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.

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.

Total synthesis of ageladine A

Sorry for the lack of post last week but I was very busy.
In reading the ASAP of JOC, I found a very interesting paper from Weinreb (ok he has already published on this topic) describing the total synthesis of ageladine A with a 6-pi-1-aza-triene eletrocyclization for the formation of the pyridine ring as key step.




More precisely with the electrocyclization of chloromethoxyimine (synthesized in a single step from a carboxylic acid using carbontetrachloride/PPh3, Methoxyamine hydrochloride with pyridine in acetonitrile with a good yield of 87%) by heating the solution in o-xylene in 150°C to afford the chloropyridine in 84% yield. I find amazing, the first tranformation because starting from a carboxylic acid to chloromethoxyimine, it is possible to achieve different type of reactions, electrocyclization as depicted here, but also cross-coupling reeactions on the chlorine, and certainly synthesize others heterocycles.

Further substitutions, deprotection and a cross-coupling on the chloropyridine have provided the ageladine A as well as analogues for biological evaluation. Interestingly, the synthesis of the imidazole precursor has been synthesized from the tribromoimidazole by sequencial regioselective bromine lithium exchange.

Application of a 6-1-Azatriene Electrocyclization Strategy to the Total Synthesis of the Marine Sponge Metabolite Ageladine A and Biological Evaluation of Synthetic Analogues

Matthew L. Meketa, Steven M. Weinreb, Yoichi Nakao, and Nobuhiro Fusetani

JOC, 2007, ASAP

Nicotine

Today, I am a little bit lazy, so I give you one more time some interesting recent literature about hetchem, for the smokers and non-smokers don't forget to read "Recent Advances in the Synthesis of Nicotine and its Derivatives" by Comins, this article is in press in Tetrahedron and should be available soon.

Synthesis of the camptothecin core

The post of today deals with the synthesis of the camptothecin core.

This synthesis described by Fortunak in 1996, has an intramolecular Diels-Alder [4+2] cycloaddition as key step between an unactivated alkyne and a imidate generated in situ by action of Me3OBF4 on a N-arylamide.

Tetrahedron Letters, Vol. 37, No. 32, pp. 5679-5682, 1996

This synthesis has been recently improved by Yao et al. using a mixture of Ph3PO and Tf2O (2:1) instead of Me3OBF4, by this methodology a wide range of tetracyclic "camptothecin-like" molecules has been synthesized.

Organic Letters, ASAP, April 14, 2007