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.

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.