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.

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Philip Garner, H. Umit Kaniskan, Charles M. Keyari, and Laksiri Weerasinghe

DOI: http://dx.doi.org/10.1021/jo200553g

Sorry for the long delay but I was a bit busy with my relocation. This piece of work was published a few weeks ago and deals with some interesting chemistry. I am not very familiar with this unusual [3 + 2] or formal [2 + 2 + 1]-cycloaddition reaction.

Let’s take a look at the retro:

Scheme 1

 

They make use of some old school and some modern chemistry. The bicyclic moiety is accessible by a Strecker reaction. A Pictet-Spengler reaction was used to produce the tetrahydroisoquinoline ring using starting material from a lactamization step. The proline-like motif in turn was formed through this odd cycloaddition step.

 Scheme 2

The aromatic part of Cyanocycline A was synthesized using some well known chemistry. Starting from anisol 1 a Friedel-Crafts acylation and subsequent Baeyer-Villiger oxidation formed 2. Regioselective bromination and saponification yielded phenol 3 which was protected as the benzyl ether 4.

Now to the first cool chemistry used in this paper: a stereoselective Grignard reaction with a D-serine-derived nitrone. The mechanistic rationale is explained at the end of this review. Hydroxylamine reduction was accomplished under Clemmensen conditions followed by Cbz-protection of the free amine to give 6. Acetonide removal and Dess-Martin oxidation then gave aldehyde 7.

Scheme 3

 

Next the formal [3 + 2]-cycloaddition is used to make three more stereocenters. Condensation of 7 with amine 8 was followed by the addition of silver acetate and methyl acrylate to give 10. Again the mechanism is discussed later on. Removal of both Cbz-groups and benzyl-groups forms the lactam ring and subsequent protection of the pyrrolidinyl nitrogen with Cbz gave 11. Boc-deprotection with TFA and a Pictet-Spengler reaction in acetic acid produced after benzylation of the free alcohol 12.

Scheme 4

 

Reduction of the Cbz group to a methyl group and cleavage of the chiral auxiliary with LAH in the presence of the amide worked fine. Oxidation of the terminal alcohol of 13 and subsequent Strecker reaction with TMSCN formed 14. Thioamide formation with Lawesson’s reagent and reductive desulfuration then gave imine 15.

 Scheme 5

Heating 15 in MeOH with some equivalents of ethylene oxide in a sealed tube formed 16. Selective debenzylation was accomplished with boron trichloride followed by benzoquinone formation with Mn3+ to give Cyanocycline A.

Scheme 6

And for those who want to know how the key steps might work, here is the mechanistic rationale. First the Grignard reaction:

Scheme 7

The authors explain the outcome of the reaction with an open transition state in which the Grignard reagent attacks the least hindered face of the nitrone. This is probably stabilized by a magnesium ion (when Grignard reagents are used). The reaction proceeds with high diastereoselectivity.

The second key step is somewhat more complicated. First the amide undergoes an imine formation with the aldehyde. Next one of the glycine protons is lost in the presence of silver which forms a tight complex with the imine nitrogen. The result is a positive charge on the nitrogen and a negative charge on one of the two vicinal carbon atoms. Moreover the silver cation forms a second complex with the acrylate which undergoes the cycloaddition and attacks the 1,3-dipole from the least hindered face to give 10.

Scheme 8

Nice chemistry don’t you think? And a really complex target. Comments?

And thx to Bobby for proofreading 😉

Straightforward four-component access to spiroindolines – Radical cyclizations of Ugi-4CR-Products

Straightforward four-component access to spiroindolines – Radical cyclizations of Ugi-4CR-Products

Laurent El Kaim, Laurence Grimaud, Xavier-Frédéric Le Goff, Martha Menes-Arzate and Luis D. Miranda

[1] DOI: http://dx.doi.org/10.1039/c1cc12236c

Earlier work:

[2] DOI: http://dx.doi.org/doi:10.1016/j.tetlet.2006.09.123

[3] DOI: http://dx.doi.org/10.1055/s-0029-1218700

[4] DOI: http://dx.doi.org/10.1021/ol701678d

I found this interesting paper [1] and decided to sum up some of the work done by the Kaim group. If you run Ugi-reactions or related ones you will frequently find a lot of stuff done by his group.

In this paper they were able to cyclize the primary Ugi-adduct under copper(II) catalysis to yield spiroindolines with drug-like structures:

Scheme 1

Btw.: this is really a nice tool (http://www.organic-chemistry.org/prog/) for having a look at the druglikeness of your substances.

I think most of you are familiar with the Ugi reaction mechanism so I skip this and show you the cool cyclization step. It was postulated that the base produces a carbanion which is directly oxidized by copper(II). This radical attacks the 3-position of the indole moiety and closes the pyrrolidine ring. The resulting radical is then oxidized to an imine. Subsequently the pyrrolidinone ring is closed by attack of the amide nitrogen onto the imine.

Scheme 2

You can run the whole reaction sequence in one pot without any need for purification. Just evaporate the methanol from the first step, add copper(II), DBU, THF, and reflux.

A lot of derivatives were made but as usual to date with the Ugi-reaction only as racemates. I was wondering if it might be possible to do the cyclization step stereoselectively because the stereocenter from the Ugi step is lost during deprotonation.

Some years ago the group started their interest in radical cyclization chemistry of Ugi-products with some different work [2]:

Scheme 3

They designed some xanthate esters and cyclised them to yield different lactams in the presence of DLP. The mechanism is shown below.

DLP generates a carbon based radical which in turn attacks the xanthate ester to give the more stable acyl radical. This cyclizes to the lactam. The resulting terminal radical attacks another xanthate ester yielding 3 and generates the next radical.

Scheme 4

Similar work was devoted towards the construction of azaspirodienones [3]. When benzylamines instead of allylamines were used, the resulting Ugi-products can be cyclized in a related manner.

Scheme 5

The last example involves a very cool radical mechanism [4]. First the usual Ugi-product is generated. In the presence of excess Mn(III) and malonate derivatives indanes are formed.

Without looking at the next chart: can anyone propose a reaction mechanism? Pretty unusual…

Scheme 6

Ok, here is their solution: First Mn(III) generates a malonate radical which attacks the terminal olefin to give a secondary radical. This attacks the ipso position of the benzene ring which results in a 1,4-aryl-shift and gives an acyl stabilized radical. Reaction of this with another equivalent of Mn(III) produces a carbocation which is quenched with acetate. Hydrolysis of the N,O-acetal deprotects the secondary amide. Probably at the same time Mn(III) generates another malonate based radical which cyclizes to give the indane.

Scheme 7

Nice stuff… I referenced the papers if you are interested in some more chemistry. Comments are as usual welcome.

And usual THX to Bobby for proofreading.

Enantioselective Total Synthesis of (+)-Conicol via Cascade Three-Component Organocatalysis

Enantioselective Total Synthesis of (+)-Conicol via Cascade

Three-Component Organocatalysis

Bor-Cherng Hong, Prakash Kotame, Chih-Wei Tsai, and Ju-Hsiou Liao

DOI: http://dx.doi.org/10.1021/ol902840x

This time some organocatalysis already published last year by a group based in Taiwan. Though not a spectacular paper I liked the first few steps and so reviewed it.

Conicol belongs to the class of meroterpenoids which were isolated from higher plants and recently from marine organisms. And as usually with these marine stuff it exhibits some cytotoxic effects against human cancer cells .

The key steps of the synthesis are a TMS-prolinol catalyzed enantioselective alkylation/Michael addition reaction followed by another Michael addition/aldol condensation to build the backbone of the whole molecule in almost 2 steps.

Additionally these two single pot sequences can be combined to one protocol giving the product in 55% yield with > 99% ee.

Scheme 1:

Scheme 2:

As mentioned above these sequences were combined to one very successful procedure. If you’re interested in the whole story have a look in here: http://dx.doi.org/10.1016/j.tetlet.2008.11.106

With all stereocenters and the carbon skeleton in hand only a few modifications were needed to give (+)-Conicol:

Scheme 3:

A decarbonylation reaction with Wilkinson catalyst was followed by double bond reduction with palladium on charcoal. Interestingly the nitro function is stable under these conditions.

Next the dimethylacetal was cleaved with hydrochloric acid, which results in elimination of the nitro function too, and an old school Wolff Kishner reduction gave Didehydroconicol.

Going on from the key intermediate the acetal was cleaved under milder conditions without causing elimination of the nitro function. This was done with DABCO, the aldehyde reduced, acetylated and eliminated under Birch conditions to give (+)-Conicol in 5% overall yield over 9 steps in the longest linear sequence.

Scheme 4:

I didn’t manage to publish this in january, sorry for that, but I’m just on the next paper so maybe I finish 3 reviews in February to keep my average of 2 reviews per month.