FREE ESSAY ON TOTAL SYNTHESIS OF CP COMPOUNDS

TOTAL SYNTHESIS OF CP COMPOUNDS

Total Synthesis of CP Compounds 
Man's fascination with the many uses that can be found with the exploitation of natural
substances has been demonstrated time and again throughout history, but the stage was set
at the turn of the century for organic chemists to begin to focus on utilizing natural
compounds for the benefit of medicinal and industrial uses. The discoveries of
penicillin, aspirin, and other naturally occurring useful compounds in the earlier parts
of the century set the stage for the utilization and exploitation of biologically active
compounds as a molecular science. However, there are limits as to how much we can do with
what nature provides us. This puts the role of the synthetic organic chemist at the
forefront of synthetic compound synthesis technology. KC Nicolaou is one such leader. The
main goal of Nicolaou's lab is the complete synthesis of naturally occurring compounds,
along with solid phase chemistry, molecular design, combinatorial synthesis, and
biological investigations; some of the results of Nicolaou's work include: the total
synthesis of the anticancer agent Toxol, the marine neurotoxins brevetoxins A and B, the
anititumor agents epothilones A and B, eleutherobin and sarcodictyins, the antibiotic
vancomycin, the cholesterol-lowering CP-molecules, the immunosuppressant agent
sanglifehrin A, the antibiotic everninomicin, and a number of bisorbicillinoids such as
trichodimerol, bisorbicillinol, and bisorbibutenolide. Another example of Dr. Nicolaou's
work is a paper published in Chemistry International entitled The Absolute Configuration
and Asymmetric Total Synthesis of the CP Molecules (co-authored by Jae-Kyu Jung, Won
Hyung Yoon, Yun He, Yong-Li Zhong, and Phil Baran.) In this paper, Nicolaou and his
associates describe how their goal was both the total synthesis of these CP compounds
(achieved in 1999) along with the determination of their absolute configurations; methods
used in initial attempts to determine absolute configuration at different carbons
included X-ray crystallography and NMR. Nicolaou set about synthesizing this compound by
thinking through possible reactions that he might use to begin to build the carbon
skeleton needed for this molecule. His team decided on a type-II intramolecular
Diels-Alder reaction as the key step to generation of the core skeleton. The Diels-Alder
reaction utilizes a dienophile in order to form new carbon-carbon bonds in a single step,
in this case to form multiple ring structures. However, Nicolaou ran into trouble when
several reagent-based enantioselective approaches with the precursor failed to yield
appreciable levels of the desired product. After much study of this problem, Nicolaou's
team came to the conclusion that a Lewis acid catalyst would be their best shot at
inducing the asymmetry needed for this particular absolute configuration. After several
more reaction steps, the team had two diastereomeric diols in a racemic mixture that were
then converted to enantiomeric aldehydes with TBAF and NaIO4 - induced oxidative
cleavage. After conversion to the indoline, the synthetic compound was compared to the
naturally derived compound using NMR, TLC, and IR spectroscopy. However, the optical
rotation of the synthetic compound was opposite in magnitude to the naturally derived CP
molecule; the synthetic compound was verified as the enantiomer of the naturally
occurring compound circular dichroism spectroscopy, and thus, the absolute configuration
was verified. This paper parallels Nicolaou's research goals by showing how this team
determined the absolute configuration of a complex compound they synthesized from a much
simpler molecule (glycidol). It also shows the importance of techniques used to determine
structure and content of complex molecules, such as NMR and IR spectroscopy. 
Bibliography 
The Absolute Configuration and Asymmetric Total Synthesis of the CP Molecules
(co-authored by Jae-Kyu Jung, Won Hyung Yoon, Yun He, Yong-Li Zhong, and Phil Baran.)
Chemistry International