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.

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

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

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!

The Rainier Metathesis Reaction

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 Isokidamycin

Total Synthesis of Isokidamycin

B. Michael O’Keefe, Douglas M. Mans, David E. Kaelin, Jr, and Stephen F. Martin
DOI: http://dx.doi.org/10.1021/ja107926f

[1] Carbohyd. Res., 19 (1971) 276-280
[2] J. Carbohydrate Chemistry, 2(2), 105-114 (1983)
[3] Aust. J. Chem, 2003, 56, 787 – 794

Dude, this needed some time… Maybe the longest review I ever wrote to date. But Isokidamycin is really a big beasty. Have a look at it:

Scheme 1

The synthesis includes various intermediates and a long linear reaction sequence so I will start right off with the red fragment.

Benzylation of the benzoquinone promoted by silver oxide was followed by monobromination. The second bromine was added with the help of pyridine tribromide, the quinone reduced to the dihydroquinone and selectively monoprotected as the methyl ether.

Scheme 2

For identifying the route to the green fragment I had to dig out some really old papers which are cited by the group. The reconstruction was done as described in the paper but might not be 100% correct. I suppose they started with the dihydropyran shown which is commercially available. Monodeprotection and subsequent tosylation was followed by reductive cleavage of the tosylate and the acetyl protecting groups. Reprotection, hydration of the double bond and azidonation delivered after acetylation the green fragment shown. The hydration/azidonation step goes through a SN2’ reaction in which water (or even hydroxide) pushes out the acetate. Protonation and azide addition on the double bond produces the product.

Scheme 3

The sugar fragment was then coupled under Lewis acid catalysis with furan (d.r. 72 : 28 with respect to the C3 stereocenter) and deprotected under standard conditions to give after chromatographic separation the major C3 epimer shown. Benzylation, azide reduction, Boc-protection and methylation gave the fully protected THP. Functionalization of the furan was accomplished by silylation followed by hydroboration/oxidation to give the terminal alcohol.

Scheme 4

Another interesting THP fragment was isolated from vancomycin (!). By protecting the natural product and heating it in a methanolic solution of HCl, the aminosugar was set free. Some protecting group manipulations furnished the second sugar unit.

It seems to be odd to destroy such an important drug like vancomycin to produce this aminosugar but the author explain this sequence with the extremely long synthesis otherwise needed.

Scheme 5

Now it’s getting interesting. The red and blue halves were combined through a Mitsonobu reaction in pretty high yield. In the presence of BuLi the 1,2-dibromonaphthalene produces an aryne intermediate which undergoes a Diels-Alder reaction with the furan ring. The ether handle was then cleaved off with TBAF and the resulting alcohol methylated.

A really nice way to build up the anthracene ring system.

Scheme 6

The oxacyclic ring was opened with TMSOTf with concomitant cleavage of the Boc protecting group. Reductive amination, TIPS protection of the free alcohol, selective debenzylation, bromination and MOM protection furnished the fully protected anthracene ring system.

Scheme 7

For the next step another intermediate was needed. A Corey-Fuchs alkynylation followed by in situ formylation gave the purple aldehyde shown.

Scheme 8

This aldehyde was added to the anthracene ring through standard conditions and the resulting alcohol oxidized with barium manganate. Addition of diethylamine to the triple bond gave rise to a vinylogous amide which cyclizes under Lewis-acid catalysis which was followed by desilylation.

Cool…

Scheme 9

Ok, we are approaching the end. Glycosidation of the advanced intermediate with the vancomycin derived aminosugar was only possible in the presence of Sc(OTf)3. During the course the acetyl protecting group was cleaved off so it was reinstalled.

Scheme 10

At last the protecting groups had to be cleaved off. Benzyl group removal was done first with BBr3, the Cbz group was removed in the presence of TMSI which was followed by reductive amination of the free monomethylated amine. The hindered acetate group was cleaved off under standard conditions and the two methyl groups removed oxidatively with cerium sulfate to give isokidamycin.

Scheme 11


Wow… what a damn long and cool synthesis. Only two papers in JACS… I bet some generations of Ph.D. students were needed to get this done.

Any comments?

Total Syntheses of (-)-Fructigenine A and (-)-5-N-Acetylardeemin

Total Syntheses of (-)-Fructigenine A and (-)-5-N-Acetylardeemin

Satoshi Takiguchi, Toshimasa Iizuka, Yuh-suke Kumakura, Kohta Murasaki, Naoko Ban, Kazuhiro Higuchi and Tomomi Kawasaki

DOI: http://dx.doi.org/10.1021/jo9023107

Scheme 1

This time my review will feature two alkaloids isolated from different fungi possessing in the first case (namely Fructigenine A) growth-inhibitory activity against leukaemia cells and in the second case (namely N-acetylardeemin) inhibitory effects of MRSA.

Enough biology J

So here’s the retro:

Scheme 2

The authors planned the syntheses by employing the U3CR with a tetrahydropyrrolo-indole core as the key intermediate, an isocyanide and an amino acid to give after further manipulations both products in high yield.

The core intermediate was prepared by an olefination/isomerization/Claisen rearrangement (OIC) and reductive cyclization (RC) of acetyl-indolinone.

Scheme 3

The synthesis starts with bromination of the ketone followed by SN2 displacement of the bromine by the chiral allylic alcohol shown. HWE reaction of the carbonyl function gives the expected olefin which isomerizes under the reaction conditions and gives directly after Claisen rearrangement the product shown. The stereochemistry is completely controlled by the allylic alcohol function and transposed into the quaternary carbon centre.

Ozonolysis and methenylation of the resulting aldehyde was followed by reductive amination with the amine formed in situ with lithium aluminium hydride. Since the acetyl protective group got lost under the HWE conditions it has to be reinstalled by Boc protection of the pyrrolo nitrogen, acetylation of the dihydroindole and Boc cleavage. After introduction of the imine double bond with TPAP the key intermediate was accessible in multigram quantities.

Scheme 4

Fructigenine was formed by stereocontrolled U3CR reaction of the key intermediate with Boc-phenylalanine and PMB-isocyanide in toluene in high yield. The Boc group was removed with TFA and the piperazine closed in refluxing toluene. Isomerization with methanolic NaOH then furnished (-)-fructigenine without removing the acetyl group.

Scheme 5

Acetylardeemin was formed in a similar manner by reaction of the key intermediate with Boc-alanine and methyl-2-isocyanobenzoate. Boc removal was accomplished with TFA and the formation of the remaining lactam rings with POCl3 in refluxing DCE.

Nice syntheses. If the key intermediate would be easier accessible the products might have some potential in a HTS and a lot of compounds could easily be made for libraries.