Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Alexander W Bird, Zoltan Maliga, Andreas Brockmeyer, Petra Janning, Anthony Hyman, Stefan Grimme, Markus Schürmann, Hans Preut, Katja Hübel, Slava Ziegler, Kamal Kumar & Herbert Waldmann
DOI: http://dx.doi.org/10.1038/NChemBio.758
I will start this write-up with a question to all readers: what is the longest cascade reaction you can think of? I mean how many separate steps occur while the compounds react and rearrange and form new bonds. [1] The longest one I thought is the Ugi-4CR with some concomitant steps e.g. condensation to form heterocycles. But all in all with a maximum of 8 reaction steps.

So have a look at this one:

Scheme 1

If you have some spare time try to figure out what happens. For all the others here is the solution the authors offer. [2]
The first step is the Michael addition of PPh3 into the triple bond of the acetylenic ester. Vinylogous aldol addition of the so formed ester enolate and subsequent Michael addition of the newly formed enolate into the unsaturated ester gave a tricyclic compound after elimination of triphenylphosphine. Then tryptamine was added followed by 1.5 eq of CSA. Tryptamine attacks the unsaturated ketone which results in elimination of the phenolate. The formed 2H-pyrane undergoes an electrocyclic ring opening which closes again to a dihydropyridine ring system.

Scheme 2


Next the dihydropyridine eliminates again the phenolate forming a pyridinium ion which is attacked again by the phenolate to give a rearranged dihydropyridine. Electrocyclic ring opening yields an imine which undergoes a Pictet-Spengler reaction with the 2-position of the indole ring. The last two steps contain another Michael addition of the tetrahydro-β-carboline nitrogen atom onto the unsaturated ketone and subsequent eliminiation of phenolate to give at last the indoloquinolizine skeleton.

Scheme 3

The yields ranged from 20 % up to 91 % in a single pot reaction and the procedure is rather simple: just mix PPh3, the aldehyde, and the acetylenic ester in hot PhMe. After about 5 minutes add the tryptamine followed by CSA and heat the mixture for another 5 to 30 minutes.

[1] For all of you admiring cascade reactions I must recommend this review by Nicolaou (for all those who did not read it yet): DOI: http://dx.doi.org/10.1002/anie.200601872
[2] The authors state that even they did not expect the last steps to happen. But some of the substances they got are very active in interfering with the mitosis of cancer cells.

Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles in Polyketide Construction

Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer
Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries,
and Premetalated Nucleophiles in Polyketide Construction

Soo Bong Han, Abbas Hassan, In Su Kim, and Michael J. Krische

DOI: http://dx.doi.org/10.1021/ja1082798

Additional information (DOI’s):

http://dx.doi.org/10.1021/ol901096d

http://dx.doi.org/10.1021/ja805722e

http://dx.doi.org/10.1039/b917243m

http://dx.doi.org/10.1021/ja802001b

This time some chemistry for all the transition metal fans out there: a very nice synthesis of (+)-Roxaticin from Krische et al. which demonstrates the outstanding potential of their stereoselective allylation chemistry. By employing the strategy developed by the Krische lab the otherwise painful synthesis of this beastie was extremely simplified. If you are interested in syntheses from other labs have a look in the supporting information of the original paper which contains an useful overview.

Or if you are equally enthusiastic about the chemistry you should have a look in the paper which I linked above under additional information.

So let’s have a brief look at our target:

Scheme 1

Obviously the molecule is perfectly suited with respect to the allylation chemistry which was employed. Before I get started with pointing out the individual steps first the syntheses of the main catalysts used:

Scheme 2

The first one was synthesized by mixing [Ir(cod)Cl]2, the BIPHEP ligand, chloro-nitro-benzoic acid and the base in the presence of allyl acetate. This in situ formed catalyst was used as such with remarkable results.

The second one was synthesized in a similar manner:

Scheme 3

As you will see in the ongoing synthesis the enantiomer of the (R)-I-Cat. was used, too.

The synthesis begins with propanediol which was converted to the bishomoallyl alcohol under standard conditions in good yield and extremely high ee and dr. Protection as the acetonide was followed by ozonolysis and reductive work-up to give the next diol. This was again converted into the bishomoallyl alcohol, protected as the TBS ether and reacted with ozone/sodium borohydride to give another diol. Allylation, conversion of the TBS ether into the acetonide and ozonolysis/reduction furnished the last diol.

Scheme 4

In only nine steps the whole “alcoholic”-part of the target was finished! Nice…

Next the C2-symmetric molecule was selectively converted on one side into the alkene by employing some Mukaiyama chemistry. First one alcohol was converted into a selenide which was oxidized and eliminated to give the terminal alkene in moderate yield. Olefin metathesis with the PMB protected homoallyl alcohol shown was followed by another allylation step of the remaining alcohol with methylallyl acetate. This time the second catalyst (S)-II was used and not less than two stereogenic centers were set up.

Scheme 5

Another olefin metathesis was employed again with Grubbs-Hoveyda-II but this time with acrolein as the chain extension. Protection of the free alcohol as the TES ether and oxidative PMB removal produced again a homoallyl alcohol. HWE-reaction of the terminal aldehyde and saponification of the ester then furnished protected (+)-Roxaticin in its open form.

Scheme 6

Yamaguchi ring macrolactonization and global deprotection with DOWEX-50 finished the synthesis in only 20 steps in the longest linear sequence.

Scheme 7

For all those who are interested in the mechanism and have to time to look in the reference, here is the mechanism of this cool allylation step:

The in situ formed catalyst first oxidizes the alcohol to the aldehyde and forms a hydrido-iridium-species. It should be noted that the reaction can also be done with the aldehyde oxidation level but in this case they were too unstable to be used.

Next fresh allyl acetate reacts with the reduced form of the catalyst to give again the allyl coordinated iridium which in turn inserts itself into the double bond an in situ formed aldehyde. By reacting with another molecule of alcohol the homoallyl alcohol was set free and the reaction cycle goes on. For clearance I skipped some intermediates but this should be sufficient to get a brief overview.

Scheme 8

I really like this sort of chemistry. Seems not applicable for multigram synthesis but for quick access to a lot of analogues it is the perfect method I think.

Comments?

Total Synthesis of (+)-Clavolonine, (-)-Deacetylfawcettiine and (+)-Acetylfawcettiine

Total Synthesis of (+)-Clavolonine, (-)-Deacetylfawcettiine and (+)-Acetylfawcettiine

Kai M. Laemmerhold and Bernhard Breit

DOI: http://dx.doi.org/10.1002/anie.200907248

It took some time but now it’s finished… I was very busy with studying, practicing and visiting the “Frontiers in Medicinal Chemistry”-symposium in Münster (Germany) the past weeks. Nice meeting with some cool posters and as the main act Prof. Fürstner himself. Really awesome stuff…

Ok, back to some chemistry: I found this paper on my desk almost a month after I printed it out during a period with only sporadically published total syntheses. It features a nice methodology and obviously that’s the one of the reasons why this work was done. Nevertheless the molecules we’re dealing with can easily be accomplished by making use of this (new) concept of synthesis the authors demonstrate here:

Overview

Syntheses of all 3 are rare and if published all except for one are racemic so an enantioselective approach might be useful for further biological evaluation.

Retro

The whole synthesis was built around this DPPB directing group which guides the rhodium catalyst and later the Lewis acid (BF3) during the synthesis. If you’re interested in this methodology in more detail you should have a look in this. Other steps include a neat Mannich- and aza-Wittig reaction. Furthermore an unusual addition of a cuprate on an alkyne

Scheme 1

The synthesis starts right off with a simple alcohol which was oxidized and elongated using Swern- and Wittig-chemistry. Saponification, acid chloride formation and alkynone formation was followed by CBS reduction of the ketone moiety. Next the TMS was cleaved with TBAF and the propargylic alcohol transformed into an allylic one by addition of a Normant cuprate (Cuprate addition of propargylic alcohols).

Scheme 2


Esterification with DPPBA was followed by the first of two hydroformylation reactions in this synthesis with very good regioselectively and yield. A stereoselective Prins-reaction then closes the first ring (or should it be named oxa-Alder-ene?). The alcohol was protected as the TIPS ether and the second alkene hydroformylated again with high yield and stereoselectivity giving this odd looking cyclohexane with 5 stereocenters already in place.

Scheme 3

Grignard reaction and protection of the resulting alcohol as the TIPS ether was followed by reductive cleavage of the DPPB group and acetylation of the free alcohol. Azide formation under Finkelstein conditions, global TIPS deprotection and DMP oxidation yields a cyclohexanone intermediate ready for some ring closing chemistry.

Scheme 4

The second ring was closed employing an aza-Wittig reaction resulting in an imine which was directly used to close the third ring by means of a Mannich reaction. The enol ether was opened with HBr in AcOH which results in cyclization and formation of (+)-clavolonine.

Nice stuff… This hydroformylation looks very promising to me especially in association with this Prins reaction.

Any comments?

Stereoselective Phosphine-Catalyzed Synthesis of Highly Functionalized Diquinanes

Stereoselective Phosphine-Catalyzed Synthesis of HighlyFunctionalized Diquinanes

Jonathan E. Wilson, Jianwei Sun, and Gregory C. Fu

DOI: http://dx.doi.org/10.1002/anie.200905125

While reviewing a nice paper from Overman I found this sweet one from Greg Fu and decided to present this to you first.

What we got here is a subsequent investigation of a procedure already published by Tomita et al. featuring a novel Baylis-Hillmann-like cyclization cascade:

The blue compounds represent the paper from Tomita et al., the red ones the paper featured in this review.

The reaction sequence is induced by the addition of about 20 mol% of tributylphopshine in a DCM/ethyl acetate mixture at room temperature to the starting material.

First a Michael addition of the phosphine to the alkyne yields an allenyl enolate which rapidly tautomerizes to an α-β-unsatured enolate. Next a Michael addition to the unsatured ester gives an ester enolate which reacts with the vinyl phosphine cation to from an ylide. This in turn yields after some tautomerization and catalyst regeneration the product:

The diastereoselectivity can easily be seen from the transition state:

Having established the right reaction conditions the group prepared some derivatives with the yields varying from 54% up to 89% respectively. Also the first formed 5 membered ring could be expanded to a 6 membered one without significant loss in yield.

And some studies towards further reactions of the produced diquinanes were employed featuring a Grignard reaction, Luche-reduction and Pd catalysed hydrogenation all in excellent diastereoselectivity:

Attempts to develop enantioselective reaction conditions by using a chiral phosphine gave very promising results:

On balance a nice reaction with some potential in natural product synthesis. What do you think?

A Phosphine-Mediated Conversion of Azides into Diazo-Compounds

A Phosphine-Mediated Conversion of Azides into Diazo-Compounds

Eddie L. Myers and Ronald T. Raines

DOI: http://dx.doi.org/10.1002/anie.200804689

While searching for some new interesting stuff I found this one again in the Angewandte (what a great Journal, isn’t it?). I thought a bit about the conversion of azides by myself and found as the most useful application the Staudinger reaction and the catalytic hydrogenation both to yield amines.

But this publication deals with another sort of application. They found that on treatment of azides with a phosphinoester the azide could be high yielding converted into a diazo-compound. The conversion of an azide to a diazo-compund is not new at all but gives almost modest yields and is limited to electron deficient arenes (doi:10.1016/j.tet.2005.09.145).

Other ways of yielding diazo-compunds were summarized below (this scheme is also found in the publication):

general

The main step of this specific reaction looks like this:

overview

The “normal” way of an azide-phosphine reaction goes through a so called Staudinger-ligation. Herein the azide decomposes through an azido-phosphetane (similar to the oxaphosphetane in a Wittig-reaction) into nitrogen and an amino-compound.

But if you combine your phosphine with an “azide trap” you can overcome the decomposition and yield a diazo-compund.

And here it is:

key-steps

The phosphine attacks as usual the electron deficient end of the azide which in turn cyclises to give an acyl-triazeniumphosphonium salt. This intermediate is then hydrolysed to give an acyl triazene which decomposes under warming and after proton exchange give the α-diazocarbonyl-compound.

They explored the scope of this method onto diverse starting azido-compounds, all giving high yields of the product:


examples

I think it’s an interesting method and a cool application of an old reaction combined with good knowledge of the reaction mechanism.

Feel free to comment and let me know when some of you used this chemistry. Maybe I can try it some time by myself…