturalvitamin E).


Peat'spatented natural progesterone formula in natural vitamin E comes in a 10%solution, one drop containing about three milligrams of progesterone. Normally, the body produces 10 to 20 milligrams per day. A dose of 3 or 4drops usually brings the blood levels up to the normal range, but this dose canbe repeated several times during the day if needed to control symptoms.

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