Oseltamivir synthesis latest

28 April 2009 - synthesis 17 to 19

Back in the news this week : oseltamivir (Tamiflu) in high demand as a last defence against the swine flu (aka Mexican flu). So time for an update on oseltamivir total synthesis (see previous post here).

Yamatsugu et al. (DOI) start their synthesis (not the first one from this group) with an asymmetric Diels-Alder reaction between dimethyl fumarate 1 and siloxy diene 2 (accessible from crotonaldehyde) catalyzed by BINAP clone 3 dubbed F2-FuijCAPO, and barium isopropoxide. After hydrolysis of 4 , the resulting dicarboxylic acid is reacted with DPPA to diacyl azide 5 and this step is followed by Curtius rearrangement in tert-butanol yielding boc protected 6. Acylated hydroxy malononitrile is an acyl synthon which is added in an allylic substitution with Pd2(dba)3 and dppf. The double bond in 8 is converted to an epoxide (trifluoroperacetic acid[) in 9 and K2CO3/EtOH hydrolyses both this epoxide and the acetoxydicyanomethyl group in 10. The final steps are aziridination and introduction of the pentyloxy group.


Ishikawa et al. (DOI) have come up with an amazing triple one-pot reaction. The first brew contains a organocatalytic Michael addition, an intramolecular Horner–Wardsworth–Emmons reaction and some protective action. Step two consists of tert-butyl deprotection by TFA and azide placement (oxalyl chloride / sodium azide). Step three is a Curtius rearrangement followed by acylation , zinc / ammonia reduction of the nitro group to the amine and retro Michael addition of the Stol group by potassium carbonate. The authors claim a 57% yield starting from the nitroalkene with cheap reagents and a minimum of workup.



Nie et al. have reported both a 13-step synthesis (DOI) they were not happy about and then a shorter 7-step synthesis (DOI) both starting from shikimic acid (harvested from Chinese star anise 3.6% yield). The synthetic plans are very similar both using sodium azide (use discouraged due to hazardous nature). The 7-step plan starts from the ethyl ester of shikimic acid with all hydroxyl groups mesylated in step one. First substitution by NaN3 is followed by ring-closure to the aziridine. Acylation, ring re-opening by 3-pentanol and seconds azide attack take place next, concluded by Lindlar catalyst reduction. The authors claim 45% yield based on shikimic acid.


Oshitari & Mandai produced a double-header with synthetic schemes for oseltamivir, one starting from L-Methionine (DOI) and another from D-mannitol (DOI). Too bad the journal they elected to have their work published in (Synlett) is utterly inaccessible.

Platencin update

26 April 2009 - total synthesis

You have been warned (previous post here), this is platencin total synthesis number 10 (Varseev & Maier 2009 DOI).

Starting material is 3-isobutoxycyclohex-2-en-1-one 1, formylation with isobutyl formate 2 is followed by nucleophilic substitution to allyl chloroformate 3 forming an E/Z mixture of allyl carbonate 4. A Carroll rearrangement introduces the quaternary carbon atom in 5 (step also performed as an asymmetric synthesis), an hydride reduction to alcohol 6 is followed by protective group addition to pivaloyl ester 7. Conversion to silyl enol ether 8 is followed by cyclization (oxygen, palladium acetate) to exocyclic alkene 9. Addition of Ketene silyl acetal 10 forming 11 is a Mukaiyama-Michael Addition.

The ketone 11 is converted to hydrazone 12. This compound reacts with NaCNBH3 and ZnCl2 to free radical intermediate 13 which rearranges the 3.2.1 platensimycin core to the 2.2.2 platencin core in 14. Conversion of the ester group in 14 to a ketone takes place through Weinreb amide 15 and MeLi , the intermediate 16 is a hemiacetal. The final steps are reduction (LiAlH4) to diol 17, Swern oxidation to aldehyde 18 and a ring-closing aldol condensation to the platencin core 19.

Spontaneous symmetry breaking

23 April 2009 - Chirality

In a now classic experiment in spontaneous symmetry breaking, Kondepudy, Kaufman and Singh in 1990 crystallized the chemical sodium chlorate from solution while stirring and surprisingly ended up with chiral crystals of either handedness, that is, if one experiment yielded exclusively D-crystals, the next one would give only the L-crystals. (Kondepudy et al. 1990 DOI). Apparently one crystal form takes the upper hand in the early stages of crystallization (a random process), then proceeds to grow while eating away at the less fortunate one. This phenomenon is of some relevance to the development of homochirality as one can envision chiral synthesis taking place on the surface of chiral crystals.

In the most recent contribution in this particular field, the Håkansson laboratory aims to extend the scope to regular organic synthesis (Lennartson et al. 2009 DOI) . The organozinc adduct of indene Zn(ind)2 was mixed with picoline in THF. it was then found that the Zn(ind)2(pic)2 crystals formed were again either left handed or right handed.

Crushing the crystals and reacting them with NCS in methanol yielded either enantiomer of 1-chloroindene in yields up to 95%. No bias was found: 51 reactions yielded (-)-1-chloroindene and 70 reactions yielded (+)-1-chloroindene.

Over in the inorganic chemistry department there is another recent development. Rao et al. added together nickel acetate, ammonium thiocyanate and the tridentate amino ligand tren and allowed the resulting octahedradral complex to crystallize from a water/methanol solution (DOI).

Even more surprising: repeated experiments only yield the left-handed chiral crystal form, as evidenced by circular dichroism and any attempts to produce the right-handed crystals have thus far failed. Solutions of Ni(NCS)2tren are of course racemic but CD characteristics of either enantiomer could be obtained by adding small amounts of D or L-arabinose (exploiting the Pfeiffer effect). It can only be hoped glassware cleaning was within specs.

Novel aromatic deamination

18 April 2009 - News

The David MacMillan group recently came up with a way to remove an amino group from an arene. In this way the amine can direct an electrophilic aromatic substitution in a specific way and later on be discarded, very much like a sulfonate group (deactivating rather than activating). The strategy employed is methylation of the amine, followed by a Birch reduction and a kind of vinylogous Hofmann elimination (DOI):
:
The novel procedure was demonstrated with a synthesis of Tolterodine:


as a sequence of an asymmetric Friedel-Crafts reaction using cinnamaldehyde, an pyrrolidinoanisole and a McMillan catalyst, followed by a reductive amination (diisopropylamine, sodium triacetoxyborohydride), removal of the pyrrolidinone group by methyl triflate and sodium/ammonia treatment, followed by ether deprotection (boron tribromide) to the phenol.

Molecular belt update

11 April 2009 - News

Acenes are compounds constructed as an array of linearly fused benzene rings and of some importance to the field of organic semiconductors. Synthesising them is tricky (the heptacene is currently the longest one) and forcing an acene in a cyclacene (folding a ribbon into a bracelet / belt / tube ) must be even more challenging. Cycloacenes are of potential interest due to their no doubt interesting electronic properties but also because they and related compounds represent a class of nanotube like building blocks. A cyclo(10)phenacene system (with alternating benzene units as in phenanthrene) was described in 2004, obtained by reducing the north- and south pole of fullerene (DOI).

In a recent contribution from the laboratory of Rolf Gleiter, a cycloacene is prepared in a one-pot reaction from a cyclooctadiyne and the cobaltocene CpCo(CO)2 as a trimer (DOI). In one of the isolated intermediates (a trimer prior to cyclisation), the cyclooctatetraene rings, surprisingly, are almost planar!.

Another recently described molecule that is guaranteed to bring down your molecular graphics editor is a pyrenophane (pyrene + cyclophane) that is exactly half a nanotube loop (DOI). Its synthesis features a McMurry reaction and a valence isomerization/dehydrogenation (VID) reaction using DDQ. The authors , Bodwell et al., are as confident today a full aromatic belt is within their reach as they were back in 2001 (DOI).

Redox economy

03 April 2009 - concepts

What: Redox economy, as recently reviewed/redefined by Burns, Baran & Hoffmann (DOI) as the reduction of the number of nonstrategic (those that do not set stereochemistry or are not skeleton-building) or corrective oxidation and reduction steps in synthesis. Redox reactions impose restrictions on functional groups, they lower the overall efficiency, are difficult to scale up and generate lots of byproduct . Isohypsic reactions are multistep synthesis sequences devoid of any changes in oxidation state (rare). A synthesis does not have to be isohypsic as long as the oxidation state gradually increases or decreases as the multistep synthesis progresses. A late-oxidation state change reduces the need for protective groups. Nature is doing a great job when it comes to redox economy which Burns, Baran & Hoffmann illustrate with Taxol biosynthesis taking place by 8 oxidation steps starting from taxadiene. Recently, Andraos ranked Oseltamivir synthesis on the hypsicity scale (see previous post here)
Related to : atom economy, green metrics
Invented by: James B. Hendrickson in 1971 DOI
Related terms: Redox neutral reactions for example the Tishchenko reaction or hydrogen borrowing.