Inception (1815–1905) In 1815 the French physicist
Jean-Baptiste Biot showed that certain chemicals could rotate the plane of a beam of polarised light, a property called
optical activity. The nature of this property remained a mystery until 1848, when
Louis Pasteur proposed that it had a molecular basis originating from some form of
dissymmetry, with the term
chirality being coined by
Lord Kelvin a year later. The origin of chirality itself was finally described in 1874, when
Jacobus Henricus van 't Hoff and
Joseph Le Bel independently proposed the
tetrahedral geometry of carbon. Structural models prior to this work had been two-dimensional, and van 't Hoff and Le Bel theorized that the arrangement of groups around this tetrahedron could dictate the optical activity of the resulting compound through what became known as the
Le Bel–van 't Hoff rule. , resulting in a slight excess of the
levorotary form of the 2-methylbutyric acid product. In 1894
Hermann Emil Fischer outlined the concept of
asymmetric induction; in which he correctly ascribed selective the formation of D-glucose by plants to be due to the influence of optically active substances within chlorophyll. Fischer also successfully performed what would now be regarded as the first example of enantioselective synthesis, by enantioselectively elongating sugars via a process which would eventually become the
Kiliani–Fischer synthesis.
natural product related to
strychnine, used successfully as an
organocatalyst by Marckwald in 1904. A slight excess of the levorotary form of the product of the reaction, 2-methylbutyric acid, was produced; as this product is also a
natural product—e.g., as a side chain of
lovastatin formed by its diketide synthase (LovF) during its
biosynthesis—this result constitutes the first recorded total synthesis with enantioselectivity, as well other firsts (as Koskinen notes, first "example of
asymmetric catalysis,
enantiotopic selection, and
organocatalysis"). Unlike Fischer, Marckwald had performed an enantioselective reaction upon an achiral,
un-natural starting material, albeit with a chiral organocatalyst (as we now understand this chemistry).
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 Bijvoet in 1951. Chiral chromatography was introduced a year later by Dalgliesh, who used
paper chromatography to separate chiral amino acids. 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.
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, 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, 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. However it raised the importance of chirality in drug design, leading to increased research into enantioselective synthesis.
Modern age (since 1965) The Cahn–Ingold–Prelog priority rules (often abbreviated as the
CIP system) were first published in 1966; allowing enantiomers to be more easily and accurately described. The same year saw first successful enantiomeric separation by
gas chromatography an important development as the technology was in common use at the time. Metal-catalysed enantioselective synthesis was pioneered by
William S. Knowles,
Ryōji Noyori and
K. Barry Sharpless; for which they would receive the 2001
Nobel Prize in Chemistry. Knowles and Noyori began with the development of
asymmetric hydrogenation, which they developed independently in 1968. Knowles replaced the achiral
triphenylphosphine ligands in
Wilkinson's catalyst with chiral
phosphine ligands. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15%
enantiomeric excess. Knowles was also the first to apply enantioselective metal catalysis to industrial-scale synthesis; while working for the
Monsanto Company he developed an enantioselective hydrogenation step for the production of
L-DOPA, utilising the
DIPAMP ligand. Noyori devised a copper complex using a chiral
Schiff base ligand, which he used for the
metal–carbenoid cyclopropanation of
styrene. In common with Knowles' findings, Noyori's results for the enantiomeric excess for this first-generation ligand were disappointingly low: 6%. However continued research eventually led to the development of the
Noyori asymmetric hydrogenation reaction. Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations (
Sharpless epoxidation,
Sharpless asymmetric dihydroxylation,
Sharpless oxyamination) during the 1970s and 1980s. With the asymmetric oxyamination reaction, using
osmium tetroxide, being the earliest. During the same period, methods were developed to allow the analysis of chiral compounds by
NMR; either using chiral derivatizing agents, such as
Mosher's acid, or
europium based shift reagents, of which Eu(DPM)3 was the earliest. Chiral auxiliaries were introduced by
E.J. Corey in 1978 and featured prominently in the work of
Dieter Enders. Around the same time enantioselective organocatalysis was developed, with pioneering work including the
Hajos–Parrish–Eder–Sauer–Wiechert reaction. Enzyme-catalyzed enantioselective reactions became more and more common during the 1980s, particularly in industry, with their applications including
asymmetric ester hydrolysis with pig-liver esterase. The emerging technology of
genetic engineering has allowed the tailoring of enzymes to specific processes, permitting an increased range of selective transformations. For example, in the asymmetric hydrogenation of
statin precursors. ==See also==