K. C. Nicolaou has received numerous awards and honorsincluding:
Terpenoid-Alkaloids: Their Biosynthetic Twist of Fate and Total Synthesis, Isr.
Enantiospecific Total Syntheses of Kapakahines B and F, J.
As a tactic, this is ideal for the preparation of huge numbers of different compounds from a single, simple precursor. It also stands as a challenging biosynthetic method to mimic due to the still fairly limited C-H oxidation toolbox we have available to use in the lab. Historically, though, aiming for things beyond our current ability has always been a great way to drive the development of new (synthetic) technologies, and this field is likely to be no exception. With their allowing access to larger amounts of taxadiene than anyone would have believed possible a few months ago, the Baran group are now in the exciting position of attempting to apply this paradigm to the taxol problem, and I for one am very excited to see how they get on.
As the name implies, crotogoudin is another natural product from the goldmine of bioactive compounds that is the Croton genus of flowering trees. Seeds of these plants have been used for hundreds of years to produce the famous , a violent emetic and purgative used in early medicine across the globe before anyone realised just how bad it really was. Now, the notorious extract is mostly used as a source of various natural products, a reproducible way of inducing pain and/or irritation in animal experiments and a case in point that things described as 100% natural can still be extremely bad for you. It also serves as the major source of the important natural product , and gave its name to crotonic and tiglic acid (and thus crotonaldehyde). Along with a number of other natural products isolated from this genus, crotogoudin displays promising cytotoxic activity, which, coupled with the rare 3,4-seco atisane skeleton, was probably one of the reasons that the Carreira group recently embarked on its total synthesis.
Nicolaou, K.C.; Montagnon, T.; Baran, P.S.
The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.
Maoecrystal V—as the advanced nature of its final letter implies—is one of a great many unusual terpinoids from the Chinese flowing plant Isodon eriocalyx. It possesses a rather intricate and complex structure, a fact illustrated by the two decades that passed between its (first) isolation in 1994 and the successful determination of its structure in 2004—a long period indeed with modern spectroscopic techniques. Its dense, cage-like structure proved a tough nut to crack and another 5 years passed before the deluge of synthetic publications for this target began in 2009. The first total synthesis, reported somewhat controversially by the Yang group the following year, has only seemingly intensified the attention that it has received.
Nicolaou, K.C.; Sugita, K.; Baran, P.
Given the massive number of people affected worldwide by neurodegenerative diseases and nerve injuries, it's not surprising that a number of synthetic groups have chosen to focus their research programs on neurotrophic natural products. Of course, it's probably coincidence that aside from their potential uses to society, a number of these compounds seem to also be structurally unique and strikingly intricate molecules. One such example is jiadifenolide, whose dense, caged seco-prezizaane-type structure has already seen 3 total syntheses since its isolation five years ago.
The amount of optimisation which has obviously gone into this route is enormous, and the paper is well worth reading for discussion of some unsuccessful approaches investigated, as well as how the final conditions were developed. For a taste of what the group are planning next, take a look at their recent review on 'two phase' taxol synthesis (). Somehow this work has gotten me far more excited about an eighth synthesis of taxol than I would have previously thought possible!
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.L.
Nicolaou, K.C.; Sugita, K.; Baran, P.S; Zhong, Y.-L.
Nicolaou, K.C.; Baran, P.S.
Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P.S.
Nicolaou, K.C.; Baran, P.
Nicolaou, K.C.; Zhong, Y.-L.; Baran, Phil S.
Nicolaou, K.C.; Zhong, Y.
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Vega, J.A.
Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde with the aromatic C-ring fragment followed by Lewis acid mediated eight-membered B-ring cyclization gave the desired ABC endo-tricarbocycle. The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene derivative, which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol stereoselectively. For introduction of the C19-methyl, the cyclopropyl ketone was prepared via cyclopropanation of the C-ring allylic alcohol or conjugate addition of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate containing the C19-methyl group. Regioselective transformation of three hydroxyl groups of this intermediate, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-oxygen functionality afforded a precursor for D-ring construction. Dihydroxylation of the allyl chloride moiety followed by basic treatment of the resulting diol gave a fully functionalized taxol skeleton. Functional group manipulation of this product including attachment of the C13 side chain provided (−)-taxol.
Nicolaou, K.C.; Zhong, Y.-L.; Baran, P.S.
And total synthesis continues to be the engine that drives organic synthesis forward, and therefore I think it is still a flourishing, exciting field of investigation.
The Nicolaou Taxol total synthesis, published by K
How is the human genome initiative going to affect total synthesis, andlikewisehow will total synthesis be used as a tool in genomics? The importance of [total synthesis] is finding ways to increase the pace of producing compounds for biological screening.
Nicolaou and his group in 1994 concerns the total synthesis of Taxol
I can mention famous compounds like taxol, brevetoxin, vancomycinthese are very famous moleculesthe CP molecules we have synthesized recently, or the epothilones which are extremely powerful anti-tumor agents.
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