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.

A General Strategy for the Stereocontrolled Preparation of Diverse 8- and 9-Membered Laurencia-Type Bromoethers

Scott A. Snyder, Daniel S. Treitler, Alexandria P. Brucks, and Wesley Sattler

DOI: http://dx.doi.org/10.1021/ja2069449

DOi: http://dx.doi.org/10.1002/anie.200903834

This time some cool methodology from the Snyder group involving the use of a recently reported new reagent: BDSB. It is formed by the reaction of diethylsulfide, SbCl₅ and bromine:

Scheme 1

With this reagent a lot of bromonium ion induced cyclization reactions are possible which do not work well with the common reagents e.g. NBS or TBCO. In a communication from 2009 the group used this reagent quite efficiently to produce fused cyclohexane systems.

Scheme 2

All these reactions were conducted with BDSB in nitromethane. No or very low yields of the products were obtained using common reagents. Encouraged by these results the group conducted some experiments to form larger ring systems in a biomimetic manner:

Scheme 3

As can be seen from scheme 3 some quite interesting motifs can be produced in a highly selective and efficient way. Recently the group reported an extension of this methodology which prompted me to write this little review.

They used BDSB to convert tetrahydropyrans into oxocane ring systems through an interesting biomimetic rearrangement reaction.

Scheme 4

By exposing the substituted THP-rings to BDSB a bromonium ion induced cyclization occurred which opens the five membered ring to an eight membered one. And all this in a stereoselective manner with high ee’s. Following this approach some members of the lauroxocane group of natural products were produced.

Scheme 5

Depending on the tetrahydropyran used a lot of diastereomers can easily be synthesized. In a representative example the group started from pentenol and methoxypropene to produce via a Claisen rearrangement 5-octenone. The second fragment derived from hexanal which was stereoselectively chlorinated using NCS and L-proline. An aldol reaction combined both halves and the resulting aldol product was exposed to anti selective reduction conditions. Cyclization to the tetrahydropyran was accomplished under high pressure in methanol.

Scheme 6

I think this is a very useful methodology to form medium sized rings otherwise not so easy to access. Because of the ease of preparing BDSB it will hopefully find more applications in literature and total synthesis.

THX to Bobby for the helpful corrections.

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and Brian M. Stoltz

DOI: http://dx.doi.org/10.1002/anie.201007814

Recently a very cool methodology was published developed by the Stoltz group for the synthesis of acylcyclopentenes . As given in the paper a lot of natural products are related to this motif so there is a need for an easy and rapid access.

Scheme 1

As can be seen from the structures given these natural products mainly derive from the MVP-pathway. Nevertheless this method should also prove useful in the synthesis of alkaloids or polyketides.

Before I present to you the main part of the paper have a brief look at the synthesis of the main precursor:

Scheme 2

Cyclopentanone 1 was enolized, protected as the TMS ether, and reacted with in situ generated dichloroketene to give cyclobutanone 3. Reductive dechlorination and Grob fragmentation/ether formation produced ketone 5 in good yield on a multigram scale.

This was then decorated with different organic residues in two steps to give ketoester 6 in moderate to good yield. Pd-catalyzed enantioselective decarboxylation/allylation was followed by reduction of the keto group to give 8. Depending on the residues three different reducing conditions are described. At last the critical contraction reaction from 8 to 9 was carried out with LiOH in THF in the presence of TFE in excellent yield.

Scheme 3

A lot of residues are described; I only added just a few to give a brief insight. For detailed information have a look in the more than 250 (!) pages thick supporting information.

The mechanism of the contraction step might look like this: the green proton leaves first and kicks out the red hydroxy group to produce directly the cyclobutanone-intermediate. This opens up with extrusion of the acetyl group to give after reprotonation and tautomerization the expected product.

If you think about the second possibility of first removing the blue proton followed by a Michael-type self-addition of the enolate, generated from deprotonation of the ketone, then you are missing the Baldwin rules (as I did at first sight).

Scheme 4

One of the many special examples which I picked out from the supporting information is the synthesis of the Hamigeran C core structure. Starting from cyclopentene 9 the terminal olefin was elongated with iodophenol in a Heck reaction to give 10. Chemoselective reduction of the styrene double bond and triflate formation was followed by another Heck reaction employing Herrmann’s catalyst to give tricyclic compound 13. First time I have seen Herrmann’s catalyst, funny German name.

Scheme 5

Nice methodology as usual from the Stoltz group. Any comments?

And special thanks to Bobby for proofreading my post in advance!