This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...

Natural Products as Sources of New Drugs from 1981 to 2014

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Microwave assisted organic synthesis-a review

In the investigation of efficient chemical transformations, the carbon-carbon bond-forming reactions play an outstanding role. In this context, organocatalytic processes have achieved considerable attention. 1 Beside their facile reaction course, selectivity, and environmental friendliness, new synthetic strategies are made possible. Particularly, the inversion of the classical reactivity (Umpolung) opens up new synthetic pathways. 2 In nature, the coenzyme thiamine (vitamin B1), a natural thiazolium salt, utilizes a catalytic variant of this concept in biochemical processes as nucleophilic acylations. 3 The catalytically active species is a nucleophilic carbene. 4

Organocatalysis by N-Heterocyclic Carbenes

N-Hydroxyphthalimide and N-hydroxysuccinimide are etherificated in the presence of a catalytic amount of TosOH to give the title products within 1h in <70% yield.

First Acid Catalyzed Entry to O‐Alkylated Hydroximides from Benzylic Alcohols.

SmI 2 mediates the in situ reductive addition of geminal bis-phenylsulfones to unhindered ketones at room temperature affording β-hydroxyphenylsulfones in good to excellent yields.

SmI2-Mediated Reductive Addition of Bis-Phenylsulfones to Ketones.

This review reports on the total synthesis of gabosines, a family of secondary metabolites containing trihydroxylated cyclohexanone or cyclohexenone cores. Analysis of the different stategies used to prepare these natural products and their stereoisomers has been carried out with special attention paid to the methods employed for the formation of the carbocyclic ring. The different methods are compared in a table, and a discussion of future directions of research in this area is presented.

Total Synthesis of Gabosines.

t-Butyl carbamates were obtained efficiently in high yields from the corresponding N-benzyl, N-trityl and N-diphenylmethyl precursors in a single-step reductive transformation employing polymethylhydrosiloxane and di-t-butyl dicarbonate under Pd(OH) 2 /C catalysis.

Single-Step Conversion of N-Benzyl, N-Trityl and N-Diphenylmethyl Amines to t-Butyl Carbamates Using Polymethylhydrosiloxane.

3-phenylsulfonyl 1,2 propane diol, readily obtainable by dihydroxylation of commercially available allylphenylsulfone, acts as an efficient and new protection reagent for both aldehydes and ketones. This protective group is elegantly removed by use of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), under nonaqueous conditions.

Srivari Chandrasekhar

Papers

First Acid Catalyzed Entry to O‐Alkylated Hydroximides from Benzylic Alcohols.

SmI2-Mediated Reductive Addition of Bis-Phenylsulfones to Ketones.

Total Synthesis of Gabosines.

Single-Step Conversion of N-Benzyl, N-Trityl and N-Diphenylmethyl Amines to t-Butyl Carbamates Using Polymethylhydrosiloxane.

Methylenephenylsulfone Appended Acetals and Ketals: New Class of Carbonyl Protective Groups Cleavable by DBU.