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.

The Rainier Metathesis Reaction

Original paper from Takai and Utimoto et al.: J. Org. Chem. 1994,59, 2668-2670

[1] DOI: http://dx.doi.org/10.1021/ja073880r

[2] DOI: http://dx.doi.org/10.1021/ol8025439

[3] DOI: http://dx.doi.org/10.1021/ol901448n

Bryostatin 1: http://dx.doi.org/10.1021/ja110198y

It’s still January and time for another review… This time I will present to you a short summary of a reaction which catched my eye in the Bryostatin 1 synthesis recently published from Keck et al.. One of their key steps is a Rainier Metathesis reaction:

Scheme 1

Originally published by Takai, Utimoto et al. the group around Rainier optimized the reaction conditions and expanded the scope of this reaction from an olefination to an olefination/metathesis process.

In 1978, Takai and Utimoto published an approach to olefins from carbonyl compounds by employing a reagent mix of CH₂Br₂ – Zn – TiCl₄. After several groups were unable to replicate the results it was found that the zinc powder Takai and Utimoto employed was contaminated with lead. In 1994 another paper was published in which they described optimized conditions and expanded the scope of the reaction to esters.

Scheme 2

Lead, or lead salts, proved to be essential to accelerate the reaction rate. A mechanism was also published in this paper in which the role of lead halides becomes clear:

Scheme 3

First the geminal halide 1 reacts with activated zinc powder to form 2. Without lead the second metal-halogen displacement is extremely slow so it was proposed that before the second metal-halogen displacement takes place a transmetallation between 2 and PbCl₂ forms the organo-lead-species 3. This is reactive enough to produce a geminal bisorganometallic species 4 which in turn reacts with in situ formed zinc halide to give 5.

Then TiCl₄ is added which displaced one or two of the zinc atoms to form a metallocyclobutane ring 6 or a Schrock carbene 7. Whatever product is formed it reacts with a carbonyl compound like the Tebbe or Petasis reagent to form an olefin.

This was all known for some time before Nicolaou discovered that the Tebbe reagent can be used in a tandem olefination/metathesis reaction.

In 2007 Rainier published a paper in which he showed that by employing Takai-Utimoto’s protocol on olefins it was possible to get metathesis products. The reaction was used to build cyclic ether of various ring sizes from ester and ethers [1], [2]. Also (bis)lactams can be accessed from amides or lactams [3]:

Scheme 4

If you are interested in more stuff check the related paper on the JACS page. Maybe one of you careful readers tried this reaction? I would be interested in some front news…

Btw: I will review the full story of Bryostatin 1 but I am currently a bit busy with my exams so be patient… J

Total Synthesis of (+)-Sieboldine A

Total Synthesis of (+)-Sieboldine A

Stephen M. Canham, David J. France, and Larry E. Overman

DOI: http://dx.doi.org/10.1021/ja103666n

Unfortunately I was very busy the last weeks with studying but now the last exam is written so I took the advantage and finished to review this nice paper from Overman et al..

Sieboldine A presents in my eyes a classical Overman target because of the rigid alkaloid structure ready for cool rearrangement chemistry. The compound itself inhibits electric eel AChE with an IC₅₀ value comparable to that of Huperzine A (http://syntheticnature.wordpress.com/2009/11/23/total-synthesis-of-huperzine-a/). But the real interest for a synthetic chemist poses the unprecedented N-hydroxyazacyclononane ring which was unknown until the isolation and structure elucidation of Sieboldine A in 2003.

Scheme 1

Retrosynthetically spoken the first step cleaves the sensitive N,O-acetal. The precursor derives from a Diels-Alder product which in turn was produced by a sweet pinacol-terminated cyclization.

Scheme 2

The synthesis starts off with the known unsaturated lactone which was opened by diastereoselective Michael addition of methylcuprate and subsequent lactonization with iodine. Exhaustive reduction with LAH furnished a diol which was selectively monoprotected and oxidized to give the ketone shown.

The second intermediate was synthesized through a known route. Michael addition of tributyltin-cuprate complex on the alkyne and quenching the reaction with MeOH gave z-vinyl tributyltin ester. This was reduced with DIBAL-H, exposed to Mitsunobu conditions to produce the phenyl ether and converted to the iodide by halogen/metal exchange.

Scheme 3

Next both intermediates were combined by reacting the iodide with sec-BuLi, transmetallate the lithium species with cerium trichloride and add to this the ketone (all at -78°C). Protection of the resulting alcohol, Swern oxidation of the terminal silyl ether (which was deprotected under the reaction conditions) and Seyferth-Gilbert homologation utilizing the Ohira-Bestmann reagent yielded the terminal alkyne ready for the first key step.

Exposure of this to a bit of gold and silver produced two of the four rings needed in a nice tandem Prins/pinacol rearrangement reaction.

Scheme 4

The mechanism might look like this:

Mechanism 1

The gold attacks the terminal alkyne which in turn is attacked by the alkene through a 5-exo-dig cyclization. The resulting tertiary carbenium ion is neutralized by a pinacol type reaction of the TES-ether to give the vinylic gold intermediate which is protonated by i-PrOH.

Having most of the carbon skeleton in place the group turned their attention on the next key step. Ozonolysis of the exo-methylene group followed by neutral work—up with dimethylsulfide and subsequent phenolate elimination produced another exo-methylene group. This underwent a europium catalyzed Diels-Alder reaction with ethyl vinyl ether. Diastereoselective reduction of the ketone was followed by facial selective expoxidation with DMDO.

Scheme 5

The resulting epoxide was opened in the presence of ethanethiol with BF₃-etherate in a sweet Overman style reaction. Desilylation, Mitsunobu reaction with double protected hydroxylamine and removal of the nosyl protecting group furnished an odd looking hemiacetal. Next some carbohydrate chemistry was utilized which is completely new to me to close the last ring (if someone has access to the paper, mail me). Oxidation of the remaining alcohol and MOM-cleavage yielded at least (+)-Sieboldine in 5% yield over 20 steps in the longest linear sequence.

Scheme 6

The Diels Alder reaction inspired me to propose the two mechanisms below. I am not sure which one is right but I favour the red one.

Mechanism 2

For a better understanding of the abbreviations some structures of the reagents possibly new to some readers:

Scheme 7

I loved the synthesis as usual when reading Overman’s work. Especially the pinacol-terminated cyclization, the Diels-Alder reaction and the ring opening/ring closing cascade.

If you have any questions do not hesitate to ask them…