To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.

Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?

Metalated heterocycles and their applications in synthetic organic chemistry.

Methods for anomeric carbon-linked and fused sugar amino Acid synthesis: the gateway to artificial glycopeptides.

The recognition of velo-cardio-facial syndrome as a specific congenital malformation syndrome is a relatively recent development for so common a disorder. The syndrome has appeared in the medical literature either as a specific and distinct diagnostic entity or as part of a discussion of broader symptoms (such as immune compromise, heart anomalies, or speech disorders) since the 1950s, but the majority of interest in the disorder did not develop until the 1990s. The earliest descriptions of the disorder were based on specific symptomatic presentations to clinicians who found the problems to be common among their caseloads. In 1978, in collaboration with a number of my colleagues, I specifically described ‘‘velocardio-facial syndrome’’ (a label I personally constructed) as a genetically caused multiple anomaly syndrome in 12 unrelated cases and one mother–daughter pair (Shprintzen et al., 1978). However, an earlier paper had already reported VCFS as a distinct syndrome in a single family that drew interest because of the presence of congenital heart anomalies and cognitive impairment (Strong, 1968), and descriptions of patients with VCFS from a symptomatic perspective can be found nearly 50 years ago in the Czechoslovakian medical literature (Sedlačková, 1955). Before going further, it would be useful for those readers who are not clinical geneticists or dysmorphologists to understand what the word ‘‘syndrome’’ connotes. Syndrome is defined as multiple anomalies in the same individual with all of those anomalies having a single cause (Smith, 1982; Shprintzen, 1997). This definition was agreed on by an International Working Group in order to differentiate the root causes of multiple anomaly disorders (Smith, 1982). Outside of the discipline of clinical genetics, the term ‘‘syndrome’’ is often applied in medicine to groupings of symptoms that do not meet the requirements for a multiple anomaly syndrome, such as postviral syndrome or AIDS (acquired immune deficiency syndrome). Familiar groupings of clinical findings are often referred to as syndromes consistent with the Greek roots for the word syndrome: syn meaning together and dramein meaning to run, or roughly translated as things that run together. However, as will be discussed later, not all things that run together meet the stricter criteria for syndrome in a genetic sense.

An Historical Overview

Addition of carbon-centered radicals to imines and related compounds

Synthesis of (+)-Furanomycin: Use of Radical Cyclization.

Synthesis of tricyclic bridgehead olefins related to the core structure of CP-225,917 and CP-263,114—solvent, strain, and substitution effects on siloxy-Cope rearrangements

Protected carbohydrates 6a-13a, having one free hydroxyl and a phenylseleno group or halogen on the adjacent carbon, were condensed with (2,2-diphenylhydrazono)acetic acid (2); the resulting esters undergo radical cyclization to afford carbohydrates fused to a 2,2-diphenylhydrazino lactone unit (6c,d-13c,d). In suitable cases (9c,d) such carbohydrate lactones can be elaborated into C-glycosyl amino acids.

Synthesis of C-Glycosyl Lactones and Protected C-Glycosyl Amino Acids: Use of Radical Cyclization.

Glyoxylic acid diphenylhydrazone (2a) and the corresponding O-benzyloxime (2b) are easily esterified in high yield by β-bromo alcohols. The resulting esters undergo radical cyclization to α-(2,2-diphenylhydrazino)- or α-[(phenylmethoxy)amino]lactones on treatment with tributyltin hydride. Esters for radical cyclization were also made using a β-(phenylseleno) alcohol and an enol ether. Several derivatives of glyoxylic acid were evaluated, but none was as effective as 2a or 2b. The imine 28 was prepared by an indirect route; it undergoes radical cyclization with displacement of the nitrogen substituent (28 → 30) so that an α-amino lactone can be generated by acid hydrolysis of the cyclization product.

Junhu Zhang

Papers

Synthesis of (+)-Furanomycin: Use of Radical Cyclization.

Synthesis of tricyclic bridgehead olefins related to the core structure of CP-225,917 and CP-263,114—solvent, strain, and substitution effects on siloxy-Cope rearrangements

Synthesis of C-Glycosyl Lactones and Protected C-Glycosyl Amino Acids: Use of Radical Cyclization.

Preparation of α-(2,2-Diphenylhydrazino)lactones and Related Compounds by Radical Cyclization: Use of Glyoxylic Acid Hydrazone Derivatives

Model studies related to CP-225,917: Stereocontrolled generation of the quaternary center