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FLP recap

26 August 2011 - Frustrated Lewis Pairs

FLP recap  This is an instant frustrated Lewis pair update: for earlier episodes see here, here, here, here, here, here and here

Grimme, Warren & Erker have added nitric oxide to the list of substrates for the Mes2PCH2CH2B(C6F5)2 system (Cardenas et al. 2011 DOI). The new compound is similar to TEMPO and contrary to it or regular NO itself it can abstract protons for example from cyclohexadiene to form the N-alcohol and benzene!. This effect is attributed to reduced electron density at the nitrogen atom.

The Grimme/Erker team also brings you the adduct of said P/B system with diphenylynone (Xu et al. 2011 DOI), the first reaction product a cyclic allene and then after heating it up a substituted enone. With the introduction of hydrogen the P/B system is capable of catalytic (metal free!) ynone hydrogenation.

Meanwhile the Stephan team have demonstrated imine hydrogenation using (catalytic) B(C6F5)3 and diisopropylamine as hydrogen source (Farrell et al. 2011 DOI).

Also in the recent literature: more substrates not save from the FLP treatment: dimethylpentafulvene (DOI), more FLP designs, for example a diborane ( DOI) and a zirconocene phosphinoaryloxide (DOI) and much mechanistic speculation: (DOI / DOI / DOI).

Methanol exonomy latest

18 August 2011 - catalysis

methyl formate hydrogenation Milstein 2011  The methanol economy is catching on (see earlier blogs here and here) and David Milsteins group at the Weizmann Institute of Science recently opened up a new avenue for research. The topic: the catalytic hydrogenation of methyl formate to methanol using hydrogen and a ruthenium catalyst re-engineered from Ru(bipy)3. More precise this reaction did not require solvent , took place at 80°C / 10 bar with 0.01% catalyst loading with complete conversion at 980 TON.

A catalytic cycle was constructed with many hints from the Milstein paper with two ingoing equivalents of hydrogen and two outgoing equivalents of methanol for each catalyst site. Note how the bipyridine group donates a proton by temporary dearomatization. The second methanol molecule popping out appears to carry hydrogen atoms from 4 different parents. Blame this blog not Milstein.

And by the way, what has methyl formate to do with carbon dioxide? The reaction of carbon dioxide and hydrogen and methanol to metyl formate is a known process. In fact the industrial production method for methyl formate is a H2/CO reaction. A tandem sequence involving carbon dioxide , hydrogen and methanol to form more methanol has suddenly become less exotic.

Amino acid inversion trick

11 August 2011 - Biochem

amino acid inversion Easton 2011  Ho, Coote and Easton treat us to an amino acid inversion in a recent JORG article (DOI). The authors have been careful to hide the relevance of the research presented but this blog as a rule takes a leisurely approach towards academic research. Less admirable, the authors also hide some key experimental details.

The challenge: how to convert natural N-methylated alanine into the opposite enantiomer? The solution: a chiral auxiliary and subtle proton acidity manipulation.

Step 1 consisted of reaction of the alanine with unnatural (R) alanine to the (R,S) cyclic dipeptide (a deketopiperazide) followed by acylation. The nature of the substituents on both reaction partners was found to have a great impact on the cis-trans ratio. For methyl groups this ratio is 7 and computational work confirms this originates from unfavorable keto and N-alkyl 1,2 interactions in the trans isomers. When the substituents get bigger 1,4-steric effects take the upper hand and the trans isomer dominates.

Step 2 was epimerization with deuterated acetone and DBU through the enolate. This method will only work if the so-called distal proton is much more acidic than the proximate proton on the other side and this is exactly why the piperazine was acylated in the first place. This acyl group makes the neighboring proton less acidic by a 10 computed orders of magnitude via a mix of resonance and inductive effect. After deuteration the cis isomer was isolated by column chromatography and the inverted amino acid liberated by acid hydrolysis. Note that regular alanine is not acidic enough to exchange protons with acetone and even then the reaction product would be a racemate only.

It is a pity that experimental data appear to be missing. It the least it makes reading and understanding the article a more difficult task it already is. This dipeptide synthesis was performed by a company based in Shanghai that is in the business of making and selling peptides. They are the first to profit from this type of research. Judging from the acknowledgments the research is sponsered by only the Australian taxpayer. The Journal of Organic Chemistry does not mandate author disclosures.

Kibdelone C part II

05 August 2011 - Total synth.

Cibdelone C Butler II  Meanwhile at the University of Texas, Butler et al. came up with their own scheme for Kibdelone C (See earlier post here). Here are the highlights.

The junction of aldehyde 1 and vinyl iodide 2 can be observed sort of in the Porco effort but the similarities end there. Methyl lithium was required to deprotonate the alcohol group and t-BuLi formed the vinyl lithium intermediate. The reaction type is a nucleophilic addition. Dess-Martin oxidation with acidic acetone and t-BuOH removed three protective groups (MOM = methoxymethyl ether), TBS = tert-butyldimethylsilyl) in one go, closed the ring to tetrahydroxanthone 4 with protection of two hydroxyl groups as an acetonide.

Bromide 5 was functionalized with an alkyne group in one Sonogashira coupling (Pd(PhCN)2)Cl2, (tBu)3P.HBF4, CuI, diisopropylamine) with TIPS protected acetylene (see: trimethylsilylacetylene) followed by TBAF deprotection and then in another Sonogashira 6 was coupled with 4 to form bridged 7 (allylpalladium chloride dimer,(tBu)3P, DABCO ) after hydrogenation (H2, Pd).

The second ring-closing step was accomplished by introducing iodine using iodine/oxygen and copper chloride. Here the Butler group explains that in a happy case of serendipitous discovery they found out this reaction required copper catalysis because one phenol batch contained copper residue from a botched coupling reaction. The ring-closing step itself (BOC protection and C-H arylation) required palladium(II) acetate, tricyclohexylphosphine. and pivalic acid in dimethylacetamide.

Yes that is again a lot of palladium and if you agree with this blog that synthetic organic chemistry is converging towards the sole use of palladium, halogens and anything with carbon and hydrogen, this sequence will only strengthen your case.