Neooxazolomycin (Part1)

Onyango, Tsurumoto, Imai, Takahashi, Ishihara, Hatakeyama. ACIEE, 2007, Early View, DOI: 10.1002/anie.200702229

Neooxazolomycin was isolated by Uemura in 1985, together with the oxazolomycin, this oxazole polyene lactam-lactone antibiotics was synthesized first by Kende in 1990.

But I find interesting the way to achieve the synthesis of the furo-pyrrole moiety (lactam-lactone) by Hatakeyama. This synthesis, I present you, starts from the reaction of heptynol (see below) and tetramethyldisilazane ((HMe2Si)2NH) provides hydromethylsilylether (not shown) which upon treatment with Pt(dvds) as catalyst in THF gives the cyclic siloxane. After iodination with I2 in presence of CsF in a DMF/MeOH mixture, the iodoalkenol is obtained in 82% (3 steps). The synthesis continues with the oxidation of the alcohol under Jones conditions, and the carboxylic acid is condensed with 2-(methylamino)malonate through the acid chloride to provide the amide in 62% Yield (3 steps). The cyclization of the alkenyl amide with the Pd(OAc)2/PPh3 couple, K2CO3 and nBu4NBr in solution in DMF results in the formation of the alkylidene-pyrrolidinone in 84% yield. The crucial step is undoubtedly the stereoselective dihydroxylation using OsO4/NMO with a concomitant lactonization to furnish lactam-lactone moiety in 88% yield.

A very interersting paper with a lot of different chemistry: Reformatsky, Stille, Nozaki-Hiyama-Kishi, Tamao hydrosilylation, Dihydroxylation.

8-hydroxyquinoline vs 4,7-dimethoxy-1,10-phenantroline

I always read paper from Buchwald, not because it is interesting, but it can be useful, and in particular the last JOC dealing with N-arylation of imidazoles and benzimidazoles. I jumped directly to the support. info. to see the synthesis of the phenantroline ligand.

The author indicates that the ligand has been synthesized according to a combination of procedures, but the most relevant is the following one: Tetrahedron 2002, 58, 9095.

The first step consists in the synthesis of the methoxyalkylidene derivative of meldrum's acid with trimethylorthoformate, and a subsequent double Michael addition of phenylene diamine to perform the disubstituted aminobenzene in 77% yield. After, a thermal decarboxylation/cyclization in diphenylether at 250°C, the 4,7-dihydroxyphenantroline is isolated in 86%. The end of the reaction is quite classical, a chlorination in refluxing POCl3 followed by a nucleophilic substitution with NaOMe in 74% over 2 steps.

Nice way to synthesize phenantrolines...

Nevertheless, if you read quickly this publication (abstract and conclusion), it seems this phenantroline is the best ligand for the N-arylation of imidazoles and benzimidazoles. According to me, it is not. Of course this ligand is excellent. But my first choice will be 8-hydroxyquinoline. Because, first, the regioselectivity concerning the 4-methylimidazole is better (63:1), otherwise in almost all the cases the yields are quite the same, and finally (the best reason) it is cheaper....

Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles

Ryan A. Altman, Erica D. Koval, and Stephen L. Buchwald

J. Org. Chem.; 2007

Lot of Work and Colorectal cancer.....

Oh My god!!!! I am just opening my RSS reader, it indicates 170 new articles ( and don't have Elsevier RSS feed), so I think I will work this week-end....after the beach.....
And a very small post for my friend Pierre who indicates me a very potent molecule for the treatment of colorectal cancer....the vatalanib a tyrosine kinase inhibitor and should be on the market in 2008...(Sorry today no chemistry).

3-MCR of Barbiturate

My boss give me a paper from Italian guys about my future research project dealing with the multi-component synthesis of barbiturates, using unsymetrical carbodiimide (N-aryl, N'-alkyl carbodiimide), malonic acid ester and an alkyl halides.

Indeed, it is a sequential multicomponent reaction, which is performed in a sealed tube. First, carbodiimide (1.1equiv.) and malonic acid ester (1equiv.) are mixed together at RT overnight in acetonitrile (0.1M), and then K2CO3 (2.1equiv.) and alkyl halide (4equiv.) were added and heated at 120°C for 30min. I think I will do this step in the microwave oven....for 5min.....

The yields obtained with this type of reaction are between 52 and 90%, which is good, but there is still drawbacks first of all the R1 must be introduced before the MCR, second, depending on the substituents needed the carbodiimides have also to be synthesized before, and third we have a racemic mixture....

Org. Lett.; (Letter); 2007; 9(5); 841-844. DOI: 10.1021/ol063074+

Neurogenesis in Skeletal Muscle

This week in JACS, Korean guys have published a very interesting paper concerning the induce neurogenesis of human skeletal muscle cells.

Upon Neurodazine (Nz) treatment of C2C12 cells (skeletal muscle cells) develop a neuronal phenotype, they have shown also using a mouse 20K DNA chips that Nz upregulated in particular gene which is involved in inducing neuronal differentiation.

From a chemical point a view, these guys have synthesized an imidazole library with different substituents in 1,2, 4 and 5 on solid support (Wang resin), with amino-conjuguated diethylene glycol, more than 300 imidazoles have been obtained with a purity >70%. Three different polymer supported platforms have been realized, you will see below only one example using a benzylamine derivative. The imidazole ring has been synthesized with the classical multicomponent reaction with an aldehyde (R1CHO) , an 1,2-dicarbonyl compound (R2COCOR3) , and with ammonium acetate.



R1, R2, and R3 are mainly aromatic compounds
To see the other platforms, chemistry and biological tests see Supporting info.

Synthetic Small Molecules that Induce Neurogenesis in Skeletal Muscle
Darren R. Williams, Myung-Ryul Lee, Young-Ah Song, Sung-Kyun Ko, Gun-Hee Kim, and Injae Shin
JACS, 2007, DOI: http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja072817z

Total synthesis of Iromycins

Today a small post concerning the synthesis of pyridone starting from pyrone, which is not only a valuable tool in Diels-Alder reaction but also for the preparation of "pyridine" ring.

Iromycins are microbial metabolites which exibit an interesting biological activity as NO synthase inhibitors, their structures are fully substituted pyridones.
Recently, von Zezschwitz et al. from Gottingen in Germany, described the synthesis of Iromycin A and different analogues via cross-coupling reaction.



This synthesis of the nucelus starts with the construction of the pyrone ring by successive condensation reactions followed by cyclization. The starting material, the ethyl 2-methyl-3-oxo-butanoate 1 is lithiated by LDA at 0°C, and alkylated with propyl iodide to provide 2 in 56% yield, a second metalation also with LDA give the acetylated intermediates 3 using N-acetylimidazole as acetylating agent. The subsequent lactonization is performed on the crude employing DBU to furnish the desired 2-pyrone 4.


The pyrone in hand, the preparation of pyrone 4 has been realized with aqueous ammoniac in dioxane at 120°C in a sealed tube, through a 1,6-michael addition-ring opening-ring closure procedure in 75%.


Interestingly, the same pyridone can be obtained by a stepwise way, with the same type of reaction in presence of hydrazine, the intermediate hydrazone 5 is hydrolyzed with potassium hydrogenolsulfate to supply the N-aminopyridone 6. The diazotation of 6 in acetic acid lead to the 2-pyrone in 88% (on 2 steps).



Of course, some guys will tell me, this type of reactions are well-known, since "century".
But I like this type chemistry, this is not the usual clockwise metalation of pyridine or synthesis of pyridine by DA reaction.....

Iromycins: A New Family of Pyridone Metabolites from Streptomyces sp. II. Convergent Total Synthesis, Streptomyces sp. II. Convergent Total Synthesis
Heydar Shojaei, Zhen Li-Bo¨hmer, and Paultheo von Zezschwitz, JOC, 2007, 72, 5091.

Synthesis of 2-methyltryptamine

As some people probably noticed, I like OPRD (Organic Process Research & Development), of course chemically speaking nothing weird, only classic chemistry but scalable synthesis and no COLUMN, for me the dream.
And sometimes we can find very interesting stuff, as this synthesis of the 2-methyltryptamine by the Grandberg methodology, which is indeed a modified Fisher indole synthesis.
This chemistry starts with the formation of the hydrazone between the phenylhydrazine and the 5-chloropentan-2-one, after cyclization and isomerization from iminium to enamine form, the rearrangment takes place to afford the tricyclic intermediates, which after loss of a proton provides the 2-methyltryptamine with 42% in almost 20 Kg scale!!!!! in A 800L reactor!!!!!!!!!!





Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine
Joel Slade, David Parker, Michael Girgis, Raeann Wu, Scott Joseph, and Oljan Repi
OPRD, 2007

Synthesis of 1-chloro-3-aminopyrazolylisoquinoline

In doing research on the latest patents on WIPO (28.06.2007), I found a patent from Hoffmann-La Roche describing the synthesis of different isoquinoline aminopyrazoles, this type of molecules are protein kinase inhibitors (Aurora A)(I don't find it on Kinasepro's blog, but maybe I am wrong, otherwise nobody's perfect...).

I present here, only the synthesis of the main nucleus.

Interestingly, this synthesis starts with 1-indanone, which upon the treatment of butylnitrite, furnishes the 2-oxime derivative in 2 hours and in 65% yield (19.5g scale). Then the 2-cyanomethylbenzoic acid is obtained with a Beckmann rearrangement of the oxime previously prepared using the para-toluenesulfonylchloride (Yield = 74%). The reaction of the 2-cyanomethylbenzoic acid and 3-amino-5-pyrazole by a microwave-assisted cyclization in acetic acid in sealed vessel provides the isoquinolone in 75% yield (2g scale). Finally, the chlorination is performed using POCl3 to deliver the 1-chloro-3-aminopyrazolylisoquinoline in 61% yield.

Of course the synthesis continues with either O or S nucleophilic substitution on the chlorine atom or by Suzuki cross-coupling, furthermore different substituents can be introduced on either the pyrazole ring or the phenyl ring of the isoquinoline.

WO/2007/071348

Synthesis of 7-Prenylindole

I have seen some days ago this publication from M. Pirrung concerning the synthesis of 7-Prenylindole starting from indoline. This molecule is key ring in many natural products. As depicted below, the synthesis starts with copper catalyzed N-alkylation of indoline with 2-chloro- 2-methylbut-3-yne in THF in 91% yield on 10 mmol scale. After the reduction of the CC triple bound in alkene, the dimethylallylindoline obtained is submitted to a micro-wave assisted aza-claisen rearrangement in 90% yield (this step has been performed in a monomode micro-wave oven in a sealed tube at 150°C). Finally, the indoline has been oxidized into indole with MnO2 in DCM in 88% Yield.



I like this synthesis first, of course because this is indole ring, but also because the author uses one of my favorite reaction, the aza-claisen rearrangement, and my favorite tool for organic synthesis, a micro-wave oven.

Practical Synthesis of 7-Prenylindole
Xin Xiong and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jo070734v

For the application of the 7-Prenylindole from the same author see:

Glyceraldehyde 3-Phosphate Dehydrogenase Is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1
Hyunsoo Kim, Liu Deng, Xin Xiong, William D. Hunter, Melissa C. Long, and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm070437i