A new tail for Taxol

22 March 2009 - news

A team of Sweden-based chemists (DOI) have come up with a new way to add the tail in the cancer-curing drug Paclitaxel or Taxol (if you feel companies should not be allowed to hijack generic names as trade names). Although Taxol is a biomolecule that can be harvested from Taxus brevifolia, more of it is produced commercially from tail-less baccatin III that can be extracted from the more handy Taxus baccata. The tail is then added by reaction with the Ojima lactam (see Taxol total synthesis).

The new method which appears less of a hassle than the Ojima method is based on an asymmetric Mannich reaction catalysed by (R)-proline. The aldehyde group is the oxidized to a carboxylic acid using Sodium chlorite and for some reason isobutene and KH2PO4 are thrown in as well. Esterfication to TES-protected baccatin III is accomplished with DMAP and DCP (di-2-pyridyl carbonate) and final deprotection with palladium on carbon and hydrochloric acid.

Phenanthrene H-H bond revisited

21 March 2009 - physical organic chemistry

Phenanthrene is a peculiar molecule that chemists are unable to cope with. The two bay hydrogen atoms are in very close proximity to each other which is prompting one group to say their interaction must be repulsive and another group to say that this interaction must be a result of bonding as in a hydrogen-hydrogen bond. The opponents in this longstanding debate do their arguing mostly through computer models but now Grimme, Erker and coworkers, in a recent article (DOI), have summoned a new powerful weapon called Experimental Evidence. As a result, they now demand the complete surrender of this hydrogen-hydrogen bond theory as applied to phenanthrene.

This evidence consists of infrared spectroscopy and Raman spectroscopy of phenanthrene with the two bay hydrogen atoms replaced by deuterium. Its synthesis leaves much to desire, but apparently 22 mg of it was all that was needed. The reason the researches aimed for the D isotopologue was that in the infrared spectrum two vital absorptions are well resolved: the coupled symmetric C-D stretching vibration and its asymmetric counterpart (with hydrogen many more C-H vibrations clutter spectra).

In the symmetrical mode the distance between the two deuterium atoms varies more than in the asymmetrical mode and Grimme & Erker expect a large energy difference between the two if the D-D interaction is either strongly attractive or strongly repulsive. In fact, they find a very small difference with a slightly higher energy for the symmetric mode which they argue is expected with a repulsive D-D interaction.

Grimme, S., Mück-Lichtenfeld, C., Erker, G., Kehr, G., Wang, H., Beckers, H., & Willner, H. (2009). When Do Interacting Atoms Form a Chemical Bond? Spectroscopic Measurements and Theoretical Analyses of Dideuteriophenanthrene Angewandte Chemie International Edition, 48 (14), 2592-2595 DOI: 10.1002/anie.200805751

Twisted amides

16 March 2009 - News

A new twisted amide has been described recently by Szostack et al. (DOI) with a twist angle of 60° and stable in water. The final step of its synthesis is a Schmidt reaction just like that other twisted amide 2-quinuclidone.

In regular amides the carbonyl group and the amine group share the same plane due to partial double bond character of the C-N bond caused by delocalization of the amine lone pair into the carbonyl oxygen. Hence, the carbonyl group does not behave as such and the amine group lacks basicity. Except when you introduce twisting.
This tweak is relevant to biochemistry : twisted amides may help explain cis-trans isomerization of amides in protein folding and amide hydrolysis by peptidase in other biochemical processes as already observed by Somayaji & Brown in 1986 (DOI).
In 2001 Kirby et al. described an adamantane based twisted amide with a larger twist angle of 90° (DOI). This compound shows rapid hydrolysis and its carbonyl group has Wittig reaction capabilities.

Another amide is reduced via Wolff-Kishner reduction to a tertiary amine (Bashor et al. 2003 DOI)

Ranking Oseltamivir

9 March 2009 - Green metrics

There are many different ways you can synthesise a molecular compound in the laboratory. In academics, your particular synthetic plan gets points for being elegant (a rather vague term) or for having incorporated a new break-through protocol. In industry it is all about costs which at least you can measure. But what if you want to rank synthetic plans in terms of greenness?.

John Androas of York University did some serious accounting and ranked 16 plans for the synthesis of oseltamivir (DOI) which is great because this blog has been keeping an eye on oseltamivir total synthesis, here, here and here.

A useful parameter in green metrics is the so-called reaction mass efficiency (RME) as the product of chemical yield, atom economy, the inverse of the stoichiometric factor (SF, taking into account excess reagent) and the material recovery parameter (MRP). In an ideal reaction a RME value of 1 means its four components have a value of 1 as well. Synthesis plans high in RME use few auxiliary reagents such as catalysts and as little solvent as possible. Chromatography and protective groups are nono's.

Androas reports the highest RME score out of 16 plans for Roche's shikimic acid route (RME = 11.5%). This plan also generated the least amount of waste: 94.1 kilograms per 1 mole of oseltamivir which is still an awful lot. For comparison, in all three plans developed by Shibasaki the RME value stays well below 1 with waste generated in excess of 6000 Kg. Big sacrificial reagents such as NBS and DEAD contribute to this poor performance.

Barry Trost almost got disqualified! This blog noted some time ago that Trost's commercially available lactone starting material is in fact not commercially available (perhaps if you buy it straight from his lab). Androas agrees, and for him to be able to make a sensible comparison between al plans he dug up an old 1952 plan for the lactone synthesis as a prefix to the Trost scheme. Turns out the lactone is synthesized from the same chemicals as Corey's synthesis.

Other interesting statistics from Androas' 26 page article (a 73 MB supplementary file contains a detailed description of all 16 plans) are a similarity index fmatch based on how target bonds are assembled and oxidation level profiles (a.k.a. hypsicity) for each plan. Apparently any redox reaction is bad news for atom economy and should be avoided. All Roche plan are isohypsic.

Andraos, J. (2009). Global Green Chemistry Metrics Analysis Algorithm and Spreadsheets: Evaluation of the Material Efficiency Performances of Synthesis Plans for Oseltamivir Phosphate (Tamiflu) as a Test Case Organic Process Research & Development, 13 (2), 161-185 DOI: 10.1021/op800157z