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Platencin total synthesis

29 August 2008 - Total synthesis

A close cousin of Platensimycin (See here) is called platencin : a metabolite of a similar strain of microbe (discovered in a soil sample collected in Mallorca), structurally similar, first reported by Merck (Wang et al. 2007 > 20 authors! DOI Jayasuriya et al. 2007 DOI) and its first total synthesis reported by the Nicolaou troupe (2008 DOI).

Highlights in this synthesis (focusing on the tetracyclic core) are a salen ligand based asymmetric Diels-Alder reaction with a Danishefsky’s diene analoque, a gold catalysed silyl enol ether / alkyne cyclization, a Barton-McCombie deoxygenation accompanied by a radical rearrangement reaction and a Wacker oxidation.

In the space of three months Hayashida & Rawal signed on for (racemic) synthesis number 2 (2008 DOI) followed by that of Yun et al.(2008 DOI) and Tiefenbacher (2008 DOI).

The Hayashida/Rawal method also hinges around a Diels-Alder reaction (the diene is a Rawal invention) that is followed by a Grieco elimination, a DIBAL reduction, a Nicod couping reaction and a ketone deoxygenation (through a hydrazone).

Tiefenbacher also uses the Rawal diene with - cleverly - common and chiral food-additive perillaldehyde. The remainder of the reaction sequence (a days work) consists of Wittig reaction converting the aldehyde to the alkene, a metathesis reaction, a NBS bromination and a reduction (chromium chloride / lithium aluminumhydride).

Please stand by for platencin synthesis 5 through 11 to published by a publishing house near you in the near future unless of course the Merck people discover their third bacteria strain.

Platensimycin briefing

22 august 2008 - The war on bugs

The chemical platensimycin is isolated from Streptomyces platensist and was found to be effective against a whole range of nasty bacteria such as MRSA by a Merck team in 2006 in high-throughput screening program (Wang et al. DOI). Structure elucidation quickly followed (Singh et al. DOI DOI) and in a record breaking 4 months also its first synthetic racemic total synthesis by Nicolaou et al. (DOI). The compound consists of a pentacyclic lipophilic core connected through a amide group with a hydrophilic dihydroxybenzoic acid tail. This antibiotic messes with the fatty acid synthesis ability of certain bacteria enzymes.

The key steps in the racemic Nicolaou synthesis are: cycloisomerization of 1 (CpRu(MeCN)3PF6), to enone 2, Saegusa oxidation(LiHMDS,TMSCl , lead acetate) to dienone 3, TBS deprotection to aldehyde 4 (HCl), single-electron reduction (samarium(II) iodide) to alcohol 5 (poor diastereoselectivity) and electrophilic addition (TFA) to ether 6.

The current total synthesis count (including the formal synthesis procedures) stands at 11 fulfilling Nicolaou's prediction in his 2006 paper that no doubt many total syntheses will be reported following this one. Two more racemic formal procedures are presented by Zou et al. (2007 DOI) and Nicolaou et al. (2007 DOI) followed by the first enantioselective procedure again by Nicolaou (2007 DOI).

The asymmetric Nicolaou version should be a straightforward asymmetric cycloisomerization of the same starting alkyne but this approach fails miserably. The backup plan calls for introduction of a carboxylic ester group through ketone protection (TMSOTf, base) and carboxylation (CN-COOMe/BuLi) followed by restoration of the ketone (IBX)and deprotection of the alcohol (HCl). Asymmetric cycloisomerization is now possible after all (BINAP / Rh(cod)2Cl2) but getting rid of the undesired ester group takes some additional steps.

More asymmetric synthesis followed in 2007 and 2008 by Kalliappan et al. (2007 DOI), Li et al. (2007 DOI), Ghosh et al. (2007 DOI) Lalic / Corey (2007 DOI), (Kim et al. 2008 DOI).

The Kim synthesis is based on conversion of chiral diazoketone 1 with rhodium(II) acetate to tetracycle 2 in a cycloaddition with key ylide intermediate A followed by hypophosphorous acid/triethylborane mediated removal of iodine in 3 (iodine is in it to change alkene electronic footprint), Horner-Emmons reaction to 4, Rhodium(I)-catalyzed hydrosilylation and DIBAL reduction to 5 and finally acid catalysed Aldol condensation to 6.

More variations: protective group free by Tiefenbacher et al. (2007 DOI) and a chiral pool synthesis (Nicolaou et al. 2008 DOI).

In addition, the platensimycin biosynthesis has been elucidated in a so-called feeding experiment whereby the bacterium in question is fed isotope labelled nutrients (Herath et al. 2007 DOI). A possible biosynthetic precursor has also been isolated (Jayasuriya et al. 2008 DOI).

Be prepared for more synthetic frenzy for its cousin platencin.

Deoxygenation unexplained

18 August 2008 updated 20 August

What should be a straightforward exercise in beta-aminoketone synthesis by several Chinese researchers (Yong Xin et al. 2008 DOI) ends up in mayhem. This info-graphic sums it all up:

Salicylaldehyde and the trimethyl silyl ether of cyclohexanone are reacted in presence of boron trifluoride expecting a double Mukaiyama aldol addition accompanied by acetal formation and condensation. Surprisingly at the end of the road one of the alkene groups is hydrogenated or as you like one of the hydroxyl groups is deoxygenated. When the ketone ring size is reduced this happens twice but the expanded ring on the other hand gives the expected product.

According to a 2006 publication ( DOI) this research group has had to face unexpected results before.

In trying to solve this mystery the experimental details are not always helpful. In the text the reaction takes place in benzene but the general procedure prescribes dichloromethane, compound labels are mixed up, the exact excess of aldehyde is ill-defined and elemental analysis for compound C lacks a complete carbon atom. The chemical yield for B is low but details on the how&why are missing.

The authors refuse flat-out to speculate about how this reaction is supposed to take place and kindly invite us to read a forthcoming paper. Surely there must be some literature out there on the use of BF3 on deoxygenations? In fact the literature offers numerous examples of reductions by this reagent in combination with a hydride donor such as triethylsilane. One report (Smonouet et al. 1988 DOI) shows how 1-phenylethanol is converted to ethylbenzene in this way with formation of a phenethyl carbocation as a rate-determining step.

Ring-strain no doubt disfavors the elimination reaction in the smaller cycle and the only thing missing in the present reaction then is the nature of the hydride donor. Three equivalent of water are generated in the reaction so that is a start.

And surely at some point in the 200 years of chemical endeavor someone must have come up with the idea to mix cyclohexanone and salicylaldehyde just for the heck of it. Surprisingly, CAS at least throws up zero results when queried. Only in one instance (check up details in the Azerbaidzhanskii Khimicheskii, page 6, 1978 if you have a copy) a salicylaldehyde derivative is given a chance to meet up with cyclohexanone.

For the only mention of the direct cyclohexanone-salicylaldehyde adduct please consult the equally informative Zhurnal Organicheskoi Khimii (1988, page 2419).

New ruling on stability

8 August 2008 - reality check for computational chemists

In a recent essay Roald Hoffmann, Paul von Rague Schleyer and Henry F. Schaefer (HSS) invite fellow computational chemists to a reality check (DOI). They observe that too often a hypothetical molecule is declared stable (example cyclic ozone or diatomic carbon) even when it is obvious you wouldn't be able to fill a bottle with it. The authors are also annoyed with the generous use of significant figures in papers on computational chemistry to the point of being silly and they also have some serious issues with computational accuracy and precision. Fortunately they have some solutions on offer.

From now on, according to the authors, the use of stability in describing hypothetical molecules is discouraged and replaced by viable and fleeting.

A viable molecule is a molecule that meets computational criteria of persistence appropriate to ambient conditions in a typical chemical laboratory environment, namely its isolation in condensed phase, near 1 atm pressure at room temperature (perhaps in the presence of a moderately humid atmosphere), or in reasonable concentration (say 0.001m) in solution. And, with that, a half-life of a day or longer. Additional criteria stipulate that such molecule will not fragmentate or dimerize, that the molecule has well defined vibrational frequencies, a sufficiently largeHOMO/LUMO gap and that an ion has a well characterized counterion. A fleeting molecule then is one with a local minimum, with barriers, (...) preventing escape from its local basin, (...) of (...) importance in interstellar chemistry, or (...) low-temperature matrix-isolation and high-vacuum environments.

More definitions redefined: precision assesses the degree to which a particular computation approaches the exact result that should have been obtained with the specified method and basis set. Precision only means that you correctly accomplished what you claimed. In this particular expect maximum precision of around 0.6 kcal/mole. Accuracy simply means absolute theoretical accuracy and because the authors note that results are not impressive (for example for benzene accuracy is of by 6 kcal/mole with the best methods) the phrase should be used only very rarely.
With respect to significant numbers HSS rather arbitrarily recommend 1.25 and not 1.254 angstrom for distances and 40.3 and not 40.269 kcal/mole for activation energies.

The Angewandte essay is accompanied by no less than 4 referee reports (a novelty) from other chemists, three of which basically agree (Bickelhaupt, DOI), (Koch, DOI), (Reiher, DOI) and one of them definitely disagreeing. In a comment, simply called No Important Suggestions (DOI), Gernot Frenking expresses his disappointment at the intellectual level of the HSS essay feeling like a guest who was invited to a gourmet restaurant where he was only served a thin soup. According to Frenking prominent molecules relevant to interstellar space are not just fleeting but very viable, he also questions the new counterion rule reminding the reader of the existence of noncoordinating anions. Frenking also asserts that most computational chemists already behave responsibly with respect to the number of decimals with which a result is presented and that only newcomers occasionally go ballistic.

This last point about chemists behaving badly can be resolved by selecting at random some recent computational chemistry articles. This blog can only conclude it is way too easy to find offender examples. Schuquel et al. (Chemical Physics 2008 DOI) present ionization energies like 117.203292 au (clearly an offence in the new HSS regime) and interestingly when measured in eV they present values like 9.21 and 10.27 as if the precision of the method mysteriously increases beyond the value of 10. Lopez at al. (J. Phys. Org. Chem. 2008, DOI) are presenting free energies in KJ/mole with up to 4 significant figures. And finally Jia et al. (Org. Lett. 2008, DOI) present bond lengths with 4 significant figures and bond angles with 5.

Roald Hoffmann, Paul von Ragué Schleyer, Henry F. Schaefer (2008). Predicting Molecules-More Realism, Please! Angewandte Chemie International Edition, 47 (38), 7164-7167 DOI: 10.1002/anie.200801206

Most cited part I

7 August 2008 - Fun with ISI

The ISI Web of Knowledge database has a new feature: sorting articles by Most Cited. So why not give it a go. Selecting all articles with topic nanotechnology published between 2000 and 2008 (excluding all reviews, news items etc.) results in 3977 items (H-index 73).

Top of the list N.C. Seeman's DNA in a material world on how DNA provides a template on how to construct new materials (2003, 410 citations DOI). Next up Goldberger et al. exploring single-crystal gallium nitride nanotubes (2003, 408 citations DOI). More nanotubes at position 3: Chen et al. report on functionalized nanotubes for biosensor applications (2003, 325 citations DOI).

Codeine total synthesis

2 August 2008 - Total synthesis

A novel racemic codeine total synthesis was presented recently by Varin et al. (DOI). Many such efforts for codeine and closely related morphine (free phenol without methoxy group) are known, for example the codeine (-)-stereoisomer DOI or the (+)-stereoisomer DOI DOI

In a nutshell the procedure consists of a esterfication of 1 and 2 to 3, Heck reaction to 4, acetal deprotection to ketone 5 with triphenylcarbenium tetrafluoroborate, organic oxidation to dienone 6 with benzeneseleninic anhydride, cascading amidation and oxa-Michael reaction with N-methylbenzylamine to furan 7 (also involving work-up with potassium sodium tartrate) and organic reduction with lithium aluminumhydride to alcohol 8.

This compound reacts in a Eschenmoser-Claisen rearrangement (decalin , 215 °C) to amide 10, reduction with phenylsilane / titanium isopropoxide leads to aldehyde 11, a Friedel-Crafts hydroxyalkylation / dehydration reaction with p-toluenesulfonic acid gives 12, the benzyl group is replaced by a tosyl group in 13 (chloroethyl chloroformate to the free amine then tosyl chloride), allylic oxidation adds a hydroxyl group in 14 but with wrong stereochemistry necessitating an additional Dess-Martin oxidation / sodium borohydride ox/red sequence to inverted 16 and hydroamination with lithium, ammonia, t-butanol yields codeine 17.

This procedure is not scoring points with respect to enantioselectivity (it is just a racemate), with respect to having to fix incorrect stereochemistry along the way and with respect to overall chemical yield: 0.72%.