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New Taxol route

29 July 2009 - almost a formal synthesis

A new stab at Taxol total synthesis by Goldring, Pattenden and Rimmington (DOI). Their strategy a free radical cascade reaction of intermediate 2 to ABC ring system 3 with AIBN (radical initiator) and tributyltin hydride as proton donor. Compounds 3 closely resembles one of the intermediates in the Kuwajima Taxol total synthesis (30+ more steps to go) therefore the efforts almost constitutes a formal synthesis.


20 July 2009 - Two minds, one idea

Every now and then two articles from two separate research groups appear at the same time having almost identical content. The coincidence of two dihalosilylene articles appearing back to back in the Angewandte this week is of course engineered by the Angewandte editors but nevertheless the question is how did this happen? Ghadwal et al. (received 1 April 2009 DOI) and Filippou et al (received 7 MayDOI) both decided to add a halosilane (tetrachlorosilane or tetrabromosilane) to cyclic diamino carbene 1 and reduce the intermediate 2 with potassium graphite to form the silylene dibromosilylene and dichlorosilylene 3. The latter compound is the silicon version of dichlorocarbene and also a family relation of lead dichloride. Key to the stability of the silyl carbene group is the presence of the diaminocarbene and without it SiCl2 polymerizes quickly to (SiCl2)n

Both groups have been paying close attention to a 2008 article by Wang et al. (DOI) in which this reaction is pioneered only with twice the amount of reducing agent and with a surprisingly different reaction product namely the carbene stabilized bis-silylene L-Si=Si-Li 4 with both silicon atoms having formal oxidation state zero. This research group has been using this reaction protocol before when they synthesised a similar looking diborene in 2007 and by now they must be pulling their hair out realizing they missed the dihalosilylene opportunity that has now presented itself.

Wender & Miller on molecular frontiers

16 July 2009 - The future

Paul Wender and Benjamin Miller in a recent contribution to Nature (DOI) discuss the future of organic synthesis. Here are some of the keywords that sum the article up. Bioinspired synthesis: many of the most important therapeutic drugs in the last 50 years were inspired by biomolecules. Natural products that can only be found in trace amounts can be artificially synthesised in large quantities provided that the so-called step-economy (minimization of the number of chemical procedures in a synthesis) requirement is met. Classic example of offer: the synthesis of cyclooctatetraene from an alkaloid (11 steps and low yield) or from acetylene (1 step with high yield). Another example is Wender's own prostratin semisynthesis. Key strategies for step-economy according to Wender & Miller: the multicomponent reaction and the cascade reaction. And when total synthesis fails to offer an advantage over harvesting from nature then at least the synthesis of analogs should open up the road to new drugs. Example on offer: the laboratory synthesis of bryostatin takes 70 steps in comparison to 30 steps for a pimped-down version.

But hey, wait a minute! In a Science review published just a day later Jesse Li and John Vederas also explore a frontier, that of drug discovery and natural products (DOI). They note that in drug companies, natural product research itself actually is in decline! Although the success rate for natural products (0.3%) is actually higher than that of high-throughput screening (HTS) (0.001%), HTS is all the rage nowadays because all-synthetic chemical libraries are easily available for example with diversity oriented synthesis. Performing HTS on natural sources such as plant extracts has the added disadvantages of intellectual property issues (the plant may be owned by the locals), availability issues (a rare plant may have gone extinct by the time R&D is ready for the next step) and an active ingredient may actually turn out to be a non-patentable known compound (a waste of effort). So what to do!. Li & Vederas list some creative ideas in the field: the creation of genomic libraries based on metagenomics - the automation of biomolecule separation prior to HTS - the automation of structure elucidation e.g. tandem HPLC-MS or even NMR. The generation of analogs is also mentioned: compare for example biomolecule lovastatin with analog zocor. And even more fancy strategies to look out for in the future: Single Molecule Real Time Sequencing, synthetic biology and 454 Sequencing.

The 8-component reaction

10 July 2009 - One-pot reactions

In multicomponent reactions several chemicals are brought together in a single reactor with formation of a single reaction product. Usually when you try this a complex mixture forms (A can react with B but also with C or D) requiring tedious separation. A successful multicomponent reaction therefore saves reaction steps, protecting/deprotecting and hence time and money. It also allows you to put together so-called chemical libraries really quickly. The current record holder, a 7-component reaction (7CR) has now been dethroned by an 8CR created by Elders/Orru et al. at the Vrije Universiteit Amsterdam (DOI).

The clever trick is that the 8CR is basically a tandem 3CR/3CR/4CR reaction with the first two also created by the Amsterdam group. The third one is a classic Ugi reaction. Imidazoline A is synthesised from a ketone , a primary amine and an alpha-acidic isocyano amide (DOI).

In B the starting amine is secondary (DOI) and with a lot of electron pushing the isonitrile group appears to be replaced by a nitrile.

In the second stage of the reaction A and B are combined with another amine and an aldehyde for the Ugi.

The final yield is modest and the reaction product a mixture of 4 diastereomers but the methodology nevertheless presents an intriguing starting point for library building. If only those isonitriles wouldn't smell so awful!.

Elders, N., van der Born, D., Hendrickx, L., Timmer, B., Krause, A., Janssen, E., de Kanter, F., Ruijter, E., & Orru, R. (2009). The Efficient One-Pot Reaction of up to Eight Components by the Union of Multicomponent Reactions Angewandte Chemie International Edition DOI: 10.1002/anie.200902683


10 July 2009 - The new miracle drug

This week Nature speculates (DOI) about the use of rapamycin as a longevity, aging-intervention or anti-ageing drug in a comment on new mouse research done by Harrison et al. (DOI). 1900 mice were found kind enough to participate in a trial where starting at the age of 600 days (that is 60 human years) they were fed a chow laced with rapamycin. The control group (obviously) were given just the chow but not the rapamycin.

Sure enough, at 90% mortality the mean lifespan increased by 9% in males and by 13% in females. By 1200 days all mice were as good as dead so it does not mean mice live longer in absolute terms. Nevertheless an exciting result.

But there is another intriguing finding in this study: "the (male) control mice ... differed from those fed rapamycin not only in exposure to rapamycin from 600 days of age but also in specific formulation of the mouse chows .... used between weaning and 600 days".

This means that the control mice were starting to die off in anticipation to the rapamycin-free diet! What was wrong with them! They must have guessed somehow they were part of "just the control group" and not the hip & longlasting rapamycin crowd!. The resulting lack of self-esteem did them in!

Back to the chemistry: rapamycin is a complex macrolide and the number of successful feats of total synthesis stands at five: the Danishefsky group (Hayward et al. 1993 DOI), the Schreiber group (Romo et al. 1993 DOI) , the Nicolaou group (1993 DOI) , the Amos B. Smith group (1995 DOI DOI DOI), the Ley group (Maddess et al. 2007 DOI).

The Ley group started working on rapamycin in 1990. The sketch below attempts to sketch it's synthesis from the raw material point of view.

The group published a 45 page "the making of" in 2009 (Maddess and 22 other authors DOI) that also details the synthesis of the two larger chunks.

Chemistry blogs

06 July 2009 - on the web part II

Once again a tour of the chemistry blogs from the past several weeks.
Useful Chemistry is an so-called Open Notebook Science project aimed at synthesizing new anti-malarial compounds. This blog is currently preoccupied with gathering solubility data. Another open source project is described by Chem-bla-ics this time not dealing with collaborative molecule making but computing.

A chemical sabbatical has an irregular feature called Poisons of the day with this years poison arsenic! because apparently it makes us susceptible to flu. The more consistent Molecule of the Day is all about Slentrol - an obesity drug for dogs? Obesity, this time in humans is on the radar in the periodic Tabloid

And then there are the minor setbacks: Carbon Based Curiosities complains about his glovebox, The Chem Blog does not like the new neighborhood he has moved to, The Chemistry Blog has some desiccator issues.

Org. Prep. Daily points our attention to an insightful article related to the pharmaceutical industry. Apparently rational drug design only brings ruin and good old fashioned luck in finding new blockbuster drugs prevail. By the way the costs in drug development is in the clinical trials, not the chemistry! Another rational-design sceptic is Corante commenting on somebody else criticizing the efficiency of high-throughput screening (the opposite approach to rational design).

Practical advice: by Curly Arrow on how to make instant dry HCl gas and by Anne Marie's Chemical blog on how to make a smoke bomb (if you feel like starting a riot). xrqcwgf is facing a difficult Grignard. Practical information: bridgehead Carbon makes quorum sensing molecules understandable or at least the quorum-sensing bacteria part. The Reactive Chemistry Blog exposes some improbable chemistry: a secret reaction between carbon dioxide and hydrogen sulfide that would eliminate two climate/environmental problems in one go although the blog has to concede the reaction can be exothermic.

See part I Here

White phosporus tamed

02 July 2009 - Part II

White phosphorus (P4) is known to react violently with oxygen and Mal et al. (DOI) have found a novel way to keep this from happening by locking the molecule into an iron cage.

This cage is prepared in water from iron sulfate , 4,4-diaminobiphenyl-2,2-disulfonic acid, 2-formylpyridine and tetramethylammonium hydroxide as phase-transfer catalyst. The hydrocarbon components condense to an extended molecule and 5 of them form the vertices of a tetrahedron which is held together by a self-assembly process as the terminal diimine groups (in red) coordinate to iron. (Mail et al. DOI). When exposed to phosporus, the water-soluble host-guest complex P4@Fe4 forms. The pore-size of 1 angstrom does not prohibit oxygen from entering the cage, rather it is theorized that any oxidation product would simply be too large to fit. Added benzene replaces the phosphorus and the process is reversible. The only disadvantage is that the phosphorus capacity of the container is only 4%.

See also: white phosphorus tamed part I

Its the contaminants, stupid!

01 July 2009 - Metal catalysis Updated 30-9

Some words of caution from Buchwald & Bolm this week in the Angewandte (DOI) on the use of catalysts. They observe that in certain cross-coupling reactions the reaction yield very much depends on the quality of the metal catalyst. In several reactions with ferric chloride, the yields range from the very low (10%-30%) with pure FeCl3 material (commercial grade > 99.99%) to high (70%-90%) with regular material (commercial > 98%) which is odd.

The regular iron salt is found to contain a small amount of copper and in fact by adding copper oxide at the ppm level to high-grade FeCl3, the yields are restored to their proper values.

So the question is, whether iron is the true catalyst or copper. The results also require a rethink on other reactions such as the copper-free Sonogashira reaction and the so-called metal-free reactions as already discussed here and here in this blog.

Update 30 Sept: Bedford et al. (DOI) also find that metal contamination , this time Pd contamination in (again) an iron catalyst can interfere with an organic reaction , this time a Suzuki reaction. Palladium is found to be an effective catalyst at the ppb level!

Buchwald, S., & Bolm, C. (2009). On the Role of Metal Contaminants in Catalyses with FeCl Angewandte Chemie International Edition DOI: 10.1002/anie.200902237