C. Pericyclic Reactions 1210 1. [4+2]-Cycloadditions 1210 2. [3+2]-Cycloadditions 1211 3. [2+2]-Cycloadditions 1212 D. Sigmatropic Rearrangements 1212 1. Claisen Rearrangement 1212 2. [2,3]-Wittig Rearrangements 1213 E. Radical Reactions 1214 IV. 1,3-Induction 1215 A. Chelation-Controlled 1,3-Induction 1215 B. Nonchelation-Controlled 1,3-Induction 1216 1. Cram−Reetz Model 1216 2. Evans Model 1216 C. 1,4-Induction 1219 V. Conclusion 1219 VI. References 1221

Around and beyond Cram's Rule.

Macrolactonizations in the Total Synthesis of Natural Products

Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrow-spectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

Natural Products as Platforms To Overcome Antibiotic Resistance

Financial support of the Spanish Ministry of Science and
Innovation (CTQ2012-38543-C03) and Generalitat Valenciana
(PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the
Spanish Ministry of Science and Education for a predoctoral
fellowship (FPU AP2007-02562) and Generalitat Valenciana for
a VALi+d postdoctoral fellowship (APOSTD/2013/041).
M.D.P. thanks the Spanish Ministry of Education for a
postdoctoral fellowship and UGC India for a Startup Grant.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

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The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

In reporting a total synthesis of erythromycin (la) we described in the preceding paper1 the synthesis of the erythronolide A seco acid derivative 2 in optically active form. In this paper we wish to report a successful transformation of 2 to 12 (synthetically equivalent to erythronolide A) via lactonization and also demonstrate that the proper functionalization of a substrate is critical for the successful lactonization.

C. H. Chen

Papers

Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system