Editing Enantioselective synthesis (section)

===Early work (1905–1965)===
The development of enantioselective synthesis was initially slow, largely due to the limited range of techniques available for their separation and analysis.
Diastereomers possess different physical properties, allowing separation by conventional means, however at the time enantiomers could only be separated by [[spontaneous resolution]] (where enantiomers separate upon crystallisation) or [[kinetic resolution]] (where one enantiomer is selectively destroyed). The only tool for analysing enantiomers was [[optical activity]] using a [[polarimeter]], a method which provides no structural data.

It was not until the 1950s that major progress really began. Driven in part by chemists such as [[R. B. Woodward]] and [[Vladimir Prelog]] but also by the development of new techniques.
The first of these was [[X-ray crystallography]], which was used to determine the [[absolute configuration]] of an organic compound by [[Johannes Martin Bijvoet|Johannes Bijvoet]] in 1951.<ref>{{cite journal|last=Bijvoet|first=J. M. |author2=Peerdeman, A. F. |author3=van Bommel, A. J.|title=Determination of the Absolute Configuration of Optically Active Compounds by Means of X-Rays|journal=Nature|year=1951|volume=168|issue=4268|pages=271–272|doi=10.1038/168271a0|bibcode=1951Natur.168..271B|s2cid=4264310 }}</ref>
Chiral chromatography was introduced a year later by Dalgliesh, who used [[paper chromatography]] to separate chiral amino acids.<ref>{{cite journal|last=Dalgliesh|first=C. E.|title=756. The optical resolution of aromatic amino-acids on paper chromatograms|journal=Journal of the Chemical Society (Resumed)|year=1952|pages=3940|doi=10.1039/JR9520003940}}</ref>
Although Dalgliesh was not the first to observe such separations, he correctly attributed the separation of enantiomers to differential retention by the chiral cellulose. This was expanded upon in 1960, when Klem and Reed first reported the use of chirally-modified silica gel for chiral [[HPLC]] separation.<ref>{{cite journal|last=Klemm|first=L.H.|author2=Reed, David|title=Optical resolution by molecular complexation chromatography|journal=Journal of Chromatography A|year=1960|volume=3|pages=364–368|doi=10.1016/S0021-9673(01)97011-6}}</ref>

[[File:Thalidomide-structures.png|thumb|300px|right|The two enantiomers of thalidomide:<br />Left: (''S'')-thalidomide<br />Right: (''R'')-thalidomide]]

====Thalidomide====
While it was known that the different enantiomers of a drug could have different activities, with significant early work being done by [[Arthur Robertson Cushny]],<ref>{{cite journal|last=Cushny|first=AR|title=Atropine and the hyoscyamines-a study of the action of optical isomers|journal=The Journal of Physiology|date=2 November 1903|volume=30|issue=2|pages=176–94|pmid=16992694|pmc=1540678|doi=10.1113/jphysiol.1903.sp000988}}</ref><ref>{{cite journal|last=Cushny|first=AR|author2=Peebles, AR|title=The action of optical isomers: II. Hyoscines|journal=The Journal of Physiology|date=13 July 1905|volume=32|issue=5–6|pages=501–10|pmid=16992790|pmc=1465734|doi=10.1113/jphysiol.1905.sp001097}}</ref> this was not accounted for in early drug design and testing. However, following the [[thalidomide]] disaster the development and licensing of drugs changed dramatically.

First synthesized in 1953, thalidomide was widely prescribed for morning sickness from 1957 to 1962, but was soon found to be seriously [[teratogenic]],<ref>{{cite journal|last=McBride|first=W. G.| title=Thalidomide and Congenital Abnormalities |journal=The Lancet|year=1961|volume=278|issue=7216|pages=1358|doi=10.1016/S0140-6736(61)90927-8}}</ref> eventually causing birth defects in more than 10,000 babies. The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the [[Kefauver-Harris Amendment]] (US) and [[Directive 65/65/EEC1]] (EU).

Early research into the teratogenic mechanism, using mice, suggested that one enantiomer of thalidomide was teratogenic while the other possessed all the therapeutic activity. This theory was later shown to be incorrect and has now been superseded by a body of research.<ref>{{cite journal |last1=Ito |first1=Takumi |last2=Ando |first2=Hideki |last3=Handa |first3=Hiroshi |title=Teratogenic effects of thalidomide: molecular mechanisms |journal=Cellular and Molecular Life Sciences |date=May 2011 |volume=68 |issue=9 |pages=1569–1579 |doi=10.1007/s00018-010-0619-9|pmid=21207098 |s2cid=12391084 |pmc=11114848 }}</ref> However it raised the importance of chirality in drug design, leading to increased research into enantioselective synthesis.