Hydrogen autotransfer

28 November 2008 - Strategies

What: Hydrogen autotransfer. An organic reaction activated by a preliminary hydrogen abstraction step and followed by a hydrogen addition step (Review DOI). First successful implementation by Edwards at al. in 2002 (DOI) in a so-called indirect Wittig reaction


and by Taguchi et al. (DOI) in 2004, allowing the direct displacement reaction of an electrophilic alcohol by a nucleophilic carbon acid for example in the reaction of 2-octanone with butanol in presence of sodium hydroxide and a iridium catalyst. Both reactions require catalytic amount of base and metal.

The alternative for this particular reaction would be tosylation (= activation) of the alcohol and use of stoichiometric base.
Also known as: hydrogen borrowing

Extension of: transfer hydrogenation (hydrogen donor is a reagent, not in-situ generated from substrate). The reaction is also a type of domino reaction.
Scope: The hydrogen autotransfer methodology has been applied in Knoevenagel reactions for example (Pridmore et al. 2008 DOI):

The Saucy-Marbet reaction

26 November 2008 - named reactions

What: The Saucy-Marbet rearrangement

Who: G. Saucy & R. Marbet (Hoffmann-La Roche) 1967 (DOI)
Why: formation of a beta keto allene by reaction of a propargyl alcohol with an alkenyl ether by heat or acid catalysis.
Mechanism: the basic reaction mechanism is a variation of the Claisen rearrangement not with an alkene but with an alkyne.
Also known as: propargyl Claisen rearrangement. Actually preceded by earlier work by Black & Landor in 1965 (DOI)
Industrial applications: synthesis of beta - ionone starting from Dehydrolinalool and ethyl acetoacetate (Link)
Scope: a 2002 patent (Link) describes synthesis of a geranyl acetone.

The reaction can be catalyzed by gold (DOI):

An example of a stereospecific reaction is provided by Hsung in 2008 (DOI):

Double metallocenes

22 November 2008 - Basics

Double metallocenes are a class of organometallic compounds in which the cyclopentadienyl ligand in a Cp2M metallocene is replaced by a pentalenyl ligand (review DOI). They are of some importance as catalysts in olefin polymerization.

The first such compound was prepared by Jonas et al in 1997 (DOI). Reaction of titanocene dichloride with the dilithium salt of pentalene forms Ti(eta8-C8H6)(Cp) with titanium simultaneously coordinating to 8 positions on the pentalene frame and 5 on the Cp frame. The related Ti(Pn)(Cp)Cl is obtained by further reaction with dichloromethane as an 18 VE compound. Interestingly, although the pentalenyl ligands are aromatic, they are not planar but have a fold angle in the range of 30 - 40°.

The bimetallic bis-pentalene sandwich compound Mo2(C8H4(1,4-Si(iPr)3)2)2 was prepared by Cloke et al. in 1998 (DOI) by reaction of K2(C8H4(1,4-Si(iPr)3)2) and molybdenum acetate. In this compound the fold angle has vanished and the two molybdenum centers form a double bond.

When the bimetallic orientation is trans rather than cis it is in principle possible to create (M(Pn))n polymers which are of potential interest as molecular wires. One of the first efforts to be recorded , a (*Cp)2PnFe2 trimer, is one by Manriquez et al. in 1988 (DOI).

Most recently the double metallocene family was extended by O'Hare et al. with a range of *Pn2M2 compounds with M vanadium through nickel and *Pn the pentalene version of pentamethylcyclopentadiene (DOI). Intriguingly the iron sandwich resists synthesis with the pentalene ligands instead opting for dimerization.

CSI in trouble

18 November 2008 - News

Members of any CSI team never venture anywhere without their Kastle-Meyer solution to probe for traces of blood. Although generally considered a reliable test (sensitivity 1 in 100,000), researchers have found a way to tamper with the evidence (DOI). It turns out that cleaning up any crime scene (by villains) with any modern detergent containing so-called active oxygen makes any blood probing reagent useless.

A colorless Kastle-Meyer solution contains the reduced form of phenolphthalein called phenolphthalin which reacts with hydrogen peroxide back to pink phenolphthalein. Significantly this reaction is catalysed by hemoglobin present in blood making it a chemical test for blood itself.

The researches have found that cleaning a blood sample containing an active oxygen component, more specifically sodium perchlorate results in negatives with this test. To make matters worse, two other methods, one using luminol and another using an Immunoassay technique called Hexagon OBTI (Link) also fail miserably. And the really interesting part is that the researchers do not have a clue why this is.

So until they find out why and even better find a way to fix it forensically speaking, picture yourself this scene from CSI: Miami where finally the show's star David Caruso bites the dust. As you may know, every episode, David has his villain in sight within 5 minutes not based on any evidence but solely on the level of the villain's arrogance. The next 45 minutes of the show is spent on the tedium bore of collecting that evidence.
David: I dont like your face , I know you committed the murder, and you did it over there !
Villan: you will never find the evidence !
David: Oh yeah, try cleaning up the mess all you like but have you never heard of Kastle & Meyer !
Villan: Oh yeah, haven't you yet read Naturwissenschaften volume 95 page 1432 !
David: ehhhhh......

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Ana Castelló, Francesc Francès, Dolores Corella, Fernando Verdú (2008). Active oxygen doctors the evidence Naturwissenschaften DOI: 10.1007/s00114-008-0466-9

Oseltamivir total synthesis part 8-12

11 November 2008 - Organic chemistry

The total count in Oseltamivir total synthesis (Tamiflu) as of November 2008 stands at 12 (see earlier post here). The Shibasaki group (also responsible for synthesis IV) rearrange in a critical curtius rearrangement a di-azide (DOI) and the Kann laboratory uses an iron carbonyl compound as starting material (Bromfield et al.DOI). The Fang lab utilizes D-xylose in one publication (Shie et al. DOI) and a cis-dihydrodiol in another (Shie et al. DOI). And finally (at least for now) Matveenko, Willis & Banwell report synthesis number 12 (DOI)

The second Fang method in a nutshell: dihydroxyl compound 2 is commercially available from enantioselective microbial oxidation of bromobenzene with for instance toluene dioxygenase. In step 1 this diol is protected as the acetal and reacts in a tin bromide catalyzed bromoacetamidation to dibromide 3. The aziridine ring in 4 forms with base LHMDS and is opened again by nucleophilic attack with 3-pentanol to form diol 5 after deprotection.

Alpha-acetoxyisobutyryl bromide adds a bromine and a acetyl group to dibromide 6 in one step and the bromine group is again removed by super hydride in 7. The alcohol group is converted to an amide group in 8 in a modified Mitsunobu reaction and the final step (after replacing bromine by iodine) is a palladium catalyzed coupling reaction with carbon monoxide captured by ethanol.

The report by Matveenko et al. concerns a formal synthesis and is a modification of the Fang method, more specifically a different route to Fang intermediate 5 starting from the same chiral diol. Although its title promises a chemoenzymatic Tamiflu synthesis you will be disappointed to see no actual enzymes at work. The authors mean that the starting dihydroxyl compound can be obtained commercially by biocatalysis but that is of course not a merit of Matveenko's work.

In other aspects the result is disappointing as well. Objective number one is selective protection of the meta alcohol group in intermediate 4 for which acetal 3 is formed in a enantioselective reaction using camphor sulfonic acid and the dimethoxy acetal of Anisaldehyde. It remains unclear however how the newly introduced chiral center can bring about selectivity in the next acetal cleavage (DIBAL) and no surprise, ultimately, selectivity is poor. Disaster strikes again when in the next step formation of carbamate 6 with carbonyldiimidazole and hydroxylamine is accompanied with oxidation to bromoaryl 5.

After protecting the alcohol group, construction of the 3-pentanol unit in 8 is catalysed by copper hexafluorophosphate, believed to take place through tricyclic aziridine 7.

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Jiun Jie Shie, Jim Min Fang, Chi Huey Wong (2008). A Concise and Flexible Synthesis of the Potent Anti-Influenza Agents Tamiflu and Tamiphosphor Angewandte Chemie International Edition, 47 (31), 5788-5791 DOI: 10.1002/anie.200801959


Also see: most recent post on Oseltamivir synthesis